Stem Cell Research: Sources of Regulation

1. Stem Cell Research: Sources of Regulation/Guidance&CIRM Site Visits

2. Sources of Regulation/Guidance on hESC Research Federal Presidential policy Agency guidance, regulations Laws Scientific community self-regulation (guidance, best practices) National Research Council/IOM Guidelines International Society of Stem Cell Research Guidelines State Policies, Laws, Regulations

3. Federal hESC Funding Policyhttp://stemcells.nih.gov/policy/ On August 9, 2001: President George W. Bush announced that federal funds may not be used for research using human embryonic stem cells unless: The stem cells were derived from an embryo that was created for reproductive purposes and was no longer needed; Informed consent was obtained for the donation of the embryo, and the donation did not involve financial remuneration; and The process of derivation was begun prior to 9 p.m. EDT on August 9, 2001.

4. NIH Registryhttp://stemcells.nih.gov/research/registry/ All hESC lines that meet the criteria of the August 9, 2001 Presidential policy are listed in an NIH Pluripotent Stem Cell Registry. Federal funds may be used (only) for hESC research using registered lines Federal funds may not be used directly or indirectly for hESC research using non-registered lines (or their derivatives).

5. Change is on the horizon�

6. Legislative Restriction re: Use of HHS Funding (The �Dickey Amendment�) Congressional rider attached to HHS Appropriations bill every year since FY 1996. Prohibits use of HHS funds for research in which human embryo is created or destroyed for research purposes Effect: Bans federal funds from being used to derive new hESC lines through Somatic Cell Nuclear Transfer (SCNT), because that method involves embryo destruction. Significance: Even if the August 9, 2001 Presidential policy changes, certain hESC research (e.g., SCNT derivation) will remain ineligible for federal funding if Dickey amendment is renewed.

7. Compliance with Federal Funding Restriction Restriction applies to both DIRECT and INDIRECT use of federal funds to support non-registered hESC research. Includes: Use of facilities, equipment, supplies Personnel salaries, fellowships Travel to conferences NIH Stem Cell Information Website: FAQs http://stemcells.nih.gov/info/faqs.asp. Guidance on complying with federal rules regarding stem cell research. Includes information on compliance with the federal funding restrictions, research and policy questions; cell line availability and the NIH registry. Basic Guidance: Grantees can comply by strictly adhering to the cost accounting rules set out in OMB Circular A-21 (http://www.whitehouse.gov/omb/circulars/a021/a21_2004.html), which will prevent shifting unallowable stem cell research costs to federally sponsored programs. ? In general, do not use resources acquired or subsidized by federal funds to conduct non-registry hESC research

8. Compliance with Federal Funding Restriction In designing compliance strategies, some may choose to go beyond what is strictly required. e.g., Federal rules do not require physical segregation of non-registry hESC Research (but establishing boundaries may ease compliance) hESC research may be subject to heightened political/public scrutiny Strict compliance with cost accounting principles in environment of heightened scrutiny can be tricky NIH Guidance leaves some issues open to interpretation CAVEATS:

9. Applicability of other Federal Rules Human Subject Regulations Stem Cells are NOT �human subjects� under the Common Rule (45 CFR 46, Subpart A). Federal regulations do NOT require IRB review unless the research involves interaction with or identifiable information about living human subjects. However, some institutions choose to have their IRBs serve stem cell research oversight function.

10. Applicability of other Federal Rules FDA Regulations No stem-cell-specific stem cell FDA regulations yet. But researchers should be aware of existing rules that may apply to research leading to clinical applications in humans. FDA rules re: �xenotransplantation� (42 USC 262) apply to any procedure that involves implantation into a human recipient of cells that have had ex vivo contact with live nonhuman animal cells. This is an issue for researchers using any of the hESC lines on the NIH registry, as they were all developed using mouse �feeder� cells. Stem-cell-based products may fall into an FDA-regulated category: biologics; drugs; devices; xenotransplantation products; cellular- and tissue-based products, and may be subject to Public Health Safety Act or other requirements.

