[Federal Register Volume 60, Number 159 (Thursday, August 17, 1995)]
[Notices]
[Pages 42948-42957]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20375]




[[Page 42947]]

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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Draft Guideline on Good 
Clinical Practice; Availability; Notice

  Federal Register / Vol. 60, No. 159 / Thursday, August 17, 1995 / 
Notices  


[[Page 42948]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

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


International Conference on Harmonisation; Draft Guideline on 
Good Clinical Practice; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
guideline entitled ``Good Clinical Practice.'' This guideline was 
prepared under the auspices of the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The draft 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.

DATES: Written comments by October 2, 1995.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 
1-23, 12420 Parklawn Dr., Rockville, MD 20857. Copies of the draft 
guideline are available from the CDER Executive Secretariat Staff (HFD-
8), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855.

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 the 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 FDA 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 Industry 
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.
    On May 9, 1995, the ICH Steering Committee agreed that a draft 
guideline entitled ``Good Clinical Practice'' should be made available 
for public comment. The draft guideline is the product of the Efficacy 
Expert Working Group of the ICH. Comments about this draft will be 
considered by FDA and the Expert Working Group. Ultimately, FDA intends 
to adopt the ICH Steering Committee's final guideline.
    The draft 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. Compliance with this standard provides public assurance that 
the rights, well-being, and confidentiality of trial subjects are 
protected and that trial data are credible. The objective of this ICH 
GCP Guideline is to provide a unified standard for the European Union, 
Japan, and the United States that is consonant with the standards of 
Australia, Canada, the Nordic countries, and the World Health 
Organization.
    This 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.
    In the past, guidelines have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidelines to state procedures or standards of general applicability 
that are not legal requirements but are acceptable to FDA. The agency 
is now in the process of revising Sec. 10.90(b). Therefore, this 
guideline is not being issued under the authority of Sec. 10.90(b), and 
it does not create or confer any rights, privileges, or benefits for or 
on any person, nor does it operate to bind FDA in any way.
    Interested persons may, on or before October 2, 1995, submit to the 
Dockets Management Branch (address above) written comments on the draft 
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 document. The 
draft guideline and received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.
    The text of the draft guideline follows:

Guideline for Good Clinical Practice

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. This standard has its origin in the Declaration of 
Helsinki. Compliance with this standard provides public assurance 
that the rights, well-being, and confidentiality of trial subjects 
are protected 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 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.

1. Glossary

1.1  Adverse Drug Reaction (ADR)
    All noxious and unintended responses to a medicinal product 
(i.e., where the relationship between an adverse event and product 
cannot be ruled out) related to any dose. 

[[Page 42949]]


1.2  Adverse Event (AE)

    Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with 
this treatment. An adverse event (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.

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.

1.5  Audit

    A systematic and independent examination to determine whether 
trial-related activities were conducted and analyzed according to 
the protocol, sponsor's standard operating procedures (SOP's), good 
clinical practice (GCP), the applicable regulatory requirement(s), 
and whether the trial reports accurately reflect the procedures 
carried out, and the data collected.

1.6  Audit Certificate

    A written statement by the sponsor's auditor documenting/
confirming that an audit of clinical trial-related activities has 
been conducted.

1.7  Audit Report

    A written evaluation by the sponsor's auditor of the accuracy of 
the audited trial data, and the adherence of the trial to the 
protocol, the sponsor's SOP's, to GCP, and to applicable regulatory 
requirement(s).

1.8  Audit Trail

    Traceable documents or proof for audit of GCP and/or applicable 
regulatory requirement(s), which include the essential documents, 
and allow reconstruction of the course of events.

1.9  Case Report Form (CRF)

    A printed, optical, or electronic document designed to record 
all of the protocol required information that is to be reported to 
the sponsor on each trial subject.

1.10  Clinical Trial

    Any systematic study in human subjects intended to discover or 
verify the clinical, pharmacological and/or other pharmacodynamic 
effects of investigational products, and/or to identify any adverse 
reactions to investigational products, and/or to study absorption, 
distribution, metabolism, and excretion of these products with the 
object of ascertaining their safety and/or efficacy.

1.11  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 
analysis are fully integrated into a single report.

1.12  Comparator (Product)

    An investigational or marketed product, or placebo, used as a 
reference in a clinical trial.

1.13  Compliance (in relation to trials)

    Adherence to all trial-related requirements, GCP requirements, 
and applicable regulatory requirements.

1.14  Confidentiality

    Maintenance of secrecy of the sponsor's proprietary information 
and the subject's source data.

1.15  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 act as the basis of a contract.

1.16  Coordinating Investigator

    An investigator assigned the responsibility for the coordination 
of investigators at different centers participating in a multicenter 
trial.
1.17  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 responsibilities.

1.18  Direct Access

    Direct access refers to permission for domestic and foreign 
regulatory authorities, and the sponsor's auditors and monitors, to 
see, review, analyze, verify, and reproduce any records and reports 
that are important to evaluation of the clinical trial. When 
accessing trial-related documents, the regulatory authorities, and 
the sponsor's monitors and auditors, will take all reasonable 
precautions within the constraints of the applicable regulatory 
requirement(s) to maintain the confidentiality of subjects' 
identities.

