Ich-gcp

ICH-GCP

Agenda §History of development of Clinical Trial Regulations §The ICH process §The ICH-GCP Guidelines

How did these principles evolve? •The Elixir Sulfanilamide incident • The infamous Tuskegee Syphilis Study (Alabama, U.S.A., 1932-1972) •In 1946, 23 Nazi physicians were put on trial at Nuremberg for “research atrocities” they had performed on prisoners •The Thalidomide Tragedy •The Harvard Fraud •

Regulations for the Use of Investigational Drugs in Humans: Regulations in Clinical Research

The Declaration of Helsinki of the World Medical Association, Finland 1964

Most well known international regulation for biomedical research Establishes the principles and rationale for research in human subjects Introduces the concepts of: Protocol approval by an independent ethics committee Investigator as responsible for the care of the participating subjects Written informed consent Content has been reviewed in Tokyo, 1975; Italy, 1983; Hong Kong, 1989; South Africa, 1996; and Edinburgh, 2000

What is ICH?

Harmonization came in 2 steps: • In Europe: European Guidelines on GCP 1991 (EU-GCP Guidelines) • In Europe + USA + Japan 1997 EU + USA + Japan= ICH = International Conference on Harmonization

The ICH Process Membership: Representatives of Regulatory Authorities and Pharmaceutical Industries of EU, US and Japan (the 3 regions) Objective: Facilitate worldwide drug development through “harmonization of requirements” Results: Have published many guidelines, one of them is the ICHGCP guideline

International Conference on Harmonization (ICH) The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration

Reduce or obviate the need to duplicate the testing of new medicines Mutual acceptance of clinical trial data by regulatory authorities

Early availability of drugs in the market

Objectives of ICH Less expensive drugs for patients

Maintaining safeguards on quality, safety and efficacy

Expert Working Groups SAFETY QUALITY MULTIDISCIPLINARY

STEERING COMMITTEE

EFFICACY

ICH Guidelines ü Q "Quality" Topics, i.e., those relating to chemical & pharmaceutical Quality Assurance. e.g. Q1 Stability Testing, Q3 Impurity Testing ü S "Safety" Topics, i.e., those relating to in vitro & in vivo pre-clinical studies. e.g. S1 Carcinogenicity Testing, S2 Genotoxicity Testing ü E "Efficacy" Topics, i.e., those relating to clinical studies in human subject. e.g. E4 Dose Response Studies, Carcinogenicity Testing, E6 Good Clinical Practices. (Note Clinical Safety Data Management is also

ICH Guidelines M "Multidisciplinary" Topics, i.e. cross-cutting topics w do not fit uniquely into one of the above categories: M1: Medical Terminology (MedDRA) M2: Electronic Standards for Transmission of Regulatory Information (ESTRI)

M3: Timing of Pre-clinical Studies in Relation to Cli Trials M4: The Common Technical Document (CTD)

M5: Data Elements & Standards for Drug Dictionar

Participants in a Clinical Trial Regulators

GCP

Institute

•Investigator •Ethics Committee •Administrator

Sponsor CRO

Contents of ICH-GCP guidelines (ICH E6) Title Page Table of contents Introduction 1. Glossary 2. The Principles of ICH-GCP 3. IRB / IEC (responsibilities of…) 4. Investigator (responsibilities of…) 5. Sponsor (responsibilities of …) 6. Clinical Trial Protocol and amendment (s) (contents of …) 7. Investigator’s Brochure (contents of …) 8. Essential Documents for the Conduct of Clinical Trial (what we need to keep on file and why)

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

Objective: To provide a unified standard for the EU, Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions

Principles of ICH / GCP

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 requirements

Principles of ICH-GCP

SUBJECTS Subject’s rights, safety and well being is of foremost importance

All foreseeable risks are weighed against anticipated benefits

Informed consent should be given freely

Principles of ICH-GCP MEDICAL COMMUNITY Each participating person should have the right qualification, training and experience (Task-oriented)

Clinical decision making and medical care by qualified physicians

Confidentiality of the subject’s identity should be maintained and such records must be protected (as per applicable rules)

Principles of ICH-GCP

CLINICAL TRIAL Trial must be scientifically sound (described in a detailed protocol)

Should be conducted after favorable approval of the IEC/IRB

All information should be recorded, handled, reported and stored so as to allow its accurate interpretation and verification

Principles of ICH-GCP INVESTIGATIONAL PRODUCT

  

IP should be sufficiently                                  supported by available                                  clinical and non-clinical data

Manufactured, handled and stored as per GMP rules

SOPs must be implemented for quality assurance

The Concept of Good Clinical Practice

International Scientific & Ethical quality Standard

R E C O RD

REPORT

DESIGN

COLLECT

Protection of trial subject’s rights, integrity and confidentiality

Ensure credibility and accuracy of data

Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)

Definitions IRB/IEC (ICH 1.27, 1.31) • An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical 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 favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in

Composition

• 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 non scientific area. of the

(c) At least one member who is independent

institution/trial site. • Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial

ROLE AND RESPONSIBILITIES OF THE INVESTIGATOR

Definitions Investigator (ICH 1.34) § A person responsible for the conduct of the trial at a trial site § “Responsible Leader” Sub Investigator (ICH 1.56) § Designated and supervised by the investigator § Performs critical trialrelated procedures &/ makes important trialrelated decisions

