Division of Microbiology
and Infectious Diseases

Good Clinical
Practice Handbook

National Institute of Allergy and Infectious Diseases
National Institutes of Health
Department of Health and Human Services

Division of Microbiology
and Infectious Diseases

Good Clinical
Practice Handbook

August 2001
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Department of Health and Human Services

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

National Institutes of Health
National Institutes of Allergy
and Infectious Diseases
Bethesda, Maryland 20892

The Division of Microbiology and Infectious Diseases (DMID), National
Institute of Allergy and Infectious Diseases (NIAID), National Institutes of
Health (NIH) is pleased to provide DMID-funded clinical researchers with this
booklet containing selected regulations and guidelines for Good Clinical
Practice (GCP). GCP standards are well-established practices for the
appropriate conduct of clinical trials. The documents in this booklet are
among the most important GCP regulations and guidelines but are not all
inclusive and may be subject to change . For definitive guidance investigators
should consult the current versions of the guidance documents (see useful
internet address on pages VII-1 through VII-4).The chart, “Organizations
Impacting Clinical Research” indicates organizations and agencies that also
have policies that may impact the conduct of clinical studies. Special
attention should be paid to local regulations, which include those of states
and non-US sites.
DMID requires adherence to GCP standards throughout the management of
a clinical trial.GCP standards apply to all aspects of a clinical trial, from
ethical and scientific study design to maintenance of accurate records and
diligent data recording. The safety and welfare of human subjects must be
rigorously maintained by all individuals who participate in the conduct of the
research study. These DMID-funded studies must include:
• Written approval by an Institutional Review Board (IRB), in compliance with
the requirements of 21 Code of Federal Regulations (CFR) 56 (Institutional
Review Boards) and 45 CFR 46 (Protection of Human Subjects) prior to
initiating any study.
• Written informed consent from all subjects or their legally acceptable
representatives, prior to participation in any research activities, in
accordance with the requirements of 21 CFR 50 and 45 CFR 46. This
requirement may be waived only in accordance with the provisions of
21 CFR 50, or 45 CFR 46.
• Compliance with all FDA requirements and guidance for GCP and with
international, state and local government regulations as appropriate.
• Conformity with the International Conference on Harmonisation (ICH)
guidelines for GCP.
• Compliance with the policies and procedures of the DMID, NIAID, and NIH.
• Appropriate medical care and treatment of study subjects.
• Retention of adequate written documentation to demonstrate regulatory
compliance with all research activities .
• Cooperation with sponsor, government or regulatory agency monitors,
inspectors and auditors.
• Compliance with the requirements of 21 CFR 312 for Investigational New
Drugs, if appropriate.
Office of Regulatory Affairs
DMID, NIAID, NIH

Office of Clinical Research Affairs
DMID, NIAID, NIH

Organizations Impacting Clinical Research

*The responsibilities of the Office for Protection from Research Risks (OPRR), NIH, have been
transferred to the Office for Human Research Protections (OHRP), DHHS (Federal Register
[FR]), June 13, 2000). Documents published by OPRR are still valid. For current OHRP
contacts, please see the OHRP web page (http://ohrp.osophs.dhhs.gov).
v

Table of Contents
I.

Human Subjects Protection..............................................................I-1
Human Subject Regulations Decision Charts .....................................I-1
45 CFR 46—Code of Federal Regulations..........................................I-6
Subpart A—Federal Policy for the Protection of
Human Subjects (Common Rule).................................................I-6
46.101 To What Does This Policy Apply?..............................I-6
46.110 Expedited Review Procedures................................I-13
46.116 General Requirements for Informed Consent.........I-16
Subpart B—Additional Protections for Pregnant Women
and Human Fetuses Involved in Research, and Pertaining
to Human In Vitro Fertilization....................................................I-21
Subpart C—Additional DHHS Protections Pertaining
to Biomedical and Behavioral Research Involving Prisoners
as Subjects.................................................................................I-26
Subpart D—Additional DHHS Protections for Children
Involved as Subjects in Research ..............................................I-29
Categories of Research That May Be Reviewed
by the Institutional Review Board (IRB) Through an Expedited
Review Procedure..............................................................................I-33

II.

Informed Consent.............................................................................II-1
FDA Regulations on Informed Consent..............................................II-1
Subpart A—General Provisions...................................................II-2
Subpart B—Informed Consent of Human Subjects.....................II-6
Tips on Informed Consent................................................................II-14

III. Subject Recruitment........................................................................III-1
Guidance for Institutional Review Boards
and Clinical Investigators ..................................................................III-1
Recruiting Study Subjects..........................................................III-1
Payment to Research Subjects..................................................III-4
Screening Tests Prior to Study Enrollment.................................III-5
IV. Research on Human Specimens: Are You Conducting
Research Using Human Subjects?................................................IV-1
Issues to Consider in the Research Use of Stored Data
or Tissues (11/7/1997)—Repositories...............................................IV-7

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Good Clinical Practice

Table of Contents (continued)
V.

Investigational New Drug Application............................................V-1
Title 21—Food and Drugs, Department of Health and
Human Services—Part 312—Investigational New Drug
Application..........................................................................................V-1
Subpart A—General Provisions ..................................................V-1
Subpart B—Investigational New Drug Application (IND) ............V-6
Subpart C—Administrative Actions...........................................V-24
Subpart D—Responsibilities of Sponsors and
Investigators ..............................................................................V-33
Subpart E—Drugs Intended to Treat Life-threatening
and Severely-debilitating Illnesses............................................V-41
Subpart F—Miscellaneous........................................................V-44
312.120 Foreign clinical studies not conducted
under an IND......................................................................V-45
Declaration of Helsinki (as amended 1989).......................V-46
Subpart G—Drugs for Investigational Use in Laborator y
Research Animals or In Vitro Tests ...........................................V-51
Information for Sponsor-Investigators Submitting Investigational
New Drug Applications (INDs)..........................................................V-53
U.S. Food and Drug Administration
Information on Submitting an Investigational New Drug
Application for a Biological Product..................................................V-56

VI. Good Clinical Practice (Guidance for Industry)...........................VI-1
Introduction........................................................................................VI-4
Glossary ............................................................................................VI-4
The Principles of ICH GCP.............................................................VI-10
Institutional Review Board/Independent Ethics Committee.............VI-11
Investigator......................................................................................VI-14
Sponsor ..........................................................................................VI-21
Clinical Trial Protocol.......................................................................VI-31
Investigator’s Brochure....................................................................VI-34
Essential Documents for the Conduct of a Clinical Trial .................VI-41
VII. Useful Internet Sites.......................................................................VII-1

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HUMAN SUBJECTS PROTECTION

I. Human Subjects Protection
Human Subject Regulations Decision Charts
The Office for Protection from Research Risks (OPRR)* provides the
following graphic aids to clarify portions of the Department of Health and
Human Services (DHHS) human subject regulations at Title 45 Code
of Federal Regulations Part 46 (45 CFR 46).These portions of the
regulations are the subject of frequent inquiries to OPRR.
Chart 1: Definition of Human Subject at Section 46.102(f)
Is the definition of “human subject”at Section 46.102(f) met in this
research activity?

1That is, the identity of the subject is or may readily be ascertained or associated with
information.
*The responsibilities of the Office for Protection from Research Risks (OPRR), NIH, have been
transferred to the Office for Human Research Protections (OHRP), DHHS (Federal Register [FR],
June 13, 2000).Documents published by OPRRare still valid. For current OHRP contacts, please
see the OHRP Web page (http://ohrp.osophs.dhhs.gov).

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GOOD CLINICAL PRACTICE
Chart 2: Exemption at Section 46.101(b)(4) regarding research involving
the collection or study of existing data, documents, records, pathological
specimens, or diagnostic specimens.
Is the research exempt in accordance with Section 46.101(b)(4)?
The regulations at 45 CFR Part 46 do not apply if the criteria for exemption
under Section 46.101(b)(4) are met.

1“Existing”means collected (i.e., on the shelf) prior to the research for a purpose other than the
proposed research.It includes data or specimens collected in research and nonresearch
activities.

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HUMAN SUBJECTS PROTECTION

CODE OF FEDERAL REGULATIONS
TITLE 45
PUBLIC WELFARE
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
OFFICE FOR PROTECTION FROM RESEARCH RISKS
PART 46
PROTECTION OF HUMAN SUBJECTS
***
Revised June 18, 1991
Effective August 19, 1991
***
Subpart A—Federal Policy for the Protection of Human Subjects
(Basic DHHS Policy for Protection of Human Research Subjects,
also known as the Common Rule)
Sec.
46.101
To what does this policy apply?
46.102
Definitions.
46.103
Assuring compliance with this policy—research conducted or
supported by any Federal Department or Agency.
46.104
[Reserved]
46.106
[Reserved]
46.107
IRB membership.
46.108
IRB functions and operations.
46.109
IRB review of research.
46.110
Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
46.111
Criteria for IRB approval of research.
46.112
Review by institution.
46.113
Suspension or termination of IRB approval of research.
46.114
Cooperative research.
46.115
IRB records.
46.116
General requirements for informed consent.
46.117
Documentation of informed consent.
46.118
Applications and proposals lacking definite plans for
involvement of human subjects.
46.119
Research undertaken without the intention of involving human
subjects.
46.120
Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal
Department or Agency.
46.121
[Reserved]
46.122
Use of Federal funds.
46.123
Early termination of research support: Evaluation of
applications and proposals.
46.124
Conditions.

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GOOD CLINICAL PRACTICE
Subpart B—Additional DHHS Protections Pertaining to Research,
Development, and Related Activities Involving Fetuses, Pregnant
Women, and Human In Vitro Fertilization
Sec.
46.201
To what do these regulations apply?
46.202
Definitions.
46.203
Duties of IRBs in connection with research involving pregnant
women, fetuses, and human in vitro fertilization.
46.204
Research involving pregnant women or fetuses prior to
delivery.
46.205
Research involving fetuses after delivery.
46.206
Research involving, after delivery, the placenta, the dead
fetus, or fetal material.
46.207
Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious
problem affecting the health or welfare of pregnant women or
fetuses.
Subpart C—Additional DHHS Protections Pertaining to Biomedical
and Behavioral Research Involving Prisoners as Subjects
Sec.
46.301
46.302
46.303
46.304
46.305
46.306

Applicability.
Purpose.
Definitions.
Composition of Institutional Review Boards where prisoners
are involved.
Additional duties of the Institutional Review Boards where
prisoners are involved.
Permitted research involving prisoners.

Subpart D—Additional DHHS Protections for Children Involved as
Subjects in Research
Sec.
46.401
To what do these regulations apply?
46.402
Definitions.
46.403
IRB duties.
46.404
Research not involving greater than minimal risk.
46.405
Research involving greater than minimal risk but presenting
the prospect of direct benefit to the individual subjects.
46.406
Research involving greater than minimal risk and no prospect
of direct benefit to individual subjects, but likely to yield
generalizable knowledge about the subject’s disorder or
condition.
46.407
Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious
problem affecting the health or welfare of children.
46.408
Requirements for permission by parents or guardians and for
assent by children.
46.409
Wards.

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HUMAN SUBJECTS PROTECTION
Authority: 5 U.S.C. 301; Sec. 474(a), 88 Stat. 352 (42 U.S.C. 2891-3(a)).
Note: As revised, Subpart A of the DHHS regulations incorporates the
Common Rule (Federal Policy) for the Protection of Human Subjects
(56 FR 28003). Subpart D of the HHS regulations has been amended at
Section 46.401(b) to reference the revised Subpart A.
The Common Rule (Federal Policy) is also codified at
7 CFR Part 1c
10 CFR Part 745
14 CFR Part 1230
15 CFR Part 27
16 CFR Part 1028
22 CFR Part 225
24 CFR Part 60
28 CFR Part 46
32 CFR Part 219
34 CFR Part 97
38 CFR Part 16
40 CFR Part 26
45 CFR Part 690
49 CFR Part 11

Department of Agriculture
Department of Energy
National Aeronautics and Space Administration
Department of Commerce
Consumer Product Safety Commission
International Development Cooperation Agency,
Agency for International Development
Department of Housing and Urban Development
Department of Justice
Department of Defense
Department of Education
Department of Veterans Affairs
Environmental Protection Agency
National Science Foundation
Department of Transportation

I–5

GOOD CLINICAL PRACTICE

TITLE 45
CODE OF FEDERAL REGULATIONS
PART 46
PROTECTION OF HUMAN SUBJECTS
***
Revised June 18, 1991
Effective August 19, 1991
***
Subpart A—Federal Policy for the Protection of Human
Subjects (Basic DHHS Policy for Protection of Human
Research Subjects)
Source: 56 FR 28003, June 18, 1991.
§46.101 To what does this policy apply?
(a) Except as provided in paragraph (b) of this section, this policy applies
to all research involving human subjects conducted, supported or otherwise
subject to regulation by any Federal Department or Agency which takes
appropriate administrative action to make the policy applicable to such
research.This includes research conducted by Federal civilian employees
or military personnel, except that each Department or Agency head may
adopt such procedural modifications as may be appropriate from an
administrative standpoint. It also includes research conducted, supported,
or otherwise subject to regulation by the Federal Government outside the
United States.
(1) Research that is conducted or supported by a Federal Department
or Agency, whether or not it is regulated as defined in §46.102(e), must
comply with all sections of this policy.
(2) Research that is neither conducted nor supported by a Federal
Department or Agency but is subject to regulation as defined in §46.102(e)
must be reviewed and approved, in compliance with §46.101, §46.102, and
§46.107 through §46.117 of this policy, by an Institutional Review Board
(IRB) that operates in accordance with the pertinent requirements of this
policy.
(b) Unless otherwise required by Department or Agency heads, research
activities in which the only involvement of human subjects will be in one or
more of the following categories are exempt from this policy: 1
(1) Research conducted in established or commonly accepted
educational settings, involving normal educational practices, such as
(i) research on regular and special education instructional strategies, or
(ii) research on the effectiveness of or the comparison among instructional
techniques, curricula, or classroom management methods.
1Institutions with DHHS-approved assurances on file will abide by provisions of Title 45 CFR
Part 46 Subparts A-D. Some of the other departments and agencies have incorporated all
provisions of Title 45 CFR Part 46 into their policies and procedures as well.However, the
exemptions at 45 CFR 46.101(b) do not apply to research involving prisoners, fetuses, pregnant
women, or human in vitro fertilization, Subparts B and C. The exemption at 45 CFR 46.101(b)(2),
for research involving survey or interview procedures or observation of public behavior, does not
apply to research with children, Subpart D, except for research involving observations of public
behavior when the investigator(s) do not participate in the activities being observed.

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HUMAN SUBJECTS PROTECTION
(2) Research involving the use of educational tests (cognitive,
diagnostic, aptitude, achievement), survey procedures, interview
procedures or observation of public behavior, unless: (i) information
obtained is recorded in such a manner that human subjects can be
identified, directly or through identifiers linked to the subjects; and (ii) any
disclosure of the human subjects’responses outside the research could
reasonably place the subjects at risk of criminal or civil liability or be
damaging to the subjects’financial standing, employability, or reputation.
(3) Research involving the use of educational tests (cognitive,
diagnostic, aptitude, achievement), survey procedures, interview
procedures, or observation of public behavior that is not exempt under
paragraph (b)(2) of this section, if: (i) the human subjects are elected or
appointed public officials or candidates for public office; or (ii) Federal
statute(s) require(s) without exception that the confidentiality of the
personally identifiable information will be maintained throughout the
research and thereafter.
(4) Research involving the collection or study of existing data,
documents, records, pathological specimens, or diagnostic specimens, if
these sources are publicly available or if the information is recorded by the
investigator in such a manner that subjects cannot be identified, directly or
through identifiers linked to the subjects.
(5) Research and demonstration projects which are conducted by or
subject to the approval of Department or Agency heads, and which are
designed to study, evaluate, or otherwise examine: (i) Public benefit or
service programs; (ii) procedures for obtaining benefits or services under
those programs; (iii) possible changes in or alternatives to those programs
or procedures; or (iv) possible changes in methods or levels of payment for
benefits or services under those programs.
(6) Taste and food quality evaluation and consumer acceptance
studies, (i) if wholesome foods without additives are consumed or (ii) if a
food is consumed that contains a food ingredient at or below the level and
for a use found to be safe, or agricultural chemical or environmental
contaminant at or below the level found to be safe, by the Food and Drug
Administration or approved by the Environmental Protection Agency or the
Food Safety and Inspection Service of the U.S. Department of Agriculture.
(c) Department or Agency heads retain final judgment as to whether a
particular activity is covered by this policy.
(d) Department or Agency heads may require that specific research
activities or classes of research activities conducted, supported, or
otherwise subject to regulation by the Department or Agency but not
otherwise covered by this policy, comply with some or all of the
requirements of this policy.
(e) Compliance with this policy requires compliance with pertinent
Federal laws or regulations which provide additional protections for human
subjects.
(f) This policy does not affect any State or local laws or regulations which
may otherwise be applicable and which provide additional protections for
human subjects.

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GOOD CLINICAL PRACTICE
(g) This policy does not affect any foreign laws or regulations which may
otherwise be applicable and which provide additional protections to human
subjects of research.
(h) When research covered by this policy takes place in foreign countries,
procedures normally followed in the foreign countries to protect human
subjects may differ from those set forth in this policy. [An example is a
foreign institution which complies with guidelines consistent with the World
Medical Assembly Declaration (Declaration of Helsinki amended 1989, see
page V-45) issued either by sovereign states or by an organization whose
function for the protection of human research subjects is internationally
recognized.] In these circumstances, if a Department or Agency head
determines that the procedures prescribed by the institution afford
protections that are at least equivalent to those provided in this policy, the
Department or Agency head may approve the substitution of the foreign
procedures in lieu of the procedural requirements provided in this policy.
Except when otherwise required by statute, Executive Order, or the
Department or Agency head, notices of these actions as they occur will be
published in the Federal Register or will be otherwise published as
provided in Department or Agency procedures.
(i) Unless otherwise required by law, Department or Agency heads may
waive the applicability of some or all of the provisions of this policy to
specific research activities or classes or research activities otherwise
covered by this policy. Except when otherwise required by statute or
Executive Order, the Department or Agency head shall forward advance
notices of these actions to the Office for Protection from Research Risks,*
National Institutes of Health, Department of Health and Human Services
(DHHS), and shall also publish them in the Federal Register or in such
other manner as provided in Department or Agency procedures.1
§46.102 Definitions.
(a) Department or Agency head means the head of any Federal
Department or Agency and any other officer or employee of any
Department or Agency to whom authority has been delegated.
(b) Institution means any public or private entity or Agency (including
Federal, State, and other agencies).
(c) Legally authorized representative means an individual or judicial or
other body authorized under applicable law to consent on behalf of a
prospective subject to the subject’s participation in the procedure(s)
involved in the research.
(d) Research means a systematic investigation, including research
development, testing and evaluation, designed to develop or contribute to
generalizable knowledge. Activities which meet this definition constitute
1Institutions with DHHS-approved assurances on file will abide by provisions of Title 45 CFR
Part 46 Subparts A-D. Some of the other departments and agencies have incorporated all
provisions of Title 45 CFR Part 46 into their policies and procedures as well.However, the
exemptions at 45 CFR 46.101(b) do not apply to research involving prisoners, fetuses, pregnant
women, or human in vitro fertilization, Subparts B and C. The exemption at 45 CFR 46.101(b)(2),
for research involving survey or interview procedures or obser vation of public behavior, does not
apply to research with children, Subpart D, except for research involving observations of public
behavior when the investigator(s) do not participate in the activities being observed.
*Now Office for Human Research Protections (OHRP).

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HUMAN SUBJECTS PROTECTION
research for purposes of this policy, whether or not they are conducted or
supported under a program which is considered research for other
purposes. For example, some demonstration and service programs may
include research activities.
(e) Research subject to regulation, and similar terms are intended to
encompass those research activities for which a Federal Department or
Agency has specific responsibility for regulating as a research activity, (for
example, Investigational New Drug requirements administered by the Food
and Drug Administration). It does not include research activities which are
incidentally regulated by a Federal Department or Agency solely as part of
the Department’s or Agency’s broader responsibility to regulate certain
types of activities whether research or non-research in nature (for example,
Wage and Hour requirements administered by the Department of Labor).
(f) Human subject means a living individual about whom an investigator
(whether professional or student) conducting research obtains
(1) data through intervention or interaction with the individual, or
(2) identifiable private information.
Intervention includes both physical procedures by which data are gathered
(for example, venipuncture) and manipulations of the subject or the
subject’s environment that are performed for research purposes. Interaction
includes communication or interpersonal contact between investigator and
subject. Private information includes information about behavior that occurs
in a context in which an individual can reasonably expect that no
observation or recording is taking place, and information which has been
provided for specific purposes by an individual and which the individual can
reasonably expect will not be made public (for example, a medical record).
Private information must be individually identifiable (i.e., the identity of the
subject is or may readily be ascertained by the investigator or associated
with the information) in order for obtaining the information to constitute
research involving human subjects.
(g) IRB means an Institutional Review Board established in accord with
and for the purposes expressed in this policy.
(h) IRB approval means the determination of the IRB that the research
has been reviewed and may be conducted at an institution within the
constraints set forth by the IRB and by other institutional and Federal
requirements.
(i) Minimal risk means that the probability and magnitude of harm or
discomfort anticipated in the research are not greater in and of themselves
than those ordinarily encountered in daily life or during the performance of
routine physical or psychological examinations or tests.
(j) Certification means the official notification by the institution to the
supporting Department or Agency, in accordance with the requirements of
this policy, that a research project or activity involving human subjects has
been reviewed and approved by an IRB in accordance with an approved
assurance.
§46.103 Assuring compliance with this policy—research conducted or
supported by any Federal Department or Agency.
(a) Each institution engaged in research which is covered by this policy
and which is conducted or supported by a Federal Department or Agency
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GOOD CLINICAL PRACTICE
shall provide written assurance satisfactory to the Department or Agency
head that it will comply with the requirements set forth in this policy. In lieu
of requiring submission of an assurance, individual Department or Agency
heads shall accept the existence of a current assurance, appropriate for the
research in question, on file with the Office for Protection from Research
Risks,* National Institutes Health, DHHS, and approved for Federal wide
use by that office. When the existence of an DHHS-approved assurance is
accepted in lieu of requiring submission of an assurance, reports (except
certification) required by this policy to be made to Department and Agency
heads shall also be made to the Office for Protection from Research Risks,
National Institutes of Health, DHHS.
(b) Departments and agencies will conduct or support research covered
by this policy only if the institution has an assurance approved as provided
in this section, and only if the institution has certified to the Department or
Agency head that the research has been reviewed and approved by an IRB
provided for in the assurance, and will be subject to continuing review by
the IRB. Assurances applicable to federally supported or conducted
research shall at a minimum include:
(1) A statement of principles governing the institution in the discharge
of its responsibilities for protecting the rights and welfare of human subjects
of research conducted at or sponsored by the institution, regardless of
whether the research is subject to Federal regulation.This may include an
appropriate existing code, declaration, or statement of ethical principles, or
a statement formulated by the institution itself. This requirement does not
preempt provisions of this policy applicable to Department- or Agencysupported or regulated research and need not be applicable to any
research exempted or waived under §46.101(b) or (i).
(2) Designation of one or more IRBs established in accordance with
the requirements of this policy, and for which provisions are made for
meeting space and sufficient staff to support the IRB’s review and
recordkeeping duties.
(3) A list of IRB members identified by name; earned degrees;
representative capacity; indications of experience such as board
certifications, licenses, etc., sufficient to describe each member’s chief
anticipated contributions to IRB deliberations; and any employment or other
relationship between each member and the institution; for example: full-time
employee, part-time employee, member of governing panel or board,
stockholder, paid or unpaid consultant. Changes in IRB membership shall
be reported to the Department or Agency head, unless in accord with
§46.103(a) of this policy, the existence of a DHHS-approved assurance is
accepted.In this case, change in IRB membership shall be reported to the
Office for Protection from Research Risks,* National Institutes of Health,
DHHS.
(4) Written procedures which the IRB will follow (i) for conducting its
initial and continuing review of research and for reporting its findings and
actions to the investigator and the institution; (ii) for determining which
projects require review more often than annually and which projects need
verification from sources other than the investigators that no material
*Now Office for Human Research Protections (OHRP).
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HUMAN SUBJECTS PROTECTION
changes have occurred since previous IRB review; and (iii) for ensuring
prompt reporting to the IRB of proposed changes in a research activity, and
for ensuring that such changes in approved research, during the period for
which IRB approval has already been given, may not be initiated without
IRB review and approval except when necessary to eliminate apparent
immediate hazards to the subject.
(5) Written procedures for ensuring prompt reporting to the IRB,
appropriate institutional officials, and the Department or Agency head of
(i) any unanticipated problems involving risks to subjects or others or any
serious or continuing noncompliance with this policy or the requirements or
determinations of the IRB; and (ii) any suspension or termination of IRB
approval.
(c) The assurance shall be executed by an individual authorized to act for
the institution and to assume on behalf of the institution the obligations
imposed by this policy and shall be filed in such form and manner as the
Department or Agency head prescribes.
(d) The Department or Agency head will evaluate all assurances
submitted in accordance with this policy through such officers and
employees of the Department or Agency and such experts or consultants
engaged for this purpose as the Department or Agency head determines to
be appropriate. The Department or Agency head’s evaluation will take into
consideration the adequacy of the proposed IRB in light of the anticipated
scope of the institution’s research activities and the types of subject
populations likely to be involved, the appropriateness of the proposed initial
and continuing review procedures in light of the probable risks, and the size
and complexity of the institution.
(e) On the basis of this evaluation, the Department or Agency head may
approve or disapprove the assurance, or enter into negotiations to develop
an approvable one. The Department or Agency head may limit the period
during which any particular approved assurance or class of approved
assurances shall remain effective or otherwise condition or restrict approval.
(f) Certification is required when the research is supported by a Federal
Department or Agency and not otherwise exempted or waived under
§46.101 (b) or (i). An institution with an approved assurance shall certify
that each application or proposal for research covered by the assurance
and by §46.103 of this policy has been reviewed and approved by the IRB.
Such certification must be submitted with the application or proposal or by
such later date as may be prescribed by the Department or Agency to
which the application or proposal is submitted.Under no condition shall
research covered by §46.103 of the policy be supported prior to receipt of
the certification that the research has been reviewed and approved by the
IRB. Institutions without an approved assurance covering the research shall
certify within 30 days after receipt of a request for such a certification from
the Department or Agency, that the application or proposal has been
approved by the IRB. If the certification is not submitted within these time
limits, the application or proposal may be returned to the institution.
(Approved by the Office of Management and Budget under Control
Number 9999-0020.)

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GOOD CLINICAL PRACTICE
§§46.104—46.106 [Reserved]
§46.107 IRB membership.
(a) Each IRB shall have at least five members, with varying backgrounds
to promote complete and adequate review of research activities commonly
conducted by the institution.The IRB shall be sufficiently qualified through
the experience and expertise of its members, and the diversity of the
members, including consideration of race, gender, and cultural backgrounds
and sensitivity to such issues as community attitudes, to promote respect
for its advice and counsel in safeguarding the rights and welfare of human
subjects. In addition to possessing the professional competence necessary
to review specific research activities, the IRB shall be able to ascertain the
acceptability of proposed research in terms of institutional commitments
and regulations, applicable law, and standards of professional conduct and
practice. The IRB shall therefore include persons knowledgeable in these
areas. If an IRB regularly reviews research that involves a vulnerable
category of subjects, such as children, prisoners, pregnant women, or
handicapped or mentally disabled persons, consideration shall be given to
the inclusion of one or more individuals who are knowledgeable about and
experienced in working with these subjects.
(b) Every nondiscriminatory effort will be made to ensure that no IRB
consists entirely of men or entirely of women, including the institution’s
consideration of qualified persons of both sexes, so long as no selection is
made to the IRB on the basis of gender. No IRB may consist entirely of
members of one profession.
(c) Each IRB shall include at least one member whose primary concerns
are in scientific areas and at least one member whose primary concerns
are in nonscientific areas.
(d) Each IRB shall include at least one member who is not otherwise
affiliated with the institution and who is not part of the immediate family of a
person who is affiliated with the institution.
(e) No IRB may have a member participate in the IRB’s initial or
continuing review of any project in which the member has a conflicting
interest, except to provide information requested by the IRB.
(f) An IRB may, in its discretion, invite individuals with competence in
special areas to assist in the review of issues which require expertise
beyond or in addition to that available on the IRB. These individuals may not
vote with the IRB.
§46.108 IRB functions and operations.
In order to fulfill the requirements of this policy each IRB shall:
(a) Follow written procedures in the same detail as described in
§46.103(b)(4) and to the extent required by §46.103(b)(5).
(b) Except when an expedited review procedure is used (see §46.110),
review proposed research at convened meetings at which a majority of the
members of the IRB are present, including at least one member whose
primary concerns are in nonscientific areas. In order for the research to be
approved, it shall receive the approval of a majority of those members
present at the meeting.

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§46.109 IRB review of research.
(a) An IRB shall review and have authority to approve, require
modifications in (to secure approval), or disapprove all research activities
covered by this policy.
(b) An IRB shall require that information given to subjects as part of
informed consent is in accordance with §46.116.The IRB may require that
information, in addition to that specifically mentioned in §46.116, be given
to the subjects when in the IRB’s judgment the information would
meaningfully add to the protection of the rights and welfare of subjects.
(c) An IRB shall require documentation of informed consent or may waive
documentation in accordance with §46.117.
(d) An IRB shall notify investigators and the institution in writing of its
decision to approve or disapprove the proposed research activity, or of
modifications required to secure IRB approval of the research activity. If the
IRB decides to disapprove a research activity, it shall include in its written
notification a statement of the reasons for its decision and give the
investigator an opportunity to respond in person or in writing.
(e) An IRB shall conduct continuing review of research covered by this
policy at intervals appropriate to the degree of risk, but not less than once
per year, and shall have authority to observe or have a third party observe
the consent process and the research. (Approved by the Office of
Management and Budget under Control Number 9999-0020.)
§46.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
(a) The Secretary, HHS, has established, and published as a Notice in
the Federal Register, a list of categories of research that may be reviewed
by the IRB through an expedited review procedure. The list will be
amended, as appropriate, after consultation with other departments and
agencies, through periodic republication by the Secretary, HHS, in the
Federal Register. A copy of the list is available from the Office for Protection
from Research Risks,* National Institutes of Health, DHHS, Bethesda,
Maryland 20892. (See page I-33.)
(b) An IRB may use the expedited review procedure to review either or
both of the following:
(1) some or all of the research appearing on the list and found by the
reviewer(s) to involve no more than minimal risk,
(2) minor changes in previously approved research during the period
(of one year or less) for which approval is authorized.
Under an expedited review procedure, the review may be carried out by the
IRB chairperson or by one or more experienced reviewers designated by
the chairperson from among members of the IRB. In reviewing the
research, the reviewers may exercise all of the authorities of the IRB except
that the reviewers may not disapprove the research. A research activity may
be disapproved only after review in accordance with the non-expedited
procedure set forth in §46.108(b).
*Now Office for Human Research Protections (OHRP).
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(c) Each IRB which uses an expedited review procedure shall adopt a
method for keeping all members advised of research proposals which have
been approved under the procedure.
(d) The Department or Agency head may restrict, suspend, terminate, or
choose not to authorize an institution’s or IRB’s use of the expedited review
procedure.
§46.111 Criteria for IRB approval of research.
(a) In order to approve research covered by this policy the IRB shall
determine that all of the following requirements are satisfied:
(1) Risks to subjects are minimized: (i) by using procedures which are
consistent with sound research design and which do not unnecessarily
expose subjects to risk, and (ii) whenever appropriate, by using procedures
already being performed on the subjects for diagnostic or treatment
purposes.
(2) Risks to subjects are reasonable in relation to anticipated benefits,
if any, to subjects, and the importance of the knowledge that may
reasonably be expected to result. In evaluating risks and benefits, the IRB
should consider only those risks and benefits that may result from the
research (as distinguished from risks and benefits of therapies subjects
would receive even if not participating in the research).The IRB should not
consider possible long-range effects of applying knowledge gained in the
research (for example, the possible effects of the research on public policy)
as among those research risks that fall within the purview of its
responsibility.
(3) Selection of subjects is equitable. In making this assessment the
IRB should take into account the purposes of the research and the setting
in which the research will be conducted and should be particularly
cognizant of the special problems of research involving vulnerable
populations, such as children, prisoners, pregnant women, mentally
disabled persons, or economically or educationally disadvantaged persons.
(4) Informed consent will be sought from each prospective subject or
the subject’s legally authorized representative, in accordance with, and to
the extent required by §46.116.
(5) Informed consent will be appropriately documented, in accordance
with, and to the extent required by §46.117.
(6) When appropriate, the research plan makes adequate provision for
monitoring the data collected to ensure the safety of subjects.
(7) When appropriate, there are adequate provisions to protect the
privacy of subjects and to maintain the confidentiality of data.
(b) When some or all of the subjects are likely to be vulnerable to
coercion or undue influence, such as children, prisoners, pregnant women,
mentally disabled persons, or economically or educationally disadvantaged
persons, additional safeguards have been included in the study to protect
the rights and welfare of these subjects.
§46.112 Review by institution.
Research covered by this policy that has been approved by an IRB may be
subject to further appropriate review and approval or disapproval by officials
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of the institution. However, those officials may not approve the research if it
has not been approved by an IRB.
§46.113 Suspension or termination of IRB approval of research.
An IRB shall have authority to suspend or terminate approval of research
that is not being conducted in accordance with the IRB’s requirements or
that has been associated with unexpected serious harm to subjects. Any
suspension or termination or approval shall include a statement of the
reasons for the IRB’s action and shall be reported promptly to the
investigator, appropriate institutional officials, and the Department or
Agency head. (Approved by the Office of Management and Budget under
Control Number 9999-0020.)
§46.114 Cooperative research.
Cooperative research projects are those projects covered by this policy
which involve more than one institution.In the conduct of cooperative
research projects, each institution is responsible for safeguarding the rights
and welfare of human subjects and for complying with this policy. With the
approval of the Department or Agency head, an institution participating in a
cooperative project may enter into a joint review arrangement, rely upon the
review of another qualified IRB, or make similar arrangements for avoiding
duplication of effort.
§46.115 IRB records.
(a) An institution, or when appropriate an IRB, shall prepare and maintain
adequate documentation of IRB activities, including the following:
(1) Copies of all research proposals reviewed, scientific evaluations, if
any, that accompany the proposals, approved sample consent documents,
progress reports submitted by investigators, and reports of injuries to
subjects.
(2) Minutes of IRB meetings which shall be in sufficient detail to show
attendance at the meetings; actions taken by the IRB; the vote on these
actions including the number of members voting for, against, and
abstaining; the basis for requiring changes in or disapproving research; and
a written summary of the discussion of controverted issues and their
resolution.
(3) Records of continuing review activities.
(4) Copies of all correspondence between the IRB and the
investigators.
(5) A list of IRB members in the same detail as described in
§46.103(b)(3).
(6) Written procedures for the IRB in the same detail as described in
§46.103(b)(4) and §46.103(b)(5).
(7) Statements of significant new findings provided to subjects, as
required by §46.116(b)(5).
(b) The records required by this policy shall be retained for at least
3 years, and records relating to research which is conducted shall be
retained for at least 3 years after completion of the research. All records
shall be accessible for inspection and copying by authorized
representatives of the Department or Agency at reasonable times and in a
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GOOD CLINICAL PRACTICE
reasonable manner. (Approved by the Office of Management and Budget
under Control Number 9999-0020.)
§46.116 General requirements for informed consent.
Except as provided elsewhere in this policy, no investigator may involve a
human being as a subject in research covered by this policy unless the
investigator has obtained the legally effective informed consent of the
subject or the subject’s legally authorized representative. An investigator
shall seek such consent only under circumstances that provide the
prospective subject or the representative sufficient opportunity to consider
whether or not to participate and that minimize the possibility of coercion or
undue influence. The information that is given to the subject or the
representative shall be in language understandable to the subject or the
representative. No informed consent, whether oral or written, may include
any exculpatory language through which the subject or the representative is
made to waive or appear to waive any of the subject’s legal rights, or
releases or appears to release the investigator, the sponsor, the institution
or its agents from liability for negligence.
(a) Basic elements of informed consent. Except as provided in paragraph
(c) or (d) of this section, in seeking informed consent the following
information shall be provided to each subject:
(1) a statement that the study involves research, an explanation of the
purposes of the research and the expected duration of the subject’s
participation, a description of the procedures to be followed, and
identification of any procedures which are experimental;
(2) a description of any reasonably foreseeable risks or discomforts to
the subject;
(3) a description of any benefits to the subject or to others which may
reasonably be expected from the research;
(4) a disclosure of appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the subject;
(5) a statement describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained;
(6) for research involving more than minimal risk, an explanation as to
whether any compensation and an explanation as to whether any medical
treatments are available if injury occurs and, if so, what they consist of, or
where further information may be obtained;
(7) an explanation of whom to contact for answers to pertinent
questions about the research and research subjects’ rights, and whom to
contact in the event of a research-related injury to the subject; and
(8) a statement that participation is voluntary, refusal to participate will
involve no penalty or loss of benefits to which the subject is otherwise
entitled, and the subject may discontinue participation at any time without
penalty or loss of benefits to which the subject is otherwise entitled.
(b) additional elements of informed consent.When appropriate, one or
more of the following elements of information shall also be provided to each
subject:

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HUMAN SUBJECTS PROTECTION
(1) a statement that the particular treatment or procedure may involve
risks to the subject (or to the embryo or fetus, if the subject is or may
become pregnant) which are currently unforeseeable;
(2) anticipated circumstances under which the subject’s participation
may be terminated by the investigator without regard to the subject’s
consent;
(3) any additional costs to the subject that may result from participation
in the research;
(4) the consequences of a subject’s decision to withdraw from the
research and procedures for orderly termination of participation by the
subject;
(5) a statement that significant new findings developed during the
course of the research which may relate to the subject’s willingness to
continue participation will be provided to the subject; and
(6) the approximate number of subjects involved in the study.
(c) An IRB may approve a consent procedure which does not include, or
which alters, some or all of the elements of informed consent set forth
above, or waive the requirement to obtain informed consent provided the
IRB finds and documents that:
(1) the research or demonstration project is to be conducted by or
subject to the approval of state or local government officials and is
designed to study, evaluate, or otherwise examine: (i) public benefit or
service programs; (ii) procedures for obtaining benefits or services under
those programs; (iii) possible changes in or alternatives to those programs
or procedures; or (iv) possible changes in methods or levels of payment for
benefits or services under those programs; and
(2) the research could not practicably be carried out without the waiver
or alteration.
(d) An IRB may approve a consent procedure which does not include, or
which alters, some or all of the elements of informed consent set forth in
this section, or waive the requirements to obtain informed consent provided
the IRB finds and documents that:
(1) the research involves no more than minimal risk to the subjects;
(2) the waiver or alteration will not adversely affect the rights and
welfare of the subjects;
(3) the research could not practicably be carried out without the waiver
or alteration; and
(4) whenever appropriate, the subjects will be provided with additional
pertinent information after participation.
(e) The informed consent requirements in this policy are not intended to
preempt any applicable Federal, State, or local laws which require
additional information to be disclosed in order for informed consent to be
legally effective.
(f) Nothing in this policy is intended to limit the authority of a physician to
provide emergency medical care, to the extent the physician is permitted to
do so under applicable Federal, State, or local law. (Approved by the Office
of Management and Budget under Control Number 9999-0020.)
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§46.117 Documentation of informed consent.
(a) Except as provided in paragraph (c) of this section, informed consent
shall be documented by the use of a written consent form approved by the
IRB and signed by the subject or the subject’s legally authorized
representative. A copy shall be given to the person signing the form.
(b) Except as provided in paragraph (c) of this section, the consent form
may be either of the following:
(1) A written consent document that embodies the elements of
informed consent required by §46.116.This form may be read to the
subject or the subject’s legally authorized representative, but in any event,
the investigator shall give either the subject or the representative adequate
opportunity to read it before it is signed; or
(2) A short form written consent document stating that the elements of
informed consent required by §46.116 have been presented orally to the
subject or the subject’s legally authorized representative. When this method
is used, there shall be a witness to the oral presentation. Also, the IRB shall
approve a written summary of what is to be said to the subject or the
representative. Only the short form itself is to be signed by the subject or
the representative. However, the witness shall sign both the short form and
a copy of the summar y, and the person actually obtaining consent shall
sign a copy of the summary. A copy of the summary shall be given to the
subject or the representative, in addition to a copy of the short form.
(c) An IRB may waive the requirement for the investigator to obtain a
signed consent form for some or all subjects if it finds either:
(1) That the only record linking the subject and the research would be
the consent document and the principal risk would be potential harm
resulting from a breach of confidentiality. Each subject will be asked
whether the subject wants documentation linking the subject with the
research, and the subject’s wishes will govern; or
(2) That the research presents no more than minimal risk of harm to
subjects and involves no procedures for which written consent is normally
required outside of the research context.
In cases in which the documentation requirement is waived, the IRB may
require the investigator to provide subjects with a written statement
regarding the research. (Approved by the Office of Management and
Budget under Control Number 9999-0020.)
§46.118 Applications and proposals lacking definite plans for
involvement of human subjects.
Certain types of applications for grants, cooperative agreements, or
contracts are submitted to departments or agencies with the knowledge
that subjects may be involved within the period of support, but definite plans
would not normally be set forth in the application or proposal.These include
activities such as institutional type grants when selection of specific projects
is the institution’s responsibility; research training grants in which the
activities involving subjects remain to be selected; and projects in which
human subjects’ involvement will depend upon completion of instruments,
prior animal studies, or purification of compounds. These applications need
not be reviewed by an IRB before an award may be made. However, except
for research exempted or waived under §46.101(b) or (i), no human
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subjects may be involved in any project supported by these awards until the
project has been reviewed and approved by the IRB, as provided in this
policy, and certification submitted, by the institution, to the Department or
Agency.
§46.119 Research undertaken without the intention of involving human
subjects.
In the event research is undertaken without the intention of involving human
subjects, but it is later proposed to involve human subjects in the research,
the research shall first be reviewed and approved by an IRB, as provided in
this policy, a certification submitted, by the institution, to the Department or
Agency, and final approval given to the proposed change by the
Department or Agency.
§46.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal Department or
Agency.
(a) The Department or Agency head will evaluate all applications and
proposals involving human subjects submitted to the Department or Agency
through such officers and employees of the Department or Agency and
such experts and consultants as the Department or Agency head
determines to be appropriate. This evaluation will take into consideration
the risks to the subjects, the adequacy of protection against these risks, the
potential benefits of the research to the subjects and others, and the
importance of the knowledge gained or to be gained.
(b) On the basis of this evaluation, the Department or Agency head may
approve or disapprove the application or proposal, or enter into negotiations
to develop an approvable one.
§46.121 [Reserved]
§46.122 Use of Federal funds.
Federal funds administered by a Department or Agency may not be
expended for research involving human subjects unless the requirements of
this policy have been satisfied.
§46.123 Early termination of research support: Evaluation of
applications and proposals.
(a) The Department or Agency head may require that Department or
Agency support for any project be terminated or suspended in the manner
prescribed in applicable program requirements, when the Department or
Agency head finds an institution has materially failed to comply with the
terms of this policy.
(b) In making decisions about supporting or approving applications or
proposals covered by this policy the Department or Agency head may take
into account, in addition to all other eligibility requirements and program
criteria, factors such as whether the applicant has been subject to a
termination or suspension under paragraph (a) of this section and whether
the applicant or the person or persons who would direct or has/have
directed the scientific and technical aspects of an activity has/have, in the
judgment of the Department or Agency head, materially failed to discharge
responsibility for the protection of the rights and welfare of human subjects
(whether or not the research was subject to Federal regulation).
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§46.124 Conditions.
With respect to any research project or any class of research projects the
Department or Agency head may impose additional conditions prior to or at
the time of approval when in the judgment of the Department or Agency
head additional conditions are necessary for the protection of human
subjects.

