ETHICAL ISSUES IN CLINICAL RESEARCH

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ETHICAL ISSUES INCLINICAL RESEARCH
Peter Wagner, M.D. Dept of Medicine,
UCSD President, American Thoracic Society
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A DISCUSSION SPARKED BY
ATS Conference on the ethical conduct of
research in critically ill patients November
21-22, 2003
Challenge to the low tidal volume trial in
ARDS (ARDSnet)
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THERE MUST BE A CLEAR NEED FOR RESEARCH
Unnecessary research is unethical
Need is based on
1. Persisting high mortality/morbidity
2. Limited understanding of disease
3. Limited specific therapeutics
4. Limited ability to predict outcome
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RESEARCH MEANS ETHICAL
ISSUES
Ethical challenges are substantial from
planning to publication
Ethical integrity must be assured
Throughout the study
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ETHICAL INTEGRITYTHROUGHOUT THE STUDY

• When the research question is posed

• As the study is designed

• During subject identification

• During the consent process

• As the study is conducted

• During data analysis

• During dissemination of results

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1. When the research question is posed

• There must be scientific validity

• There must be social value

• There must be independent review

• Equipoise should exist

Medical community genuinely uncertain
about the value of the intervention
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2. As the study is designed

• There must be scientific validity

• The control arm must be chosen wisely

• There must be justice (equitable risk
• across subjects)

• The riskbenefit ratio must be acceptable

• The rules for stopping must be defined

• Adverse event handling must be defined

• Conflict of interest must be minimized

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Control Groups

• Proper design important to scientific validity
• In mechanistic or efficacy trials, protocol
  driven control group isolates effect of
  intervention studied
• In large effectiveness trials, control group
  should be within range of best practice
• Consensus on best practice may be difficult
• Subject to certain conditions, there is
  justification for protocolizing care in the
  control arm the investigator must attempt to
  insure the protocol is reflective of the best
  current practice. Careful explanation of these
  distinctions is mandatory in informed consent.

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3. During subject identification

• Selection to allow generalization (mostly)

• Consideration for vulnerable groups

• There must be justice (equitable
• access across subjects)

• The riskbenefit ratio must be acceptable

• Obligation to avoid harm, provide benefit

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4. During the consent process

• Who can/should/cannot give consent

• Timing of obtaining consent

• Who should seek consent

• Person giving consent must be informed

• Person giving consent must understand

• Assure consent is truly voluntary

• Assure the process follows the law

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Waiver of Consent - 1996

• 1996 CFR Modification Waiver of consent possible
  if
• Life threatening available treatments unproven
  or
• unsatisfactory
• Obtaining consent not feasible
• Participation has prospect of direct benefit to
  subjects
• Risks are reasonable relative to the medical
  condition of
• subjects
• Research not possible without waiver
• Investigator attempts to contact surrogate within
  
• prespecified time
• Local IRB reviews and approves

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5. As the study is conducted

• Patient safety (DSMB)

• Patient respect, privacy

• Oversight for stopping (DSMB)

• Investigator conflicts of interest

• Best experimental methods, records

• Conflict between caregiving and research

• Staying within IRB approved limits

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6. During data analysis

• Integrity during data processing

• Patient privacy during data processing

• Avoiding unnecessary delay in analysis

• Appropriate sharing of data

• Maintaining security of data

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7. During dissemination of results

• Integrity in reporting

• Patient respect, privacy

• Avoiding unnecessary delay in reporting

• Appropriate involvement by all involved

• Consider sharing results with subjects

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Major Recommendations

• Separate research practice for study
  participants
• 3rd party consent if research clinical care are
  mixed
• Clinicians satisfied with study to have pts
  participate
• Incorporate ethical checklists
• Need laws recognizing surrogate consent for
  research
• Revisit consent decisions during study
• Share results of study with participants
• Participant informed of possible individual
  benefit
• Need to improve regulatory effectiveness
  efficiency
• Standardize DSMB
• Better identify manage conflict of interest

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Ethical Checklist for Clinical Research Design

• Will study results matter?
• Is the study design scientifically valid?
• Has design undergone independent review?
• Appropriate participant selection?
• Is riskbenefit ratio favorable?
• Appropriate informed consent?
• Procedures to insure respect for
  participants?
• Are data and safety monitoring in place?
• Conflicts of interest identified
  minimized?

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Sources of Conflict of Interest

• Consultancies
• Stock ownership
• Patent rights
• Industry funding
• Competition for funding
• Professional status or jealousies
• Publish or perish rule
• Personal curiosity

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CONCLUSIONS

• Major need for research must exist

• Ethical challenges abound

• At every stage from planning to reporting

• These challenges must be faced

• Perhaps most difficult are
• The issue of informed consent
• When researcher and caregiver are one
• Other conflicts of interest
• Selecting the control treatment