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Kusum Verma A.I.I.M.S. New Delhi. WHY - CONCERN Research essential for advancement of scientific knowledge. Newer technologies & treatments. Require participation.

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Presentation on theme: "Kusum Verma A.I.I.M.S. New Delhi. WHY - CONCERN Research essential for advancement of scientific knowledge. Newer technologies & treatments. Require participation."— Presentation transcript:

1 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 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  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


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