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Subpart B—Additional DHHS Protections Pertaining to
Research, Development, and Related Activities Involving
Fetuses, Pregnant Women, and Human In Vitro Fertilization
Source: 40 FR 33528, Aug. 8, 1975; 43 FR 1758, January 11, 1978.
Note:This rule is under revision. Please refer to the OHRP Web page
for the most recent information.
§46.201 Applicability.
(a) The regulations in this subpart are applicable to all Department of
Health and Human Services grants and contracts supporting research,
development, and related activities involving: (1) the fetus, (2) pregnant
women, and (3) human in vitro fertilization.
(b) Nothing in this subpart shall be construed as indicating that
compliance with the procedures set forth herein will in any way render
inapplicable pertinent State or local laws bearing upon activities covered by
this subpart.
(c) The requirements of this subpart are in addition to those imposed
under the other subparts of this part.
§46.202 Purpose.
It is the purpose of this subpart to provide additional safeguards in
reviewing activities to which this subpart is applicable to assure that they
conform to appropriate ethical standards and relate to important societal
needs.
§46.203 Definitions.
As used in this subpart:
(a) “Secretary” means the Secretary of Health and Human Services and
any other officer or employee of the Department of Health and Human
Services (DHHS) to whom authority has been delegated.
(b) “Pregnancy” encompasses the period of time from confirmation of
implantation (through any of the presumptive signs of pregnancy, such as
missed menses, or by a medically acceptable pregnancy test), until
expulsion or extraction of the fetus.
(c) “Fetus” means the product of conception from the time of implantation
(as evidenced by any of the presumptive signs of pregnancy, such as
missed menses, or a medically acceptable pregnancy test), until a
determination is made, following expulsion or extraction of the fetus, that it
is viable.
(d) “Viable” as it pertains to the fetus means being able, after either
spontaneous or induced delivery, to survive (given the benefit of available
medical therapy) to the point of independently maintaining heartbeat and
respiration.The Secretary may from time to time, taking into account
medical advances, publish in the Federal Register guidelines to assist in
determining whether a fetus is viable for purposes of this subpart. If a fetus
is viable after delivery, it is a premature infant.
(e) “Nonviable fetus” means a fetus ex utero which, although living, is not
viable.
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(f) “Dead fetus” means a fetus ex utero which exhibits neither heartbeat,
spontaneous respiratory activity, spontaneous movement of voluntary
muscles, nor pulsation of the umbilical cord (if still attached).
(g) “In vitro fertilization” means any fertilization of human ova, which
occurs outside the body of a female, either through a mixture of donor
human sperm and ova or by any other means.
§46.204 Ethical Advisory Boards.
(a) One or more Ethical Advisory Boards shall be established by the
Secretary. Members of these Board(s) shall be so selected that the
Board(s) will be competent to deal with medical, legal, social, ethical, and
related issues and may include, for example, research scientists,
physicians, psychologists, sociologists, educators, lawyers, and ethicists, as
well as representatives of the general public. No Board member may be a
regular, full-time employee of the Department of Health and Human
Services.
(b) At the request of the Secretary, the Ethical Advisory Board shall
render advice consistent with the policies and requirements of this part as
to ethical issues, involving activities covered by this subpart, raised by
individual applications or proposals. In addition, upon request by the
Secretary, the Board shall render advice as to classes of applications or
proposals and general policies, guidelines, and procedures.
(c) A Board may establish, with the approval of the Secretar y, classes of
applications or proposals which: (1) must be submitted to the Board, or
(2) need not be submitted to the Board.Where the Board so establishes a
class of applications or proposals which must be submitted, no application
or proposal within the class may be funded by the Department or any
component thereof until the application or proposal has been reviewed by
the Board and the Board has rendered advice as to its acceptability from an
ethical standpoint.
(d) [Nullified under Public Law 103-43, June 10, 1993]
§46.205 Additional duties of the Institutional Review Boards in
connection with activities involving fetuses, pregnant women, or
human in vitro fertilization.
(a) In addition to the responsibilities prescribed for Institutional Review
Boards under Subpart A of this part, the applicant's or offeror’s Board shall,
with respect to activities covered by this subpart, carry out the following
additional duties:
(1) determine that all aspects of the activity meet the requirements of
this subpart;
(2) determine that adequate consideration has been given to the
manner in which potential subjects will be selected, and adequate provision
has been made by the applicant or offeror for monitoring the actual
informed consent process (e.g., through such mechanisms, when
appropriate, as participation by the Institutional Review Board or subject
advocates in: (i) overseeing the actual process by which individual consents
required by this subpart are secured either by approving induction of each
individual into the activity or verifying, perhaps through sampling, that
approved procedures for induction of individuals into the activity are being
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followed, and (ii) monitoring the progress of the activity and intervening as
necessary through such steps as visits to the activity site and continuing
evaluation to determine if any unanticipated risks have arisen);
(3) carry out such other responsibilities as may be assigned by the
Secretary.
(b) No award may be issued until the applicant or offeror has certified to
the Secretary that the Institutional Review Board has made the
determinations required under paragraph (a) of this section and the
Secretary has approved these determinations, as provided in §46.120 of
Subpart A of this part.
(c) Applicants or offerors seeking support for activities covered by this
subpart must provide for the designation of an Institutional Review Board,
subject to approval by the Secretary, where no such Board has been
established under Subpart A of this part.
§46.206 General limitations.
(a) No activity to which this subpart is applicable may be undertaken
unless:
(1) appropriate studies on animals and nonpregnant individuals have
been completed;
(2) except where the purpose of the activity is to meet the health
needs of the mother or the particular fetus, the risk to the fetus is minimal
and, in all cases, is the least possible risk for achieving the objectives of
the activity;
(3) individuals engaged in the activity will have no part in: (i) any
decisions as to the timing, method, and procedures used to terminate the
pregnancy, and (ii) determining the viability of the fetus at the termination of
the pregnancy; and
(4) no procedural changes which may cause greater than minimal risk
to the fetus or the pregnant woman will be introduced into the procedure for
terminating the pregnancy solely in the interest of the activity.
(b) No inducements, monetary or otherwise, may be offered to terminate
pregnancy for purposes of the activity.
Source: 40 FR 33528, Aug. 8, 1975, as amended at 40 FR 51638, Nov. 6,
1975.
§46.207 Activities directed toward pregnant women as subjects.
(a) No pregnant woman may be involved as a subject in an activity
covered by this subpart unless: (1) the purpose of the activity is to meet the
health needs of the mother and the fetus will be placed at risk only to the
minimum extent necessary to meet such needs, or (2) the risk to the fetus
is minimal.
(b) An activity permitted under paragraph (a) of this section may be
conducted only if the mother and father are legally competent and have
given their informed consent after having been fully informed regarding
possible impact on the fetus, except that the father's informed consent need
not be secured if: (1) the purpose of the activity is to meet the health needs
of the mother; (2) his identity or whereabouts cannot reasonably be

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ascertained; (3) he is not reasonably available; or (4) the pregnancy
resulted from rape.
§46.208 Activities directed toward fetuses in utero as subjects.
(a) No fetus in utero may be involved as a subject in any activity covered
by this subpart unless: (1) the purpose of the activity is to meet the health
needs of the particular fetus and the fetus will be placed at risk only to the
minimum extent necessary to meet such needs, or (2) the risk to the fetus
imposed by the research is minimal and the purpose of the activity is the
development of important biomedical knowledge which cannot be obtained
by other means.
(b) An activity permitted under paragraph (a) of this section may be
conducted only if the mother and father are legally competent and have
given their informed consent, except that the father's consent need not be
secured if: (1) his identity or whereabouts cannot reasonably be
ascertained, (2) he is not reasonably available, or (3) the pregnancy
resulted from rape.
§46.209 Activities directed toward fetuses ex utero, including
nonviable fetuses, as subjects.
(a) Until it has been ascertained whether or not a fetus ex utero is viable,
a fetus ex utero may not be involved as a subject in an activity covered by
this subpart unless:
(1) there will be no added risk to the fetus resulting from the activity,
and the purpose of the activity is the development of important biomedical
knowledge which cannot be obtained by other means, or
(2) the purpose of the activity is to enhance the possibility of survival of
the particular fetus to the point of viability.
(b) No nonviable fetus may be involved as a subject in an activity covered
by this subpart unless:
(1) vital functions of the fetus will not be artificially maintained,
(2) experimental activities which of themselves would terminate the
heartbeat or respiration of the fetus will not be employed, and
(3) the purpose of the activity is the development of important
biomedical knowledge which cannot be obtained by other means.
(c) In the event the fetus ex utero is found to be viable, it may be included
as a subject in the activity only to the extent permitted by and in
accordance with the requirements of other subparts of this part.
(d) An activity permitted under paragraph (a) or (b) of this section may be
conducted only if the mother and father are legally competent and have
given their informed consent, except that the father’s informed consent
need not be secured if: (1) his identity or whereabouts cannot reasonably
be ascertained, (2) he is not reasonably available, or (3) the pregnancy
resulted from rape.
§46.210 Activities involving the dead fetus, fetal material, or the
placenta.
Activities involving the dead fetus, mascerated fetal material, or cells,
tissue, or organs excised from a dead fetus shall be conducted only in
accordance with any applicable State or local laws regarding such activities.
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HUMAN SUBJECTS PROTECTION
§46.211 Modification or waiver of specific requirements.
Upon the request of an applicant or offeror (with the approval of its
Institutional Review Board), the Secretary may modify or waive specific
requirements of this subpart, with the approval of the Ethical Advisory
Board after such opportunity for public comment as the Ethical Advisory
Board considers appropriate in the particular instance. In making such
decisions, the Secretary will consider whether the risks to the subject are
so outweighed by the sum of the benefit to the subject and the importance
of the knowledge to be gained as to warrant such modification or waiver
and that such benefits cannot be gained except through a modification or
waiver. Any such modifications or waivers will be published as notices in the
Federal Register.

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GOOD CLINICAL PRACTICE

Subpart C—Additional DHHS Protections Pertaining to
Biomedical and Behavioral Research Involving Prisoners
as Subjects
Source: 43 FR 53655, Nov. 16, 1978.
§46.301 Applicability.
(a) The regulations in this subpart are applicable to all biomedical and
behavioral research conducted or supported by the Department of Health
and Human Services involving prisoners as subjects.
(b) Nothing in this subpart shall be construed as indicating that
compliance with the procedures set forth herein will authorize research
involving prisoners as subjects, to the extent such research is limited or
barred by applicable State or local law.
(c) The requirements of this subpart are in addition to those imposed
under the other subparts of this part.
§46.302 Purpose.
Inasmuch as prisoners may be under constraints because of their
incarceration which could affect their ability to make a truly voluntary and
uncoerced decision whether or not to participate as subjects in research, it
is the purpose of this subpart to provide additional safeguards for the
protection of prisoners involved in activities to which this subpart is
applicable.
§46.303 Definitions.
As used in this subpart:
(a) “Secretary” means the Secretary of Health and Human Services and
any other officer or employee of the Department of Health and Human
Services to whom authority has been delegated.
(b) “DHHS” means the Department of Health and Human Services.
(c) “Prisoner” means any individual involuntarily confined or detained in a
penal institution.The term is intended to encompass individuals sentenced
to such an institution under a criminal or civil statute, individuals detained in
other facilities by virtue of statutes or commitment procedures which
provide alternatives to criminal prosecution or incarceration in a penal
institution, and individuals detained pending arraignment, trial, or
sentencing.
(d) “Minimal risk” is the probability and magnitude of physical or
psychological harm that is normally encountered in the daily lives, or in the
routine medical, dental, or psychological examination of healthy persons.
§46.304 Composition of Institutional Review Boards where prisoners
are involved.
In addition to satisfying the requirements in §46.107 of this part, an
Institutional Review Board, carrying out responsibilities under this part with
respect to research covered by this subpart, shall also meet the following
specific requirements:

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HUMAN SUBJECTS PROTECTION
(a) A majority of the Board (exclusive of prisoner members) shall have no
association with the prison(s) involved, apart from their membership on the
Board.
(b) At least one member of the Board shall be a prisoner, or a prisoner
representative with appropriate background and experience to serve in that
capacity, except that where a particular research project is reviewed by
more than one Board only one Board need satisfy this requirement.
§46.305 Additional duties of the Institutional Review Boards where
prisoners are involved.
(a) In addition to all other responsibilities prescribed for Institutional
Review Boards under this part, the Board shall review research covered by
this subpart and approve such research only if it finds that:
(1) the research under review represents one of the categories of
research permissible under §46.306(a)(2);
(2) any possible advantages accruing to the prisoner through his or her
participation in the research, when compared to the general living
conditions, medical care, quality of food, amenities and opportunity for
earnings in the prison, are not of such a magnitude that his or her ability to
weigh the risks of the research against the value of such advantages in the
limited choice environment of the prison is impaired;
(3) the risks involved in the research are commensurate with risks that
would be accepted by nonprisoner volunteers;
(4) procedures for the selection of subjects within the prison are fair to
all prisoners and immune from arbitrary intervention by prison authorities or
prisoners. Unless the principal investigator provides to the Board
justification in writing for following some other procedures, control subjects
must be selected randomly from the group of available prisoners who meet
the characteristics needed for that particular research project;
(5) the information is presented in language which is understandable to
the subject population;
(6) adequate assurance exists that parole boards will not take into
account a prisoner’s participation in the research in making decisions
regarding parole, and each prisoner is clearly informed in advance that
participation in the research will have no effect on his or her parole; and
(7) where the Board finds there may be a need for follow-up
examination or care of participants after the end of their participation,
adequate provision has been made for such examination or care, taking
into account the varying lengths of individual prisoners’ sentences, and for
informing participants of this fact.
(b) The Board shall carry out such other duties as may be assigned by
the Secretary.
(c) The institution shall certify to the Secretary, in such form and manner
as the Secretary may require, that the duties of the Board under this
section have been fulfilled.

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GOOD CLINICAL PRACTICE
§46.306 Permitted research involving prisoners.
(a) Biomedical or behavioral research conducted or supported by DHHS
may involve prisoners as subjects only if:
(1) the institution responsible for the conduct of the research has
certified to the Secretary that the Institutional Review Board has approved
the research under §46.305 of this subpart; and
(2) in the judgment of the Secretary the proposed research involves
solely the following:
(A) study of the possible causes, effects, and processes of
incarceration, and of criminal behavior, provided that the study presents no
more than minimal risk and no more than inconvenience to the subjects;
(B) study of prisons as institutional structures or of prisoners as
incarcerated persons, provided that the study presents no more than
minimal risk and no more than inconvenience to the subjects;
(C) research on conditions particularly affecting prisoners as a class
(for example, vaccine trials and other research on hepatitis which is much
more prevalent in prisons than elsewhere; and research on social and
psychological problems such as alcoholism, drug addiction, and sexual
assaults) provided that the study may proceed only after the Secretary has
consulted with appropriate experts including experts in penology, medicine,
and ethics, and published notice, in the Federal Register, of his intent to
approve such research; or
(D) research on practices, both innovative and accepted, which have
the intent and reasonable probability of improving the health or well-being
of the subject. In cases in which those studies require the assignment of
prisoners in a manner consistent with protocols approved by the IRB to
control groups which may not benefit from the research, the study may
proceed only after the Secretary has consulted with appropriate experts,
including experts in penology, medicine, and ethics, and published notice, in
the Federal Register, of the intent to approve such research.
(b) Except as provided in paragraph (a) of this section, biomedical or
behavioral research conducted or supported by DHHS shall not involve
prisoners as subjects.

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HUMAN SUBJECTS PROTECTION

Subpart D—Additional DHHS Protections for Children
Involved as Subjects in Research
Source: 48 FR 9818, March 8, 1983; 56 FR 28032, June 18, 1991.
§46.401 To what do these regulations apply?
(a) This subpart applies to all research involving children as subjects,
conducted or supported by the Department of Health and Human Services.
(1) This includes research conducted by Department employees,
except that each head of an Operating Division of the Department may
adopt such nonsubstantive, procedural modifications as may be appropriate
from an administrative standpoint.
(2) It also includes research conducted or supported by the
Department of Health and Human Services outside the United States, but
in appropriate circumstances, the Secretary may, under paragraph (i) of
§46.101 of Subpart A, waive the applicability of some or all of the
requirements of these regulations for research of this type.
(b) Exemptions at §46.101(b)(1) and (b)(3) through (b)(6) are applicable
to this subpart.The exemption at §46.101(b)(2) regarding educational tests
is also applicable to this subpart. However, the exemption at §46.101(b)(2)
for research involving survey or interview procedures or observations of
public behavior does not apply to research covered by this subpart, except
for research involving observation of public behavior when the
investigator(s) do not participate in the activities being observed.
(c) The exceptions, additions, and provisions for waiver as they appear in
paragraphs (c) through (i) of §46.101 of Subpart A are applicable to this
subpart.
§46.402 Definitions.
The definitions in §46.102 of Subpart A shall be applicable to this subpart
as well.In addition, as used in this subpart:
(a) “Children” are persons who have not attained the legal age for
consent to treatments or procedures involved in the research, under the
applicable law of the jurisdiction in which the research will be conducted.
(b) “Assent” means a child’s affirmative agreement to participate in
research. Mere failure to object should not, absent affirmative agreement,
be construed as assent.
(c) “Permission” means the agreement of parent(s) or guardian to the
participation of their child or ward in research.
(d) “Parent” means a child’s biological or adoptive parent.
(e) “Guardian” means an individual who is authorized under applicable
State or local law to consent on behalf of a child to general medical care.
§46.403 IRB duties.
In addition to other responsibilities assigned to IRB’s under this part, each
IRB shall review research covered by this subpart and approve only
research which satisfies the conditions of all applicable sections of this
subpart.

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GOOD CLINICAL PRACTICE
§46.404 Research not involving greater than minimal risk.
DHHS will conduct or fund research in which the IRB finds that no greater
than minimal risk to children is presented, only if the IRB finds that
adequate provisions are made for soliciting the assent of the children and
the permission of their parents or guardians, as set forth in §46.408.
§46.405 Research involving greater than minimal risk but presenting
the prospect of direct benefit to the individual subjects.
DHHS will conduct or fund research in which the IRB finds that more than
minimal risk to children is presented by an intervention or procedure that
holds out the prospect of direct benefit for the individual subject, or by a
monitoring procedure that is likely to contribute to the subject’s well-being,
only if the IRB finds that:
(a) the risk is justified by the anticipated benefit to the subjects;
(b) the relation of the anticipated benefit to the risk is at least as favorable
to the subjects as that presented by available alternative approaches; and
(c) adequate provisions are made for soliciting the assent of the children
and permission of their parents or guardians, as set forth in §46.408.
§46.406 Research involving greater than minimal risk and no prospect
of direct benefit to individual subjects, but likely to yield generalizable
knowledge about the subject’s disorder or condition.
DHHS will conduct or fund research in which the IRB finds that more than
minimal risk to children is presented by an intervention or procedure that
does not hold out the prospect of direct benefit for the individual subject, or
by a monitoring procedure which is not likely to contribute to the well-being
of the subject, only if the IRB finds that:
(a) the risk represents a minor increase over minimal risk;
(b) the intervention or procedure presents experiences to subjects that
are reasonably commensurate with those inherent in their actual or
expected medical, dental, psychological, social, or educational situations;
(c) the intervention or procedure is likely to yield generalizable knowledge
about the subjects’ disorder or condition which is of vital importance for the
understanding or amelioration of the subjects’disorder or condition; and
(d) adequate provisions are made for soliciting assent of the children and
permission of their parents or guardians, as set forth in §46.408.
§46.407 Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious problem
affecting the health or welfare of children.
DHHS will conduct or fund research that the IRB does not believe meets
the requirements of §46.404, §46.405, or §46.406 only if:
(a) the IRB finds that the research presents a reasonable opportunity to
further the understanding, prevention, or alleviation of a serious problem
affecting the health or welfare of children; and
(b) the Secretary, after consultation with a panel of experts in pertinent
disciplines (for example: science, medicine, education, ethics, law) and
following opportunity for public review and comment, has determined either:

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HUMAN SUBJECTS PROTECTION
(1) that the research in fact satisfies the conditions of §46.404,
§46.405, or §46.406, as applicable, or
(2) the following:
(i) the research presents a reasonable opportunity to further the
understanding, prevention, or alleviation of a serious problem affecting the
health or welfare of children;
(ii) the research will be conducted in accordance with sound ethical
principles;
(iii) adequate provisions are made for soliciting the assent of children
and the permission of their parents or guardians, as set forth in §46.408.
§46.408 Requirements for permission by parents or guardians and for
assent by children.
(a) In addition to the determinations required under other applicable
sections of this subpart, the IRB shall determine that adequate provisions
are made for soliciting the assent of the children, when in the judgment of
the IRB the children are capable of providing assent. In determining
whether children are capable of assenting, the IRB shall take into account
the ages, maturity, and psychological state of the children involved.This
judgment may be made for all children to be involved in research under a
particular protocol, or for each child, as the IRB deems appropriate. If the
IRB determines that the capability of some or all of the children is so limited
that they cannot reasonably be consulted or that the intervention or
procedure involved in the research holds out a prospect of direct benefit
that is important to the health or well-being of the children and is available
only in the context of the research, the assent of the children is not a
necessary condition for proceeding with the research. Even where the IRB
determines that the subjects are capable of assenting, the IRB may still
waive the assent requirement under circumstances in which consent may
be waived in accord with §46.116 of Subpart A.
(b) In addition to the determinations required under other applicable
sections of this subpart, the IRB shall determine, in accordance with and to
the extent that consent is required by §46.116 of Subpart A, that adequate
provisions are made for soliciting the permission of each child’s parents or
guardian.Where parental permission is to be obtained, the IRB may find
that the permission of one parent is sufficient for research to be conducted
under §46.404 or §46.405.Where research is covered by §46.406 and
§46.407 and permission is to be obtained from parents, both parents must
give their permission unless one parent is deceased, unknown,
incompetent, or not reasonably available, or when only one parent has legal
responsibility for the care and custody of the child.
(c) In addition to the provisions for waiver contained in §46.116 of
Subpart A, if the IRB determines that a research protocol is designed for
conditions or for a subject population for which parental or guardian
permission is not a reasonable requirement to protect the subjects (for
example, neglected or abused children), it may waive the consent
requirements in Subpart A of this part and paragraph (b) of this section,
provided an appropriate mechanism for protecting the children who will
participate as subjects in the research is substituted, and provided further

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GOOD CLINICAL PRACTICE
that the waiver is not inconsistent with Federal, State, or local law. The
choice of an appropriate mechanism would depend upon the nature and
purpose of the activities described in the protocol, the risk and anticipated
benefit to the research subjects, and their age, maturity, status, and
condition.
(d) Permission by parents or guardians shall be documented in
accordance with and to the extent required by §46.117 of Subpart A.
(e) When the IRB determines that assent is required, it shall also
determine whether and how assent must be documented.
§46.409 Wards.
(a) Children who are wards of the State or any other agency, institution,
or entity can be included in research approved under §46.406 or §46.407
only if such research is:
(1) related to their status as wards; or
(2) conducted in schools, camps, hospitals, institutions, or similar
settings in which the majority of children involved as subjects are not
wards.
(b) If the research is approved under paragraph (a) of this section, the
IRB shall require appointment of an advocate for each child who is a ward,
in addition to any other individual acting on behalf of the child as guardian
or in loco parentis. One individual may serve as advocate for more than one
child.The advocate shall be an individual who has the background and
experience to act in, and agrees to act in, the best interests of the child for
the duration of the child’s participation in the research and who is not
associated in any way (except in the role as advocate or member of the
IRB) with the research, the investigator(s), or the guardian organization.

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HUMAN SUBJECTS PROTECTION

Categories of Research That May Be Reviewed
by the Institutional Review Board (IRB)
Through an Expedited Review Procedure 1
Applicability
(A) Research activities that (1) present no more than minimal risk to
human subjects, and (2) involve only procedures listed in one or more of
the following categories, may be reviewed by the IRB through the expedited
review procedure authorized by 45 CFR 46.110 and 21 CFR 56 110.The
activities listed should not be deemed to be of minimal risk simply because
they are included on this list. Inclusion on this list merely means that the
activity is eligible for review through the expedited review procedure when
the specific circumstances of the proposed research involve no more than
minimal risk to human subjects.
(B) The categories in this list apply regardless of the age of subjects,
except as noted.
(C) The expedited review procedure may not be used where identification
of the subjects and/or their responses would reasonably place them at risk
of criminal or civil liability or be damaging to the subjects’financial standing,
employability, insurability, reputation, or be stigmatizing, unless reasonable
and appropriate protections will be implemented so that risks related to
invasion of privacy and breach of confidentiality are no greater than
minimal.
(D) The expedited review procedure may not be used for classified
research involving human subjects.
(E) IRBs are reminded that the standard requirements for informed
consent (or its waiver, alteration, or exception) apply regardless of the type
of review—expedited or convened—utilized by the IRB.
(F) Categories one (1) through seven (7) pertain to both initial and
continuing IRB review.
Research Categories
(1) Clinical studies of drugs and medical devices only when condition
(a) or (b) is met.
(a) Research on drugs for which an investigational new drug
application (21 CFR Part 312) is not required. (Note: Research on marketed
drugs that significantly increases the risks or decreases the acceptability of
the risks associated with the use of the product is not eligible for expedited
review.)
(b) Research on medical devices for which (i) an investigational
device exemption application (21 CFR Part 312) is not required; or (ii) the
medical device is cleared/approved for marketing and the medical device is
being used in accordance with its cleared/approved labeling.
(2) Collection of blood samples by finger stick, heel stick, ear stick, or
venipuncture as follows:
1An expedited review procedure consists of a review of research in volving human subjects
by the IRB chairperson or by one or more experienced reviewers designated by the
chairperson from among members of the IRB in accordance with the requirements set forth in
45 CFR 46.110.

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GOOD CLINICAL PRACTICE
(a) from healthy, nonpregnant adults who weigh at least 110 pounds.
For these subjects, the amounts drawn may not exceed 550 ml in an
8 week period and collection may not occur more frequently than 2 times
per week; or
(b) from other adults and children,2 considering the age, weight, and
health of the subjects, the collection procedure, the amount of blood to be
collected, and the frequency with which it will be collected. For these
subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per
kg in an 8 week period and collection may not occur more frequently than
2 times per week.
(3) Prospective collection of biological specimens for research
purposes by noninvasive means.
Examples: (a) hair and nail clippings in a nondisfiguring manner;
(b) deciduous teeth at time of exfoliation or if routine patient care indicates
a need for extraction; (c) permanent teeth if routine patient care indicates a
need for extraction; (d) excreta and external secretions (including sweat);
(e) uncannulated saliva collected either in an unstimulated fashion or
stimulated by chewing gumbase or wax or by applying a dilute citric solution
to the tongue; (f) placenta removed at delivery; (g) amniotic fluid obtained at
the time of rupture of the membrane prior to or during labor; (h) supra- and
subgingival dental plaque and calculus, provided the collection procedure is
not more invasive than routine prophylactic scaling of the teeth and the
process is accomplished in accordance with accepted prophylactic
techniques; (i) mucosal and skin cells collected by buccal scraping or swab,
skin swab, or mouth washings; (j) sputum collected after saline mist
nebulization.
(4) Collection of data through noninvasive procedures (not involving
general anesthesia or sedation) routinely employed in clinical practice,
excluding procedures involving x-rays or microwaves. Where medical
devices are employed, they must be cleared/approved for marketing.
(Studies intended to evaluate the safety and effectiveness of the medical
device are not generally eligible for expedited review, including studies of
cleared medical devices for new indications.)
Examples: (a) physical sensors that are applied either to the surface of
the body or at a distance and do not involve input of significant amounts
of energy into the subject or an invasion of the subject’s privacy;
(b) weighing or testing sensory acuity; (c) magnetic resonance imaging;
(d) electrocardiography, electroencephalography, thermography, detection of
naturally occurring radioactivity, electroretinography, ultrasound, diagnostic
infrared imaging, doppler blood flow, and echocardiography; (e) moderate
exercise, muscular strength testing, body composition assessment, and
flexibility testing where appropriate given the age, weight, and health of the
individual.
(5) Research involving materials (data, documents, records, or
specimens) that have been collected, or will be collected solely for
nonresearch purposes (such as medical treatment or diagnosis). (NOTE:
2Children are defined in the HHS regulations as “persons who have not attained the legal age
for consent to treatments or procedures involved in the research, under the applicable law of the
jurisdiction in which the research will be conducted.” 45 CFR 46.402(a).

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HUMAN SUBJECTS PROTECTION
Some research in this category may be exempt from the HHS regulations
for the protection of human subjects. 45 CFR 46.101(b)(4).This listing
refers only to research that is not exempt.)
(6) Collection of data from voice, video, digital, or image recordings
made for research purposes.
(7) Research on individual or group characteristics or behavior
(including, but not limited to, research on perception, cognition, motivation,
identity, language, communication, cultural beliefs or practices, and
social behavior) or research employing sur vey, interview, oral history,
focus group, program evaluation, human factors evaluation, or quality
assurance methodologies. (NOTE: Some research in this category may be
exempt from the HHS regulations for the protection of human subjects.
45 CFR 46.101(b)(2) and (b)(3).This listing refers only to research that is
not exempt.)
(8) Continuing review of research previously approved by the convened
IRB as follows:
(a) where (i) the research is permanently closed to the enrollment of
new subjects; (ii) all subjects have completed all research-related
interventions; and (iii) the research remains active only for long-term followup of subjects; or
(b) where no subjects have been enrolled and no additional risks
have been identified; or
(c) where the remaining research activities are limited to data
analysis.
(9) Continuing review of research, not conducted under an
investigational new drug application or investigational device exemption
where categories two (2) through eight (8) do not apply but the IRB has
determined and documented at a convened meeting that the research
involves no greater than minimal risk and no additional risks have been
identified.
[Source: 63 FR 60364-60367, November 9, 1998.]

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INFORMED CONSENT

II. Informed Consent
FDA Regulations on Informed Consent
21 CFR PART 50—PROTECTION OF HUMAN SUBJECTS
[Source: 45 FR 36390, May 30, 1980, unless otherwise noted.]
Subpart A—General Provisions
Sec.
50.1
Scope.
50.3
Definitions.
Subpart B—Informed Consent of Human Subjects
Sec.
50.20
50.21
50.23
50.24
50.25
50.27

General requirements for informed consent.
Effective date.
Exception from general requirements.
Exception from informed consent requirements for
emergency research
Elements of informed consent.
Documentation of informed consent.

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GOOD CLINICAL PRACTICE

Subpart A—General Provisions
§50.1 Scope.
(a) This part applies to all clinical investigations regulated by the Food
and Drug Administration under sections 505(i) 507(d), and 520(g) of the
Federal Food, Drug, and Cosmetic Act, as well as clinical investigations that
support applications for research or marketing permits for products
regulated by the Food and Drug Administration, including food and color
additives, drugs for human use, medical devices for human use, biological
products for human use, and electronic products. Additional specific
obligations and commitments of, and standards of conduct for, persons who
sponsor or monitor clinical investigations involving particular test articles
may also be found in other parts (e.g., 21 CFR parts 312 and 812).
Compliance with these parts is intended to protect the rights and safety of
subjects involved in investigations filed with the Food and Drug
Administration pursuant to §406, §409, §502, §503, §505, §506, §507,
§510, §§513-516, §518, §520, §706, and §801 of the Federal Food, Drug
and Cosmetic Act and §351 and §§354-360F of the Public Health Service
Act.
(b) References in this part to regulatory sections of the Code of Federal
Regulations are to chapter I of title 21, unless otherwise noted.
[45 FR 36390, May 30, 1980; 46 FR 8979, Jan. 27, 1981]

§50.3 Definitions.
As used in this part:
(a) Act means the Federal Food, Drug, and Cosmetic Act, as amended
(§§ 201-902, 52 Stat. 1040 et seq. as amended (21 U.S.C. 321-392)).
(b) Application for research or marketing permit includes:
(1) A color additive petition, described in part 71.
(2) A food additive petition, described in parts 171 and 571.
(3) Data and information about a substance submitted as part of the
procedures for establishing that the substance is generally recognized as
safe for use that results or may reasonably be expected to result, directly or
indirectly, in its becoming a component or otherwise affecting the
characteristics of any food, described in §170.30 and §570.30.
(4) Data and information about a food additive submitted as part of the
procedures for food additives permitted to be used on an interim basis
pending additional study, described in §180.1.
(5) Data and information about a substance submitted as part of the
procedures for establishing a tolerance for unavoidable contaminants in
food and food-packaging materials described in §406 of the act.
(6) An investigational new drug application, described in part 312 of
this chapter.
(7) A new drug application, described in part 314.
(8) Data and information about the bioavailability or bioequivalence of
drugs for human use submitted as part of the procedures for issuing,
amending, or repealing a bioequivalence requirement, described in
part 320.
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INFORMED CONSENT
(9) Data and information about an over-the-counter drug for human
use submitted as part of the procedures for classifying these drugs as
generally recognized as safe and effective and not misbranded, described
in part 330.
(10) Data and information about a prescription drug for human use
submitted as part of the procedures for classifying these drugs as generally
recognized as safe and effective and not misbranded, described in this
chapter.
(11) Data and information about an antibiotic drug submitted as part of
the procedures for issuing, amending or repealing regulations for these
drugs, described in §314.300 of this chapter.
(12) An application for a biological product license, described in
part 601.
(13) Data and information about a biological product submitted as part
of the procedures for determining that licensed biological products are safe
and effective and not misbranded, described in part 601.
(14) Data and information about an in vitro diagnostic product
submitted as part of the procedures for establishing, amending, or
repealing a standard for these products, described in part 809.
(15) An Application for an Investigational Device Exemption, described
in part 812.
(16) Data and information about a medical device submitted as part of
the procedures for classifying these devices, described in §513.
(17) Data and information about a medical device submitted as part of
the procedures for establishing, amending, or repealing a standard for
these devices, described in §514.
(18) An application for premarket approval of a medical device,
described in §515.
(19) A product development protocol for a medical device, described in
§515.
(20) Data and information about an electronic product submitted as
part of the procedures for establishing, amending or repealing a standard
for these products, described in §358 of the Public Health Service Act.
(21) Data and information about an electronic product submitted as
part of the procedures for obtaining a variance from any electronic product
performance standard, as described in §1010.4.
(22) Data and information about an electronic product submitted as
part of the procedures for granting amending, or extending an exemption
from a radiation safety performance standard, as described in §1010.5.
(c) Clinical investigation means any experiment that involves a test
article and one or more human subjects and that either is subject to
requirements for prior submission to the Food and Drug Administration
under §505(i), §507(d), or §520(g) of the act, or is not subject to
requirements for prior submission to the Food and Drug Administration
under these sections of the act, but the results of which are intended to be
submitted later to, or held for inspection by, the Food and Drug
Administration as part of an application for a research or marketing permit.
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GOOD CLINICAL PRACTICE
The term does not include experiments that are subject to the provisions of
part 58 of this chapter, regarding nonclinical laboratory studies.
(d) Investigator means an individual who actually conducts a clinical
investigation, i.e., under whose immediate direction the test article is
administered or dispensed to or used involving, a subject, or, in the event of
an investigation conducted by a team of individuals, is the responsible
leader of that team.
(e) Sponsor means a person who initiates a clinical investigation, but
who does not actually conduct the investigation, i.e., the test article is
administered or dispensed to or used involving, a subject under the
immediate direction of another individual. A person other than an individual
(e.g., corporation or agency) that uses one or more of its own employees to
conduct a clinical investigation it has initiated is considered to be a sponsor
(not a sponsor-investigator) and the employees are considered to be
investigators.
(f) Sponsor-investigator means an individual who both initiates and
actually conducts, alone or with others a clinical investigation, i.e., under
whose immediate direction the test article is administered or dispensed to,
or used involving, a subject.The term does not include any person other
than an individual, e.g., corporation or agency.
(g) Human subject means an individual who is or becomes a participant
in research, either as a recipient of the test article as a control.A subject
may be either a healthy human or a patient.
(h) Institution means any public or private entity or Agency (including
Federal, State, and other agencies).The word facility as used in §520(g) of
the act is deemed to be synonymous with the term institution for purposes
of this part.
(i) Institutional review board (IRB) means any board, committee, or
other group formally designated by an institution to review biomedical
research involving humans as subjects, to approve the initiation of and
conduct periodic review of such research.The term has the same meaning
as the phrase institutional review committee as used in §520(g) of the act.
(j) Test article means any drug (including a biological product for human
use), medical device for human use, human food additive, color additive,
electronic product, or any other article subject to regulation under the
act or under §351 and §§354-360F of the Public Health Service Act
(42 U.S.C. 262 and 263b-263n).
(k) Minimal risk means that the probability and magnitude of harm or
discomfort anticipated in the research are not greater in and of themselves
than those ordinarily encountered in daily life or during the performance of
routine physical or psychological examinations or tests.
(l) Legally authorized representative means an individual or judicial or
other body authorized under applicable law to consent on behalf of a
prospective subject to the subject’s participation in the procedure(s)
involved in the research.