11. Scientific Community GuidanceNational Research Council/Institute of Medicine Guidelines for hESC Research Voluntary guidelines that make recommendations about a number of issues related to conduct and institutional oversight of hESC research. Although not binding, a number of researchers and institutions have used them as a source of guidance in adopting local practices, policies, procedures in this emerging area. Original Guidelines, issued 2005: http://books.nap.edu/catalog.php?record_id=11278 Amendments, issued 2007, 2008 http://books.nap.edu/catalog.php?record_id=11871 http://books.nap.edu/catalog.php?record_id=12260

12. Scientific Community GuidanceInternational Society of Stem Cell Research Guidelines for hESC Research (12/21/06) http://www.isscr.org/guidelines/index.htm Voluntary guidelines developed by an international task force of experts in science and medicine, ethics, and law from 14 countries. Intended to facilitate international collaboration by encouraging investigators and institutions to adhere to uniform set of research practices. Includes recommendations regarding conduct and institutional oversight of hESC research; facilitation of international collaborations; recommended levels of review for different types of research; procurement of materials and procedures for ensuring donor protections; principles for derivations, banking and distribution of new lines; dispute resolution

13. State-Specific Policy, Law, Guidance Sources of state law/guidance include: State Constitution � Article XXXV (Medical Research) http://www.leginfo.ca.gov/cgi-bin/waisgate?waisdocid=76297528920+0+0+0&waisaction=retrieve State Statutes (various sections of Health & Safety Code) CA Department of Public Health Guidelines on Stem Cell Research (developed pursuant to CA H&S Code �125118) http://www.cdph.ca.gov/services/boards/HSCR/Documents/MO-HSCRGuidelines-10-2008.pdf California Institute for Regenerative Medicine policies, regulations, and guidance documents http://www.cirm.ca.gov/reg/default.asp http://www.cirm.ca.gov/workgroups/stds.asp

14. Proposition 71approved by voters in 2004 Established California Institute for Regenerative Medicine; $3B in bond funding over ten years for hESC and other stem cell research. Established Constitutional right (Article XXXV) to conduct stem cell research (including SCNT). Enacted state statutes (H&S Code �125290.10 et seq.) implementing Prop 71. Under Prop 71, CIRM-funded research is governed by specific rules and regulations enacted by CIRM (i.e., most other state laws do not apply). �125290.35(a). Efforts have been made to harmonize CIRM rules and other state rules regarding stem cell research; nonetheless, you must know where funding comes from to determine which rules apply.

15. State Statutory Requirements(Non-CIRM) Requirements relating to Institutional Review/Oversight hESC Research: All research involving derivation or use of hESCs must be reviewed and approved by an institutional stem cell research oversight (SCRO) committee. H&S Code � 125119 Adult Stem Cell Research: SCRO committee review (not approval) required for research involving derivation and use of human adult stem cells. H&S Code �125300. SCRO committees must perform annual reviews of approved hESC projects and report certain information annually (as well as unanticipated problems or serious PI noncompliance) to the State Department of Public Health. H&S Code �125118 et seq.

16. State Requirements Requirements relating to Donors/Subjects Donors of embryos remaining after fertility treatment: Health care providers must provide specific info as part of informed consent for donating embryos for research. H&S Code �125315. (Applies to CIRM and non-CIRM funded research). Donors of Oocytes for Research: Special informed consent provisions apply. Restrictions on payments made to oocyte donors (to avoid inducement), Requirement that donors be provided (at no cost to them) with medical care required as a result of the research donation Prohibition on stem cell researchers or their families, employees or key personnel from serving as oocyte donors for the research. H&S Code �125330 et seq. DPHS Informed Consent Checklist is available at: http://www.cdph.ca.gov/services/boards/HSCR/Documents/MO-InfConsent-05-2008.pdf

17. State Requirements(Non-CIRM) Requirements Relating to Donors/Subjects (cont.) Documentation/Reporting: Institutions must keep written records containing info on every oocyte donated or used, demographics of egg donors, and adverse health outcomes, and must report to DPHS. H&S Code �125342. CDPH hESC and Oocyte Reporting requirements not applicable to research FULLY funded by CIRM. Other Related Statutes: Prohibition on sale of human embryos, oocytes, or embryonic or cadaveric fetal tissue for research. CA H&S Code ��125320; 125350. Prohibition on Human Cloning: No human reproductive cloning, and no attempting to create a human through SCNT for purpose of implanting to initiate pregnancy. CA H&S Code �24185.

