Topic 5: Regulatory and Ethical Challenges of ePCTs 5... · 2018-05-16 · Informed consent. Data...
Transcript of Topic 5: Regulatory and Ethical Challenges of ePCTs 5... · 2018-05-16 · Informed consent. Data...
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Collaboratory ePCT Training Workshop
Kevin Weinfurt, PhDDuke Clinical Research Institute
Topic 5: Regulatory and Ethical Challenges of ePCTs
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Introduction
Whose rights/welfare need to be protected?
What are different approaches for notification and authorization?
Working with human subjects oversight bodies
A plea
Overview12
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Introduction1
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ePCTs are motivated by ethical imperatives
ePCTs also raise interesting ethical and regulatory questions
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Informed consentData monitoringDefining minimal riskResearch/quality improvement distinctionVulnerable subjectsIRB harmonization
Evolving understanding of unique ethical/regulatory issues for ePCTs
Identifying direct and indirect subjectsGatekeepersFDA-regulated productsNature of ePCT interventionsPrivacy
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Current ethics/reg environment is in flux
1/19/2017Revised Common Rule published
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Current ethics/reg environment is in flux
1/19/2018Original compliance date
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7/19/2018Delayed compliance date
Further delay is possible (likely?)
Current ethics/reg environment is in flux
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And more . . .(Certificates of Confidentiality, single IRB review of multisite
trials, etc.)
Current ethics/reg environment is in flux
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Your dedicated ethics/regulatory liaison
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Whose rights/welfare need to be protected?
2
(Ethical, not regulatory question)
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Direct Indirect
Types of participants in an
ePCT
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Immediate and/or mediated target of the intervention
Direct participant
Intervention
Intervention
Intervention
Patients
Providers
Clinics
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Immediate and/or mediated target of the intervention
Direct participant
Intervention
Immediate target
Mediated target
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PCTs may affect people by way of routine exposure to the environment
Indirect participant
Intervention
eg, family/caregivers
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Example: Active Bathing to Eliminate Infection (ABATE) trial
Routine Care Decolonization
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Direct Indirect
Types of participants in an
ePCT
Rights and welfare reviewed by IRB
Rights and welfare reviewed by gatekeepers
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Who are the direct and indirect participants for your study?
What are the potential risks and benefits for each?
1 min 4 min
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What are different approaches for notification
and authorization?
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Informed consent
Alterations
Non-disclosure
Approaches
Broad notification Opt-out Opt-in
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Informed Consent
Alterations
Non-disclosure
Approaches
Broad notification Opt-out Opt-in
Require a waiver
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An IRB may waive or alter the requirements of informed consent if all of the below are deemed true:
• “The research involves no more than minimal risk to the subjects;
• The waiver or alteration will not adversely affect the rights and welfare of the subjects;
• The research could not practicably be carried out without the waiver or alteration; and
• Whenever appropriate, the subjects will be provided with additional pertinent information after participation.” §46.116
Conditions for waiver of consent
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“In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).”
Common Rule: CFR 46.111 (a)(2)
“The reasonably foreseeable risks of research include already identified risks of the standards of care being evaluated as a purpose of the research.”
From the OHRP Draft Guidance
Minimal risk
Some debate here!!!
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Informed consent
Alterations
Non-disclosure
Approaches
Broad notification Opt-out
Opt-in
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Informed consent
Alterations
Non-disclosure
Approaches
Broad notification Opt-out
Opt-in
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• Time to Reduce Mortality in End-stage renal (TiME) disease hypotheses: Facility implementation of ≥4.25-hour dialysis session duration improves outcomes compared with usual care
• Patients starting dialysis at participating facilities are given a brief information document with:• Purpose of the trial• How session duration will be affected by the trial• Toll-free telephone number to obtain additional
information from the research team and to opt-out of participation
• Informational posters in participating dialysis facilities throughout the duration of the trial
TiME consent process
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Broad notification
Informed consent
Alterations
Non-disclosure
Approaches
Opt-out Opt-in
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Broad notification
Informed consent
Alterations
Non-disclosure
Approaches
Opt-out Opt-in
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• Tests whether inserting epidemiological evidence in lumbar spine imaging reports will reduce subsequent diagnostic and therapeutic interventions
• Waiver of consent was granted • Risk of contacting subjects deemed greater
than the risk of study procedures• By informing primary care providers and
patients, they risk invalidating the results
LIRE trial
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What do data suggest about different approaches?