Investigator: Responsibilities

Qualifications and Agreements (ICH - GCP 4.1)

§ Should comply with GCP, protocol and regulatory requirements

§ Should maintain a list of appropriately

qualified persons to whom trial related duties have been delegated

§ Should permit monitoring and auditing by sponsor/CRO and inspection by the regulatory authorities

Adequate Resources (ICH - GCP 4.2) Resources

Investigator: Responsibilities

− Potential recruitment − Time − Qualified and informed staff − Facilities

Medical Care of Trial Subjects (ICH - GCP 4.3) § Responsible for all trial-related medical

Investigator: Responsibilities

decisions § Should ensure adequate medical care to the subject for any adverse events and intercurrent illnesses during the trial § Should exert “reasonable efforts” to ascertain patient’s reasons for withdrawing

Communication with IRB/IEC (ICH - GCP 4.4

Investigator: Responsibilities

Ap o pr d ve

§ Should obtain written and dated approval for Protocol, ICF and other recruitment documents before start of the study

§ Should provide the IRB/EC with the current/updated copy of the Investigator’s Brochure

§ Should provide the IRB/EC all documents

Compliance with Protocol (ICH - GCP 4.5) Pro

Investigator: Responsibilities

toc ol

§ Should conduct the trial in compliance with the protocol § Should not implement changes or deviations to Protocol unless approved by Sponsor and EC § Should document and explain any deviation from the approved protocol

Investigational Product(s)- IP (ICH - GCP 4.6

Investigator: Responsibilities

§ May assign duties for IP accountability to appropriate individual under supervision of the investigator § Designated individual should maintain a record of delivery, use and return of investigational product received from the sponsor § Investigational product should be stored in a secure location and under appropriate conditions (as specified by sponsor) § Should ensure that the IP is used only in accordance with the approved protocol

Randomization &Unblinding - IP (ICH - GCP 4.7)

Investigator: Responsibilities

•Should follow the trial's randomization procedures, if any •Should ensure that the code is broken only in accordance with the protocol

• If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product (s).

Informed Consent of Trial Subjects (ICH - GCP 4.8) xCo § Should obtain written approval from nse nt

For In t m his con stud d y u Pro cted , you fessor by X the will v XX, isit l a b on t orat and hree d ory ays …

Investigator: Responsibilities

IRB/EC X

___

___

__

§ Should obtain written Informed consent from each study subject prior to inclusion in the study § Should ensure that the ICF is signed and

Records and Reports (ICH - GCP 4.9)

Investigator: Responsibilities

§ Should ensure that data are − Accurate − Complete − Legible − Reported in time § Corrections in CRF’s should be recorded and duly endorsed by the investigator § Ensure documentation of financial aspects of the study

CRF

Consistent with

Source Doc

§ Maintain essential documents − Keep at least 2 years after • last marketing application approval in an ICH region • or discontinuation of development § Access to all trial related original records

Records and Reports (ICH - GCP 4.9) Document ! en t!

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Investigator: Responsibilities

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Document ! Document !

Investigator: Responsibilities

Progress Reports (ICH - GCP 4.10)

Investigator

or IRB/IEC Written summaries of the trial status - annually or more frequently as requested

IRB/IEC

Sponsor

Written reports about any changes: •which affect trial conduct •which increase risk to subject

Safety Reporting (ICH - GCP 4.11) SAEs (Initial +Follow-up reports) AEs/Lab abnormalities

Investigator: Responsibilities

Deaths (Autopsy reports)

Investigator

IRB/IEC

Sponsor HA

Premature termination or suspension of a trial (ICH - GCP 4.12)

Investigator: Responsibilities

If the trial is prematurely terminated 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 should inform the IRB/IEC, Sponsor and the regulatory authority(ies) (as applicable)

Investigator

IRB/IEC

Sponsor

Investigator: Responsibilities

Final Report (s) (ICH - GCP 4.13)

Investigator 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

ICH GCP 5.19

GCP Audits and Inspections

GCP Audits and Inspections

… please be aware that this is a possibility for any study!!!

Health Authority (HA) Inspections § Monitoring activities by Health Authorities to ensure: § Scientific integrity and reliability of data submitted in marketing applications § Adequate protection of study subjects § Compliance with protocol, GCP requirements, local laws § Assess quality systems in place § Can occur during or after completion of the trial

GCP FDA Inspection Observations

§ Failure to follow protocol § Failure to maintain adequate & accurate medical records § Discrepancies between source documents and CRFs § Irregular submission of periodic reports to Ethics Committee § Lack of computer validation § Lack of raw data and SOPs

Documentation § Availability of key documents prior to, during, after the trial § Appropriate delegation of activities and training. Perform only activities for which training received § Clear definition and availability of supportive source data – paper and/or electronic § Follow the protocol, document all deviations, reasons and corrective actions § Document any important correspondence § Interact with the monitors who are there to help……….

Documentati on § ‘There is one unwritten rule in this work, GET IT DOWN ON PAPER! § ‘If it is not documented, it did not happen!

And finally……. Ethics is not separable from scientific, social, and political questions in clinical research. Ethics is what all the partners in research can share. We must insist on ethics having the upper hand in clinical research.

Thank You