Guidance for Industry

E6 Good Clinical Practice:

Consolidated Guidance

ICH

April 1996
Guidance for Industry

E6 Good Clinical Practice: 

Consolidated Guidance

Additional copies are available from:

 the Drug Information Branch (HFD-210),

Center for Drug Evaluation and Research (CDER),

5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

or

Office of Communication,

Training, and Manufacturers Assistance (HFM-40)

Center for Biologics Evaluation and Research (CBER)

1401 Rockville Pike, Rockville, MD 20852-1448,

http://www.fda.gov/cber/guidelines.htm

(Fax) 888-CBERFAX or 301-827-3844

(Voice Information) 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

April 1996

ICH
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Table of Contents

INTRODUCTION .......................................................... 1

1. GLOSSARY ......................................................... 1

2. THE PRINCIPLES OF ICH GCP ......................................... 8

3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE

(IRB/IEC) .......................................................... 10

3.1 Responsibilities ................................................. 10

3.2 Composition, Functions, and Operations .............................. 11

3.3 Procedures .................................................... 12

3.4 Records ...................................................... 13

4. INVESTIGATOR .................................................... 13

4.1 Investigator's Qualifications and Agreements .......................... 13

4.2 Adequate Resources ............................................. 14

4.3 Medical Care of Trial Subjects ..................................... 14

4.4 Communication with IRB/IEC ..................................... 15

4.5 Compliance with Protocol ........................................ 15

4.6 Investigational Product(s) ......................................... 16

4.7 Randomization Procedures and Unblinding ............................ 16

4.8 Informed Consent of Trial Subjects .................................. 17

4.9 Records and Reports ............................................ 21

4.10 Progress Reports ............................................... 22

4.11 Safety Reporting ................................................ 22

4.12 Premature Termination or Suspension of a Trial ........................ 23

4.13 Final Report(s) by Investigator/Institution ............................. 23

5. SPONSOR .......................................................... 24

5.1 Quality Assurance and Quality Control ............................... 24

5.2 Contract Research Organization (CRO) .............................. 24

5.3 Medical Expertise ............................................... 24

5.4 Trial Design ................................................... 25

5.5 Trial Management, Data Handling, Recordkeeping, and Independent Data

Monitoring Committee ........................................... 25

5.6 Investigator Selection ............................................ 27

5.7 Allocation of Duties and Functions .................................. 27

5.8 Compensation to Subjects and Investigators ........................... 28

5.9 Financing ..................................................... 28

5.10 Notification/Submission to Regulatory Authority(ies) .................... 28
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5.11 Confirmation of Review by IRB/IEC ................................ 28

5.12 Information on Investigational Product(s) ............................. 29

5.13 Manufacturing, Packaging, Labeling, and Coding Investigational ........... 29

5.14 Supplying and Handling Investigational Product(s) ...................... 30

5.15 Record Access ................................................. 31

5.16 Safety Information .............................................. 31

5.17 Adverse Drug Reaction Reporting .................................. 31

5.18 Monitoring .................................................... 32

5.19 Audit ........................................................ 36

5.20 Noncompliance ................................................. 37

5.21 Premature Termination or Suspension of a Trial ........................ 37

5.22 Clinical Trial/Study Reports ....................................... 37

5.23 Multicenter Trials ............................................... 37

6. CLINICAL TRIAL PROTOCOL AND PROTOCOL ......................... 38

6.1 General Information ............................................. 38

6.2 Background Information .......................................... 39

6.3 Trial Objectives and Purpose ...................................... 39

6.4 Trial Design ................................................... 39

6.5 Selection and Withdrawal of Subjects ................................ 40

6.6 Treatment of Subjects ............................................ 40

6.7 Assessment of Efficacy ........................................... 41

6.8 Assessment of Safety ............................................ 41

6.9 Statistics ...................................................... 41

6.10 Direct Access to Source Data/Documents ............................. 42

6.11 Quality Control and Quality Assurance ............................... 42

6.12 Ethics ........................................................ 42

6.13 Data Handling and Recordkeeping .................................. 42

6.14 Financing and Insurance .......................................... 42

6.15 Publication Policy ............................................... 42

6.16 Supplements ................................................... 42

7. INVESTIGATOR'S BROCHURE ........................................ 42

7.1 Introduction ................................................... 42

7.2 General Considerations ........................................... 43

7.3 Contents of the Investigator’s Brochure .............................. 44

7.4 Appendix 1 .................................................... 48

7.5 Appendix 2 .................................................... 49

8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL ..... 50

8.1 Introduction ................................................... 50

8.2 Before the Clinical Phase of the Trial Commences ...................... 51
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8.3 During the Clinical Conduct of the Trial .............................. 55

8.4 After Completion or Termination of the Trial .......................... 58
This guidance was developed within the Expert Working Group (Efficacy) of the International Conference on 1

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been

subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed

by the ICH Steering Committee at Step 4 of the ICH process, April 1996. At Step 4 of the process, the final draft is

recommended for adoption to the regulatory bodies of the European Union, Japan and the United States. This guidance

was published in the Federal Register on May 9, 1997 (62 FR 25692), and is applicable to drug and biological

products. This guidance represents the Agency’s current thinking on good clinical practices. It does not create or confer

any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if

such approach satisfies the requirements of the applicable statute, regulations, or both.

GUIDANCE FOR INDUSTRY1

E6 Good Clinical Practice: Consolidated Guidance

INTRODUCTION

Good clinical practice (GCP) is an international ethical and scientific quality standard for

designing, conducting, recording, and reporting trials that involve the participation of human

subjects. Compliance with this standard provides public assurance that the rights, safety, and wellbeing of trial subjects are protected, consistent with the principles that have their origin in the

Declaration of Helsinki, and that the clinical trial data are credible.

The objective of this ICH GCP guidance is to provide a unified standard for the European Union

(EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the

regulatory authorities in these jurisdictions.

The guidance was developed with consideration of the current good clinical practices of the

European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic

countries, and the World Health Organization (WHO).

This guidance should be followed when generating clinical trial data that are intended to be

submitted to regulatory authorities.

The principles established in this guidance may also be applied to other clinical investigations that

may have an impact on the safety and well-being of human subjects.

1. GLOSSARY

1.1 Adverse drug reaction (ADR): In the preapproval clinical experience with a new

medicinal product or its new usages, particularly as the therapeutic dose(s) may not be

established, all noxious and unintended responses to a medicinal product related to any

dose should be considered adverse drug reactions. The phrase "responses to a medicinal
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product" means that a causal relationship between a medicinal product and an adverse

event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.

