1. ETHICAL ISSUES IN MEDICAL RESEARCH Eligius Lyamuya MD, MMed, PhD Department of Microbiology and Immunology, Muhimbili University College of Health sciences

2. Learning objectives  Know the Basic Research ethics documents  Understand the Principles of Research Ethics  Understand Informed Consent  Know the Local regulations

3. Disposition  Preamble  Background  Basic Research ethics documents  Principles of Research Ethics  Informed Consent  Local Regulations

4. Preamble: Definitions - 1  Research is a systematic investigation designed to develop or to contribute to generalizable knowledge.  Health research makes discoveries about how to improve health  Health research involves many disciplines, including biomedical and social sciences

5. Definitions - 2  A human subject is a living individual from or about whom an investigator conducting research obtains data through intervention, interaction or identifiable private information  Intervention includes both physical procedures for data gathering and manipulations of the subject or the subject’s environment that are performed for research purposes

6. Definitions - 3  Interaction includes communication or interpersonal contact between investigator and subject  Direct interactions, such as obtaining data by taking medical history, interview, drawing blood samples etc.  Indirect interactions, such as analysis of specimens or data already obtained from people

7. Definitions - 4  Private information includes information about behaviour that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place; also includes information that has been provided for specific purposes by an individual and which will not be made public.

8. Background  Three parties have legitimate interests in any research involving human subjects:  Investigator, who initiates it  Society, that provides conditions for it  Subjects, who participate in it  It is essential to prevent conflict of interest between these parties

9. Basic Research Ethics documents  1964:Nuremberg code  1974:The Declaration of Helsinki  1978:Belmont Report  1993:Council for International Organizations of Medical Sciences (CIOMS) Guidelines

10. 1946: Nuremberg code: History  Development of ethical guidelines for the conduct of research involving humans began in late 1940s.  1946, 23 Nazi defendants (20 of them physicians) tried for war crimes and crimes against humanity  16 guilty: 7 hanged, 9 sentenced to prison terms, 10 years-life

11. Nuremberg code  Out of the Nazi experience grew a set of principles known as the Nuremberg Code  Intended to apply primarily for medical research, but are also useful for other types of research (behavioural and social science)

12. Principles from the Nuremberg code-1 1.The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved, as to enable him to make an understanding and enlightened decision. This latter element requires that, before the acceptance of an affirmative decision by the experimental subject, there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person, which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

13. Principles from the Nuremberg code -2 2.The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3.The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study, that the anticipated results will justify the performance of the experiment. 4.The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

14. Principles from the Nuremberg code -3 5.No experiment should be conducted, where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. 6.The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7.Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

15. Principles from the Nuremberg code -4 8.The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9.During the course of the experiment, the human subject should be at liberty to bring the experiment to an end, if he has reached the physical or mental state, where continuation of the experiment seemed to him to be impossible. 10.During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgement required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

16. 1964; revised 2001: The Declaration of Helsinki  The well-being of the human subject should take precedence over the interests of science and society  Consent should be in writing  Use caution if participant is in dependent relationship with researcher  Limit use of placebo  Participants benefit from research

17. 1974: From the Belmont Report to the Code of Federal Regulations Evolution of research ethics in the United States of America  The Tuskegee study: Ethical problems with research are identified  The Belmont Report: Fundamental principles for the ethical conduct of research are advocated  The Code of Federal Regulations: Specific regulations are adopted

18. Tuskegee syphilis study-1  Research began in 1932 in the USA; involving 600 men, all poor and all black, funded by Public Health Service  Study purportedly designed to monitor and record their health, some told they had “bad blood” but none were told they had syphilis  Given free medical attention, hot meal and promise of government support to cover their burial expenses

19. Tuskegee syphilis study-2  2/3 had evidence of tertiary syphilis at recruitment; many control subjects acquired disease during course of study  However, even after penicillin was discovered to be a cure for syphilis in 1943, it was not offered to the subjects as treatment

20. Tuskegee syphilis study-3  Project ended in 1972 after press reports of details of the study  Senator Edward Kennedy held hearings on the study, government sued, case settled for $10 million in 1974, to be shared among surviving subjects and the heirs of the deceased  1997 President Clinton formally apologized on behalf of the government to the survivors