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INFORMED CONSENT
(m) Family member means any one of the following legally competent
persons: Spouse; parents; children (including adopted children); brothers
and sisters; and any individual related by blood or affinity whose close
association with the subject is the equivalent of a family relationship.
[45 FR 36390, May 30, 1980, as amended at 46 FR 8950 Jan.27,1981;
54 FR 9038, Mar. 3, 1989; 56 FR 28028, June 18, 1991; 61 FR 51497,
Oct. 2, 1996;62 FR 39440, July 23, 1997]

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GOOD CLINICAL PRACTICE

Subpart B—Informed Consent of Human Subjects
Source: 46 FR 8951, Jan. 27, 1981, unless otherwise noted.
§50.20 General requirements for informed consent.
Except as provided in §50.23 and §50.24, no investigator may involve a
human being as a subject in research covered by these regulations unless
the investigator has obtained the legally effective informed consent of the
subject or the subject’s legally authorized representative. An investigator
shall seek such consent only under circumstances that provide the
prospective subject or the representative sufficient opportunity to consider
whether or not to participate and that minimize the possibility of coercion or
undue influence. The information that is given to the subject or the
representative shall be in language understandable to the subject or the
representative. No informed consent, whether oral or written, may include
any exculpatory language through which the subject or the representative is
made to waive or appear to waive any of the subject’s legal rights, or
releases or appears to release the investigator, the sponsor, the institution,
or its agents from liability for negligence.
[46 FR 8951, Jan. 27, 1981, as amended at 64 FR 10942, Mar. 8, 1999]
§50.23 Exception from general requirements.
(a) The obtaining of informed consent shall be deemed feasible unless,
before use of the test article (except as provided in paragraph (b) of this
section), both the investigator and a physician who is not otherwise
participating in the clinical investigation certify in writing all of the following:
(1) The human subject is confronted by a life-threatening situation
necessitating the use of the test article.
(2) Informed consent cannot be obtained from the subject because of
an inability to communicate with, or obtain legally effective consent from,
the subject.
(3) Time is not sufficient to obtain consent from the subject’s legal
representative.
(4) There is available no alternative method of approved or generally
recognized therapy that provides an equal or greater likelihood of saving
the life of the subject.
(b) If immediate use of the test article is, in the investigator’s opinion,
required to preserve the life of the subject, and time is not sufficient to
obtain the independent determination required in paragraph (a) of this in
advance of using the test article, the determinations of the clinical
investigator shall be made and, within 5 working days after the use of the
article, be reviewed and evaluated in writing by a physician who is not
participating in the clinical investigation.
(c) The documentation required in paragraph (a) or (b) of this section
shall be submitted to the IRB within 5 working days after the use of the test
article.
(d)(1) Under 10 U.S.C. 1107(f) the President may waive the prior consent
requirement for the administration of an investigational new drug to a
member of the armed forces in connection with the member’s participation
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INFORMED CONSENT
in a particular military operation.The statute specifies that only the
President may waive informed consent in this connection and the President
may grant such a waiver only if the President determines in writing that
obtaining consent:Is not feasible; is contrary to the best interests of the
military member; or is not in the interests of national security. The statute
further provides that in making a determination to waive prior informed
consent on the ground that it is not feasible or the ground that it is
contrary to the best interests of the military members involved, the
President shall apply the standards and criteria that are set forth in the
relevant FDA regulations for a waiver of the prior informed consent
requirements of §505(i)(4) of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. §355(i)(4)).Before such a determination may be made that
obtaining informed consent from military personnel prior to the use of an
investigational drug (including an antibiotic or biological product) in a
specific protocol under an investigational new drug application (IND)
sponsored by the Department of Defense (DOD) and limited to specific
military personnel involved in a particular military operation is not feasible
or is contrary to the best interests of the military members involved the
Secretary of Defense must first request such a determination from the
President, and certify and document to the President that the following
standards and criteria contained in paragraphs (d)(1) through (d)(4) of this
section have been met.
(i) The extent and strength of evidence of the safety and
effectiveness of the investigational new drug in relation to the medical risk
that could be encountered during the military operation supports the drug’s
administration under an IND.
(ii) The military operation presents a substantial risk that military
personnel may be subject to a chemical, biological, nuclear, or other
exposure likely to produce death or serious or life-threatening injury or
illness.
(iii) There is no available satisfactory alternative therapeutic or
preventive treatment in relation to the intended use of the investigational
new drug.
(iv) Conditioning use of the investigational new drug on the voluntar y
participation of each member could significantly risk the safety and health
of any individual member who would decline its use, the safety of other
military personnel, and the accomplishment of the military mission.
(v) A duly constituted institutional review board (IRB) established and
operated in accordance with the requirements of paragraphs (d)(2) and
(d)(3) of this section, responsible for review of the study, has reviewed and
approved the investigational new drug protocol and the administration of the
investigational new drug without informed consent. DOD’s request is to
include the documentation required by §56.115(a)(2) of this chapter.
(vi) DOD has explained:
(A) The context in which the investigational drug will be
administered, e.g., the setting or whether it will be self-administered or it will
be administered by a health professional;
(B) The nature of the disease or condition for which the preventive
or therapeutic treatment is intended; and

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GOOD CLINICAL PRACTICE
(C) To the extent there are existing data or information available,
information on conditions that could alter the effects of the investigational
drug.
(vii) DOD’s recordkeeping system is capable of tracking and will be
used to track the proposed treatment from supplier to the individual
recipient.
(viii) Each member involved in the military operation will be given,
prior to the administration of the investigational new drug, a specific written
information sheet (including information required by 10 U.S.C. 1107(d))
concerning the investigational new drug, the risks and benefits of its use,
potential side effects, and other pertinent information about the appropriate
use of the product.
(ix) Medical records of members involved in the military operation will
accurately document the receipt by members of the notification required by
paragraph (d)(1)(viii) of this section.
(x) Medical records of members involved in the military operation will
accurately document the receipt by members of any investigational new
drugs in accordance with FDA regulations including part 312 of this chapter.
(xi) DOD will provide adequate followup to assess whether there are
beneficial or adverse health consequences that result from the use of the
investigational product.
(xii) DOD is pursuing drug development, including a time line, and
marketing approval with due diligence.
(xiii) FDA has concluded that the investigational new drug protocol
may proceed subject to a decision by the President on the informed
consent waiver request.
(xiv) DOD will provide training to the appropriate medical personnel
and potential recipients on the specific investigational new drug to be
administered prior to its use.
(xv) DOD has stated and justified the time period for which the waiver
is needed, not to exceed one year, unless separately renewed under these
standards and criteria.
(xvi) DOD shall have a continuing obligation to report to the FDA and
to the President any changed circumstances relating to these standards
and criteria (including the time period referred to in paragraph (d)(1)(xv) of
this section) or that otherwise might affect the determination to use an
investigational new drug without informed consent.
(xvii) DOD is to provide public notice as soon as practicable and
consistent with classification requirements through notice in the Federal
Register describing each waiver of informed consent determination, a
summary of the most updated scientific information on the products used,
and other pertinent information.
(xviii) Use of the investigational drug without informed consent
otherwise conforms with applicable law.
(2) The duly constituted institutional review board, described in
paragraph (d)(1)(v) of this section, must include at least 3 nonaffiliated
members who shall not be employees or officers of the Federal
Government (other than for purposes of membership on the IRB) and shall
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INFORMED CONSENT
be required to obtain any necessary security clearances. This IRB shall
review the proposed IND protocol at a convened meeting at which a
majority of the members are present including at least one member whose
primary concerns are in nonscientific areas and, if feasible, including a
majority of the nonaffiliated members.
The information required by Sec. 56.115(a)(2) of this chapter is to be
provided to the Secretary of Defense for further review.
(3) The duly constituted institutional review board, described in
paragraph (d)(1)(v) of this section, must review and approve:
(i) The required information sheet;
(ii) The adequacy of the plan to disseminate information, including
distribution of the information sheet to potential recipients, on the
investigational product (e.g., in forms other than written);
(iii) The adequacy of the information and plans for its dissemination
to health care providers, including potential side effects, contraindications,
potential interactions, and other pertinent considerations; and
(iv) An informed consent form as required by part 50 of this chapter,
in those circumstances in which DOD determines that informed consent
may be obtained from some or all personnel involved.
(4) DOD is to submit to FDA summaries of institutional review board
meetings at which the proposed protocol has been reviewed.
(5) Nothing in these criteria or standards is intended to preempt or limit
FDA’s and DOD’s authority or obligations under applicable statutes and
regulations.
[46 FR 8951, Jan. 27, 1981, as amended at 55 FR 52817, Dec.21, 1990;
64 FR 399, Jan. 5, 1999; 64 FR 54188, Oct. 5, 1999]
§50.24 Exception from informed consent requirements for emergency
research.
(a) The IRB responsible for the review, approval, and continuing review of
the clinical investigation described in this section may approve that
investigation without requiring that informed consent of all research subjects
be obtained if the IRB (with the concurrence of a licensed physician who is
a member of or consultant to the IRB and who is not otherwise participating
in the clinical investigation) finds and documents each of the following:
(1) The human subjects are in a life-threatening situation, available
treatments are unproven or unsatisfactory, and the collection of valid
scientific evidence, which may include evidence obtained through
randomized placebo-controlled investigations, is necessary to determine
the safety and effectiveness of particular interventions.
(2) Obtaining informed consent is not feasible because:
(i) The subjects will not be able to give their informed consent as a
result of their medical condition;
(ii) The intervention under investigation must be administered before
consent from the subjects’ legally authorized representatives is feasible;
and

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GOOD CLINICAL PRACTICE
(iii) There is no reasonable way to identify prospectively the
individuals likely to become eligible for participation in the clinical
investigation.
(3) Participation in the research holds out the prospect of direct benefit
to the subjects because:
(i) Subjects are facing a life-threatening situation that necessitates
intervention;
(ii) Appropriate animal and other preclinical studies have been
conducted, and the information derived from those studies and related
evidence support the potential for the intervention to provide a direct benefit
to the individual subjects; and
(iii) Risks associated with the investigation are reasonable in relation
to what is known about the medical condition of the potential class of
subjects, the risks and benefits of standard therapy, if any, and what is
known about the risks and benefits of the proposed intervention or activity.
(4) The clinical investigation could not practicably be carried out
without the waiver.
(5) The proposed investigational plan defines the length of the potential
therapeutic window based on scientific evidence, and the investigator has
committed to attempting to contact a legally authorized representative for
each subject within that window of time and, if feasible, to asking the legally
authorized representative contacted for consent within that window rather
than proceeding without consent.The investigator will summarize efforts
made to contact legally authorized representatives and make this
information available to the IRB at the time of continuing review.
(6) The IRB has reviewed and approved informed consent procedures
and an informed consent document consistent with §50.25.These
procedures and the informed consent document are to be used with
subjects or their legally authorized representatives in situations where use
of such procedures and documents is feasible. The IRB has reviewed and
approved procedures and information to be used when providing an
opportunity for a family member to object to a subject’s participation in the
clinical investigation consistent with paragraph (a)(7)(v) of this section.
(7) Additional protections of the rights and welfare of the subjects will
be provided, including, at least:
(i) Consultation (including, where appropriate, consultation carried
out by the IRB) with representatives of the communities in which the clinical
investigation will be conducted and from which the subjects will be drawn;
(ii) Public disclosure to the communities in which the clinical
investigation will be conducted and from which the subjects will be drawn,
prior to initiation of the clinical investigation, of plans for the investigation
and its risks and expected benefits;
(iii) Public disclosure of sufficient information following completion of
the clinical investigation to apprise the community and researchers of the
study, including the demographic characteristics of the research population,
and its results;
(iv) Establishment of an independent data monitoring committee to
exercise oversight of the clinical investigation; and
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INFORMED CONSENT
(v) If obtaining informed consent is not feasible and a legally
authorized representative is not reasonably available, the investigator has
committed, if feasible, to attempting to contact within the therapeutic
window the subject’s family member who is not a legally authorized
representative, and asking whether he or she objects to the subject’s
participation in the clinical investigation.The investigator will summarize
efforts made to contact family members and make this information available
to the IRB at the time of continuing review.
(b) The IRB is responsible for ensuring that procedures are in place to
inform, at the earliest feasible opportunity, each subject, or if the subject
remains incapacitated, a legally authorized representative of the subject, or
if such a representative is not reasonably available, a family member, of the
subject’s inclusion in the clinical investigation, the details of the investigation
and other information contained in the informed consent document.The
IRB shall also ensure that there is a procedure to inform the subject, or if
the subject remains incapacitated, a legally authorized representative of the
subject, or if such a representative is not reasonably available, a family
member, that he or she may discontinue the subject’s participation at any
time without penalty or loss of benefits to which the subject is otherwise
entitled. If a legally authorized representative or family member is told about
the clinical investigation and the subject’s condition improves, the subject is
also to be informed as soon as feasible. If a subject is entered into a clinical
investigation with waived consent and the subject dies before a legally
authorized representative or family member can be contacted, information
about the clinical investigation is to be provided to the subject’s legally
authorized representative or family member, if feasible.
(c) The IRB determinations required by paragraph (a) of this section and
the documentation required by paragraph (e) of this section are to be
retained by the IRB for at least 3 years after completion of the clinical
investigation, and the records shall be accessible for inspection and copying
by FDA in accordance with §56.115(b) of this chapter.
(d) Protocols involving an exception to the informed consent requirement
under this section must be performed under a separate investigational new
drug application (IND) or investigational device exemption (IDE) that clearly
identifies such protocols as protocols that may include subjects who are
unable to consent.The submission of those protocols in a separate
IND/IDE is required even if an IND for the same drug product or an IDE for
the same device already exists. Applications for investigations under this
section may not be submitted as amendments under §312.30 or §812.35 of
this chapter.
(e) If an IRB determines that it cannot approve a clinical investigation
because the investigation does not meet the criteria in the exception
provided under paragraph (a) of this section or because of other relevant
ethical concerns, the IRB must document its findings and provide these
findings promptly in writing to the clinical investigator and to the sponsor of
the clinical investigation.The sponsor of the clinical investigation must
promptly disclose this information to FDA and to the sponsor’s clinical
investigators who are participating or are asked to participate in this or a
substantially equivalent clinical investigation of the sponsor, and to other
IRB’s that have been, or are, asked to review this or a substantially
equivalent investigation by that sponsor. [61 FR 51528, Oct. 2, 1996]
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GOOD CLINICAL PRACTICE
§50.25 Elements of informed consent.
(a) Basic elements of informed consent. In seeking informed consent, the
following information shall be provided to each subject:
(1) A statement that the study involves research, an explanation of the
purposes of the research and the expected duration of the subject’s
participation, a description of the procedures to be followed, and
identification of any procedures which are experimental.
(2) A description of any reasonably foreseeable risks or discomforts to
the subject.
(3) A description of any benefits to the subject or to others which may
reasonably be expected from the research.
(4) A disclosure of appropriate alternative procedures or courses of
treatment, if any, that might be advantageous to the subject.
(5) A statement describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained and that notes the
possibility that the Food and Drug Administration may inspect the records.
(6) For research involving more than minimal risk, an explanation as to
whether any compensation and an explanation as to whether any medical
treatments are available if injury occurs and, if so, what they consist of, or
where further information may be obtained.
(7) An explanation of whom to contact for answers to pertinent
questions about the research and research subjects’ rights, and whom to
contact in the event of a research-related injury to the subject.
(8) A statement that participation is voluntary, that refusal to participate
will involve no penalty or loss of benefits to which the subject is otherwise
entitled, and that the subject may discontinue participation at any time
without penalty or loss of benefits to which the subject is otherwise entitled.
(b) Additional elements of informed consent.When appropriate, one or
more of the following elements of information shall also be provided to each
subject:
(1) A statement that the particular treatment or procedure may involve
risks to the subject (or to the embryo or fetus, if the subject is or may
become pregnant) which are currently unforeseeable.
(2) Anticipated circumstances under which the subject’s participation
may be terminated by the investigator without regard to the subject’s
consent.
(3) Any additional costs to the subject that may result from participation
in the research.
(4) The consequences of a subject’s decision to withdraw from the
research and procedures for orderly termination of participation by the
subject.
(5) A statement that significant new findings developed during the
course of the research which may relate to the subject’s willingness to
continue participation will be provided to the subject.
(6) The approximate number of subjects involved in the study.

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INFORMED CONSENT
(c) The informed consent requirements in these regulations are not
intended to preempt any applicable Federal, State, or local laws which
require additional information to be disclosed for informed consent to be
legally effective.
(d) Nothing in these regulations is intended to limit the authority of a
physician to provide emergency medical care to the extent the physician is
permitted to do so under applicable Federal, State, or local law.
§50.27 Documentation of informed consent.
(a) Except as provided in §56.109(c), informed consent shall be
documented by the use of a written consent form approved by the IRB and
signed and dated by the subject or the subject’s legally authorized
representative at the time of consent. A copy shall be given to the person
signing the form.
(b) Except as provided in §56.109(c), the consent form may be either of
the following:
(1) A written consent document that embodies the elements of
informed consent required by §50.25.This form may be read to the subject
or the subject’s legally authorized representative, but, in any event, the
investigator shall give either the subject or the representative adequate
opportunity to read it before it is signed.
(2) A short form written consent document stating that the elements of
informed consent required by §50.25 have been presented orally to the
subject or the subject’s legally authorized representative. When this method
is used, there shall be a witness to the oral presentation. Also, the IRB shall
approve a written summary of what is to be said to the subject or the
representative. Only the short form itself is to be signed by the subject or
the representative. However, the witness shall sign both the short form and
a copy of the summary, and the person actually obtaining the consent shall
sign a copy of the summary. A copy of the summary shall be given to the
subject or the representative in addition to a copy of the short form.
[46 FR 8951, Jan. 27, 1981, as amended at 61 FR 57280, Nov. 5, 1996]
[61FR 51497, October 2, 1996]

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GOOD CLINICAL PRACTICE

Office for Protection from Research Risks*
TIPS ON INFORMED CONSENT
The process of obtaining informed consent must comply with the
requirements of 45 CFR 46.116.The documentation of informed consent
must comply with 45 CFR 46.117. The following comments may help in the
development of an approach and proposed language by investigators for
obtaining consent and its approval by IRBs:
• Informed consent is a process, not just a form. Information must be
presented to enable persons to voluntarily decide whether or not to
participate as a research subject. It is a fundamental mechanism to
ensure respect for persons through provision of thoughtful consent for a
voluntary act.The procedures used in obtaining informed consent should
be designed to educate the subject population in terms that they can
understand.Therefore, informed consent language and its documentation
(especially explanation of the study’s purpose, duration, experimental
procedures, alternatives, risks, and benefits) must be written in “lay
language”, (i.e. understandable to the people being asked to participate).
The written presentation of information is used to document the basis for
consent and for the subjects’ future reference. The consent document
should be revised when deficiencies are noted or when additional
information will improve the consent process.
• Use of the first person (e.g., “I understand that ...”) can be interpreted as
suggestive, may be relied upon as a substitute for sufficient factual
information, and can constitute coercive influence over a subject. Use of
scientific jargon and legalese is not appropriate. Think of the document
primarily as a teaching tool not as a legal instrument.
• Describe the overall experience that will be encountered. Explain the
research activity, how it is experimental (e.g., a new drug, extra tests,
separate research records, or nonstandard means of management, such
as flipping a coin for random assignment or other design issues). Inform
the human subjects of the reasonably foreseeable harms, discomforts,
inconvenience and risks that are associated with the research activity. If
additional risks are identified during the course of the research, the
consent process and documentation will require revisions to inform
subjects as they are recontacted or newly contacted.
• Describe the benefits that subjects may reasonably expect to
encounter. There may be none other than a sense of helping the public at
large. If payment is given to defray the incurred expense for participation, it
must not be coercive in amount or method of distribution.
• Describe any alternatives to participating in the research project. For
example, in drug studies the medication(s) may be available through their
family doctor or clinic without the need to volunteer for the research
activity.

*Now Office for Human Research Protections (OHRP).
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TIPS

ON INFORMED

CONSENT

• The regulations insist that the subjects be told the extent to which
their personally identifiable private information will be held in
confidence. For example, some studies require disclosure of information
to other parties. Some studies inherently are in need of a Certificate of
Confidentiality which protects the investigator from involuntary release
(e.g., subpoena) of the names or other identifying characteristics of
research subjects. The IRB will determine the level of adequate
requirements for confidentiality in light of its mandate to ensure
minimization of risk and determination that the residual risks warrant
involvement of subjects.
• If research-related injury (i.e. physical, psychological, social,
financial, or otherwise) is possible in research that is more than
minimal risk (see 45 CFR 46.102[g]), an explanation must be given of
whatever voluntary compensation and treatment will be provided.
Note that the regulations do not limit injury to “physical injury”.This is a
common misinterpretation.
• The regulations prohibit waiving or appearing to waive any legal
rights of subjects. Therefore, for example, consent language must be
carefully selected that deals with what the institution is voluntarily willing to
do under circumstances, such as providing for compensation beyond the
provision of immediate or therapeutic inter vention in response to a
research-related injury. In short, subjects should not be given the
impression that they have agreed to and are without recourse to seek
satisfaction beyond the institution’s voluntarily chosen limits.
• The regulations provide for the identification of contact persons who
would be knowledgeable to answer questions of subjects about the
research, rights as a research subject, and research-related injuries.
These three areas must be explicitly stated and addressed in the
consent process and documentation. Furthermore, a single person is
not likely to be appropriate to answer questions in all areas. This is
because of potential conflicts of interest or the appearance of such.
Questions about the research are frequently best answered by the
investigator(s).However, questions about the rights of research subjects or
research-related injuries (where applicable) may best be referred to those
not on the research team.These questions could be addressed to the
IRB, an ombudsman, an ethics committee, or other informed
administrative body. Therefore, each consent document can be expected
to have at least two names with local telephone numbers for contacts to
answer questions in these specified areas.
• The statement regarding voluntary participation and the right to
withdraw at any time can be taken almost verbatim from the
regulations (45 CFR 46.116[a][8]). It is important not to overlook the need
to point out that no penalty or loss of benefits will occur as a result of both
not participating or withdrawing at any time. It is equally important to alert
potential subjects to any foreseeable consequences to them should they
unilaterally withdraw while dependent on some intervention to maintain
normal function.
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GOOD CLINICAL PRACTICE
• Don’t forget to ensure provision for appropriate additional requirements
which concern consent. Some of these requirements can be found
in §§46.116(b), 46.205(a)(2), 46.207(b), 46.208(b), 46.209(d),
46.305(a)(5-6), 46.408(c), and 46.409(b).The IRB may impose additional
requirements that are not specifically listed in the regulations to ensure
that adequate information is presented in accordance with institutional
policy and local law.
Revised 3/16/93

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SUBJECT RECRUITMENT

III. Subject Recruitment
Guidance for Institutional Review Boards and Clinical
Investigators (from FDA Information Sheets)
Recruiting Study Subjects
FDA requires that an Institutional Review Board (IRB) review and have
authority to approve, require modifications in, or disapprove all research
activities covered by the IRB regulations [21 CFR 56.109(a)]. An IRB is
required to ensure that appropriate safeguards exist to protect the rights
and welfare of research subjects [21 CFR 56.107(a) and 56.111]. In fulfilling
these responsibilities, an IRB is expected to review all the research
documents and activities that bear directly on the rights and welfare of the
subjects of proposed research.The protocol, the consent document and, for
studies conducted under the Investigational New Drug (IND) regulations,
the investigator’s brochure are examples of documents that the IRB
should review. The IRB should also review the methods and material
that investigators propose to use to recruit subjects.
A. Media Advertising.
Direct advertising for research subjects, i.e., advertising that is intended to
be seen or heard by prospective subjects to solicit their participation in a
study, is not in and of itself, an objectionable practice. Direct advertising
includes, but is not necessarily limited to: newspaper, radio, TV, bulletin
boards, posters, and flyers that are intended for prospective subjects. Not
included are: (1) communications intended to be seen or heard by health
professionals, such as “dear doctor” letters and doctor-to-doctor letters
(even when soliciting for study subjects), (2) news stories and (3) publicity
intended for other audiences, such as financial page advertisements
directed toward prospective investors.
IRB review and approval of listings of clinical trials on the internet would
provide no additional safeguard and is not required when the system
format limits the information provided to basic trial information, such as:
the title; purpose of the study; protocol summary; basic eligibility criteria;
study site location(s); and how to contact the site for further information.
Examples of clinical trial listing services that do not require prospective
IRB approval include the National Cancer Institute’s cancer clinical trial
listing (PDQ) and the government-sponsored AIDS Clinical Trials
Information Service (ACTIS). However, when the opportunity to add
additional descriptive information is not precluded by the data base
system, IRB review and approval may assure that the additional information
does not promise or imply a certainty of cure or other benefit beyond what
is contained in the protocol and the informed consent document.
FDA considers direct advertising for study subjects to be the start of the
informed consent and subject selection process. Advertisements should be
reviewed and approved by the IRB as part of the package for initial review.
However, when the clinical investigator decides at a later date to advertise
for subjects, the advertising may be considered an amendment to the
ongoing study. When such advertisements are easily compared to the
approved consent document, the IRB chair, or other designated IRB

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member, may review and approve by expedited means, as provided by
21 CFR 56.110(b)(2).When the IRB reviewer has doubts or other
complicating issues are involved, the advertising should be reviewed at a
convened meeting of the IRB.
FDA expects IRBs to review the advertising to assure that it is not unduly
coercive and does not promise a certainty of cure beyond what is outlined
in the consent and the protocol.This is especially critical when a study may
involve subjects who are likely to be vulnerable to undue influence.
[21 CFR 50.20, 50.25, 56.111(a)(3), 56.111(b) and 812.20(b)(11).]
When direct advertising is to be used, the IRB should review the
information contained in the advertisement and the mode of its
communication, to determine that the procedure for recruiting subjects is
not coercive and does not state or imply a certainty of favorable outcome or
other benefits beyond what is outlined in the consent document and the
protocol.The IRB should review the final copy of printed advertisements to
evaluate the relative size of type used and other visual effects. When
advertisements are to be taped for broadcast, the IRB should review the
final audio/video tape. The IRB may review and approve the wording of the
advertisement prior to taping to preclude re-taping because of inappropriate
wording.The review of the final taped message prepared from IRBapproved text may be accomplished through expedited procedures. The
IRB may wish to caution the clinical investigators to obtain IRB approval of
message text prior to taping, in order to avoid re-taping because of
inappropriate wording.
No claims should be made, either explicitly or implicitly, that the drug,
biologic or device is safe or effective for the purposes under investigation,
or that the test article is known to be equivalent or superior to any other
drug, biologic or device. Such representation would not only be misleading
to subjects but would also be a violation of the Agency’s regulations
concerning the promotion of investigational drugs [21 CFR 312.7(a)] and of
investigational devices [21 CFR 812.7(d)].
Advertising for recruitment into investigational drug, biologic or device
studies should not use terms such as “new treatment,” “new medication” or
“new drug” without explaining that the test article is investigational. A phrase
such as “receive new treatments” leads study subjects to believe they will
be receiving newly improved products of proven worth.
Advertisements should not promise “free medical treatment,” when the
intent is only to say subjects will not be charged for taking part in the
investigation. Advertisements may state that subjects will be paid, but
should not emphasize the payment or the amount to be paid, by such
means as larger or bold type.
Generally, FDA believes that any advertisement to recruit subjects should
be limited to the information the prospective subjects need to determine
their eligibility and interest.When appropriately worded, the following items
may be included in advertisements. It should be noted, however, that FDA
does not require inclusion of all of the listed items.
1. the name and address of the clinical investigator and/or research
facility;
2. the condition under study and/or the purpose of the research;
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3. in summary form, the criteria that will be used to determine eligibility
for the study;
4. a brief list of participation benefits, if any (e.g., a no-cost health
examination);
5. the time or other commitment required of the subjects; and
6. the location of the research and the person or office to contact for
further information.
B. Receptionist Scripts.
The first contact prospective study subjects make is often with a
receptionist who follows a script to determine basic eligibility for the specific
study. The IRB should assure the procedures followed adequately protect
the rights and welfare of the prospective subjects. In some cases personal
and sensitive information is gathered about the individual.The IRB should
have assurance that the information will be appropriately handled.A simple
statement such as “confidentiality will be maintained” does not adequately
inform the IRB of the procedures that will be used.
Examples of issues that are appropriate for IRB review:What happens to
personal information if the caller ends the interview or simply hangs up?
Are the data gathered by a marketing company? If so, are names, etc. sold
to others? Are names of non-eligibles maintained in case they would qualify
for another study? Are paper copies of records shredded or are readable
copies put out as trash? The acceptability of the procedures would depend
on the sensitivity of the data gathered, including personal, medical and
financial.
Also see FDA Information Sheets: “A Guide to Informed Consent
Documents” and “Payment to Research Subjects.”

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Payment to Research Subjects
The Institutional Review Board (IRB) should determine that the
risks to subjects are reasonable in relation to anticipated benefits
[21 CFR 56.111(a)(2)] and that the consent document contains an
adequate description of the study procedures [21 CFR 50.25(a)(1)] as well
as the risks [21 CFR 50.25(a)(2)] and benefits [21 CFR 50.25(a)(3)].It is
not uncommon for subjects to be paid for their participation in research,
especially in the early phases of investigational drug, biologic or device
development. Payment to research subjects for participation in studies is
not considered a benefit, it is a recruitment incentive. Financial incentives
are often used when health benefits to subjects are remote or non-existent.
The amount and schedule of all payments should be presented to the IRB
at the time of initial review. The IRB should review both the amount of
payment and the proposed method and timing of disbursement to assure
that neither are coercive or present undue influence [21 CFR 50.20].
Any credit for payment should accrue as the study progresses and not be
contingent upon the subject completing the entire study. Unless it creates
undue inconvenience or a coercive practice, payment to subjects who
withdraw from the study may be made at the time they would have
completed the study (or completed a phase of the study) had they not
withdrawn. For example, in a study lasting only a few days, an IRB may find
it permissible to allow a single payment date at the end of the study, even
to subjects who had withdrawn before that date.
While the entire payment should not be contingent upon completion of the
entire study, payment of a small proportion as an incentive for completion of
the study is acceptable to FDA, providing that such incentive is not
coercive. The IRB should determine that the amount paid as a bonus for
completion is reasonable and not so large as to unduly induce subjects to
stay in the study when they would otherwise have withdrawn. All information
concerning payment, including the amount and schedule of payment(s),
should be set forth in the informed consent document.
Also see FDA Information Sheets: “A Guide to Informed Consent
Documents” and “Recruiting Study Subjects.”

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Screening Tests Prior to Study Enrollment
For some studies, the use of screening tests to assess whether prospective
subjects are appropriate candidates for inclusion in studies is an
appropriate pre-entry activity. While an investigator may discuss availability
of studies and the possibility of entry into a study with a prospective subject
without first obtaining consent, informed consent must be obtained prior to
initiation of any clinical procedures that are performed solely for the
purpose of determining eligibility for research, including withdrawal from
medication (wash-out).When wash-out is done in anticipation of or in
preparation for the research, it is part of the research.
Procedures that are to be performed as part of the practice of medicine and
which would be done whether or not study entry was contemplated, such
as for diagnosis or treatment of a disease or medical condition, may be
performed and the results subsequently used for determining study
eligibility without first obtaining consent. On the other hand, informed
consent must be obtained prior to initiation of any clinical screening
procedures that are performed solely for the purpose of determining
eligibility for research.When a doctor-patient relationship exists, prospective
subjects may not realize that clinical tests performed solely for determining
eligibility for research enrollment are not required for their medical care.
Physician-investigators should take extra care to clarify with their patientsubjects why certain tests are being conducted.
Clinical screening procedures for research eligibility are considered part of
the subject selection and recruitment process and, therefore, require IRB
oversight.If the screening qualifies as a minimal risk procedure
[21 CFR 56.102(i)], the IRB may choose to use expedited review
procedures [21 CFR 56.110].The IRB should receive a written outline of
the screening procedure to be followed and how consent for screening will
be obtained.The IRB may find it appropriate to limit the scope of the
screening consent to a description of the screening tests and to the
reasons for performing the tests including a brief summary description of
the study in which they may be asked to participate. Unless the screening
tests involve more than minimal risk or involve a procedure for which written
consent is normally required outside the research context, the IRB may
decide that prospective study subjects need not sign a consent document
[21 CFR 56.109(c)]. If the screening indicates that the prospective subject
is eligible, the informed consent procedures for the study, as approved by
the IRB, would then be followed.
Certain clinical tests, such as for HIV infection, may have State
requirements regarding (1) the information that must be provided to the
participant, (2) which organizations have access to the test results and
(3) whether a positive result has to be reported to the health department.
Prospective subjects should be informed of any such requirements and how
an unfavorable test result could affect employment or insurance before the
test is conducted.The IRB may wish to confirm that such tests are required
by the protocol of the study.
Also see FDA Information Sheet: “Recruiting Study Subjects.”

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HUMAN SPECIMENS

IV. Research on Human Specimens: Are You Conducting
Research Using Human Subjects?
(http://www-cdp.ims.nci.nih.gov/brochure.html)
Are You Conducting Research Using Human Subjects?
(http://www-cdp.ims.nci.nih.gov /brochure.html#conducting)
What is the Role of My Institutional Review Board?
(http://www-cdp.ims.nci.nih.gov /brochure.html#role)
What Consent is Required for the Use of Human Tissue Specimens?
(http://www-cdp.ims.nci.nih.gov /brochure.html#consent)
Is my research exempt from IRB review?
(http://www-cdp.ims.nci.nih.gov /brochure.html#research)
If I obtain all my specimens from collaborators, do the regulations apply?
(http://www-cdp.ims.nci.nih.gov /brochure.html#obtain)
What key points should I address in my research grant application or
contract proposal to the NIH?
(http://www-cdp.ims.nci.nih.gov /brochure.html#key)
Where can you find help and additional information?
(http://www-cdp.ims.nci.nih.gov /brochure.html#where)

ARE YOU CONDUCTING RESEARCH USING HUMAN
SUBJECTS?
A ‘human subject’is a living individual about whom an investigator obtains
either (1) data through intervention or interaction with the individual, or
(2) identifiable private information. 1 Legal requirements to protect human
subjects apply to a much broader range of research than many
investigators realize, and researchers using human tissue specimens are
often unsure about how regulations apply to their research. Legal
obligations to protect human subjects apply, for example, to research that
uses:
• Bodily materials, such as cells, blood or urine, tissues, organs, hair or
nail clippings, even if you did not collect these materials
• Residual diagnostic specimens, including specimens obtained for
routine patient care that would have been discarded if not used for
research
• Private information, such as medical information, that can be readily
identified with individuals, even if the information was not specifically
collected for the study in question. Research on cell lines or DNA
samples that can be associated with individuals falls into this category.

IF SO YOU MUST…
Comply with your institution’s rules and the requirements of your
Institutional Review Board (IRB) as well as meeting Federal requirements1
in order to carry out your research.Some institutions have requirements

1Title 45 Code of Federal Regulations, Part 46 (June 18, 1991).

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GOOD CLINICAL PRACTICE
that exceed those of the Federal regulations. If you have any question or
uncertainty about whether you need IRB approval, you should ask your
IRB office for clarification. 2 If you apply for an NIH grant or respond
to a Request for Contract (RFC), failure to follow your institution’s
procedures or to document the use of human tissues or data in your
grant application or contract proposal can create problems and may
delay funding or preclude award.

WHAT IS THE ROLE OF MY INSTITUTIONAL REVIEW BOARD?
The IRB at your institution must review and approve research if it involves
human subjects. This process is designed to ensure that the research
protects the rights and welfare of human subjects-for example, by
minimizing risks, selecting subjects equitably, obtaining informed consent
and ensuring privacy and confidentiality.
IRB approval must precede initiation of any work involving human
subjects. No NIH grant or contract can be awarded until IRB approval is
obtained. If the research continues, the IRB must review and approve the
project at least once a year. When changes occur in the procedures with
human subjects, the IRB must review and approve these changes.
If human subjects are harmed, including physical injury, improper disclosure
of private information, economic loss or other harmful occurrences, the IRB
must be notified.

TYPES OF IRB REVIEW
Full Board Review—Review of proposed research at a convened meeting
at which a valid quorum of IRB members is present. For the research to be
approved, it must receive the approval of a majority of those members
present.
Expedited Review—Review of proposed research by the IRB chair or a
designated voting member or group of voting members rather than by the
entire IRB. Federal rules permit expedited review for certain kinds of
research involving no more than minimal risk and for minor changes in
approved research.

WHAT CONSENT IS REQUIRED FOR THE USE OF HUMAN
TISSUE SPECIMENS?
IRBs are responsible for determining whether or not informed consent is
required from the subjects from whom the specimens were obtained.The
IRB may waive the requirement for informed consent if the risk to the
subjects is minimal and if certain other conditions are met.3
You should not assume that your research poses minimal risk just
because it involves tissue specimens. Loss of confidentiality can cause
harm to patients and their relatives; IRBs will consider whether privacy and
confidentiality protections are adequate.

2If your institution has no IRB you may establish an IRB at your own institution and obtain
Federal approval for the newly-created IRB, or you may obtain approval for your use of human
subjects from an IRB elsewhere that satisfies all Federal requirements. For more information
about these options contact the Office for Human Research Protections (OHRP), formerly known
as the.Office of Protection from Research Risks.
3Title 45 Code of Federal Regulations, Part 46.116.

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HUMAN SPECIMENS

IS MY RESEARCH EXEMPT FROM IRB REVIEW?
Research with specimens and data from living persons is exempt from the
requirement for IRB approval when it is determined that the research either
does not involve human subjects as defined in the Code of Federal
Regulations (CFR) or the only involvement of human subjects is in one of
the “exempt” categories listed in the Code. The exemption that is most
pertinent to work with human tissue specimens is exemption #4.
As stated in 45 CFR 46.101(b):
“Unless otherwise required by Department or Agency heads, research
activities in which the only involvement of human subjects will be in
one or more of the following categories are exempt from this policy:
...(4) Research involving the collection or study of existing data, documents,
records, pathological specimens, or diagnostic specimens, if these sources
are publicly available or if the information is recorded by the investigator in
such a manner that subjects cannot be identified, directly or through
identifiers linked to the subjects.”
Some researchers mistakenly believe that any studies on existing pathology
specimens are exempt. Exemption #4 does not apply to specimens that
are linked to patient identity, even if the subject identifiers are locked
up or kept by someone other than the researcher. It does not matter if
the tissue would otherwise have been discarded. You should be aware that
many institutions require an IRB to determine whether or not the research
is exempt.
What is meant by “existing”data or specimens?
Exemption #4 applies to retrospective studies of specimens that have
already been collected.The materials must be “on the shelf” (or in the
freezer) at the time the protocol is initiated. For research supported on NIH
grants and contracts, the specimens should be in place at the time the
proposal is submitted for review.
What about specimens obtained from a tissue bank?
Use of tissue specimens obtained from an established tissue repository
may be exempt, even though the bank continues to procure new specimens
while the research project proceeds. There are many kinds of tissue banks
that operate in different ways. Your IRB will need to determine whether the
bank you are using meets the requirements of the exemption.
What is meant by “publicly available sources”?
This language in the regulation was intended to apply to public sources of
data, such as death certificates. Its meaning with respect to human tissue
specimens is widely debated. Although there are organizations that make
human cells and tissues broadly accessible at reasonable cost to the
research community, these materials are not usually available to the public
at large. Even if you obtain specimens from such a source, you should not
assume that it meets the definition of “publicly available.” It is up to your IRB
to decide.
What is meant by “identifiers linked to the subjects”?
Identifiers such as names, Social Security numbers or pathology accession
numbers permit specimens to be linked to individual people and perhaps
also to associated medical information. Exemption #4 applies most clearly
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GOOD CLINICAL PRACTICE
to specimens where such personal information was never collected. It may
apply to specimens provided by a tissue bank or other repository, so long
as the specimens are provided without identifiers and the repository has
firm policies and procedures, reviewed by its own IRB, to prevent the
release of personal information. It generally does not apply in situations
where a researcher receives “coded”specimens from a collaborator if
the collaborator retains the key to the code, even though the
researcher may have no access to patient identities.
How can I determine if my research is exempt?
The humans subjects regulations decision charts from the Office for
Protection from Research Risks (OPRR)* (http://ohrp.osophs.dhhs.gov/
humansubjects/guidance/decisioncharts.htm) will help you to see whether
your research falls under the human subjects regulations and if so, whether
it is likely to require full IRB review or is a candidate for expedited review.
You should be aware, however, that institutions vary in their requirements
for IRB review. Many institutions require some form of IRB review for
exempt studies. You must check with your institutional officials to
determine whether full, expedited, or no IRB review is required for
your proposed project.

IF I OBTAIN ALL MY SPECIMENS FROM COLLABORATORS, DO
THE REGULATIONS APPLY?
YES! Unless your research is exempt, BOTH you and your collaborator
must have approvals from the IRBs at your respective institutions.
What if my collaborator is located outside the U.S.?
Your collaborator will need to obtain approval from the IRB at his or her
institution. In addition, your collaborator’s institution will probably need to
contact OPRR* and provide documentation that its IRB meets the
requirements defined in U.S. laws. An assurance coordinator at OPRR* can
assist you with this process. Finally, your NIH program official may need to
request State Department clearance for your project.
The key is: start early! Obtaining approvals and assurances takes time,
particularly if institutions are located overseas. No NIH grant or contract can
be awarded until the necessary approvals and assurances are in place.

WHAT KEY POINTS SHOULD I ADDRESS IN MY RESEARCH
GRANT APPLICATION OR CONTRACT PROPOSAL TO THE
NIH?
The PHS 398 application kit (http://grantsi.nih.gov/grants/funding/
phs398.html) for a Public Health Service grant requires information about
the involvement of human subjects in the proposed research.The face page
of the application asks you to certify whether or not human subjects are
involved, and, if so, whether an exemption is claimed and the exemption
number. In the case of a research contract proposal the Optional Form 310
will serve in lieu of the PHS 398 Form. If your institution has an applicable
Multiple Project Assurance 4 on file with OPRR,* and the research is not
exempt, you or your business office must provide an Assurance of

*Now Office for Human Research Protections (OHRP).
4For current information on Assurances, please contact OHRP.
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Compliance Number, the IRB approval date, and indicate whether the
approval was by full IRB review or by expedited review. If your proposal is
selected by the NIH for an award and your institution does not have a
Multiple Project Assurance,5 then it must contact OPRR.*
Additional information must be provided in the Human Subjects section of
the Research Plan. If you have claimed an exemption on the face page (or
on Optional Form 310 for a contract proposal), you should provide sufficient
information in the Human Subjects section and in the body of the proposal
to show that the exemption is appropriate. It is important to state whether
the specimens already exist or will be collected prospectively and whether
the specimens can be linked to subject identifiers.
This information should be provided for all specimens, including those
obtained from collaborators. (Include the letters of collaboration with your
proposal, rather than placing them in the Appendix.) Also remember that
any NIH grant application or contract proposal involving human subjects
must address the inclusion of women, minorities and children. Failure to
provide this information could delay or prevent the award of your grant or
contract.
The NIH Scientific Initial Review Group will review the information you
provide in the grant or contract proposal to determine whether plans and
approvals for use of human subjects are appropriate. Any comments or
concerns noted by the Scientific Review Group are transmitted to the NIH
awarding unit, institute/center’s council and the OPRR.* The NIH awarding
unit staff, in consultation with OPRR,* are responsible for ensuring that any
human subjects concerns are resolved prior to funding. NIH staff members
are responsible for ensuring on an annual basis that there are no major
changes in the human subjects research and that annual IRB approvals are
obtained.
From time to time changes are made in the human subjects
regulations and in their interpretation by IRBs and by OPRR.* It is
important to thoroughly review and understand the most current
regulations before submitting your grant application and particularly
before starting research. Check with your local IRB for guidance .

*Now Office for Human Research Protections (OHRP).
5For current information on Assurances, please contact OHRP.
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GOOD CLINICAL PRACTICE

WHERE CAN YOU FIND HELP AND ADDITIONAL
INFORMATION?
• Your institution’s IRB
• The Office for Protection from Research Risks (OPRR)*
• Your NIH institute/center Program Official
• The following web sites:
Office for Protection from Research Risks*
(http://ohrp.osophs.dhs.gov/)
NCI Resources Development Branch
(http://www-cdp.ims.nci.nih.gov/rdb.html)
Bioethics Resources on the WEB
(http://www.nih.gov/sigs/bioethics)
NHGRI Ethical Legal and Social Issues Program
(http://www.nhgri.nih.gov/ELSI)
National Bioethics Advisory Commission
(http://bioethics.gov/cgi-bin/bioeth_counter.pl)
American Society for Investigative Pathology
(http://asip.uthscsa.edu)
NIH Pub. No. 00-4767

*Now Office for Human Research Protections (OHRP).
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HUMAN SPECIMENS

Issues to Consider in the Research Use of Stored Data
or Tissues (11/7/1997)—Repositories
OFFICE FOR PROTECTION FROM RESEARCH RISKS*
Issues to Consider in the Research Use of Stored Data or Tissues
November 7, 1997
• Human Tissue Repositories collect, store, and distribute human tissue
materials for research purposes. Repository activities involve three
components: (i) the collectors of tissue samples; (ii) the repository
storage and data management center ; and (iii) the recipient
investigators.
• If supported by the Department of Health and Human Services (HHS),
each component must satisfy certain regulatory requirements.

Operation of the Repository and its data management center should be
subject to oversight by an Institutional Review Board (IRB). The IRB
should review and approve a protocol specifying the conditions under which
data and specimens may be accepted and shared, and ensuring adequate
provisions to protect the privacy of subjects and maintain the confidentiality
of data.The IRB should also review and approve a sample collection
protocol and informed consent document for distribution to tissue collectors
and their local IRBs. A Certificate of Confidentiality should be obtained to
protect confidentiality of repository specimens and data.
For Additional Information:
Office for Human Research Protections
Department of Health and Human Services
6100 Executive Boulevard, Suite 3B01, MSC-7507
Rockville, MD 20892-7507
301-402-5189 / FAX 301-402-2071 / E-MAIL ohrp@osophs.dhhs.gov
*Now Office for Human Research Protections (OHRP).
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GOOD CLINICAL PRACTICE
August 19, 1996
TO: Professional Staff
Division of Human Subject Protections
FROM: Melody H. Lin, Ph.D.
Acting Director
Division of Human Subject Protections
SUBJECT:

Operation of Human Cell Repositories
Under HHS Regulations at 45 CFR 46
OPRR* offers the following guidance concerning operation of human cell
repositories under Department of Health and Human Services (HHS)
regulations for the protection of human subjects (45 CFR 46).The guidance
assumes that repository activities include nonexempt human subjects
research as defined under HHS regulations.
(1) The operation of any HHS-supported human cell repository and its data
management center should be subject to oversight by an Institutional
Review Board (IRB) convened under an applicable OPRR*-approved
Assurance of Compliance. This IRB should set the conditions under which
data and specimens may be accepted and shared. OPRR* strongly
recommends that one such condition stipulate that recipient-investigators
not be provided access to the identities of donor-subjects or to information
through which the identities of donor-subjects may readily be ascertained.
(2) Collection of data and specimens should be subject to oversight by local
IRBs convened under applicable OPRR*-approved Assurances
(3) Written informed consent should be obtained from each donor-subject in
accordance with HHS regulations at 45 CFR 46.116.Included among the
basic elements of informed consent should be a clear description of (i) the
operation of the cell repository; (ii) the specific types of research to be
conducted; (iii) the conditions under which data and specimens will be
released to recipient-investigators; and (iv) procedures for protecting the
privacy of subjects and maintaining the confidentiality of data.
(4) Informed consent information describing the nature and purposes of the
research should be as specific as possible.
(5) Where human genetic research is anticipated, informed consent
information should include information about the consequences of DNA
typing (e.g., regarding possible paternity determinations).
(6) Informed consent documents may not include any exculpatory language
through which subjects are made to waive or appear to waive any legal
rights.
(7 ) OPRR* recommends that the cell repository develop a sample
collection protocol and informed consent document for distribution to
collector-investigators and their local IRBs.
(8) A written submittal agreement for collector-investigators should require
written informed consent of the donor-subjects utilizing an informed consent
document approved by the local IRB. It should also contain an

*Now Office for Human Research Protections (OHRP).
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HUMAN SPECIMENS

acknowledgment that collector-investigators are prohibited from providing
recipient-investigators with access to the identities of donor-subjects or to
information through which the identities of donor-subjects may readily be
ascertained.
(9) A written usage agreement for recipient-investigators should include the
following:
“Recipient acknowledges that the conditions for use of this research
material are governed by the cell repository Institutional Review Board
(IRB) in accordance with Department of Health and Human Services
regulations at 45 CFR 46. Recipient agrees to comply fully with all such
conditions and to report promptly to the cell repository any proposed
changes in the research project and any unanticipated problems involving
risks to subjects or others. Recipient remains subject to applicable State or
local laws or regulations and institutional policies which provide additional
protections for human subjects.
This research material may only be utilized in accordance with the
conditions stipulated by the cell repository IRB. Any additional use of this
material requires prior review and approval by the cell repository IRB and,
where appropriate, by an IRB at the recipient site, which must be convened
under an applicable OPRR*-approved Assurance.”
(10) OPRR* recommends that a Certificate of Confidentiality be obtained to
protect confidentiality of human cell repository specimens and data.