Regarding marketed medicinal products: A response to a drug that is noxious and

unintended and that occurs at doses normally used in man for prophylaxis, diagnosis, or

therapy of diseases or for modification of physiological function (see the ICH guidance for

Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

1.2 Adverse event (AE): An AE is any untoward medical occurrence in a patient or

clinical investigation subject administered a pharmaceutical product and that does not

necessarily have a causal relationship with this treatment. An AE can therefore be any

unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or

disease temporally associated with the use of a medicinal (investigational) product,

whether or not related to the medicinal (investigational) product (see the ICH guidance for

Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

1.3 Amendment (to the protocol): See Protocol Amendment.

1.4 Applicable regulatory requirement(s): Any law(s) and regulation(s) addressing

the conduct of clinical trials of investigational products of the jurisdiction where trial is

conducted.

1.5 Approval (in relation to institutional review boards (IRBs)): The affirmative

decision of the IRB that the clinical trial has been reviewed and may be conducted at the

institution site within the constraints set forth by the IRB, the institution, good clinical

practice (GCP), and the applicable regulatory requirements.

1.6 Audit: A systematic and independent examination of trial-related activities and

documents to determine whether the evaluated trial-related activities were conducted, and

the data were recorded, analyzed, and accurately reported according to the protocol,

sponsor's standard operating procedures (SOPs), good clinical practice (GCP), and the

applicable regulatory requirement(s).

1.7 Audit certificate: A declaration of confirmation by the auditor that an audit has

taken place.

1.8 Audit report: A written evaluation by the sponsor's auditor of the results of the

audit.

1.9 Audit trail: Documentation that allows reconstruction of the course of events.

1.10 Blinding/masking: A procedure in which one or more parties to the trial are kept

unaware of the treatment assignment(s). Single blinding usually refers to the subject(s)
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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 Guidance for Structure and Content of Clinical Study Reports).

1.14 Comparator (Product): An investigational or marketed product (i.e., active

control), or placebo, used as a reference in a clinical trial.

1.15 Compliance (in relation to trials): Adherence to all the trial-related

requirements, good clinical practice (GCP) requirements, and the applicable regulatory

requirements.

1.16 Confidentiality: Prevention of disclosure, to other than authorized individuals, of

a sponsor's proprietary information or of a subject's identity.

1.17 Contract: A written, dated, and signed agreement between two or more involved

parties that sets out any arrangements on delegation and distribution of tasks and

obligations and, if appropriate, on financial matters. The protocol may serve as the basis

of a contract.

1.18 Coordinating Committee: A committee that a sponsor may organize to

coordinate the conduct of a multicenter trial.

1.19 Coordinating Investigator: An investigator assigned the responsibility for the

coordination of investigators at different centers participating in a multicenter trial.

1.20 Contract Research Organization (CRO): A person or an organization

(commercial, academic, or other) contracted by the sponsor to perform one or more of a

sponsor's trial-related duties and functions.
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1.21 Direct Access: Permission to examine, analyze, verify, and reproduce any records

and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic

and foreign regulatory authorities, sponsors, monitors, and auditors) with direct access

should take all reasonable precautions within the constraints of the applicable regulatory

requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s

proprietary information.

1.22 Documentation: All records, in any form (including, but not limited to, written,

electronic, magnetic, and optical records; and scans, x-rays, and electrocardiograms) that

describe or record the methods, conduct, and/or results of a trial, the factors affecting a

trial, and the actions taken.

1.23 Essential Documents: Documents that individually and collectively permit

evaluation of the conduct of a study and the quality of the data produced (see section 8.

"Essential Documents for the Conduct of a Clinical Trial"). 

1.24 Good Clinical Practice (GCP): A standard for the design, conduct, performance,

monitoring, auditing, recording, analyses, and reporting of clinical trials that provides

assurance that the data and reported results are credible and accurate, and that the rights,

integrity, and confidentiality of trial subjects are protected.

1.25 Independent Data Monitoring Committee (IDMC) (Data and Safety

Monitoring Board, Monitoring Committee, Data Monitoring Committee): An

independent data monitoring committee that may be established by the sponsor to assess

at intervals the progress of a clinical trial, the safety data, and the critical efficacy

endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.

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.
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The legal status, composition, function, operations, and regulatory requirements pertaining

to Independent Ethics Committees may differ among countries, but should allow the

Independent Ethics Committee to act in agreement with GCP as described in this

guidance.

1.28 Informed Consent: A process by which a subject voluntarily confirms his or her 

willingness to participate in a particular trial, after having been informed of all aspects of

the trial that are relevant to the subject's decision to participate. Informed consent is

documented by means of a written, signed, and dated informed consent form.

1.29 Inspection: The act by a regulatory authority(ies) of conducting an official review

of documents, facilities, records, and any other resources that are deemed by the

authority(ies) to be related to the clinical trial and that may be located at the site of the

trial, at the sponsor's and/or contract research organization’s (CROs) facilities, or at other

establishments deemed appropriate by the regulatory authority(ies).

1.30 Institution (medical): Any public or private entity or agency or medical or dental

facility where clinical trials are conducted.

1.31 Institutional Review Board (IRB): An independent body constituted of medical,

scientific, and nonscientific members, whose responsibility it is to ensure the protection of

the rights, safety, and well-being of human subjects involved in a trial by, among other

things, reviewing, approving, and providing continuing review of trials, of protocols and

amendments, and of the methods and material to be used in obtaining and documenting

informed consent of the trial subjects.

1.32 Interim Clinical Trial/Study Report: A report of intermediate results and their

evaluation based on analyses performed during the course of a trial.

1.33 Investigational Product: A pharmaceutical form of an active ingredient or

placebo being tested or used as a reference in a clinical trial, including a product with a

marketing authorization when used or assembled (formulated or packaged) in a way

different from the approved form, or when used for an unapproved indication, or when

used to gain further information about an approved use.

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."
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1.36 Investigator's Brochure: A compilation of the clinical and nonclinical data on the

investigational product(s) that is relevant to the study of the investigational product(s) in

human subjects (see section 7. "Investigator’s Brochure"). 

1.37 Legally Acceptable Representative: An individual or juridical or other body

authorized under applicable law to consent, on behalf of a prospective subject, to the

subject's participation in the clinical trial.

1.38 Monitoring: The act of overseeing the progress of a clinical trial, and of ensuring

that it is conducted, recorded, and reported in accordance with the protocol, standard

operating procedures (SOPs), GCP, and the applicable regulatory requirement(s). 

1.39 Monitoring Report: A written report from the monitor to the sponsor after each

site visit and/or other trial-related communication according to the sponsor’s SOPs.

1.40 Multicenter Trial: A clinical trial conducted according to a single protocol but at

more than one site, and, therefore, carried out by more than one investigator.

1.41 Nonclinical Study: Biomedical studies not performed on human subjects.

1.42 Opinion (in relation to Independent Ethics Committee): The judgment and/or

the advice provided by an Independent Ethics Committee (IEC). 

1.43 Original Medical Record: See Source Documents.

1.44 Protocol: A document that describes the objective(s), design, methodology,

statistical considerations, and organization of a trial. The protocol usually also gives the

background and rationale for the trial, but these could be provided in other protocol

referenced documents. Throughout the ICH GCP Guidance, the term protocol refers to

protocol and protocol amendments.

