Benjamin E. Berkman, JD, MPH Office of the Clinical Director, NHGRI

and Department of Bioethics, Clinical Center

National Institutes of Health

Blurring the Line between Research and Clinical Care in a Genomic Age

Disclaimer

• The following presentation does not reflect the official views of the NHGRI, NIH, or DHHS.

Advancing Sequencing Capacity Next-Gen Sequencing

En Route to Routine Whole-Genome Sequencing

Targeted Genetic Research

Whole ‘Exome’

Whole Genome

Now

Time

Then Soon!

The Future of Genomic Medicine

Green, et. al., Nature, 2011, “The Future is Bright”.

The Blurring Distinction between Research and Clinical Care • At least partially resulting from the gap between discovery of

therapeutic benefits and actual adoption into clinical practice • Particularly acute in the field of genomics

• Rare genetic disorders • “informed fishing trip” (Parker et al., BMJ, 2004)

• Cancer genetics • Investigators view “the relationship between research and clinical

care as flexible, permeable, and permanently shifting” (Hallowell et al., J. Med. Ethics, 2009)

Roadmap • Why do we care about the blurring distinction between research

and clinical care • The problem of too much data • Defining the scope of a researcher’s obligation to disclose findings • Three evolving issues

• Terminological Confusion • Duty to Look • Legal Liability

Why do we care about the line between research and clinical care? • Important distinctions between research and clinical care

• Goals • Methodologies • Justifications for exposure to risk • Role responsibilities

• Helps delineate which biomedical activities require additional oversight to protect human subjects

• Enables investigators and clinicians to demarcate extent of their responsibilities to participants/subjects

Problem of too much data • Genomic sequencing raises questions about how to manage

the massive amount of data that will be produced

• An obligation to disclose incidental or secondary findings to research subjects • Investigator responsibility to help subjects • Or unfair conflation of research and clinical care

Three evolving issues • Terminological confusion • Duty to look • Liability

Terminological confusion • What counts as an “incidental” or “secondary” finding?

• Threshold question for determining whether there is an obligation to disclose a given finding

• Four definitional features

• Relationship of finding to research aims and objectives • Relationship of finding to research methods • Relevance/importance of information to subject • Foreseeability of the finding

• Reject distinction between “primary” and “secondary” or “incidental” findings

• Research finding: “A new piece of information that relates to a particular

individual discovered by virtue of research procedures”

The 3V Framework

Duty to look • ACMG recommendations

• Explicitly clinical, but could influence debate in research setting • Assuming that there is some obligation to return incidental findings

that one stumbles upon, do investigators have a duty to look for incidental findings?

• Standard view: Don’t look, don’t tell: • “Researchers generally have no obligation to act as clinicians and

affirmatively search for IFs” (Wolf et al.) • Plausible to argue that a duty to disclose implies a duty to look

• High benefit • Strong need • Low burden

Duty to look

BENEFIT

NEED

BURDEN

Now Intermediate Future

time

Duty to look • Validated lists of clinically significant variants • Possible implications

• Blur goals of research and clinical care • Require creation of new (clinical) infrastructure in the research

realm • Changing motivations of participants

Legal liability for failure to disclose incidental findings ►There is a gap between:

• The emerging view that researchers have an ethical obligation to return at least some IFs,

• the reality that some, but not all, researchers choose to return Ifs

►There has been much concern about the potential for legal liability arising from inconsistent approaches to returning IFs • Without clear guidance researcher practice varies widely

• Remain silent • Return nothing • Return only in some circumstances • Exercise clinical judgment • Solicit participant preferences

• Often appeal to mushy terms like • Clinical significance/utility/relevance • Actionability

Liability? ►A researcher studying a specific infectious disease is using

genomic sequencing of affected participants in order to learn more about genetic susceptibility to the disease. One of these participants later contracts hereditary non-polyposis colorectal cancer, an aggressive kind of cancer that is not normally caught with standard colonoscopies. The research participant brings suit, arguing that had she known about her genetic risk for this cancer, she could have sought targeted screening that would have caught her cancer earlier, and could have led to a better prognosis. Her suit alleges that the researcher had access to her entire genome, and should have known that she possessed the relevant genetic variant. Her lawyer presents testimony from similarly situated researchers that had contemporaneous policies in place that would have resulted in discovery and disclosure of the genetic variant, arguing that the researcher violated the prevailing standard of care.

Ethics Driving Liability?

Tort law duties

Prevailing standard of care

Recognition of an ethical

obligation

Conclusion • Debate about return of genetic research findings is at least

partly due to the muddying of the line between research and clinical care

• Problematic because it has led to inconsistent practice and could threaten efficient conduct of genomic research

• But it isn’t necessary to maintain an absolute division between research and clinical care

• Deliberative rather than extemporaneous approach

Questions • Contact:

• berkmanbe@mail.nih.gov • Some further reading

• Berkman BE, Hull SC, Eckstein L. The Unintended Implication of Blurring the Line between Research and Clinical Care in a Genomic Age. Personalized Medicine, forthcoming (2014)

• Eckstein L, Garrett JR, Berkman BE. A Framework for Analyzing the Ethics of Disclosing Genetic Research Findings. Journal of Law, Medicine and Ethics, forthcoming (2014).

• Pike ER, Rothenberg K, Berkman BE. Finding Fault?: Exploring Legal Duties to Return Incidental Findings in Genomic Research. Georgetown Law Journal 102(3); 795-843 (2014).

• Gliwa C, Berkman BE. Do researchers have an obligation to actively look for genetic incidental findings? American Journal of Bioethics 13(2): 32-42 (2013).