*Now Office for Human Research Protections (OHRP).
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Guidance on Protections for Human Subjects in the
National Institute of General Medical Sciences Human
Genetic Mutant Cell Repository (5/21/1997)
OFFICE FOR PROTECTION FROM RESEARCH RISKS*
The Office for Protection from Research Risks (OPRR)* provides the
following guidance in response to requests from Institutional Review
Boards, the National Institute of General Medical Sciences (NIGMS), and
the research community.
(1) Local IRB Review. Collection of data and specimens for inclusion
in the NIGMS Human Genetic Mutant Cell Repository should be subject to
oversight by local Institutional Review Boards (IRBs) convened by the
collecting institutions under OPRR*-approved Assurances.1 The local IRB is
familiar with the particular circumstances of its research setting and is in
the best position to weigh critical considerations like local professional and
community standards, institutional policies and resources, and the needs of
differing patient or subject populations.
(2) Informed Consent. Written informed consent should be obtained
from each donor-subject in accordance with Department of Health and
Human Services (HHS) regulations at 45 CFR 46.116.
Included among the basic elements of informed consent should be a clear
description of (i) the operation of the cell repository; (ii) the specific types of
research to be conducted; (iii) conditions under which data and specimens
will be released to recipient-investigators; and (iv) procedures for protecting
the privacy of subjects and maintaining the confidentiality of data. Informed
consent information describing the nature and purposes of the research
should be as specific as possible. Where human genetic research is
anticipated, informed consent information should include information about
the consequences of DNA typing (e.g., regarding possible paternity
determinations). Informed consent documents may not include any
exculpatory language through which subjects are made to waive or appear
to waive any legal rights.
The Cell Repository should provide tissue collectors with an NIGMSapproved sample informed consent document containing these elements
and with a sample protocol for tissue collection. IRBs may request copies of
these sample documents to assist in their review of local informed consent
documents and protocols.
(3) Oversight of Repository Activities. Operation of the NIGMS
Human Genetic Mutant Cell Repository and its data management center
should be subject to oversight by an Institutional Review Board (IRB)
convened by the Coriell Institute of Medical Research under an OPRR*approved Assurance of Compliance. The IRB should review and approve a
protocol specifying the conditions under which data and specimens may be
accepted and shared, and ensuring adequate provisions to protect the
privacy of subjects and maintain the confidentiality of data.The IRB should
1Under certain circumstances, collecting institutions may elect to rely upon the Cell Repository
IRB at Coriell Institute. This requires a written Cooperative Amendment, signed by the collecting
institution and the Coriell Institute, and approved by OPRR*.Contact OPRR* for details.
*Now Office for Human Research Protections (OHRP).

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RESEARCH

ON

HUMAN SPECIMENS

also review and approve a sample collection protocol and informed consent
document for distribution to tissue collectors and their local IRBs. A
Certificate of Confidentiality should be obtained to protect confidentiality of
repository specimens and data.
(4) Submittal Agreement. A written submittal agreement for tissue
collectors should require written informed consent of the donor-subjects
utilizing an informed consent document approved by the local IRB. It should
also contain an acknowledgment that collectors are prohibited from
providing recipient-investigators with access to the identities of donorsubjects or to information through which the identities of donor-subjects
may readily be ascertained.
(5) Usage Agreement. A written usage agreement for recipientinvestigators should include the following: “Recipient acknowledges that the
conditions for use of this research material are governed by the cell
repository Institutional Review Board (IRB) in accordance with Department
of Health and Human Services regulations at 45 CFR 46. Recipient agrees
to comply fully with all such conditions and to report promptly to the cell
repository any proposed changes in the research project and any
unanticipated problems involving risks to subjects or others. Recipient
remains subject to applicable State or local laws or regulations and
institutional policies which provide additional protections for human
subjects. This research material may only be utilized in accordance with the
conditions stipulated by the cell repository IRB. Any additional use of this
material requires prior review and approval by the cell repository IRB and,
where appropriate, by an IRB at the recipient site, which must be convened
under an applicable OPRR*-approved Assurance.”
For Additional Information:
Office for Human Research Protections
Department of Health and Human Services
6100 Executive Boulevard, Suite 3B01, MSC-7507
Rockville, MD 20892-7507
301-402-5189 / FAX 301-402-2071 / E-MAIL ohrp@osophs.dhhs.gov

*Now Office for Human Research Protections (OHRP).
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GOOD CLINICAL PRACTICE

Protections for Human Subjects in the NIGMS Human
Genetic Mutant Cell Repository
Submission of Non-Identifiable Materials to the
Repository (5/22/1997)
OFFICE FOR PROTECTION FROM RESEARCH RISKS*
In response to requests from the National Institute of General Medical
Sciences (NIGMS), the Office for Protection from Research Risks (OPRR)*
provides the following clarification regarding submission of “non-identifiable”
materials to the Human Genetic Mutant Cell Repository.
As the chart (on page I-1) illustrates, human subjects are involved in
research when the research involves (i) an inter vention or interaction with a
living individual that would not occur (or would occur in some other fashion)
but for the research; or (ii) the use of identifiable private data or information
in a form associable with a living individual [also see 45 CFR 46.102(f)].
Human subjects would not be involved when material submitted to the
Repository satisfies both of the following conditions:
(1) The material, in its entirety, was collected for purposes other than
submission to the Repository (e.g., the material was collected solely for
clinical purposes, or for legitimate but unrelated research purposes, with no
“extra” material collected for submission to the Repository)
and
(2) The material is submitted to the Repository without any identifiable
private data or information (i.e., no codes or linkers of any sort may be
maintained, either by the Submitter or by the Repository, that would permit
access to identifiable private data or information about the living individual
from whom the material was obtained).
While OPRR* requires neither an Assurance of Compliance nor a
Certification of Institutional Review Board (IRB) review [45 CFR
46.103(a),(f)] for activities that do not involve human subjects, local
institutional requirements regarding review of such activities are,
nevertheless, binding. Some institutions may require IRB or administrative
review of all research activities involving human materials, even where
“human subjects” are not involved.
For Additional Information:
Office for Human Research Protections
Department of Health and Human Services
6100 Executive Boulevard, Suite 3B01, MSC-7507
Rockville, MD 20892-7507
301-402-5189 / FAX 301-402-2071 / E-MAIL ohrp@osophs.dhhs.gov

*Now Office for Human Research Protections (OHRP).
IV–12

INVESTIGATIONAL NEW DRUG APPLICATION

V. TITLE 21—FOOD AND DRUGS
DEPARTMENT OF HEALTH AND HUMAN SERVICES—
PART 312—INVESTIGATIONAL NEW DRUG APPLICATION
Subpart A—General Provisions
§312.1 Scope.
(a) This part contains procedures and requirements governing the use
of investigational new drugs, including procedures and requirements for
the submission to, and review by, the Food and Drug Administration of
investigational new drug applications (IND’s).An investigational new drug
for which an IND is in effect in accordance with this part is exempt from
the premarketing approval requirements that are otherwise applicable
and may be shipped lawfully for the purpose of conducting clinical
investigations of that drug.
(b) References in this part to regulations in the Code of Federal
Regulations are to chapter I of title 21, unless otherwise noted.
§312.2 Applicability.
(a) Applicability. Except as provided in this section, this part applies to
all clinical investigations of products that are subject to §505 of the Federal
Food, Drug, and Cosmetic Act or to the licensing provisions of the Public
Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)).
(b) Exemptions.
(1) The clinical investigation of a drug product that is lawfully marketed
in the United States is exempt from the requirements of this part if all the
following apply:
(i) The investigation is not intended to be reported to FDA as a
well-controlled study in support of a new indication for use nor intended
to be used to support any other significant change in the labeling for
the drug;
(ii) If the drug that is undergoing investigation is lawfully marketed
as a prescription drug product, the investigation is not intended to support
a significant change in the advertising for the product;
(iii) The investigation does not involve a route of administration
or dosage level or use in a patient population or other factor that
significantly increases the risks (or decreases the acceptability of the
risks) associated with the use of the drug product;
(iv) The investigation is conducted in compliance with the
requirements for institutional review set forth in part 56 and with the
requirements for informed consent set forth in part 50; and
(v) The investigation is conducted in compliance with the
requirements of §312.7.
(2)(i) A clinical investigation involving an in vitro diagnostic biological
product listed in paragraph (b)(2)(ii) of this section is exempt from the
requirements of this part if (a) it is intended to be used in a diagnostic
procedure that confirms the diagnosis made by another, medically
established, diagnostic product or procedure and (b) it is shipped in
compliance with §312.160.
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GOOD CLINICAL PRACTICE
(ii) In accordance with paragraph (b)(2)(i) of this section, the following
products are exempt from the requirements of this part: (a) blood grouping
serum; (b) reagent red blood cells; and (c) anti-human globulin.
(3) A drug intended solely for tests in vitro or in laboratory research
animals is exempt from the requirements of this part if shipped in
accordance with §312.160.
(4) FDA will not accept an application for an investigation that is
exempt under the provisions of paragraph (b)(1) of this section.
(5) A clinical investigation involving use of a placebo is exempt from
the requirements of this part if the investigation does not otherwise require
submission of an IND.
(6) A clinical investigation involving an exception from informed
consent under §50.24 of this chapter is not exempt from the requirements
of this part.
(c) Bioavailability studies. The applicability of this part to in vivo
bioavailability studies in humans is subject to the provisions of §320.31.
(d) Unlabeled indication. This part does not apply to the use in the
practice of medicine for an unlabeled indication of a new drug product
approved under part 314 or of a licensed biological product.
(e) Guidance. FDA may, on its own initiative, issue guidance on the
applicability of this part to particular investigational uses of drugs. On
request, FDA will advise on the applicability of this part to a planned clinical
investigation.
§312.3 Definitions and interpretations.
(a) The definitions and interpretations of terms contained in §201 of the
Act apply to those terms when used in this part:
(b) The following definitions of terms also apply to this part: Act means
the Federal Food, Drug, and Cosmetic Act (§§201-902, 52 Stat. 1040 et
seq., as amended (21 U.S.C. 301-392)).
Clinical investigation means any experiment in which a drug is
administered or dispensed to, or used involving, one or more human
subjects. For the purposes of this part, an experiment is any use of a drug
except for the use of a marketed drug in the course of medical practice.
Contract research organization means a person that assumes, as an
independent contractor with the sponsor, one or more of the obligations of a
sponsor, e.g., design of a protocol, selection or monitoring of investigations,
evaluation of reports, and preparation of materials to be submitted to the
Food and Drug Administration.
FDA means the Food and Drug Administration.
IND means an investigational new drug application. For purposes of this
part, “IND” is synonymous with “Notice of Claimed Investigational
Exemption for a New Drug.”
Investigational new drug means a new drug or biological drug that is
used in a clinical investigation.The term also includes a biological product
that is used in vitro for diagnostic purposes. The terms “investigational drug”
and “investigational new drug” are deemed to be synonymous for purposes
of this part.
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INVESTIGATIONAL NEW DRUG APPLICATION
Investigator means an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug is
administered or dispensed to a subject). In the event an investigation is
conducted by a team of individuals, the investigator is the responsible
leader of the team.“Subinvestigator” includes any other individual member
of that team.
Marketing application means an application for a new drug submitted
under §505(b) of the Act or a product license application for a biological
product submitted under the Public Health Service Act.
Sponsor means a person who takes responsibility for and initiates a
clinical investigation.The sponsor may be an individual or pharmaceutical
company, governmental agency, academic institution, private organization,
or other organization.The sponsor does not actually conduct the
investigation unless the sponsor is a sponsor-investigator. A person other
than an individual that uses one or more of its own employees to conduct
an investigation that it has initiated is a sponsor, not a sponsor-investigator,
and the employees are investigators.
Sponsor-Investigator means an individual who both initiates and
conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed.The term does not
include any person other than an individual.The requirements applicable to
a sponsor-investigator under this part include both those applicable to an
investigator and a sponsor.
Subject means a human who participates in an investigation, either as a
recipient of the investigational new drug or as a control. A subject may be a
healthy human or a patient with a disease.
§312.6 Labeling of an investigational new drug.
(a) The immediate package of an investigational new drug intended for
human use shall bear a label with the statement.
CAUTION: New Drug—Limited by Federal (or United States)
law to investigational use.
(b) The label or labeling of an investigational new drug shall not bear any
statement that is false or misleading in any particular and shall not
represent that the investigational new drug is safe or effective for the
purposes for which it is being investigated.
§312.7 Promotion and charging for investigational drugs.
(a) Promotion of an investigational new drug. A sponsor or
investigator, or any person acting on behalf of a sponsor or investigator,
shall not represent in a promotional context that an investigational new drug
is safe or effective for the purposes for which it is under investigation or
otherwise promote the drug.This provision is not intended to restrict the full
exchange of scientific information concerning the drug, including
dissemination of scientific findings in scientific or lay media. Rather, its
intent is to restrict promotional claims of safety or effectiveness of the drug
for a use for which it is under investigation and to preclude
commercialization of the drug before it is approved for commercial
distribution.

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GOOD CLINICAL PRACTICE
(b) Commercial distribution of an investigational new drug. A
sponsor or investigator shall not commercially distribute or test market an
investigational new drug.
(c) Prolonging an investigation. A sponsor shall not unduly prolong an
investigation after finding that the results of the investigation appear to
establish sufficient data to support a marketing application.
(d) Charging for and commercialization of investigational drugs.
(1) Clinical trials under an IND. Charging for an investigational drug
in a clinical trial under an IND is not permitted without the prior written
approval of FDA. In requesting such approval, the sponsor shall provide a
full written explanation of why charging is necessary in order for the
sponsor to undertake or continue the clinical trial, e.g., why distribution of
the drug to test subjects should not be considered part of the normal cost
of doing business.
(2) Treatment protocol or treatment IND. A sponsor or investigator
may charge for an investigational drug for a treatment use under a
treatment protocol or treatment IND provided: (i) There is adequate
enrollment in the ongoing clinical investigations under the authorized IND;
(ii) charging does not constitute commercial marketing of a new drug for
which a marketing application has not been approved; (iii) the drug is not
being commercially promoted or advertised; and (iv) the sponsor of the
drug is actively pursuing mar keting approval with due diligence. FDA must
be notified in writing in advance of commencing any such charges, in an
information amendment submitted under §312.31. Authorization for
charging goes into effect automatically 30 days after receipt by FDA of the
information amendment, unless the sponsor is notified to the contrary.
(3) Noncommercialization of investigational drug. Under this
section, the sponsor may not commercialize an investigational drug by
charging a price larger than that necessary to recover costs of
manufacture, research, development, and handling of the investigational
drug.
(4) Withdrawal of authorization. Authorization to charge for an
investigational drug under this section may be withdrawn by FDA if the
agency finds that the conditions underlying the authorization are no longer
satisfied.
§312.10 Waivers.
(a) A sponsor may request FDA to waive applicable requirement under
this part. A waiver request may be submitted either in an IND or in an
information amendment to an IND. In an emergency, a request may be
made by telephone or other rapid communication means. A waiver request
is required to contain at least one of the following:
(1) An explanation why the sponsor’s compliance with the requirement
is unnecessary or cannot be achieved;
(2) A description of an alternative submission or course of action that
satisfies the purpose of the requirement; or
(3) Other information justifying a waiver.

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INVESTIGATIONAL NEW DRUG APPLICATION
(b) FDA may grant a waiver if it finds that the sponsor’s noncompliance
would not pose a significant and unreasonable risk to human subjects of
the investigation and that one of the following is met:
(1) The sponsor’s compliance with the requirement is unnecessary for
the agency to evaluate the application, or compliance cannot be achieved;
(2) The sponsor’s proposed alternative satisfies the requirement; or
(3) The applicant’s submission otherwise justifies a waiver.

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GOOD CLINICAL PRACTICE

Subpart B—Investigational New Drug Application (IND)
§312.20 Requirement for an IND.
(a) A sponsor shall submit an IND to FDA if the sponsor intends to
conduct a clinical investigation with an investigational new drug that is
subject to §312.2(a).
(b) A sponsor shall not begin a clinical investigation subject to §312.2(a)
until the investigation is subject to an IND which is in effect in accordance
with §312.40.
(c) A sponsor shall submit a separate IND for any clinical investigation
involving an exception from informed consent under §50.24 of this chapter.
Such a clinical investigation is not permitted to proceed without the prior
written authorization from FDA. FDA shall provide a written determination
30 days after FDA receives the IND or earlier.
§312.21 Phases of an investigation.
An IND may be submitted for one or more phases of an investigation.The
clinical investigation of a previously untested drug is generally divided into
three phases. Although in general the phases are conducted sequentially,
they may overlap. These three phases of an investigation are as follows:
(a) Phase 1.
(1) Phase 1 includes the initial introduction of an investigational new
drug into humans. Phase 1 studies are typically closely monitored and may
be conducted in patients or normal volunteer subjects. These studies are
designed to determine the metabolism and pharmacologic actions of the
drug in humans, the side effects associated with increasing doses, and, if
possible, to gain early evidence on effectiveness. During Phase 1, sufficient
information about the drug’s pharmacokinetics and pharmacological effects
should be obtained to permit the design of well-controlled, scientifically
valid, Phase 2 studies. The total number of subjects and patients included
in Phase 1 studies varies with the drug, but is generally in the range of
20 to 80.
(2) Phase 1 studies also include studies of drug metabolism, structureactivity relationships, and mechanism of action in humans, as well as
studies in which investigational drugs are used as research tools to explore
biological phenomena or disease processes.
(b) Phase 2. Phase 2 includes the controlled clinical studies conducted to
evaluate the effectiveness of the drug for a particular indication or
indications in patients with the disease or condition under study and to
determine the common short-term side effects and risks associated with
the drug.Phase 2 studies are typically well controlled, closely monitored,
and conducted in a relatively small number of patients, usually involving no
more than several hundred subjects.
(c) Phase 3. Phase 3 studies are expanded controlled and uncontrolled
trials. They are performed after preliminary evidence suggesting
effectiveness of the drug has been obtained, and are intended to gather the
additional information about effectiveness and safety that is needed to
evaluate the overall benefit-risk relationship of the drug and to provide an

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INVESTIGATIONAL NEW DRUG APPLICATION
adequate basis for physician labeling. Phase 3 studies usually include from
several hundred to several thousand subjects.
§312.22 General principles of the IND submission.
(a) FDA’s primary objectives in reviewing an IND are, in all phases of the
investigation, to assure the safety and rights of subjects, and, in Phase 2
and 3, to help assure that the quality of the scientific evaluation of drugs is
adequate to permit an evaluation of the drug’s effectiveness and safety.
Therefore, although FDA’s review of Phase 1 submissions will focus on
assessing the safety of Phase 1 investigations, FDA’s review of Phases 2
and 3 submissions will also include an assessment of the scientific quality
of the clinical investigations and the likelihood that the investigations will
yield data capable of meeting statutory standards for marketing approval.
(b) The amount of information on a particular drug that must be submitted
in an IND to assure the accomplishment of the objectives described in
paragraph (a) of this section depends upon such factors as the novelty of
the drug, the extent to which it has been studied previously, the known or
suspected risks, and the developmental phase of the drug.
(c) The central focus of the initial IND submission should be on the
general investigational plan and the protocols for specific human studies.
Subsequent amendments to the IND that contain new or revised protocols
should build logically on previous submissions and should be supported by
additional information, including the results of animal toxicology studies or
other human studies as appropriate. Annual reports to the IND should
serve as the focus for reporting the status of studies being conducted under
the IND and should update the general investigational plan for the coming
year.
(d) The IND format set forth in §312.23 should be followed routinely by
sponsors in the interest of fostering an efficient review of applications.
Sponsors are expected to exercise considerable discretion, however,
regarding the content of information submitted in each section, depending
upon the kind of drug being studied and the nature of the available
information. §312.23 outlines the information needed for a commercially
sponsored IND for a new molecular entity. A sponsor-investigator who uses,
as a research tool, an investigational new drug that is already subject to a
manufacturer’s IND or marketing application should follow the same general
format, but ordinarily may, if authorized by the manufacturer, refer to the
manufacturer’s IND or marketing application in providing the technical
information supporting the proposed clinical investigation. A sponsorinvestigator who uses an investigational drug not subject to a
manufacturer’s IND or marketing application is ordinarily required to submit
all technical information supporting the IND, unless such information may
be referenced from the scientific literature.
§312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation subject to
this part shall submit an “Investigational New Drug Application” (IND)
including, in the following order :
(1) Cover sheet (Form FDA-1571). A cover sheet for the application
containing the following:

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GOOD CLINICAL PRACTICE
(i) The name, address, and telephone number of the sponsor, the
date of the application, and the name of the investigational new drug.
(ii) Identification of the phase or phases of the clinical investigation to
be conducted.
(iii) A commitment not to begin clinical investigations until an IND
covering the investigations is in effect.
(iv) A commitment that an Institutional Review Board (IRB) that
complies with the requirements set forth in part 56 will be responsible for
the initial and continuing review and approval of each of the studies in the
proposed clinical investigation and that the investigator will report to the IRB
proposed changes in the research activity in accordance with the
requirements of part 56.
(v) A commitment to conduct the investigation in accordance with all
other applicable regulatory requirements.
(vi) The name and title of the person responsible for monitoring the
conduct and progress of the clinical investigations.
(vii) The name(s) and title(s) of the person(s) responsible under
§312.32 for review and evaluation of information relevant to the safety of
the drug.
(viii) If a sponsor has transferred any obligations for the conduct of
any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations transferred.
If all obligations governing the conduct of the study have been transferred,
a general statement of this transfer—in lieu of a listing of the specific
obligations transferred—may be submitted.
(ix) The signature of the sponsor or the sponsor’s authorized
representative. If the person signing the application does not reside or have
a place of business within the United States, the IND is required to contain
the name and address of, and be countersigned by, an attorney, agent, or
other authorized official who resides or maintains a place of business within
the United States.
(2) A table of contents.
(3) Introductory statement and general investigational plan.
(i) A brief introductory statement giving the name of the drug and all
active ingredients, the drug’s pharmacological class, the structural formula
of the drug (if known), the formulation of the dosage form(s) to be used, the
route of administration, and the broad objectives and planned duration of
the proposed clinical investigation(s).
(ii) A brief summary of previous human experience with the drug,
with reference to other IND’s if pertinent, and to investigational or marketing
experience in other countries that may be relevant to the safety of the
proposed clinical investigation(s).
(iii) If the drug has been withdrawn from investigation or marketing in
any country for any reason related to safety or effectiveness, identification
of the country(ies) where the drug was withdrawn and the reasons for the
withdrawal.
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INVESTIGATIONAL NEW DRUG APPLICATION
(iv) A brief description of the overall plan for investigating the drug
product for the following year. The plan should include the following:
(a) The rationale for the drug or the research study; (b) the indication(s) to
be studied; (c) the general approach to be followed in evaluating the drug;
(d) the kinds of clinical trials to be conducted in the first year following the
submission (if plans are not developed for the entire year, the sponsor
should so indicate); (e) the estimated number of patients to be given the
drug in those studies;and (f) any risks of particular severity or seriousness
anticipated on the basis of the toxicological data in animals or prior studies
in humans with the drug or related drugs.
(4) [Reserved]
(5) Investigator’s brochure. If required under §312.55, a copy of the
investigator’s brochure, containing the following information:
(i) A brief description of the drug substance and the formulation,
including the structural formula, if known.
(ii) A summary of the pharmacological and toxicological effects of the
drug in animals and, to the extent known, in humans.
(iii) A summary of the pharmacokinetics and biological disposition of
the drug in animals and, if known, in humans.
(iv) A summary of information relating to safety and effectiveness in
humans obtained from prior clinical studies. (Reprints of published articles
on such studies may be appended when useful.)
(v) A description of possible risks and side effects to be anticipated
on the basis of prior experience with the drug under investigation or with
related drugs, and of precautions or special monitoring to be done as part
of the investigational use of the drug.
(6) Protocols.
(i) A protocol for each planned study. (Protocols for studies not
submitted initially in the IND should be submitted in accordance with
§312.30(a).) In general, protocols for Phase 1 studies may be less detailed
and more flexible than protocols for Phase 2 and 3 studies. Phase 1
protocols should be directed primarily at providing an outline of the
investigation—an estimate of the number of patients to be involved, a
description of safety exclusions, and a description of the dosing plan
including duration, dose, or method to be used in determining dose—and
should specify in detail only those elements of the study that are critical to
safety, such as necessary monitoring of vital signs and blood chemistries.
Modifications of the experimental design of Phase 1 studies that do not
affect critical safety assessments are required to be reported to FDA only in
the annual report.
(ii) In Phases 2 and 3, detailed protocols describing all aspects of the
study should be submitted. A protocol for a Phase 2 or 3 investigation
should be designed in such a way that, if the sponsor anticipates that some
deviation from the study design may become necessary as the investigation
progresses, alternatives or contingencies to provide for such deviation are
built into the protocols at the outset. For example, a protocol for a controlled
short-term study might include a plan for an early crossover of
nonresponders to an alternative therapy.
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GOOD CLINICAL PRACTICE
(iii) A protocol is required to contain the following, with the specific
elements and detail of the protocol reflecting the above distinctions
depending on the phase of study:
(a) A statement of the objectives and purpose of the study.
(b) The name and address and a statement of the qualifications
(curriculum vitae or other statement of qualifications) of each investigator,
and the name of each subinvestigator (e.g., research fellow, resident)
working under the supervision of the investigator; the name and address of
the research facilities to be used; and the name and address of each
reviewing Institutional Review Board.
(c) The criteria for patient selection and for exclusion of patients
and an estimate of the number of patients to be studied.
(d) A description of the design of the study, including the kind of
control group to be used, if any, and a description of methods to be used to
minimize bias on the part of subjects, investigators, and analysts.
(e) The method for determining the dose(s) to be administered, the
planned maximum dosage, and the duration of individual patient exposure
to the drug.
(f) A description of the observations and measurements to be
made to fulfill the objectives of the study.
(g) A description of clinical procedures, laboratory tests, or other
measures to be taken to monitor the effects of the drug in human subjects
and to minimize risk.
(7) Chemistry, manufacturing, and control information.
(i) As appropriate for the particular investigations covered by the
IND, a section describing the composition, manufacture, and control of
the drug substance and the drug product. Although in each phase of the
investigation sufficient information is required to be submitted to assure the
proper identification, quality, purity, and strength of the investigational drug,
the amount of information needed to make that assurance will vary with the
phase of the investigation, the proposed duration of the investigation, the
dosage form, and the amount of information otherwise available. FDA
recognizes that modifications to the method of preparation of the new drug
substance and dosage form and changes in the dosage form itself are likely
as the investigation progresses. Therefore, the emphasis in an initial Phase
1 submission should generally be placed on the identification and control of
the raw materials and the new drug substance. Final specifications for the
drug substance and drug product are not expected until the end of the
investigational process.
(ii) It should be emphasized that the amount of information to be
submitted depends upon the scope of the proposed clinical investigation.
For example, although stability data are required in all phases of the IND to
demonstrate that the new drug substance and drug product are within
acceptable chemical and physical limits for the planned duration of the
proposed clinical investigation, if very short-term tests are proposed, the
supporting stability data can be correspondingly limited.
(iii) As drug development proceeds and as the scale or production is
changed from the pilot-scale production appropriate for the limited initial
clinical investigations to the larger-scale production needed for expanded
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clinical trials, the sponsor should submit information amendments to
supplement the initial information submitted on the chemistry,
manufacturing, and control processes with information appropriate to the
expanded scope of the investigation.
(iv) Reflecting the distinctions described in this paragraph (a)(7), and
based on the phase(s) to be studied, the submission is required to contain
the following:
(a) Drug substance. A description of the drug substance, including
its physical, chemical, or biological characteristics; the name and address of
its manufacturer; the general method of preparation of the drug substance;
the acceptable limits and analytical methods used to assure the identity,
strength, quality, and purity of the drug substance; and information sufficient
to support stability of the drug substance during the toxicological studies
and the planned clinical studies. Reference to the current edition of the
United States Pharmacopeia—National For mulary may satisfy relevant
requirements in this paragraph.
(b) Drug product. A list of all components, which may include
reasonable alternatives for inactive compounds, used in the manufacture of
the investigational drug product, including both those components intended
to appear in the drug product and those which may not appear but which
are used in the manufacturing process, and, where applicable, the
quantitative composition of the investigational drug product, including any
reasonable variations that may be expected during the investigational
stage; the name and address of the drug product manufacturer; a brief
general description of the manufacturing and packaging procedure as
appropriate for the product; the acceptable limits and analytical methods
used to assure the identity, strength, quality, and purity of the drug product;
and information sufficient to assure the product’s stability during the
planned clinical studies. Reference to the current edition of the United
States Pharmacopeia—National Formulary may satisfy certain
requirements in this paragraph.
(c) A brief general description of the composition, manufacture,
and control of any placebo used in a controlled clinical trial.
(d) Labeling. A copy of all labels and labeling to be provided to
each investigator.
(e) Environmental analysis requirements. A claim for categorical
exclusion under §25.30 or §25.31 or an environmental assessment under
§25.40.
(8) Pharmacology and toxicology information. Adequate information
about pharmacological and toxicological studies of the drug involving
laboratory animals or in vitro, on the basis of which the sponsor has
concluded that it is reasonably safe to conduct the proposed clinical
investigations. The kind, duration, and scope of animal and other tests
required varies with the duration and nature of the proposed clinical
investigations. Guidelines are available from FDA that describe ways in
which these requirements may be met.Such information is required to
include the identification and qualifications of the individuals who evaluated
the results of such studies and concluded that it is reasonably safe to begin
the proposed investigations and a statement of where the investigations
were conducted and where the records are available for inspection. As drug
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development proceeds, the sponsor is required to submit informational
amendments, as appropriate, with additional information pertinent to safety.
(i) Pharmacology and drug disposition. A section describing the
pharmacological effects and mechanism(s) of action of the drug in animals,
and information on the absorption, distribution, metabolism, and excretion
of the drug, if known.
(ii) Toxicology.
(a) An integrated summary of the toxicological effects of the drug
in animals and in vitro. Depending on the nature of the drug and the phase
of the investigation, the description is to include the results of acute,
subacute, and chronic toxicity tests; tests of the drug’s effects on
reproduction and the developing fetus; any special toxicity test related to the
drug’s particular mode of administration or conditions of use (e.g.,
inhalation, dermal, or ocular toxicology); and any in vitro studies intended to
evaluate drug toxicity.
(b) For each toxicology study that is intended primarily to support
the safety of the proposed clinical investigation, a full tabulation of data
suitable for detailed review.
(iii) For each nonclinical laboratory study subject to the good
laboratory practice regulations under part 58, a statement that the study
was conducted in compliance with the good laboratory practice regulations
in part 58, or, if the study was not conducted in compliance with those
regulations, a brief statement of the reason for the noncompliance.
(9) Previous human experience with the investigational drug. A
summary of previous human experience known to the applicant, if any, with
the investigational drug.The information is required to include the following:
(i) If the investigational drug has been investigated or marketed
previously, either in the United States or other countries, detailed
information about such experience that is relevant to the safety of the
proposed investigation or to the investigation’s rationale. If the drug has
been the subject of controlled trials, detailed information on such trials that
is relevant to an assessment of the drug’s effectiveness for the proposed
investigational use(s) should also be provided. Any published material that
is relevant to the safety of the proposed investigation or to an assessment
of the drug’s effectiveness for its proposed investigational use should be
provided in full. Published material that is less directly relevant may be
supplied by a bibliography.
(ii) If the drug is a combination of drugs previously investigated or
marketed, the information required under paragraph (a)(9)(i) of this section
should be provided for each active drug component. However, if any
component in such combination is subject to an approved marketing
application or is otherwise lawfully marketed in the United States, the
sponsor is not required to submit published material concerning that active
drug component unless such material relates directly to the proposed
investigational use (including publications relevant to componentcomponent interaction).
(iii) If the drug has been marketed outside the United States, a list of
the countries in which the drug has been marketed and a list of the

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countries in which the drug has been withdrawn from marketing for reasons
potentially related to safety or effectiveness.
(10) Additional information. In certain applications, as described
below, information on special topics may be needed. Such information shall
be submitted in this section as follows:
(i) Drug dependence and abuse potential. If the drug is a
psychotropic substance or otherwise has abuse potential, a section
describing relevant clinical studies and experience and studies in test
animals.
(ii) Radioactive drugs. If the drug is a radioactive drug, sufficient data
from animal or human studies to allow a reasonable calculation of radiationabsorbed dose to the whole body and critical organs upon administration to
a human subject. Phase 1 studies of radioactive drugs must include studies
which will obtain sufficient data for dosimetry calculations.
(iii) Pediatric studies. Plans for assessing pediatric safety and
effectiveness.
(iv) Other information. A brief statement of any other information that
would aid evaluation of the proposed clinical investigations with respect to
their safety or their design and potential as controlled clinical trials to
support marketing of the drug.
(11) Relevant information. If requested by FDA, any other relevant
information needed for review of the application.
(b) Information previously submitted. The sponsor ordinarily is not
required to resubmit information previously submitted, but may incorporate
the information by reference. A reference to information submitted
previously must identify the file by name, reference number, volume, and
page number where the information can be found.A reference to
information submitted to the agency by a person other than the sponsor is
required to contain a written statement that authorizes the reference and
that is signed by the person who submitted the information.
(c) Material in a foreign language. The sponsor shall submit an
accurate and complete English translation of each part of the IND that is
not in English.The sponsor shall also submit a copy of each original
literature publication for which an English translation is submitted.
(d) Number of copies. The sponsor shall submit an original and two
copies of all submissions to the IND file, including the original submission
and all amendments and reports.
(e) Numbering of IND submissions. Each submission relating to an IND
is required to be numbered serially using a single, three-digit serial number.
The initial IND is required to be numbered 000; each subsequent
submission (e.g., amendment, report, or correspondence) is required to be
numbered chronologically in sequence.
(f) Identification of exception from informed consent. If the
investigation involves an exception from informed consent under §50.24 of
this chapter, the sponsor shall prominently identify on the cover sheet that
the investigation is subject to the requirements in §50.24 of this chapter.

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§312.30 Protocol amendments.
Once an IND is in effect, a sponsor shall amend it as needed to ensure that
the clinical investigations are conducted according to protocols included in
the application.This section sets forth the provisions under which new
protocols may be submitted and changes in previously submitted protocols
may be made. Whenever a sponsor intends to conduct a clinical
investigation with an exception from informed consent for emergency
research as set forth in §50.24 of this chapter, the sponsor shall submit a
separate IND for such investigation.
(a) New protocol. Whenever a sponsor intends to conduct a study that is
not covered by a protocol already contained in the IND, the sponsor shall
submit to FDA a protocol amendment containing the protocol for the study.
Such study may begin provided two conditions are met:
(1) The sponsor has submitted the protocol to FDA for its review; and
(2) the protocol has been approved by the Institutional Review Board
(IRB) with responsibility for review and approval of the study in accordance
with the requirements of part 56.The sponsor may comply with these two
conditions in either order.
(b) Changes in a protocol.
(1) A sponsor shall submit a protocol amendment describing any
change in a Phase 1 protocol that significantly affects the safety of subjects
or any change in a Phase 2 or 3 protocol that significantly affects the safety
of subjects, the scope of the investigation, or the scientific quality of the
study. Examples of changes requiring an amendment under this paragraph
include:
(i) Any increase in drug dosage or duration of exposure of individual
subjects to the drug beyond that in the current protocol, or any significant
increase in the number of subjects under study.
(ii) Any significant change in the design of a protocol (such as the
addition or dropping of a control group).
(iii) The addition of a new test or procedure that is intended to
improve monitoring for, or reduce the risk of, a side effect or adverse event;
or the dropping of a test intended to monitor safety.
(2)(i) A protocol change under paragraph (b)(1) of this section may be
made provided two conditions are met:
(a) The sponsor has submitted the change to FDA for its review;
and
(b) The change has been approved by the IRB with responsibility
for review and approval of the study. The sponsor may comply with these
two conditions in either order.
(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol
change intended to eliminate an apparent immediate hazard to subjects
may be implemented immediately provided FDA is subsequently notified by
protocol amendment and the reviewing IRB is notified in accordance with
§56.104(c).
(c) New investigator. A sponsor shall submit a protocol amendment
when a new investigator is added to carry out a previously submitted
protocol, except that a protocol amendment is not required when a licensed
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practitioner is added in the case of a treatment protocol under §312.34.
Once the investigator is added to the study, the investigational drug may be
shipped to the investigator and the investigator may begin participating in
the study. The sponsor shall notify FDA of the new investigator within
30 days of the investigator being added.
(d) Content and format. A protocol amendment is required to be
prominently identified as such (i.e., “Protocol Amendment: New Protocol,”
“Protocol Amendment: Change in Protocol,” or “Protocol Amendment: New
Investigator”), and to contain the following:
(1)(i) In the case of a new protocol, a copy of the new protocol and a
brief description of the most clinically significant differences between it and
previous protocols.
(ii) In the case of a change in protocol, a brief description of the
change and reference (date and number) to the submission that contained
the protocol.
(iii) In the case of a new investigator, the investigator’s name, the
qualifications to conduct the investigation, reference to the previously
submitted protocol, and all additional information about the investigator’s
study as is required under §312.23(a)(6)(iii)(b).
(2) Reference, if necessary, to specific technical information in the IND
or in a concurrently submitted information amendment to the IND that the
sponsor relies on to support any clinically significant change in the new or
amended protocol.If the reference is made to supporting information
already in the IND, the sponsor shall identify by name, reference number,
volume, and page number the location of the information.
(3) If the sponsor desires FDA to comment on the submission, a
request for such comment and the specific questions FDA’s response
should address.
(e) When submitted. A sponsor shall submit a protocol amendment for a
new protocol or a change in protocol before its implementation. Protocol
amendments to add a new investigator or to provide additional information
about investigators may be grouped and submitted at 30-day intervals.
When several submissions of new protocols or protocol changes are
anticipated during a short period, the sponsor is encouraged, to the extent
feasible, to include these all in a single submission.
§312.31 Information amendments.
(a) Requirement for information amendment. A sponsor shall report in
an information amendment essential information on the IND that is not
within the scope of a protocol amendment, IND safety reports, or annual
report. Examples of information requiring an information amendment
include:
(1) New toxicology, chemistry, or other technical information; or
(2) A report regarding the discontinuance of a clinical investigation.
(b) Content and format of an information amendment. An information
amendment is required to bear prominent identification of its contents (e.g.,
“Information Amendment: Chemistry, Manufacturing, and Control,”
“Information Amendment: Pharmacology-Toxicology,” “Information
Amendment: Clinical”), and to contain the following:
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(1) A statement of the nature and purpose of the amendment.
(2) An organized submission of the data in a format appropriate for
scientific review.
(3) If the sponsor desires FDA to comment on an information
amendment, a request for such comment.
(c) When submitted. Information amendments to the IND should be
submitted as necessary but, to the extent feasible, not more than every
30 days.
§312.32 IND safety reports.
(a) Definitions. The following definitions of terms apply to this section:Associated with the use of the drug.There is a reasonable possibility that
the experience may have been caused by the drug.
Disability. A substantial disruption of a person’s ability to conduct normal
life functions.
Life-threatening adverse drug experience. Any adverse drug
experience that places the patient or subject, in the view of the investigator,
at immediate risk of death from the reaction as it occurred, i.e., it does not
include a reaction that, had it occurred in a more severe form, might have
caused death.
Serious adverse drug experience. Any adverse drug experience
occurring at any dose that results in any of the following outcomes: Death,
a life-threatening adverse drug experience, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important medical
events that may not result in death, be life-threatening, or require
hospitalization may be considered a serious adverse drug experience
when, based upon appropriate medical judgment, they may jeopardize the
patient or subject and may require medical or surgical intervention to
prevent one of the outcomes listed in this definition. Examples of such
medical events include allergic bronchospasm requiring intensive treatment
in an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Unexpected adverse drug experience. Any adverse drug experience,
the specificity or severity of which is not consistent with the current
investigator brochure; or, if an investigator brochure is not required or
available, the specificity or severity of which is not consistent with the risk
information described in the general investigational plan or elsewhere in the
current application, as amended. For example, under this definition, hepatic
necrosis would be unexpected (by virtue of greater severity) if the
investigator brochure only referred to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if the investigator brochure only
listed cerebral vascular accidents. “Unexpected,” as used in this definition,
refers to an adverse drug experience that has not been previously observed
(e.g., included in the investigator brochure) rather than from the perspective
of such experience not being anticipated from the pharmacological
properties of the pharmaceutical product.
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(b) Review of safety information. The sponsor shall promptly review all
information relevant to the safety of the drug obtained or otherwise received
by the sponsor from any source, foreign or domestic, including information
derived from any clinical or epidemiological investigations, animal
investigations, commercial marketing experience, reports in the scientific
literature, and unpublished scientific papers, as well as reports from foreign
regulatory authorities that have not already been previously reported to the
agency by the sponsor.
(c) IND safety reports.
(1) Written reports.
(i) The sponsor shall notify FDA and all participating investigators in a
written IND safety report of:
(A) Any adverse experience associated with the use of the drug
that is both serious and unexpected; or
(B) Any finding from tests in laboratory animals that suggests a
significant risk for human subjects including reports of mutagenicity,
teratogenicity, or carcinogenicity. Each notification shall be made as soon
as possible and in no event later than 15 calendar days after the sponsor’s
initial receipt of the information. Each written notification may be submitted
on FDA Form 3500A or in a narrative format (foreign events may be
submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I
form; reports from animal or epidemiological studies shall be submitted in a
narrative format) and shall bear prominent identification of its contents, i.e.,
“IND Safety Report.” Each written notification to FDA shall be transmitted to
the FDA new drug review division in the Center for Drug Evaluation and
Research or the product review division in the Center for Biologics
Evaluation and Research that has responsibility for review of the IND. If
FDA determines that additional data are needed, the agency may require
further data to be submitted.
(ii) In each written IND safety report, the sponsor shall identify all
safety reports previously filed with the IND concerning a similar adverse
experience, and shall analyze the significance of the adverse experience in
light of the previous, similar reports.
(2) Telephone and facsimile transmission safety reports. The
sponsor shall also notify FDA by telephone or by facsimile transmission of
any unexpected fatal or life-threatening experience associated with the use
of the drug as soon as possible but in no event later than 7 calendar days
after the sponsor’s initial receipt of the information. Each telephone call or
facsimile transmission to FDA shall be transmitted to the FDA new drug
review division in the Center for Drug Evaluation and Research or the
product review division in the Center for Biologics Evaluation and Research
that has responsibility for review of the IND.
(3) Reporting format or frequency. FDA may request a sponsor to
submit IND safety reports in a format or at a frequency different than that
required under this paragraph.The sponsor may also propose and adopt a
different reporting format or frequency if the change is agreed to in
advance by the director of the new drug review division in the Center for
Drug Evaluation and Research or the director of the products review
division in the Center for Biologics Evaluation and Research which is
responsible for review of the IND.
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(4) A sponsor of a clinical study of a marketed drug is not required to
make a safety report for any adverse experience associated with use of the
drug that is not from the clinical study itself.
(d) Followup.
(1) The sponsor shall promptly investigate all safety information
received by it.
(2) Followup information to a safety report shall be submitted as soon
as the relevant information is available.
(3) If the results of a sponsor’s investigation show that an adverse drug
experience not initially determined to be reportable under paragraph (c) of
this section is so reportable, the sponsor shall report such experience in
a written safety report as soon as possible, but in no event later than
15 calendar days after the determination is made.
(4) Results of a sponsor’s investigation of other safety information shall
be submitted, as appropriate, in an information amendment or annual
report.
(e) Disclaimer. A safety report or other information submitted by a
sponsor under this part (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the sponsor or
FDA that the report or information constitutes an admission that the drug
caused or contributed to an adverse experience. A sponsor need not admit,
and may deny, that the report or information submitted by the sponsor
constitutes an admission that the drug caused or contributed to an adverse
experience.
§312.33 Annual reports.
A sponsor shall within 60 days of the anniversary date that the IND went
into effect, submit a brief report of the progress of the investigation that
includes:
(a) Individual study information. A brief summary of the status of each
study in progress and each study completed during the previous year. The
summary is required to include the following information for each study:
(1) The title of the study (with any appropriate study identifiers such as
protocol number), its purpose, a brief statement identifying the patient
population, and a statement as to whether the study is completed.
(2) The total number of subjects initially planned for inclusion in the
study; the number entered into the study to date, tabulated by age group,
gender, and race; the number whose participation in the study was
completed as planned; and the number who dropped out of the study for
any reason.
(3) If the study has been completed, or if interim results are known, a
brief description of any available study results.
(b) Summary information. Information obtained during the previous
year’s clinical and nonclinical investigations, including:
(1) A narrative or tabular summary showing the most frequent and
most serious adverse experiences by body system.
(2) A summary of all IND safety reports submitted during the past year.

