[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]
[[Page 25691]]
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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.
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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
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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).
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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).
[[Page 25700]]
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