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From Personalized Medicine to Personalized Research
Michelle N. Meyer, J.D., Ph.D.Academic Fellow, Harvard Law School
http://www.law.harvard.edu/programs/petrie-flom/fellowship/meyer.htmlPapers available at: http://ssrn.com/author=1338101
Medicine“Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”
— Sir William Osler, “On the Educational Value of the Medical Society” Yale Medical Journal, Vol. IX, No. 10 (April 1903), p. 325
Philosophy “There is no reason that all human existence should be construed on some one or some small number of patterns. . . . The same things which are helps to one person towards the cultivation of his higher nature are hindrances to another. The same mode of life is a healthy excitement to one, . . . while to another it is a distracting burden . . . . Such are the differences among human beings in their sources of pleasure, their susceptibilities of pain, and the operation on them of different physical and moral agencies, that unless there is a corresponding diversity in their modes of life, they neither obtain their fair share of happiness, nor grow up to the mental, moral, and aesthetic stature of which their nature is capable.””
— John Stuart Mill, On Liberty (1869)
Economics[S]cientific knowledge is not the sum of all knowledge. . . . [T]here is [also] . . . the knowledge of the particular circumstances of time and place. It is with respect to this that practically every individual has some advantage over all others in that he possesses unique information of which beneficial use might be made, but of which use can be made only if the decisions depending on it are left to him or are made with his active cooperation.”
— Friederich Hayek, “The Use of Knowledge in Society,” Am. Econ. Rev. (1945)
The Heterogeneity Problem
• Factual claim: People are different• Genes, environment, preferences/values
• Normative claim: If possible, try to treat individuals/allow them to live in ways that reflect differences
• Pragmatic insights: • Information necessary to maximize welfare dispersed
• Requires shared decision-making
• Problem: How to do this?
Evidence-Based Medicine Personalized Medicine
• People vary in their response to interventions (incl. drugs)
• Thus: Same intervention will have different risk-benefit profile for different patients
• Yet: Most interventions rely on data derived from RCTs and large observational studies, applied to “statistically average” patient
• Personalized medicine aspires to more granularity:
NOT: “Does this drug work or not?” BUT: “Will this drug have an effect for this person?” AND: “How do we decide if this drug is right for this person?”
(D. Roden, Chancellor’s Lecture 2012)
Heterogeneity Problem in Research?
8
Research: Vital Link in the Innovation Chain
Incentives to innovate
Information dissemination
Bridging the Efficacy-Effectiveness Gap: “More Research Is Needed”
• Meyer, “From Evidence-Based Medicine to Evidence-Based Practice,” 43 Hastings Center Rep. (March–Apr. 2013)
• Meyer, “Legal Experimentation: Legal and Ethical Challenges to Evidence-Based Practice in Law, Medicine and Policymaking” (workshop/book prospectus)
Research: Vital Link in the Innovation Chain
Incentives to innovate
Information dissemination
“The risk/benefit assessment is not a technical one valid under all circumstances; rather, it is a judgment that often depends upon prevailing community standards and subjective determinations of risk and benefit. Consequently, different IRBs may arrive at different assessments of a particular risk/benefit ratio.”
— OPRR, IRB Guidebook (1993)
Research
“[T]olerance for discomfort and inconvenience may vary considerably, causing what may be perceived as ordinary discomfort or inconvenience by some subjects to escalate to significant harm for others. Examples include a bronchoscopy or bone marrow biopsy, which may be experienced as unpleasant by some subjects and as severe discomfort by others, or a sleep study that reverses day and night, which upon completion may require no readjustment by some subjects and a psychologically difficult readjustment by others.”