1.45 Protocol Amendment: A written description of a change(s) to or formal

clarification of a protocol.

1.46 Quality Assurance (QA): All those planned and systematic actions that are

established to ensure that the trial is performed and the data are generated, documented

(recorded), and reported in compliance with GCP and the applicable regulatory

requirement(s). 

1.47 Quality Control (QC): The operational techniques and activities undertaken

within the quality assurance system to verify that the requirements for quality of the trialrelated activities have been fulfilled.
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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

guidance, the expression "Regulatory Authorities" includes the authorities that review

submitted clinical data and those that conduct inspections (see section 1.29). These

bodies are sometimes referred to as competent authorities.

1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious

ADR): Any untoward medical occurrence that at any dose:

! Results in death,

! Is life-threatening,

! Requires inpatient hospitalization or prolongation of existing hospitalization,

! Results in persistent or significant disability/incapacity, or

! Is a congenital anomaly/birth defect. 

(See the ICH guidance 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.
8

1.55 Standard Operating Procedures (SOPs): Detailed, written instructions to

achieve uniformity of the performance of a specific function.

1.56 Subinvestigator: Any individual member of the clinical trial team designated and

supervised by the investigator at a trial site to perform critical trial-related procedures

and/or to make important trial-related decisions (e.g., associates, residents, research

fellows). See also Investigator.

1.57 Subject/Trial Subject: An individual who participates in a clinical trial, either as

a recipient of the investigational product(s) or as a control.

1.58 Subject Identification Code: A unique identifier assigned by the investigator to

each trial subject to protect the subject's identity and used in lieu of the subject's name

when the investigator reports adverse events and/or other trial-related data.

1.59 Trial Site: The location(s) where trial-related activities are actually conducted.

1.60 Unexpected Adverse Drug Reaction: An adverse reaction, the nature or severity

of which is not consistent with the applicable product information (e.g., Investigator's

Brochure for an unapproved investigational product or package insert/summary of

product characteristics for an approved product). (See the ICH Guidance for Clinical

Safety Data Management: Definitions and Standards for Expedited Reporting.)

1.61 Vulnerable Subjects: Individuals whose willingness to volunteer in a clinical trial

may be unduly influenced by the expectation, whether justified or not, of benefits

associated with participation, or of a retaliatory response from senior members of a

hierarchy in case of refusal to participate. Examples are members of a group with a

hierarchical structure, such as medical, pharmacy, dental, and nursing students,

subordinate hospital and laboratory personnel, employees of the pharmaceutical industry,

members of the armed forces, and persons kept in detention. Other vulnerable subjects

include patients with incurable diseases, persons in nursing homes, unemployed or

impoverished persons, patients in emergency situations, ethnic minority groups, homeless

persons, nomads, refugees, minors, and those incapable of giving consent.

1.62 Well-being (of the trial subjects): The physical and mental integrity of the

subjects participating in a clinical trial.

2. THE PRINCIPLES OF ICH GCP

2.1 Clinical trials should be conducted in accordance with the ethical principles that

have their origin in the Declaration of Helsinki, and that are consistent with GCP and the

applicable regulatory requirement(s).
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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.

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.
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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 fulfil 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 sections 4.8.12, 4.8.14), the

IRB/IEC should determine that the proposed protocol and/or other document(s)
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adequately addresses relevant ethical concerns and meets applicable regulatory

requirements for such trials.

3.1.7 Where the protocol indicates that prior consent of the trial subject or the

subject’s legally acceptable representative is not possible (see section 4.8.15), the

IRB/IEC should determine that the proposed protocol and/or other document(s)

adequately addresses relevant ethical concerns and meets applicable regulatory

requirements for such trials (i.e., in emergency situations).

3.1.8 The IRB/IEC should review both the amount and method of payment to

subjects to assure that neither presents problems of coercion or undue influence on

the trial subjects. Payments to a subject should be prorated and not wholly

contingent on completion of the trial by the subject.

3.1.9 The IRB/IEC should ensure that information regarding payment to subjects,

including the methods, amounts, and schedule of payment to trial subjects, is set

forth in the written informed consent form and any other written information to be

provided to subjects. The way payment will be prorated should be specified.

3.2 Composition, Functions, and Operations

3.2.1 The IRB/IEC should consist of a reasonable number of members, who

collectively have the qualifications and experience to review and evaluate the

science, medical aspects, and ethics of the proposed trial. It is recommended that

the IRB/IEC should include:

(a) At least five members.

(b) At least one member whose primary area of interest is in a 

nonscientific area.

(c) At least one member who is independent of the institution/trial site.

Only those IRB/IEC members who are independent of the investigator and the

sponsor of the trial should vote/provide opinion on a trial-related matter.

A list of IRB/IEC members and their qualifications should be maintained.

3.2.2 The IRB/IEC should perform its functions according to written operating

procedures, should maintain written records of its activities and minutes of its

meetings, and should comply with GCP and with the applicable regulatory

requirement(s).

3.2.3 An IRB/IEC should make its decisions at announced meetings at which at

least a quorum, as stipulated in its written operating procedures, is present.
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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 section

4.5.2).

3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:

(a) Deviations from, or changes of, the protocol to eliminate immediate

hazards to the trial subjects (see sections 3.3.7, 4.5.2, 4.5.4).
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(b) Changes increasing the risk to subjects and/or affecting significantly the

conduct of the trial (see section 4.10.2). 

(c) All adverse drug reactions (ADRs) that are both serious and

unexpected. 

(d) New information that may affect adversely the safety of the subjects or

the conduct of the trial.

3.3.9 Ensuring that the IRB/IEC promptly notify in writing the

investigator/institution concerning:

(a) Its trial-related decisions/opinions.

(b) The reasons for its decisions/opinions.

(c) Procedures for appeal of its decisions/opinions.

3.4 Records

The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists,

lists of occupations/affiliations of members, submitted documents, minutes of meetings,

and correspondence) for a period of at least 3 years after completion of the trial and make

them available upon request from the regulatory authority(ies).

The IRB/IEC may be asked by investigators, sponsors, or regulatory authorities to provide

copies of its written procedures and membership lists.

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.
14

4.1.3 The investigator should be aware of, and should comply with, GCP and the

applicable regulatory requirements.

4.1.4 The investigator/institution should permit monitoring and auditing by the

sponsor, and inspection by the appropriate regulatory authority(ies).

4.1.5 The investigator should maintain a list of appropriately qualified persons to

whom the investigator has delegated significant trial-related duties.

4.2 Adequate Resources

4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective

data) a potential for recruiting the required number of suitable subjects within the

agreed recruitment period.

4.2.2 The investigator should have sufficient time to properly conduct and

complete the trial within the agreed trial period.

4.2.3 The investigator should have available an adequate number of qualified staff

and adequate facilities for the foreseen duration of the trial to conduct the trial

properly and safely.

