Good clinical practices

Good clinical practices-drug discovery

1. Dr. Dhruva Kumar Sharma Department of Pharmacology SMU/SMIMS Saturday, the 19 th Of July, 2014

2. Evolution of Good Clinical Practices: An overview 2

3. PROTOCOL Nazi war crimes Tuskegee syphilis trial Thalidomide disaster Jews chronic disease trial Neuremberg trial code Declaration of helsinki Belmonte report ICH/GCP Guidelines 3

4. Good Clinical Practice (GCP): Meaning 4 Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

5. The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. 5

6. History Why Do We Need Guidelines? Why Are We Regulated?

7. Nazi Medical War Crimes: during World War II Experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected Typically, the experiments resulted in death,  disfigurement  or permanent   disability , and as such are considered as examples of  medical torture

8. Nazi Medical War Crimes "Medical experiments" were performed on thousands of concentration camp prisoners and included deadly studies and tortures such as- Injecting people with gasoline and live viruses Immersing people in ice water Forcing people to ingest poisons

9. 9 Incisions made by medical personnel that were purposely infected with bacteria, dirt, and slivers of glass

10. Victim of a tuberculosis medical experiment 10

11. Prisoner in a compression chamber 11 An experiment to determine altitudes at which aircraft crews could survive without oxygen

12. Immersing people in ice water With the intent of discovering means to prevent and treat hypothermia . 280 to 300 victims One study forced subjects to endure a tank of ice water for up to five hours. 12

13. In 1946, an American military tribunal opened criminal proceedings against 23 leading German physicians :  Doctors' Trial Sixteen of the doctors were found guilty Seven were sentenced to death Development of the  Nuremberg Code  of  medical ethics 13 THE DOCTORS TRIAL

14. The Tuskegee Syphilis Study Research participants was the long-term study of black males conducted at Tuskegee, Alabama by the United States Public Health Service.  (1930s-1970) - examination of the natural history of untreated syphilis More than 400 African-American men with syphilis participated The men were recruited without informed consent and, in fact, were misinformed that some of the procedures done in the interest of the research (e.g., spinal taps) were actually " special free treatment ."

15. The Tuskegee Syphilis Study In the 1940s, penicillin was found to be effective in the treatment of syphilis.  The study continued, however, and the men were neither informed of nor treated with the antibiotic. The first accounts of this study appeared in the national press in 1972.  Belmont report 1978 (Ethical Principles and guidelines for the protection of human subjects of research)- Tuskegee syphilis study

16. The Jewish Chronic Disease Hospital Study In 1963, studies were undertaken at New York's Jewish Chronic Disease Hospital to understand whether the body's inability to reject cancer cells was due to cancer or debilitation.  Previous studies had indicated that healthy persons reject cancer cells promptly, and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate compared to healthy participants.

17. The Jewish Chronic Disease Hospital Study Further, patients were not told that they would receive cancer cells, because the researchers felt it would unnecessarily frighten them It was found that the study had not been presented to the hospital's research committee and that the physicians responsible for the patients' care had not been consulted.  The researchers were found guilty of fraud, deceit, and unprofessional conduct.

18. The Willowbrook Study Institutionalized children, as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School, a New York institution for "mentally defective" children.  In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances, newly admitted children were deliberately infected with the hepatitis virus.  In some cases, parents found they were unable to admit their children to Willowbrook unless they agreed to their child’s participation in the studies.

19. The Willowbrook Study This controversial case raised important questions about the adequacy and freedom of consent , inadequate disclosure of the child's risk of later developing chronic liver disease

20. The Milgram Study The ‘teachers’ were instructed to give the ‘learners’ electrical shocks in response to incorrect answers on verbally given ‘tests’. Participants were deceived as to the nature of the study, being told it was to test new teaching-learning techniques.

21. Thalidomide tragedy Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. 21

22. Within a few years of the widespread use of thalidomide in Europe, Australia, and Japan, approximately 10,000 children were born with phocomelia , leading to the ban of thalidomide in most countries in 1961 22

23. The thalidomide tragedy marked a turning point in toxicity testing , as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols The thalidomide tragedy also brought into sharp focus the importance of rigorous and relevant testing of pharmaceuticals prior to their introduction into the market place ( Kelsey, 1988 ). 23 Thalidomide tragedy

24. Nuremberg Code-1947 On April 17, 1947, United States Counsel for War Crimes came out with six points defining “ legitimate research” . The verdict of August 19 reiterated almost all of these points in a section entitled  "Permissible Medical Experiments"  and revised the original six points into ten . Subsequently, the ten points became known as the "Nuremberg Code." 24

25. Codes and Guidelines Nuremberg Code (1947). W.M.A’s Declaration of Helsinki (1964). Belmont Report (USA) (1979) - Tuskegee syphilis study C ouncil for I nternational O rganizations of M edical S ciences ( CIOMS) 1993. I nternational C onference on H armonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) , in 1996 , Guideline on G ood C linical P ractice ,E6 (GCP).