1.19  Documentation

    All records, in any form (including, but not limited to, 
written, electronic, magnetic, and optical records, and scans, x-
rays, and EKG's) that describe or record the methods, conduct, and/
or results of a trial, the factors affecting a trial, and the 
actions taken.

1.20  Essential Documents

    Documents which individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced.

1.21  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.

1.22  Identification Code

    A unique identifier assigned by the investigator to each trial 
subject to protect the subject's identity and used in lieu of 
subjects' names when the investigator reports on adverse events and 
other trial data.

1.23  Impartial Witness

    A person, who is independent of the trial, who cannot be 
unfairly influenced by people involved with the trial, who 
participates in the informed consent process, and who documents (by 
signing and dating the written informed consent form) that the 
subject freely gave informed consent to participate in the trial.

1.24  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 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, the trial 
protocols and amendment(s), and the methods and material to be used 
in obtaining and documenting informed consent of the trial subjects.

1.25  Informed Consent

    A subject's voluntary confirmation of 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 
informed consent form that contains relevant information about the 
trial and that is signed and dated by the subject or the subject's 
legally acceptable representative.

1.26  Inspection

    The act by regulatory authorities of conducting an official 
review of documents, facilities, records, and any other resources 
deemed by them to be related to the clinical trial that may be 
located at the site of the trial, at the sponsor's facilities, at 
CRO's, or at other establishments deemed appropriate by such 
authorities.

1.27  Institution (medical)
    Any public or private entity or agency or medical or dental 
facility where clinical trials are conducted.

1.28  Institutional Review Board (IRB)

    See Independent Ethics Committee (IEC).

1.29  Interim Clinical Trial/Study Report

    A report of intermediate results and their evaluation based on 
analyses performed during the course of a trial.

1.30  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 other 
than as authorized, i.e., in a way different from the approved form, 
or when used in a clinical setting other than the one approved, or 
when used to gain further information about the approved use.

1.31  Investigator

    A person responsible for the conduct of the clinical trial at a 
trial site. In the event that 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 

[[Page 42950]]
called the principal investigator. See also Subinvestigator.

1.32  Investigator/Institution

    Expression meaning ``the investigator or institution, if 
required by the applicable laws and regulations.''

1.33  Investigator's Brochure

    A compilation of the clinical and nonclinical data on the 
investigational product that are relevant to its study in human 
subjects.

1.34  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.

1.35  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, GCP, and the applicable regulatory 
requirement(s). A person, designated by the sponsor, who is 
responsible for the monitoring is a monitor.

1.36  Monitoring Report

    A written report from the monitor to the sponsor after each site 
visit and after all trial-related communications (audit trail 
concept). Reports should include findings and any actions taken.

1.37  Multicenter Trial

    A clinical trial conducted according to one single protocol but 
at different centers (institutions), and therefore, carried out by 
more than one investigator.

1.38  Nonclinical Study

    Biomedical studies not performed on human subjects.

1.39  Opinion (in relation to Independent Ethics Committee)

    A professional judgment and/or advice provided by an Independent 
Ethics Committee (IEC).

1.40  Original Medical Record

    See Source Documents.
1.41  Protocol

    A document that provides the background, rationale, and 
objective(s) of the trial and describes its design, methodology, and 
organization, including statistical considerations.

1.42  Protocol Amendment

    A written description of the change(s) to a protocol.

1.43  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).

1.44  Quality Control (QC)

    The operational techniques and activities undertaken within the 
quality assurance system to verify that the requirements for quality 
of the trial have been fulfilled. Quality control activities are 
undertaken by all members of the investigational team, including the 
staff of the sponsor or contract research organization (CRO), 
involved with planning, conducting, monitoring, data processing/
management, documenting (recording), analyzing, evaluating, and 
reporting a trial with the objective of performing the trial in 
compliance with the protocol, GCP, and applicable regulatory 
requirement(s) and drawing conclusions from reliable data.

1.45  Randomization

    The process of assigning trial subjects to treatment or control 
groups using a procedure by which only chance (unbiased) determines 
the assignments (random allocation).

1.46  Serious Adverse Event (SAE)

    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
--Results in a congenital anomaly/birth defect.

1.47  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).

1.48  Source Documents

    Original documents and records (e.g., 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 
copies, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, and subject files) kept at the pharmacy, the 
laboratories, and at medico-technical departments involved in the 
clinical trial.

1.49  Sponsor

    An individual, a company, an institution, or an organization 
which takes responsibility for the initiation, management, and/or 
financing of a clinical trial.

1.50  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.

1.51  Standard Operating Procedures (SOP's)

    Detailed, written instructions to achieve uniformity of the 
performance of a specific function.

1.52  Subinvestigator

    Any individual member of the clinical trial team designated and 
supervised by the investigator at a trial site.
    See also Investigator.

1.53  Subject

    An individual who participates in a clinical trial, either as a 
recipient of the investigational product(s) or as a control.