18. CDPH Guidelines for Human Stem Cell Research  Apply only to non-CIRM funded hESC derivation or use research; Define certain types of research not permitted in CA (e.g., introduction of hESCs into nonhuman primate embryos); Set out review and reporting requirements for SCRO committees; Require that stem cell materials used for research be �acceptably derived� (and set out informed consent and other requirements that must be met to satisfy this standard); Set out standards for oocyte donation for research; Set out provisions related to clinical trials; Require institutions to keep records on every gamete, somatic cell, embryo, or SCNT product donated, created or used in SC research. DPH reporting forms can be found at: http://www.cdph.ca.gov/programs/HSCR/Pages/HumanStemCellResearchReportingForms.aspx

19. Rules Applicable to CIRM-funded research Rules re: ethical oversight, review, protections SCRO review and approval required for work involving procurement or use of oocytes; use of human embryos; derivation of covered stem cell lines; introducing covered SCs into animals or humans; introducing neural progenitor cells into animals Purely in vitro work using covered SC lines requires SCRO notification only. Enhanced informed consent (limits acceptable cell lines). Prohibition on human reproductive cloning Special rules re fetal tissue donation and oocyte retrieval. Prohibition on sale of embryos, oocytes, fetal tissue Time limits for obtaining cells from embryos

20. Rules Applicable to CIRM-funded research Rules re: ethical oversight, review, protections (cont). AAALAC Accreditation: Sites where CIRM-funded animal research is conducted must be accredited by or seeking accreditation; Restriction on payment to donors of gametes, embryos, somatic cells or tissue used for SC derivation. 2009: CIRM considering change to allow use of excess embryos created during IVF, even if gamete donors received payment Induced Pluripotent SC research: Currently, CIRM requires SCRO approval of iPS work using human somatic cells (i.e., not gametes). In 2009, CIRM is considering a change to require SCRO notification only.

21. Rules Applicable to CIRM-funded research Special IP provisions: Revenue sharing (25% of net revenues over $500k) Limit on granting exclusive licenses In case of drugs developed, requirement for plan for providing access to uninsured Californians. Invention and licensing reporting requirements Requirement to report publications, submit abstract w/i 60 days of publication Grant Administration Policy: Includes preference for California suppliers

22. CIRM Site Visits: Reviewing Grantee Compliance CIRM plans to visit most major grantee institutions Visits review the grantee�s program for ensuring effective compliance with applicable rules and the grantee�s documentation of their review/oversight process. Visited 4 UC campuses so far (UCSF, UCSD, UCI, UCLA) What to expect: 2-3 weeks advance notification Request to meet with officials involved in administration and oversight of research (including SCRO officials), and with PIs; Selection of 3 or more grants for in-depth review; Request for SCRO committee documentation � agendas, minutes, summaries, correspondence supporting review/approval, documenting compliance, communicating with PIs

23. CIRM Site Visits: What to do in advance Ensure that you have sound policies and procedures in place to ensure compliance with CIRM review and oversight requirements and with CIRM grant administration policy. Ensure that your policies and procedures are well- documented, and that your administrators and PIs are well-versed in them. Ensure that you have documentation that shows careful SCRO review/consideration of relevant issues and appropriate follow-up (particularly w/respect to the specific grants being reviewed). Ensure that your PIs know about CIRM policy requirements governing invention and publication disclosure; Be able to answer questions about financial record-keeping (e.g., accounting records showing payment of stipends).

24. Questions?