26. Nuremberg Code (1947) Voluntary and Informed consent-absolutely essential. Anticipate scientific benefits, Useful. Animal experimentation first. Avoid physical and mental suffering. Benefits outweigh risks. No intentional death or disability. Protection from harm. Subject free to withdraw. Qualified investigators. Investigator will stop if harm occurs.

27. THE DECLARATION OF HELSINKI-1964

28. Is an international standard for the conduct of clinical research adopted by International Conference on Harmonization(ICH) Good Clinical Practice standards. A global ethical standard for medical research and was approved at the WMA General Assembly by a majority vote of 75%. It is the mission of the clinical research professionals to safeguard the health of the people. THE DECLARATION OF HELSINKI-1964

29. Historical Overview:- Its origin has been found in the Nazi Disaster and has undergone several modifications. Prior to 1947 Nuremberg Code, there was no accepted code of conduct governing the ethical aspects of human research.

30. World Medical Association It is an international organization of physicians, established on September 17, 1947 . First general Assembly of WMA was held in Paris, France. Mission:- Serve humanity by endeavoring to achieve the highest international standards in medical education, science, ethics and health care for all peoples of the world.

31. Declaration of Helsinki 1964 Adapted from Nuremberg Code by the World Medical Association (WMA). First adopted in Helsinki, Finland, 1964

32. WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI- 2008 Ethical Principles for Medical Research Involving Human Subjects Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 53th WMA General Assembly, Washington 2002 ( Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 2004 ( Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008

33. Seven Ethical Pillars of Clinical Research AUTONOMY BENEFICENCE NON – MALFEASANCE FIDELITY TRUTHFULNESS CONFIDENTIALITY JUSTICE

34. Declaration of Helsinki Autonomy Consent Para 20 The subjects must be volunteers and informed participants in the research project. Para 22 freely-given informed consent , preferably in writing .

35. Declaration of Helsinki Para 5 well-being of the human subject should take precedence over the interests of science and society. Beneficence

36. Declaration of Helsinki Para 16 Preceded by careful assessment of predictable risks and burdens Attempt to avoid any act or treatment plan that would harm the patient Non Malfeasance

37. Declaration of Helsinki Para 11 Medical research involving human subjects must be based on generally accepted scientific principles , thorough knowledge of the scientific literature and on adequate laboratory and, where appropriate, animal experimentation. Para 15 Conducted only by clinically competent medical person. Fidelity – duty of care

38. Declaration of Helsinki Para 27 Both authors & investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published Truthfulness - Honesty

39. Declaration of Helsinki Para 21 Every precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's information Confidentiality

40. Declaration of Helsinki Para 30 Every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. Para 9 Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects Para 17 Physicians should cease any investigation if the risks outweigh the potential benefits Justice

41. DECLARATION OF HELSINKI :- Basic Principles Conform to accepted scientific principles. Design formulated in experimental protocol, reviewed by IEC. Conducted by qualified and trained persons. Importance in proportion to inherent risk. Assessment of risks vs. benefits. Safeguard subject’s integrity (privacy). Abstain unless hazards are predictable. Preserve accuracy when publishing. Adequately inform or right to withdraw. Obtain true informed consent in writing. Reliance on legal guardian. State compliance with Declaration.

42. Ethical Principles and Guidelines for the Protection of Human Subjects of Research Tuskegee Syphilis Study  (1932–1972) Named the  Belmont Report , for the  Belmont Conference Center , where the National Commission met when first drafting the report 42 Belmont Report: 1979

43. Belmont Report: 1979 Three ethical principles related to research on human subjects: Respect for Persons Beneficence: "Do no harm" while maximizing benefits for research project and minimizing risks to the research subjects Justice: ensuring reasonable, non-exploitative, and well-considered procedures are administered

44. Overview of ICH GCP

45. What is ICH? The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)- is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific and technical aspects of drug registration. 45

46. What is ICH? Since its inception in 1990, ICH has gradually evolved ICH's mission is to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner

