[Federal Register Volume 62, Number 90 (Friday, May 9, 1997)]
[Notices]
[Pages 25692-25709]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-12138]



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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Good Clinical Practice: 
Consolidated Guideline; Notice of Availability

  Federal Register / Vol. 62, No. 90 / Friday, May 9, 1997 / Notices  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 95D-0219]


International Conference on Harmonisation; Good Clinical 
Practice: Consolidated Guideline; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a 
guideline entitled ``Good Clinical Practice: Consolidated Guideline.'' 
The guideline was prepared under the auspices of the International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). The guideline is intended to 
define ``Good Clinical Practice'' and to provide a unified standard for 
designing, conducting, recording, and reporting trials that involve the 
participation of human subjects. The guideline also describes the 
minimum information that should be included in an Investigator's 
Brochure (IB) and provides a suggested format. In addition, the 
guideline describes the essential documents that individually and 
collectively permit evaluation of the conduct of a clinical study and 
the quality of the data produced.

DATES:  Effective May 9, 1997. Written comments may be submitted at any 
time.

ADDRESSES: Submit written requests for single copies of ``Good Clinical 
Practice: Consolidated Guideline'' to the Drug Information Branch (HFD-
210), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4573. 
Send two self-addressed adhesive labels to assist that office in 
processing your requests. Submit written comments on the guideline to 
the Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Two copies of any 
comments are to be submitted, except that individuals may submit one 
copy. The ``Good Clinical Practice: Consolidated Guideline'' and 
received comments are available for public examination in the Dockets 
Management Branch (address above) between 9 a.m. and 4 p.m., Monday 
through Friday.

FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Bette L. Barton, Center for Drug 
Evaluation and Research (HFD-344), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1032.
    Regarding ICH: Janet J. Showalter, Office of Health Affairs (HFY-
20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-827-0864.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote international harmonization of regulatory 
requirements. FDA has participated in many meetings designed to enhance 
harmonization and is committed to seeking scientifically based 
harmonized technical procedures for pharmaceutical development. One of 
the goals of harmonization is to identify and then reduce differences 
in technical requirements for drug development among regulatory 
agencies.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
consumer representatives and others. ICH is concerned with 
harmonization of technical requirements for the registration of 
pharmaceutical products among three regions: The European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission, the European Federation of Pharmaceutical Industries 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, the Centers for Drug 
Evaluation and Research and Biologics Evaluation and Research, FDA, and 
the Pharmaceutical Research and Manufacturers of America. The ICH 
Secretariat, which coordinates the preparation of documentation, is 
provided by the International Federation of Pharmaceutical 
Manufacturers Associations (IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization, the Canadian Health Protection Branch, and the 
European Free Trade Area.
    In the Federal Register of August 17, 1995 (60 FR 42948), FDA 
published a draft tripartite guideline entitled ``Good Clinical 
Practice.'' In the Federal Register of August 9, 1994, FDA published 
draft tripartite guidelines entitled ``Guideline for the Investigator's 
Brochure'' (59 FR 40772) and ``Guideline for Essential Documents for 
the Conduct of a Clinical Study'' (59 FR 40774). The notices gave 
interested persons an opportunity to submit comments.
    After consideration of the comments received and revisions to the 
guidelines, the three guidelines were consolidated into one guideline 
on good clinical practice. The consolidated guideline was submitted to 
the ICH Steering Committee and endorsed by the three participating 
regulatory agencies at the ICH meeting held on April 30, 1996.
    The guideline defines ``Good Clinical Practice'' and provides a 
unified standard for designing, conducting, recording, and reporting 
trials that involve the participation of human subjects. Compliance 
with Good Clinical Practice provides public assurance that the rights, 
well-being, and confidentiality of trial subjects are protected and 
that trial data are credible. The guideline should be followed when 
generating clinical data that are intended to be submitted to 
regulatory authorities. The principles established in this guideline 
should also be applied to other investigations that involve therapeutic 
intervention in, or observation of, human subjects.
    The guideline also describes the minimum information that should be 
included in an IB, such as information on the drug's physical, 
chemical, and pharmaceutical properties, and its effect in humans; a 
suggested format for the IB is also provided. The guideline also 
describes the purpose of essential documents in a clinical study and 
explains whether the documents should be filed in the investigator's 
files or the sponsor's files.
    This guideline 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 statutes, regulations, or both.
    As with all of FDA's guidelines, the public is encouraged to submit 
written comments with new data or other new information pertinent to 
this guideline. The comments in the docket will be periodically 
reviewed, and, where appropriate, the guideline will be amended. The 
public will be notified of any such amendments through a notice in the 
Federal Register.
    Interested persons may, at any time, submit to the Dockets 
Management Branch (address above) written comments on the guideline. 
Two copies of any comments are to be submitted, except that individuals 
may submit one copy. Comments are to be identified with the docket 
number found in brackets in the heading of this