21. Belmont Report: Ethical principles  Following Kennedy hearings in 1974, National Research Act passed, National Commission for Protection of Human Subjects of Biomedical and Behavioural Research created.  Commission produced the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects in Research, published in 1978 which developed ethical principles of research:  Respect for persons  Beneficence  Justice

22. 1993; revised 2002: Council for International Organizations of Medical Sciences (CIOMS) Guidelines  Prepared by CIOMS in collaboration with WHO  21 specific guidelines, each followed by interpretative commentaries  Indicate how the Declaration of Helsinki could be effectively applied, particularly in developing countries, given the socioeconomic circumstances, laws and regulations, and executive and administrative arrangements

23. Summary: Research Ethics documents  From Nuremberg to CIOMS  Three Universal principles  Protection of the participant

24. Fundamental Principles of Research Ethics-1  The Belmont report enumerates three basic principles for investigators conducting research with human subjects:  Respect for persons  Beneficence  Justice  These remain to be the universal fundamental principles of Research Ethics

25. Fundamental Principles of Research Ethics-2  These are considered to be universal; they have no national, cultural, legal or economic boundaries  Every researcher should understand and follow them  Availability of resources needed to maintain these principles is not universal of evenly distributed

26. Respect for persons  Each individual:  Is autonomous, unique and free  Has the right and capacity to decide  Has value and dignity  Has the right to informed consent  Vulnerable persons are entitled to special protections  Minors, pregnant women, prisoners, mentally disabled, illiterates (or limited formal education), persons with limited access to health services, women in some settings

27. Beneficence  Latin = to do good  Researchers must:  Do no harm (non-maleficience) by protecting physical, mental and social well-being of study participants  Maximize possible benefits and minimize possible harms

28. Justice  Researchers must:  Conduct equitable recruitment of research participants  Ensure fair distribution of risks and benefits of participation  Provide special protection for vulnerable groups

29. Summary: Principles of Research Ethics  Health research is conducted according to 3 universal principles:  Respect for persons  Beneficence  Justice  Researchers must work for the well-being of populations that participate in their studies.  These principles were developed to provide guidance and ensure that the well-being of each participant is always considered.

30. Informed consent-1  Consent given by a competent individual who:  Has received the necessary information  Has adequately understood the information (comprehension)  After considering the information, has arrived at a decision without having been subjected to coercion, undue influence or inducement, or intimidation (voluntary decision)

31. Informed consent-2  4-step process:  Step 1: Information is provided  Step 2: Information is understood (Comprehension)  Step 3: A Voluntary decision is made  Step 4: Comprehension is monitored and maintained

32. Informed consent-3  Essential elements: 1.Research description 2.Risks 3.Benefits 4.Alternatives 5.Confidentiality 6.Compensation 7.Contacts 8.Voluntary participation and withdrawal 9.Documentation

33. Description of the Research  Research study  Objectives of the study  Expected responsibilities  Procedures involved  Study duration  Explanation of randomization or placebo

34. Description of Risks  Anticipated or foreseeable  Physical, social, psychological  Likelihood, severity, duration

35. Description of Benefits  Reasonably expected  Not overstated or exaggerated  Duration

36. Available Alternatives  Alternative procedures or treatment  Advantages and disadvantages  Availability

37. Confidentiality  Degree of confidentiality  Indicate persons or organizations who may have access to the information  Anticipated future use of data or biological samples

38. Compensation  Fully explained and not coercive  Fair payment for time, travel and inconvenience  Possibility of treatment and compensation in case of research-related injury or complications  Degree of health care to be made available

39. Contact Persons  Research team  Ethics committee  Special groups

40. Voluntary Participation  Free of coercion and undue influence  Right to discontinue at any time  No penalty for refusal or withdrawal

41. Documentation  Is only part of the informed consent process  Signatures may not always be possible  Waiving of documentation requires ethics committee review and approval

42. Summary: Informed Consent  Ethical, not just legal requirement  Free of coercion  Documentation needed  Comprehensibility essential  Support materials helpful  Pilot-testing encouraged

43. Local Regulations and Guidelines  Rapid growth of international research  Many countries, including Tanzania, now have national guidelines  Greatest need in developing countries

44. From Fundamental Ethical Principles to Local Guidelines National regulations and international recommendations Local/Institution operational guidelines 3 principles Respect for persons Beneficence Justice

45. Conclusion  Research ethics is a growing field of study generating a great deal of attention.  International research ethics should guide research conducted at any level to ensure that international expectations and standards are followed.