Since President Bush’s announcement of federal policy regarding embryonic stem cell research in 2001, the public debate has focused primarily on funding issues. As research money has increased, however, matters surrounding oversight have become just as important and policymakers have raised concerns about the ethical oversight of research—whether it is funded by the National Institutes of Health, state governments, or private entities.

At a recent congressional hearing, several Members of Congress articulated the view that more regulation is necessary. Rep. Diana DeGette (D-CO) announced that in addition to working to change funding rules, she was developing legislation to increase federal ethical oversight of stem cell research, possibly by creating a new oversight body within the National Institutes of Health that would be responsible for monitoring all stem cell research in the United States, regardless of the source of funding.^[1] In response, prominent researchers noted that stem cell research is already subject to significant oversight at institutions across the country.^[2]

Stem cell research—embryonic and adult—and the processes used to turn this research into therapies are already extensively regulated.

While academic research advances, companies are also making progress translating that research into therapies. Osiris Therapeutics of Columbia, MD and Aldagen of Durham, NC have demonstrated scientific successes using adult stem cell products, and Geron Corp. of Menlo Park, CA recently filed the first Investigational New Drug, or IND, application for an embryonic stem cell based product.^[3] In anticipation of future filings, the Food and Drug Administration’s Cellular, Tissue and Gene Therapies Advisory Committee recently held a public meeting to discuss the creation of standards for the approval of embryonic stem cell based products.

These developments have led to increased emphasis by research advocates on the issues surrounding regulatory oversight of such products. At the CTGTAC meeting, Amy Rick, President of the Coalition for the Advancement of Medical Research, an organization historically focused on changing NIH funding rules, spoke about the agency’s drug approval standards. She urged the FDA not to apply “an extra layer of risk averseness or safety requirements” on embryonic stem cell products simply because this technology has been controversial.^[4]

Thus, it is appropriate to review all the oversight mechanisms currently in place at each stage of the research and development process for stem cell based products. Similar to previous literature,^[5] we use the term “stem cell based products” to include the use of embryonic pluripotent or adult multipotent stem cells to create human tissues for transplantation into patients with medical conditions caused by the degeneration or injury of cells, tissues, and organs. Such replacement tissues derived from stem cell lines may or may not include undifferentiated stem cells in the final product. In some cases, multipotent cells might be transplanted, while in others all the cells will have already differentiated in culture prior to transplantation.^[6]

Stem cell research—embryonic and adult—and the processes used to turn this research into therapies are already extensively regulated. The FDA enforces long-standing regulations for preclinical development and clinical testing of cell-based products. The NIH applies oversight rules that govern research by grantees. Moreover, the National Academies provide research guidelines that have been widely adopted, and house a national stem cell research advisory committee. Legislation by individual state governments and review committees at research institutions also serve to prevent improper conduct.

In combination, these structures govern scientific, legal, and ethical considerations and appropriately balance patient protections with the need to promote product development. There is no evidence to suggest that this system is not working. Efforts to change or “strengthen” these rules, however well intentioned, should be carefully considered prior to adoption. Moreover, the regulations currently in place have governed many generations of previous biotech products, ensuring that patients with unmet medical needs have access to safe, effective treatments as fast as possible. Proponents of change have the burden of demonstrating why their proposed modifications are needed.

Food & Drug Administration

The Food and Drug Administration regulates all stem cell based products under the Tissue Action Plan, a set of rules designed to regulate human cells, tissues, and cellular and tissue-based products, or HCT/Ps. The FDA defines HCT/Ps as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” This includes, but is not limited to, “hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, and semen or other reproductive tissues.”^[7] The TAP regulations are intended to prevent the use of contaminated tissues and the improper handling and processing of materials and products, as well as to ensure clinical safety and effectiveness for highly processed tissue.^[8]