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document. A copy of the guideline and received comments may be seen in 
the office above between 9 a.m. and 4 p.m., Monday through Friday.
    An electronic version of this guideline is available via Internet. 
Type http://www.fda.gov/cder and go to the ``Regulatory Guidance'' 
section.
    The text of the guideline follows:

Good Clinical Practice: Consolidated Guideline

Table of Contents

Introduction
1. Glossary
2. The Principles of ICH CGP
3. Institutional Review Board/Independent Ethics Committee (IRB/IEC)
    3.1 Responsibilities
    3.2 Composition, Functions, and Operations
    3.3 Procedures
    3.4 Records
4. Investigator
    4.1 Investigator's Qualifications and Agreements
    4.2 Adequate Resources
    4.3 Medical Care of Trial Subjects
    4.4 Communication with IRB/IEC
    4.5 Compliance with Protocol
    4.6 Investigational Product(s)
    4.7 Randomization Procedures and Unblinding
    4.8 Informed Consent of Trial Subjects
    4.9 Records and Reports
    4.10 Progress Reports
    4.11 Safety Reporting
    4.12 Premature Termination or Suspension of a Trial
    4.13 Final Report(s) by Investigator/Institution
5. Sponsor
    5.1 Quality Assurance and Quality Control
    5.2 Contract Research Organization (CRO)
    5.3 Medical Expertise
    5.4 Trial Design
    5.5 Trial Management, Data Handling, Recordkeeping, and 
Independent Data Monitoring Committee
    5.6 Investigator Selection
    5.7 Allocation of Duties and Functions
    5.8 Compensation to Subjects and Investigators
    5.9 Financing
    5.10 Notification/Submission to Regulatory Authority(ies)
    5.11 Confirmation of Review by IRB/IEC
    5.12 Information on Investigational Product(s)
    5.13 Manufacturing, Packaging, Labeling, and Coding 
Investigational Product(s)
    5.14 Supplying and Handling Investigational Product(s)
    5.15 Record Access
    5.16 Safety Information
    5.17 Adverse Drug Reaction Reporting
    5.18 Monitoring
      5.18.1 Purpose
      5.18.2 Selection and Qualifications of Monitors
      5.18.3 Extent and Nature of Monitoring
      5.18.4 Monitor's Responsibilities
      5.18.5 Monitoring Procedures
      5.18.6 Monitoring Report
    5.19 Audit
      5.19.1 Purpose
      5.19.2 Selection and Qualification of Auditors
      5.19.3 Auditing Procedures
    5.20 Noncompliance
    5.21 Premature Termination or Suspension of a Trial
    5.22 Clinical Trial/Study Reports
    5.23 Multicenter Trials
6. Clinical Trial Protocol and Protocol Amendment(s)
    6.1 General Information
    6.2 Background Information
    6.3 Trial Objectives and Purpose
    6.4 Trial Design
    6.5 Selection and Withdrawal of Subjects
    6.6 Treatment of Subjects
    6.7 Assessment of Efficacy
    6.8 Assessment of Safety
    6.9 Statistics
    6.10 Direct Access to Source Data/Documents
    6.11 Quality Control and Quality Assurance
    6.12 Ethics
    6.13 Data Handling and Recordkeeping
    6.14 Financing and Insurance
    6.15 Publication Policy
    6.16 Supplements
7. Investigator's Brochure
    7.1 Introduction
    7.2 General Considerations
      7.2.1 Title Page
      7.2.2 Confidentiality Statement
    7.3 Contents of the Investigator's Brochure
      7.3.1 Table of Contents
      7.3.2 Summary
      7.3.3 Introduction
      7.3.4 Physical, Chemical, and Pharmaceutical Properties and 
Formulation
      7.3.5 Nonclinical Studies
      7.3.6 Effects in Humans
      7.3.7 Summary of Data and Guidance for the Investigator
    7.4 Appendix 1
    7.5 Appendix 2
8. Essential Documents for the Conduct of a Clinical Trial
    8.1 Introduction
    8.2 Before the Clinical Phase of the Trial Commences
    8.3 During the Clinical Conduct of the Trial
    8.4 After Completion or Termination of the Trial

