Kusum Verma

1
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)
• 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
• 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 ConsentGenetic 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
• 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 ConsentFetal Embryonic Tissue
Transplants

• Consent from mother sufficient, unless father
  objects in writing
• Mothers consent
• 2 stages
• For abortion
• For donation of fetal tissue

30
Informed ConsentFetal 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 patients 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 - 5-10
• - 12-15 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 IRBs 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 studiesEthical 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