Principle of good clinical practice

1. Principles of Good Clinical Practice Jamalludin Ab Rahman MD MPH Department of Community Medicine International Islamic University Malaysia

2. 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

3. Research regulatory Not regulated GLP GCP GMP

4. Clinical Trial

5. HUMAN RESEARCH & REGULATIONS

6. (US) Historical perspective of human research conducts Nuremberg Code, 1946 Kefauver Amendments, 1962 – Thalidomide Declaration of Helsinki, 1964 National Research Act, 1974 - Tuskegee Syphilis Study (1932-1972) Belmont Report, 1979

7. 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 .

8. 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

9. Declaration of Helsinki World Medical Association - recommendations guiding medical doctors in biomedical research involving human participants Research with humans should be based on the results from laboratory and animal experimentation Research protocols should be reviewed by an independent committee prior to initiation Informed consent from research participants is necessary Research should be conducted by medically/scientifically qualified individuals Risks should not exceed benefits Revised - 1975, 1983, 1989, 1996, 2000, 2002, 2004, 2008

10. 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)

11. Belmont Report Three basic ethical principals Autonomy/respect for persons (Individuals should be treated as autonomous agents & Persons with diminished autonomy are entitled to protection) Beneficence (Human participants should not be harmed & Research should maximize possible benefits and minimize possible risks) and Justice (benefits and risks of research must be distributed fairly) which are the cornerstone for regulations involving human participants.

12. GCP & ICH

13. What is GCP 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.

14. Evolution of GCP 1930s – 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

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

16. 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

17. Observers Non voting members

18. Co-sponsors (voting right) European Commission European Federation of Pharmaceutical Industries’ Associations ( EFPIA) Japanese Ministry of Health, Labour and Welfare (JMHLW) Japan Pharmaceutical Manufacturers Association (JPMA ) United States Food and Drug Administration (FDA) Pharmaceutical Research and Manufacturers of America ( PhRMA )

19. Aims of ICH Unify registration requirements for new products Reduce medicinal product development costs: more economical use of animal, human and material resources . Accelerate medicinal product licensing times: avoid repeat testing in different regions. Increases patent protection times through reducing delay in licensing times.

20. ICH represents 17 countries comprising 15 % of the world’s population 90 % of the US$ 320 billion global pharmaceutical sales of the year 2000

21. Harmonisation

22. The Steps

23. Evolution GCP in Malaysia 1997 1st Malaysian Workshop in GCP (Liver Update 96) 1999 May 2nd Workshop in GCP June 3rd Workshop in GCP (Liver Update 99) August 4th Workshop in GCP Consensus Dec Launch of Malaysian Guidelines 5 th Workshop in GCP 2004 2nd Malaysian GCP 2011 3rd Malaysian GCP

24. PrincipleS of ICH GCP

25. 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 .

26. 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.

27. 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.

28. 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).

29. 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 .

30. 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.

31. The summary of the principles Conduct trials according to GCP Weigh risks vs. benefits Subjects wellbeing exceed the science Have adequate information to justify trial Write a sound protocol Receive IRB/IEC approval Use qualified physicians Use qualified & trained support staff Obtain informed consent Record information appropriately Confidentiality & data protection Handle investigational products appropriately Quality assurance

32. Ensure subject wellbeing at all time

33. The APPLICATIONS

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

35. Clinical trial process

36. …… 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!

37. 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!

38. The 5 Purposes of the Law in Medicine, maqasid al shari’at fi al tibb Protection of ddiin , hifdh al ddiin Protection of life, hifdh al nafs Protection of progeny, hifdh al nasl Protection of the mind, hifdh al ‘ aql Protection of wealth, hifdh al mal

39. Thanks