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 Guideline 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 guideline 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 guideline should be followed when generating clinical trial 
data that are intended to be submitted to regulatory authorities.
    The principles established in this guideline 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 Guideline for 
Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).
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 Guideline 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 a trial 
is conducted.
1.5 Approval (in relation to Institutional Review Boards (IRB's))
    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

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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 (SOP's), 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 
analyses are fully integrated into a single report (see the ICH 
Guideline 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 
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.
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 
guideline.
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 (CRO's) 
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.
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

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investigational product(s) in human subjects (see 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 (SOP's), 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 SOP's.
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 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 Guideline, 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.
1.49 Regulatory Authorities 
    Bodies having the power to regulate. In the ICH GCP guideline, 
the expression ``Regulatory Authorities'' includes the authorities 
that review submitted clinical data and those that conduct 
inspections (see 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 for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting.)
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 (SOP's)
    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.
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 Guideline 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.
    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.

[[Page 25696]]

    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.
3.1.6 When a nontherapeutic trial is to be carried out with the 
consent of the subject's legally acceptable representative (see 
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 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.
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 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 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 4.10.2).
    (c) All adverse drug reactions (ADR's) 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.
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

[[Page 25697]]

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 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.
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 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 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

[[Page 25698]]

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.
    (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 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 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 CRF's 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 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 CRF's made by sponsor's designated 
representatives are documented, are necessary, and 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 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 
5.5.12).

[[Page 25699]]

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 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 (SAE's) should be reported 
immediately to the sponsor except for those SAE's 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.
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 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 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 SOP's 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 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.
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 guideline 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 CRF's 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 6.), the ICH Guideline for 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).
    (b) Maintain SOP's 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 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 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 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).

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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 
sponsor-specific 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 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 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 4.9.5).
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 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 4.1.4).
    (d) To retain the essential documents that should be in the 
investigator/institution files (see 8.) until the sponsor informs 
the investigator/institution these documents are no longer needed 
(see 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 
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 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.
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)).

[[Page 25701]]

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 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.
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 (ADR's) that are both serious and unexpected.
5.17.2 Such expedited reports should comply with the applicable 
regulatory requirement(s) and with the ICH Guideline 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 SOP's, GCP, and the applicable regulatory 
requirement(s).
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 on-site 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 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 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 CRF's 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 CRF's.
    (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 CRF's.
    (v) All withdrawals and dropouts of enrolled subjects from the 
trial are reported and explained on the CRF's.
    (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 (AE's) are 
appropriately reported within the time periods required by GCP, the 
protocol, the IRB/IEC, the sponsor, the applicable regulatory 
requirement(s), and indicated in the ICH Guideline for Clinical 
Safety Data Management: Definitions and Standards for Expedited 
Reporting.

[[Page 25702]]

    (p) Determining whether the investigator is maintaining the 
essential documents. (See 8. ``Essential Documents for the Conduct 
of a Clinical Trial.'')
    (q) Communicating deviations from the protocol, SOP's, 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 
SOP's as well as those procedures that are specified by the sponsor 
for monitoring a specific trial.
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, SOP's, 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-by-case basis, when evidence of serious GCP 
noncompliance exists, or in the course of legal proceedings or 
investigations.
    (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, SOP's, GCP, and/or 
applicable regulatory requirement(s) by an investigator/institution, 
or by member(s) of 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 
regulatory 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 marketing 
applications meet the standards of the ICH Guideline for Structure 
and Content of Clinical Study Reports. (NOTE: The ICH Guideline 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 CRF's are designed to capture the required data at all 
multicenter trial sites. For those investigators who are collecting 
additional data, supplemental CRF's 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 CRF's.
5.23.5 Communication between investigators is facilitated.
6. Clinical Trial Protocol and Protocol Amendment(s)
    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.
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., double-blind, 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):