1.54  Trial Site

    The location(s) where trial-related activities are actually 
conducted.

1.55  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 for an approved product).
1.56   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 the hierarchy or institution 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 rooms, 
ethnic minority groups, homeless persons, nomads, refugees, 
children, and those incapable of giving consent.

1.57   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 
and amendment(s) that have received prior institutional review board 
(IRB)/independent ethics committee (IEC) approval/favorable opinion. 


[[Page 42951]]

    2.7  The medical care given to, and medical decisions made for, 
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.
    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 
and amendment(s).
    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  To fulfill its responsibilities, the following documents 
should be submitted to the IRB/IEC: Trial protocols, protocol 
amendment(s), written informed consent forms, consent form updates, 
subject recruitment procedures (e.g., advertisements), written 
information to be provided to subjects, Investigator's Brochure 
(IB), safety reports, documents related to payments and compensation 
available to subjects, and any other documents that the IRB/IEC may 
require.
    The IRB/IEC should review a proposed clinical trial within a 
reasonable time limit and document their views in writing, clearly 
identifying the trial, the documents reviewed, and the dates for the 
following:
    Approval/favorable opinion;
    Modifications required prior to approval/favorable opinion;
    Disapproval/negative opinion; and
    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.
    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 should require that more information than is 
outlined in paragraph 4.8.10 for written informed consent forms, and 
for written information to be provided to subjects, be given to 
subjects when, in the judgment of the IRB/IEC, the additional 
information is necessary to protect the rights and/or well-being of 
the subjects.
    3.1.6  The IRB/IEC should review both the amount and method of 
payment to subjects to assure that neither present problems of 
coercion or undue influence on the trial subjects.
    3.1.7  The IRB/IEC should ensure that all information regarding 
payment, including amounts and schedule of payment to trial 
subjects, is set forth in the written informed consent form. Such 
payments should not be wholly contingent upon the trial subject's 
completion of the trial. Prorated payment should be specified in the 
written informed consent form.
    3.1.8  Except where national law does not permit, the IRB/IEC 
should evaluate whether remuneration is coercive by reviewing the 
extent to which investigators/institutions may be rewarded/
compensated for participation (see 4.4.2, 5.9).

3.2  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 properly the science 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 concern is in a 
nonscientific area.
    (c) All members independent of the investigator and the sponsor.
    (d) At least one member who is independent of the trial site.
    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 where 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 advice.
    3.2.5  The investigator may provide information on any aspect of 
the trial, but at the time the IRB/IEC makes a decision, the 
investigator should not participate in the vote/opinion.
    3.2.6  An IRB/IEC may invite nonmembers who have expertise in 
special areas for assistance.
    3.3  Procedures
    The IRB/IEC should establish, document in writing, and follow 
its procedures that include:
    3.3.1  Determining its composition (names and qualifications of 
the members and the authority under which the committee 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.
    3.3.5  Providing expedited review and approval/favorable opinion 
of trials involving no more than minimal risk or of change(s) not 
increasing the risk for a trial for which approval/favorable opinion 
was provided by the IRB/IEC.
    3.3.6  Prohibiting admission of subjects to a trial before the 
IRB/IEC issues its written approval/favorable opinion of the trial.
    3.3.7  Prohibiting initiation of changes in the protocol without 
prior IRB/IEC approval/favorable opinion of an appropriate 
amendment, except when necessary to eliminate immediate hazards to 
the human subjects or when the change involves logistical or 
administrative aspects of the trial (e.g., change in monitor, phone 
number).
    3.3.8  Providing that the investigator promptly reports to the 
IRB/IEC:
    (a) Changes in a trial implemented to eliminate immediate 
hazards to the trial subjects.
    (b) Changes affecting significantly the conduct of the trial, 
and/or increasing the risk to subjects.
    (c) All serious and unexpected adverse drug reactions (ADR's).
    (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.
    (b) The reasons for its decisions.
    (c) Procedures for appeal of its decisions.

3.4  Records

    Where required by applicable regulation, the IRB/IEC should 
retain all relevant records (e.g., written procedures, membership 
lists, 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).
    Written procedures and membership lists should be made available 
upon request from the investigator(s), and/or the sponsor(s), except 
where national law does not permit.

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 required by 
the applicable regulatory requirements, and should provide evidence 
of such qualifications through up- to-date curriculum vitae and 
other credentials.
    4.1.2  The investigator should be thoroughly familiar with the 
appropriate use of the investigational product(s), as described in 
the protocol/amendment(s), in the current Investigator's Brochure, 
in other information sources provided by the sponsor, and in the 
available literature.
    4.1.3  The investigator should be aware of, and should comply 
with, GCP and the applicable regulations.
    4.1.4  The investigator/institution should permit monitoring and 
auditing by the sponsor, and inspecting by the appropriate 
regulatory authorities.
    4.1.5  The investigator should maintain a written record of 
appropriately qualified persons, delegated to assume specified 
investigator trial responsibilities. 