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(3) A list of subjects who died during participation in the investigation,
with the cause of death for each subject.
(4) A list of subjects who dropped out during the course of the
investigation in association with any adverse experience, whether or not
thought to be drug related.
(5) A brief description of what, if anything, was obtained that is
pertinent to an understanding of the drug’s actions, including, for example,
information about dose response, information from controlled trials, and
information about bioavailability.
(6) A list of the preclinical studies (including animal studies) completed
or in progress during the past year and a summary of the major preclinical
findings.
(7) A summary of any significant manufacturing or microbiological
changes made during the past year.
(c) A description of the general investigational plan for the coming year to
replace that submitted 1 year earlier. The general investigational plan shall
contain the information required under §312.23(a)(3)(iv).
(d) If the investigator brochure has been revised, a description of the
revision and a copy of the new brochure.
(e) A description of any significant Phase 1 protocol modifications made
during the previous year and not previously reported to the IND in a
protocol amendment.
(f) A brief summary of significant foreign marketing developments with the
drug during the past year, such as approval of marketing in any country or
withdrawal or suspension from marketing in any countr y.
(g) If desired by the sponsor, a log of any outstanding business with
respect to the IND for which the sponsor requests or expects a reply,
comment, or meeting.
§312.34 Treatment use of an investigational new drug.
(a) General. A drug that is not approved for marketing may be under
clinical investigation for a serious or immediately life-threatening disease
condition in patients for whom no comparable or satisfactory alternative
drug or other therapy is available. During the clinical investigation of the
drug, it may be appropriate to use the drug in the treatment of patients not
in the clinical trials, in accordance with a treatment protocol or treatment
IND. The purpose of this section is to facilitate the availability of promising
new drugs to desperately ill patients as early in the drug development
process as possible, before general marketing begins, and to obtain
additional data on the drug’s safety and effectiveness. In the case of a
serious disease, a drug ordinarily may be made available for treatment use
under this section during Phase 3 investigations or after all clinical trials
have been completed; however, in appropriate circumstances, a drug may
be made available for treatment use during Phase 2. In the case of an
immediately life-threatening disease, a drug may be made available for
treatment use under this section earlier than Phase 3, but ordinarily not
earlier than Phase 2. For purposes of this section, the “treatment use” of a
drug includes the use of a drug for diagnostic purposes. If a protocol for an
investigational drug meets the criteria of this section, the protocol is to be
submitted as a treatment protocol under the provisions of this section.
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(b) Criteria.
(1) FDA shall permit an investigational drug to be used for a treatment
use under a treatment protocol or treatment IND if:
(i) The drug is intended to treat a serious or immediately lifethreatening disease;
(ii) There is no comparable or satisfactory alternative drug or other
therapy available to treat that stage of the disease in the intended patient
population;
(iii) The drug is under investigation in a controlled clinical trial under
an IND in effect for the trial, or all clinical trials have been completed; and
(iv) The sponsor of the controlled clinical trial is actively pursuing
marketing approval of the investigational drug with due diligence.
(2) Serious disease. For a drug intended to treat a serious disease,
the Commissioner may deny a request for treatment use under a treatment
protocol or treatment IND if there is insufficient evidence of safety and
effectiveness to support such use.
(3) Immediately life-threatening disease.
(i) For a drug intended to treat an immediately life-threatening
disease, the Commissioner may deny a request for treatment use of an
investigational drug under a treatment protocol or treatment IND if the
available scientific evidence, taken as a whole, fails to provide a reasonable
basis for concluding that the drug:
(A) May be effective for its intended use in its intended patient
population; or
(B) Would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk of illness or
injury.
(ii) For the purpose of this section, an “immediately life-threatening”
disease means a stage of a disease in which there is a reasonable
likelihood that death will occur within a matter of months or in which
premature death is likely without early treatment.
(c) Safeguards. Treatment use of an investigational drug is conditioned
on the sponsor and investigators complying with the safeguards of the
IND process, including the regulations governing informed consent
(21 CFR part 50) and institutional review boards (21 CFR part 56) and the
applicable provisions of part 312, including distribution of the drug through
qualified experts, maintenance of adequate manufacturing facilities, and
submission of IND safety reports.
(d) Clinical hold. FDA may place on clinical hold a proposed or ongoing
treatment protocol or treatment IND in accordance with §312.42.
§312.35 Submissions for treatment use.
(a) Treatment protocol submitted by IND sponsor. Any sponsor of a
clinical investigation of a drug who intends to sponsor a treatment use for
the drug shall submit to FDA a treatment protocol under §312.34 if the
sponsor believes the criteria of §312.34 are satisfied.If a protocol is not
submitted under §312.34, but FDA believes that the protocol should have
been submitted under this section, FDA may deem the protocol to be
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INVESTIGATIONAL NEW DRUG APPLICATION
submitted under §312.34. A treatment use under a treatment protocol may
begin 30 days after FDA receives the protocol or on earlier notification by
FDA that the treatment use described in the protocol may begin.
(1) A treatment protocol is required to contain the following:
(i) The intended use of the drug.
(ii) An explanation of the rationale for use of the drug, including, as
appropriate, either a list of what available regimens ordinarily should be
tried before using the investigational drug or an explanation of why the use
of the investigational drug is preferable to the use of available marketed
treatments.
(iii) A brief description of the criteria for patient selection.
(iv) The method of administration of the drug and the dosages.
(v) A description of clinical procedures, laboratory tests, or other
measures to monitor the effects of the drug and to minimize risk.
(2) A treatment protocol is to be supported by the following:
(i) Informational brochure for supplying to each treating physician.
(ii) The technical information that is relevant to safety and
effectiveness of the drug for the intended treatment purpose. Information
contained in the sponsor’s IND may be incorporated by reference.
(iii) A commitment by the sponsor to assure compliance of all
participating investigators with the informed consent requirements of
21 CFR part 50.
(3) A licensed practitioner who receives an investigational drug for
treatment use under a treatment protocol is an “investigator” under the
protocol and is responsible for meeting all applicable investigator
responsibilities under this part and 21 CFR parts 50 and 56.
(b) Treatment IND submitted by licensed practitioner.
(1) If a licensed medical practitioner wants to obtain an
investigational drug subject to a controlled clinical trial for a treatment use,
the practitioner should first attempt to obtain the drug from the sponsor of
the controlled trial under a treatment protocol. If the sponsor of the
controlled clinical investigation of the drug will not establish a treatment
protocol for the drug under paragraph (a) of this section, the licensed
medical practitioner may seek to obtain the drug from the sponsor and
submit a treatment IND to FDA requesting authorization to use the
investigational drug for treatment use. A treatment use under a treatment
IND may begin 30 days after FDA receives the IND or on earlier notification
by FDA that the treatment use under the IND may begin. A treatment IND is
required to contain the following:
(i) A cover sheet (Form FDA 1571) meeting §312.23(g)(1).
(ii) Information (when not provided by the sponsor) on the drug’s
chemistry, manufacturing, and controls, and prior clinical and nonclinical
experience with the drug submitted in accordance with §312.23. A sponsor
of a clinical investigation subject to an IND who supplies an investigational
drug to a licensed medical practitioner for purposes of a separate treatment

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clinical investigation shall be deemed to authorize the incorporation-byreference of the technical information contained in the sponsor’s IND into
the medical practitioner’s treatment IND.
(iii) A statement of the steps taken by the practitioner to obtain the
drug under a treatment protocol from the drug sponsor.
(iv) A treatment protocol containing the same information listed in
paragraph (a)(1) of this section.
(v) A statement of the practitioner’s qualifications to use the
investigational drug for the intended treatment use.
(vi) The practitioner’s statement of familiarity with information on the
drug’s safety and effectiveness derived from previous clinical and
nonclinical experience with the drug.
(vii) Agreement to report to FDA safety information in accordance
with §312.32.
(2) A licensed practitioner who submits a treatment IND under this
section is the sponsor-investigator for such IND and is responsible for
meeting all applicable sponsor and investigator responsibilities under this
part and 21 CFR parts 50 and 56.
§312.36 Emergency use of an investigational new drug.
Need for an investigational drug may arise in an emergency situation that
does not allow time for submission of an IND in accordance with §312.23 or
§312.34. In such a case, FDA may authorize shipment of the drug for a
specified use in advance of submission of an IND. A request for such
authorization may be transmitted to FDA by telephone or other rapid
communication means. For investigational biological drugs, the request
should be directed to the Division of Biological Investigational New Drugs
(HFB-230), Center for Biologics Evaluation and Research, 8800 Rockville
Pike, Bethesda, MD 20892, 301-443-4864.1 For all other investigational
drugs, the request for authorization should be directed to the Document
Management and Reporting Branch (HFD-53), Center for Drug Evaluation
and Research, 5600 Fishers Lane, Rockville, MD 20857, 301-443-4320.
After normal working hours, eastern standard time, the request should be
directed to the FDA Division of Emergency and Epidemiological Operations,
202-857-8400. Except in extraordinary circumstances, such authorization
will be conditioned on the sponsor making an appropriate IND submission
as soon as practicable after receiving the authorization.
§312.38 Withdrawal of an IND.
(a) At any time a sponsor may withdraw an effective IND without
prejudice.
(b) If an IND is withdrawn, FDA shall be so notified, all clinical
investigations conducted under the IND shall be ended, all current
investigators notified, and all stocks of the drug returned to the sponsor or

1The phone numbers for obtaining an Emergency IND have changed:

For drug products, 301-827-4573; for biological blood products, 301-827-3518; for biological
vaccine products, 301-827-0648; for biological therapeutic products, 301-594-2860;on nights and
weekends, 301-443-1240.
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otherwise disposed of at the request of the sponsor in accordance with
§312.59.
(c) If an IND is withdrawn because of a safety reason, the sponsor shall
promptly so inform FDA, all participating investigators, and all reviewing
Institutional Review Boards, together with the reasons for such withdrawal.

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Subpart C—Administrative Actions
§312.40 General requirements for use of an investigational new drug
in a clinical investigation.
(a) An investigational new drug may be used in a clinical investigation if
the following conditions are met:
(1) The sponsor of the investigation submits an IND for the drug to
FDA; the IND is in effect under paragraph (b) of this section; and the
sponsor complies with all applicable requirements in this part and parts
50 and 56 with respect to the conduct of the clinical investigations; and
(2) Each participating investigator conducts his or her investigation in
compliance with the requirements of this part and parts 50 and 56.
(b) An IND goes into effect:
(1) Thirty days after FDA receives the IND, unless FDA notifies the
sponsor that the investigations described in the IND are subject to a clinical
hold under §312.42; or
(2) On earlier notification by FDA that the clinical investigations in the
IND may begin. FDA will notify the sponsor in writing of the date it receives
the IND.
(c) A sponsor may ship an investigational new drug to investigators
named in the IND:
(1) Thirty days after FDA receives the IND; or
(2) On earlier FDA authorization to ship the drug.
(d) An investigator may not administer an investigational new drug to
human subjects until the IND goes into effect under paragraph (b) of this
section.
§312.41 Comment and advice on an IND.
(a) FDA may at any time during the course of the investigation
communicate with the sponsor orally or in writing about deficiencies in the
IND or about FDA’s need for more data or information.
(b) On the sponsor’s request, FDA will provide advice on specific matters
relating to an IND. Examples of such advice may include advice on the
adequacy of technical data to support an investigational plan, on the design
of a clinical trial, and on whether proposed investigations are likely to
produce the data and information that is needed to meet requirements for a
marketing application.
(c) Unless the communication is accompanied by a clinical hold order
under §312.42, FDA communications with a sponsor under this section are
solely advisory and do not require any modification in the planned or
ongoing clinical investigations or response to the agency.
§312.42 Clinical holds and requests for modification.
(a) General. A clinical hold is an order issued by FDA to the sponsor to
delay a proposed clinical investigation or to suspend an ongoing
investigation.The clinical hold order may apply to one or more of the
investigations covered by an IND. When a proposed study is placed on
clinical hold, subjects may not be given the investigational drug.When an
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ongoing study is placed on clinical hold, no new subjects may be recruited
to the study and placed on the investigational drug; patients already in the
study should be taken off therapy involving the investigational drug unless
specifically permitted by FDA in the interest of patient safety.
(b) Grounds for imposition of clinical hold.
(1) Clinical hold of a Phase 1 study under an IND. FDA may place a
proposed or ongoing Phase 1 investigation on clinical hold if it finds that:
(i) Human subjects are or would be exposed to an unreasonable and
significant risk of illness or injury;
(ii) The clinical investigators named in the IND are not qualified by
reason of their scientific training and experience to conduct the investigation
described in the IND;
(iii) The investigator brochure is misleading, erroneous, or materially
incomplete; or
(iv) The IND does not contain sufficient information required under
§312.23 to assess the risks to subjects of the proposed studies.
(2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may
place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it
finds that:
(i) Any of the conditions in paragraph (b)(1)(i) through (iv) of this
section apply; or
(ii) The plan or protocol for the investigation is clearly deficient in
design to meet its stated objectives.
(3) Clinical hold of a treatment IND or treatment protocol.
(i) Proposed use. FDA may place a proposed treatment IND or
treatment protocol on clinical hold if it is determined that:
(A) The pertinent criteria in §312.34(b) for permitting the treatment
use to begin are not satisfied; or
(B) The treatment protocol or treatment IND does not contain the
information required under §312.35 (a) or (b) to make the specified
determination under §312.34(b).
(ii) Ongoing use. FDA may place an ongoing treatment protocol or
treatment IND on clinical hold if it is determined that:
(A) There becomes available a comparable or satisfactory
alternative drug or other therapy to treat that stage of the disease in the
intended patient population for which the investigational drug is being used;
(B) The investigational drug is not under investigation in a
controlled clinical trial under an IND in effect for the trial and not all
controlled clinical trials necessary to support a marketing application have
been completed, or a clinical study under the IND has been placed on
clinical hold;
(C) The sponsor of the controlled clinical trial is not pursuing
marketing approval with due diligence;
(D) If the treatment IND or treatment protocol is intended for a
serious disease, there is insufficient evidence of safety and effectiveness to
support such use; or
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(E) If the treatment protocol or treatment IND was based on an
immediately life-threatening disease, the available scientific evidence, taken
as a whole, fails to provide a reasonable basis for concluding that the drug:
(1) May be effective for its intended use in its intended
population; or
(2) Would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk of illness or
injury.
(iii) FDA may place a proposed or ongoing treatment IND or
treatment protocol on clinical hold if it finds that any of the conditions in
paragraph (b)(4)(i) through (b)(4)(viii) of this section apply.
(4) Clinical hold of any study that is not designed to be adequate
and well-controlled. FDA may place a proposed or ongoing investigation
that is not designed to be adequate and well-controlled on clinical hold if it
finds that:
(i) Any of the conditions in paragraph (b)(1) or (b)(2) of this section
apply; or
(ii) There is reasonable evidence the investigation that is not
designed to be adequate and well-controlled is impeding enrollment in, or
otherwise interfering with the conduct or completion of, a study that is
designed to be an adequate and well-controlled investigation of the same or
another investigational drug; or
(iii) Insufficient quantities of the investigational drug exist to
adequately conduct both the investigation that is not designed to be
adequate and well-controlled and the investigations that are designed to be
adequate and well-controlled; or
(iv) The drug has been studied in one or more adequate and wellcontrolled investigations that strongly suggest lack of effectiveness; or
(v) Another drug under investigation or approved for the same
indication and available to the same patient population has demonstrated a
better potential benefit/risk balance; or
(vi) The drug has received marketing approval for the same indication
in the same patient population; or
(vii) The sponsor of the study that is designed to be an adequate and
well-controlled investigation is not actively pursuing marketing approval of
the investigational drug with due diligence; or
(viii) The Commissioner determines that it would not be in the public
interest for the study to be conducted or continued. FDA ordinarily intends
that clinical holds under paragraphs (b)(4)(ii),(b)(4)(iii) and (b)(4)(v) of this
section would only apply to additional enrollment in nonconcurrently
controlled trials rather than eliminating continued access to individuals
already receiving the investigational drug.
(5) Clinical hold of any investigation involving an exception from
informed consent under §50.24 of this chapter. FDA may place a
proposed or ongoing investigation involving an exception from informed
consent under §50.24 of this chapter on clinical hold if it is determined that:
(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this section
apply; or
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(ii) The pertinent criteria in §50.24 of this chapter for such an
investigation to begin or continue are not submitted or not satisfied.
(c) Discussion of deficiency. Whenever FDA concludes that a
deficiency exists in a clinical investigation that may be grounds for the
imposition of clinical hold FDA will, unless patients are exposed to
immediate and serious risk, attempt to discuss and satisfactorily resolve the
matter with the sponsor before issuing the clinical hold order.
(d) Imposition of clinical hold. The clinical hold order may be made by
telephone or other means of rapid communication or in writing.The clinical
hold order will identify the studies under the IND to which the hold applies,
and will briefly explain the basis for the action.The clinical hold order will be
made by or on behalf of the Division Director with responsibility for review
of the IND. As soon as possible, and no more than 30 days after imposition
of the clinical hold, the Division Director will provide the sponsor a written
explanation of the basis for the hold.
(e) Resumption of clinical investigations. An investigation may only
resume after FDA (usually the Division Director, or the Director’s designee,
with responsibility for review of the IND) has notified the sponsor that the
investigation may proceed. Resumption of the affected investigation(s) will
be authorized when the sponsor corrects the deficiency(ies) previously
cited or otherwise satisfies the agency that the investigation(s) can
proceed. FDA may notify a sponsor of its determination regarding the
clinical hold by telephone or other means of rapid communication. If a
sponsor of an IND that has been placed on clinical hold requests in writing
that the clinical hold be removed and submits a complete response to the
issue(s) identified in the clinical hold order, FDA shall respond in writing to
the sponsor within 30-calendar days of receipt of the request and the
complete response. FDA’s response will either remove or maintain the
clinical hold, and will state the reasons for such determination.
Notwithstanding the 30-calendar day response time, a sponsor may not
proceed with a clinical trial on which a clinical hold has been imposed until
the sponsor has been notified by FDA that the hold has been lifted.
(f) Appeal. If the sponsor disagrees with the reasons cited for the clinical
hold, the sponsor may request reconsideration of the decision in
accordance with §312.48.
(g) Conversion of IND on clinical hold to inactive status. If all
investigations covered by an IND remain on clinical hold for 1 year or more,
the IND may be placed on inactive status by FDA under §312.45.
§312.44 Termination.
(a) General. This section describes the procedures under which FDA
may terminate an IND. If an IND is terminated, the sponsor shall end all
clinical investigations conducted under the IND and recall or otherwise
provide for the disposition of all unused supplies of the drug. A termination
action may be based on deficiencies in the IND or in the conduct of an
investigation under an IND. Except as provided in paragraph (d) of this
section, a termination shall be preceded by a proposal to terminate by FDA
and an opportunity for the sponsor to respond. FDA will, in general, only
initiate an action under this section after first attempting to resolve
differences informally or, when appropriate, through the clinical hold
procedures described in §312.42.
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(b) Grounds for termination.
(1) Phase 1. FDA may propose to terminate an IND during Phase 1 if
it finds that:
(i) Human subjects would be exposed to an unreasonable and
significant risk of illness or injury.
(ii) The IND does not contain sufficient information required under
§312.23 to assess the safety to subjects of the clinical investigations.
(iii) The methods, facilities, and controls used for the manufacturing,
processing, and packing of the investigational drug are inadequate to
establish and maintain appropriate standards of identity, strength, quality,
and purity as needed for subject safety.
(iv) The clinical investigations are being conducted in a manner
substantially different than that described in the protocols submitted in the
IND.
(v) The drug is being promoted or distributed for commercial
purposes not justified by the requirements of the investigation or permitted
by §312.7.
(vi) The IND, or any amendment or report to the IND, contains an
untrue statement of a material fact or omits material information required by
this part.
(vii) The sponsor fails promptly to investigate and inform the Food
and Drug Administration and all investigators of serious and unexpected
adverse experiences in accordance with §312.32 or fails to make any other
report required under this part.
(viii) The sponsor fails to submit an accurate annual report of the
investigations in accordance with §312.33.
(ix) The sponsor fails to comply with any other applicable requirement
of this part, part 50, or part 56.
(x) The IND has remained on inactive status for 5 years or more.
(xi) The sponsor fails to delay a proposed investigation under the IND
or to suspend an ongoing investigation that has been placed on clinical
hold under §312.42(b)(4).
(2) Phase 2 or 3. FDA may propose to terminate an IND during Phase
2 or Phase 3 if FDA finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi) of
this section apply; or
(ii) The investigational plan or protocol(s) is not reasonable as a bona
fide scientific plan to determine whether or not the drug is safe and effective
for use; or
(iii) There is convincing evidence that the drug is not effective for the
purpose for which it is being investigated.
(3) FDA may propose to terminate a treatment IND if it finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (x) of this
section apply;or
(ii) Any of the conditions in §312.42(b)(3) apply.
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(c) Opportunity for sponsor response.
(1) If FDA proposes to terminate an IND, FDA will notify the sponsor in
writing, and invite correction or explanation within a period of 30 days.
(2) On such notification, the sponsor may provide a written explanation
or correction or may request a conference with FDA to provide the
requested explanation or correction.If the sponsor does not respond to the
notification within the allocated time, the IND shall be terminated.
(3) If the sponsor responds but FDA does not accept the explanation or
correction submitted, FDA shall inform the sponsor in writing of the reason
for the nonacceptance and provide the sponsor with an opportunity for a
regulatory hearing before FDA under part 16 on the question of whether
the IND should be terminated.The sponsor’s request for a regulatory
hearing must be made within 10 days of the sponsor’s receipt of FDA’s
notification of nonacceptance.
(d) Immediate termination of IND. Notwithstanding paragraphs (a)
through (c) of this section, if at any time FDA concludes that continuation of
the investigation presents an immediate and substantial danger to the
health of individuals, the agency shall immediately, by written notice to the
sponsor from the Director of the Center for Drug Evaluation and Research
or the Director of the Center for Biologics Evaluation and Research,
terminate the IND. An IND so terminated is subject to reinstatement by the
Director on the basis of additional submissions that eliminate such danger.
If an IND is terminated under this paragraph, the agency will afford the
sponsor an opportunity for a regulatory hearing under part 16 on the
question of whether the IND should be reinstated.
§312.45 Inactive status.
(a) If no subjects are entered into clinical studies for a period of 2 years
or more under an IND, or if all investigations under an IND remain on
clinical hold for 1 year or more, the IND may be placed by FDA on inactive
status. This action may be taken by FDA either on request of the sponsor or
on FDA’s own initiative. If FDA seeks to act on its own initiative under this
section, it shall first notify the sponsor in writing of the proposed inactive
status. Upon receipt of such notification, the sponsor shall have 30 days to
respond as to why the IND should continue to remain active.
(b) If an IND is placed on inactive status, all investigators shall be so
notified and all stocks of the drug shall be returned or otherwise disposed
of in accordance with §312.59.
(c) A sponsor is not required to submit annual reports to an IND on
inactive status. An inactive IND is, however, still in effect for purposes of the
public disclosure of data and information under §312.130.
§312.47 Meetings.
(a) General. Meetings between a sponsor and the agency are frequently
useful in resolving questions and issues raised during the course of a
clinical investigation. FDA encourages such meetings to the extent that they
aid in the evaluation of the drug and in the solution of scientific problems
concerning the drug, to the extent that FDA’s resources permit.The general
principle underlying the conduct of such meetings is that there should be
free, full, and open communication about any scientific or medical question
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that may arise during the clinical investigation.These meetings shall be
conducted and documented in accordance with part 10.
(b) “End-of-Phase 2”meetings and meetings held before submission
of a marketing application. At specific times during the drug investigation
process, meetings between FDA and a sponsor can be especially helpful in
minimizing wasteful expenditures of time and money and thus in speeding
the drug development and evaluation process. In particular, FDA has found
that meetings at the end of Phase 2 of an investigation (end-of-Phase 2
meetings) are of considerable assistance in planning later studies and that
meetings held near completion of Phase 3 and before submission of a
marketing application (“pre-NDA” meetings) are helpful in developing
methods of presentation and submission of data in the marketing
application that facilitate review and allow timely FDA response.
(1) End-of-Phase 2 meetings.
(i) Purpose. The purpose of an end-of-phase 2 meeting is to
determine the safety of proceeding to Phase 3, to evaluate the Phase 3
plan and protocols and the adequacy of current studies and plans to
assess pediatric safety and effectiveness, and to identify any additional
information necessary to support a marketing application for the uses under
investigation.
(ii) Eligibility for meeting. While the end-of-Phase 2 meeting is
designed primarily for IND’s involving new molecular entities or major new
uses of marketed drugs, a sponsor of any IND may request and obtain an
end-of-Phase 2 meeting.
(iii) Timing. To be most useful to the sponsor, end-of-Phase 2
meetings should be held before major commitments of effort and resources
to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2
meeting is not, however, intended to delay the transition of an investigation
from Phase 2 to Phase 3.
(iv) Advance information. At least 1 month in advance of an end-ofPhase 2 meeting, the sponsor should submit background information on the
sponsor’s plan for Phase 3, including summaries of the Phase 1 and 2
investigations, the specific protocols for Phase 3 clinical studies, plans for
any additional nonclinical studies, plans for pediatric studies, including a
time line for protocol finalization, enrollment, completion, and data analysis,
or information to support any planned request for waiver or deferral of
pediatric studies, and, if available, tentative labeling for the drug.The
recommended contents of such a submission are described more fully in
FDA Staff Manual Guide 4850.7 that is publicly available under FDA’s public
information regulations in part 20.
(v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting
are to be made with the division in FDA’s Center for Drug Evaluation and
Research or the Center for Biologics Evaluation and Research which is
responsible for review of the IND. The meeting will be scheduled by FDA at
a time convenient to both FDA and the sponsor. Both the sponsor and FDA
may bring consultants to the meeting.The meeting should be directed
primarily at establishing agreement between FDA and the sponsor of the
overall plan for Phase 3 and the objectives and design of particular studies.
The adequacy of the technical information to support Phase 3 studies
and/or a marketing application may also be discussed. FDA will also
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provide its best judgment, at that time, of the pediatric studies that will be
required for the drug product and whether their submission will be deferred
until after approval.Agreements reached at the meeting on these matters
will be recorded in minutes of the conference that will be taken by FDA in
accordance with §10.65 and provided to the sponsor. The minutes along
with any other written material provided to the sponsor will serve as a
permanent record of any agreements reached. Barring a significant
scientific development that requires otherwise, studies conducted in
accordance with the agreement shall be presumed to be sufficient in
objective and design for the purpose of obtaining marketing approval for the
drug.
(2) “Pre-NDA”and “pre-BLA”meetings. FDA has found that delays
associated with the initial review of a marketing application may be reduced
by exchanges of information about a proposed marketing application.The
primary purpose of this kind of exchange is to uncover any major
unresolved problems, to identify those studies that the sponsor is relying on
as adequate and well-controlled to establish the drug’s effectiveness, to
identify the status of ongoing or needed studies adequate to assess
pediatric safety and effectiveness, to acquaint FDA reviewers with the
general information to be submitted in the marketing application (including
technical information), to discuss appropriate methods for statistical
analysis of the data, and to discuss the best approach to the presentation
and formatting of data in the marketing application. Arrangements for such
a meeting are to be initiated by the sponsor with the division responsible for
review of the IND. To permit FDA to provide the sponsor with the most
useful advice on preparing a marketing application, the sponsor should
submit to FDA’s reviewing division at least 1 month in advance of the
meeting the following information:
(i) A brief summary of the clinical studies to be submitted in the
application.
(ii) A proposed format for organizing the submission, including
methods for presenting the data.
(iii) Information on the status of needed or ongoing pediatric studies.
(iv) Any other information for discussion at the meeting.
§312.48 Dispute resolution.
(a) General. The Food and Drug Administration is committed to resolving
differences between sponsors and FDA reviewing divisions with respect to
requirements for IND’s as quickly and amicably as possible through the
cooperative exchange of information and views.
(b) Administrative and procedural issues. When administrative or
procedural disputes arise, the sponsor should first attempt to resolve the
matter with the division in FDA’s Center for Drug Evaluation and Research
or Center for Biologics Evaluation and Research which is responsible for
review of the IND, beginning with the consumer safety officer assigned to
the application. If the dispute is not resolved, the sponsor may raise the
matter with the person designated as ombudsman, whose function shall be
to investigate what has happened and to facilitate a timely and equitable
resolution. Appropriate issues to raise with the ombudsman include
resolving difficulties in scheduling meetings and obtaining timely replies to
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inquiries. Further details on this procedure are contained in FDA Staff
Manual Guide 4820.7 that is publicly available under FDA’s public
information regulations in part 20.
(c) Scientific and medical disputes.
(1) When scientific or medical disputes arise during the drug
investigation process, sponsors should discuss the matter directly with the
responsible reviewing officials. If necessary, sponsors may request a
meeting with the appropriate reviewing officials and management
representatives in order to seek a resolution. Requests for such meetings
shall be directed to the director of the division in FDA’s Center for Drug
Evaluation and Research or Center for Biologics Evaluation and Research
which is responsible for review of the IND. FDA will make every attempt to
grant requests for meetings that involve important issues and that can be
scheduled at mutually convenient times.
(2) The “end-of-Phase 2” and “pre-NDA” meetings described in
§312.47(b) will also provide a timely forum for discussing and resolving
scientific and medical issues on which the sponsor disagrees with the
agency.
(3) In requesting a meeting designed to resolve a scientific or medical
dispute, applicants may suggest that FDA seek the advice of outside
experts, in which case FDA may, in its discretion, invite to the meeting one
or more of its advisory committee members or other consultants, as
designated by the agency. Applicants may rely on, and may bring to any
meeting, their own consultants. For major scientific and medical policy
issues not resolved by informal meetings, FDA may refer the matter to one
of its standing advisory committees for its consideration and
recommendations.

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Subpart D—Responsibilities of Sponsors and Investigators
§312.50 General responsibilities of sponsors.
Sponsors are responsible for selecting qualified investigators, providing
them with the information they need to conduct an investigation properly,
ensuring proper monitoring of the investigation(s), ensuring that the
investigation(s) is conducted in accordance with the general investigational
plan and protocols contained in the IND, maintaining an effective IND with
respect to the investigations, and ensuring that FDA and all participating
investigators are promptly informed of significant new adverse effects or
risks with respect to the drug. Additional specific responsibilities of
sponsors are described elsewhere in this part.
§312.52 Transfer of obligations to a contract research organization.
(a) A sponsor may transfer responsibility for any or all of the obligations
set forth in this part to a contract research organization.Any such transfer
shall be described in writing. If not all obligations are transferred, the writing
is required to describe each of the obligations being assumed by the
contract research organization. If all obligations are transferred, a general
statement that all obligations have been transferred is acceptable. Any
obligation not covered by the written description shall be deemed not to
have been transferred.
(b) A contract research organization that assumes any obligation of a
sponsor shall comply with the specific regulations in this chapter applicable
to this obligation and shall be subject to the same regulatory action as a
sponsor for failure to comply with any obligation assumed under these
regulations. Thus, all references to “sponsor” in this part apply to a contract
research organization to the extent that it assumes one or more obligations
of the sponsor.
§312.53 Selecting investigators and monitors.
(a) Selecting investigators. A sponsor shall select only investigators
qualified by training and experience as appropriate experts to investigate
the drug.
(b) Control of drug. A sponsor shall ship investigational new drugs only
to investigators participating in the investigation.
(c) Obtaining information from the investigator. Before permitting an
investigator to begin participation in an investigation, the sponsor shall
obtain the following:
(1) A signed investigator statement (Form FDA-1572) containing:
(i) The name and address of the investigator;
(ii) The name and code number, if any, of the protocol(s) in the IND
identifying the study(ies) to be conducted by the investigator;
(iii) The name and address of any medical school, hospital, or other
research facility where the clinical investigation(s) will be conducted;
(iv) The name and address of any clinical laboratory facilities to be
used in the study;
(v) The name and address of the IRB that is responsible for review
and approval of the study(ies);
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(vi) A commitment by the investigator that he or she:
(a) Will conduct the study(ies) in accordance with the relevant,
current protocol(s) and will only make changes in a protocol after notifying
the sponsor, except when necessary to protect the safety, the rights, or
welfare of subjects;
(b) Will comply with all requirements regarding the obligations of
clinical investigators and all other pertinent requirements in this part;
(c) Will personally conduct or supervise the described
investigation(s);
(d) Will inform any potential subjects that the drugs are being used
for investigational purposes and will ensure that the requirements relating to
obtaining informed consent (21 CFR part 50) and institutional review board
review and approval (21 CFR part 56) are met;
(e) Will report to the sponsor adverse experiences that occur in the
course of the investigation(s) in accordance with §312.64;
(f) Has read and understands the information in the investigator’s
brochure, including the potential risks and side effects of the drug; and
(g) Will ensure that all associates, colleagues, and employees
assisting in the conduct of the study(ies) are informed about their
obligations in meeting the above commitments.
(vii) A commitment by the investigator that, for an investigation
subject to an institutional review requirement under part 56, an IRB that
complies with the requirements of that part will be responsible for the initial
and continuing review and approval of the clinical investigation and that the
investigator will promptly report to the IRB all changes in the research
activity and all unanticipated problems involving risks to human subjects or
others, and will not make any changes in the research without IRB
approval, except where necessary to eliminate apparent immediate hazards
to the human subjects.
(viii) A list of the names of the subinvestigators (e.g., research
fellows, residents) who will be assisting the investigator in the conduct of
the investigation(s).
(2) Curriculum vitae. A curriculum vitae or other statement of
qualifications of the investigator showing the education, training, and
experience that qualifies the investigator as an expert in the clinical
investigation of the drug for the use under investigation.
(3) Clinical protocol.
(i) For Phase 1 investigations, a general outline of the planned
investigation including the estimated duration of the study and the
maximum number of subjects that will be involved.
(ii) For Phase 2 or 3 investigations, an outline of the study protocol
including an approximation of the number of subjects to be treated with the
drug and the number to be employed as controls, if any; the clinical uses to
be investigated; characteristics of subjects by age, sex, and condition; the
kind of clinical obser vations and laboratory tests to be conducted; the
estimated duration of the study; and copies or a description of case report
forms to be used.
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(4) Financial disclosure information. Sufficient accurate financial
information to allow the sponsor to submit complete and accurate
certification or disclosure statements required under part 54 of this chapter.
The sponsor shall obtain a commitment from the clinical investigator to
promptly update this information if any relevant changes occur during the
course of the investigation and for 1 year following the completion of the
study.
(d) Selecting monitors. A sponsor shall select a monitor qualified by
training and experience to monitor the progress of the investigation.
§312.54 Emergency research under §50.24 of this chapter.
(a) The sponsor shall monitor the progress of all investigations involving
an exception from informed consent under §50.24 of this chapter. When
the sponsor receives from the IRB information concerning the public
disclosures required by §50.24(a)(7)(ii) and (a)(7)(iii) of this chapter,
the sponsor promptly shall submit to the IND file and to Docket Number
95S-0158 in the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857, copies
of the information that was disclosed, identified by the IND number.
(b) The sponsor also shall monitor such investigations to identify when an
IRB determines that it cannot approve the research because it does not
meet the criteria in the exception in §50.24(a) of this chapter or because of
other relevant ethical concerns. The sponsor promptly shall provide this
information in writing to FDA, investigators who are asked to participate in
this or a substantially equivalent clinical investigation, and other IRB’s that
are asked to review this or a substantially equivalent investigation.
§312.55 Informing investigators.
(a) Before the investigation begins, a sponsor (other than a sponsorinvestigator) shall give each participating clinical investigator an investigator
brochure containing the information described in §312.23(a)(5).
(b) The sponsor shall, as the overall investigation proceeds, keep each
participating investigator informed of new obser vations discovered by or
reported to the sponsor on the drug, particularly with respect to adverse
effects and safe use. Such information may be distributed to investigators
by means of periodically revised investigator brochures, reprints or
published studies, reports or letters to clinical investigators, or other
appropriate means. Important safety information is required to be relayed to
investigators in accordance with §312.32.
§312.56 Review of ongoing investigations.
(a) The sponsor shall monitor the progress of all clinical investigations
being conducted under its IND.
(b) A sponsor who discovers that an investigator is not complying with the
signed agreement (Form FDA-1572), the general investigational plan, or the
requirements of this part or other applicable parts shall promptly either
secure compliance or discontinue shipments of the investigational new drug
to the investigator and end the investigator’s participation in the
investigation. If the investigator’s participation in the investigation is ended,
the sponsor shall require that the investigator dispose of or return the
investigational drug in accordance with the requirements of §312.59 and
shall notify FDA.
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(c) The sponsor shall review and evaluate the evidence relating to the
safety and effectiveness of the drug as it is obtained from the investigator.
The sponsors shall make such reports to FDA regarding information
relevant to the safety of the drug as are required under §312.32.The
sponsor shall make annual reports on the progress of the investigation in
accordance with §312.33.
(d) A sponsor who determines that its investigational drug presents an
unreasonable and significant risk to subjects shall discontinue those
investigations that present the risk, notify FDA, all institutional review
boards, and all investigators who have at any time participated in the
investigation of the discontinuance, assure the disposition of all stocks of
the drug outstanding as required by §312.59, and furnish FDA with a full
report of the sponsor’s actions. The sponsor shall discontinue the
investigation as soon as possible, and in no event later than 5 working days
after making the determination that the investigation should be
discontinued. Upon request, FDA will confer with a sponsor on the need to
discontinue an investigation.
§312.57 Recordkeeping and record retention.
(a) A sponsor shall maintain adequate records showing the receipt,
shipment, or other disposition of the investigational drug.These records are
required to include, as appropriate, the name of the investigator to whom
the drug is shipped, and the date, quantity, and batch or code mark of each
such shipment.
(b) A sponsor shall maintain complete and accurate records showing any
financial interest in §54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this
chapter paid to clinical investigators by the sponsor of the covered study. A
sponsor shall also maintain complete and accurate records concerning all
other financial interests of investigators subject to part 54 of this chapter.
(c) A sponsor shall retain the records and reports required by this part for
2 years after a mar keting application is approved for the drug; or, if an
application is not approved for the drug, until 2 years after shipment and
delivery of the drug for investigational use is discontinued and FDA has
been so notified.
(d) A sponsor shall retain reserve samples of any test article and
reference standard identified in, and used in any of the bioequivalence or
bioavailability studies described in, §320.38 or §320.63 of this chapter, and
release the reserve samples to FDA upon request, in accordance with, and
for the period specified in §320.38.
§312.58 Inspection of sponsor’s records and reports.
(a) FDA inspection. A sponsor shall upon request from any properly
authorized officer or employee of the Food and Drug Administration, at
reasonable times, permit such officer or employee to have access to and
copy and verify any records and reports relating to a clinical investigation
conducted under this part.Upon written request by FDA, the sponsor shall
submit the records or reports (or copies of them) to FDA.The sponsor shall
discontinue shipments of the drug to any investigator who has failed to
maintain or make available records or reports of the investigation as
required by this part.

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(b) Controlled substances. If an investigational new drug is a substance
listed in any schedule of the Controlled Substances Act (21 U.S.C. 801;
21 CFR part 1308), records concerning shipment, delivery, receipt, and
disposition of the drug, which are required to be kept under this part or
other applicable parts of this chapter shall, upon the request of a properly
authorized employee of the Drug Enforcement Administration of the U.S.
Department of Justice, be made available by the investigator or sponsor to
whom the request is made, for inspection and copying.In addition, the
sponsor shall assure that adequate precautions are taken, including
storage of the investigational drug in a securely locked, substantially
constructed cabinet, or other securely locked, substantially constructed
enclosure, access to which is limited, to prevent theft or diversion of the
substance into illegal channels of distribution.
§312.59 Disposition of unused supply of investigational drug.
The sponsor shall assure the return of all unused supplies of the
investigational drug from each individual investigator whose participation in
the investigation is discontinued or terminated.The sponsor may authorize
alternative disposition of unused supplies of the investigational drug
provided this alternative disposition does not expose humans to risks from
the drug.The sponsor shall maintain written records of any disposition of
the drug in accordance with §312.57.
§312.60 General responsibilities of investigators.
An investigator is responsible for ensuring that an investigation is conducted
according to the signed investigator statement, the investigational plan, and
applicable regulations; for protecting the rights, safety, and welfare of
subjects under the investigator’s care; and for the control of drugs under
investigation. An investigator shall, in accordance with the provisions of part
50 of this chapter, obtain the informed consent of each human subject to
whom the drug is administered, except as provided in §§50.23 or 50.24 of
this chapter. Additional specific responsibilities of clinical investigators are
set forth in this part and in parts 50 and 56 of this chapter.
§312.61 Control of the investigational drug.
An investigator shall administer the drug only to subjects under the
investigator’s personal supervision or under the supervision of a
subinvestigator responsible to the investigator. The investigator shall not
supply the investigational drug to any person not authorized under this part
to receive it.
§312.62 Investigator recordkeeping and record retention.
(a) Disposition of drug. An investigator is required to maintain adequate
records of the disposition of the drug, including dates, quantity, and use by
subjects. If the investigation is terminated, suspended, discontinued, or
completed, the investigator shall return the unused supplies of the drug to
the sponsor, or otherwise provide for disposition of the unused supplies of
the drug under §312.59.
(b) Case histories. An investigator is required to prepare and maintain
adequate and accurate case histories that record all observations and other
data pertinent to the investigation on each individual administered the
investigational drug or employed as a control in the investigation.Case
histories include the case report forms and supporting data including, for
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example, signed and dated consent forms and medical records including,
for example, progress notes of the physician, the individual’s hospital
chart(s), and the nurses’ notes. The case history for each individual shall
document that informed consent was obtained prior to participation in the
study.
(c) Record retention. An investigator shall retain records required to be
maintained under this part for a period of 2 years following the date a
marketing application is approved for the drug for the indication for which it
is being investigated; or, if no application is to be filed or if the application is
not approved for such indication, until 2 years after the investigation is
discontinued and FDA is notified.
§312.64 Investigator reports.
(a) Progress reports. The investigator shall furnish all reports to the
sponsor of the drug who is responsible for collecting and evaluating the
results obtained.The sponsor is required under §312.33 to submit annual
reports to FDA on the progress of the clinical investigations.
(b) Safety reports. An investigator shall promptly report to the sponsor
any adverse effect that may reasonably be regarded as caused by, or
probably caused by, the drug. If the adverse effect is alarming, the
investigator shall report the adverse effect immediately.
(c) Final report. An investigator shall provide the sponsor with an
adequate report shortly after completion of the investigator’s participation in
the investigation.
(d) Financial disclosure reports. The clinical investigator shall provide
the sponsor with sufficient accurate financial information to allow an
applicant to submit complete and accurate certification or disclosure
statements as required under part 54 of this chapter. The clinical
investigator shall promptly update this information if any relevant changes
occur during the course of the investigation and for 1 year following the
completion of the study.
§312.66 Assurance of IRB review.
An investigator shall assure that an IRB that complies with the requirements
set forth in part 56 will be responsible for the initial and continuing review
and approval of the proposed clinical study. The investigator shall also
assure that he or she will promptly report to the IRB all changes in the
research activity and all unanticipated problems involving risk to human
subjects or others, and that he or she will not make any changes in the
research without IRB approval, except where necessary to eliminate
apparent immediate hazards to human subjects.
§312.68 Inspection of investigator’s records and reports.
An investigator shall upon request from any properly authorized officer or
employee of FDA, at reasonable times, permit such officer or employee to
have access to, and copy and verify any records or reports made by the
investigator pursuant to §312.62.The investigator is not required to divulge
subject names unless the records of particular individuals require a more
detailed study of the cases, or unless there is reason to believe that the
records do not represent actual case studies, or do not represent actual
results obtained.
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§312.69 Handling of controlled substances.
If the investigational drug is subject to the Controlled Substances Act, the
investigator shall take adequate precautions, including storage of the
investigational drug in a securely locked, substantially constructed cabinet,
or other securely locked, substantially constructed enclosure, access to
which is limited, to prevent theft or diversion of the substance into illegal
channels of distribution.
§312.70 Disqualification of a clinical investigator.
(a) If FDA has information indicating that an investigator (including a
sponsor-investigator) has repeatedly or deliberately failed to comply with
the requirements of this part, part 50, or part 56 of this chapter, or has
submitted to FDA or to the sponsor false information in any required report,
the Center for Drug Evaluation and Research or the Center for Biologics
Evaluation and Research will furnish the investigator written notice of the
matter complained of and offer the investigator an opportunity to explain the
matter in writing, or, at the option of the investigator, in an informal
conference. If an explanation is offered but not accepted by the Center for
Drug Evaluation and Research or the Center for Biologics Evaluation and
Research, the investigator will be given an opportunity for a regulatory
hearing under part 16 on the question of whether the investigator is entitled
to receive investigational new drugs.
(b) After evaluating all available information, including any explanation
presented by the investigator, if the Commissioner determines that the
investigator has repeatedly or deliberately failed to comply with the
requirements of this part, part 50, or part 56 of this chapter, or has
deliberately or repeatedly submitted false information to FDA or to the
sponsor in any required report, the Commissioner will notify the investigator
and the sponsor of any investigation in which the investigator has been
named as a participant that the investigator is not entitled to receive
investigational drugs. The notification will provide a statement of basis for
such determination.
(c) Each IND and each approved application submitted under part 314
containing data reported by an investigator who has been determined to be
ineligible to receive investigational drugs will be examined to determine
whether the investigator has submitted unreliable data that are essential to
the continuation of the investigation or essential to the approval of any
marketing application.
(d) If the Commissioner determines, after the unreliable data submitted
by the investigator are eliminated from consideration, that the data
remaining are inadequate to support a conclusion that it is reasonably safe
to continue the investigation, the Commissioner will notify the sponsor who
shall have an opportunity for a regulatory hearing under part 16. If a danger
to the public health exists, however, the Commissioner shall terminate the
IND immediately and notify the sponsor of the determination. In such case,
the sponsor shall have an opportunity for a regulatory hearing before FDA
under part 16 on the question of whether the IND should be reinstated.

