1. Kusum Verma A.I.I.M.S. New Delhi
ETHICAL ISSUES
IN HEALTH RESEARCH
Kusum Verma
A.I.I.M.S.
New Delhi

2. WHY - CONCERN
Research essential for advancement of scientific knowledge.
Newer technologies & treatments.
Require participation by human subjects.
Essential that rights of research participants are protected as public willingness to participate depends on a trust that research is conducted according to strict ethical standards.

3. Historical Perspectives
Nuremberg trial (1946) – 23 Nazi physicians
Crimes against prisoners of war
mutilating surgeries;
infections with lethal pathogens;
exposure to extremes of temp.
Nuremberg Code (1947) – fundamental ethical code
Voluntary informed consent
Scientifically valid research design

4. Misuse of Research Japanese war crimes Us radiation experiments
Tuskegee syphilis studies
Willowbrook studies on hepatitis in Institutional children

5. Historical Perspectives
World Medical Association (1964) – Declaration of Helsinki : Recommendations guiding medical doctors in medical research involving human subjects.
Revised – 1975, 1983, 1989, 1996, 2000

6. Historical Perspectives
Council for International organisations of Medical Sciences (CIOMS) and WHO (1982) – International ethical guidelines for biomedical research involving human subjects
Revised – 1993, 2002
International conf. Harmonisation – Good clinical practice (ICH-GCP)-1996)
International ethical and scientific quality standard for designing, conducting, recording and reporting trials involving human subjects.

7. Landmark article on US abuses –Beecher (NEJM, 1966)
Front line research in medical schools and major medical journals
Dangerous research
No or little benefit to patient
No informed consent

8. Ethical Principles Belmont Report (1979) Principles
Established three fundamental ethical principles relevant to all research involving human subjects.
Principles
Respect for persons
Beneficence & Non-male ficence
Justice & Equity

9. Guidelines in India
ICMR - `Policy statement on ethical considerations involved in Research on human subjects’ (1982)
`Ethical guidelines for Biomedical research on Human subjects’ (2000)
?Legislation
DBT-guidelines for genetic research (2002)

10. Concern of all guidelines is to protect and respect rights and welfare of human subjects as participants in research.
OHRP – Office for Human Research Protections.

11. Human beings have equal worth; their lives are equally valuable; and they deserve equal respect. We may not treat them as worthless, use them as mear means to our ends; misinform them; increase their risks of becoming ill or die; violate the integrity of their intimate relationships and treat with contempt what they deeply value.

12. Respect for Person Self determination
Individuals treated as autonomous agents
Enters into research VOLUNTARILY and with adequate information – INFORMED CONSENT.
Persons with diminished autonomy are entitled to protection

13. Diminished/Reduced Autonomy
Impaired decision making capacity
Prisoners
Students
Subordinate Employees
Services personnel
Adequate justification for their involvement as research subjects

14. Informed Consent - Elements
Information
Patient/subject information sheet
Comprehension
Simple and understandable language
Local language translations
Voluntariness
Consent

15. Patient/Subject Information
State & Describe
Nature & purpose of study
Duration of participation
Procedures to be followed
Experimental procedure, if any, to be identified
Describe – reasonably forseeable risks & discomforts
Describe – benefits to
Subject
Community/others
Medical professionals
Contd…

16. Patient/Subject Information
Explain if project involves more than minimal risk
Policy on compensation
Availability of medical treatment for such injuries
Disclose – alternative procedures or treatments
Describe – steps for insuring confidentiality
State
Voluntary participation
No loss of benefits on withdrawal
Explain - whom to contact for questions on more information or in case of injury
Contd…

17. Patient/Subject Information
Studies involving DNA Banking/Genetic material
Right to prevent use of his/her biological sample (DNA/cell line) at any time during conduct of research.

18. Patient/Subject Information
Disclosure to patient should be continuous
New knowledge must be informed as and when available.

19. Patient/Subject Information
Incomplete disclosure-justified
Truly necessary to accomplish the goals of research
No undisclosed risks to subjects that are more than minimal
There is adequate plan for debriefing subjects, when appropriate; and for dissemination of research results to them

20. Patient/Subject Information
Information about risks be never witheld
Truthful answers be always given to direct questions

21. Informed Consent
Consent valid only for research for which it is given by participant (Primary use).
Information/samples to be used for other purposes or sharing with other investigators (secondary use)-clear mention made during process of obtaining informed consent
New consent needed for any use for which consent not obtained explicitly
Consent not needed-unidentified/unlinked samples.

