1. CRISPR and Regulatory Oversight - through the lens of the IRB - P. Pearl O’Rourke, MD Partners HealthCare Boston, MA

2. Context: Institutional Review Board (IRB) Charged with the oversight of human subjects research – Common Rule, definition of human subject : A living individual about whom an investigator conducting research obtains: –Data through intervention or interaction with the individual, or –Identifiable information IRB processes and decisions consider: – Laws: Common Rule, FDA Regs, HIPAA, state laws – Case law – Condition of funding – The Boston Globe/Washington Post/NYT

3. IRB Involvement in: CRISPR Basic Research Access to tissue from a human subject* – If tissue obtained specifically for research or tissue is identifiable – Is there a reason to exceptionalize this research? Access to embryos – While not by definition a human subject, IRBs may be involved and must consider: Identifiability of embryo ‘donors’ Type of research use; e.g. hESC research – Funding limitations must be considered Funding prohibitions (E.g., Dickey-Wicker) vs legal prohibitions * Note potential change proposed in NPRM for Common Rule

4. IRB Involvement in: CRISPR Clinical research in human subjects ‘Routine’ IRB review of risk and benefit Specific questions/concerns: – What is the experimental design? How is success defined? Long-term follow-up: what is expected of participants? – Adequacy of evidence – esp. with innovative approach Risk of off-target effects Long-term risk and potential benefit – Who are potential participants? Children versus adults – Must consider when children achieve age of majority Desperate patients/desperate parents – Rare diseases – Limited or no other options

5. IRB Involvement in: CRISPR Clinical research in human subjects Specific questions/concerns: – Blurred research-clinical care interface Realistic expectations? Who pays for long-term follow-up? – Manufacturing standards Determined how and by whom? – A complex informed consent form and process

6. IRB Involvement in: CRISPR Clinical application in embryos No existing ‘routine’ approach Who is the subject? – ‘Parents’ of the embryo? – What happens at birth? What happens at age of majority? – What of progeny? The gestational mother: – Any specific research intervention/follow-up? – Any additional risk?

7. Can existing experience/s be helpful? Forum for national dialogue and review – Recombinant DNA Advisory Committee – NAS Guidelines for hESC research Collaborate with oversight agencies re: – Research involving embryos The existing gap will encourage disharmonious approaches – ‘Exceptionalization’ of this research? Opportunity to re-evaluate oversight of emerging technologies – Lessons from ESCRO (Embryonic Stem Cell Research Oversight) Committees – a good model?

8. Can existing experience/s be helpful? Standardization: – Product/manufacturing – Follow-up Sharing of results – Collaboration between investigators is critical – Consider a formal registry

9. Remember… Oversight is determined by: – Laws There are gaps Heterogeneity of state and international law – Case law Evolving – Condition of funding Prohibitions based on funding source – not legality – Public opinion