[[Page 42952]]


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  To conduct the trial properly and safely, the 
investigator should have available an adequate number of qualified 
staff and adequate facilities for the foreseen duration of the 
trial.
    4.2.4  The investigator should ensure that all persons assisting 
with the trial are adequately informed about the protocol/
amendment(s), the investigational product(s), and their trial-
related responsibilities.

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  For the duration of a subject's participation in a trial, 
the investigator should ensure that adequate medical care (or dental 
care, when appropriate) is made available to the subject for trial-
related illness(es)/adverse event(s). The investigator should inform 
the subject when medical care is needed for intercurrent illness(es) 
of which the investigator becomes aware. Following a subject's 
participation in a trial, the investigator should ensure that 
adequate medical care is provided for any adverse events, including 
clinically significant laboratory values, related to the trial.
    4.3.3  It is recommended that the investigator inform the 
subject's primary physician, when there is one, with the subject's 
consent, about the participation in the trial.
    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 should have 
written and dated approval/favorable opinion from the IRB/IEC for 
the trial protocol/amendment(s), written informed consent form, 
consent form updates, subject recruitment procedures (e.g., 
advertisements), and written information to be provided to subjects.
    4.4.2  Except where national law does not permit, the 
investigator also should obtain approval/favorable opinion from the 
IRB/IEC for the trial-related costs and payments (see 3.1.8, 5.9, 
5.11).
    4.4.3  As part of the investigator's written application to the 
IRB/IEC, the investigator should provide the IRB/IEC with a current 
copy of the Investigator's Brochure. If the updated Investigator's 
Brochure contains important updates on safety information and 
clinical trial analyses, the investigator should supply a copy to 
the IRB/IEC.
    4.4.4  During the trial the investigator should provide to the 
IRB/IEC all documents subject to review (see 3.1.2, 3.1.5, 3.1.7, 
3.3.8, 4.10, 4.11).

4.5  Compliance with Protocol/Amendment(s)

    4.5.1  The investigator/institution should conduct the trial in 
compliance with the protocol/amendment(s) agreed to by the sponsor, 
and the IRB/IEC and, if required, by the appropriate authority(ies). 
The investigator/institution and the sponsor should sign the 
protocol/amendment(s), or an alternative contract, to confirm 
agreement.
    4.5.2  The investigator should not implement any changes in a 
trial without agreement by the sponsor and prior review or expedited 
review by the IRB/IEC, and without documented approval/favorable 
opinion of an appropriate amendment, except when the change involves 
logistical or administrative aspects of the trial.
    4.5.3  The investigator, or person designated by the 
investigator, should document and explain any deviation from the 
approved protocol/amendment(s).
    4.5.4  The investigator may implement a deviation, where 
necessary, to eliminate an immediate hazard(s) to trial subjects 
without prior IRB/IEC approval/favorable opinion. As soon as 
possible, the implemented deviation, the reasons, and, if 
appropriate, the proposed protocol amendment(s) should be submitted: 
(1) to the IRB/IEC for review and approval/favorable opinion, (2) to 
the sponsor for agreement, and, if required, (3) to the appropriate 
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.
    4.6.2  Where allowed/required, the investigator may/should 
assign some/all of the investigator's duties for investigational 
product(s) accountability at the trial site(s) to an appropriate 
pharmacist.
    4.6.3  The investigator should ensure that the investigational 
product(s) are used only in accordance with the approved protocol/
amendment(s).
    4.6.4  The investigator, or a person designated by the 
investigator, should clearly explain the correct use of the 
investigational product(s) to each subject and should check, at each 
subject visit, that the subject is using the product(s) properly.
    4.6.5  The investigator and/or pharmacist 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/amendment(s) and 
reconcile all investigational product(s) received from the sponsor.
    4.6.6  The investigational product(s) should be properly and 
safely stored in accordance with applicable regulatory 
requirement(s).

4.7  Randomization Procedures

    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 document and explain any unblinding of the 
investigational product(s) promptly to the sponsor.

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 written information to be provided to 
subjects.
    4.8.2  The written informed consent form and written information 
to be provided to subjects should be revised whenever new 
information becomes available that may be relevant to the subject. 
Any revised written informed consent form, and written trial 
information should receive the IRB/IEC's approval/favorable opinion 
in advance of use.
    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 as approved/received favorable opinion from 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 nontechnical and should be understandable to the subject or the 
subject's legally acceptable representative.
    4.8.7  Before informed consent is given, the investigator, or a 
person designated by the investigator, should provide the subject or 
the subject's legally acceptable representative ample time to decide 
and opportunity to inquire about details of the trial. All questions 
about the trial should be answered to the satisfaction of the 
subject or the subject's legally acceptable representative.
    4.8.8  Prior to participation in the trial, the written informed 
consent form should be signed and personally dated by the subject, 
or the subject's legally acceptable representative, and by the 
person who conducted the informed consent discussion.
    4.8.9  If the subject or the subject's legally acceptable 
representative is unable to read, 