The TAP requires: registration of all HCT/P products by all establishments conducting HCT/P development, donor eligibility screening and testing, and the use of Current Good Tissue Practices, or cGTP. cGTP includes requirements relating to: facilities; environmental controls; equipment; supplies and reagents; processing and process controls; labeling controls; storage, receipt, pre-distribution shipment, and distribution of an HCT/P; donor eligibility determinations; and donor screening and testing.^[9] The FDA conducts inspections to determine compliance with these regulations through site visits. In response to violations, the FDA has the authority to issue orders for retention, recall, or destruction of HCT/Ps.^[10]

The FDA anticipates using a certain degree of flexibility, within regulations, for these new and innovative technologies, working early with sponsor companies to help with study and test design.

If a stem cell based product entails more than “minimal manipulation” or cells for other than “homologous use,” the FDA will also impose its regulations for biologics (or devices).^[11] It is expected that most stem cell products as currently envisioned will be regulated in this manner.^[12] Regulation of stem cell based products as biologics will be performed by the FDA’s Center for Biologics Evaluation and Research and its Office of Cellular, Tissue and Gene Therapies. Prior to obtaining permission for a Phase I safety study in humans, the sponsor of a clinical trial must provide “adequate information about the pharmacological and toxicological studies…on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required vary with the duration and nature of the proposed clinical investigations.”^[13] These studies need to demonstrate, using the best science available, the product’s safety and efficacy via proof of sterility, purity, potency, identity, and stability. Since it may be difficult to characterize the composition of a stem cell based product, having detailed knowledge of the source and manufacturing processes of the product is essential.^[14] Thus, as with other biologics, the FDA is likely to evaluate manufacturing processes used during production in addition to analyzing the product itself. Only once the FDA is satisfied that safety requirements are met will an Investigational New Drug be approved for human clinical trials.

Additionally, some human embryonic stem cell products will fit the definition of xenotransplantation as written in CBER guidance documents, and therefore will be regulated by the Xenotransplantation Action Plan.^[15] Some cell lines are established using nonhuman feeder cell layers (typically murine-based, meaning they are derived from mice or lab rats) or grown using nonhuman serum media that have the potential to contain nonhuman viruses and endogenous retroviruses and bacteria. As part of the safety and efficacy evaluations of these INDs, it must be demonstrated that the product is free from these potential infectious agents and will not pose a risk of transmission to recipients.

The FDA anticipates using a certain degree of flexibility, within regulations, for these new and innovative technologies, working early with sponsor companies to help with study and test design. Sponsor companies are not only invited to schedule the typical “pre-IND” meetings with the FDA, but are also encouraged to interact early during development, “pre-pre-IND,” to informally discuss progress with the agency.^[16] These additional interactions can increase the FDA’s knowledge and ability to regulate stem cell based product development.

As part of efforts to better understand scientific issues, the Cellular, Tissue and Gene Therapies Advisory Committee, housed within the Center for Biologics Evaluation and Research, held a meeting in April 2008 regarding cellular therapies derived from human embryonic stem cells. Attendees discussed the scientific considerations of preclinical safety testing that would be part of an IND application before testing is allowed in humans. The meeting focused on the issues of uncontrolled differentiation and tumorigenicity, and on whether sufficient science exists both to characterize cells being implanted and to monitor cell fate after infusion. In the past, other advisory committee proceedings have led to the development of guidance documents and product-class-specific standards for safety and efficacy.

