Good Clinical PracticeDR. VENKATA SUBBA REDDY A

MBBS;MD(PHARMACOLOGY)

FOUNDER & CHIEF EDITORWWW.THEPHARMACOLOGY.COM

At the end of this presentation you should be able to know…..

Define GCP Outline the principles of GCP The players involved in GCP Should follow GCP

What is GCP

Clinical Trials or Studies

Designing

Conducting

Monitoring

Recording

Analysis

Reporting

A standard for designing, conducting, recording and reporting of studies involving human subjects.

Public assurance that the rights, safety and well-being of trial subjects are protected.

Research regulatory

Basic Research Disease Recovery Drug Recovery Preclinical

Development Clinical Trials Manufacturing

Not regulatedGLP

GCPGMP

History ofHUMAN RESEARCH & REGULATIONS

Nuremberg Code

December 9, 1946 - American military tribunal opened criminal proceedings against 23 leading German physicians and administrators for crimes against humanity – 16 found guilty

German Physicians conducted medical experiments on thousands of camp prisoners without their consent.

Most of the participants of these experiments died or were permanently crippled. The Nuremberg Code was established in 1948, stating that "The voluntary consent

of the human participant is absolutely essential," It did not carry the force of law, but the Nuremberg Code was the first

international document which advocated voluntary participation and informed consent.

Kefauver Amendments 1960s – Thalidomide as anti emetic in

pregnancy used in Europe (but not approved by US FDA)

Deformities in foetus No informed consent (not approved

by FDA) 1962 US Senate hearings Kefauver

Amendments passed into law - For the first time, drug manufacturers were required to prove to the FDA the effectiveness of their products before marketing them

Declaration of Helsinki

World Medical Association - recommendations guiding medical doctors in biomedical research involving human participants1. Research with humans should be based on the results from animal

and laboratory experimentation.2. Research protocols should be reviewed by an independent

committee prior to initiation3. Informed consent from research participants is necessary4. Research should be conducted by medically/scientifically qualified

individuals5. Risks should not exceed benefits

Revised - 1975, 1983, 1989, 1996, 2000, 2002, 2004, 2008

Tuskegee Syphilis Study

Study on 600 low income African-American by U.S. Public Health Service

Free medical examination – but not told of diagnosis Many died of syphilis Stopped in 1973 by the U.S. Department of Health, Education,

and Welfare 1974 National Research Act passed - National Commission for the

Protection of Human Subjects of Biomedical and Behavioural Research established

The commission produce Belmont Report (1979)

Belmont Report

Three basic ethical principals

1. Autonomy/respect for persons (Individuals should be treated as autonomous agents & Persons with diminished autonomy are entitled to protection)

2. Beneficence (Human participants should not be harmed & Research should maximize possible benefits and minimize

possible risks) and 3. Justice (benefits and risks of research must be distributed

fairly)which are the cornerstone for regulations involving human participants.

Evolution of GCP1930s – US Food Drug & Cosmetic Act1947 – Nuremberg Code1962 - Kefauver Amendments (US) (following Thalidomide tragedy)1964 – Declaration of Helsinki1974 – National Research Act (US)1979 - Belmont Report (US)1986 – England – ABPI Guideline1987 - France - Bonnes Pratiques Clinique1989 – Scandinavia - Nordic Guidelines , Good Clinical Trial Practice1990 – France – Huriet Law1990 - EC - Good Clinical Practice for Trials on Medicinal Products in the European Community1992 - WHO Guidelines, Australian Guidelines1997 – ICH GCP became law in some countries1999 - Malaysian GCP

A comprehensive representation of the development of GCP can be found in a literature review of …..

Declaration of Helsinki

The common rule

The Belmont report

World Health Organisation Guidelines for GCP

International Conference on Harmonization

FDA GCP

What is ICH?

International Conference on Harmonisation Realisation to have independent evaluation of

medical products mostly driven by tragedy 1960-1970s - rapid increase in laws, regulations and guidelines for reporting

and evaluating the data on safety, quality and efficacy Varied from country to country – need to harmonise Pioneered by European Community (EC) (now the European Union) in 1980s WHO Conference of Drug Regulatory Authorities (ICDRA), in Paris, in 1989 ICH was initiated on April 1990, in a meeting hosted by EFPIA (European

Federation of Pharmaceutical Industries and Associations) in Brussels Main outcome - Tripartite ICH Guidelines on Safety, Quality and Efficacy

Aims of ICH

1. Unify registration requirements for new products2. Reduce medicinal product development costs: more economical

use of animal, human and material resources.3. Accelerate medicinal product licensing times: avoid repeat

testing in different regions.4. Increases patent protection times through reducing delay in

licensing times.

ICH represents

17 countries comprising 15% of the world’s population 90% of the US$ 320 billion global pharmaceutical sales of the

year 2000

PrincipleS of ICH GCP

The summary of the principles...!!!

