1. Retha Britz Copyright 2013 All rights reserved for this presentation 1 Background of bioethics & history of research guidelines Retha Britz

2. Nuremburg Code (1947)  Gruesome experiments conducted by Nazi doctors in German concentration camps during WW II  22 doctors found guilty of research misconduct during the Nuremburg Trial  Nuremburg Code followed as a result  10 principles: 2

3. Nuremburg Code (1947) (continue)  Voluntary IC is essential  Experiment to be for the good of society  Based on animal studies  Avoid physical & mental suffering and injury  Pts to be protected against injury, disability and death  Weigh risks against benefits  No expectation of death or disability  Human experimentation to be conducted only by scientifically qualified individuals  Pts can terminate involvement  Investigators can terminate the experiment if injury, disability or death is likely to occur 3

4. Some research still conducted without IC despite strict requirement for it in the Nuremburg Code Thalidomide studies in late 1950s to determine safety and efficacy as a sedative Also used by pregnant woman 10,000 - 20,000 infants globally with severe teratogenic/neuropathy side effects 4

5. Declaration of Helsinki (1964)  World Medical Association published DoH  DoH superseded the Nuremburg Code  DoH objective: Interests of science and society do not take precedence over well- being of research pts  Revised 8 times (latest version is 2008)  2008 version currently under revision [2014] 5

6. Declaration of Helsinki (2008)  Research physician to protect the life, health, dignity, integrity, right to self-determination, privacy and confidentiality of personal information of research pts  Research must conform to generally accepted scientific principles: based on animal experimentation  Appropriate caution exercised in conduct of research that may harm the environment  Study protocol should be available  Protocol submitted to a research EC before study commence  Research only to be conducted by individuals with appropriate scientific training and qualifications 6

7. Declaration of Helsinki (2008) (continue)  Research in disadvantaged/vulnerable population is only justified if research is responsive to health needs and priorities of this population benefit from results  Assessment of predictable risks and burdens benefits should be foreseeable  Trials to be registered in a publicly accessible database  Research physicians to be confident that risks involved have been adequately assessed and managed  Important that the objective outweigh the inherent risks and burdens  Voluntary participation  Protect privacy of research pts and confidentiality of their personal information  Pts to be adequately informed of all aspects of the trial 7

8. Declaration of Helsinki (2008) (continue)  Consent given for collection, analysis, storage and/or reuse of identifiable human material or data  No pts in a dependent relationship with the investigator or consent under duress  For incompetent potential pts, consent to be obtained from the legally authorized representative  In case the incompetent potential pt can give assent, the physician should seek assent in addition to consent of the legally authorized representative. Dissent should be respected 8

9. Declaration of Helsinki (2008) (continue)  In case physical or mental incapability is a necessary characteristic of the research population, IC to be obtained from a legally authorized representative or EC IC asap from pt or representative  Authors, editors and publishers all have ethical obligations with regards to the publication of the research results 9

10. Bioethics (1932-1972)  US Public Health Services conducted a syphilis study in Tuskegee to determine the natural Hx of untreated syphilis  400 African-American men with syphilis were pts  200 without syphilis served as controls  Pts were recruited without IC  Pts were told that they are treated for “bad blood” and was left intentionally untreated  Transport was provided to and from clinics  Hot meals were provided at the clinic 10

11. Bioethics (1932-1972) (continue)  Free medical care for any disease other than medical care  Pts were offered a free funeral policy if they agree to a post mortem  Pts not aware that they are in a research study  1945: Penicillin was found to be effective against syphilis, but it was never offered/administered Study was revealed in the New York Times on 26 July 1972 11

12.  The US Government (President Clinton) formally apologised to the pts and their families in 1997  74 of the untreated pts were still living 12

13. Belmont Report (1979) Autonomy, Beneficence & Justice based on Principle-based ethics (moral theory) US follows Belmont Report [acknowledge DoH] 13

14. Appearance of Various Guidelines  1970s: FDA Guidelines and IND Regulations  1980s: National Codes - European countries  1990: Japanese GCP Guidelines  1991: European GCP Guidelines to improve the process for developing and registering new medicinal products USA, Europe and Japan Regulatory Authorities and Pharmaceutical Companies plus observers from Scandinavia, Australia, Canada and the WHO held a series of meetings to develop a set of GCP that would facilitate the universal acceptance of clinical trial data 14

