1. The role of IRBs in Ethical Interventional Stem Cell Research 6 th Annual Columbia University IRB Conference Boston, MA Patrick Taylor Children’s Hospital Boston, Harvard Medical School, Petrie-Flom Center, Harvard Law School

2. Agenda Describe some problems you won’t have. Describe some problems you still will have in different form, but with special resources to manage them. Describe some new ideas to help manage risks.

3. What will we see? We fear Pseudoscientific stem cell human research protocols presenting great risks, unknowably larger than the known risks of cancer, and uncertain benefit; Desperate patients for whom the voluntariness of consent is questionable, yet also presenting an extremely strong sort of claim for respect for autonomous choices Nondeterminative, or no, preclinical data And little regulatory guidance With industry trial issues and regulatory judgments confidential and inaccessible to others.

4. But actually the area has been preparing: Ethics – Generally recognized ethical separation between donation/derivation and uses of derived lines for research purposes. disputed ethical issues are outside IRB review is – Consensus standards on most ethical issues involving the original donation, informed consent, and provenance – the criteria for IRB acceptance and reliance including the elements of informed consent (literature, NIH, ISSCR and NAS). – Registries and stem cell distributional banks using those ethical criteria to collect, and making data and certifications available to investigators and IRBs. – Ethical standards for use of animals and chimeras useful in translational context.

5. Scientific path; regulatory + ethical integration – Connecting the dots scientifically from pluripotency to differentiation to controlled applications of derivatives – Direct attention to genes and factors affecting cancer risks and uncontrolled development – Development of pluripotent alternatives w select oncogene deletions for iPS cells – Agreement on certain elements of “production” pathway: FDA tissue regulatory framework – Scientific agreement on strict, transparent, data-based and controlled translational and clinical pathway.

6. Mechanisms for standards generation NAS: standards thru scientific experts; ESCROs with specialized representation and authority ISSCR: global scientific and ethical discussion; public comment; general uniformity with some local differences in substance and process; model consents and MTA International and national stem cell registries and banks Local specialized academic institutional review committees Education, policy-sharing and development through PRIM&R and others

7. Effects of preparation Translational path: standards for peer and scientific review – institutions, funders and regulators Scientifically well-characterized materials with substantiated ethics histories Regulatory path with ISSCR standards and basic FDA tissue framework provides a basis for addressing certain major risks Unique preclinical and translational tools provide unusual opportunities for testing risks, control mechanisms, etc. Eventually, substantial literature on factors affecting some risks Growing literature on mechanisms of action Specialized pre-review to work with standards Model consents + MTA with substantial literature behind them

8. Challenges: Donor Consent Unusual ethical demands on an IVF system typically governed by nonresearch standards Research purpose specificity, vs unusual or unanticipated uses vs waivers re unanticipated uses – does the net result harm autonomy more? Protection of donor privacy vs privacy intrusion arising from rigorous examination of pt information and donated materials (infectious diseases, genetic information. Protecting privacy vs retaining donor traceability: donor history, follow-up on newly identified genetic traits pertinent to clinical uses.

9. Challenges re participants in treatment trials Therapeutic misconception, situational need and vulnerability Acceptance of unknown and unknowable risks, re form of risk, severity and probability, life implications, physicians and Medicine’s lack of knowledge about course of adverse events, treatability and care costs Burdens and compliance w long term monitoring Justice issues, particularly re research access and therapeutic access

10. Challenges: safety, risk and benefit Variability in cell lines – sources, maintenance and behavior– and unknown participant variation. Persistence, potential variation in expression over time, and long-term safety and effectiveness Genetic modifications Complexity of development factors affecting gene expression Xeno issues

11. Tools Standard: adherence to specified incremental pathway specially abundant in preclinical data and literature on mechanism of action, generally and re the proposed study Standard: Well-established and characterized therapeutic materials, biologically and in terms of donor consent and legal use restrictions. Prior review is both scientific and ethical, without binding IRB. Model consents For hospital-based studies, link safety/QI/M&M systems to detecting Adv Events (patterns and individually) and unanticipated risks, and resourcing help Problem-sharing conferences: PRIM&R, AAHRPP

12. THANK YOU!