gcp for investigators by valentyna

GCP and Clinical Research

by Valentyna Korniyenko

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Clinical Trials is 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.

What are Clinical Trials?

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What is GCP ?

GCP (Good Clinical Practice) is 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.

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Why GCP?

GOOD CLINICAL PRACTICE

International Cooperation

Possibility of publications

Protection of rights, safety

and well-being of trial subjects

Protection against unreasonable

legal proceedings

Eligible data for Healthcare Authorities

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Why ICH-GCP?

The birth of ICH* took place at a meeting in April 1990, hosted by EFPIA in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the US met, primarily, to plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH.

At the first ICH Steering Committee (SC) meeting of ICH the Terms of Reference were agreed and it was decided that the Topics selected for harmonization would be divided into Safety, Quality and Efficacy to reflect the three criteria which are the basis for approving and authorizing new medicinal products.

*(at that time - the International Conference on Harmonization, nowadays - the International Council for Harmonization)

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Why ICH-GCP under E6?

“E” heading means Efficacy and is concerned with the design, conduct, safety and reporting of clinical trials.

As of November 2005, With the new codification revisions to an ICH Guideline are shown as (R1), (R2), (R3) depending on the number of revisions. Annexes or Addenda to Guidelines have now been incorporated into the core Guidelines and are indicated as revisions to the core Guideline (e.g., R1).

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When was ICH-GCP published? Any Addendum?

• The tripartite harmonized ICH Guideline was finalized under Step 4 in May 1996.

This Good Clinical Practices document describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs.

• The E6(R2) Integrated Addendum has reached Step 2 of the ICH process in June 2015.To complement the harmonized ICH E6 Guideline, which was finalized in May 1996, this Addendum is proposed to modernize ICH E6 to enable implementation of innovative approaches to clinical trial design, management, oversight, conduct, documentation, and reporting that will better ensure human subject protection and data quality.

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GCP requirements

•Patients’ well-being is the priority

•Clinical trials must be conducted in compliance with the scientifically well-grounded protocols

•Preliminary Ethical Expert Review by independent ethics committees

•Patients’ Informed Consent

•High quality eligible source records and secondary data

•Safety reporting

•Study Drug Accountability

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Investigator’s Responsibilities

E6 Good Clinical Practice: Consolidated Guidance4. Investigator

21 CFR Part 312: Investigational New Drug Application(These regulations, which resemble GCP guidelines, are enforceable in the United States.)

For studies conducted outside of the U.S. but in ICH regions, compliance with the provisions of GCP Guidelines ICH E6 ensures that that the studies will be accepted for review by FDA as non-U.S., non-IND studies (under FDA regulations for accepting such non-U.S., non-IND studies).

VS

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Investigator’s Responsibilities according to GCP

•Responsibilities in the preparation for clinical trials

•Responsibilities during clinical trials start-up

•Responsibilities within clinical trials conduct

•Responsibilities after study closure

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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). (GCP Guideline, 4.1.1)

Responsibilities in the preparation for clinical trials

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•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.

•The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties (they should know the study protocol, the appropriate use of the investigational product(s) and be aware of their responsibilities within the clinical trial).

(GCP Guidelines, 4.1, 4.2, 4.4)


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•Inclusion / Exclusion criteria

•Study Flowchart (describing study procedures)

Protocol Review/Assessment


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Assess inclusion/exclusion criteriaReview Informed Consent FormCheck annual statistics recordsThink how the patients would perceive the study informationEvaluate risk–benefit ratio for the patients

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. (GCP Guideline, 4.2.1)


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Responsibilities during clinical trials start-up

The investigator 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).(GCP Guideline, 4.1.1)

Documents to be Provided:Curricula Vitae of the Principal Investigator and his/her Study Team Signature (Delegation of Responsibilities) LogFDA 1572 Form (21 CFR, 312.53)Financial Disclosure Form (21 CFR, Part 54)

The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.(GCP Guideline, 4.1.5)

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The financial aspects of the trial should be documented in an agreementbetween the sponsor and the investigator/institution.(GCP Guidelines, 4.9.6, 8.2.4)

Study Agreement between Sponsor and:Hospital Principal Investigator

Responsibilities during clinical trials start-up

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–Responsibilities before the patients–Responsibilities in regards to the study protocol–Responsibilities before the Ethics Committee–Responsibilities before the Sponsor–Responsibility of the Medical Institution

Responsibilities within clinical trials conduct

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•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.

•Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.

(GCP Guidelines, 4.8.8, 4.8.3)

1. Responsibilities before the patients

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•The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.

•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.(GCP Guidelines, 4.3.2, 4.3.3)


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•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.

(GCP Guideline, 4.3.4)

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2. Responsibilities in regards to the study protocol


•The investigator/institution should conduct the trial in compliance with the protocol. •The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable 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 in monitor(s), change of telephone number(s)). (GCP Guidelines, 4.5.1, 4.5.2)

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•The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.

•The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. (GCP Guidelines, 4.5.3, 4.5.4)

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•As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted: (a) to the IRB/IEC for review and approval/favourable opinion, (b) to the sponsor for agreement and, if required, (c) to the regulatory authority(ies). (GCP Guideline, 4.5.4)

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3. Responsibilities before the Ethics CommitteeThe 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.

(ICH E6, 3.3.8; 4.10.2; 4.11)

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3. Responsibilities before the Ethics Committee

The investigator should provide the following documents to the IRB/IEC:

a current copy of the Investigator's Brochure or, if the Investigator's Brochure is updated during the trial, a copy of the updated Investigator’s Brochure. written summaries of the trial status - annually, or more frequently, if requested by the IRB/IEC. 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).

(GCP Guidelines, 4.4.2; 4.10.1; 4.11.3)

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4. Responsibilities before the Sponsor

• 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.• 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).• Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.(GCP Guidelines, 4.9.1, 4.9.2, 4.9.3, 4.9.7)

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•Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.

•The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.

•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.

(GCP Guidelines, 4.6.1, 4.6.5, 4.6.6)


4. Responsibilities before the Sponsor

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Responsibilities after study closure

1. Completion of the Trial

•Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.(GCP Guidelines, 4.13)

•The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.

(GCP Guidelines, 4.9.4)

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Responsibilities after study closure

2. Premature Termination or Suspension of a Trial

• If the sponsor terminates or suspends a trial (see 5.21), the investigator should

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

of the termination or suspension.

• If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

(GCP Guideline, 4.12)

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Thank you!Questions?