[[Page 42953]]
an impartial witness should be present during the entire informed 
consent discussion. After the written informed consent form is read 
to the subject and orally consented to, and signed and personally 
dated by the subject, if capable of doing so, or the subject's 
legally acceptable representative, the witness should also sign and 
personally date the consent form, attesting 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 should include clear explanations of the 
following:
    (a) The trial involves research.
    (b) The purpose of the trial.
    (c) The trial treatment(s).
    (d) The trial procedures to be followed, including all invasive 
procedures.
    (e) The subject's responsibilities.
    (f) Those trial features that are experimental.
    (g) The reasonably foreseeable risks or inconveniences to the 
subject.
    (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 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 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 confidentiality of records that identify the subject 
will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and/or regulations.
    (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 
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 circumstances under which the subject's participation in 
the trial may be terminated without the subject's consent.
    (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  The subject or the subject's legally acceptable 
representative should receive a copy of the signed and dated written 
informed consent form and signed and dated consent form updates, and 
a copy of the written trial information to be provided to subjects 
and its amendment(s).
    4.8.12  To the extent that a minor child is capable of 
understanding and granting informed consent, the minor should give 
consent and, in addition to the minor's legally acceptable 
representative, the minor should sign and personally date the 
written informed consent form if the minor is capable of doing so.
    4.8.13  In a nontherapeutic trial (i.e., when there is no 
anticipated direct clinical benefit to the subject), consent should 
always be given by the subject and the written consent form should 
be signed and personally dated by the subject.
    4.8.14  Where prior consent of the trial subject is not 
possible, the protocol submitted to the IRB/IEC may provide that 
such consent need not be obtained and that only the consent of the 
subject's legally acceptable representative, if present, should be 
solicited. Absence of the subject's legally acceptable 
representative should require other measures that are described in 
the protocol to ensure compliance with applicable regulatory 
requirements. The trial subject or the subject's legally acceptable 
representative should be informed as soon as possible and consent 
should be requested.

4.9 Records and Reports

    4.9.1  The source documents should support the data reported on 
the CRF, should identify the trial, and should document the dates of 
the subject's participation.
    4.9.2  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.
    4.9.3  Any correction to a CRF should not obscure the original 
entry; this applies to both written and electronic corrections (see 
5.18.5(n)). Sponsors should provide guidance to investigators or the 
investigators' designated representatives on making such 
corrections. Sponsors should have written procedures to assure that 
changes made by sponsor's designated representatives in CRF's are 
necessary, documented by an audit trail, and endorsed by the 
investigator.
    4.9.4  The investigator/institution should maintain the trial 
documents as specified in the ICH Guideline for ``Essential 
Documents for the Conduct of a Clinical Trial,'' and as required by 
the applicable regulatory requirements. The investigator/institution 
should take measures to prevent accidental or premature destruction 
of records, including the subject's original medical records and 
accountability records for the investigational product(s).
    4.9.5  Where there are no applicable regulatory requirements 
that require the retention of the essential documents for at least 2 
years after the last marketing application approval or 2 years after 
formal discontinuation of the clinical development of the 
investigational product, the investigator/institution should prevent 
accidental or premature destruction of records for the period 
specified in the agreement with the sponsor, which should be at 
least as long as indicated above.
    4.9.6  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  The investigator should routinely submit written 
summaries of the status of the trial to the IRB/IEC. These reports 
should be submitted annually or more frequently if required by the 
IRB/IEC.
    4.10.2  The investigator should promptly provide written reports 
to the sponsor and the IRB/IEC (see 3.3.8) on any problems, changes, 
or occurrences 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 unless the protocol or other document 
(e.g., Investigator's Brochure) identifies certain expected SAE's as 
not needing immediate reporting. This immediate reporting should be 
followed promptly by detailed, written reports, which should 
identify subjects by unique code numbers assigned to the trial 
subjects instead of by the subjects' names, personal identification 
numbers, and/or addresses. The investigator should also comply with 
local regulatory requirements related to the reporting of unexpected 
serious adverse drug reactions to the regulatory authority(ies) and/
or the IRB/IEC.
    4.11.2  In addition, those adverse events and/or laboratory 
abnormalities, which are identified in the protocol/amendment(s) as 
critical to safety evaluations, should be reported to the sponsor 
according to the reporting requirements and within the time periods 
that are specified by the sponsor in the protocol/amendments.
    4.11.3  For all reported deaths, the investigator should supply 
the sponsor and, where required, the IRB/IEC with relevant 
information including autopsy reports and terminal medical reports.

4.12 Trial Termination or Suspension

    4.12.1  If the trial is terminated or suspended by the 
investigator without prior agreement of the sponsor, the 
investigator should inform the institution where applicable and the 
investigator/institution should provide promptly to the sponsor and 
the IRB/IEC a detailed explanation of the termination/suspension.
    4.12.2  If the trial is terminated/suspended by the sponsor, the 
investigator should provide promptly to the IRB/IEC and the 
institution, where required, a detailed explanation of the 
termination/suspension.
    4.12.3  If the IRB/IEC terminates or suspends a trial, the 
investigator should immediately notify the sponsor and provide the 
sponsor with a detailed written explanation of the termination/
suspension. 