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(e) If the Commissioner determines, after the unreliable data submitted
by the investigator are eliminated from consideration, that the continued
approval of the drug product for which the data were submitted cannot be
justified, the Commissioner will proceed to withdraw approval of the drug
product in accordance with the applicable provisions of the act.
(f) An investigator who has been determined to be ineligible to receive
investigational drugs may be reinstated as eligible when the Commissioner
determines that the investigator has presented adequate assurances that
the investigator will employ investigational drugs solely in compliance with
the provisions of this part and of parts 50 and 56.

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Subpart E—Drugs Intended to Treat
Life-threatening and Severely-debilitating Illnesses
Authority: 21 U.S.C. 351, 352, 353, 355, 371; 42 U.S.C. 262.
§312.80 Purpose.
The purpose of this section is to establish procedures designed to expedite
the development, evaluation, and marketing of new therapies intended to
treat persons with life-threatening and severely-debilitating illnesses,
especially where no satisfactory alternative therapy exists. As stated in
§314.105(c) of this chapter, while the statutory standards of safety and
effectiveness apply to all drugs, the many kinds of drugs that are subject to
them, and the wide range of uses for those drugs, demand flexibility in
applying the standards. The Food and Drug Administration (FDA) has
determined that it is appropriate to exercise the broadest flexibility in
applying the statutory standards, while preserving appropriate guarantees
for safety and effectiveness. These procedures reflect the recognition that
physicians and patients are generally willing to accept greater risks or side
effects from products that treat life-threatening and severely-debilitating
illnesses, than they would accept from products that treat less serious
illnesses. These procedures also reflect the recognition that the benefits of
the drug need to be evaluated in light of the severity of the disease being
treated.The procedure outlined in this section should be interpreted
consistent with that purpose.
§312.81 Scope.
This section applies to new drug and biological products that are being
studied for their safety and effectiveness in treating life-threatening or
severely-debilitating diseases.
(a) For purposes of this section, the term “life-threatening” means:
(1) Diseases or conditions where the likelihood of death is high unless
the course of the disease is interrupted; and
(2) Diseases or conditions with potentially fatal outcomes, where the
end point of clinical trial analysis is survival.
(b) For purposes of this section, the term “severely debilitating” means
diseases or conditions that cause major irreversible morbidity.
(c) Sponsors are encouraged to consult with FDA on the applicability of
these procedures to specific products.
§312.82 Early consultation.
For products intended to treat life-threatening or severely-debilitating
illnesses, sponsors may request to meet with FDA-reviewing officials early
in the drug development process to review and reach agreement on the
design of necessary preclinical and clinical studies. Where appropriate,
FDA will invite to such meetings one or more outside expert scientific
consultants or advisory committee members. To the extent FDA resources
permit, agency reviewing officials will honor requests for such meetings.
(a) Pre-investigational new drug (IND) meetings. Prior to the
submission of the initial IND, the sponsor may request a meeting with FDAreviewing officials. The primary purpose of this meeting is to review and
reach agreement on the design of animal studies needed to initiate human
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testing.The meeting may also provide an opportunity for discussing the
scope and design of phase 1 testing, plans for studying the drug product in
pediatric populations, and the best approach for presentation and
formatting of data in the IND.
(b) End-of-phase 1 meetings. When data from phase 1 clinical testing
are available, the sponsor may again request a meeting with FDA-reviewing
officials. The primary purpose of this meeting is to review and reach
agreement on the design of phase 2 controlled clinical trials, with the goal
that such testing will be adequate to provide sufficient data on the drug’s
safety and effectiveness to support a decision on its approvability for
marketing, and to discuss the need for, as well as the design and timing of,
studies of the drug in pediatric patients. For drugs for life-threatening
diseases, FDA will provide its best judgment, at that time, whether pediatric
studies will be required and whether their submission will be deferred until
after approval.The procedures outlined in §312.47(b)(1) with respect to
end-of-phase 2 conferences, including documentation of agreements
reached, would also be used for end-of-phase 1 meetings.
§312.83 Treatment protocols.
If the preliminary analysis of phase 2 test results appears promising, FDA
may ask the sponsor to submit a treatment protocol to be reviewed under
the procedures and criteria listed in §§312.34 and 312.35. Such a treatment
protocol, if requested and granted, would normally remain in effect while the
complete data necessary for a marketing application are being assembled
by the sponsor and reviewed by FDA (unless grounds exist for clinical hold
of ongoing protocols, as provided in §312.42(b)(3)(ii)).
§312.84 Risk-benefit analysis in review of marketing applications for
drugs to treat life-threatening and severely-debilitating illnesses.
(a) FDA’s application of the statutory standards for marketing approval
shall recognize the need for a medical risk-benefit judgment in making the
final decision on approvability. As part of this evaluation, consistent with the
statement of purpose in §312.80, FDA will consider whether the benefits of
the drug outweigh the known and potential risks of the drug and the need
to answer remaining questions about risks and benefits of the drug, taking
into consideration the severity of the disease and the absence of
satisfactory alternative therapy.
(b) In making decisions on whether to grant marketing approval for
products that have been the subject of an end-of-phase 1 meeting under
§312.82, FDA will usually seek the advice of outside expert scientific
consultants or advisory committees. Upon the filing of such a marketing
application under §314.101 or part 601 of this chapter, FDA will notify the
members of the relevant standing advisory committee of the application’s
filing and its availability for review.
(c) If FDA concludes that the data presented are not sufficient for
marketing approval, FDA will issue (for a drug) a not approvable letter
pursuant to §314.120 of this chapter, or (for a biologic) a deficiencies letter
consistent with the biological product licensing procedures. Such letter, in
describing the deficiencies in the application, will address why the results of
the research design agreed to under §312.82, or in subsequent meetings,
have not provided sufficient evidence for marketing approval. Such letter will
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also describe any recommendations made by the advisory committee
regarding the application.
(d) Marketing applications submitted under the procedures contained in
this section will be subject to the requirements and procedures contained in
part 314 or part 600 of this chapter, as well as those in this subpart.
§312.85 Phase 4 studies.
Concurrent with marketing approval, FDA may seek agreement from the
sponsor to conduct certain postmarketing (phase 4) studies to delineate
additional information about the drug’s risks, benefits, and optimal use.
These studies could include, but would not be limited to, studying different
doses or schedules of administration than were used in phase 2 studies,
use of the drug in other patient populations or other stages of the disease,
or use of the drug over a longer period of time.
§312.86 Focused FDA regulatory research.
At the discretion of the agency, FDA may undertake focused regulatory
research on critical rate-limiting aspects of the preclinical, chemical/
manufacturing, and clinical phases of drug development and evaluation.
When initiated, FDA will undertake such research efforts as a means for
meeting a public health need in facilitating the development of therapies to
treat life-threatening or severely debilitating illnesses.
§312.87 Active monitoring of conduct and evaluation of clinical trials.
For drugs covered under this section, the Commissioner and other agency
officials will monitor the progress of the conduct and evaluation of clinical
trials and be involved in facilitating their appropriate progress.
§312.88 Safeguards for patient safety.
All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of
this chapter designed to ensure the safety of clinical testing and the safety
of products following marketing approval apply to drugs covered by this
section.This includes the requirements for informed consent (part 50 of this
chapter) and institutional review boards (part 56 of this chapter).These
safeguards further include the review of animal studies prior to initial human
testing (§312.23), and the monitoring of adverse drug experiences through
the requirements of IND safety reports (§312.32), safety update reports
during agency review of a marketing application (§314.50 of this chapter),
and postmarketing adverse reaction reporting (§314.80 of this chapter).

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Subpart F—Miscellaneous
§312.110 Import and export requirements.
(a) Imports. An investigational new drug offered for import into the United
States complies with the requirements of this part if it is subject to an IND
that is in effect for it under §312.40 and: (1) The consignee in the United
States is the sponsor of the IND; (2) the consignee is a qualified
investigator named in the IND; or (3) the consignee is the domestic agent of
a foreign sponsor, is responsible for the control and distribution of the
investigational drug, and the IND identifies the consignee and describes
what, if any, actions the consignee will take with respect to the
investigational drug.
(b) Exports. An investigational new drug intended for export from the
United States complies with the requirements of this part as follows:
(1) If an IND is in effect for the drug under §312.40 and each person
who receives the drug is an investigator named in the application; or
(2) If FDA authorizes shipment of the drug for use in a clinical
investigation. Authorization may be obtained as follows:
(i) Through submission to the International Affairs Staff (HFY-50),
Associate Commissioner for Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857 of a written request from the
person that seeks to export the drug. A request must provide adequate
information about the drug to satisfy FDA that the drug is appropriate for
the proposed investigational use in humans, that the drug will be used for
investigational purposes only, and that the drug may be legally used by that
consignee in the importing country for the proposed investigational use. The
request shall specify the quantity of the drug to be shipped per shipment
and the frequency of expected shipments. If FDA authorizes exportation
under this paragraph, the agency shall concurrently notify the government
of the importing country of such authorization.
(ii) Through submission to the International Affairs Staff (HFY-50),
Associate Commissioner for Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, of a formal request from an
authorized official of the government of the country to which the drug is
proposed to be shipped. A request must specify that the foreign
government has adequate information about the drug and the proposed
investigational use, that the drug will be used for investigational purposes
only, and that the foreign government is satisfied that the drug may legally
be used by the intended consignee in that country. Such a request shall
specify the quantity of drug to be shipped per shipment and the frequency
of expected shipments.
(iii) Authorization to export an investigational drug under paragraph
(b)(2)(i) or (ii) of this section may be revoked by FDA if the agency finds
that the conditions underlying its authorization are no longer met.
(3) This paragraph applies only where the drug is to be used for the
purpose of clinical investigation.
(4) This paragraph does not apply to the export of new drugs (including
biological products, antibiotic drugs, and insulin) approved or
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authorized for export under §802 of the act (21 U.S.C. 382) or §351(h)(1)(A)
of the Public Health Service Act (42 U.S.C. 262(h)(1)(A)).
§312.120 Foreign clinical studies not conducted under an IND.
(a) Introduction. This section describes the criteria for acceptance by
FDA of foreign clinical studies not conducted under an IND. In general, FDA
accepts such studies provided they are well designed, well conducted,
performed by qualified investigators, and conducted in accordance with
ethical principles acceptable to the world community. Studies meeting these
criteria may be utilized to support clinical investigations in the United States
and/or marketing approval. Marketing approval of a new drug based solely
on foreign clinical data is governed by §314.106.
(b) Data submissions. A sponsor who wishes to rely on a foreign clinical
study to support an IND or to support an application for marketing approval
shall submit to FDA the following information:
(1) A description of the investigator’s qualifications;
(2) A description of the research facilities;
(3) A detailed summary of the protocol and results of the study, and,
should FDA request, case records maintained by the investigator or
additional background data such as hospital or other institutional records;
(4) A description of the drug substance and drug product used in the
study, including a description of components, formulation, specifications,
and bioavailability of the specific drug product used in the clinical study, if
available; and
(5) If the study is intended to support the effectiveness of a drug
product, information showing that the study is adequate and well controlled
under §314.126.
(c) Conformance with ethical principles.
(1) Foreign clinical research is required to have been conducted in
accordance with the ethical principles stated in the “Declaration of Helsinki”
(see paragraph (c)(4) of this section) or the laws and regulations of the
country in which the research was conducted, whichever represents the
greater protection of the individual.
(2) For each foreign clinical study submitted under this section, the
sponsor shall explain how the research conformed to the ethical principles
contained in the “Declaration of Helsinki” or the foreign country’s standards,
whichever were used. If the foreign country’s standards were used, the
sponsor shall explain in detail how those standards differ from the
“Declaration of Helsinki” and how they offer greater protection.
(3) When the research has been approved by an independent review
committee, the sponsor shall submit to FDA documentation of such review
and approval, including the names and qualifications of the members of the
committee. In this regard, a “review committee” means a committee
composed of scientists and, where practicable, individuals who are
otherwise qualified (e.g., other health professionals or laymen).The
investigator may not vote on any aspect of the review of his or her protocol
by a review committee.

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(4) The “Declaration of Helsinki” states as follows:2

Recommendations Guiding Physicians in Biomedical
Research Involving Human Subjects
Introduction
It is the mission of the physician to safeguard the health of the people. His
or her knowledge and conscience are dedicated to the fulfillment of this
mission.
The Declaration of Geneva of the World Medical Association binds the
physician with the words, “The health of my patient will be my first
consideration,” and the International Code of Medical Ethics declares that,
“A physician shall act only in the patient’s interest when providing medical
care which might have the effect of weakening the physical and mental
condition of the patient.”
The purpose of biomedical research involving human subjects must be to
improve diagnostic, therapeutic and prophylactic procedures and the
understanding of the aetiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic
procedures involve hazards. This applies especially to biomedical research.
Medical progress is based on research which ultimately must rest in part
on experimentation involving human subjects.
In the field of biomedical research a fundamental distinction must be
recognized between medical research in which the aim is essentially
diagnostic or therapeutic for a patient, and medical research, the essential
object of which is purely scientific and without implying direct diagnostic or
therapeutic value to the person subjected to the research.
Special caution must be exercised in the conduct of research which may
affect the environment, and the welfare of animals used for research must
be respected.
Because it is essential that the results of laboratory experiments be
applied to human beings to further scientific knowledge and to help
suffering humanity, the World Medical Association has prepared the
following recommendations as a guide to every physician in biomedical
research involving human subjects. They should be kept under review in the
future. It must be stressed that the standards as drafted are only a guide to
physicians all over the world. Physicians are not relieved from criminal, civil
and ethical responsibilities under the laws of their own countries.
I. Basic Principles
1. Biomedical research involving human subjects must conform to
generally accepted scientific principles and should be based on adequately
performed laboratory and animal experimentation and on a thorough
knowledge of the scientific literature.
2.The design and performance of each experimental procedure
involving human subjects should be clearly formulated in an experimental

2World Medical Assembly Declaration, amended 1989.

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protocol which should be transmitted for consideration, comment and
guidance to a specially appointed committee independent of the
investigator and the sponsor provided that this independent committee is in
conformity with the laws and regulations of the country in which the
research experiment is performed.
3. Biomedical research involving human subjects should be conducted
only by scientifically qualified persons and under the supervision of a
clinically competent medical person.The responsibility for the human
subject must always rest with a medically qualified person and never rest
on the subject of the research, even though the subject has given his or her
consent.
4. Biomedical research involving human subjects cannot legitimately be
carried out unless the importance of the objective is in proportion to the
inherent risk to the subject.
5. Every biomedical research project involving human subjects should
be preceded by careful assessment of predictable risks in comparison with
foreseeable benefits to the subject or to others. Concern for the interests of
the subject must always prevail over the interests of science and society.
6.The right of the research subject to safeguard his or her integrity
must always be respected. Every precaution should be taken to respect the
privacy of the subject and to minimize the impact of the study on the
subject’s physical and mental integrity and on the personality of the subject.
7. Physicians should abstain from engaging in research projects
involving human subjects unless they are satisfied that the hazards
involved are believed to be predictable. Physicians should cease any
investigation if the hazards are found to outweigh the potential benefits.
8. In publication of the results of his or her research, the physician is
obliged to preserve the accuracy of the results. Reports of experimentation
not in accordance with the principles laid down in this Declaration should
not be accepted for publication.
9. In any research on human beings, each potential subject must be
adequately informed of the aims, methods, anticipated benefits and
potential hazards of the study and the discomfort it may entail. He or she
should be informed that he or she is at liberty to abstain from participation
in the study and that he or she is free to withdraw his or her consent to
participation at any time. The physician should then obtain the subject’s
freely-given informed consent, preferably in writing.
10.When obtaining informed consent for the research project the
physician should be particularly cautious if the subject is in a dependent
relationship to him or her or may consent under duress. In that case the
informed consent should be obtained by a physician who is not engaged in
the investigation and who is completely independent of this official
relationship.
11.In case of legal incompetence, informed consent should be
obtained from the legal guardian in accordance with national legislation.
Where physical or mental incapacity makes it impossible to obtain informed
consent, or when the subject is a minor, permission from the responsible
relative replaces that of the subject in accordance with national legislation.

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GOOD CLINICAL PRACTICE
Whenever the minor child is in fact able to give a consent, the minor’s
consent must be obtained in addition to the consent of the minor’s legal
guardian.
12.The research protocol should always contain a statement of the
ethical considerations involved and should indicate that the principles
enunciated in the present Declaration are complied with.
II. Medical Research Combined with Professional Care (Clinical
Research)
1. In the treatment of the sick person, the physician must be free to
use a new diagnostic and therapeutic measure, if in his or her judgment it
offers hope of saving life, reestablishing health or alleviating suffering.
2.The potential benefits, hazards and discomfort of a new method
should be weighed against the advantages of the best current diagnostic
and therapeutic methods.
3. In any medical study, every patient—including those of a control
group, if any—should be assured of the best proven diagnostic and
therapeutic method.
4.The refusal of the patient to participate in a study must never
interfere with the physician-patient relationship.
5. If the physician considers it essential not to obtain informed consent,
the specific reasons for this proposal should be stated in the experimental
protocol for transmission to the independent committee (I, 2).
6.The physician can combine medical research with professional care,
the objective being the acquisition of new medical knowledge, only to the
extent that medical research is justified by its potential diagnostic or
therapeutic value for the patient.
III. Non-Therapeutic Biomedical Research Involving Human Subjects
(Non-Clinical Biomedical Research)
1. In the purely scientific application of medical research carried out on
a human being, it is the duty of the physician to remain the protector of the
life and health of that person on whom biomedical research is being carried
out.
2.The subjects should be volunteers—either healthy persons or
patients for whom the experimental design is not related to the patient’s
illness.
3.The investigator or the investigating team should discontinue the
research if in his/her or their judgment it may, if continued, be harmful to
the individual.
4. In research on man, the interest of science and society should never
take precedence over considerations related to the well-being of the
subject.

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INVESTIGATIONAL NEW DRUG APPLICATION
§312.130 Availability for public disclosure of data and information in
an IND.
(a) The existence of an investigational new drug application will not be
disclosed by FDA unless it has previously been publicly disclosed or
acknowledged.
(b) The availability for public disclosure of all data and information in an
investigational new drug application for a new drug will be handled in
accordance with the provisions established in §314.430 for the
confidentiality of data and information in applications submitted in part 314.
The availability for public disclosure of all data and information in an
investigational new drug application for a biological product will be
governed by the provisions of §§601.50 and 601.51.
(c) Notwithstanding the provisions of §314.430, FDA shall disclose upon
request to an individual to whom an investigational new drug has been
given a copy of any IND safety report relating to the use in the individual.
(d) The availability of information required to be publicly disclosed for
investigations involving an exception from informed consent under
§50.24 of this chapter will be handled as follows: Persons wishing to
request the publicly disclosable information in the IND that was required to
be filed in Docket Number 95S-0158 in the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm.
1-23, Rockville, MD 20857, shall submit a request under the Freedom of
Information Act.
§312.140 Address for correspondence .
(a) Except as provided in paragraph (b) of this section, a sponsor shall
send an initial IND submission to the Central Document Room, Center for
Drug Evaluation and Research, Food and Drug Administration, Park Bldg.,
Rm. 214, 12420 Parklawn Dr., Rockville, MD 20852. On receiving the IND,
FDA will inform the sponsor which one of the divisions in the Center for
Drug Evaluation and Research or the Center for Biologics Evaluation and
Research is responsible for the IND. Amendments, reports, and other
correspondence relating to matters covered by the IND should be directed
to the appropriate division.The outside wrapper of each submission shall
state what is contained in the submission, for example, “IND Application”,
“Protocol Amendment”, etc.
(b) Applications for the products listed below should be submitted to the
Division of Biological Investigational New Drugs (HFB-230), Center for
Biologics Evaluation and Research, Food and Drug Administration,
8800 Rockville Pike, Bethesda, MD 20892. 3 (1) Products subject to the
licensing provisions of the Public Health Service Act of July 1, 1944
(58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or subject to part 600;
(2) ingredients packaged together with containers intended for the
collection, processing, or storage of blood or blood components;

3This address has changed to:

Center for Biologics Evaluation and Research
HFM-99, Room 200N
1401 Rockville Pike
Rockville, MD 20852-1448
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GOOD CLINICAL PRACTICE
(3) urokinase products; (4) plasma volume expanders and hydroxyethyl
starch for leukapheresis;and (5) coupled antibodies, i.e., products that
consist of an antibody component coupled with a drug or radionuclide
component in which both components provide a pharmacological effect but
the biological component determines the site of action.
(c) All correspondence relating to biological products for human use
which are also radioactive drugs shall be submitted to the Division of
Oncology and Radiopharmaceutical Drug Products (HFD-150), Center
for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, except that applications for
coupled antibodies shall be submitted in accordance with paragraph (b) of
this section.
(d) All correspondence relating to export of an investigational drug under
§312.110(b)(2) shall be submitted to the International Affairs Staff
(HFY-50), Office of Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857.
§312.145 Guidelines.
(a) FDA has made available guidelines under §10.90(b) to help persons
to comply with certain requirements of this part.
(b) The Center for Drug Evaluation and Research and the Center for
Biologics Evaluation and Research maintain lists of guidelines that apply to
the Centers’ regulations. The lists state how a person can obtain a copy of
each guideline. A request for a copy of the lists should be directed to the
CDER Executive Secretariat Staff (HFD-8), Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, for drug products, and the Congressional, Consumer, and
International Affairs Staff (HFB-142), Center for Biologics Evaluation and
Research, Food and Drug Administration, 8800 Rockville Pike, Bethesda,
MD 20892, for biological products.4

4This address has changed to:

Center for Biologics Evaluation and Research
1409 Rockville Pike
Rockville, MD 20852-1448
V–50

INVESTIGATIONAL NEW DRUG APPLICATION

Subpart G—Drugs for Investigational Use
in Laboratory Research Animals or In Vitro Tests
§312.160 Drugs for investigational use in laboratory research animals
or in vitro tests.
(a) Authorization to ship.
(1)(i) A person may ship a drug intended solely for tests in vitro or in
animals used only for laboratory research purposes if it is labeled as
follows:
CAUTION: Contains a new drug for investigational use only
in laboratory research animals, or for tests in vitro. Not for
use in humans.
(ii) A person may ship a biological product for investigational in vitro
diagnostic use that is listed in §312.2(b)(2)(ii) if it is labeled as follows:
CAUTION: Contains a biological product for investigational in
vitro diagnostic tests only.
(2) A person shipping a drug under paragraph (a) of this section shall
use due diligence to assure that the consignee is regularly engaged in
conducting such tests and that the shipment of the new drug will actually
be used for tests in vitro or in animals used only for laboratory research.
(3) A person who ships a drug under paragraph (a) of this section shall
maintain adequate records showing the name and post office address of
the expert to whom the drug is shipped and the date, quantity, and batch or
code mark of each shipment and delivery. Records of shipments under
paragraph (a)(1)(i) of this section are to be maintained for a period of
2 years after the shipment. Records and reports of data and shipments
under paragraph (a)(1)(ii) of this section are to be maintained in
accordance with §312.57(b).The person who ships the drug shall upon
request from any properly authorized officer or employee of the Food and
Drug Administration, at reasonable times, permit such officer or employee
to have access to and copy and verify records required to be maintained
under this section.
(b) Termination of authorization to ship. FDA may terminate
authorization to ship a drug under this section if it finds that:
(1) The sponsor of the investigation has failed to comply with any of
the conditions for shipment established under this section; or
(2) The continuance of the investigation is unsafe or otherwise contrary
to the public interest or the drug is used for purposes other than bona fide
scientific investigation. FDA will notify the person shipping the drug of its
finding and invite immediate correction. If correction is not immediately
made, the person shall have an opportunity for a regulatory hearing before
FDA pursuant to part 16.
(c) Disposition of unused drug. The person who ships the drug under
paragraph (a) of this section shall assure the return of all unused supplies
of the drug from individual investigators whenever the investigation
discontinues or the investigation is terminated.The person who ships the
drug may authorize in writing alternative disposition of unused supplies of

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GOOD CLINICAL PRACTICE
the drug provided this alternative disposition does not expose humans to
risks from the drug, either directly or indirectly (e.g., through food-producing
animals).The shipper shall maintain records of any alternative disposition.

V–52

INVESTIGATIONAL NEW DRUG APPLICATION

Information for Sponsor-Investigators Submitting
Investigational New Drug Applications (INDs)
Center for Drug Evaluation and Research
An Investigational New Drug Application (IND) is a request for Food and
Drug Administration (FDA) authorization to administer an investigational
drug to humans. Such authorization must be secured prior to interstate
shipment and administration of any new drug that is not the subject of an
approved new drug application.
IND regulations are contained in Title 21, Code of Federal Regulations,
Part 312. Copies of the regulations, further guidance regarding IND
procedures, and additional forms are available from the FDA Center for
Drug Evaluation and Research, Drug Information Branch (HFD-210),
5600 Fishers Lane, Rockville, Maryland 20857, telephone (301) 827-4573
or toll free at 1-888-INFOFDA.In addition, forms, regulations, guidances,
and a wide variety of additional information is available online at
http://www.fda.gov/cder/. Forms may be accessed directly at either
http://www.fda.gov/opacom/morechoices/fdaforms/cder.html or
http://forms.psc.dhhs.gov/fdaforms.htm.
The following instructions address only the administrative aspects of
preparing and submitting an IND, and are intended primarily to provide
assistance to individual Sponsor-Investigator applicants, not pharmaceutical
companies.
WHERE TO SEND THE APPLICATION:
The initial IND submission and each subsequent submission to the
IND should be accompanied by a Form FDA 1571 and must be
submitted in triplicate (the original and two photocopies are
acceptable). Mailing addresses for initial IND submissions are:
For a Drug:
Food and Drug Administration
Center for Drug Evaluation
and Research
Central Document Room
12229 Wilkins Ave.
Rockville, MD 20852-1833

For a Biologic:
Food and Drug Administration
Center for Biologics Evaluation
and Research, HFM-99, Rm 200N
1401 Rockville Pike
Rockville, MD 20852-1448

FILLING OUT THE FORM FDA 1571: (The numbers below correspond to
the numbered boxes on the Form FDA 1571.)
1.The sponsor is the person who takes responsibility for and initiates a
clinical investigation.The sponsor may be a pharmaceutical company, a
private or academic organization, or an individual. A Sponsor-Investigator
is an individual who both initiates and conducts a clinical
investigation and under whose immediate direction the investigational
drug is being administered or dispensed. For administrative reasons,
only one individual should be designated as sponsor.
If a pharmaceutical company will be supplying the drug, but will not itself be
submitting the IND, the company is not the sponsor.

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GOOD CLINICAL PRACTICE
2. The date of submission is the date that the application is mailed to FDA.
3.The address is the address to which written correspondence from
FDA should be directed.If this address is a post office box number, a street
address must also be provided.
4.The telephone number is the number where the sponsor is usually
available during normal working hours. A telephone number must be
provided.
5. For name(s) of drug, list the generic name(s) and trade name, if
available. Also, state the dosage form(s).
6. If an emergency IND number was previously assigned by FDA, or
the Form FDA 1571 is being included with an amendment to the original
IND, then that IND number should be entered here; otherwise, the space
should be left blank.
7. Self-explanatory.
8.This section is to be completed by pharmaceutical firms that are
conducting clinical studies in support of a marketing application. SponsorInvestigators need not complete this section.
9. It is necessary for the sponsor to submit certain information with an
IND (such as manufacturing and controls information, pharmacology and
toxicology data, or data from prior human studies) unless that information
has previously been submitted to FDA, AND the sponsor of the previously
submitted information provides a letter authorizing FDA to refer to the
information. In this case, the letter of authorization including the file
identification (IND/DMF/NDA number) must be: 1) submitted to the
authorizer’s application and, 2) included in the initial submission of the new
sponsor’s IND. The sole exception to this requirement is when a marketed
drug is used in the study, without modification to its approved packaging, in
which case the marketed drug product must be identified by trade name,
established name, dosage form, strength, and lot number.
10. Numbering of submissions is primarily intended for pharmaceutical
firms. Sponsor-Investigators do not have to complete this section.
11. For an original IND submission, only the “Initial Investigational New
Drug Application (IND)” box should be checked. For subsequent
submissions, check ALL the boxes that apply since the submission may
contain more than one type of information.
Requests to charge and Treatment Protocols must be submitted separately.
Treatment INDs and Treatment Protocols are special cases and are not
intended for single patient use. Before checking either of these boxes, the
sponsor should be thoroughly familiar with the cited regulations and contact
the appropriate FDA reviewing division to discuss the proposed treatment
use.
12. For a Sponsor-Investigator IND, items 2, 3, and 4 may be briefly
addressed in the cover letter or in a summary.
Where the investigational drug is obtained from a supplier in a final dosage
form, items 5, 7, 8, and 9 may be referenced if authorization is given by the
supplier (see explanation in section 9 above). If the investigational drug is
prepared or altered in any way after shipment by the supplier, complete

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INVESTIGATIONAL NEW DRUG APPLICATION
manufacturing (or compounding) and controls information, including
information on sterility and pyrogenicity testing for parenteral drugs, must
be submitted for that process in Item 7.
Item 6 requires that the protocol be submitted, along with information on
the investigators, facilities, and Institutional Review Board (copies of the
completed Form FDA 1572 with attachments would suffice for 6 b-d).
Item 7 also requires submission of either a claim of categorical exclusion
from the requirement to submit an environmental assessment or an
environmental assessment (21 CFR 25.15[a]).When claiming a categorical
exclusion, the sponsor should include the following statements:“I claim
categorical exclusion (under 21 CFR 25.31[e]) for the study(ies) under this
IND. To my knowledge, no extraordinary circumstances exist.”
13.This section does not pertain to a Sponsor-Investigator.
14-15. For a pharmaceutical firm, the name of the person responsible
for monitoring the conduct of the clinical investigation, and reviewing and
evaluating safety information, should be entered. For Sponsor-Investigator
INDs, the investigator has this responsibility.
N.B. Certain important commitments that the IND sponsor makes by
signing the form FDA 1571 are listed below box 15.
16-17. For an IND sponsored by a pharmaceutical firm or research
organization, the name of the sponsor’s authorizing representative would
be entered and that individual must sign the form. For a SponsorInvestigator IND, the Sponsor-Investigator should be named and must sign
the form.
18-19. Box 18 and 19 need not be completed if they duplicate boxes
3 and 4.
20.The date here is the date the form is signed by the sponsor.
FORM FDA 1572:
Copies of Form FDA 1572 with its attachments may be sent by the
Sponsor-Investigator to FDA to satisfy Form FDA 1571, box 12, item 6 b-d.
Information can be supplied in the form of attachments (such as a
curriculum vitae) rather than entering that information directly onto the form,
but this should be so noted under the relevant section numbers.
FDA RECEIPT OF THE IND:
Upon receipt of the IND by FDA, an IND number will be assigned, and the
application will be forwarded to the appropriate reviewing division.The
reviewing division will send a letter to the Sponsor-Investigator providing
notification of the IND number assigned, date of receipt of the original
application, address where future submissions to the IND should be sent,
and the name and telephone number of the FDA person to whom questions
about the application should be directed. Studies shall not be initiated until
30 days after the date of receipt of the IND by FDA unless you receive
earlier notification by FDA that studies may begin.

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GOOD CLINICAL PRACTICE

U.S. Food and Drug Administration
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
Information on Submitting an Investigational New Drug
Application for a Biological Product
Source: http://www.fda.gov/cber/ind/ind.htm
An Investigational New Drug Application (IND) is a request for authorization
from the Food and Drug Administration (FDA) to administer an
investigational drug or biological product to humans. Such authorization
must be secured prior to interstate shipment and administration of any new
drug or biological product that is not the subject of an approved New Drug
Application or Biologics/Product License Application.
The following forms and informational material are provided for assistance
in preparing and submitting an IND for a biological product.
1. Investigational New Drug Application (PDF) (Form FDA 1571)—Outlines
the information required in an IND. All sections on form FDA 1571 must be
addressed in the submission. Also, in signing the form, the sponsor agrees
to certain important conditions that are summarized just above the section
for the sponsor’s signature.
2. Statement of Investigator (PDF) (Form FDA 1572)—When this form is
completed by each investigator, the original signed copy must be given to
the IND sponsor.
3. IND Regulations (PDF)—Title 21 of the Code of Federal Regulations
(CFR), Part 312 (21 CFR 312)
4. Current Good Manufacturing Practice in Manufacturing, Processing,
Packaging or Holding of Drugs; General (PDF)—21 CFR 210
5. Current Good Manufacturing Practice for Finished Pharmaceuticals
(PDF)—21 CFR 211
6. Biological Products: General (PDF) (21 CFR 600) and General Biological
Products Standards (PDF) (21 CFR 610)—These regulations include
descriptions of the General Safety and Sterility tests that are performed on
biological products administered by parenteral routes. The General Safety
test is performed primarily as a check on the adequacy of the filling
procedure of the final containers and is not intended as a safety test of the
product itself. Both bulk and final container sterility tests should be
performed as described in §610.12.The lot number together with the
results of all tests performed on each lot of product should be submitted
prior to use in clinical trials.
7. Adequate and Well-controlled Clinical Trials (PDF) (21 CFR 314.126)—
Pertains to studies submitted in support of new drug applications (NDAs)
for drugs, but most of the concepts are also relevant to biological products.
8. Informed Consent of Human Subjects (PDF) (21 CFR 50, Subpart B) and
Institutional Review Boards (PDF) (21 CFR 56, Subpart A)
9. Good Laboratory Practices for Nonclinical Laboratory Studies (PDF)—
(21 CFR 58)

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INVESTIGATIONAL NEW DRUG APPLICATION
10. Instructions for obtaining information from the Center for Biologics
Evaluation and Research (CBER). Guidelines/guidances are available on
the internet at http://www.fda.gov/cber/guidelines.htm.
Information on ordering current and complete copies of the regulations over
which FDA has jurisdiction (21 CFR), and how to subscribe to the Federal
Register, may be obtained from the Superintendent of Documents,
U.S Government Printing Office, Washington, D.C. 20402, 202-783-3238.
All Biological IND submissions must be made in triplicate and should be
addressed as follows:
Center for Biologics Evaluation and Research
HFM-99, Room 200N
1401 Rockville Pike
Rockville, MD 20852-1448
Questions regarding IND submissions may be directed to the
Manufacturers Assistance and Technical Training Branch, 301-827-2000.
[12/09/1998], Web Page Updated: February 17, 2000

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GOOD CLINICAL PRACTICE

VI. Good Clinical Practice

Guidance for Industry
E6 Good Clinical Practice:
Consolidated Guidance

Additional copies are available from:
the Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research (CDER),
5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication,
Training, and Manufacturers Assistance (HFM-40)
Center for Biologics Evaluation and Research (CBER)
1401 Rockville Pike, Rockville, MD 20852-1448,
http://www.fda.gov/cber/guidelines.htm
(Fax) 888-CBERFAX or 301-827-3844
(Voice Information) 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
April 1996
ICH

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GOOD CLINICAL PRACTICE

Table of Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-4
1.

GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-4

2.

THE PRINCIPLES OF ICH GCP . . . . . . . . . . . . . . . . . . . . .VI-10

3.

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS
COMMITTEE (IRB/IEC) . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-11
3.1
Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-11
3.2
Composition, Functions, and Operations . . . . . . . .VI-12
3.3
Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-13
3.4
Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-13

4.

INVESTIGATOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-14
4.1
Investigator’s Qualifications and Agreements . . . . .VI-14
4.2
Adequate Resources . . . . . . . . . . . . . . . . . . . . . . .VI-14
4.3
Medical Care of Trial Subjects . . . . . . . . . . . . . . . .VI-14
4.4
Communication with IRB/IEC . . . . . . . . . . . . . . . . .VI-15
4.5
Compliance with Protocol . . . . . . . . . . . . . . . . . . . .VI-15
4.6
Investigational Product(s) . . . . . . . . . . . . . . . . . . . .VI-15
4.7
Randomization Procedures and Unblinding . . . . . .VI-16
4.8
Informed Consent of Trial Subjects . . . . . . . . . . . . .VI-16
4.9
Records and Reports . . . . . . . . . . . . . . . . . . . . . . .VI-19
4.10
Progress Reports . . . . . . . . . . . . . . . . . . . . . . . . . .VI-20
4.11
Safety Reporting . . . . . . . . . . . . . . . . . . . . . . . . . .VI-20
4.12
Premature Termination or Suspension of a Trial . . .VI-21
4.13
Final Report(s) by Investigator/Institution . . . . . . . .VI-21

5.

SPONSOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-21
5.1
Quality Assurance and Quality Control . . . . . . . . . .VI-21
5.2
Contract Research Organization (CRO) . . . . . . . . .VI-22
5.3
Medical Expertise . . . . . . . . . . . . . . . . . . . . . . . . .VI-22
5.4
Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-22
5.5
Trial Management, Data Handling,
Recordkeeping, and Independent
Data Monitoring Committee . . . . . . . . . . . . . . . . . .VI-22
5.6
Investigator Selection . . . . . . . . . . . . . . . . . . . . . . .VI-24
5.7
Allocation of Duties and Functions . . . . . . . . . . . . .VI-24
5.8
Compensation to Subjects and Investigators . . . . .VI-24
5.9
Financing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-24
5.10
Notification/Submission to Regulatory
Authority(ies) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-24
5.11
Confirmation of Review by IRB/IEC . . . . . . . . . . . .VI-25
5.12
Information on Investigational Product(s) . . . . . . . .VI-25
5.13
Manufacturing, Packaging, Labeling,
and Coding Investigational Product(s) . . . . . . . . . .VI-25

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GOOD CLINICAL PRACTICE

Table of Contents (continued)
5.14
5.15
5.16
5.17
5.18
5.19
5.20
5.21
5.22
5.23

Supplying and Handling Investigational
Product(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-26
Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-27
Safety Information . . . . . . . . . . . . . . . . . . . . . . . . .VI-27
Adverse Drug Reaction Reporting . . . . . . . . . . . . .VI-27
Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-27
Audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-30
Noncompliance . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-30
Premature Termination or Suspension of a Trial . . .VI-31
Clinical Trial/Study Reports . . . . . . . . . . . . . . . . . .VI-31
Multicenter Trials . . . . . . . . . . . . . . . . . . . . . . . . . .VI-31

6.

CLINICAL TRIAL PROTOCOL AND PROTOCOL
AMENDMENT(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-31
6.1
General Information . . . . . . . . . . . . . . . . . . . . . . . .VI-32
6.2
Background Information . . . . . . . . . . . . . . . . . . . . .VI-32
6.3
Trial Objectives and Purpose . . . . . . . . . . . . . . . . .VI-32
6.4
Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-32
6.5
Selection and Withdrawal of Subjects . . . . . . . . . . .VI-33
6.6
Treatment of Subjects . . . . . . . . . . . . . . . . . . . . . .VI-33
6.7
Assessment of Efficacy . . . . . . . . . . . . . . . . . . . . .VI-33
6.8
Assessment of Safety . . . . . . . . . . . . . . . . . . . . . .VI-33
6.9
Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-34
6.10
Direct Access to Source Data/Documents . . . . . . .VI-34
6.11
Quality Control and Quality Assurance . . . . . . . . . .VI-34
6.12
Ethics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-34
6.13
Data Handling and Recordkeeping . . . . . . . . . . . . .VI-34
6.14
Financing and Insurance . . . . . . . . . . . . . . . . . . . .VI-34
6.15
Publication Policy . . . . . . . . . . . . . . . . . . . . . . . . . .VI-34
6.16
Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-34

7.

INVESTIGATOR’S BROCHURE . . . . . . . . . . . . . . . . . . . . .VI-34
7.1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-34
7.2
General Considerations . . . . . . . . . . . . . . . . . . . . .VI-35
7.3
Contents of the Investigator’s Brochure . . . . . . . . .VI-36
7.4
Appendix 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-40
7.5
Appendix 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-40

8.

ESSENTIAL DOCUMENTS FOR THE CONDUCT
OF A CLINICAL TRIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-40
8.1
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI-40
8.2
Before the Clinical Phase of the Trial Commences .VI-42
8.3
During the Clinical Conduct of the Trial . . . . . . . . . .VI-46
8.4
After Completion or Termination of the Trial . . . . . .VI-48

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GUIDANCE FOR INDUSTRY1
E6 Good Clinical Practice: Consolidated Guidance
INTRODUCTION
Good clinical practice (GCP) is an international ethical and scientific quality
standard for designing, conducting, recording, and reporting trials that
involve the participation of human subjects. Compliance with this standard
provides public assurance that the rights, safety, and well-being of trial
subjects are protected, consistent with the principles that have their origin
in the Declaration of Helsinki, and that the clinical trial data are credible.
The objective of this ICH GCP guidance is to provide a unified standard for
the European Union (EU), Japan, and the United States to facilitate the
mutual acceptance of clinical data by the regulatory authorities in these
jurisdictions.
The guidance was developed with consideration of the current good clinical
practices of the European Union, Japan, and the United States, as well as
those of Australia, Canada, the Nordic countries, and the World Health
Organization (WHO).
This guidance should be followed when generating clinical trial data that are
intended to be submitted to regulatory authorities.
The principles established in this guidance may also be applied to other
clinical investigations that may have an impact on the safety and well-being
of human subjects.

