Kusum VermaA.I.I.M.S.

New Delhi

WHY - CONCERNResearch 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.

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

Misuse of Research

Japanese war crimesUs radiation experimentsTuskegee syphilis studiesWillowbrook studies on hepatitis in Institutional children

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

Historical PerspectivesCouncil 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.

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

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

Guidelines in IndiaICMR - `Policy statement on ethical considerations involved in Research on human subjects’ (1982)`Ethical guidelines for Biomedical research on Human subjects’ (2000)?LegislationDBT-guidelines for genetic research (2002)

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.

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.

Respect for Person

Self determinationIndividuals treated as autonomous agents Enters into research VOLUNTARILY

and with adequate information – INFORMED CONSENT.

Persons with diminished autonomy are entitled to protection

Diminished/Reduced Autonomy

Impaired decision making capacityPrisonersStudentsSubordinate EmployeesServices personnelAdequate justification for their involvement as research subjects

Informed Consent - Elements

Information Patient/subject information sheet

Comprehension Simple and understandable language Local language translations

VoluntarinessConsent

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 & discomfortsDescribe – benefits to Subject Community/others Medical professionals

Contd…

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 treatmentsDescribe – steps for insuring confidentialityState Voluntary participation No loss of benefits on withdrawal

Explain - whom to contact for questions on more information or in case of injury

Contd…

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.

Patient/Subject Information

Disclosure to patient should be continuousNew knowledge must be informed as and when available.

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

Patient/Subject Information

Information about risks be never witheldTruthful answers be always given to direct questions

Informed ConsentConsent 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 consentNew consent needed for any use for which consent not obtained explicitlyConsent not needed-unidentified/unlinked samples.

Informed ConsentCommunity 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

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.

Genetic Databases

Source Family Hx/Pedigree Phenotype studies DNA/RNA/Protein sequence

Samples Identified Annonymous Deidentified (code stored separately)

Genetic Databases

Not to be collected for use Discrimination Pursuing eugenics

Appropriate ethical approval mechanism needed to oversee creation and maintenance of genetic databases

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

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

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

Informed ConsentFetal & Embryonic Tissue Transplants

Consent from mother sufficient, unless father objects in writingMother’s consent 2 stages For abortion For donation of fetal tissue

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 researchFetal tissue transplant in humans Approval local EC National/Central EC

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.

Informed Consent

Written or Oral

ConfidentialityEC-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 resultsConsent to be obtained specifically for revealing information to other family members.Codification of biological samples.

Confidentiality Vs.

Beneficence & Harm

Risk-Benefit RatioRisks of research be acceptable in relation to likely benefitsRisks Physical harm Psychosocial

Discrimination Stigmatisation Breach of confidentiality

Risks can be reduced by screening potential participants and monitoring participants for adverse events.

Risk-Benefit Ratio

Essentiality of research – should lead to advancement of knowledge for the benefit of all members of human speciesResearch design is soundResearch conducted by professionally competent persons.

Research Related Injury

Inbuilt mechanism for

compensation/treatment of

unforseeable risks

Treatment – best possible

treatment in the country.

Compensation to Participants

No inducements to participate in the studyInvestigator 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

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.

JusticeVulnerable 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 subjectsShould not be targeted if other populations would also be suitable

Special Groups- Research Subjects

Pregnant/Nursing womenOnly 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.

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.

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”.

Ethics Committee - RoleWatch dogTo adequately protect rights & welfare of human subjects in clinical research.Committee is “patient’s advocate”.EC helps and guides but does not give ordersEducate faculty members on principles of biomedical ethics

IRB/EC-Composition

Multidisciplinary and multisectorialIndependentCompetentNumber - 5-10

- 12-15 max. recommendedQuorumChairperson – 0utside institutionMember-Secretary – Same institution

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.

Practice Vs. ResearchPractice – “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 togetherLike when research is designed to evaluate safety and efficacy of a therapy.If any element of research in an activity – should undergo review.

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.

IRB Review – Exempt Research

Educational tests, survey procedures, interview procedures or observation of public behaviour unlessHuman subjects can be identified directly or indirectlyDisclosure of subjects responses could place them at risk for legal liability, damage financial standing, employability or reputation.

? 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.

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.

Flow Chart IRB Review

Research Proposal

Scientifically sound

Risk Benefit Ratio

Procedures for obtaining informed consent

Procedures for selections of subjects equitable

IRB

Initial review of projectProgress reportAmendments to protocol, informed consentSerious adverse eventsTermination of studies

IRB-Expedited ReviewBy 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.

Placebo

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

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.

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

Randomised Trials

Ethical basis Treatment by both arms of the

protocol are in equipoise – current evidence does not indicate superiority of one over another

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.

Epidemiological studiesEthical Aspects

Studies carry minimal risk to study subjectsInformed consent normally required except in very large cohort studies conducted exclusively by examining medical records.

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

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

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 IRBThese should be banned

Conflicts of InterestDouble blind studyInvestigator not aware of intervention being given to a patientIndependent monitoring boardInvestigator to have Unrestricted access to primary data Freedom to publish

Disclose conflicting interests to potential participantsBan certain situations

Authorship

Ghost AuthorHonorary AuthorsPlagiarismFabricated Data