— N.Y. St. Dep’t of Health Workgroup on IRB Guidelines, Safeguarding Healthy Research Subjects: Protecting Volunteers From Harm (1999)
Heterogeneity in Risk
Athlete/manual laborer vs. desk jockey
Greatest Generation vs. Facebook Generation
Varying ability to absorb financial loss
Varying career vulnerability
Wide range of tolerance
Varying resilience
Heterogeneity in Expected Benefits
• Altruism (“warm glow utility”)• Other intangibles: curiosity satisfaction, entertainment,
human interaction• Payment, compensation in-kind• Clinical benefit
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Benefits: “A valued or desired outcome; an advantage.”
— OPRR, IRB Guidebook (1993)
Heterogeneity in Risk-Benefit Reasonableness
• Preferences for risk-taking• Preferences for fairness/altruism/exploitation
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The research subject is “in essence, a volunteer.”
— Belmont Report (1978)
April 15, 202316
IRB Risk-(Expected) Benefit Analysis
Reasonableness
45 CFR § 46.111(a)(2)
Example
Trauma research and the risk of revictimization
17
Information Problem
04/15/2318
Aggregation Problem
04/15/2319
Units of expected harm
The Costs of Ignoring the Heterogeneity Problem
• Ought can; moral distress (Kant)
• Research freedom
• Flouting the law (J. Nadler, Northwestern Law)
• Reduced knowledge production (how much?)
• Denial of opportunities to participate in research that would be potentially welfare-enhancing for (some) participants
20
Asking the Right QuestionsPersonalized Medicine
NOT: “Does this drug work or not?” BUT: “Will this drug have an effect for this person?” AND: “How do we decide if this drug is right for this person?”
(D. Roden, Chancellor’s Lecture 2012)
Personalized Research?
NOT: “Are risks to participants reasonable in relation to anticipated benefits, if any, to participants, and the importance of the knowledge that may reasonably be expected to result?” 45 C.F.R. § 46.111(a)(2)
BUT: “Are risks to this participant reasonable in relation to anticipated benefits, if any, to this participant, and the importance of the knowledge that may reasonably be expected to result?”AND: “How do we decide if…?”
Option 1: Bring Individualized Information to
Agencies & IRBs
Meyer, “Three Challenges for Risk-Based (Research) Regulation: Heterogeneity among Regulated Activities, Regulator Bias, and
Stakeholder Heterogeneity”
in THE FUTURE OF HUMAN SUBJECTS RESEARCH REGULATION (I. Glenn Cohen & Holly Fernandez Lynch, eds., MIT Press forth. 2014)
04/15/2322
“Evidence-based” Risk-Benefit Analysis?The idea (e.g., ANPRM July 2011; MacDonald et al. (forth. MIT 2014))
• Collect participant outcomes data
• Feedback loops at IRB (evidence-based RBA) and agency (risk-based regulation) levels
But:
• Crudely addresses information problem
• Ignores aggregation problem
Could make risk-benefit tradeoffs that reflect “average” participant, but:
• Sacrifices welfare of outliers
• IRBs may undershoot “average” protections due to “double risk aversion” (Atanasov 2010)
“Evidence-based” Risk-Benefit Analysis?
04/15/2324
Units of expected harm
Risk-benefit reasonableness
Option 2: Personalized Research?
Meyer, “Research Contracts: Towards a Paternalistic Market in Research Risks and Benefits” (in progress)
Example
Trauma research and the risk of revictimization
26
Thought ExperimentAltering IRB risk-benefit analysis
Prevent IRBs from blocking, altering, delaying HSR based on finding of risk-benefit “unreasonableness”
Make IRB finding of risk-benefit unreasonableness non-binding on researchers (and participants!)
Exclusions:
Incompetent participants
Deceptive research
Negative externalities (e.g., xenotransplantation research)
Normative justification
Participant welfare
Respect for participant autonomy
Thought Experiment
Retain:
Informed consent & IRB review of information disclosures
Risk minimization
Inalienable right to withdraw
Ban on exculpatory clauses
Worries
Information and rationality failures
PGP model: exploit individual differences in comprehension by conditioning participation on entrance exam
Thank you!
04/15/2329