[[Page 25703]]

    (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 
CRF's (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.
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 trial-related 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 Guideline for Structure and Content of Clinical Study 
Reports.)
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 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 guideline 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 
necessary. Where permitted by regulatory 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 (IRB's)/Independent Ethics 
Committees (IEC's) 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 IRB's/IEC's. 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 sponsor-investigator should provide, as a substitute, an 
expanded background information section in the trial protocol that 
contains the minimum current information described in this 
guideline.
7.2 General Considerations
    The IB 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.
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,

[[Page 25704]]

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;
    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).
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., 
formulations, 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.
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

[[Page 25705]]

the pharmacology of the investigational product.
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)
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)
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 serve 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 guideline may be 
subject to, and should be available for, audit by the sponsor's 
auditor and inspection by the regulatory authority(ies).
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.

                                                                                                                
----------------------------------------------------------------------------------------------------------------
                                                                                    Located in Files of         
                                                                          --------------------------------------
                   Title of Document                   Purpose                Investigator/                     
                                                                               Institution           Sponsor    
----------------------------------------------------------------------------------------------------------------
8.2.1       Investigator's brochure         To document that relevant and  X                    X               
                                             current scientific                                                 
                                             information about the                                              
                                             investigational product has                                        
                                             been provided to the                                               
                                             investigator                                                       
8.2.2       Signed protocol and             To document investigator and   X                    X               
             amendments, if any, and         sponsor agreement to the                                           
             sample case report form (CRF)   protocol/amendment(s) and                                          
                                             CRF                                                                
8.2.3       Information given to trial      To document the informed       X                    X               
             subject                         consent                                                            
            - Informed consent form                                                                             
             (Including all applicable                                     X                    X               
             translations)                  To document that subjects                                           
            - Any other written              will be given appropriate                                          
             information                     written information (content                                       
                                             and wording) to support       X                                    
                                             their ability to give fully                                        
                                             informed consent                                                   
            - Advertisement for subject     To document that recruitment                                        
             recruitment (if used)           measures are appropriate and                                       
                                             not coercive                                                       
8.2.4       Financial aspects of the trial  To document the financial      X                    X               
                                             agreement between the                                              
                                             investigator/institution and                                       
                                             the sponsor for the trial                                          
8.2.5       Insurance statement (where      To document that compensation  X                    X               
             required)                       to subject(s) for trial-                                           
                                             related injury will be                                             
                                             available                                                          
8.2.6       Signed agreement between        To document agreements                                              
             involved parties, e.g.:                                                                            
            - Investigator/institution and                                 X                    X               
             sponsor                                                       X                    X (Where        
            - Investigator/institution and                                                       required)      
             CRO                                                           X                    X               
            - Sponsor and CRO                                                                   X               
            - Investigator/institution and                                                                      
             authority(ies) (Where                                                                              
             required)                                                                                          

[[Page 25706]]