4.2.4 The investigator should ensure that all persons assisting with the trial are

adequately informed about the protocol, the investigational product(s), and their

trial-related duties and functions.

4.3 Medical Care of Trial Subjects

4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator

or a subinvestigator for the trial, should be responsible for all trial-related medical

(or dental) decisions. 

4.3.2 During and following a subject's participation in a trial, the

investigator/institution should ensure that adequate medical care is provided to a

subject for any adverse events, including clinically significant laboratory values,

related to the trial. The investigator/institution should inform a subject when

medical care is needed for intercurrent illness(es) of which the investigator

becomes aware. 

4.3.3 It is recommended that the investigator inform the subject's primary

physician about the subject's participation in the trial if the subject has a primary

physician and if the subject agrees to the primary physician being informed.
15

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
16

 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 sections 5.13.2 and 5.14.3) and in accordance with applicable regulatory

requirement(s).

4.6.5 The investigator should ensure that the investigational product(s) are used

only in accordance with the approved protocol.

4.6.6 The investigator, or a person designated by the investigator/institution,

should explain the correct use of the investigational product(s) to each subject and

should check, at intervals appropriate for the trial, that each subject is following

the instructions properly.

4.7 Randomization Procedures and Unblinding

The investigator should follow the trial's randomization procedures, if any, and should

ensure that the code is broken only in accordance with the protocol. If the trial is blinded,
17

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. 
18

4.8.7 Before informed consent may be obtained, the investigator, or a person

designated by the investigator, should provide the subject or the subject's legally

acceptable representative ample time and opportunity to inquire about details of

the trial and to decide whether or not to participate in the trial. All questions

about the trial should be answered to the satisfaction of the subject or the subject's

legally acceptable representative.

4.8.8 Prior to a subject’s participation in the trial, the written informed consent

form should be signed and personally dated by the subject or by the subject's

legally acceptable representative, and by the person who conducted the informed

consent discussion. 

4.8.9 If a subject is unable to read or if a legally acceptable representative is

unable to read, an impartial witness should be present during the entire informed

consent discussion. After the written informed consent form and any other written

information to be provided to subjects is read and explained to the subject or the

subject’s legally acceptable representative, and after the subject or the subject’s

legally acceptable representative has orally consented to the subject’s participation

in the trial, and, if capable of doing so, has signed and personally dated the

informed consent form, the witness should sign and personally date the consent

form. By signing the consent form, the witness attests that the information in the

consent form and any other written information was accurately explained to, and

apparently understood by, the subject or the subject's legally acceptable

representative, and that informed consent was freely given by the subject or the

subject’s legally acceptable representative.

4.8.10 Both the informed consent discussion and the written informed consent

form and any other written information to be provided to subjects should include

explanations of the following:

(a) That the trial involves research.

(b) The purpose of the trial.

(c) The trial treatment(s) and the probability for random assignment to

each treatment.

(d) The trial procedures to be followed, including all invasive procedures.

(e) The subject's responsibilities.

(f) Those aspects of the trial that are experimental.
19

(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. 
20

(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. 
21

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 wellbeing of the subject and to ensure compliance with applicable regulatory

requirements. The subject or the subject's legally acceptable representative should

be informed about the trial as soon as possible and consent to continue and other

consent as appropriate (see section 4.8.10) should be requested.

4.9 Records and Reports

4.9.1 The investigator should ensure the accuracy, completeness, legibility, and

timeliness of the data reported to the sponsor in the CRFs and in all required

reports.

4.9.2 Data reported on the CRF, which are derived from source documents,

should be consistent with the source documents or the discrepancies should be

explained.

4.9.3 Any change or correction to a CRF should be dated, initialed, and explained

(if necessary) and should not obscure the original entry (i.e., an audit trail should

be maintained); this applies to both written and electronic changes or corrections

(see section 5.18.4(n)). Sponsors should provide guidance to investigators and/or

the investigators' designated representatives on making such corrections. Sponsors

should have written procedures to assure that changes or corrections in CRFs

made by sponsor's designated representatives are documented, are 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 section 8.) and as

required by the applicable regulatory requirement(s). The investigator/institution

should take measures to prevent accidental or premature destruction of these

documents.
22

4.9.5 Essential documents should be retained until at least 2 years after the last

approval of a marketing application in an ICH region and until there are no

pending or contemplated marketing applications in an ICH region or at least 2

years have elapsed since the formal discontinuation of clinical development of the

investigational product. These documents should be retained for a longer period,

however, if required by the applicable regulatory requirements or by an agreement

with the sponsor. It is the responsibility of the sponsor to inform the

investigator/institution as to when these documents no longer need to be retained

(see section 5.5.12).

4.9.6 The financial aspects of the trial should be documented in an agreement

between the sponsor and the investigator/institution.

4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the

investigator/institution should make available for direct access all requested trialrelated records. 

4.10 Progress Reports

4.10.1 Where required by the applicable regulatory requirements, the investigator

should submit written summaries of the trial’s status to the institution. The

investigator/institution should submit written summaries of the status of the trial to

the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.

4.10.2 The investigator should promptly provide written reports to the sponsor,

the IRB/IEC (see section 3.3.8), and, where required by the applicable regulatory

requirements, the institution on any changes significantly affecting the conduct of

the trial, and/or increasing the risk to subjects.

4.11 Safety Reporting

4.11.1 All serious adverse events (SAEs) should be reported immediately to the

sponsor except for those SAEs that the protocol or other document (e.g.,

Investigator's Brochure) identifies as not needing immediate reporting. The

immediate reports should be followed promptly by detailed, written reports. The

immediate and follow-up reports should identify subjects by unique code numbers

assigned to the trial subjects rather than by the subjects' names, personal

identification numbers, and/or addresses. The investigator should also comply

with the applicable regulatory requirement(s) related to the reporting of

unexpected serious adverse drug reactions to the regulatory authority(ies) and the

IRB/IEC.
23

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 section 5.21), the

investigator should promptly inform the institution, where required by the

applicable regulatory requirements, and the investigator/institution should

promptly inform the IRB/IEC and provide the IRB/IEC a detailed written

explanation of the termination or suspension.

4.12.3 If the IRB/IEC terminates or suspends its approval/favorable opinion of a

trial (see sections 3.1.2 and 3.3.9), the investigator should inform the institution,

where required by the applicable regulatory requirements, and the

investigator/institution should promptly notify the sponsor and provide the sponsor

with a detailed written explanation of the termination or suspension.

4.13 Final Report(s) by Investigator/Institution

Upon completion of the trial, the investigator should, where required by the applicable

regulatory requirements, inform the institution, and the investigator/institution should

provide the sponsor with all required reports, the IRB/IEC with a summary of the trial’s

outcome, and the regulatory authority(ies) with any report(s) they require of the

investigator/institution.
24

5. SPONSOR

5.1 Quality Assurance and Quality Control

5.1.1 The sponsor is responsible for implementing and maintaining quality

assurance and quality control systems with written SOPs to ensure that trials are

conducted and data are generated, documented (recorded), and reported in

compliance with the protocol, GCP, and the applicable regulatory requirement(s).

