3. Oocyte Procurement Risks Ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome Ovarian torsion Ovarian torsion Hospitalization (1% or more) Hospitalization (1% or more) Renal failure Renal failure Infertility Infertility Death Death

4. Donation of excess IVF oocytes, embryos- How are risks covered Clinical consent for procedure to procure oocytes Clinical consent for procedure to procure oocytes Research consent (plus NAS issues) for use of biological material Research consent (plus NAS issues) for use of biological material Research consent for clinical trials using material Research consent for clinical trials using material

5. Non-medical oocyte donors If untraceable to researchers, they are investigators but may not be doing human subjects research If untraceable to researchers, they are investigators but may not be doing human subjects research Physician who procures oocytes is not an investigator, but may be doing human subjects research Physician who procures oocytes is not an investigator, but may be doing human subjects research Physician who prescribes meds and monitors donor is neither an investigator, nor doing human subjects research--what is relationship to donor? Physician who prescribes meds and monitors donor is neither an investigator, nor doing human subjects research--what is relationship to donor? Problem--what is the donors status? Problem--what is the donors status?

6. Non-medical oocyte donation Clinical consent? Clinical consent? Donor is not a pt Donor is not a pt Risk but no benefit to donor Risk but no benefit to donor Research consent? Focus on bio material Risk not associated with the “research” aspect, but with procurement Fails to capture relationship between procurer and procuree

7. New Category--Research Donors Distinct from research subjects Distinct from research subjects Distinct from other kinds of donors of biological material (genetic, sperm) where risks of procurement are minimal Distinct from other kinds of donors of biological material (genetic, sperm) where risks of procurement are minimal

8. Analogy with live organ donation Problems with conceptualizing as pt. Problems with conceptualizing as pt. Risks to donor but no benefit Risks to donor but no benefit Result: Result: Close scrutiny of motives of donors Close scrutiny of motives of donors Psychological screening Psychological screening Serious weighing of benefits of donation versus risk Serious weighing of benefits of donation versus risk

9. Ethical Issues in Stem Cell Clinical Trials

10. How soon? Geron has publicly stated they will soon seek an IND for clinical trials to treat accute spinal chord injury Geron has publicly stated they will soon seek an IND for clinical trials to treat accute spinal chord injury Derived both oligodendrocytes and dopaminergic neurons from hESCs and are testing in mouse models and rats Derived both oligodendrocytes and dopaminergic neurons from hESCs and are testing in mouse models and rats

11. When is an hESC intervention ready for human clinical trial? Safety Safety What kind of animal models? Will primate data be necessary? What kind of animal models? Will primate data be necessary? How successful are attempts to purify cell lines? How successful are attempts to purify cell lines? Efficacy Efficacy How good are the model organisms? How good are the model organisms? Is there evidence of clinical effect on model organisms or surrogate endpoints? Is there evidence of clinical effect on model organisms or surrogate endpoints?

12. Protecting subjects at the frontier Siegler; Wiggins, et. al. Sound scientific basis for trial Sound scientific basis for trial Field strength Field strength Skill and experience of team doing trial, including all relevant sciences, biostatistics, relevant clinical and surgical expertise and psychological support Skill and experience of team doing trial, including all relevant sciences, biostatistics, relevant clinical and surgical expertise and psychological support Strong ethical climate of institution (including adequate oversight, monitoring) Strong ethical climate of institution (including adequate oversight, monitoring) Public discourse and disclosure prior to proceeding Public discourse and disclosure prior to proceeding

13. Informed Consent Right to knowledge of source Right to knowledge of source Therapeutic misconception Therapeutic misconception

14. Source of cells Many oppose hESC research and would oppose participating in research that is derived in such a way as to require destruction of something that they regard as a moral being Many oppose hESC research and would oppose participating in research that is derived in such a way as to require destruction of something that they regard as a moral being Analogous to justification of consent for gamete donors Analogous to justification of consent for gamete donors To date, neither NAS, ISSCR guidelines, nor CIRM regulations require such consent To date, neither NAS, ISSCR guidelines, nor CIRM regulations require such consent