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Written consent (with clinical risks included)
Written consent
Oral consent + info sheet
Oral consent
General notification (with opt-out)
Post-notification after study done
Approaches to Notification & Authorization
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Difficulty understanding aspects of pragmatic trials of accepted medical practices
1
2
3
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5
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“There will be no extra follow-up calls or visits that patients need to do related to the study.”
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Therapeutic Misconception
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Difficulty understanding aspects of pragmatic trials of accepted medical practices
Nontrivial consent bias, but it’s the same for all approaches for N&A
Less active approaches to N&A viewed as unacceptable for some types of pragmatic research
1
2
3
4
5
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GN
POST
POST
GN
GN
GN
GNGN
GNGN
OO
OO
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Difficulty understanding aspects of pragmatic trials of accepted medical practices
Nontrivial consent bias, but it’s the same for all approaches for N&A
Less active approaches to N&A viewed as unacceptable for some types of pragmatic research
Including descriptions of background clinical risks increased length of form, but did not change any outcome
Active alternatives to written consent—such as oral consent—may not be expected to compromise consent quality
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2
3
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5
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Difficulty understanding aspects of pragmatic trials of accepted medical practices
Nontrivial consent bias, but it’s the same for all approaches for N&A
Less active approaches to N&A viewed as unacceptable for some types of pragmatic research
Including descriptions of background clinical risks increased length of form, but did not change any outcome
Active alternatives to written consent—such as oral consent—may not be expected to compromise consent quality
1
2
3
4
5
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Working with human subjects oversight bodies: IRBs and Data
Safety and Monitoring Committees
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Single IRB review
Lack of experience reviewing/monitoring
ePCTs
Major Issues
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• NIH policy on sIRB review, effective January 25, 2018• Revised Common Rule requires U.S.-based
institutions engaged in cooperative research to use a single IRB for regulatory review
• The sites involved in research that uses a single IRB need to• Sign a reliance agreement, which outlines who is
responsible for what (usually for each protocol)• Develop systems for fulfilling institutional
responsibilities• Develop mechanisms for reporting relevant
institutional information to reviewing IRB
Single IRB review
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• University of Washington IRB does not have capacity for “centralization”
• Western IRB (WIRB) serves as the centralized IRB
• No single administrative contact• Only 4 sites “cede” to centralized WIRB
review• 20 individual site IRB submissions (out
of 24 sites)
TSOS “single” IRB experience
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Lack of experience reviewing/monitoring
ePCTs
Single IRB review
Major Issues
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Budget sufficient time for initial and continuing education/negotiation
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Group of experts that reviews the ongoing conduct of a clinical trial to ensure continuing patient safety as well as the validity and scientific merit of the trial
Data monitoring committee
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• Poor adherence to intervention: problem or finding?
• Inference about adverse events• Availability of clinical data to assess
relatedness• Should AEs still be monitored?
• Limited/delayed access to study outcomes during study conduct
• Are interim analyses actionable?
Unique considerations for monitoring ePCTs
Adapted from Greg Simon, MD, Collaboratory Grand Rounds, December 8, 2017
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A plea5
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Ethics/morality
Empirical researchRegulations
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Describe current practices and beliefs
Test assumptions of an ethical argument
Measure potential impact of different regulatory policies
Collect data to contribute to the learning!
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Important things to know
• Ethical analysis for ePCTs is a work in progress
• Federal and local policies regarding the oversight of ePCTs are in flux
• There is often confusion and misunderstanding about ePCTs on part of patients, providers, IRBs, and DSMBs
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• Designate someone to track local and federal regulatory developments and serve as liaison with regulatory/oversight bodies
• Budget sufficient time for proactive education and negotiations with relevant regulatory/oversight bodies
• Identify all parties who might be affected by the study and its findings; consider protections
• Look for opportunities to contribute to evolving empirical data on different approaches
Important things to do