5.1.2 The sponsor is responsible for securing agreement from all involved parties

to ensure direct access (see section 1.21) to all trial- related sites, source

data/documents, and reports for the purpose of monitoring and auditing by the

sponsor, and inspection by domestic and foreign regulatory authorities.

5.1.3 Quality control should be applied to each stage of data handling to ensure

that all data are reliable and have been processed correctly.

5.1.4 Agreements, made by the sponsor with the investigator/institution and/or

with any other parties involved with the clinical trial, should be in writing, as part

of the protocol or in a separate agreement.

5.2 Contract Research Organization (CRO)

5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and

functions to a CRO, but the ultimate responsibility for the quality and integrity of

the trial data always resides with the sponsor. The CRO should implement quality

assurance and quality control.

5.2.2 Any trial-related duty and function that is transferred to and assumed by a

CRO should be specified in writing.

5.2.3 Any trial-related duties and functions not specifically transferred to and

assumed by a CRO are retained by the sponsor.

5.2.4 All references to a sponsor in this guidance also apply to a CRO to the

extent that a CRO has assumed the trial-related duties and functions of a sponsor.

5.3 Medical Expertise

The sponsor should designate appropriately qualified medical personnel who will be

readily available to advise on trial-related medical questions or problems. If necessary,

outside consultant(s) may be appointed for this purpose. 
25

5.4 Trial Design

5.4.1 The sponsor should utilize qualified individuals (e.g., biostatisticians,

clinical pharmacologists, and physicians) as appropriate, throughout all stages of

the trial process, from designing the protocol and CRFs and planning the analyses

to analyzing and preparing interim and final clinical trial/study reports.

5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s)

(see section 6.), the ICH Guidance 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 SOPs for using these systems.

(c) Ensure that the systems are designed to permit data changes in such a

way that the data changes are documented and that there is no deletion of

entered data (i.e., maintain an audit trail, data trail, edit trail).

(d) Maintain a security system that prevents unauthorized access to the

data.

(e) Maintain a list of the individuals who are authorized to make data

changes (see sections 4.1.5 and 4.9.3).
26

(f) Maintain adequate backup of the data.

(g) Safeguard the blinding, if any (e.g., maintain the blinding during data

entry and processing).

5.5.4 If data are transformed during processing, it should always be possible to

compare the original data and observations with the processed data.

5.5.5 The sponsor should use an unambiguous subject identification code (see

section 1.58) that allows identification of all the data reported for each subject.

5.5.6 The sponsor, or other owners of the data, should retain all of the sponsorspecific essential documents pertaining to the trial. (See section 8. "Essential

Documents for the Conduct of a Clinical Trial.") 

5.5.7 The sponsor should retain all sponsor-specific essential documents in

conformance with the applicable regulatory requirement(s) of the country(ies)

where the product is approved, and/or where the sponsor intends to apply for

approval(s).

5.5.8 If the sponsor discontinues the clinical development of an investigational

product (i.e., for any or all indications, routes of administration, or dosage forms),

the sponsor should maintain all 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.
27

5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of

the need for record retention and should notify the investigator(s)/institution(s) in

writing when the trial-related records are no longer needed (see section 4.9.5).

5.6 Investigator Selection

5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). 

Each investigator should be qualified by training and experience and should have

adequate resources (see sections 4.1, 4.2) to properly conduct the trial for which

the investigator is selected. If a coordinating committee and/or coordinating

investigator(s) are to be utilized in multicenter trials, their organization and/or

selection are the sponsor's responsibility.

5.6.2 Before entering an agreement with an investigator/institution to conduct a

trial, the sponsor should provide the investigator(s)/institution(s) with the protocol

and an up-to-date Investigator's Brochure, and should provide sufficient time for

the investigator/institution to review the protocol and the information provided.

5.6.3 The sponsor should obtain the investigator's/institution's agreement:

(a) To conduct the trial in compliance with GCP, with the applicable

regulatory requirement(s), and with the protocol agreed to by the sponsor

and given approval/favorable opinion by the IRB/IEC; 

(b) To comply with procedures for data recording/reporting: and

(c) To permit monitoring, auditing, and inspection (see section 4.1.4). 

(d) To retain the essential documents that should be in the

investigator/institution files (see section 8.) until the sponsor informs the

investigator/institution these documents are no longer needed (see sections

4.9.4, 4.9.5, and 5.5.12).

The sponsor and the investigator/institution should sign the protocol, or an

alternative document, to confirm this agreement.

5.7 Allocation of Duties and Functions

Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related

duties and functions.
28

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. 
29

5.11.2 If the IRB/IEC conditions its approval/favorable opinion upon change(s) in

any aspect of the trial, such as modification(s) of the protocol, written informed

consent form and any other written information to be provided to subjects, and/or

other procedures, the sponsor should obtain from the investigator/institution a

copy of the modification(s) made and the date approval/favorable opinion was

given by the IRB/IEC.

5.11.3 The sponsor should obtain from the investigator/institution documentation

and dates of any IRB/IEC reapprovals/reevaluations with favorable opinion, and of

any withdrawals or suspensions of approval/favorable opinion. 

5.12 Information on Investigational Product(s)

5.12.1 When planning trials, the sponsor should ensure that sufficient safety and

efficacy data from nonclinical studies and/or clinical trials are available to support

human exposure by the route, at the dosages, for the duration, and in the trial

population to be studied.

5.12.2 The sponsor should update the Investigator's Brochure as significant new

information becomes available. (See section 7. "Investigator's Brochure.")

5.13 Manufacturing, Packaging, Labeling, and Coding Investigational Product(s)

5.13.1 The sponsor should ensure that the investigational product(s) (including

active comparator(s) and placebo, if applicable) is characterized as appropriate to

the stage of development of the product(s), is manufactured in accordance with

any applicable GMP, and is coded and labeled in a manner that protects the

blinding, if applicable. In addition, the labeling should comply with applicable

regulatory requirement(s).

5.13.2 The sponsor should determine, for the investigational product(s),

acceptable storage temperatures, storage conditions (e.g., protection from light),

storage times, reconstitution fluids and procedures, and devices for product

infusion, if any. The sponsor should inform all involved parties (e.g., monitors,

investigators, pharmacists, storage managers) of these determinations.

5.13.3 The investigational product(s) should be packaged to prevent

contamination and unacceptable deterioration during transport and storage.

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.
30

5.13.5 If significant formulation changes are made in the investigational or

comparator product(s) during the course of clinical development, the results of

any additional studies of the formulated product(s) (e.g., stability, dissolution rate,

bioavailability) needed to assess whether these changes would significantly alter

the pharmacokinetic profile of the product should be available prior to the use of

the new formulation in clinical trials.

