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?

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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)

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IRB Risk-(Expected) Benefit Analysis

Reasonableness

45 CFR § 46.111(a)(2)

Example

Trauma research and the risk of revictimization

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Information Problem

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Aggregation Problem

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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

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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)

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“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?

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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

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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!

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