1. GLOSSARY
1.1 Adverse drug reaction (ADR): In the preapproval clinical experience
with a new medicinal product or its new usages, particularly as the
therapeutic dose(s) may not be established, all noxious and unintended
responses to a medicinal product related to any dose should be considered
adverse drug reactions. The phrase “responses to a medicinal product”
means that a causal relationship between a medicinal product and an
adverse event is at least a reasonable possibility, i.e., the relationship
cannot be ruled out.
Regarding marketed medicinal products: A response to a drug that is
noxious and unintended and that occurs at doses normally used in man for
prophylaxis, diagnosis, or therapy of diseases or for modification of
physiological function (see the ICH guidance for Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting).

1This guidance was developed within the Exper t Working Group (Efficacy) of the International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance
with the ICH process. This document has been endorsed by the ICH Steering Committee at
Step4 of the ICH process, April 1996.At Step 4 of the process, the final draft is recommended
for adoption to the regulatory bodies of the European Union, Japan and the United States. This
guidance was published in the Federal Register on May 9, 1997 (62 FR 25692), and is applicable
to drug and biological products . This guidance represents the Agency's current thinking on good
clinical practices. It does not create or confer any rights for or on any person and does not
operate to bind FDA or the public.An alternative approach may be used if such approach
satisfies the requirements of the applicable statute, regulations, or both.

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1.2 Adverse event (AE): An AE is any untoward medical occurrence in a
patient or clinical investigation subject administered a pharmaceutical
product and that does not necessarily have a causal relationship with this
treatment. An AE can therefore be any unfavorable and unintended sign
(including an abnormal laboratory finding), symptom, or disease temporally
associated with the use of a medicinal (investigational) product, whether or
not related to the medicinal (investigational) product (see the ICH guidance
for Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting).
1.3 Amendment (to the protocol): See Protocol Amendment.
1.4 Applicable regulatory requirement(s): Any law(s) and regulation(s)
addressing the conduct of clinical trials of investigational products of the
jurisdiction where trial is conducted.
1.5 Approval (in relation to institutional review boards (IRBs)): The
affirmative decision of the IRB that the clinical trial has been reviewed and
may be conducted at the institution site within the constraints set forth by
the IRB, the institution, good clinical practice (GCP), and the applicable
regulatory requirements.
1.6 Audit: A systematic and independent examination of trial-related
activities and documents to determine whether the evaluated trial-related
activities were conducted, and the data were recorded, analyzed, and
accurately reported according to the protocol, sponsor’s standard operating
procedures (SOPs), good clinical practice (GCP), and the applicable
regulatory requirement(s).
1.7 Audit certificate: A declaration of confirmation by the auditor that an
audit has taken place.
1.8 Audit report: A written evaluation by the sponsor’s auditor of the
results of the audit.
1.9 Audit trail: Documentation that allows reconstruction of the course of
events.
1.10 Blinding/masking: A procedure in which one or more parties to the
trial are kept unaware of the treatment assignment(s). Single blinding
usually refers to the subject(s) being unaware, and double blinding usually
refers to the subject(s), investigator(s), monitor, and, in some cases, data
analyst(s) being unaware of the treatment assignment(s).
1.11 Case report form (CRF): A printed, optical, or electronic document
designed to record all of the protocol-required information to be reported to
the sponsor on each trial subject.
1.12 Clinical trial/study: Any investigation in human subjects intended
to discover or verify the clinical, pharmacological, and/or other
pharmacodynamic effects of an investigational product(s), and/or to identify
any adverse reactions to an investigational product(s), and/or to study
absorption, distribution, metabolism, and excretion of an investigational
product(s) with the object of ascertaining its safety and/or efficacy. The
terms clinical trial and clinical study are synonymous.
1.13 Clinical Trial/Study Report: A written description of a trial/study of
any therapeutic, prophylactic, or diagnostic agent conducted in human
subjects, in which the clinical and statistical description, presentations, and
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analyses are fully integrated into a single report (see the ICH Guidance for
Structure and Content of Clinical Study Reports).
1.14 Comparator (Product): An investigational or marketed product (i.e.,
active control), or placebo, used as a reference in a clinical trial.
1.15 Compliance (in relation to trials): Adherence to all the trial-related
requirements, good clinical practice (GCP) requirements, and the applicable
regulatory requirements.
1.16 Confidentiality: Prevention of disclosure, to other than authorized
individuals, of a sponsor’s proprietary information or of a subject’s identity.
1.17 Contract: A written, dated, and signed agreement between two or
more involved parties that sets out any arrangements on delegation and
distribution of tasks and obligations and, if appropriate, on financial matters.
The protocol may serve as the basis of a contract.
1.18 Coordinating Committee: A committee that a sponsor may organize
to coordinate the conduct of a multicenter trial.
1.19 Coordinating Investigator: An investigator assigned the responsibility
for the coordination of investigators at different centers participating in a
multicenter trial.
1.20 Contract Research Organization (CRO): A person or an organization
(commercial, academic, or other) contracted by the sponsor to perform one
or more of a sponsor’s trial-related duties and functions.
1.21 Direct Access: Permission to examine, analyze, verify, and reproduce
any records and reports that are important to evaluation of a clinical trial.
Any party (e.g., domestic and foreign regulatory authorities, sponsors,
monitors, and auditors) with direct access should take all reasonable
precautions within the constraints of the applicable regulatory
requirement(s) to maintain the confidentiality of subjects’ identities and
sponsor’s proprietary information.
1.22 Documentation: All records, in any form (including, but not limited to,
written, electronic, magnetic, and optical records; and scans, x-rays, and
electrocardiograms) that describe or record the methods, conduct, and/or
results of a trial, the factors affecting a trial, and the actions taken.
1.23 Essential Documents: Documents that individually and collectively
permit evaluation of the conduct of a study and the quality of the data
produced (see section 8.“Essential Documents for the Conduct of a Clinical
Trial”).
1.24 Good Clinical Practice (GCP): A standard for the design, conduct,
performance, monitoring, auditing, recording, analyses, and reporting of
clinical trials that provides assurance that the data and reported results are
credible and accurate, and that the rights, integrity, and confidentiality of
trial subjects are protected.
1.25 Independent Data Monitoring Committee (IDMC) (Data and Safety
Monitoring Board, Monitoring Committee, Data Monitoring
Committee): An independent data monitoring committee that may be
established by the sponsor to assess at intervals the progress of a clinical
trial, the safety data, and the critical efficacy endpoints, and to recommend
to the sponsor whether to continue, modify, or stop a trial.

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1.26 Impartial Witness: A person, who is independent of the trial, who
cannot be unfairly influenced by people involved with the trial, who attends
the informed consent process if the subject or the subject’s legally
acceptable representative cannot read, and who reads the informed
consent form and any other written information supplied to the subject.
1.27 Independent Ethics Committee (IEC): An independent body
(a review board or a committee, institutional, regional, national, or
supranational), constituted of medical/scientific professionals and
nonmedical/nonscientific members, whose responsibility it is to ensure the
protection of the rights, safety, and well-being of human subjects involved in
a trial and to provide public assurance of that protection, by, among other
things, reviewing and approving/providing favorable opinion on the trial
protocol, the suitability of the investigator(s), facilities, and the methods and
material to be used in obtaining and documenting informed consent of the
trial subjects.
The legal status, composition, function, operations, and regulatory
requirements pertaining to Independent Ethics Committees may differ
among countries, but should allow the Independent Ethics Committee to act
in agreement with GCP as described in this guidance.
1.28 Informed Consent: A process by which a subject voluntarily confirms
his or her willingness to participate in a particular trial, after having been
informed of all aspects of the trial that are relevant to the subject’s decision
to participate. Informed consent is documented by means of a written,
signed, and dated informed consent form.
1.29 Inspection: The act by a regulatory authority(ies) of conducting an
official review of documents, facilities, records, and any other resources that
are deemed by the authority(ies) to be related to the clinical trial and that
may be located at the site of the trial, at the sponsor’s and/or contract
research organization’s (CROs) facilities, or at other establishments
deemed appropriate by the regulatory authority(ies).
1.30 Institution (medical): Any public or private entity or agency or
medical or dental facility where clinical trials are conducted.
1.31 Institutional Review Board (IRB): An independent body constituted
of medical, scientific, and nonscientific members, whose responsibility it is
to ensure the protection of the rights, safety, and well-being of human
subjects involved in a trial by, among other things, reviewing, approving,
and providing continuing review of trials, of protocols and amendments, and
of the methods and material to be used in obtaining and documenting
informed consent of the trial subjects.
1.32 Interim Clinical Trial/Study Report: A report of intermediate results
and their evaluation based on analyses performed during the course of a
trial.
1.33 Investigational Product: A pharmaceutical form of an active
ingredient or placebo being tested or used as a reference in a clinical trial,
including a product with a marketing authorization when used or assembled
(formulated or packaged) in a way different from the approved form, or
when used for an unapproved indication, or when used to gain further
information about an approved use.

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1.34 Investigator: A person responsible for the conduct of the clinical trial
at a trial site. If a trial is conducted by a team of individuals at a trial site,
the investigator is the responsible leader of the team and may be called the
principal investigator. See also Subinvestigator.
1.35 Investigator/Institution: An expression meaning “the investigator
and/or institution, where required by the applicable regulatory
requirements.”
1.36 Investigator’s Brochure: A compilation of the clinical and nonclinical
data on the investigational product(s) that is relevant to the study of the
investigational product(s) in human subjects (see section 7.“Investigator’s
Brochure”).
1.37 Legally Acceptable Representative: An individual or juridical or
other body authorized under applicable law to consent, on behalf of a
prospective subject, to the subject’s participation in the clinical trial.
1.38 Monitoring: The act of overseeing the progress of a clinical trial, and
of ensuring that it is conducted, recorded, and reported in accordance with
the protocol, standard operating procedures (SOPs), GCP, and the
applicable regulatory requirement(s).
1.39 Monitoring Report: A written report from the monitor to the sponsor
after each site visit and/or other trial-related communication according to
the sponsor’s SOPs.
1.40 Multicenter Trial: A clinical trial conducted according to a single
protocol but at more than one site, and, therefore, carried out by more than
one investigator.
1.41 Nonclinical Study: Biomedical studies not performed on human
subjects.
1.42 Opinion (in relation to Independent Ethics Committee): The
judgment and/or the advice provided by an Independent Ethics Committee
(IEC).
1.43 Original Medical Record: See 1.52 Source Documents.
1.44 Protocol: A document that describes the objective(s), design,
methodology, statistical considerations, and organization of a trial.The
protocol usually also gives the background and rationale for the trial, but
these could be provided in other protocol referenced documents.
Throughout the ICH GCP Guidance, the term protocol refers to protocol
and protocol amendments.
1.45 Protocol Amendment: A written description of a change(s) to or
formal clarification of a protocol.
1.46 Quality Assurance (QA): All those planned and systematic actions
that are established to ensure that the trial is performed and the data are
generated, documented (recorded), and reported in compliance with GCP
and the applicable regulatory requirement(s).
1.47 Quality Control (QC): The operational techniques and activities
undertaken within the quality assurance system to verify that the
requirements for quality of the trial-related activities have been fulfilled.
1.48 Randomization: The process of assigning trial subjects to treatment
or control groups using an element of chance to determine the assignments
in order to reduce bias.
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1.49 Regulatory Authorities: Bodies having the power to regulate. In the
ICH GCP guidance, the expression “Regulatory Authorities” includes the
authorities that review submitted clinical data and those that conduct
inspections (see section 1.29).These bodies are sometimes referred to as
competent authorities.
1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction
(Serious ADR): Any untoward medical occurrence that at any dose:
• Results in death,
• Is life-threatening,
• Requires inpatient hospitalization or prolongation of existing
hospitalization,
• Results in persistent or significant disability/incapacity, or
• Is a congenital anomaly/birth defect.
(See the ICH Guideline E2A Safety Data Management: Definitions and
Standards for Expedited Reporting. [http://www.ifpma.org/pdfifpma/e2a.pdf])
1.51 Source Data: All information in original records and certified copies of
original records of clinical findings, observations, or other activities in a
clinical trial necessary for the reconstruction and evaluation of the trial.
Source data are contained in source documents (original records or
certified copies).
1.52 Source Documents: Original documents, data, and records (e.g.,
hospital records, clinical and office charts, laboratory notes, memoranda,
subjects’ diaries or evaluation checklists, pharmacy dispensing records,
recorded data from automated instruments, copies or transcriptions certified
after verification as being accurate and complete, microfiches, photographic
negatives, microfilm or magnetic media, x-rays, subject files, and records
kept at the pharmacy, at the laboratories, and at medico-technical
departments involved in the clinical trial).
1.53 Sponsor: An individual, company, institution, or organization that
takes responsibility for the initiation, management, and/or financing of a
clinical trial.
1.54 Sponsor-Investigator: An individual who both initiates and conducts,
alone or with others, a clinical trial, and under whose immediate direction
the investigational product is administered to, dispensed to, or used by a
subject.The term does not include any person other than an individual
(e.g., it does not include a corporation or an agency).
The obligations of a sponsor-investigator include both those of a sponsor
and those of an investigator.
1.55 Standard Operating Procedures (SOPs): Detailed, written
instructions to achieve uniformity of the performance of a specific function.
1.56 Subinvestigator: Any individual member of the clinical trial team
designated and supervised by the investigator at a trial site to perform
critical trial-related procedures and/or to make important trial-related
decisions (e.g., associates, residents, research fellows). See also
Investigator.
1.57 Subject/Trial Subject: An individual who participates in a clinical trial,
either as a recipient of the investigational product(s) or as a control.
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1.58 Subject Identification Code: A unique identifier assigned by the
investigator to each trial subject to protect the subject’s identity and used in
lieu of the subject’s name when the investigator reports adverse events
and/or other trial-related data.
1.59 Trial Site: The location(s) where trial-related activities are actually
conducted.
1.60 Unexpected Adverse Drug Reaction: An adverse reaction, the
nature or severity of which is not consistent with the applicable product
information (e.g., Investigator’s Brochure for an unapproved investigational
product or package insert/summary of product characteristics for an
approved product).(See the ICH Guidance for Clinical Safety Data
Management:Definitions and Standards for Expedited Reporting.)
1.61 Vulnerable Subjects: Individuals whose willingness to volunteer in a
clinical trial may be unduly influenced by the expectation, whether justified
or not, of benefits associated with participation, or of a retaliatory response
from senior members of a hierarchy in case of refusal to participate.
Examples are members of a group with a hierarchical structure, such as
medical, pharmacy, dental, and nursing students, subordinate hospital and
laboratory personnel, employees of the pharmaceutical industry, members
of the armed forces, and persons kept in detention. Other vulnerable
subjects include patients with incurable diseases, persons in nursing
homes, unemployed or impoverished persons, patients in emergency
situations, ethnic minority groups, homeless persons, nomads, refugees,
minors, and those incapable of giving consent.
1.62 Well-being (of the trial subjects): The physical and mental integrity
of the subjects participating in a clinical trial.

2.THE PRINCIPLES OF ICH GCP
2.1 Clinical trials should be conducted in accordance with the ethical
principles that have their origin in the Declaration of Helsinki, and that are
consistent with GCP and the applicable regulatory requirement(s).
2.2 Before a trial is initiated, foreseeable risks and inconveniences should
be weighed against the anticipated benefit for the individual trial subject
and society. A trial should be initiated and continued only if the anticipated
benefits justify the risks.
2.3 The rights, safety, and well-being of the trial subjects are the most
important considerations and should prevail over interests of science and
society.
2.4 The available nonclinical and clinical information on an investigational
product should be adequate to support the proposed clinical trial.
2.5 Clinical trials should be scientifically sound, and described in a clear,
detailed protocol.
2.6 A trial should be conducted in compliance with the protocol that has
received prior institutional review board (IRB)/independent ethics committee
(IEC) approval/favorable opinion.
2.7 The medical care given to, and medical decisions made on behalf of,
subjects should always be the responsibility of a qualified physician or,
when appropriate, of a qualified dentist.

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2.8 Each individual involved in conducting a trial should be qualified by
education, training, and experience to perform his or her respective task(s).
2.9 Freely given informed consent should be obtained from every subject
prior to clinical trial participation.
2.10 All clinical trial information should be recorded, handled, and stored in
a way that allows its accurate reporting, interpretation, and verification.
2.11 The confidentiality of records that could identify subjects should be
protected, respecting the privacy and confidentiality rules in accordance
with the applicable regulatory requirement(s).
2.12 Investigational products should be manufactured, handled, and stored
in accordance with applicable good manufacturing practice (GMP).They
should be used in accordance with the approved protocol.
2.13 Systems with procedures that assure the quality of every aspect of the
trial should be implemented.

3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS
COMMITTEE (IRB/IEC)
3.1 Responsibilities
3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all
trial subjects. Special attention should be paid to trials that may include
vulnerable subjects.
3.1.2 The IRB/IEC should obtain the following documents:
Trial protocol(s)/amendment(s), written informed consent form(s) and
consent form updates that the investigator proposes for use in the trial,
subject recruitment procedures (e.g., advertisements), written information to
be provided to subjects, Investigator’s Brochure (IB), available safety
information, information about payments and compensation available to
subjects, the investigator’s current curriculum vitae and/or other
documentation evidencing qualifications, and any other documents that the
IRB/IEC may require to fulfill its responsibilities.
The IRB/IEC should review a proposed clinical trial within a reasonable time
and document its views in writing, clearly identifying the trial, the
documents reviewed, and the dates for the following:
• Approval/favorable opinion;
• Modifications required prior to its approval/favorable opinion;
• Disapproval/negative opinion; and
• Termination/suspension of any prior approval/favorable opinion.
3.1.3 The IRB/IEC should consider the qualifications of the investigator for
the proposed trial, as documented by a current curriculum vitae and/or by
any other relevant documentation the IRB/IEC requests.
3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at
intervals appropriate to the degree of risk to human subjects, but at least
once per year.
3.1.5 The IRB/IEC may request more information than is outlined in
paragraph 4.8.10 be given to subjects when, in the judgment of the
IRB/IEC, the additional information would add meaningfully to the protection
of the rights, safety, and/or well-being of the subjects.
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3.1.6 When a nontherapeutic trial is to be carried out with the consent of
the subject’s legally acceptable representative (see sections 4.8.12, 4.8.14),
the IRB/IEC should determine that the proposed protocol and/or other
document(s) adequately addresses relevant ethical concerns and meets
applicable regulatory requirements for such trials.
3.1.7 Where the protocol indicates that prior consent of the trial subject or
the subject’s legally acceptable representative is not possible (see section
4.8.15), the IRB/IEC should determine that the proposed protocol and/or
other document(s) adequately addresses relevant ethical concerns and
meets applicable regulatory requirements for such trials (i.e., in emergency
situations).
3.1.8 The IRB/IEC should review both the amount and method of payment
to subjects to assure that neither presents problems of coercion or undue
influence on the trial subjects. Payments to a subject should be prorated
and not wholly contingent on completion of the trial by the subject.
3.1.9 The IRB/IEC should ensure that information regarding payment to
subjects, including the methods, amounts, and schedule of payment to trial
subjects, is set forth in the written informed consent form and any other
written information to be provided to subjects. The way payment will be
prorated should be specified.
3.2 Composition, Functions, and Operations
3.2.1 The IRB/IEC should consist of a reasonable number of members, who
collectively have the qualifications and experience to review and evaluate
the science, medical aspects, and ethics of the proposed trial. It is
recommended that the IRB/IEC should include:
(a) At least five members.
(b) At least one member whose primary area of interest is in a
nonscientific area.
(c) At least one member who is independent of the institution/trial site.
Only those IRB/IEC members who are independent of the investigator and
the sponsor of the trial should vote/provide opinion on a trial-related matter.
A list of IRB/IEC members and their qualifications should be maintained.
3.2.2 The IRB/IEC should perform its functions according to written
operating procedures, should maintain written records of its activities and
minutes of its meetings, and should comply with GCP and with the
applicable regulatory requirement(s).
3.2.3 An IRB/IEC should make its decisions at announced meetings at
which at least a quorum, as stipulated in its written operating procedures, is
present.
3.2.4 Only members who participate in the IRB/IEC review and discussion
should vote/provide their opinion and/or advise.
3.2.5 The investigator may provide information on any aspect of the trial,
but should not participate in the deliberations of the IRB/IEC or in the
vote/opinion of the IRB/IEC.
3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas
for assistance.

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3.3 Procedures
The IRB/IEC should establish, document in writing, and follow its
procedures, which should include:
3.3.1 Determining its composition (names and qualifications of the
members) and the authority under which it is established.
3.3.2 Scheduling, notifying its members of, and conducting its meetings.
3.3.3 Conducting initial and continuing review of trials.
3.3.4 Determining the frequency of continuing review, as appropriate.
3.3.5 Providing, according to the applicable regulatory requirements,
expedited review and approval/favorable opinion of minor change(s) in
ongoing trials that have the approval/favorable opinion of the IRB/IEC.
3.3.6 Specifying that no subject should be admitted to a trial before the
IRB/IEC issues its written approval/favorable opinion of the trial.
3.3.7 Specifying that no deviations from, or changes of, the protocol should
be initiated without prior written IRB/IEC approval/favorable opinion of an
appropriate amendment, except when necessary to eliminate immediate
hazards to the subjects or when the change(s) involves only logistical or
administrative aspects of the trial (e.g., change of monitor(s), telephone
number(s)) (see section 4.5.2).
3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
(a) Deviations from, or changes of, the protocol to eliminate immediate
hazards to the trial subjects (see sections 3.3.7, 4.5.2, 4.5.4)
(b) Changes increasing the risk to subjects and/or affecting significantly
the conduct of the trial (see section 4.10.2).
(c) All adverse drug reactions (ADRs) that are both serious and
unexpected.
(d) New information that may affect adversely the safety of the subjects or
the conduct of the trial.
3.3.9 Ensuring that the IRB/IEC promptly notify in writing the
investigator/institution concerning:
(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.
3.4 Records
The IRB/IEC should retain all relevant records (e.g., written procedures,
membership lists, lists of occupations/affiliations of members, submitted
documents, minutes of meetings, and correspondence) for a period of at
least 3 years after completion of the trial and make them available upon
request from the regulatory authority(ies).
The IRB/IEC may be asked by investigators, sponsors, or regulatory
authorities to provide copies of its written procedures and membership lists.

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4. INVESTIGATOR
4.1 Investigator’s Qualifications and Agreements
4.1.1 The investigator(s) should be qualified by education, training, and
experience to assume responsibility for the proper conduct of the trial,
should meet all the qualifications specified by the applicable regulatory
requirement(s), and should provide evidence of such qualifications through
up-to-date curriculum vitae and/or other relevant documentation requested
by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
4.1.2 The investigator should be thoroughly familiar with the appropriate
use of the investigational product(s), as described in the protocol, in the
current Investigator’s Brochure, in the product information, and in other
information sources provided by the sponsor.
4.1.3 The investigator should be aware of, and should comply with, GCP
and the applicable regulatory requirements.
4.1.4 The investigator/institution should permit monitoring and auditing by
the sponsor, and inspection by the appropriate regulatory authority(ies).
4.1.5 The investigator should maintain a list of appropriately qualified
persons to whom the investigator has delegated significant trial-related
duties.
4.2 Adequate Resources
4.2.1 The investigator should be able to demonstrate (e.g., based on
retrospective data) a potential for recruiting the required number of suitable
subjects within the agreed recruitment period.
4.2.2 The investigator should have sufficient time to properly conduct and
complete the trial within the agreed trial period.
4.2.3 The investigator should have available an adequate number of
qualified staff and adequate facilities for the foreseen duration of the trial to
conduct the trial properly and safely.
4.2.4 The investigator should ensure that all persons assisting with the trial
are adequately informed about the protocol, the investigational product(s),
and their trial-related duties and functions.
4.3 Medical Care of Trial Subjects
4.3.1 A qualified physician (or dentist, when appropriate), who is an
investigator or a subinvestigator for the trial, should be responsible for all
trial-related medical (or dental) decisions.
4.3.2 During and following a subject’s participation in a trial, the
investigator/institution should ensure that adequate medical care is
provided to a subject for any adverse events, including clinically significant
laboratory values, related to the trial.The investigator/institution should
inform a subject when medical care is needed for intercurrent illness(es) of
which the investigator becomes aware.
4.3.3 It is recommended that the investigator inform the subject’s primary
physician about the subject’s participation in the trial if the subject has a
primary physician and if the subject agrees to the primary physician being
informed.
4.3.4 Although a subject is not obliged to give his/her reason(s) for
withdrawing prematurely from a trial, the investigator should make a
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reasonable effort to ascertain the reason(s), while fully respecting the
subject’s rights.
4.4 Communication with IRB/IEC
4.4.1 Before initiating a trial, the investigator/institution should have written
and dated approval/favorable opinion from the IRB/IEC for the trial protocol,
written informed consent form, consent form updates, subject recruitment
procedures (e.g., advertisements), and any other written information to be
provided to subjects.
4.4.2 As part of the investigator’s/institution’s written application to the
IRB/IEC, the investigator/institution should provide the IRB/IEC with a
current copy of the Investigator’s Brochure. If the Investigator’s Brochure is
updated during the trial, the investigator/institution should supply a copy of
the updated Investigator’s Brochure to the IRB/IEC.
4.4.3 During the trial the investigator/institution should provide to the
IRB/IEC all documents subject to its review.
4.5 Compliance with Protocol
4.5.1 The investigator/institution should conduct the trial in compliance with
the protocol agreed to by the sponsor and, if required, by the regulatory
authority(ies), and which was given approval/favorable opinion by the
IRB/IEC. The investigator/institution and the sponsor should sign the
protocol, or an alternative contract, to confirm their agreement.
4.5.2 The investigator should not implement any deviation from, or changes
of, the protocol without agreement by the sponsor and prior review and
documented approval/favorable opinion from the IRB/IEC of an amendment,
except where necessary to eliminate an immediate hazard(s) to trial
subjects, or when the change(s) involves only logistical or administrative
aspects of the trial (e.g., change of monitor(s), change of telephone
number(s)).
4.5.3 The investigator, or person designated by the investigator, should
document and explain any deviation from the approved protocol.
4.5.4 The investigator may implement a deviation from, or a change in, the
protocol to eliminate an immediate hazard(s) to trial subjects without prior
IRB/IEC approval/favorable opinion. As soon as possible, the implemented
deviation or change, the reasons for it, and, if appropriate, the proposed
protocol amendment(s) should be submitted:
(a) To the IRB/IEC for review and approval/favorable opinion;
(b) To the sponsor for agreement and, if required;
(c) To the regulatory authority(ies).
4.6 Investigational Product(s)
4.6.1 Responsibility for investigational product(s) accountability at the trial
site(s) rests with the investigator/institution.
4.6.2 Where allowed/required, the investigator/institution may/should assign
some or all of the investigator’s/institution’s duties for investigational
product(s) accountability at the trial site(s) to an appropriate pharmacist or
another appropriate individual who is under the supervision of the
investigator/institution.

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4.6.3 The investigator/institution and/or a pharmacist or other appropriate
individual, who is designated by the investigator/institution, should maintain
records of the product’s delivery to the trial site, the inventory at the site,
the use by each subject, and the return to the sponsor or alternative
disposition of unused product(s).These records should include dates,
quantities, batch/serial numbers, expiration dates (if applicable), and the
unique code numbers assigned to the investigational product(s) and trial
subjects. Investigators should maintain records that document adequately
that the subjects were provided the doses specified by the protocol and
reconcile all investigational product(s) received from the sponsor.
4.6.4 The investigational product(s) should be stored as specified by the
sponsor (see sections 5.13.2 and 5.14.3) and in accordance with applicable
regulatory requirement(s).
4.6.5 The investigator should ensure that the investigational product(s) are
used only in accordance with the approved protocol.
4.6.6 The investigator, or a person designated by the investigator/institution,
should explain the correct use of the investigational product(s) to each
subject and should check, at intervals appropriate for the trial, that each
subject is following the instructions properly.
4.7 Randomization Procedures and Unblinding
The investigator should follow the trial’s randomization procedures, if any,
and should ensure that the code is broken only in accordance with the
protocol. If the trial is blinded, the investigator should promptly document
and explain to the sponsor any premature unblinding (e.g., accidental
unblinding, unblinding due to a serious adverse event) of the investigational
product(s).
4.8 Informed Consent of Trial Subjects
4.8.1 In obtaining and documenting informed consent, the investigator
should comply with the applicable regulatory requirement(s), and should
adhere to GCP and to the ethical principles that have their origin in the
Declaration of Helsinki.
Prior to the beginning of the trial, the investigator should have the IRB/IEC’s
written approval/favorable opinion of the written informed consent form and
any other written information to be provided to subjects.
4.8.2 The written informed consent form and any other written information
to be provided to subjects should be revised whenever important new
information becomes available that may be relevant to the subject’s
consent. Any revised written informed consent form and written information
should receive the IRB/IEC’s approval/favorable opinion in advance of use.
The subject or the subject’s legally acceptable representative should be
informed in a timely manner if new information becomes available that may
be relevant to the subject’s willingness to continue participation in the trial.
The communication of this information should be documented.
4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly
influence a subject to participate or to continue to participate in a trial.
4.8.4 None of the oral and written information concerning the trial, including
the written informed consent form, should contain any language that causes
the subject or the subject’s legally acceptable representative to waive or to
appear to waive any legal rights, or that releases or appears to release the
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investigator, the institution, the sponsor, or their agents from liability for
negligence.
4.8.5 The investigator, or a person designated by the investigator, should
fully inform the subject or, if the subject is unable to provide informed
consent, the subject’s legally acceptable representative, of all pertinent
aspects of the trial including the written information given approval/favorable
opinion by the IRB/IEC.
4.8.6 The language used in the oral and written information about the trial,
including the written informed consent form, should be as nontechnical as
practical and should be understandable to the subject or the subject’s
legally acceptable representative and the impartial witness, where
applicable.
4.8.7 Before informed consent may be obtained, the investigator, or a
person designated by the investigator, should provide the subject or the
subject’s legally acceptable representative ample time and opportunity to
inquire about details of the trial and to decide whether or not to participate
in the trial.All questions about the trial should be answered to the
satisfaction of the subject or the subject’s legally acceptable representative.
4.8.8 Prior to a subject’s participation in the trial, the written informed
consent form should be signed and personally dated by the subject or by
the subject’s legally acceptable representative, and by the person who
conducted the informed consent discussion.
4.8.9 If a subject is unable to read or if a legally acceptable representative
is unable to read, an impartial witness should be present during the entire
informed consent discussion. After the written informed consent form and
any other written information to be provided to subjects is read and
explained to the subject or the subject’s legally acceptable representative,
and after the subject or the subject’s legally acceptable representative has
orally consented to the subject’s participation in the trial, and, if capable of
doing so, has signed and personally dated the informed consent form, the
witness should sign and personally date the consent form. By signing the
consent form, the witness attests that the information in the consent form
and any other written information was accurately explained to, and
apparently understood by, the subject or the subject’s legally acceptable
representative, and that informed consent was freely given by the subject or
the subject’s legally acceptable representative.
4.8.10 Both the informed consent discussion and the written informed
consent form and any other written information to be provided to subjects
should include explanations of the following:
(a) That the trial involves research.
(b) The purpose of the trial.
(c) The trial treatment(s) and the probability for random assignment to
each treatment.
(d) The trial procedures to be followed, including all invasive procedures.
(e) The subject’s responsibilities.
(f) Those aspects of the trial that are experimental.
(g) The reasonably foreseeable risks or inconveniences to the subject
and, when applicable, to an embryo, fetus, or nursing infant.
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(h) The reasonably expected benefits. When there is no intended clinical
benefit to the subject, the subject should be made aware of this.
(i) The alternative procedure(s) or course(s) of treatment that may be
available to the subject, and their important potential benefits and risks.
(j) The compensation and/or treatment available to the subject in the
event of trial-related injury.
(k) The anticipated prorated payment, if any, to the subject for
participating in the trial.
(l) The anticipated expenses, if any, to the subject for participating in the
trial.
(m) That the subject’s participation in the trial is voluntary and that the
subject may refuse to participate or withdraw from the trial, at any time,
without penalty or loss of benefits to which the subject is otherwise entitled.
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory
authority(ies) will be granted direct access to the subject’s original medical
records for verification of clinical trial procedures and/or data, without
violating the confidentiality of the subject, to the extent permitted by the
applicable laws and regulations and that, by signing a written informed
consent form, the subject or the subject’s legally acceptable representative
is authorizing such access.
(o) That records identifying the subject will be kept confidential and, to
the extent permitted by the applicable laws and/or regulations, will not be
made publicly available. If the results of the trial are published, the subject’s
identity will remain confidential.
(p) That the subject or the subject’s legally acceptable representative will
be informed in a timely manner if information becomes available that may
be relevant to the subject’s willingness to continue participation in the trial.
(q) The person(s) to contact for further information regarding the trial and
the rights of trial subjects, and whom to contact in the event of trial-related
injury.
(r) The foreseeable circumstances and/or reasons under which the
subject’s participation in the trial may be terminated.
(s) The expected duration of the subject’s participation in the trial.
(t) The approximate number of subjects involved in the trial.
4.8.11 Prior to participation in the trial, the subject or the subject’s legally
acceptable representative should receive a copy of the signed and dated
written informed consent form and any other written information provided to
the subjects.
During a subject’s participation in the trial, the subject or the subject’s
legally acceptable representative should receive a copy of the signed and
dated consent form updates and a copy of any amendments to the written
information provided to subjects.
4.8.12 When a clinical trial (therapeutic or nontherapeutic) includes subjects
who can only be enrolled in the trial with the consent of the subject’s legally
acceptable representative (e.g., minors, or patients with severe dementia),
the subject should be informed about the trial to the extent compatible with

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the subject’s understanding and, if capable, the subject should assent, sign
and personally date the written informed consent.
4.8.13 Except as described in 4.8.14, a nontherapeutic trial (i.e., a trial in
which there is no anticipated direct clinical benefit to the subject) should be
conducted in subjects who personally give consent and who sign and date
the written informed consent form.
4.8.14 Nontherapeutic trials may be conducted in subjects with consent of a
legally acceptable representative provided the following conditions are
fulfilled:
(a) The objectives of the trial cannot be met by means of a trial in
subjects who can give informed consent personally.
(b) The foreseeable risks to the subjects are low.
(c) The negative impact on the subject’s well-being is minimized and low.
(d) The trial is not prohibited by law.
(e) The approval/favorable opinion of the IRB/IEC is expressly sought on
the inclusion of such subjects, and the written approval/favorable opinion
covers this aspect.
Such trials, unless an exception is justified, should be conducted in patients
having a disease or condition for which the investigational product is
intended.Subjects in these trials should be particularly closely monitored
and should be withdrawn if they appear to be unduly distressed.
4.8.15 In emergency situations, when prior consent of the subject is not
possible, the consent of the subject’s legally acceptable representative, if
present, should be requested.When prior consent of the subject is not
possible, and the subject’s legally acceptable representative is not available,
enrollment of the subject should require measures described in the protocol
and/or elsewhere, with documented approval/favorable opinion by the
IRB/IEC, to protect the rights, safety, and well-being of the subject and to
ensure compliance with applicable regulatory requirements. The subject or
the subject’s legally acceptable representative should be informed about the
trial as soon as possible and consent to continue and other consent as
appropriate (see section 4.8.10) should be requested.
4.9 Records and Reports
4.9.1 The investigator should ensure the accuracy, completeness, legibility,
and timeliness of the data reported to the sponsor in the CRFs and in all
required reports.
4.9.2 Data reported on the CRF, which are derived from source documents,
should be consistent with the source documents or the discrepancies
should be explained.
4.9.3 Any change or correction to a CRF should be dated, initialed, and
explained (if necessary) and should not obscure the original entry (i.e., an
audit trail should be maintained); this applies to both written and electronic
changes or corrections (see section 5.18.4(n)). Sponsors should provide
guidance to investigators and/or the investigators’designated
representatives on making such corrections. Sponsors should have written
procedures to assure that changes or corrections in CRFs made by
sponsor’s designated representatives are documented, are necessar y, and
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are endorsed by the investigator. The investigator should retain records of
the changes and corrections.
4.9.4 The investigator/institution should maintain the trial documents as
specified in Essential Documents for the Conduct of a Clinical Trial (see
section 8.) and as required by the applicable regulatory requirement(s).The
investigator/institution should take measures to prevent accidental or
premature destruction of these documents.
4.9.5 Essential documents should be retained until at least 2 years after the
last approval of a marketing application in an ICH region and until there are
no pending or contemplated marketing applications in an ICH region or at
least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product.These documents should be
retained for a longer period, however, if required by the applicable
regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when
these documents no longer need to be retained (see section 5.5.12).
4.9.6 The financial aspects of the trial should be documented in an
agreement between the sponsor and the investigator/institution.
4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority,
the investigator/institution should make available for direct access all
requested trial-related records.
4.10 Progress Reports
4.10.1 Where required by the applicable regulatory requirements, the
investigator should submit written summaries of the trial’s status to the
institution.The investigator/institution should submit written summaries of
the status of the trial to the IRB/IEC annually, or more frequently, if
requested by the IRB/IEC.
4.10.2 The investigator should promptly provide written reports to the
sponsor, the IRB/IEC (see section 3.3.8), and, where required by the
applicable regulatory requirements, the institution on any changes
significantly affecting the conduct of the trial, and/or increasing the risk to
subjects.
4.11 Safety Reporting
4.11.1 All serious adverse events (SAEs) should be reported immediately to
the sponsor except for those SAEs that the protocol or other document
(e.g., Investigator’s Brochure) identifies as not needing immediate reporting.
The immediate reports should be followed promptly by detailed, written
reports. The immediate and follow-up reports should identify subjects by
unique code numbers assigned to the trial subjects rather than by the
subjects’ names, personal identification numbers, and/or addresses. The
investigator should also comply with the applicable regulatory
requirement(s) related to the reporting of unexpected serious adverse drug
reactions to the regulatory authority(ies) and the IRB/IEC.
4.11.2 Adverse events and/or laboratory abnormalities identified in the
protocol as critical to safety evaluations should be reported to the sponsor
according to the reporting requirements and within the time periods
specified by the sponsor in the protocol.

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4.11.3 For reported deaths, the investigator should supply the sponsor and
the IRB/IEC with any additional requested information (e.g., autopsy reports
and terminal medical reports).
4.12 Premature Termination or Suspension of a Trial
If the trial is terminated prematurely or suspended for any reason, the
investigator/institution should promptly inform the trial subjects, should
assure appropriate therapy and follow-up for the subjects, and, where
required by the applicable regulatory requirement(s), should inform the
regulatory authority(ies).In addition:
4.12.1 If the investigator terminates or suspends a trial without prior
agreement of the sponsor, the investigator should inform the institution,
where required by the applicable regulatory requirements, and the
investigator/institution should promptly inform the sponsor and the IRB/IEC,
and should provide the sponsor and the IRB/IEC a detailed written
explanation of the termination or suspension.
4.12.2 If the sponsor terminates or suspends a trial (see section 5.21), the
investigator should promptly inform the institution, where required by the
applicable regulatory requirements, and the investigator/institution should
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written
explanation of the termination or suspension.
4.12.3 If the IRB/IEC terminates or suspends its approval/favorable opinion
of a trial (see sections 3.1.2 and 3.3.9), the investigator should inform the
institution, where required by the applicable regulatory requirements, and
the investigator/institution should promptly notify the sponsor and provide
the sponsor with a detailed written explanation of the termination or
suspension.
4.13 Final Report(s) by Investigator/Institution
Upon completion of the trial, the investigator should, where required by the
applicable regulatory requirements, inform the institution, and the
investigator/institution should provide the sponsor with all required reports,
the IRB/IEC with a summary of the trial’s outcome, and the regulatory
authority(ies) with any report(s) they require of the investigator/institution.

5. SPONSOR
5.1 Quality Assurance and Quality Control
5.1.1 The sponsor is responsible for implementing and maintaining quality
assurance and quality control systems with written SOPs to ensure that
trials are conducted and data are generated, documented (recorded), and
reported in compliance with the protocol, GCP, and the applicable
regulatory requirement(s).
5.1.2 The sponsor is responsible for securing agreement from all involved
parties to ensure direct access (see section 1.21) to all trial-related sites,
source data/documents, and reports for the purpose of monitoring and
auditing by the sponsor, and inspection by domestic and foreign regulatory
authorities.
5.1.3 Quality control should be applied to each stage of data handling to
ensure that all data are reliable and have been processed correctly.