5.14 Supplying and Handling Investigational Product(s)

5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s)

with the investigational product(s).

5.14.2 The sponsor should not supply an investigator/institution with the

investigational product(s) until the sponsor obtains all required documentation

(e.g., approval/favorable opinion from IRB/IEC and regulatory authority(ies)).

5.14.3 The sponsor should ensure that written procedures include instructions that

the investigator/institution should follow for the handling and storage of

investigational product(s) for the trial and documentation thereof. The procedures

should address adequate and safe receipt, handling, storage, dispensing, retrieval of

unused product from subjects, and return of unused investigational product(s) to

the sponsor (or alternative disposition if authorized by the sponsor and in

compliance with the applicable regulatory requirement(s)). 

5.14.4 The sponsor should:

(a) Ensure timely delivery of investigational product(s) to the

investigator(s).

(b) Maintain records that document shipment, receipt, disposition, return,

and destruction of the investigational product(s). (See section 8. "Essential

Documents for the Conduct of a Clinical Trial.")

(c) Maintain a system for retrieving investigational products and

documenting this retrieval (e.g., for deficient product recall, reclaim after

trial completion, expired product reclaim). 

(d) Maintain a system for the disposition of unused investigational

product(s) and for the documentation of this disposition. 
31

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 (ADRs) that are both serious

and unexpected.

5.17.2 Such expedited reports should comply with the applicable regulatory

requirement(s) and with the ICH Guidance for Clinical Safety Data Management:

Definitions and Standards for Expedited Reporting.
32

5.17.3 The sponsor should submit to the regulatory authority(ies) all safety

updates and periodic reports, as required by applicable regulatory requirement(s).

5.18 Monitoring

5.18.1 Purpose The purposes of trial monitoring are to verify that:

(a) The rights and well-being of human subjects are protected.

(b) The reported trial data are accurate, complete, and verifiable from

source documents.

(c) The conduct of the trial is in compliance with the currently approved

protocol/amendment(s), with GCP, and with applicable regulatory

requirement(s).

5.18.2 Selection and Qualifications of Monitors

(a) Monitors should be appointed by the sponsor.

(b) Monitors should be appropriately trained, and should have the

scientific and/or clinical knowledge needed to monitor the trial adequately.

A monitor’s qualifications should be documented. 

(c) Monitors should be thoroughly familiar with the investigational

product(s), the protocol, written informed consent form and any other

written information to be provided to subjects, the sponsor’s SOPs, GCP,

and the applicable regulatory requirement(s). 

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.
33

5.18.4 Monitor's Responsibilities

The monitor(s), in accordance with the sponsor’s requirements, should ensure that

the trial is conducted and documented properly by carrying out the following

activities when relevant and necessary to the trial and the trial site:

(a) Acting as the main line of communication between the sponsor and the

investigator.

(b) Verifying that the investigator has adequate qualifications and

resources (see sections 4.1, 4.2, 5.6) and these remain adequate throughout

the trial period, and that the staff and facilities, including laboratories and

equipment, are adequate to safely and properly conduct the trial and these

remain adequate throughout the trial period. 

(c) Verifying, for the investigational product(s):

(i) That storage times and conditions are acceptable, and that

supplies are sufficient throughout the trial.

(ii) That the investigational product(s) are supplied only to subjects

who are eligible to receive it and at the protocol specified dose(s).

(iii) That subjects are provided with necessary instruction on

properly using, handling, storing, and returning the investigational

product(s).

(iv) That the receipt, use, and return of the investigational

product(s) at the trial sites are controlled and documented

adequately.

(v) That the disposition of unused investigational product(s) at the

trial sites complies with applicable regulatory requirement(s) and is

in accordance with the sponsor’s authorized procedures.

(d) Verifying that the investigator follows the approved protocol and all

approved amendment(s), if any. 

(e) Verifying that written informed consent was obtained before each

subject's participation in the trial. 
34

(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

CRFs and are consistent with the source data/documents.

(ii) Any dose and/or therapy modifications are well documented for

each of the trial subjects. 

(iii) Adverse events, concomitant medications, and intercurrent

illnesses are reported in accordance with the protocol on the CRFs. 

(iv) Visits that the subjects fail to make, tests that are not

conducted, and examinations that are not performed are clearly

reported as such on the CRFs. 

(v) All withdrawals and dropouts of enrolled subjects from the trial

are reported and explained on the CRFs. 
35

(n) Informing the investigator of any CRF entry error, omission, or

illegibility. The monitor should ensure that appropriate corrections,

additions, or deletions are made, dated, explained (if necessary), and

initialed by the investigator or by a member of the investigator's trial staff

who is authorized to initial CRF changes for the investigator. This

authorization should be documented.

(o) Determining whether all adverse events (AEs) are appropriately

reported within the time periods required by GCP, the ICH Guidance for

Clinical Safety Data Management: Definitions and Standards for

Expedited Reporting, the protocol, the IRB/IEC, the sponsor, and the

applicable regulatory requirement(s).

(p) Determining whether the investigator is maintaining the essential

documents. (See section 8. "Essential Documents for the Conduct of a

Clinical Trial.")

(q) Communicating deviations from the protocol, SOPs, GCP, and the

applicable regulatory requirements to the investigator and taking

appropriate action designed to prevent recurrence of the detected

deviations.

5.18.5 Monitoring Procedures

The monitor(s) should follow the sponsor’s established written SOPs as well as

those procedures that are specified by the sponsor for monitoring a specific trial.

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. 
36

5.19 Audit

If or when sponsors perform audits, as part of implementing quality assurance, they should

consider:

5.19.1 Purpose

The purpose of a sponsor's audit, which is independent of and separate from

routine monitoring or quality control functions, should be to evaluate trial conduct

and compliance with the protocol, SOPs, GCP, and the applicable regulatory

requirements.

5.19.2 Selection and Qualification of Auditors

(a) The sponsor should appoint individuals, who are independent of the

clinical trial/data collection system(s), to conduct audits. 

(b) The sponsor should ensure that the auditors are qualified by training

and experience to conduct audits properly. An auditor’s qualifications

should be documented.

5.19.3 Auditing Procedures

(a) The sponsor should ensure that the auditing of clinical trials/systems is

conducted in accordance with the sponsor's written procedures on what to

audit, how to audit, the frequency of audits, and the form and content of

audit reports. 

(b) The sponsor's audit plan and procedures for a trial audit should be

guided by the importance of the trial to submissions to regulatory

authorities, the number of subjects in the trial, the type and complexity of

the trial, the level of risks to the trial subjects, and any identified

problem(s).

(c) The observations and findings of the auditor(s) should be documented.

(d) To preserve the independence and value of the audit function, the

regulatory authority(ies) should not routinely request the audit reports. 

