1. Why Research Ethics? History and Principles Henry Silverman, MD, MA University of Maryland School of Medicine

2. Balancing Two Goals Advancement of Science Protection of Subject Welfare/Rights

3. History of Research Ethics  Before 20 th century ◦ Small scale, involving few individuals  Beginning of 20 th century ◦ Larger scale clinical trials ◦ collect systematic data ◦ groups of individuals ◦ vulnerable groups Prisoners Orphans Mentally ill No Formal Codes of Research Ethics

4. World War II

5. Nuremburg Nazi Doctors’ Trial (1947) Nazi doctors and scientists put on trial for the murder of concentration camp inmates who were used as research subjects 15 of 23 guilty, 7 hanged, 5 life sentences

6. Relevance of the Hippocratic Oath? Expand on Hippocratic Ethics to Protect Research Subjects In the context of research Could not protect human welfare Could not respect human rights Why did the Nazi doctors purposefully inflict harm?

7. + Concept of Human Rights Nuremberg Code Do No Harm

8. Nuremberg Code (1947) First C odification of Research Guidelines Human Rights + Welfare of Subjects The first and longest principle Article (9) Subjects have the right to withdraw at any time “The voluntary consent of the human subject is absolutely essential.” Articles (2-8, 10) Scientific value Favorable risk/benefit ratio Suffering by subjects should be avoided

9. Research Abuses  Henry Beecher: Published 22 examples of abuses  Withholding antibiotics from patients with rheumatic fever  Purposely infecting institutionalized children with hepatitis  Injecting live cancer cells into nursing home patients Abuses and exploitations of humans in research continued despite having ethics codes Significance of Article?

10.  Tuskegee, Alabama ◦ High prevalence of syphilis ◦ Although treatment existed, blacks in the rural southern town were not receiving treatment ◦ Lack of funds/Lack of doctors  Study natural course of syphilis ◦ Enrolled 400 black males infected with syphilis ◦ Not an experiment but rather a “study in nature”

11. Tuskegee Syphilis Study (1932 - 1972) Ethical Issues Inadequate disclosure of information Subjects believed they were getting free treatment Told that spinal taps was therapy US Gov’t actively prevented men from receiving penicillin 1972 press reports caused the U.S. Gov’t to stop the study

12. Balancing Two Goals Without an Adequate Framework of Research Ethics Advancement of Science Protection of Subject Welfare/Rights >>>

13. Response to Ethical Lapses U.S. National Research Act (1974)  The National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.  The Commission charge was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human participants  To develop guidelines which should be followed to assure that such research is conducted in accordance with those principles.  Carrying out its charge, the Commission prepared the Belmont Report in 1979.

14. الفائده Beneficence ﺣﻖ ﺍﻻﺨﺘﻴﺎ ﺭ ﺍﻠﻋﺪﻞ Justice Respect of persons إحترام الأشخاص Right to make a decision

15.  Respect for Persons –Individuals should be treated as autonomous agents –Individuals with diminished autonomy are entitled to protections  Beneficence ◦ Maximum possible benefits, and minimize potential harms  Justice ◦ Fair distribution of burdens and benefits of research ◦ Do not exploit those who are readily available or malleable

16.  The Belmont Report has served as an ethical framework for protecting human subjects for over 25 years.  To obtain a full appreciation of the Belmont Report, the report can be found @ http://www.fda.gov/oc/ohrt/IRBS/belmont.html http://www.fda.gov/oc/ohrt/IRBS/belmont.html  National Regulations ◦ Force of law  Independent review of research by Institutional Review Boards (IRBs)

17. Declaration of Helsinki (1964)  World Medical Association - 1953  Interprets Nuremberg Code for research that involves patients who are receiving medical care  Some risks justified by “potential therapeutic or diagnostic value for the patient”.  In case of legal incompetence, informed consent should be obtained from the legal guardian  Review of research by an independent review committee

18. CIOMS 2002  Council for International Organizations of Medical Sciences: International Ethical Guidelines for Biomedical Research Involving Human Subjects  Apply Helsinki to the conduct of International Clinical Trials

19.  1900 the Kingdom of Prussia established the Berlin Code of Ethics, a series of ethical rules regarding human experiments to test new treatments.  In 1931, the German Ministry of the Interior issued ‘‘directives for new therapies and experiments in humans’’ which incorporated the legal doctrine of informed consent.  It was forbidden to experiment on patients who were dying, poor, or socially disadvantaged. It was also stated that proportionality of risk and benefit must be respected and that experiments should first be done in animals.