1. Conduct trials according to GCP2. Weigh risks vs. benefits3. Subjects wellbeing exceed the science4. Have adequate information to justify trial5. Write a sound protocol6. Receive IRB/IEC approval7. Use qualified physicians8. Use qualified & trained support staff9. Obtain informed consent10. Record information appropriately11. Confidentiality & data protection12. Handle investigational products appropriately13. Quality assurance

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 requirement(s).

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.

The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

Principles of ICH GCP……. The available nonclinical and clinical information on an

investigational product should be adequate to support the proposed clinical trial.

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

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.

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

Principles of ICH GCP……. 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.

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.

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

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

Principles of ICH GCP……. All clinical trial information should be recorded, handled, and

stored in a way that allows its accurate reporting, interpretation and verification

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).

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.

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

The summary of the principles...!!!

1. Conduct trials according to GCP2. Weigh risks vs. benefits3. Subjects wellbeing exceed the science4. Have adequate information to justify trial5. Write a sound protocol6. Receive IRB/IEC approval7. Use qualified physicians8. Use qualified & trained support staff9. Obtain informed consent10. Record information appropriately11. Confidentiality & data protection12. Handle investigational products appropriately13. Quality assurance

The Players

Institutional Review Board/ Ethics committee The Investigator The Sponsor The Monitor

Institutional Review Board/ Ethics committee

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

The IRB/IEC should obtain the following documents

Trial protocol(s)/ Amendment(s) Written informed consent form(s) Subject recruitment procedures Written information to subjects Investigator`s brochure(IB) Available safety information Information about payments and compensation available to

subjects The investigator`s current curriculum vitae Undertaking by investigator Bio Equivalence No Objection Certificate

Institutional Review Board/ Ethics committee

The IRB/IEC should review a proposed clinical trial within a reasonable time 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 one per year Adequately addresses relevant ethical concerns and meets applicable regulatory

requirements for such trials The IRB/IEC should review both the amount and method of payment to subjects to

assure that neither presents problem 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

Investigator The investigator 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 requirements

The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), shoulld be aware of, and should comply with, GCP and the applicable regulatory requirements

Should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authorities

A qualified physician, who is an investigator or a sub-investigator for the trial, should be responsible for all trial related medical decisions

Should comply with the sponsors for timely completion of the project and recording of all clinical and non clinical data.

Adverse drug reactions must be manages appropriately followed by reporting to regulatory authority, IRB/IEC and sponsor

Investigator

If the trial is terminated permanently or suspended for any reason, the investigator should promptly inform the trial subjects, should assure appropriate therapy and follow up for the subjects, and, where required by the applicable regulatory requirements, should inform the regulatory authority.

Upon completion of the trial, the investigator should inform the institution, and should provide the sponsor with all required reports, the IRB/IEC with a summary of the trial`s outcome, and the regulatory authority with reports they require of the investigator/institution

Sponsor Sponsor takes the responsibility for the initiation,

management and/or financing of a clinical trial A sponsor can be

An Individual A Company An Institution An Organization

Responsibilities of Sponsor Quality assurance and quality control Contract research organization (CRO) Medical expertise Trial design Trial management, Data handling, Record

keeping Independent data monitoring committee Investigator selection Allocation of duties and functions Compensation to subjects and investigators Financing

Responsibilities of Sponsor… Notification/ Submission to regulatory authority Information on investigational product Manufacturing, packaging, labeling, coding,

supplying and handling investigational product Record access Safety information Adverse drug reaction reporting Trial monitoring Trial audit Premature termination or suspension of a trial

Monitor Acts as main line of communication between the sponsor and

investigator Should be appointed by the sponsor Should be appropriately trained, and should have the scientific and/or

clinical knowledge needed to monitor the trial adequately

Responsibilities of Monitor Verify that the resources, staff and facilities, including

laboratories and equipment, are adequate to conduct the trial safely and properly and these remain adequate through out trial period

Verifying the investigational product Verifying that the investigator follows the approved protocol,

all approved amendment(s) and informed consent Verifying enrollment and recruitment of subjects Verifying that source data/documents and other trial records

are accurate, complete, kept up-to-date, and maintained

Ensure subject wellbeing at all time….

• Review protocol

• Review investigator

• CRA• Ensure

communication between

• QA & QC• CRO• Trial

management

• Qualified• Sound protocol• Informed consent• Progress report• Safety report

Investigator Sponsor

IRB/ IECStudy Monitor

Clinical trial process

Planning

Protocol & CRF

Regulatory

Documents & Materials

Pre-select Investigators Pre-study

Patient Recruitment

Routine Monitoring

CRF Retrieval

Database Design Data entry

SAP Presentation

Skeleton Report

Production

Data Review

Drug/Disease Coding

Programming, Tables,

Figures & Listings

Draft Files

Database Audit

Final Files

Statistical Analysis

Internal Report

QA Report

Final Report

Thank You….!!!