Regulatory authority(ies) may seek access to an audit report on a case-bycase basis, when evidence of serious GCP noncompliance exists, or in the

course of legal proceedings.
37

(e) Where required by applicable law or regulation, the sponsor should

provide an audit certificate. 

5.20 Noncompliance

5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable

regulatory requirement(s) by an investigator/institution, or by member(s) of 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

Guidance for Structure and Content of Clinical Study Reports. (NOTE: The ICH

Guidance for Structure and Content of Clinical Study Reports specifies that abbreviated

study reports may be acceptable in certain cases.)

5.23 Multicenter Trials

For multicenter trials, the sponsor should ensure that:

5.23.1 All investigators conduct the trial in strict compliance with the protocol

agreed to by the sponsor and, if required, by the regulatory authority(ies), and

given approval/favorable opinion by the IRB/IEC.
38

5.23.2 The CRFs are designed to capture the required data at all multicenter trial

sites. For those investigators who are collecting additional data, supplemental

CRFs should also be provided that are designed to capture the additional data.

5.23.3 The responsibilities of the coordinating investigator(s) and the other

participating investigators are documented prior to the start of the trial.

5.23.4 All investigators are given instructions on following the protocol, on

complying with a uniform set of standards for the assessment of clinical and

laboratory findings, and on completing the CRFs.

5.23.5 Communication between investigators is facilitated.

6. CLINICAL TRIAL PROTOCOL AND PROTOCOL

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.
39

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):

(a) Randomization.

(b) Blinding.
40

6.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of

the investigational product(s). Also include a description of the dosage form,

packaging, and labeling of the investigational product(s).

6.4.5 The expected duration of subject participation, and a description of the

sequence and duration of all trial periods, including follow-up, if any.

6.4.6 A description of the "stopping rules" or "discontinuation criteria" for

individual subjects, parts of trial, and entire trial.

6.4.7 Accountability procedures for the investigational product(s), including the

placebo(s) and comparator(s), if any.

6.4.8 Maintenance of trial treatment randomization codes and procedures for

breaking codes.

6.4.9 The identification of any data to be recorded directly on the CRFs (i.e., no

prior written or electronic record of data), and to be considered to be source data.

6.5 Selection and Withdrawal of Subjects

6.5.1 Subject inclusion criteria.

6.5.2 Subject exclusion criteria.

6.5.3 Subject withdrawal criteria (i.e., terminating investigational product

treatment/trial treatment) and procedures specifying:

(a) When and how to withdraw subjects from the trial/ investigational

product treatment.

(b) The type and timing of the data to be collected for withdrawn subjects.

(c) Whether and how subjects are to be replaced.

(d) The follow-up for subjects withdrawn from investigational product

treatment/trial treatment.

6.6 Treatment of Subjects

6.6.1 The treatment(s) to be administered, including the name(s) of all the

product(s), the dose(s), the dosing schedule(s), the route/mode(s) of

administration, and the treatment period(s), including the follow-up period(s) for
41

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.
42

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 Guidance 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
43

the information to facilitate their understanding of the rationale for, and their compliance

with, many key features of the protocol, such as the dose, dose frequency/interval,

methods of administration, and safety monitoring procedures. The IB also provides

insight to support the clinical management of the study subjects during the course of the

clinical trial. The information should be presented in a concise, simple, objective,

balanced, and nonpromotional form that enables a clinician, or potential investigator, to

understand it and make his/her own unbiased risk-benefit assessment of the

appropriateness of the proposed trial. For this reason, a medically qualified person should

generally participate in the editing of an IB, but the contents of the IB should be approved

by the disciplines that generated the described data.

This guidance delineates the minimum information that should be included in an IB and

provides suggestions for its layout. It is expected that the type and extent of information

available will vary with the stage of development of the investigational product. If the

investigational product is marketed and its pharmacology is widely understood by medical

practitioners, an extensive IB may not be 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 (IRBs)/Independent Ethics Committees (IECs)

and/or regulatory authorities before it is included in a revised IB.

Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available

to the investigator(s) and the investigators are responsible for providing the up-to-date IB

to the responsible IRBs/IECs. In the case of an investigator- sponsored trial, the sponsorinvestigator 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 guidance.

7.2 General Considerations

The IB should include:

7.2.1 Title Page This should provide the sponsor's name, the identity of each
44

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, 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.
45

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. 
46

(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. 
47

(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).
48

(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 the

pharmacology of the investigational product.

7.4 Appendix 1

TITLE PAGE OF INVESTIGATOR'S BROCHURE (Example)

Sponsor's Name:

Product:

Research Number:
49

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
50

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 guidance may be subject to, and should be

available for, audit by the sponsor’s auditor and inspection by the regulatory

authority(ies).
51

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.

Title of Document Purpose

Located in Files of 

Investigator/ Sponsor

Institution

 

8.2.1 Investigator’s brochure To document that relevant and current X X

scientific information about the

investigational product has been

provided to the investigator

8.2.2 Signed protocol and amendments, if any, To document investigator and sponsor X X

and sample case report form (CRF) agreement to the protocol/amendment(s)

and CRF

8.2.3 Information given to trial subject To document the informed consent X X

- Informed consent form

(Including all applicable translations)

- Any other written information To document that subjects will be given X

- Advertisement for subject recruitment are appropriate and not coercive

(if used) X

appropriate written information (content

and wording) to support their ability to X

give fully informed consent

To document that recruitment measures

8.2.4 Financial aspects of the trial To document the financial agreement X X

between the investigator/institution and

the sponsor for the trial

8.2.5 Insurance statement (where required) To document that compensation to X X

subject(s) for trial-related injury will be

available
Title of Document Purpose

Located in Files of 

Investigator/ Sponsor

Institution

 

52

8.2.6 Signed agreement between involved To document agreements

parties, e.g.:

- Investigator/institution and sponsor X X

- Investigator/institution and CRO

- Sponsor and CRO required)

- Investigator/institution and X

authority(ies) (Where required)

 X X

 X

(where

 X

8.2.7 Dated, documented approval/favorable To document that the trial has been X X

opinion of IRB/IEC of the following: subject to IRB/IEC review and given

- Protocol and any amendments the version number and date of the

- 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 

approval/favorable opinion. To identify

document(s).