                                                                                                                
8.2.7       Dated, documented approval/     To document that the trial     X                    X               
             favorable opinion of IRB/IEC    has been subject to IRB/IEC                                        
             of the following:               review and given approval/                                         
                                             favorable opinion. To                                              
                                             identify the version number                                        
            - Protocol and any amendments    and date of the document(s).                                       
            - CRF (if applicable)                                                                               
            - Informed consent form(s)                                                                          
            - Any other written                                                                                 
             information to be provided to                                                                      
             the subject(s)                                                                                     
            - Advertisement for subject                                                                         
             recruitment (if used)                                                                              
            - Subject compensation (if                                                                          
             any)                                                                                               
            - Any other documents given                                                                         
             approval/favorable opinion                                                                         
8.2.8       Institutional review board/     To document that the IRB/IEC   X                    X (where        
             independent ethics committee    is constituted in agreement                         required)      
             composition                     with GCP                                                           
8.2.9       Regulatory authority(ies)       To document appropriate        X (where required)   X (where        
             authorization/approval/         authorization/approval/                             required)      
             notification of protocol        notification by the                                                
             (where required)                regulatory authority(ies)                                          
                                             has been obtained prior to                                         
                                             initiation of the trial in                                         
                                             compliance with the                                                
                                             applicable regulatory                                              
                                             requirement(s)                                                     
8.2.10      Curriculum vitae and/or other   To document qualifications     X                    X               
             relevant documents evidencing   and eligibility to conduct                                         
             qualifications of               trial and/or provide medical                                       
             investigator(s) and             supervision of subjects                                            
             subinvestigators                                                                                   
8.2.11      Normal value(s)/range(s) for    To document normal values and/ X                    X               
             medical/laboratory/technical    or ranges of the tests                                             
             procedure(s) and/or test(s)                                                                        
             included in the protocol                                                                           
8.2.12      Medical/laboratory/technical    To document competence of      X (where required)   X               
             procedures/tests                facility to perform required                                       
                                             test(s), and support                                               
                                             reliability of results                                             
            - Certification or                                                                                  
            - Accreditation or                                                                                  
            - Established quality control                                                                       
             and/or external quality                                                                            
             assessment or                                                                                      
            - Other validation (where                                                                           
             required)                                                                                          
8.2.13      Sample of label(s) attached to  To document compliance with    X                    X               
             investigational product         applicable labeling                                                
             container(s)                    regulations and                                                    
                                             appropriateness of                                                 
                                             instructions provided to the                                       
                                             subjects                                                           
8.2.14      Instructions for handling of    To document instructions       X                    X               
             investigational product(s)      needed to ensure proper                                            
             and trial-related materials     storage, packaging,                                                
             (if not included in protocol    dispensing, and disposition                                        
             or Investigator's Brochure)     of investigational products                                        
                                             and trial-related materials                                        
8.2.15      Shipping records for            To document shipment dates,    X                    X               
             investigational product(s)      batch numbers, and method of                                       
             and trial-related materials     shipment of investigational                                        
                                             product(s) and trial-related                                       
                                             materials. Allows tracking                                         
                                             of product batch, review of                                        
                                             shipping conditions, and                                           
                                             accountability.                                                    
8.2.16      Certificate(s) of analysis of   To document identity, purity,                       X               
             investigational product(s)      and strength of                                                    
             shipped                         investigational products to                                        
                                             be used in the trial.                                              
8.2.17      Decoding procedures for         To document how, in case of    X                    X (third party  
             blinded trials                  an emergency, identity of                           if applicable) 
                                             blinded investigational                                            
                                             product can be revealed                                            
                                             without breaking the blind                                         
                                             for the remaining subjects'                                        
                                             treatment                                                          
8.2.18      Master randomization list       To document method for                              X (third party  
                                             randomization of trial                              if applicable) 
                                             population                                                         
8.2.19      Pretrial monitoring report      To document that the site is                        X               
                                             suitable for the trial (may                                        
                                             be combined with 8.2.20)                                           
8.2.20      Trial initiation monitoring     To document that trial         X                    X               
             report                          procedures were reviewed                                           
                                             with the investigator and                                          
                                             investigator's trial staff                                         
                                             (may be combined with                                              
                                             8.2.19)                                                            
----------------------------------------------------------------------------------------------------------------

8.3 During the Clinical Conduct of the Trial
    In addition to having on file 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.

[[Page 25707]]