15. ICH GCP (1996) April 1996 was the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human use ICH GCP Purpose of ICH GCP: To provide a unified standard to facilitate the mutual acceptance of clinical data by the Regulatory Authorities 15

16. What is GCP? “A standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial subjects are protected” SA GCP Glossary p.89 16

17. Ethics in Health Research: Principles, Structures and Processes (2004)  Contain the SA National Policy on specific needs in SA and aims for “enhancing the dignity of South African citizens”  Intended to be followed by investigators of clinical research, RECs, administrators, health care practitioners, policy-makers and community representatives  The NHA section 72(6)(a) mandates that REC uses this “blue book”  2004 version currently under revision by the NHREC 17

18. Guiding Principles as per “Blue Book”  Respect and dignity  Relevance of the research  Scientific integrity  Investigator competence  Principal Investigator responsibility  Informed consent  Privacy and confidentiality  In- and exclusion criteria  Risk and benefits  Publication of results  Conflict of interest  Safety monitoring  Multi-centre studies  Standard of care  Placebo-controlled studies  Ethical review  Distributive justice 18

19. Ethics in Health Research: Principles, Structures and Processes (2004) (continue) Section 4: Ethics Committees  Composition and appointment of members  Procedures  Monitoring  Suspension/discontinuation of research  Reports to the NHREC etc. Section 5: Research requiring additional attention  Minors  Vulnerable communities  Prisoners etc. 19

20. SA GCP (2006)  1st ed. published in 2000  Based on ICH GCP and other guidance documents such as DoH (2004)  Differences between ICH & SA GCP e.g. section on Informed Consent  Mainly for researchers conducting clinical trials  No separate guidelines for other researchers conducting research on/with human  Includes composition of RECs, functioning and monitoring by RECs 20

21. “”Clinical trials" means a systematic study, involving human subjects that aims to answer specific questions about the safety or efficacy of or method of treatment.” NHA, Section 72 (7) “An investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmadynamic effects of an investigational product, and or to identify an adverse reaction to an investigational product and/or to study absorption, distribution, metabolism and excretion of an IP with the objective of ascertaining its safety and/or efficacy.” ICH GCP 1.12, p.3 21

22. CIOMS Guidelines (1982)  Council for International Organizations or Medical Sciences Guidelines  Intend to apply DoH in developing countries  Specific attention to large-scale vaccine trials and medications  Includes section on compensation for injuries related to research  Shortcomings: Lacks separate section devoted to risk-benefit ratios 22

23. Other useful guidance documents  International Review Board (IRB) Guidebook. Office for the Protection from Research Risks – National Institute of Health, USA, 1993  World Health Organisation 2000. Operational Guidelines for Ethics Committees that Review Biomedical Research. Geneva 23

24. Animal Research  MRC Guideline Book 3: Use of animals in research and training (2004) prescribes:  Ethical principles involves  Ethical code of behaviour for researchers, educators and animal care staff  Human obligation/duties  A legal mandate for animal studies  Ethical review process for animal research 24

25. Animal Research (continue)  Replacement: of sentient animals with non-sentient research models or systems  Reduction: of numbers of animals in experiments by design strategies that facilitates the use of the smallest number that will allow valid information to be obtained  Refinement: of animal sourcing to minimise or remove physical or psychological distress 25

26. References  DHAI, A., CLEATON-JONES, P. & TSOTSI, N. 2011. The ethics of research. (In Dhai, A. & McQuoid-Mason, D., eds. Bioethics, human rights and health law: principles and practice. Claremont: Juta. p. 166-170.)  MOODLEY, K. 2011. Research ethics and scientific integrity. (In Moodley, K., ed. Medical ethics, law and human rights. Pretoria: Van Schaik Publishers. p. 317-337.) SCHÜKLENK, U. 2005. Module one: introduction to research ethics. Developing world bioethics, 5(1):1-13. WORLD MEDICAL ASSOCIATION. 2008. Declaration of Helsinki. (59 th WMA General Assembly, Seoul, October.) http://www.wma.net/e/ethicxsunit/helsinki.htm Date of access: 21 May 2010. http://www.wma.net/e/ethicxsunit/helsinki.htm