22. Informed Consent Community studies – Consent needed from Children
Community – group consent
Individuals
Children
Parent/guardian
Assent of child to his/her capability
Mentally Ill
Close biological relative
Legally authorised person
Certificate from psychiatrist
Illiterate persons
Who explains
Thumb impression
Videotape

23. Informed Consent Genetic Studies
Necessary & to be taken before
Screening (except mandatory newborn screening).
Diagnostic genetic testing
Treatment
Research
Written consent not necessary for procedures that form part of routine care.

24. Genetic Databases Source Samples Family Hx/Pedigree Phenotype studies
DNA/RNA/Protein sequence
Samples
Identified
Annonymous
Deidentified (code stored separately)

25. Genetic Databases Not to be collected for use
Discrimination
Pursuing eugenics
Appropriate ethical approval mechanism needed to oversee creation and maintenance of genetic databases

26. Informed Consent DNA Banking
Inform Donors/Patients
Conditions under which samples will be provided to other researchers
How long samples will be preserved
Cost to individual researcher to obtain sample from repository
Commercial benefits – donor, sample collector & repository director

27. Informed Consent DNA Banking
Donor to have right to order destruction of his/her sample from repository at any time.
Fresh EC clearance for secondary use of material from DNA bank

28. Informed Consent Transplantation
Cadaveric Donors
By person in lawful possession of the body
Living will
Live Donors
By donor
Interest of donor to take priority over that of the recepient
Children, mentally incompetent persons, persons with restricted patient autonomy – not as donors

29. Informed Consent Fetal & Embryonic Tissue Transplants
Consent from mother sufficient, unless father objects in writing
Mother’s consent
2 stages
For abortion
For donation of fetal tissue

30. Informed Consent Fetal Tissue Transplants
Tissue from aborted fetuses can be cultured and banked for use in research.
Fresh EC clearance for use of stored tissue in research
Fetal tissue transplant in humans
Approval local EC
National/Central EC

31. Informed Consent-Waiver
May be considered in conditions of emergency if study or use of drug has been earlier approved by EC.
Patient/guardian be informed after he/she regains consciousness or is able to understand the study.

32. Informed Consent
Written or Oral

33. Confidentiality EC-How ensured?
Special value in genetic studies & research; and genetic databases.
Indiscriminate disclosure of data may lead to
Psychosocial harm
Stigmatisation
Discrimination
Family members not entitled to know each others diagnosis/test results
Consent to be obtained specifically for revealing information to other family members.
Codification of biological samples.

34. Confidentiality Vs. Beneficence & Harm

35. Risk-Benefit Ratio
Risks of research be acceptable in relation to likely benefits
Risks
Physical harm
Psychosocial
Discrimination
Stigmatisation
Breach of confidentiality
Risks can be reduced by screening potential participants and monitoring participants for adverse events.

36. Risk-Benefit Ratio
Essentiality of research – should lead to advancement of knowledge for the benefit of all members of human species
Research design is sound
Research conducted by professionally competent persons.

37. Research Related Injury
Inbuilt mechanism for compensation/treatment of unforseeable risks
Treatment – best possible treatment in the country.

38. Compensation to Participants
No inducements to participate in the study
Investigator may provide for
Cost of travel to hospitals
Various visits
Mandays lost for above visits
Inbuilt mechanism for all foreseeable and unforseeable risks due to research-provide for remedial action.
Insurance cover/other mechanism
All payments, reimbursements to be approved by EC

39. Justice & Equity
Requires that benefits & burdens are distributed fairly.
Subjects for research selected in a way that burdens and benefits of the research are distributed without arbitrariness, discrimination or caprice.
Economically or socially disadvantaged subjects not to be used to benefit those who are better off than them.

40. Justice Vulnerable populations
With poor access to health care
With impaired decision making capacity
Residents of old age/nursing homes
Prisoners
Students
Service personnel
Adequate justification for involvement as subjects
Should not be targeted if other populations would also be suitable

41. Special Groups- Research Subjects
Pregnant/Nursing women
Only if objective of research to obtain new knowledge about foetus, pregnancy and lactation; and research carries no more than minimal risk to the fetus or nursing infant.

42. Special Groups- Research Subjects
Children
Not to be involved in research that could be carried out equally well with adults.
New drug trial – in children be carried out after Phase III clinical trials in adults.
New drug trial can be carried out in children only if the drug has a therapeutic value in a primary disease of the chilrdren.

43. Mandatory that all proposals on biomedical research involving human subjects are cleared by the institutional ethics committee.
Rationale is “that an objective review of research activities involving human subjects by a group of diverse individuals is most likely to protect human subjects and promote ethically sound research”.