20. Henry Silverman, MD, MA University of Maryland School of Medicine

21. Increase in Clinical Trials in Developing Countries

22. Country Number (2008) Number (2011) Number (2013) Iran111373534 Egypt83261401 Jordan1354142 Kuwait72920 Lebanon24128140 Sudan91116 Qatar62325 Saudi Arabia45164172 UAE144953 Syria187 www.clinical trials.gov

23. Outsourcing of Clinical Trials Developed World to Developing World Advantages to Host Countries  Exposure to recent technologies and drug therapies  Training to local health professionals  Incentives to local health institutions (new technology)  A road paving to upgrade of local drug/biotech industry Advantages to Pharma  Large population  Disease pattern ◦ CVD ◦ Diabetes ◦ Cancer  Lower costs  Faster patient recruitment  Avoid regulatory restrictions  Avoid elaborate safety and compensation requirements

25. Panel Faults Pfizer in '96 Clinical Trial In Nigeria: Unapproved Drug Tested on Children May, 2006 Cameroon suspends trial AIDS drug after protests Growth of clinical trial outsourcing raises issues Feb, 2009 Feb, 2005

26. Advancement of Science Protection of Subject Welfare/Rights

29. Countr y Regulation EgyptNone JordanClinical Research Law 2001 http://www.jfda.jo/custom/law/23.dochttp://www.jfda.jo/custom/law/23.doc Yemen None Sudan National Guidelines for Ethical Conduct of Research (2008): http://sites.google.com/site/healthresearchlibrary/national-guidelines http://sites.google.com/site/healthresearchlibrary/national-guidelines Lebanon None Syria None Morocco None Saudi Arabia Law of Ethics of Research on Living Things. National Committee of BioEthics http://www.kacst.edu.sa/ar/depts/bioethics/Pages/WShp.aspxhttp://www.kacst.edu.sa/ar/depts/bioethics/Pages/WShp.aspx Qatar Guidelines, Regulations and Policies for Research Involving Human Subjects UAE Guidance for Conducting Clinical Trials Based on Drugs/Medical Products & Good Clinical Practice National Regulations

31. Confidentiality Informed Consen t REC Review N 43 (88%) 37 (76%) 28 (58%) 49 Biological Samples 30 (100%) 19 (65%) 10 (33%) 30 Qualitative Studies

32. Confidentiality Informed Consen t REC Review N 43 (88%) 37 (76%) 28 (58%) 49 Biological Samples 30 (100%) 19 (65%) 10 (33%) 30 Qualitative Studies Ethics Review and Informed Consent is Imperfectly Realized in the EMR

34. Asem A, et. al. PRIM&R 2009 52%

35. El-Dessouky H, et.al. International Journal of Dentistry 2011 62%

36. Kandeel A. In Press 2011 52% 18% 30%

37. No Prior Exposure to Research Ethics 28 – 62%

38. Barriers to Functioning of Research Ethics Committees

40. Gaps in Research Ethics in the Middle East CategoryGaps in Research Ethics National Capacity Lack or insufficient national guidelines Lack of efficient NRA Institutional Commitments Inadequate institutional policies (e.g., conflict of interest policies, etc.). Lack of degree programs in research/ethics Research Ethics Committee Capacity Suboptimal administrative structures Inadequate budgets Inadequate Membership diversity Lack of training Researchers Inadequate knowledge of research ethics. Responsible conduct in research. Human Subjects Many are not aware of their rights