8.2.8 Institutional review board/independent To document that the IRB/IEC is X X

ethics committee composition constituted in agreement with GCP (where

 required)

8.2.9 Regulatory authority(ies) To document appropriate X X

authorization/approval/ authorization/approval/ notification by (where (where 

notification of protocol the regulatory authority(ies) has been required) required)

(where required) obtained prior to initiation of the trial in

compliance with the applicable

regulatory requirement(s)
Title of Document Purpose

Located in Files of 

Investigator/ Sponsor

Institution

 

53

8.2.10 Curriculum vitae and/or other relevant To document qualifications and X X

documents evidencing qualifications of eligibility to conduct trial and/or provide

investigator(s) and subinvestigators medical supervision of subjects

8.2.11 Normal value(s)/range(s) for To document normal values and/or X X

medical/laboratory/technical ranges of the tests

procedure(s) and/or test(s) included in

the protocol

8.2.12 Medical/laboratory/technical To document competence of facility to X X

procedures/tests perform required test(s), and support (where

- Certification or

- Accreditation or

- Established quality control and/or

external quality assessment or

- Other validation (where required)

reliability of results required)

8.2.13 Sample of label(s) attached to To document compliance with X

investigational product container(s) applicable labeling regulations and

appropriateness of instructions provided

to the subjects

8.2.14 Instructions for handling of To document instructions needed to X X

investigational product(s) and trial- ensure proper storage, packaging,

related materials dispensing, and disposition of

(if not included in protocol or investigational products and trial-related

Investigator’s Brochure) materials

8.2.15 Shipping records for investigational To document shipment dates, batch X X

product(s) and trial-related materials numbers, and method of shipment of

investigational product(s) and trialrelated materials. Allows tracking of

product batch, review of shipping

conditions, and accountability.

8.2.16 Certificate(s) of analysis of To document identity, purity, and X

investigational product(s) shipped strength of investigational products to

be used in the trial.

8.2.17 Decoding procedures for blinded trials To document how, in case of an X X

emergency, identity of blinded (third party if

investigational product can be revealed applic-able)

without breaking the blind for the

remaining subjects’ treatment

8.2.18 Master randomization list To document method for randomization X

of trial population (third party if

applicable)
Title of Document Purpose

Located in Files of 

Investigator/ Sponsor

Institution

 

54

8.2.19 Pretrial monitoring report To document that the site is suitable for X

the trial (may be combined with 8.2.20)

8.2.20 Trial initiation monitoring report To document that trial procedures were X X

reviewed with the investigator and

investigator’s trial staff (may be

combined with 8.2.19)
55

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.

Title of Document Purpose

Located in Files of

Investigator/ Sponsor

Institution

8.3.1 Investigator’s Brochure updates To document that investigator is X X

informed in a timely manner of relevant

information as it becomes available

8.3.2 Any revisions to: To document revisions of these trial- X X

- Protocol/amendment(s) and CRF trial

- Informed consent form

- Any other written information provided

to subjects

- Advertisement for subject recruitment

(if used)

related documents that take effect during

8.3.3 Dated, documented approval/favorable To document that the amendment(s) X X

opinion of institutional review board and/or revision(s) have been subject to

(IRB)/independent ethics committee IRB/IEC review and were given

(IEC) of the following: approval/favorable opinion. To identify

- Protocol amendment(s) 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 section

3.1.4)

the version number and date of the

8.3.4 Regulatory authority(ies) To document compliance with X X

authorizations/ approvals/notifications applicable regulatory requirements (where

where required for: required)

- Protocol amendment(s) and other

documents

8.3.5 Curriculum vitae for new investigator(s) (See section 8.2.10) X X

and/or subinvestigators
Title of Document Purpose

Located in Files of

Investigator/ Sponsor

Institution

56

8.3.6 Updates to normal value(s)/range(s) for To document normal values and ranges X X

medical laboratory/technical that are revised during the trial (see

procedure(s)/test(s) included in the section 8.2.11)

protocol

8.3.7 Updates of medical/ laboratory/technical To document that tests remain adequate X X

procedures/tests throughout the trial period (see section (where

- Certification or

- Accreditation or

- Established quality control and/or

external quality assessment or

- Other validation (where required)

8.2.12) required)

8.3.8 Documentation of investigational (See section 8.2.15) X X

product(s) and trial-related materials

shipment

8.3.9 Certificate(s) of analysis for new batches (See section 8.2.16) X

of investigational products

8.3.10 Monitoring visit reports To document site visits by, and findings X

of, the monitor

8.3.11 Relevant communications other than site To document any agreements or X X

visits significant discussions regarding trial

- Letters conduct, adverse event (AE) reporting

- Meeting notes

- Notes of telephone calls

administration, protocol violations, trial

8.3.12 Signed informed consent forms To document that consent is obtained in X

accordance with GCP and protocol and

dated prior to participation of each

subject in trial. Also to document direct

access permission (see section 8.2.3)

8.3.13 Source documents To document the existence of the X

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 case report To document that the investigator or X X

forms (CRFs) authorized member of the investigator’s (copy) (original)

staff confirms the observations recorded

8.3.15 Documentation of CRF corrections To document all changes/ additions or X X

corrections made to CRF after initial (copy) (original)

data were recorded
Title of Document Purpose

Located in Files of

Investigator/ Sponsor

Institution

57

8.3.16 Notification by originating investigator to Notification by originating investigator X X

sponsor of serious adverse events and to sponsor of serious adverse events and

related reports related reports in accordance with 4.11

8.3.17 Notification by sponsor and/or Notification by sponsor and/or X X

investigator, where applicable, to investigator, where applicable, to (where

regulatory authority(ies) and regulatory authorities and IRB(s)/IEC(s) required)

IRB(s)/IEC(s) of unexpected serious of unexpected serious adverse drug

adverse drug reactions and of other safety reactions in accordance with 5.17 and

information 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 investigators Notification by sponsor to investigators X X

of safety information of safety information in accordance with

5.16.2

8.3.19 Interim or annual reports to IRB/IEC and Interim or annual reports provided to X X

authority(ies) IRB/IEC in accordance with 4.10 and to (where

authority(ies) in accordance with 5.17.3 required)

8.3.20 Subject screening log To document identification of subjects X X

who entered pretrial screening (where

required)

8.3.21 Subject identification code list To document that investigator/institution X

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 enrollment X

of subjects by trial number

8.3.23 Investigational product(s) To document that investigational X X

accountability at the site products(s) have been used

according to the protocol

8.3.24 Signature sheet To document signatures and initials of X X

all persons authorized to make entries

and/or corrections on CRFs

8.3.25 Record of retained body fluids/tissue To document location and identification X X

samples (if any) of retained samples if assays need to be

repeated
58

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:

Title of Document Purpose

Located in Files of

Investigator/ Sponsor

Institution

8.4.1 Investigational product(s) accountability To document that the investigational X X

at site 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 investigational To document destruction of unused X X

product(s) destruction investigational product(s) by sponsor or (if destroyed

at site at site)

8.4.3 Completed subject identification code list To permit identification of all subjects X

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 required) To document that audit was performed X

(if required) (see section 5.19.3(e))

8.4.5 Final trial close-out monitoring report To document that all activities required X

for trial close-out are completed, and

copies of essential documents are held

in the appropriate files

8.4.6 Treatment allocation and decoding Returned to sponsor to document any X

documentation decoding that may have occurred

8.4.7 Final report by investigator/institution to To document completion of the trial X

IRB/IEC where required, and where

applicable, to the regulatory

authority(ies) (see section 4.13)

8.4.8 Clinical study report (see section 5.22) To document results and interpretation X X

of trial (if

applicable)