ICH GCP Overview

What is ICH?

ICH is a joint initiative involving both the regulators and the industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines.

How did it evolve?

o Public disasters, serious fraud and

abuse of human rights. o  Trials of War criminals-Nuremberg

code 1949 o Thalidomide- Declaration of Helsinki

1964

How did it evolve?

o Belmont report

n  Conference center – April 18th 1979 n  Ethical Principles and guidelines for the protection of human

subjects of research)-Tuskegee syphilis study n  Created by the US Dept of Health, Education and Welfare

(Health and Human Services)

History

1962 US FDA IND Guidelines 1964 Declaration of Helsinki 1968 Committee on Safety of Medicines, uk 1978 GCP, US FDA 1991 GCP, Europe 1996 ICH GCP 1997 ICH GCP Guideline

When did it begin? o  Ist conf. in 1990 in Brussels 3 regions participated o Representatives from

ICH parties

o  EU European Commission o  EFPIA European federation of pharmaceutical industries’ associations

o  MHLW Ministry of health, Labor and welfare, Japan

o  JPMA Japan Pharmaceuticals manufacturers Association

o  US FDA o  PhRMA Pharmaceutical Research & Manufacturers of America (1958)

o  WHO, TPP(Canada) o  International federation of Pharmaceutical

manufacturer’s association

Key objective

o To discuss and define the minimum standards for the development and registration of investigational products

The result?

Many guidelines made

o Most important- ICH GCP guidelines o Evolved in several steps o Consolidated guideline ICH E6 Sept

1997

ICH Guidelines: examples o  Efficacy:

clinical trials etc

o  Safety: pharmacovigilance, adverse drug reaction

reporting, safety letters

o  Quality: raw materials, impurities, residual solvents etc

o  Multidisciplinary: common technical document, electronic

submission, coding systems

The ICH Story

Who: Regulatory authorities and research-based industry of the EU, US and Japan; WHO, Canada observers and EFTA (Iceland, Lichtenstein, Norway, Switzerland)

Why: Reduce unnecessary duplication and thereby contribute to the efficiency of drug development and registration for new pharmaceuticals

How: Through the development of science-based, international guidelines and standards

What is GCP? A standard for the design, conduct,

performance, monitoring ,auditing, recording, analyses and reporting of clinical trials that provide assurance that the data and the reported results are credible, accurate and that the rights, integrity and confidentiality of trial subjects are protected.

Main finding involved in monitoring and FDA audits.

Why is it needed?

o To ensure the rights, safety and well being of the trial subjects are protected

n  Informed Consent n  Belmont Report

o Ensure the credibility of clinical trial data

The ICH GCP guideline

o  No acceptance of foreign clinical data o  Regional variation in reg guidelines o  Escalating costs o  Extended time for registration o  ICH region covers 85% of Pharm. sales

The ICH GCP guideline

o  Provide a unified standard for the EU, Japan and USA regions to facilitate mutual acceptance of clinical trial data by the regulatory authorities in these regions.

o  8 sections

ICH GCP guideline 1. Glossary Common language for investigators/

sponsors/ethics committees Most if not all are on FDA-CFR

ICH GCP guideline 1. Glossary *AE: means any untoward medical occurrence associated with the use of

a drug in humans, whether or not considered drug related *SAE: AE that in the view of either the investigator or sponsor, it results in

any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.

**Blinded Study: A type of masking in which two or more parties involved with the clinical trial do not know which participants have been assigned which interventions. Typically, this includes the investigator and participant

*21CFR312 ** Clinical Trials.gov

ICH GCP guideline 2.Principles of Good Clinical Practice 13 tenets of ICH GCP 3.Requirements for IRB/IEC Roles responsibilities and

composition 4.Responsibilities of the investigator

ICH GCP guideline 5.Responsibilities of the sponsor 6.Requirements for clinical trial protocol

and protocol amendments 7.Responsibility of the sponsor in the

development of investigator’s brochure.

8.Essential documents

Principles of ICH GCP

q Ethical conduct as per Declaration of Helsinki GCP Regulatory Requirements

q Risk- Benefit Primary concern- Subject

Principles of ICH GCP o Supportive data

o Protocol Scientifically sound, clear, detailed

o Ethical Clearance Study to be conducted in compliance to

the protocol which has received EC approval

Principles of ICH GCP

o Subject Care Medical decisions responsibility of

qualified physician o Qualified staff By education, training, experience in

their area of responsibility o  Informed Consent

Principles of ICH GCP

o Clinical Trial data Recorded, handled and stored to enable

accurate reporting, interpretation and verification

o Confidentiality

Principles of ICH GCP

o  Investigational Product Manufactured, handled and stored as

per GMP

q Used as per the protocol

Principles of ICH GCP

o Quality Assurance

Systems and procedures to ensure the Quality of every aspect of the trial

ICH Vs. non-ICH

o  ICH: 17 countries o  15% world population o  82% drug production o  90% drug sales o  95% R&D o  New Chemical Entities o  Chronic & lifestyle

diseases o  Strong DRAs o  $$$$$

o  “non-ICH”: 176 countries o  85% world population o  18% drug production o  10% drug sales o  5% R&D o  Mainly generics o  Life-threatening diseases

o  Weak DRAs (Drug regulatory affairs)

o  $

Issues in Developing Countries

o The informed consent process o Economic Vulnerability o Patient doctor relationship o Education level

o  Good clinical practice (gcp) is an international ethical & scientific standard for conducting clinical trials that involve the participation of human subjects

o  Compliance with this standard provides public assurance that the rights, safety & well-being of trial subjects are protected, which is consistent with the principles outlined in the declaration of helsinki

o  GCP also ensures the credibility of clinical trial data.