National Institutes of Health

The NIH oversees stem cell research at institutions receiving NIH funding through the grant review process and through the activities of the Recombinant DNA Advisory Committee, known as the RAC. Currently, NIH grants for human embryonic stem cell research can only be obtained for research involving an approved cell line or lines that must be identified at the time of the grant application. Grants for adult stem cell research must also meet other NIH guidelines.^[17] By reviewing the scientific merit and ethical implications of research at the time of grant proposals, the NIH oversees research to prevent misconduct. The RAC reviews research if it involves “protocols that raise novel or particularly important scientific, safety, or ethical considerations.”^[18]

To ensure that federal funds support only embryonic stem cell research that is scientifically sound, legal, and ethical, NIH examines stem cell lines and maintains a registry of lines that satisfy the criteria established in NIH guidelines.^[19] NIH guidelines state that the agency will only fund research using embryonic stem cells if it meets the following conditions:^[20]

• Removal of cells from the embryo must have been initiated before August 9, 2001.
• The embryo from which the stem cell line was derived must no longer have had the possibility of developing further as a human being.
• The embryo must have been created for reproductive purposes but no longer be needed for them.
• Informed consent must have been obtained from the parent(s) for the donation of the embryo, with no financial inducements.

Institutions and companies that do not receive NIH funding are not required to follow any NIH guidelines, but NIH standards have become almost universally accepted as safe scientific practice. Additionally, peer-reviewed scientific journals may require compliance with these guidelines in order for a researcher to publish results.

National Academy of Sciences

The National Academies provide additional guidance for oversight of stem cell research. The Guidelines for Human Embryonic Stem Cell Research, first published in 2005 and updated in 2007, “offer[s] a common set of ethical standards for a field that, due to the absence of comprehensive federal funding, was lacking national standards for research.”^[21] The Guidelines are intended for use by the scientific community, including researchers in universities, industry, or other private-sector organizations. They cover all derivations of human embryonic stem, or hES, cell lines and all research using hES cells derived from (1) blastocysts made for reproductive purposes and later obtained for research from in vitro fertilization clinics, (2) blastocysts made specifically for research using IVF, and (3) somatic cell nuclear transfer. Many guidelines also apply to research with adult stem cells, fetal stem cells, or embryonic germ cells derived from fetal tissues. The Guidelines address: procurement of gametes, blastocysts or cells; derivation of cell lines; banking and distribution of cell lines; research use of cell lines; international collaboration; and recommended actions by the community to ensure the Guidelines are implemented.^[22]

The Guidelines made recommendations that led to the creation of a new system of oversight specifically for embryonic stem cell research. Under these recommendations, oversight of the research at an institution should be performed by an Embryonic Stem Cell Research Oversight, or ESCRO, committee.^[23] These committees should include members of the lay public as well as experts in scientific, legal, and ethical aspects of stem cell research. Committees are charged with:

1. Providing institutional oversight over all issues related to derivation and use of human embryonic stem cell lines
2. Reviewing and approving the scientific merit of research protocols
3. Reviewing compliance of all in-house hES cell research with all relevant regulations and these guidelines
4. Maintaining registries of hES cell research conducted at the institution and hES cell lines derived or imported by institutional investigators
5. Facilitating education of investigators involved in hES cell research.^[24]

While there are no comprehensive statistics yet published, it is generally believed that most institutions in the United States that are engaged in stem cell research have established ESCROs per the Guidelines.^[25] Additionally, some state and private funding for research requires review by an ESCRO.^[26]

To facilitate national discussions about stem cell research and to create periodic updates to the Guidelines, the National Academies created the Human Embryonic Stem Cell Research Advisory Committee in May 2006. The committee held its first meeting in July 2006 and has held four subsequent meetings, the last in February 2008.^[27] In addition to these meetings, the committee hosted a public symposium in November 2006 on “Emerging Issues in Human Embryonic Stem Cell Research” and several regional workshops in 2007 focused on implementation of the Guidelines.^[28] Discussions at these events led to the 2007 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research, which provided clarifications to the policies. As new issues arise and the science progresses, the committee may publish further amendments as necessary. The National Academies and the committee have also created a listserv to facilitate discussions among those involved in the oversight at institutions around the United States.^[29]

Local Institutional Committees

Committees at each institution where research takes place provide additional oversight. An institution’s ESCRO committee performs the majority of the evaluation of proposed stem cell research. Stem cell research is also overseen by all the same processes as other institutional research, which may include examination by committees focusing on the conduct of research, science and technology policy, radiation safety, conflicts of interest, animal care and use, biosafety, protection of human subjects, and others issues as appropriate.