[[Page 42954]]


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(s), GCP, and the applicable regulatory requirements.
    5.1.2  The sponsor is responsible for securing agreement from 
all involved parties to ensure the availability of all trial-related 
sites and source data/documents, and reports for the purpose of 
monitoring and auditing by the sponsor, and inspecting 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 any other parties involved with the clinical trial, 
should be in writing, as part of the protocol or a written contract, 
to assure the quality of the trial-related activities.

5.2  Contract Research Organization (CRO)

    5.2.1  A sponsor may transfer any or all of the sponsor's trial-
related responsibilities to a CRO. However, the ultimate 
responsibility for the quality and integrity of the trial data 
should always reside with the sponsor. The sponsor should ensure 
that the CRO has and implements quality assurance and quality 
control.
    5.2.2  Each trial-related responsibility that is transferred to 
and assumed by a CRO should be specified in a written contract.
    5.2.3  All trial-related responsibilities not specifically 
transferred to and assumed by a CRO should be considered to be 
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 
responsibilities of a sponsor.

5.3  Medical Expertise

    The sponsor should designate appropriately qualified medical 
personnel, who are readily available to advise on trial-related 
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 experts (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 analysis to 
analyzing and preparing interim and final clinical trial reports.
    5.4.2  See Chapter 6 ``Clinical Trial Protocol and Protocol 
Amendment(s),'' and the ICH Guideline for ``Structure and Content of 
Clinical Study Reports,'' and other appropriate ICH guidance on 
trial design and protocols.

5.5  Trial Management, Data Handling, and Recordkeeping

    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  When using electronic trial data handling and/or remote 
electronic trial data systems, the sponsor should:
    (a) Ensure that only validated data processing systems are used.
    (b) Maintain SOP's for using these systems.
    (c) Ensure that the systems are designed to allow data changes 
without any deletion of entered data (i.e., maintain an audit 
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.
    (f) Maintain adequate backup of the data.
    (g) Safeguard the blinding, if any.
    5.5.3  The sponsor should ensure the greatest possible accuracy 
when processing data. If data are transformed during processing, it 
should always be possible to compare the original data and 
observations with the processed data.
    5.5.4  The sponsor should use an unambiguous subject code that 
enables identification of all the data reported for each subject.
    5.5.5  The sponsor, or other owners of the data, should retain 
all of the sponsor-specific essential documents pertaining to the 
trial. (See ICH Guideline for ``Essential Documents for the Conduct 
of a Clinical Trial.'')
    5.5.6  The sponsor should retain all sponsor-specific essential 
documents in conformance with the applicable regulatory 
requirement(s) of the country(ies) where the product is approved, 
and/or where the sponsor intends to apply for approval(s).
    5.5.7  If the sponsor discontinues the clinical development of 
an investigational product 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).
    5.5.8  If the sponsor discontinues the clinical development of 
an investigational product, the sponsor should notify all the trial 
investigators and all the appropriate regulatory authorities.
    5.5.9  Any transfer of ownership of the data should be reported 
to the appropriate authority(ies), as required by the applicable 
regulatory requirement(s).
    5.5.10  Where there are no applicable regulatory requirement(s) 
that require the investigator/institution to retain the trial-
related essential documents for at least 2 years after the last 
marketing application approval or 2 years after formal 
discontinuation of the clinical development of the investigational 
product for any or all indications, routes of administration, or 
dosage forms, it is recommended that the sponsor agree with the 
investigator/institution to prevent accidental or premature 
destruction of the essential documents, for a period, which should 
be at least as long as indicated above.

5.6  Investigator Selection

    5.6.1  The sponsor is responsible for selecting the 
investigator(s)/institution(s). The sponsor should select the 
investigator(s) who is/are qualified by training and experience to 
conduct the trial(s) and have adequate resources (see 4.1, 4.2). If 
coordinating committees and/or selection of coordinating 
investigator(s) are appropriate in multicenter trials, the 
organization and/or selection is 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 to conduct the trial in compliance with the 
agreed to and/or approved protocol/amendment(s), and with GCP and 
the applicable regulatory requirement(s), and to accept procedures 
for data recording/reporting, monitoring, auditing, and inspecting. 
The sponsor and the investigator/institution should sign the 
protocol/amendment(s), or an alternative document, to confirm this 
agreement.

5.7  Allocation of Responsibilities

    Prior to initiating a trial, the sponsor should define, 
establish, and allocate all trial-related responsibilities to either 
the sponsor, investigator(s), and/or other parties.

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/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 should comply with applicable regulatory requirement(s).

5.9  Financing

    Except where national law does not permit, the financial aspects 
of the trial should be documented as an agreement between the 
sponsor and the investigator/institution, and should be reviewed by 
the IRB/IEC and by the appropriate authority(ies) to evaluate if 
remuneration is not coercive (see 3.1.8, 4.4.2).

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/
amendment(s). 

