Principles of Good Clinical PracticeJamalludin Ab Rahman MD MPH

Department of Community MedicineInternational Islamic University Malaysia

At the end of this lecture you should be able to Describe the history of human research Describe evolution of regulations in human

research Define GCP (based on ICH) Outline the principles of GCP

Research regulatory

Basic Research Disease Recovery Drug Recovery Preclinical

Development Clinical Trials Manufacturing

Not regulatedGLP

GCP

GMP

Clinical Trial

Phase I

• Checking for safety

• 10-20 healthy volunteers

• Unexpected side effects may occurs

Phase II

• Checking for efficacy

• ~ 200 samples

• How good is the intervention

• If not good, normally detect here

Phase III

• Checking effectiveness

• ~ 1000s samples

• Looking for rare side effect

Phase IV

• Test long term safety

• Real patients• Involve

untested group of people

HUMAN RESEARCH & REGULATIONS

(US) Historical perspective of human research conducts1. Nuremberg Code, 1946

2. Kefauver Amendments, 1962 – Thalidomide

3. Declaration of Helsinki, 1964

4. National Research Act, 1974 - Tuskegee Syphilis Study (1932-1972)

5. Belmont Report, 1979

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 sedative 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

laboratory and animal experimentation2. 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.

GCP & ICH

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.

Evolution of GCP1930s – US Food Drug & Cosmetic Act

1947 – Nuremberg Code

1962 - Kefauver Amendments (US) (following Thalidomide tragedy)

1964 – Declaration of Helsinki

1974 – National Research Act (US)

1979 - Belmont Report (US)

1986 – England – ABPI Guideline

1987 - France - Bonnes Pratiques Clinique

1989 – Scandinavia - Nordic Guidelines , Good Clinical Trial Practice

1990 – France – Huriet Law

1990 - EC - Good Clinical Practice for Trials on Medicinal Products in the European Community

1992 - WHO Guidelines, Australian Guidelines

1997 – ICH GCP became law in some countries

1999 - Malaysian GCP

GCP in Asia Singapore GCP 1998 Malaysian GCP 1999, 2004, 2011 Chinese GCP 1999 Thailand GCP 2000 Indonesia 2001

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

Observers

Non voting members

Co-sponsors (voting right)

1. European Commission

2. European Federation of Pharmaceutical Industries’ Associations (EFPIA)

3. Japanese Ministry of Health, Labour and Welfare (JMHLW)

4. Japan Pharmaceutical Manufacturers Association (JPMA)

5. United States Food and Drug Administration (FDA)

6. Pharmaceutical Research and Manufacturers of America (PhRMA)

Aims of ICH1. Unify registration requirements for new products

2. 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

Harmonisation

The Steps

Evolution GCP in Malaysia1997 1st Malaysian Workshop in GCP (Liver Update 96)

1999 May 2nd Workshop in GCPJune 3rd Workshop in GCP (Liver

Update 99)August4th Workshop in GCP Consensus Dec Launch of Malaysian

Guidelines 5th Workshop in GCP

2004 2nd Malaysian GCP

2011 3rd Malaysian GCP

PRINCIPLES OF ICH GCP

Principles of ICH GCP (Page 8 of E6)

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).

2.2 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.

Principles of ICH GCP……. 2.3 The rights, safety, and well-being of the trial

subjects are the most important considerations and should prevail over interests of science and society.

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

Principles of ICH GCP…….2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.2.6 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.

Principles of ICH GCP……. 2.7 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.

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

Principles of ICH GCP…….2.9 Freely given informed consent should be obtained from every subject prior to clinical trial participation.

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

Principles of ICH GCP……. 2.11 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).

2.12 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.

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

The summary of the principles1. Conduct trials according to GCP

2. Weigh risks vs. benefits

3. Subjects wellbeing exceed the science

4. Have adequate information to justify trial

5. Write a sound protocol

6. Receive IRB/IEC approval

7. Use qualified physicians

8. Use qualified & trained support staff

9. Obtain informed consent

10. Record information appropriately

11. Confidentiality & data protection

12. Handle investigational products appropriately

13. Quality assurance

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

THE APPLICATIONS

Source: http://www.asbestos.com/images

Clinical trial processPlanning

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

……the authors note an average of 4-5 years for a company to take a new drug from the lab through enough initial safety studies in animals to get to clinical trials. After that, there is another 7.5 years before a promising drug makes it to FDA approval!

all of the other regulatory steps also happened in parallel so that they all finished at the same time, without eliminating any steps!

The final result is that the trial took only 46 days from protocol submission to enrolling the first patient on trial, and only 2 days from IND approval from the FDA! A month and a half. Not years, not six months, but six weeks!

The 5 Purposes of the Law in Medicine, maqasid al shari’at fi al tibb

1. Protection of ddiin, hifdh al ddiin

2. Protection of life, hifdh al nafs

3. Protection of progeny, hifdh al nasl

4. Protection of the mind, hifdh al ‘aql

5. Protection of wealth, hifdh al mal

Thanks