15. Informed Consent in Gene Transfer Research Desperate pts may hear what they want to hear Desperate pts may hear what they want to hear Do researchers and consent forms reinforce misconception? Do researchers and consent forms reinforce misconception? Language matters Language matters Gene transfer research vs gene therapy Gene transfer research vs gene therapy Cf. Innovative therapy vs Non-validated practice Cf. Innovative therapy vs Non-validated practice

16. Kimmelman and Lenenstadt (2005) Study of 286 Phase I HGT protocols Study of 286 Phase I HGT protocols 50% described as gene therapy 50% described as gene therapy 23% as gene transfer 23% as gene transfer 14% stated benefit unlikely in intro section 14% stated benefit unlikely in intro section 28% in benefits section 28% in benefits section Only 41% provided comfort care as alternative tx option Only 41% provided comfort care as alternative tx option

17. King, et al (2005) Survey of 321 HGT consent forms--mostly Phase I Survey of 321 HGT consent forms--mostly Phase I Only 14% stated that direct benefit to subjects unlikely (20% of the Phase I forms) Only 14% stated that direct benefit to subjects unlikely (20% of the Phase I forms) “treat” or “treatment” 39% of forms “treat” or “treatment” 39% of forms “patients” rather than “subjects” 49% of forms “patients” rather than “subjects” 49% of forms

18. Example language Kimmelman and Lennestadt (2005) “In this study, a team of physicians, and scientists will treat your [disease] by delivery of a pair of genes to your [organ].” “In this study, a team of physicians, and scientists will treat your [disease] by delivery of a pair of genes to your [organ].” “We would like you to be in a research study of a treatment designed to make your immune system fight the cancer.” “We would like you to be in a research study of a treatment designed to make your immune system fight the cancer.” “This study is designed to treat cancer patients with…” “This study is designed to treat cancer patients with…”

19. Example Language King, et al (2005) “Gene therapy works by using a virus vector to carry the new gene into the patient’s cells. Once there, the new gene makes the protein that patients like you lack. The investigators hope that gene therapy will be an effective treatment for your disease.” “Gene therapy works by using a virus vector to carry the new gene into the patient’s cells. Once there, the new gene makes the protein that patients like you lack. The investigators hope that gene therapy will be an effective treatment for your disease.”

20. Example Language King et. al. “The hope is that we can improve your symptoms and prolong your life with this treatment…The purpose of this study is to determine whether this procedure is safe and to evaluate the effect of this treatment on your disease.” from Purpose “The hope is that we can improve your symptoms and prolong your life with this treatment…The purpose of this study is to determine whether this procedure is safe and to evaluate the effect of this treatment on your disease.” from Purpose From Benefits section: “It is not possible to predict whether or not any personal benefit will result.” From Benefits section: “It is not possible to predict whether or not any personal benefit will result.”

21. Lessons for hESC trials Care must be taken to avoid therapeutic misconception Care must be taken to avoid therapeutic misconception Subjects must have a clear understanding of the nature of the research and how preliminary it is--particularly for first hESC trials and for very early Phase I subjects (non- therapeutic doses) Subjects must have a clear understanding of the nature of the research and how preliminary it is--particularly for first hESC trials and for very early Phase I subjects (non- therapeutic doses) Language matters--no such thing as therapeutic cloning Language matters--no such thing as therapeutic cloning

22. Justice Research populations should be diverse to address health needs of under- represented groups (including women, children) Research populations should be diverse to address health needs of under- represented groups (including women, children) May be a challenge if cells largely derived from excess IVF clinics May be a challenge if cells largely derived from excess IVF clinics

23. New proposed guidelines on clinical trials from CDHS SCRO review of all protocols SCRO review of all protocols Scientific rationale Scientific rationale Adequate Institutional Field Strength Adequate Institutional Field Strength Sufficient knowledge of risks and benefits Sufficient knowledge of risks and benefits Risks minimized and reasonable in relation to benefits Risks minimized and reasonable in relation to benefits Address diversity of research population Address diversity of research population IRB requirements IRB requirements Informed consent on source of therapy Informed consent on source of therapy No unrealistic impression of benefit in consent No unrealistic impression of benefit in consent DSMB DSMB Address any potential germ line modification issues Address any potential germ line modification issues