Guideline for GCP E6 (R2)

Question 1

What is GCP?

Answer 1

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.

Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

Question 2

Principles of ICH GCP

Answer 2

1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

2 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.

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.

4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion.

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.

8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

9 Freely given informed consent should be obtained from every subject prior to clinical trial participation.

10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.

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).

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.

13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Question 3

IRB/IEC Responsibilities

Answer 3

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.
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 need 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/favourable opinion;
   - modifications required prior to its approval/favourable opinion;
   - disapproval / negative opinion; and
   - termination/suspension of any prior approval/favourable opinion.
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.
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.
5. The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects.
6. When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.
7. Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e., in emergency situations).
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.
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.

Question 4

IRB/IEC Composition, Functions and Operations

Answer 4

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.
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. 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.
4. Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise.
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.
6. An IRB/IEC may invite nonmembers with expertise in special areas for assistance.

Question 5

IRB/IEC Procedures

Answer 5

The IRB/IEC should establish, document in writing, and follow its procedures, which should include:

1. Determining its composition (names and qualifications of the members) and the authority under which it is established.
2. Scheduling, notifying its members of, and conducting its meetings.
3. Conducting initial and continuing review of trials.
4. Determining the frequency of continuing review, as appropriate.
5. Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC.
6. Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable opinion of the trial.
7. Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).

8.Specifying that the investigator should promptly report to the IRB/IEC:
(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
(c) All adverse drug reactions (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.

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.

Question 6

IRB/IEC Records

Answer 6

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 its written procedures and membership lists.

Question 7

Investigator’s Qualifications and Agreements

Answer 7

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).
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.
3. The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
4. The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).
5. The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.

Question 8

Investigator Adequate Resources

Answer 8

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.
2. The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.
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. 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.
5. The investigator is responsible for supervising any individual or party to whom the investigator delegates trial-related duties and functions conducted at the trial site.
6. If the investigator/institution retains the services of any individual or party to perform trial-related duties and functions, the investigator/institution should ensure this individual or party is qualified to perform those trial-related duties and functions and should implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated.

Question 9

Investigator Medical Care of Trial Subjects

Answer 9

1. A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
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.
3. It is recommended that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
4. 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.

Question 10

Investigator Communication with IRB/IEC

Answer 10

1. Before initiating a trial, the investigator/institution should have written and dated approval/favourable 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.
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.
3. During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.

Question 11

Investigator Compliance with Protocol

Question 12

Investigator Investigational Product(s)

Question 13

Investigator Randomization Procedures and Unblinding

Question 14

Investigator Informed Consent of Trial Subjects

Question 15

Investigator Records and Reports

Question 16

Investigator Progress Reports

Question 17

Investigator Safety Reports

Question 18

Investigator Premature Termination or Suspension of Trial

Question 19

Investigator Final Report(s) by Investigator

Question 20

Sponsor - Quality Management

Question 21

Critical Process and Data Identification

Question 22

Risk Identification

Question 23

Risk Evaluation

Question 24

Risk Control

Question 25

Risk Communication

Question 26

Risk Review

Question 27

Risk Reporting

Question 28

Sponsor - Quality Assurance and Quality Control

Question 29

Sponsor - Contract Research Organization (CRO)

Question 30

Sponsor - Medical Expertise

Question 31

Sponsor - Trial Design

Question 32

Sponsor - Trial Management, Data Handling, and Record Keeping

Question 33

Sponsor - Investigator Selection

Question 34

Sponsor - Allocation of Responsibilities

Question 35

Sponsor - Compensation to Subjects/Investigators