Six co-sponsors (EU, EFPIA, MHLW, JPMA, FDA, PhRMA) has had two seats on the SC. Other parties have a significant interest in ICH and have been invited to nominate Observers to the SC. The three Observers are the World Health Organization (WHO), Health Canada and the European Free Trade Association (EFTA). The IFPMA participates as a non-voting member of the SC.
Principle of good clinical practice
Principles of GoodClinical PracticeJamalludin Ab Rahman MDMPHDepartment of Community MedicineInternational Islamic University Malaysia
At the end of this lecture you shouldbe 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 Disease Preclinical Basic Research Drug Recovery Clinical Trials Manufacturing Recovery Development Not regulated GLP GCP GMP
Clinical Trial Phase I Phase II Phase III Phase IV• Checking for • Checking for • Checking • Test long safety efficacy effectiveness term safety• 10-20 healthy • ~ 200 • ~ 1000s • Real patients volunteers samples samples • Involve• Unexpected • How good is • Looking for untested side effects the rare side group of may occurs intervention effect people • If not good, normally detect here
(US) Historical perspective of humanresearch conducts1. Nuremberg Code, 19462. Kefauver Amendments, 1962 – Thalidomide3. Declaration of Helsinki, 19644. 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 participants 1. Research with humans should be based on the results from laboratory and animal experimentation 2. Research protocols should be reviewed by an independent committee prior to initiation 3. Informed consent from research participants is necessary 4. Research should be conducted by medically/scientifically qualified individuals 5. 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 involvinghuman participants.
What is GCP A standard for Designing designing, conducting, recording and Reporting Conducting reporting of studies Clinical involving human Trials or Studies subjects. Analysis Monitoring Public assurance that the rights, safety and Recording well-being of trial subjects are protected.
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
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
Co-sponsors (voting right)1. European Commission2. 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 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
Evolution GCP in Malaysia1997 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 5th Workshop in GCP2004 2nd Malaysian GCP2011 3rd Malaysian GCP
Principles of ICH GCP (Page 8 of E6)2.1 Clinical trials should be conducted in accordancewith the ethical principles that have their origin inthe Declaration of Helsinki, and that are consistentwith GCP and the applicable regulatoryrequirement(s).2.2 Before a trial is initiated, foreseeable risks andinconveniences should be weighed against theanticipated benefit for the individual trial subject andsociety. A trial should be initiated and continued onlyif 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, anddescribed in a clear, detailed protocol.2.6 A trial should be conducted in compliance with theprotocol that has received prior institutional reviewboard (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 beobtained from every subject prior to clinical trialparticipation.2.10 All clinical trial information should be recorded,handled, and stored in a way that allows its accuratereporting, 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 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
Ensure subject wellbeing at all time • Qualified • QA & QC • Sound protocol • CRO • Informed consent • Trial • Progress report management • Safety report Investigator Sponsor Study IRB/ IEC Monitor • CRA • Review • Ensure protocol communicatio • Review n between investigator
Clinical trial process Database Statistical Planning Data entry Internal Report Design Analysis SAP Protocol & CRF CRF Retrieval Final Files QA Report Presentation Routine Skeleton Report Regulatory Database Audit Final Report Monitoring Production Documents & Patient Data Review Draft Files Materials Recruitment Programming, Pre-select Drug/Disease Pre-study Tables, Figures Investigators Coding & Listings
……the authors note an averageof 4-5 years for a company totake a new drug from the labthrough enough initial safetystudies in animals to get toclinical trials. After that, there isanother 7.5 years before apromising drug makes it to FDAapproval!
all of the other regulatorysteps also happened inparallel so that they allfinished at the same time,without eliminating anysteps!The final result is that the trialtook only 46 days fromprotocol submission toenrolling the first patient ontrial, and only 2 days fromIND approval from the FDA! Amonth 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 tibb1. Protection of ddiin, hifdh al ddiin2. Protection of life, hifdh al nafs3. Protection of progeny, hifdh al nasl4. Protection of the mind, hifdh al ‘aql5. Protection of wealth, hifdh al mal