[[Page 42955]]


5.11  Confirmation of Review by IRB/IEC

    5.11.1  The sponsor should obtain from each investigator:
    (a) The name and address of the investigator's IRB/IEC.
    (b) Statement from the IRB/IEC that it complies with GCP and the 
applicable laws and regulations.
    (c) Documented IRB/IEC approval/favorable opinion and, where 
required, a current copy of protocol/amendment(s), written informed 
consent forms, and written information to be provided to subjects, 
subject recruiting procedures, documents related to payments and 
compensation available to the subjects, and any other documents that 
the IRB/IEC may require.
    5.11.2  If the IRB/IEC conditions its approval/favorable opinion 
of the protocol and/or amendment(s), written informed consent form, 
written information to be provided to subjects and other procedures 
upon modifications, the sponsor should obtain from the investigator:
    (a) A copy of the modification(s) as approved/received favorable 
opinion by the IRB/IEC.
    (b) Documentation that the modification(s) was/were approved/
received favorable opinion by the IRB/IEC and the date of the IRB/
IEC's approval/favorable opinion.
    5.11.3  The sponsor should obtain documentation and dates of any 
reapprovals/re-evaluations 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 the 
availability of sufficient safety and efficacy data for the 
product(s), including the available data from investigations and/or 
marketing worldwide. Sufficient safety and efficacy data from 
nonclinical studies and/or clinical trials should be available to 
justify human exposure by the route, at the dosages, and for the 
duration proposed to be studied during the trial and should be 
appropriate to the phase, type, and target population of the 
proposed trial.
    5.12.2  The sponsor should update the Investigator's Brochure as 
significant new information becomes available. (See ICH Guideline 
for ``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 comparators and placebo, if applicable) 
is characterized as appropriate to the stage of development of the 
product(s), manufactured in accordance with any applicable GMP, and 
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 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 during the course of the 
clinical development/trial, the results of additional studies (e.g., 
stability, comparative dissolution rate, comparative 
bioavailability) demonstrating that these changes would not be 
expected to alter the pharmacokinetic profile or other clinical 
characteristics of the product should be available prior to the use 
of the new formulation in the clinical trial.

5.14  Supplying and Handling Investigational Product(s)

    5.14.1  The sponsor is responsible for supplying the 
investigator(s) with the investigational product(s).
    5.14.2  The sponsor should not supply an investigator with the 
investigational product(s) until the sponsor obtains documentation 
of all required approvals (e.g., IRB/IEC and authorities).
    5.14.3  The sponsor should ensure that written procedures 
include the requirements that the investigator/institution follow 
for the handling and storage of investigational product(s) for the 
trial and documentation thereof. The procedures should address 
adequate and safe receipt, handling, storage, dispensing, retrieval 
of unused product from subjects, and return of unused 
investigational product(s) to the sponsor (or alternative 
disposition if authorized by the sponsor and in compliance with the 
applicable regulatory requirement(s)).
    5.14.4  The sponsor should:
    (a) Ensure timely delivery of investigational product(s) to the 
investigator(s).
    (b) Maintain records that document shipment, delivery, receipt, 
disposition, return, and destruction of the investigational 
product(s). (See ICH Guideline for ``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 documenting this disposition.
    5.14.5  Where GMP does not apply to investigational product(s), 
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 batch samples of the 
investigational product(s) in order to reconfirm specifications, if 
it appears necessary, and maintain records of batch sample analyses 
and characteristics. To the extent stability permits, batch samples 
should be retained either until the statistical analyses 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 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 the 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.
    (c) Monitors should be thoroughly familiar with the 
investigational product(s), the protocol/amendment(s), written 
informed consent form, written information to be provided to 
subjects, GCP, and the applicable regulatory requirement(s).
    5.18.3  Number of Monitors
    The sponsor should ensure that the trials are appropriately 
monitored at the trial sites. 

[[Page 42956]]

    The number of monitors needed to ensure adequate monitoring of a 
trial depends primarily on the complexity of the trial, the number 
and locations of trial sites, and the number of trial subjects.
    5.18.4  Monitoring Schedule
    The monitor(s) should visit the trial site(s) before, during, 
and after the trial. The on-site visits should be frequent enough to 
monitor the trial adequately.
    5.18.5  Monitor's Responsibilities
    The monitor(s) should ensure that the trial is conducted and 
documented properly by:
    (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 remain adequate throughout the 
trial period, that facilities, including laboratories, equipment, 
and staff, are adequate to safely and properly conduct the trial and 
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.
    (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, as per written 
agreement between the sponsor and the investigator/institution, and 
have not delegated these functions to unauthorized or unapproved 
individuals.
    (i) Verifying that the investigator is enrolling only eligible 
subjects.
    (j) Reporting the subject recruitment rate.
    (k) Verifying that accurate, complete, and current source 
documents and trial records are 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 
against the subjects' source documents and other trial-related 
records. 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 documents.
    (ii) Any dose and/or therapy modifications are well documented 
for each of the trial subjects.
    (iii) 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 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, and the applicable regulatory 
requirement(s).
    (p) Determining whether the investigator is maintaining the 
essential documents. (See Guideline for ``Essential Documents for 
the Conduct of a Clinical Trial.'')
    (q) Communicating significant deviations to the investigator and 
taking appropriate action to prevent recurrence of the detected 
deviations.
    5.18.6  Monitoring Procedures
    The monitor should follow established written Standard Operating 
Procedures.
    5.18.7  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 time, date, site, name of the 
monitor, and name of the investigator or other individual(s) 
contacted.
    (c) Reports should include 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 followup of the monitoring report with the 
sponsor should be documented.