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5.1.4 Agreements, made by the sponsor with the investigator/institution
and/or with any other parties involved with the clinical trial, should be in
writing, as part of the protocol or in a separate agreement.
5.2 Contract Research Organization (CRO)
5.2.1 A sponsor may transfer any or all of the sponsor’s trial-related duties
and functions to a CRO, but the ultimate responsibility for the quality and
integrity of the trial data always resides with the sponsor. The CRO should
implement quality assurance and quality control.
5.2.2 Any trial-related duty and function that is transferred to and assumed
by a CRO should be specified in writing.
5.2.3 Any trial-related duties and functions not specifically transferred to
and assumed by a CRO are retained by the sponsor.
5.2.4 All references to a sponsor in this guidance also apply to a CRO to
the extent that a CRO has assumed the trial-related duties and functions of
a sponsor.
5.3 Medical Expertise
The sponsor should designate appropriately qualified medical personnel
who will be readily available to advise on trial-related medical questions or
problems. If necessary, outside consultant(s) may be appointed for this
purpose.
5.4 Trial Design
5.4.1 The sponsor should utilize qualified individuals (e.g., biostatisticians,
clinical pharmacologists, and physicians) as appropriate, throughout all
stages of the trial process, from designing the protocol and CRFs and
planning the analyses to analyzing and preparing interim and final clinical
trial/study reports.
5.4.2 For further guidance: Clinical Trial Protocol and Protocol
Amendment(s) (see section 6), the ICH Guidance E3:
[http://www.ifpma.org/pdfifpma/e3.pdf] Structure and Content of Clinical
Study Reports, and other appropriate ICH guidance on trial design,
protocol, and conduct.
5.5 Trial Management, Data Handling, Recordkeeping, and Independent
Data Monitoring Committee
5.5.1 The sponsor should utilize appropriately qualified individuals to
supervise the overall conduct of the trial, to handle the data, to verify the
data, to conduct the statistical analyses, and to prepare the trial reports.
5.5.2 The sponsor may consider establishing an independent data
monitoring committee (IDMC) to assess the progress of a clinical trial,
including the safety data and the critical efficacy endpoints at intervals, and
to recommend to the sponsor whether to continue, modify, or stop a trial.
The IDMC should have written operating procedures and maintain written
records of all its meetings.
5.5.3 When using electronic trial data handling and/or remote electronic trial
data systems, the sponsor should:
(a) Ensure and document that the electronic data processing system(s)
conforms to the sponsor’s established requirements for completeness,
accuracy, reliability, and consistent intended performance (i.e., validation).
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(b) Maintain SOPs for using these systems.
(c) Ensure that the systems are designed to permit data changes in such
a way that the data changes are documented and that there is no deletion
of entered data (i.e., maintain an audit trail, data trail, edit trail).
(d) Maintain a security system that prevents unauthorized access to the
data.
(e) Maintain a list of the individuals who are authorized to make data
changes (see sections 4.1.5 and 4.9.3).
(f) Maintain adequate backup of the data.
(g) Safeguard the blinding, if any (e.g., maintain the blinding during data
entry and processing).
5.5.4 If data are transformed during processing, it should always be
possible to compare the original data and observations with the processed
data.
5.5.5 The sponsor should use an unambiguous subject identification code
(see section 1.58) that allows identification of all the data reported for each
subject.
5.5.6 The sponsor, or other owners of the data, should retain all of the
sponsor-specific essential documents pertaining to the trial. (See section 8.
“Essential Documents for the Conduct of a Clinical Trial.”)
5.5.7 The sponsor should retain all sponsor-specific essential documents in
conformance with the applicable regulatory requirement(s) of the
country(ies) where the product is approved, and/or where the sponsor
intends to apply for approval(s).
5.5.8 If the sponsor discontinues the clinical development of an
investigational product (i.e., for any or all indications, routes of
administration, or dosage forms), the sponsor should maintain all sponsorspecific essential documents for at least 2 years after formal discontinuation
or in conformance with the applicable regulatory requirement(s).
5.5.9 If the sponsor discontinues the clinical development of an
investigational product, the sponsor should notify all the trial
investigators/institutions and all the appropriate regulatory authorities.
5.5.10 Any transfer of ownership of the data should be reported to the
appropriate authority(ies), as required by the applicable regulatory
requirement(s).
5.5.11 The sponsor-specific essential documents should be retained until at
least 2 years after the last approval of a mar keting application in an ICH
region and until there are no pending or contemplated marketing
applications in an ICH region or at least 2 years have elapsed since the
formal discontinuation of clinical development of the investigational product.
These documents should be retained for a longer period, however, if
required by the applicable regulatory requirement(s) or if needed by the
sponsor.
5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing
of the need for record retention and should notify the investigator(s)/
institution(s) in writing when the trial-related records are no longer needed
(see section 4.9.5).
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5.6 Investigator Selection
5.6.1 The sponsor is responsible for selecting the investigator(s)/
institution(s). Each investigator should be qualified by training and
experience and should have adequate resources (see sections 4.1, 4.2) to
properly conduct the trial for which the investigator is selected.If a
coordinating committee and/or coordinating investigator(s) are to be utilized
in multicenter trials, their organization and/or selection are the sponsor’s
responsibility.
5.6.2 Before entering an agreement with an investigator/institution to
conduct a trial, the sponsor should provide the investigator(s)/institution(s)
with the protocol and an up-to-date Investigator’s Brochure, and should
provide sufficient time for the investigator/institution to review the protocol
and the information provided.
5.6.3 The sponsor should obtain the investigator’s/institution’s agreement:
(a) To conduct the trial in compliance with GCP, with the applicable
regulatory requirement(s), and with the protocol agreed to by the sponsor
and given approval/favorable opinion by the IRB/IEC;
(b) To comply with procedures for data recording/reporting: and
(c) To permit monitoring, auditing, and inspection (see section 4.1.4).
(d) To retain the essential documents that should be in the
investigator/institution files (see section 8) until the sponsor informs the
investigator/institution these documents are no longer needed (see sections
4.9.4, 4.9.5, and 5.5.12).
The sponsor and the investigator/institution should sign the protocol, or an
alternative document, to confirm this agreement.
5.7 Allocation of Duties and Functions
Prior to initiating a trial, the sponsor should define, establish, and allocate
all trial-related duties and functions.
5.8 Compensation to Subjects and Investigators
5.8.1 If required by the applicable regulatory requirement(s), the sponsor
should provide insurance or should indemnify (legal and financial coverage)
the investigator/the institution against claims arising from the trial, except for
claims that arise from malpractice and/or negligence.
5.8.2 The sponsor’s policies and procedures should address the costs of
treatment of trial subjects in the event of trial-related injuries in accordance
with the applicable regulatory requirement(s).
5.8.3 When trial subjects receive compensation, the method and manner of
compensation should comply with applicable regulatory requirement(s).
5.9 Financing
The financial aspects of the trial should be documented in an agreement
between the sponsor and the investigator/institution.
5.10 Notification/Submission to Regulatory Authority(ies)
Before initiating the clinical trial(s), the sponsor (or the sponsor and the
investigator, if required by the applicable regulatory requirement(s)), should
submit any required application(s) to the appropriate authority(ies) for
review, acceptance, and/or permission (as required by the applicable
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regulatory requirement(s)) to begin the trial(s).Any notification/submission
should be dated and contain sufficient information to identify the protocol.
5.11 Confirmation of Review by IRB/IEC
5.11.1 The sponsor should obtain from the investigator/institution:
(a) The name and address of the investigator’s/institution’s IRB/IEC.
(b) A statement obtained from the IRB/IEC that it is organized and
operates according to GCP and the applicable laws and regulations.
(c) Documented IRB/IEC approval/favorable opinion and, if requested by
the sponsor, a current copy of protocol, written informed consent form(s)
and any other written information to be provided to subjects, subject
recruiting procedures, and documents related to payments and
compensation available to the subjects, and any other documents that the
IRB/IEC may have requested.
5.11.2 If the IRB/IEC conditions its approval/favorable opinion upon
change(s) in any aspect of the trial, such as modification(s) of the protocol,
written informed consent form and any other written information to be
provided to subjects, and/or other procedures, the sponsor should obtain
from the investigator/institution a copy of the modification(s) made and the
date approval/favorable opinion was given by the IRB/IEC.
5.11.3 The sponsor should obtain from the investigator/institution
documentation and dates of any IRB/IEC reapprovals/reevaluations with
favorable opinion, and of any withdrawals or suspensions of approval/
favorable opinion.
5.12 Information on Investigational Product(s)
5.12.1 When planning trials, the sponsor should ensure that sufficient safety
and efficacy data from nonclinical studies and/or clinical trials are available
to support human exposure by the route, at the dosages, for the duration,
and in the trial population to be studied.
5.12.2 The sponsor should update the Investigator’s Brochure as significant
new information becomes available. (See section 7.“Investigator’s
Brochure.”)
5.13 Manufacturing, Packaging, Labeling, and Coding Investigational
Product(s)
5.13.1 The sponsor should ensure that the investigational product(s)
(including active comparator(s) and placebo, if applicable) is characterized
as appropriate to the stage of development of the product(s), is
manufactured in accordance with any applicable GMP, and is coded and
labeled in a manner that protects the blinding, if applicable. In addition, the
labeling should comply with applicable regulatory requirement(s).
5.13.2 The sponsor should determine, for the investigational product(s),
acceptable storage temperatures, storage conditions (e.g., protection from
light), storage times, reconstitution fluids and procedures, and devices for
product infusion, if any. The sponsor should inform all involved parties (e.g.,
monitors, investigators, pharmacists, storage managers) of these
determinations.
5.13.3 The investigational product(s) should be packaged to prevent
contamination and unacceptable deterioration during transport and storage.
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5.13.4 In blinded trials, the coding system for the investigational product(s)
should include a mechanism that permits rapid identification of the
product(s) in case of a medical emergency, but does not permit
undetectable breaks of the blinding.
5.13.5 If significant formulation changes are made in the investigational or
comparator product(s) during the course of clinical development, the results
of any additional studies of the formulated product(s) (e.g., stability,
dissolution rate, bioavailability) needed to assess whether these changes
would significantly alter the pharmacokinetic profile of the product should
be available prior to the use of the new formulation in clinical trials.
5.14 Supplying and Handling Investigational Product(s)
5.14.1 The sponsor is responsible for supplying the investigator(s)/
institution(s) with the investigational product(s).
5.14.2 The sponsor should not supply an investigator/institution with the
investigational product(s) until the sponsor obtains all required
documentation (e.g., approval/favorable opinion from IRB/IEC and
regulatory authority(ies)).
5.14.3 The sponsor should ensure that written procedures include
instructions that the investigator/institution should follow for the handling
and storage of investigational product(s) for the trial and documentation
thereof. The procedures should address adequate and safe receipt,
handling, storage, dispensing, retrieval of unused product from subjects,
and return of unused investigational product(s) to the sponsor (or
alternative disposition if authorized by the sponsor and in compliance with
the applicable regulatory requirement(s)).
5.14.4 The sponsor should:
(a) Ensure timely delivery of investigational product(s) to the
investigator(s).
(b) Maintain records that document shipment, receipt, disposition, return,
and destruction of the investigational product(s). (See section 8.“Essential
Documents for the Conduct of a Clinical Trial.”)
(c) Maintain a system for retrieving investigational products and
documenting this retrieval (e.g., for deficient product recall, reclaim after
trial completion, expired product reclaim).
(d) Maintain a system for the disposition of unused investigational
product(s) and for the documentation of this disposition.
5.14.5 The sponsor should:
(a) Take steps to ensure that the investigational product(s) are stable over
the period of use.
(b) Maintain sufficient quantities of the investigational product(s) used in
the trials to reconfirm specifications, should this become necessary, and
maintain records of batch sample analyses and characteristics. To the
extent stability permits, samples should be retained either until the analyses
of the trial data are complete or as required by the applicable regulatory
requirement(s), whichever represents the longer retention period.

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5.15 Record Access
5.15.1 The sponsor should ensure that it is specified in the protocol or other
written agreement that the investigator(s)/institution(s) provide direct access
to source data/documents for trial-related monitoring, audits, IRB/IEC
review, and regulatory inspection.
5.15.2 The sponsor should verify that each subject has consented, in
writing, to direct access to his/her original medical records for trial-related
monitoring, audit, IRB/IEC review, and regulatory inspection.
5.16 Safety Information
5.16.1 The sponsor is responsible for the ongoing safety evaluation of the
investigational product(s).
5.16.2 The sponsor should promptly notify all concerned investigator(s)/
institution(s) and the regulatory authority(ies) of findings that could affect
adversely the safety of subjects, impact the conduct of the trial, or alter the
IRB/IEC’s approval/favorable opinion to continue the trial.
5.17 Adverse Drug Reaction Reporting
5.17.1 The sponsor should expedite the reporting to all concerned
investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to
the regulatory authority(ies) of all adverse drug reactions (ADRs) that are
both serious and unexpected.
5.17.2 Such expedited reports should comply with the applicable regulatory
requirement(s) and with the ICH Guidance for Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting.
5.17.3 The sponsor should submit to the regulatory authority(ies) all safety
updates and periodic reports, as required by applicable regulatory
requirement(s).
5.18 Monitoring
5.18.1 Purpose. The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from
source documents.
(c) The conduct of the trial is in compliance with the currently approved
protocol/amendment(s), with GCP, and with applicable regulatory
requirement(s).
5.18.2 Selection and Qualifications of Monitors
(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the
scientific and/or clinical knowledge needed to monitor the trial adequately.
A monitor’s qualifications should be documented.
(c) Monitors should be thoroughly familiar with the investigational
product(s), the protocol, written informed consent form and any other
written information to be provided to subjects, the sponsor’s SOPs, GCP,
and the applicable regulatory requirement(s).

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5.18.3 Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored.The
sponsor should determine the appropriate extent and nature of monitoring.
The determination of the extent and nature of monitoring should be based
on considerations such as the objective, purpose, design, complexity,
blinding, size, and endpoints of the trial. In general there is a need for onsite monitoring, before, during, and after the trial; however, in exceptional
circumstances the sponsor may determine that central monitoring in
conjunction with procedures such as investigators’training and meetings,
and extensive written guidance can assure appropriate conduct of the trial
in accordance with GCP. Statistically controlled sampling may be an
acceptable method for selecting the data to be verified.
5.18.4 Monitor’s Responsibilities
The monitor(s), in accordance with the sponsor’s requirements, should
ensure that the trial is conducted and documented properly by carrying out
the following activities when relevant and necessary to the trial and the trial
site:
(a) Acting as the main line of communication between the sponsor and
the investigator.
(b) Verifying that the investigator has adequate qualifications and
resources (see sections 4.1, 4.2, 5.6) and these remain adequate
throughout the trial period, and that the staff and facilities, including
laboratories and equipment, are adequate to safely and properly conduct
the trial and these remain adequate throughout the trial period.
(c) Verifying, for the investigational product(s):
(i) That storage times and conditions are acceptable, and that
supplies are sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects
who are eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly
using, handling, storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s)
at the trial sites are controlled and documented adequately.
(v) That the disposition of unused investigational product(s) at the
trial sites complies with applicable regulatory requirement(s) and is in
accordance with the sponsor’s authorized procedures.
(d) Verifying that the investigator follows the approved protocol and all
approved amendment(s), if any.
(e) Verifying that written informed consent was obtained before each
subject’s participation in the trial.
(f) Ensuring that the investigator receives the current Investigator’s
Brochure, all documents, and all trial supplies needed to conduct the trial
properly and to comply with the applicable regulatory requirement(s).
(g) Ensuring that the investigator and the investigator’s trial staff are
adequately informed about the trial.
(h) Verifying that the investigator and the investigator’s trial staff are
performing the specified trial functions, in accordance with the protocol and
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any other written agreement between the sponsor and the
investigator/institution, and have not delegated these functions to
unauthorized individuals.
(i) Verifying that the investigator is enrolling only eligible subjects.
(j) Reporting the subject recruitment rate.
(k) Verifying that source data/documents and other trial records are
accurate, complete, kept up-to-date, and maintained.
(l) Verifying that the investigator provides all the required reports,
notifications, applications, and submissions, and that these documents are
accurate, complete, timely, legible, dated, and identify the trial.
(m) Checking the accuracy and completeness of the CRF entries, source
data/documents, and other trial-related records against each other. The
monitor specifically should verify that:
(i) The data required by the protocol are reported accurately on the
CRFs and are consistent with the source data/documents.
(ii) Any dose and/or therapy modifications are well documented for
each of the trial subjects.
(iii) Adverse events, concomitant medications, and intercurrent
illnesses are reported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not conducted,
and examinations that are not performed are clearly reported as such on
the CRFs.
(v) All withdrawals and dropouts of enrolled subjects from the trial are
reported and explained on the CRFs.
(n) Informing the investigator of any CRF entry error, omission, or
illegibility. The monitor should ensure that appropriate corrections, additions,
or deletions are made, dated, explained (if necessary), and initialed by the
investigator or by a member of the investigator’s trial staff who is authorized
to initial CRF changes for the investigator. This authorization should be
documented.
(o) Determining whether all adverse events (AEs) are appropriately
reported within the time periods required by GCP, the ICH Guidance for
Clinical Safety Data Management: Definitions and Standards for Expedited
Reporting, the protocol, the IRB/IEC, the sponsor, and the applicable
regulatory requirement(s).
(p) Determining whether the investigator is maintaining the essential
documents. (See section 8.“Essential Documents for the Conduct of a
Clinical Trial.”)
(q) Communicating deviations from the protocol, SOPs, GCP, and the
applicable regulatory requirements to the investigator and taking
appropriate action designed to prevent recurrence of the detected
deviations.
5.18.5 Monitoring Procedures
The monitor(s) should follow the sponsor’s established written SOPs as well
as those procedures that are specified by the sponsor for monitoring a
specific trial.
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5.18.6 Monitoring Report
(a) The monitor should submit a written report to the sponsor after each
trial-site visit or trial-related communication.
(b) Reports should include the date, site, name of the monitor, and name
of the investigator or other individual(s) contacted.
(c) Reports should include a summary of what the monitor reviewed and
the monitor’s statements concerning the significant findings/facts, deviations
and deficiencies, conclusions, actions taken or to be taken, and/or actions
recommended to secure compliance.
(d) The review and follow-up of the monitoring report by the sponsor
should be documented by the sponsor’s designated representative.
5.19 Audit
If or when sponsors perform audits, as part of implementing quality
assurance, they should consider:
5.19.1 Purpose
The purpose of a sponsor’s audit, which is independent of and separate
from routine monitoring or quality control functions, should be to evaluate
trial conduct and compliance with the protocol, SOPs, GCP, and the
applicable regulatory requirements.
5.19.2 Selection and Qualification of Auditors
(a) The sponsor should appoint individuals, who are independent of the
clinical trial/data collection system(s), to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by training
and experience to conduct audits properly. An auditor’s qualifications should
be documented.
5.19.3 Auditing Procedures
(a) The sponsor should ensure that the auditing of clinical trials/systems
is conducted in accordance with the sponsor’s written procedures on what
to audit, how to audit, the frequency of audits, and the form and content of
audit reports.
(b) The sponsor’s audit plan and procedures for a trial audit should be
guided by the importance of the trial to submissions to regulatory
authorities, the number of subjects in the trial, the type and complexity of
the trial, the level of risks to the trial subjects, and any identified problem(s).
(c) The observations and findings of the auditor(s) should be
documented.
(d) To preserve the independence and value of the audit function, the
regulatory authority(ies) should not routinely request the audit reports.
Regulatory authority(ies) may seek access to an audit report on a case-bycase basis, when evidence of serious GCP noncompliance exists, or in the
course of legal proceedings.
(e) Where required by applicable law or regulation, the sponsor should
provide an audit certificate.
5.20 Noncompliance
5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable
regulatory requirement(s) by an investigator/institution, or by member(s) of
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the sponsor’s staff should lead to prompt action by the sponsor to secure
compliance.
5.20.2 If the monitoring and/or auditing identifies serious and/or persistent
noncompliance on the part of an investigator/institution, the sponsor should
terminate the investigator’s/institution’s participation in the trial.When an
investigator’s/institution’s participation is terminated because of
noncompliance, the sponsor should notify promptly the regulatory
authority(ies).
5.21 Premature Termination or Suspension of a Trial
If a trial is terminated prematurely or suspended, the sponsor should
promptly inform the investigators/institutions, and the regulator y
authority(ies) of the termination or suspension and the reason(s) for the
termination or suspension.The IRB/IEC should also be informed promptly
and provided the reason(s) for the termination or suspension by the
sponsor or by the investigator/institution, as specified by the applicable
regulatory requirement(s).
5.22 Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the sponsor
should ensure that the clinical trial/study reports are prepared and provided
to the regulatory agency(ies) as required by the applicable regulatory
requirement(s).The sponsor should also ensure that the clinical trial/study
reports in mar keting applications meet the standards of the ICH Guidance
for Structure and Content of Clinical Study Reports. (NOTE:The ICH
Guidance for Structure and Content of Clinical Study Reports specifies that
abbreviated study reports may be acceptable in certain cases.)
5.23 Multicenter Trials
For multicenter trials, the sponsor should ensure that:
5.23.1 All investigators conduct the trial in strict compliance with the
protocol agreed to by the sponsor and, if required, by the regulatory
authority(ies), and given approval/favorable opinion by the IRB/IEC.
5.23.2 The CRFs are designed to capture the required data at all
multicenter trial sites. For those investigators who are collecting additional
data, supplemental CRFs should also be provided that are designed to
capture the additional data.
5.23.3 The responsibilities of the coordinating investigator(s) and the other
participating investigators are documented prior to the start of the trial.
5.23.4 All investigators are given instructions on following the protocol, on
complying with a uniform set of standards for the assessment of clinical and
laboratory findings, and on completing the CRFs.
5.23.5 Communication between investigators is facilitated.

6. CLINICAL TRIAL PROTOCOL AND PROTOCOL
AMENDMENTS
The contents of a trial protocol should generally include the following topics.
However, site specific information may be provided on separate protocol
page(s), or addressed in a separate agreement, and some of the
information listed below may be contained in other protocol referenced
documents, such as an Investigator’s Brochure.
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6.1 General Information
6.1.1 Protocol title, protocol identifying number, and date. Any
amendment(s) should also bear the amendment number(s) and date(s).
6.1.2 Name and address of the sponsor and monitor (if other than the
sponsor).
6.1.3 Name and title of the person(s) authorized to sign the protocol and
the protocol amendment(s) for the sponsor.
6.1.4 Name, title, address, and telephone number(s) of the sponsor’s
medical expert (or dentist when appropriate) for the trial.
6.1.5 Name and title of the investigator(s) who is (are) responsible for
conducting the trial, and the address and telephone number(s) of the trial
site(s).
6.1.6 Name, title, address, and telephone number(s) of the qualified
physician (or dentist, if applicable) who is responsible for all trial-site related
medical (or dental) decisions (if other than investigator).
6.1.7 Name(s) and address(es) of the clinical laboratory(ies) and other
medical and/or technical department(s) and/or institutions involved in the
trial.
6.2 Background Information
6.2.1 Name and description of the investigational product(s).
6.2.2 A summary of findings from nonclinical studies that potentially have
clinical significance and from clinical trials that are relevant to the trial.
6.2.3 Summary of the known and potential risks and benefits, if any, to
human subjects.
6.2.4 Description of and justification for the route of administration, dosage,
dosage regimen, and treatment period(s).
6.2.5 A statement that the trial will be conducted in compliance with the
protocol, GCP, and the applicable regulatory requirement(s).
6.2.6 Description of the population to be studied.
6.2.7 References to literature and data that are relevant to the trial, and that
provide background for the trial.
6.3 Trial Objectives and Purpose
A detailed description of the objectives and the purpose of the trial.
6.4 Trial Design
The scientific integrity of the trial and the credibility of the data from the trial
depend substantially on the trial design. A description of the trial design
should include:
6.4.1 A specific statement of the primary endpoints and the secondary
endpoints, if any, to be measured during the trial.
6.4.2 A description of the type/design of trial to be conducted (e.g., doubleblind, placebo-controlled, parallel design) and a schematic diagram of trial
design, procedures, and stages.
6.4.3 A description of the measures taken to minimize/avoid bias, including
(for example):
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(a) Randomization.
(b) Blinding.
6.4.4 A description of the trial treatment(s) and the dosage and dosage
regimen of the investigational product(s). Also include a description of the
dosage form, packaging, and labeling of the investigational product(s).
6.4.5 The expected duration of subject participation, and a description of
the sequence and duration of all trial periods, including follow-up, if any.
6.4.6 A description of the “stopping rules” or “discontinuation criteria” for
individual subjects, parts of trial, and entire trial.
6.4.7 Accountability procedures for the investigational product(s), including
the placebo(s) and comparator(s), if any.
6.4.8 Maintenance of trial treatment randomization codes and procedures
for breaking codes.
6.4.9 The identification of any data to be recorded directly on the CRFs
(i.e., no prior written or electronic record of data), and to be considered to
be source data.
6.5 Selection and Withdrawal of Subjects
6.5.1 Subject inclusion criteria.
6.5.2 Subject exclusion criteria.
6.5.3 Subject withdrawal criteria (i.e., terminating investigational product
treatment/trial treatment) and procedures specifying:
(a) When and how to withdraw subjects from the trial/investigational
product treatment.
(b) The type and timing of the data to be collected for withdrawn subjects.
(c) Whether and how subjects are to be replaced.
(d) The follow-up for subjects withdrawn from investigational product
treatment/trial treatment.
6.6 Treatment of Subjects
6.6.1 The treatment(s) to be administered, including the name(s) of all the
product(s), the dose(s), the dosing schedule(s), the route/mode(s) of
administration, and the treatment period(s), including the follow-up period(s)
for subjects for each investigational product treatment/trial treatment
group/arm of the trial.
6.6.2 Medication(s)/treatment(s) permitted (including rescue medication)
and not permitted before and/or during the trial.
6.6.3 Procedures for monitoring subject compliance.
6.7 Assessment of Efficacy
6.7.1 Specification of the efficacy parameters.
6.7.2 Methods and timing for assessing, recording, and analyzing efficacy
parameters.
6.8 Assessment of Safety
6.8.1 Specification of safety parameters.
6.8.2 The methods and timing for assessing, recording, and analyzing
safety parameters.
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6.8.3 Procedures for eliciting reports of and for recording and reporting
adverse event and intercurrent illnesses.
6.8.4 The type and duration of the follow-up of subjects after adverse
events.
6.9 Statistics
6.9.1 A description of the statistical methods to be employed, including
timing of any planned interim analysis(ses).
6.9.2 The number of subjects planned to be enrolled. In multicenter trials,
the number of enrolled subjects projected for each trial site should be
specified.
Reason for choice of sample size, including reflections on (or calculations
of) the power of the trial and clinical justification.
6.9.3 The level of significance to be used.
6.9.4 Criteria for the termination of the trial.
6.9.5 Procedure for accounting for missing, unused, and spurious data.
6.9.6 Procedures for reporting any deviation(s) from the original statistical
plan (any deviation(s) from the original statistical plan should be described
and justified in the protocol and/or in the final report, as appropriate).
6.9.7 The selection of subjects to be included in the analyses (e.g., all
randomized subjects, all dosed subjects, all eligible subjects, evaluate-able
subjects).
6.10 Direct Access to Source Data/Documents
The sponsor should ensure that it is specified in the protocol or other
written agreement that the investigator(s)/institution(s) will permit trialrelated monitoring, audits, IRB/IEC review, and regulatory inspection(s) by
providing direct access to source data/documents.
6.11 Quality Control and Quality Assurance
6.12 Ethics
Description of ethical considerations relating to the trial.
6.13 Data Handling and Recordkeeping
6.14 Financing and Insurance
Financing and insurance if not addressed in a separate agreement.
6.15 Publication Policy
Publication policy, if not addressed in a separate agreement.
6.16 Supplements
(NOTE: Since the protocol and the clinical trial/study report are closely
related, further relevant information can be found in the ICH Guidance for
Structure and Content of Clinical Study Reports.
(E3: [http://www.ifpma.org/pdfifpma/e3.pdf])

7. INVESTIGATOR’S BROCHURE
7.1 Introduction
The Investigator’s Brochure (IB) is a compilation of the clinical and
nonclinical data on the investigational product(s) that are relevant to the
study of the product(s) in human subjects. Its purpose is to provide the
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investigators and others involved in the trial with the information to facilitate
their understanding of the rationale for, and their compliance with, many key
features of the protocol, such as the dose, dose frequency/interval,
methods of administration, and safety monitoring procedures. The IB also
provides insight to support the clinical management of the study subjects
during the course of the clinical trial.The information should be presented
in a concise, simple, objective, balanced, and nonpromotional form that
enables a clinician, or potential investigator, to understand it and make
his/her own unbiased risk-benefit assessment of the appropriateness of the
proposed trial. For this reason, a medically qualified person should
generally participate in the editing of an IB, but the contents of the IB
should be approved by the disciplines that generated the described data.
This guidance delineates the minimum information that should be included
in an IB and provides suggestions for its layout. It is expected that the type
and extent of information available will vary with the stage of development
of the investigational product. If the investigational product is marketed and
its pharmacology is widely understood by medical practitioners, an
extensive IB may not be necessar y. Where permitted by regulator y
authorities, a basic product information brochure, package leaflet, or
labeling may be an appropriate alternative, provided that it includes current,
comprehensive, and detailed information on all aspects of the
investigational product that might be of importance to the investigator. If a
marketed product is being studied for a new use (i.e., a new indication), an
IB specific to that new use should be prepared.The IB should be reviewed
at least annually and revised as necessary in compliance with a sponsor’s
written procedures.
More frequent revision may be appropriate depending on the stage of
development and the generation of relevant new information. However, in
accordance with GCP, relevant new information may be so important that it
should be communicated to the investigators, and possibly to the
Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs)
and/or regulatory authorities before it is included in a revised IB.
Generally, the sponsor is responsible for ensuring that an up-to-date IB is
made available to the investigator(s) and the investigators are responsible
for providing the up-to-date IB to the responsible IRBs/IECs. In the case of
an investigator-sponsored trial, the sponsor-investigator should determine
whether a brochure is available from the commercial manufacturer. If the
investigational product is provided by the sponsor-investigator, then he or
she should provide the necessary information to the trial personnel. In
cases where preparation of a formal IB is impractical, the sponsorinvestigator should provide, as a substitute, an expanded background
information section in the trial protocol that contains the minimum current
information described in this guidance.
7.2 General Considerations
The Investigator’s Brochure should include:
7.2.1 Title Page This should provide the sponsor’s name, the identity of
each investigational product (i.e., research number, chemical or approved
generic name, and trade name(s) where legally permissible and desired by
the sponsor), and the release date. It is also suggested that an edition
number, and a reference to the number and date of the edition it
supersedes, be provided. An example is given in Appendix 1.
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7.2.2 Confidentiality Statement The sponsor may wish to include a
statement instructing the investigator/recipients to treat the IB as a
confidential document for the sole information and use of the investigator’s
team and the IRB/IEC.
7.3 Contents of the Investigator’s Brochure
The IB should contain the following sections, each with literature references
where appropriate:
7.3.1 Table of Contents An example of the Table of Contents is given in
Appendix 2.
7.3.2 Summary A brief summary (preferably not exceeding two pages)
should be given, highlighting the significant physical, chemical,
pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic,
and clinical information available that is relevant to the stage of clinical
development of the investigational product.
7.3.3 Introduction A brief introductory statement should be provided that
contains the chemical name (and generic and trade name(s) when
approved) of the investigational product(s), all active ingredients, the
investigational product(s) pharmacological class and its expected position
within this class (e.g., advantages), the rationale for performing research
with the investigational product(s), and the anticipated prophylactic,
therapeutic, or diagnostic indication(s). Finally, the introductory statement
should provide the general approach to be followed in evaluating the
investigational product.
7.3.4 Physical, Chemical, and Pharmaceutical Properties and
Formulation
A description should be provided of the investigational product substance(s)
(including the chemical and/or structural formula(e)), and a brief summary
should be given of the relevant physical, chemical, and pharmaceutical
properties.
To permit appropriate safety measures to be taken in the course of the trial,
a description of the formulation(s) to be used, including excipients, should
be provided and justified if clinically relevant.Instructions for the storage
and handling of the dosage form(s) should also be given.
Any structural similarities to other known compounds should be mentioned.
7.3.5 Nonclinical Studies
Introduction:
The results of all relevant nonclinical pharmacology, toxicology,
pharmacokinetic, and investigational product metabolism studies should be
provided in summary form.This summary should address the methodology
used, the results, and a discussion of the relevance of the findings to the
investigated therapeutic and the possible unfavorable and unintended
effects in humans.
The information provided may include the following, as appropriate, if
known/available:
Species tested;
Number and sex of animals in each group;
Unit dose (e.g., milligram/kilogram (mg/kg));
Dose interval;
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Route of administration;
Duration of dosing;
Information on systemic distribution;
Duration of post-exposure follow-up;
Results, including the following aspects:
• Nature and frequency of pharmacological or toxic effects;
• Severity or intensity of pharmacological or toxic effects;
• Time to onset of effects;
• Reversibility of effects;
• Duration of effects;
• Dose response.
Tabular format/listings should be used whenever possible to enhance the
clarity of the presentation.
The following sections should discuss the most important findings from the
studies, including the dose response of observed effects, the relevance to
humans, and any aspects to be studied in humans. If applicable, the
effective and nontoxic dose findings in the same animal species should be
compared (i.e., the therapeutic index should be discussed).The relevance
of this information to the proposed human dosing should be addressed.
Whenever possible, comparisons should be made in terms of blood/tissue
levels rather than on a mg/kg basis.
(a) Nonclinical Pharmacology
A summary of the pharmacological aspects of the investigational product
and, where appropriate, its significant metabolites studied in animals should
be included.Such a summary should incorporate studies that assess
potential therapeutic activity (e.g., efficacy models, receptor binding, and
specificity) as well as those that assess safety (e.g., special studies to
assess pharmacological actions other than the intended therapeutic
effect(s)).
(b) Pharmacokinetics and Product Metabolism in Animals
A summary of the pharmacokinetics and biological transformation and
disposition of the investigational product in all species studied should be
given.The discussion of the findings should address the absorption and the
local and systemic bioavailability of the investigational product and its
metabolites, and their relationship to the pharmacological and toxicological
findings in animal species.
(c) Toxicology
A summary of the toxicological effects found in relevant studies conducted
in different animal species should be described under the following
headings where appropriate:
Single dose;
Repeated dose;
Carcinogenicity;
Special studies (e.g., irritancy and sensitization);
Reproductive toxicity;
Genotoxicity (mutagenicity).
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7.3.6 Effects in Humans
Introduction:
A thorough discussion of the known effects of the investigational product(s)
in humans should be provided, including information on pharmacokinetics,
metabolism, pharmacodynamics, dose response, safety, efficacy, and other
pharmacological activities. Where possible, a summary of each completed
clinical trial should be provided. Information should also be provided
regarding results from any use of the investigational product(s) other than in
clinical trials, such as from experience during marketing.
(a) Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the investigational
product(s) should be presented, including the following, if available:
Pharmacokinetics (including metabolism, as appropriate, and absorption,
plasma protein binding, distribution, and elimination).
Bioavailability of the investigational product (absolute, where possible,
and/or relative) using a reference dosage form.
Population subgroups (e.g., gender, age, and impaired organ function).
Interactions (e.g., product-product interactions and effects of food).
Other pharmacokinetic data (e.g., results of population studies performed
within clinical trial(s)).
(b) Safety and Efficacy
A summary of information should be provided about the investigational
product’s/products’ (including metabolites, where appropriate) safety,
pharmacodynamics, efficacy, and dose response that were obtained from
preceding trials in humans (healthy volunteers and/or patients).The
implications of this information should be discussed. In cases where a
number of clinical trials have been completed, the use of summaries of
safety and efficacy across multiple trials by indications in subgroups may
provide a clear presentation of the data. Tabular summaries of adverse drug
reactions for all the clinical trials (including those for all the studied
indications) would be useful. Important differences in adverse drug reaction
patterns/incidences across indications or subgroups should be discussed.
The IB should provide a description of the possible risks and adverse drug
reactions to be anticipated on the basis of prior experiences with the
product under investigation and with related products. A description should
also be provided of the precautions or special monitoring to be done as
part of the investigational use of the product(s).
(c) Marketing Experience
The IB should identify countries where the investigational product has been
marketed or approved. Any significant information arising from the marketed
use should be summarized (e.g., for mulations, dosages, routes of
administration, and adverse product reactions).The IB should also identify
all the countries where the investigational product did not receive
approval/registration for marketing or was withdrawn from
marketing/registration.

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7.3.7 Summary of Data and Guidance for the Investigator
This section should provide an overall discussion of the nonclinical and
clinical data, and should summarize the information from various sources
on different aspects of the investigational product(s), wherever possible. In
this way, the investigator can be provided with the most informative
interpretation of the available data and with an assessment of the
implications of the information for future clinical trials.
Where appropriate, the published reports on related products should be
discussed.
This could help the investigator to anticipate adverse drug reactions or
other problems in clinical trials.
The overall aim of this section is to provide the investigator with a clear
understanding of the possible risks and adverse reactions, and of the
specific tests, observations, and precautions that may be needed for a
clinical trial.This understanding should be based on the available physical,
chemical, pharmaceutical, pharmacological, toxicological, and clinical
information on the investigational product(s). Guidance should also be
provided to the clinical investigator on the recognition and treatment of
possible overdose and adverse drug reactions that is based on previous
human experience and on the pharmacology of the investigational product.

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7.4 Appendix 1
TITLE PAGE OF INVESTIGATOR’S BROCHURE (Example)
Sponsor’s Name:
Product:
Research Number:
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
INVESTIGATOR’S BROCHURE
Edition Number:
Release Date:
Replaces Previous Edition Number:
Date:
7.5 Appendix 2
TABLE OF CONTENTS OF INVESTIGATOR’S BROCHURE (Example)
• Confidentiality Statement (optional)
• Signature Page (optional)
1. Table of Contents
2. Summary
3. Introduction
4. Physical, Chemical, and Pharmaceutical Properties and Formulation
5. Nonclinical Studies
5.1 Nonclinical Pharmacology
5.2 Pharmacokinetics and Product Metabolism in Animals
5.3 Toxicology
6. Effects in Humans
6.1 Pharmacokinetics and Product Metabolism in Humans
6.2 Safety and Efficacy
6.3 Marketing Experience
7. Summary of Data and Guidance for the Investigator
NB: References on
1. Publications
2. Reports.
These references should be found at the end of each chapter.
Appendices (if any)

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8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A
CLINICAL TRIAL
8.1 Introduction
Essential Documents are those documents that individually and collectively
permit evaluation of the conduct of a trial and the quality of the data
produced.These documents serve to demonstrate the compliance of the
investigator, sponsor, and monitor with the standards of GCP and with all
applicable regulatory requirements.
Essential Documents also ser ve a number of other important purposes.
Filing essential documents at the investigator/institution and sponsor sites
in a timely manner can greatly assist in the successful management of a
trial by the investigator, sponsor, and monitor.
These documents are also the ones that are usually audited by the
sponsor’s independent audit function and inspected by the regulatory
authority(ies) as part of the process to confirm the validity of the trial
conduct and the integrity of data collected.
The minimum list of essential documents that has been developed follows.
The various documents are grouped in three sections according to the
stage of the trial during which they will normally be generated (1) before the
clinical phase of the trial commences, (2) during the clinical conduct of the
trial, and (3) after completion or termination of the trial.
A description is given of the purpose of each document, and whether it
should be filed in either the investigator/institution or sponsor files, or both.
It is acceptable to combine some of the documents, provided the individual
elements are readily identifiable.
Trial master files should be established at the beginning of the trial, both at
the investigator/institution’s site and at the sponsor’s office. A final close-out
of a trial can only be done when the monitor has reviewed both
investigator/institution and sponsor files and confirmed that all necessary
documents are in the appropriate files.
Any or all of the documents addressed in this guidance may be subject to,
and should be available for, audit by the sponsor’s auditor and inspection by
the regulatory authority(ies).

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8.2 Before the Clinical Phase of the Trial Commences
During this planning stage the following documents should be generated
and should be on file before the trial formally starts.

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8.3 During the Clinical Conduct of the Trial
In addition to having the above documents, the following should be added
to the files during the trial as evidence that all new relevant information is
documented as it becomes available.

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8.4 After Completion or Termination of the Trial
After completion or termination of the trial, all of the documents identified in
sections 8.2 and 8.3 should be in the file together with the following:

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VII. USEFUL INTERNET SITES
HOMEPAGES
National Institutes of Health (NIH)
http://www.nih.gov/
NIH Office of Human Subjects Research
http://helix.nih.gov:8001/ohsr/
Grants, Office of Extramural Research
http://grants.nih.gov/grants/oer.htm
National Institute of Allergy and Infectious Diseases (NIAID)
http://www.niaid.nih.gov/
Division of Microbiology and Infectious Diseases (DMID), NIAID
http://www.niaid.nih.gov/research/dmid.htm
DHHS Office for Human Research Protections (OHRP)
http://ohrp.osophs.dhhs.gov/polasur.htm
U.S. Food and Drug Administration (FDA)
http://www.fda.gov/default.htm
FDA Information for Health Professionals
http://www.fda.gov/oc/oha/default.htm
FDA Center for Biologics Evaluation and Research (CBER) Regulatory Page
http://www.fda.gov/cber/index.html
FDA Center for Drug Evaluation and Research (CDER) Regulatory Page
http://www.fda.gov/cder/regulatory/default.htm
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH) Topics and
Guidelines
http://www.ifpma.org/ich5.html
US ARMY Medical Research and Materiel Command HomePage
Human Subjects Protection and Regulatory Divisions—
“Regulatory Compliance and Quality”
http://mrmc-www.army.mil/
Navy Medical Research Center IRB
http://www.nmri.nnmc.navy.mil/ORA/cphs.html
Veterans Health Administration Manual M-3, “Research and Development in
Medicine,” Part I, “General,” Chapter 9. Requirements for the Protection of
Human Subjects
http://www.va.gov/publ/direc/health/manual/03019.doc
Centers for Disease Control and Prevention (CDC) Human Subjects
Requirements
http://www.cdc.gov/od/ads/hsr2.htm
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GOOD CLINICAL PRACTICE
World Health Organization (WHO)
http://www.who.int/
Pan American Health Organization (PAHO)
http://www.paho.org/
European Forum for Good Clinical Practice
http://www.efgcp.org/

PROTECTION OF HUMAN SUBJECTS PARTICIPATING IN
CLINICAL RESEARCH
Belmont Report
http://www.fda.gov/oc/oha/IRB/toc11.html#The Belmont Repor t
Declaration of Helsinki (2000)
http://www.wma.net/e/policy/17-c_e.html
45CFR46-Human Subjects Protection
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm
Human Subject Regulations Decision Charts
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/decisioncharts.htm
NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/hsdc98-03.htm
National Institutes of Health (NIH) Guidelines on the Inclusion of Women
and Minorities as Subjects in Clinical Research
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/hsdc94-01.htm
FDA Office of Health Affairs: Clinical Trials and Human Subjects Protection
http://www.fda.gov/oc/health/hsp.html
World Wide Web Sites of Interest for Human Subject Protection Information
http://www.fda.gov/oc/oha/IRB/toc12.html#WORLD WIDE WEB SITES OF
INTEREST
SBIR/STTR: Human Subject Requirements (6/1/00) (slide show)
http://ohrp.osophs.dhhs.gov/humansubjects/assurance/sbirsttr/requirements
.htm
FDA Information Sheets: Guidance for Institutional Review Boards and
Clinical Investigators
http://www.fda.gov/oc/oha/IRB/toc.html

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USEFUL INTERNET SITES

Clinical Research
NIAID:What is a Clinical Trial?
http://www.niaid.nih.gov/clintrials/clinictrial.htm
FDA Good Clinical Practice (ICH E6)
http://www.fda.gov/cder/guidance/959fnl.pdf
National Cancer Institute Toxicity Table
http://ctep.info.nih.gov/handbook/HandBookText/Appendix_XII.htm#Att_3
http://ctep.info.nih.gov/CTC3/ctc_ind_term.htm
DMID Toxicity Table
http://www.niaid.nih.gov/dmid/
CBER Guidances/Guidelines
http://www.fda.gov/cber/guidelines.htm
CBER Points to Consider
http://www.fda.gov/cber/points.htm
CBER Information Sheets
http://www.fda.gov/cber/infosheets.htm
CBER Proposed/Final Rules
http://www.fda.gov/cber/rules.htm

RESEARCH INVOLVING HUMAN-DERIVED
MATERIALS/STORED SPECIMENS
Research on Human Specimens: Are You Conducting Research Using
Human Subjects?
http://www-cdp.ims.nci.nih.gov/brochure.html
OHRP Issues to Consider in the Research Use of Stored Data or Tissues
(11/7/1997)
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/reposit.htm

FDA INVESTIGATIONAL NEW DRUG APPLICATION (IND)
21CFR312— INVESTIGATIONAL NEW DRUG APPLICATION.
http://www.fda.gov/cber/ind/21cfr312.pdf

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INSTITUTIONAL REVIEW BOARD/ETHICAL
COMMITTEE (IRB/EC)
21CFR56-Institutional Review Boards
http://www.fda.gov/oc/oha/IRB/toc10.html#AppendixC
Important FDA Contacts for IRBs and Clinical Investigators
http://www.fda.gov/oc/oha/IRB/toc12.html#Important FDA Contacts for IRBs
and Clinical Investigators
FDA IRB Information Sheets: Guidance for Institutional Review Boards and
Clinical Investigators (1998 Update)
http://www.fda.gov/oc/oha/IRB/toc.html
Exempt Research and Research That May Undergo Expedited Review
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/hsdc95-02.htm
Categories of Research That May Be Reviewed by the Institutional Review
Board (IRB) Through an Expedited Review Procedure
http://ohrp.osophs.dhhs.gov/ expedited98.htm humansubjects/guidance/
IRB Review of Applications for HHS Suppor t
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/aplrev.htm

INFORMED CONSENT PROCESS
21CFR50-FDA Informed Consent Regulations
http://www.fda.gov/oc/oha/IRB/toc10.html#AppendixB
Tips on Informed Consent
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/ictips.htm
NCI Consent Documents and Guidance
http://cancertrials.nci.nih.gov/understanding/index.html
http://cancertrials.nci.nih.gov/researchers/safeguards/consent/index.html
DMID Informed Consent Documents and Guidance
http://www.niaid.nih.gov/dmid/
Suggested Language for Informed Consent for Future Use of Biological
Specimens Collected Under Clinical Protocols
http://www.niaid.nih.gov/dmid/

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