                                                                                                                
----------------------------------------------------------------------------------------------------------------
                                                                                   Located in Files of          
                                                                        ----------------------------------------
                 Title of Document                   Purpose                Investigator/                       
                                                                             Institution            Sponsor     
----------------------------------------------------------------------------------------------------------------
8.3.1      Investigator's Brochure        To document that investigator  X                    X                 
            updates                        is informed in a timely                                              
                                           manner of relevant                                                   
                                           information as it becomes                                            
                                           available                                                            
8.3.2      Any revisions to:              To document revisions of       X                    X                 
                                           these trial-related                                                  
           - Protocol/amendment(s) and     documents that take effect                                           
            CRF                            during trial                                                         
           - Informed consent form                                                                              
           - Any other written                                                                                  
            information provided to                                                                             
            subjects                                                                                            
           - Advertisement for subject                                                                          
            recruitment (if used)                                                                               
8.3.3      Dated, documented approval/    To document that the           X                    X                 
            favorable opinion of           amendment(s) and/or                                                  
            institutional review board     revision(s) have been                                                
            (IRB)/independent ethics       subject to IRB/IEC review                                            
            committee (IEC) of the         and were given approval/                                             
            following:                     favorable opinion. To                                                
                                           identify the version number                                          
           - Protocol amendment(s)         and date of the document(s)                                          
           - Revision(s) of:                                                                                    
             - Informed consent form                                                                            
             - Any other written                                                                                
            information to be provided                                                                          
            to the subject                                                                                      
             - Advertisement for subject                                                                        
            recruitment (if used)                                                                               
           - Any other documents given                                                                          
            approval/favorable opinion                                                                          
           - Continuing review of trial                                                                         
            (see 3.1.4)                                                                                         
8.3.4      Regulatory authority(ies)      To document compliance with    X (where required)   X                 
            authorizations/ approvals/     applicable regulatory                                                
            notifications where required   requirements                                                         
            for:                                                                                                
           - Protocol amendment(s) and                                                                          
            other documents                                                                                     
8.3.5      Curriculum vitae for new       (See 8.2.10)                   X                    X                 
            investigator(s) and/or                                                                              
            subinvestigators                                                                                    
8.3.6      Updates to normal value(s)/    To document normal values and  X                    X                 
            range(s) for medical           ranges that are revised                                              
            laboratory/technical           during the trial (see                                                
            procedure(s)/test(s)           8.2.11)                                                              
            included in the protocol                                                                            
8.3.7      Updates of medical/laboratory/ To document that tests remain  X (where required)   X                 
            technical procedures/tests     adequate throughout the                                              
           - Certification or              trial period (see 8.2.12)                                            
           - Accreditation or                                                                                   
           - Established quality control                                                                        
            and/or external quality                                                                             
            assessment or                                                                                       
           - Other validation (where                                                                            
            required)                                                                                           
8.3.8      Documentation of               (See 8.2.15)                   X                    X                 
            investigational product(s)                                                                          
            and trial-related materials                                                                         
            shipment                                                                                            
8.3.9      Certificate(s) of analysis     (See 8.2.16)                                        X                 
            for new batches of                                                                                  
            investigational products                                                                            
8.3.10     Monitoring visit reports       To document site visits by,                         X                 
                                           and findings of, the monitor                                         
8.3.11     Relevant communications other  To document any agreements or  X                    X                 
            than site visits               significant discussions                                              
           - Letters                       regarding trial                                                      
           - Meeting notes                 administration, protocol                                             
           - Notes of telephone calls      violations, trial conduct,                                           
                                           adverse event (AE) reporting                                         
8.3.12     Signed informed consent forms  To document that consent is    X                                      
                                           obtained in accordance with                                          
                                           GCP and protocol and dated                                           
                                           prior to participation of                                            
                                           each subject in trial. Also                                          
                                           to document direct access                                            
                                           permission (see 8.2.3)                                               
8.3.13     Source documents               To document the existence of   X                                      
                                           the subject and substantiate                                         
                                           integrity of trial data                                              
                                           collected. To include                                                
                                           original documents related                                           
                                           to the trial, to medical                                             
                                           treatment, and history of                                            
                                           subject                                                              
8.3.14     Signed, dated, and completed   To document that the           X (copy)             X (original)      
            case report forms (CRF's)      investigator or authorized                                           
                                           member of the investigator's                                         
                                           staff confirms the                                                   
                                           observations recorded                                                

[[Page 25708]]