5.19  Audit

    If or when, as part of implementing quality assurance, the 
sponsors performing audits 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, protocol compliance, and GCP 
compliance.
    5.19.2  Selection and Qualification of Auditors
    (a) The sponsor should appoint individuals who are independent 
of the trial to conduct audits.
    (b) The sponsor should ensure that the auditors are qualified by 
training and experience to conduct audits properly.
    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 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 in an audit report.
    (d) The audit reports should not routinely be made available for 
inspection, but should be made available for inspection upon request 
by the regulatory authority(ies).
    (e) When required by applicable law or regulation, the sponsor 
should provide an audit certificate.

5.20  Noncompliance

    5.20.1  Noncompliance with the protocol, 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 monitoring and/or auditing identified serious and/or 
persistent noncompliance of an investigator, the sponsor should 
terminate the investigator's participation in the trial. When an 
investigator's participation is terminated because of noncompliance, 
the sponsor should notify promptly the responsible IRB(s)/IEC(s) and 
the appropriate authority(ies).

5.21  Premature Termination of a Trial

    If a trial is prematurely terminated, the sponsor should 
promptly inform the investigators/institutions, the IRB(s)/IEC(s), 
and the appropriate regulatory authority(ies) of the termination and 
the reason(s) for the termination.

5.22  Clinical Trial Reports

    Whether the trial is completed or prematurely terminated, the 
sponsor should ensure that the clinical trial 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 reports meet the standards of the ICH 
guideline entitled, ``Structure and Content of Clinical Study 
Reports.''
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 same protocol, or with well-documented amended protocols 
that are agreed to by the sponsor and approved/provided a favorable 
opinion by 

[[Page 42957]]
the IRB/IEC and authorities, when required, for specific sites.
    5.23.2  The CRF's are designed to capture the required data at 
all multicenter trial sites, with exceptions for those investigators 
who are collecting additional data.
    5.23.3  The responsibilities of a coordinating investigator and 
the other participating investigators are documented prior to the 
start of the trial.
    5.23.4  All investigators are given sufficient instructions on 
how to follow the protocol and to comply with a uniform set of 
standards for assessment of the clinical and laboratory findings and 
for completing the CRF's.
    5.23.5  Communication between investigators is possible.

6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)

    The contents of a trial protocol should generally include the 
following topics:
    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 phone 
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 and address of the clinical laboratory and other 
medical and/or technical department(s) involved in the trial.
    6.1.8  Site specific information may be provided on separate 
protocol page(s), if not addressed in a separate agreement.

6.2  Background Information

    6.2.1  Name and description of the investigational product(s).
    6.2.2  A summary of clinically significant findings from 
nonclinical studies and 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 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

    (NOTE: 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, including:

    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:
    (a) Randomization.
    (b) Blinding.
    6.4.4  A description of the dosage and dosage regimen of the 
trial treatment(s).
    6.4.5  The expected duration of subject participation, and a 
description of the sequence and duration of all trial periods, 
including followup, if any.
    6.4.6  A description of the ``stopping rules'' or 
``discontinuation criteria'' for individual subjects, parts of 
trial, and entire trial. Criteria for removing subjects from the 
trial should be outlined.
    6.4.7  Investigational product accountability procedures.
    6.4.8  Maintenance of trial treatment randomization codes and 
procedures for breaking codes.

6.5  Selection and Withdrawal of Subjects

    6.5.1  Subject inclusion criteria.
    6.5.2  Exclusion criteria.
    6.5.3  Withdrawal criteria and procedures specifying:
    (a) When and how to withdraw subjects from the trial.
    (b) The type and timing of the data to be collected for 
withdrawn subjects.

6.6  Treatment of Subjects

    6.6.1  The treatment(s) to be administered, including the name 
of the product(s), the dose(s), the dosing schedule(s), the route/
mode of administration, and the treatment period(s) for the 
product(s).
    6.6.2  Medication(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 of efficacy parameters.

6.8  Assessment of Safety

    6.8.1  Specification of safety parameters.
    6.8.2  Procedures for eliciting reports of and recording and 
reporting adverse events.
    6.8.3  The duration of the followup period(s) 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 included. In 
multicenter trials, the numbers of 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 protocol amendment(s) and/or in the final 
report, as appropriate.)

6.10  Quality Control and Quality Assurance Procedures

    Monitoring and audit procedures, if not addressed in a separate 
agreement.

6.11  Ethics

    Description of ethical considerations relating to the trial.

6.12  Data Handling and Recordkeeping

    6.13  Financing and Insurance
    Financing and insurance, if not addressed in a separate 
agreement.

6.14  Publication Policy

    Publication policy, if not addressed in a separate agreement.

6.15  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.'')

    Dated: August 11, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-20375 Filed 8-16-95; 8:45 am]
BILLING CODE 4160-01-P