47. How did it evolve? The need to harmonize Public disasters, serious fraud and abuse of human rights. Trials of War criminals-Nuremberg code 1949 Thalidomide- Declaration of Helsinki 1964 Belmont report 1978 ( Ethical Principles and guidelines for the protection of human subjects of research)-Tuskegee syphilis study

48. 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

49. When did it begin? I st conf. in 1990 in Brussels 3 regions participated Representatives from Industry Academia Ministry of health

50. ICH parties 6 parties EU EFPIA European federation of pharmaceutical industries’ associations MHLW Ministry of health, Labor and welfare, Japan JPMA Japan Pharmaceuticals manufacturers Association US FDA PhRMA Observers : WHO, TPP(canada) International federation of Pharmaceutical manufacturer’s association

51. Key objective To discuss and define the minimum standards for the development and registration of investigational products

52. The result? Many guidelines made Most important- ICH GCP guidelines Evolved in several steps Consolidated guideline ICH E6 Sept 1997

53. ICH Guidelines: examples Efficacy: clinical trials etc Safety: pharmacovigilance , adverse drug reaction reporting Quality: raw materials, impurities, residual solvents etc Multidisciplinary: common technical document, electronic submission, coding systems

54. 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.

55. Why is it needed? To ensure the rights, safety and well being of the trial subjects are protected Ensure the credibility of clinical trial data

56. The ICH GCP guideline 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 . 8 sections

57. ICH GCP guideline 1. Glossary Common language for investigators/sponsors/ethics committees 2.Principles of Good Clinical Practice 13 tenets of ICH GCP 3.Requirements for IRB/IEC Roles responsibilities and composition

58. ICH GCP guideline 4.Responsibilities of the investigator 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

59. Principles of ICH GCP Ethical conduct as per Declaration of Helsinki GCP Regulatory Requirements Risk- Benefit Primary concern- Subject

60. Principles of ICH GCP Supportive data Protocol Scientifically sound, clear, detailed Ethical Clearance Study to be conducted in compliance to the protocol which has received EC approval

61. Principles of ICH GCP Subject Care Medical decisions responsibility of qualified physician Qualified staff By education, training, experience in their area of responsibility Informed Consent

62. Principles of ICH GCP Clinical Trial data Recorded, handled and stored to enable accurate reporting, interpretation and verification Confidentiality

63. Principles of ICH GCP Investigational Product Manufactured, handled and stored as per GMP

64. Principles of ICH GCP Quality Assurance Systems and procedures to ensure the Quality of every aspect of the trial

65. Indian GCP guidelines Released in Dec 2001(Developed by CDCSO and endorsed by DCGI) In general, in line with ICH GCP Has Revised Schedule Y (Jan 2005) addressed discrepancies?

66. SAFEGUARD PUBLIC HEALTH ASSURE CONSUMER PROTECTION STANDARDS FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE PRODUCTS ELIMINATE INCONSISTENT STANDARDS INTERNATIONALLY FACILITATE MUTUAL ACCEPTANCE OF DATA FROM CLINICAL TRIALS GOALS OF INTERNATIONAL HARMONIZATION OF REGULATORY REQUIREMENTS

67. Study Documentation During the study The investigator must keep: Source documents Medical records (including access to computer records) Laboratory reports ECGs, X-rays, etc. Any other medical records, reports or notes (hospital admissions and discharges) A subject identification list Copies of all study related documentation

68. Medical Records In particular, they should contain notes on: Sufficient information to support subject eligibility This should be well documented (signed and dated) Subject’s participation in the study Dates of visits Procedures, investigations done Observations, diagnoses Medications taken (including study medication) Adverse events Completion or withdrawal (reason) from the study

69. Study Documentation After the study The sponsor needs from the investigator: Final drug accountability records All used and unused supplies and medication All required documents completed

70. Conclusion 70 Thanks..... “When a doctor [goes] wrong, he is the first of criminals. He has nerve and he has knowledge.” - Sherlock Holmes

71. References: http://www.wma.net/e/policy/b3.htm www.hhs.gov/ohrp/humansubjects/guidance/ belmont .html www.hhs.gov/ohrp/references/nurcode.html www.icmr .nic.in/ guidelines /GCLP www. cdsco .nic.in/ www.ub.edu/recerca/Bioetica/doc/Declaracio_ Helsinki _2013 www.jewishvirtuallibrary.org/jsource/Holocaust/ nazi _ experiments www. ich .org/fileadmin/Public_Web.../ ICH .../E6_R1__Guideline