                                                                                                                
8.3.15     Documentation of CRF           To document all changes/       X (copy)             X (original)      
            corrections                    additions or corrections                                             
                                           made to CRF after initial                                            
                                           data were recorded                                                   
8.3.16     Notification by originating    Notification by originating    X                    X                 
            investigator to sponsor of     investigator to sponsor of                                           
            serious adverse events and     serious adverse events and                                           
            related reports                related reports in                                                   
                                           accordance with 4.11                                                 
8.3.17     Notification by sponsor and/   Notification by sponsor and/   X (where required)   X                 
            or investigator, where         or investigator, where                                               
            applicable, to regulatory      applicable, to regulatory                                            
            authority(ies) and IRB(s)/     authorities and IRB(s)/                                              
            IEC(s) of unexpected serious   IEC(s) of unexpected serious                                         
            adverse drug reactions and     adverse drug reactions in                                            
            of other safety information    accordance with 5.17 and                                             
                                           4.11.1 and of other safety                                           
                                           information in accordance                                            
                                           with 4.11.2 and 5.16.2                                               
8.3.18     Notification by sponsor to     Notification by sponsor to     X                    X                 
            investigators of safety        investigators of safety                                              
            information                    information in accordance                                            
                                           with 5.16.2                                                          
8.3.19     Interim or annual reports to   Interim or annual reports      X                    X (where required)
            IRB/IEC and authority(ies)     provided to IRB/IEC in                                               
                                           accordance with 4.10 and to                                          
                                           authority(ies) in accordance                                         
                                           with 5.17.3                                                          
8.3.20     Subject screening log          To document identification of  X                    X (where required)
                                           subjects who entered                                                 
                                           pretrial screening                                                   
8.3.21     Subject identification code    To document that investigator/ X                                      
            list                           institution keeps a                                                  
                                           confidential list of names                                           
                                           of all subjects allocated to                                         
                                           trial numbers on enrolling                                           
                                           in the trial. Allows                                                 
                                           investigator/institution to                                          
                                           reveal identity of any                                               
                                           subject                                                              
8.3.22     Subject enrollment log         To document chronological      X                                      
                                           enrollment of subjects by                                            
                                           trial number                                                         
8.3.23     Investigational product(s)     To document that               X                    X                 
            accountability at the site     investigational products(s)                                          
                                           have been used according to                                          
                                           the protocol                                                         
8.3.24     Signature sheet                To document signatures and     X                    X                 
                                           initials of all persons                                              
                                           authorized to make entries                                           
                                           and/or corrections on CRF's                                          
8.3.25     Record of retained body        To document location and       X                    X                 
            fluids/tissue samples (if      identification of retained                                           
            any)                           samples if assays need to be                                         
                                           repeated                                                             
----------------------------------------------------------------------------------------------------------------

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:

                                                                                                                
----------------------------------------------------------------------------------------------------------------
                                                                                    Located in Files of         
                                                                          --------------------------------------
                   Title of Document                   Purpose                Investigator/                     
                                                                               Institution           Sponsor    
----------------------------------------------------------------------------------------------------------------
8.4.1       Investigational product(s)      To document that the           X                    X               
             accountability at site          investigational product(s)                                         
                                             have been used according to                                        
                                             the protocol. To document                                          
                                             the final accounting of                                            
                                             investigational product(s)                                         
                                             received at the site,                                              
                                             dispensed to subjects,                                             
                                             returned by the subjects,                                          
                                             and returned to sponsor                                            
8.4.2       Documentation of                To document destruction of     X (if destroyed at   X               
             investigational product(s)      unused investigational         site)                               
             destruction                     product(s) by sponsor or at                                        
                                             site                                                               
8.4.3       Completed subject               To permit identification of    X                                    
             identification code list        all subjects enrolled in the                                       
                                             trial in case follow-up is                                         
                                             required. List should be                                           
                                             kept in a confidential                                             
                                             manner and for agreed upon                                         
                                             time                                                               
8.4.4       Audit certificate (if           To document that audit was                          X               
             required)                       performed (if required) (see                                       
                                             5.19.3(e))                                                         
8.4.5       Final trial close-out           To document that all                                X               
             monitoring report               activities required for                                            
                                             trial close-out are                                                
                                             completed, and copies of                                           
                                             essential documents are held                                       
                                             in the appropriate files                                           

[[Page 25709]]

                                                                                                                
8.4.6       Treatment allocation and        Returned to sponsor to                              X               
             decoding documentation          document any decoding that                                         
                                             may have occurred                                                  
8.4.7       Final report by investigator/   To document completion of the  X                                    
             institution to IRB/IEC where    trial                                                              
             required, and where                                                                                
             applicable, to the regulatory                                                                      
             authority(ies) (see 4.13)                                                                          
8.4.8       Clinical study report (see      To document results and        X (if applicable)    X               
             5.22)                           interpretation of trial                                            
----------------------------------------------------------------------------------------------------------------


    Dated: April 30, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-12138 Filed 5-8-97; 8:45 am]
BILLING CODE 4160-01-F