44. Ethics Committee - Role
Watch dog
To adequately protect rights & welfare of human subjects in clinical research.
Committee is “patient’s advocate”.
EC helps and guides but does not give orders
Educate faculty members on principles of biomedical ethics

45. IRB/EC-Composition Multidisciplinary and multisectorial Independent
Competent
Number
max. recommended
Quorum
Chairperson – 0utside institution
Member-Secretary – Same institution

46. IRB/EC-Composition Membership
Medical & non-medical
Scientific & non-scientific
Legal expert
Social scientist
Philosopher/ethicist
Lay person
Adequate representation of age, gender, community etc. to safeguard the interests and welfare of all sections of community/ society.

47. Practice Vs. Research
Practice – “interventions that are designed solely to enhance the well-being of an individual patient that has a reasonable expectation of success”
Research – “activity designed to test an hypothesis’ permit conclusions to be drawn; and thereby develop or contribute to generalizable knowledge”.
Distinction blurred as both often occur together
Like when research is designed to evaluate safety and efficacy of a therapy.
If any element of research in an activity – should undergo review.

48. IRB Review-Exempt. Research
Research on normal educational practices.
Study of existing records, data, documents, pathological specimens or diagnostic specimens
If publicly available
If information recorded in such a manner that subjects cannot be identified directly or through identifiers linked to subjects.

49. IRB Review – Exempt Research
Educational tests, survey procedures, interview procedures or observation of public behaviour unless
Human subjects can be identified directly or indirectly
Disclosure of subjects responses could place them at risk for legal liability, damage financial standing, employability or reputation.

50. ? Exemption Collection and study of Samples from deceased individuals
Samples collected for diagnostic purposes.
Samples or data available from commercial or public repositories or registries
Established cell lines publicly available to qualified investigators.
Self sustaining, cell free derivative preparations – viral isolates, cloned DNA or RNA.

51. Ethical Review
Scientific review and ethical review cannot be separated.
Scientifically unsound research is unethical that it may expose human subjects to risk or inconvenience to no purpose. Even if no risk of injury, wasting of participants time is loss of valuable resource.

52. Flow Chart IRB Review Research Proposal Scientifically sound
Risk Benefit Ratio
Procedures for obtaining informed consent
Procedures for selections of subjects equitable

53. IRB Initial review of project Progress report
Amendments to protocol, informed consent
Serious adverse events
Termination of studies

54. IRB-Expedited Review By a single reviewer rather than full committee.
Research involves no more than minimal risk
Minor changes in previously approved research
Research study of minor nature such as examination of case records
Urgent proposal of national interest
Decisions taken to be brought to notice of main committee.

55. Placebo
Placebo may be used as a comparator, if there is no proven best treatment or procedure that can be used as a comparator

56. Placebo Placebo controls may be justified
Short term studies that do not offer serious risks to subjects
Potential subjects need to be informed of effective interventions available outside the research study.

57. IRB Review – Multicenter studies
To be approved by all IRB;s concerned.
Situation
Study approved by IRB of one institution and not by IRB of another institution
Resolved
Discussions that clarity perceived problems
Modifications

58. Randomised Trials Ethical basis
Treatment by both arms of the protocol are in equipoise – current evidence does not indicate superiority of one over another

59. Clinical Trials
Unethical to continue a clinical trial after demonstration that one therapy is safer or more effective.
Trial that will not answer the research question in an acceptable time frame – wrong to continue.

60. Epidemiological studies Ethical Aspects
Studies carry minimal risk to study subjects
Informed consent normally required except in very large cohort studies conducted exclusively by examining medical records.

61. IRB-Powers
IRB have no authority to impose sanctions on researchers who violate ethical standards.
IRB can withdraw ethical approval of a research project if judged necessary

62. Conflicts of Interest-Project support
Funded projects – Pharmaceutical firms.
Investigator has
Little or no input into trial design
Limited access to raw data
Limited participation in data interpretation
Results of trial may not be published if unfavourable to sponsor

63. Conflicts of Interest
Investment of investigator in a company or service on company advisory committee whose product is being tested.
Such conflicts must be disclosed to IRB
These should be banned

64. Conflicts of Interest Double blind study
Investigator not aware of intervention being given to a patient
Independent monitoring board
Investigator to have
Unrestricted access to primary data
Freedom to publish
Disclose conflicting interests to potential participants
Ban certain situations

65. Authorship
Ghost Author
Honorary Authors
Plagiarism
Fabricated Data