Role of GCP

INTERNATIONAL ETHICAL STANDARDS

o  Professional standards for the protection of human subjects in research did not exist till late 1940’s.

o  Nuremberg tribunal held in 1945 and 1946 that “voluntary consent of the human subject is absolutely essential”

o  The Declaration of Helsinki outlines 12 principles by which physicians must conduct research in therapeutic & non-therapeutic interventions.

o  RESPECT FOR PERSONS: Acknowledges the dignity & autonomy of individuals. This principle requires that subjects give their informed consent prior to participating in research.

o  BENEFICENCE: Obligates researchers to treat subjects fairly.

o  JUSTICE: requires the equitable selection of subjects in light of research setting & research purposes.

Fundamental Ethical Principles Guiding Protection of Human Subjects In Biomedical Research

o  Before initiating any clinical trial, ANTICIPATED RISKS should be weighed against EXPECTED BENEFITS for the trial subject & society

•  The RIGHTS, SAFETY & WELL BEING of trial subjects are the most important considerations & should prevail over the interests of science & society.

•  The entire study procedure should be scientifically sound & detailed in a trial protocol. This protocol should receive a prior APPROVAL FROM AN IRB (Institutional Review Board)

Principles Behind GCP

ETHICAL REVIEW SHOULD DEFINE JUSTIFIABLE BOUNDARIES BETWEEN THE RIGHTS OF THE SUBJECT AND THE BENEFITS THAT MIGHT ACCRUE TO SOCIETY THROUGH SCIENTIFIC INFORMATION DEVELOPED IN

CLINICAL TRIALS.

Regulations have been established internationally, to ensure ethical & scientific conduct of trials

o  SAFEGUARD PUBLIC HEALTH o  ASSURE CONSUMER PROTECTION STANDARDS o  FACILITATE AVAILABILITY OF SAFE AND

EFFECTIVE PRODUCTS o  ELIMINATE INCONSISTENT STANDARDS

INTERNATIONALLY o  FACILITATE MUTUAL ACCEPTANCE OF DATA

FROM CLINICAL TRIALS

GOALS OF INTERNATIONAL HARMONIZATION OF REGULATORY REQUIREMENTS

STAKEHOLDERS & THEIR RELATIONSHIPS

SUBJECT

REGULATORY AUTHORITY

SPONSOR IRB

INVESTIGATOR

o  Play a vital role in protecting human subjects in clinical trials.

o  They review trial protocols to ensure that…. n  informed consents are obtained from the subjects n  subjects are not exposed to unreasonable risks

o  Establishment of EC’s has become a cornerstone of protection of human subjects in clinical research

Role of IRB’s

Protection of Human Subjects

The investigator must request IRB approval for: n  Protocol n  Informed Consent Form/Advertisements/Other

Information n  Protocol amendment and /or Informed Consent

Amendments n  All sites at which patient activity will occur

Protection of Human Subjects

o  The investigator must request IRB approval for any change in the research activity

o  The investigator must submit progress reports to the IRB as required

o  The subject must be informed of any new information which might affect their decision to continue participation in the trial

q  Conduct the research in accordance with the protocol and Good Clinical Practice (GCP)

q Protect the rights, safety, and welfare of the subjects

q Report all adverse events (serious and non-serious)

q Retain study documents and medical records

q Control the distribution and use of the study medication

Responsibilities of the Investigator

o  The sponsor is responsible for implementing and maintaining quality assurance of data generated in compliance with the protocol

o  Sponsor is responsible for securing agreement from all involved parties to ensure direct access to all sites, source data & reports for the purpose of monitoring & auditing by regulatory authorities

o  Agreements made by the sponsor with the investigator should be in writing

Responsibilities of the Sponsor

o During and following a subject’s participation in a trial, the investigator & institution should ensure that adequate medical care is provided to deal with adverse events related to the trial

o The investigator should inform the subject’s primary physician about the trial & the subject’s participation

Medical Care of Trial Subjects

Protection of Human Subjects

o  Must be signed and dated by the subject prior to study start

o  Language understandable to the subject o  Subject Information Sheet approved by the

Ethics Committee o  The Consent Form must contain the

elements required by GCP o  Subject must be given a copy

Study Documentation

n  IRB approval letter n  Members of IRB and their qualifications/

affiliation n  Normal ranges of clinical laboratory

Study Documentation

The investigator must keep: n  Source documents

p Medical records (including access to computer records)

p Laboratory reports p ECGs, X-rays, etc. p Any other medical records, reports or notes

(hospital admissions and discharges) n  A subject identification list n  Copies of all study related documentation

Medical Records

o  Sufficient information to support subject eligibility o  This should be well documented (signed and dated) o  Subject’s participation in the study o  Dates of visits o  Procedures, investigations done o  Observations, diagnoses o  Medications taken (including study medication) o  Adverse events / SAE’s o  Completion or withdrawal (reason) from the study o  Source documents

Study Documentation

The sponsor needs from the investigator: n  Final drug accountability records n  All used and unused supplies and medication n  All required documents completed n  Destruction or return of IP is also part of source

docs

INVESTIGATIONAL PRODUCT

o  The trial subjects should be explained the correct use of the investigational product and compliance to these instructions should be checked periodically

o  Investigator should maintain records of

the delivery of the product, the inventory, use by each subject as per protocol

n  The rights & well-being of human subjects are protected

n  The reported data are accurate, complete & verifiable from source documents

n  The conduct of the trial is in compliance with approved protocol & with applicable regulatory requirements

Monitoring

Questions?

……Thank you!