The committees most commonly reviewing stem cell research are focused on human subjects protection, animal care and use, biosafety, and radiation safety. If any research involves human subjects or donors for stem cell line derivation, the Institutional Review Board will provide regulatory and ethical review, including overseeing the creation and application of appropriate consent documentation and addressing issues such as subject reimbursement. If the research involves animals, the Institutional Animal Care and Use Committee, or IACUC, will evaluate and approve the protocols. If recombinant DNA technology is involved in the derivation, maintenance, or differentiation of cell lines, the Institutional BioSafety Committee, or IBC, will also need to approve the research protocols. If radiation is used in the preparation of stem cell research materials, researchers must follow the institution’s radiation safety regulations. Many of these institutional committees are affiliated with national oversight bodies. Each IBC is registered with the Recombinant DNA Advisory Committee at the National Institutes of Health, and the FDA Office for Human Research Trials or the Department of Health and Human Services Office for Human Research Protections may oversee each IRB.

State Laws & Policies

While it is not our intention to provide a comprehensive overview of the state stem cell regulation landscape in this report, it is important to note state policies that have contributed to the oversight of stem cell research. Of course, some states either prohibit embryonic stem cell research outright or restrict the use of state funds. States that do authorize stem cell research address oversight in different ways. For example, California, Connecticut, New Jersey, and New York require research to be reviewed by ESCRO committees created under the National Academies Guidelines. Grant applications in Maryland must include a section covering the ethics of proposed research and applicants are encouraged to reference guidelines from the National Academies or other professional societies. Massachusetts requires grantees to identify any institutional research policies or protocols that apply to the project and to state how they are addressed.^[30]

All states require that funded research comply with all applicable institutional, state, and federal policies and regulations about human subjects, animal welfare, and safe research practices. Databases of state policies and pending legislation are available online from the National Conference of State Legislatures and other organizations.^[31]

Conclusion

The existing oversight structure for stem cell research and product development is extensive and appropriately accounts for scientific, legal, and ethical concerns. Figure 1 (below) provides a summary of the oversight system for basic research. Figure 2 (below) provides a summary of the oversight of products for clinical applications in humans. With certain necessary exceptions, primarily regarding use of embryos, stem cell based products are treated in the same manner as other cell based therapies and biologics or devices. In general, this type of oversight has allowed scientists to develop generations of biological products safely and get them to the market to treat unmet medical needs as quickly as possible. Policymakers seeking to modify these rules have the burden of demonstrating why the existing system is inadequate and how any proposed changes will improve, rather than hamper, patient access to new therapies.

Michael J. Werner is President of The Werner Group, a Washington DC-based firm that provides lobbying, regulatory, and bioethics consulting services for life sciences companies, health care organizations, investors, and broad-based coalitions.

Hans Smith is a Research Associate with The Werner Group and is pursuing a Master of Bioscience degree at the Keck Graduate Institute in Claremont, CA.  He can be contacted via email at Hans_Smith@kgi.edu.

Notes

[1] Reps. DeGette and Mike Castle (D-DE) working on new bill to regulate embryonic stem cell research, BNA Medical Research Law and Policy (May 21, 2008).

^[2] “We did not have the opportunity to respond to her, that all institutions are complying with ESCRO guidelines. We’re not just doing what we want.” – John Gearhart, MD. “Legislator proposes NIH provide ‘ethical oversight’ for all US stem-cell research,” available at http://blogs.nature.com/reports/theniche/2008/05/legislator_proposes_nih_provid.html (last accessed July 29, 2008).

^[3] As of this writing, this IND is being reviewed by the FDA and is on hold.

[4] “[O]n behalf of CAMR and the patient communities [we request] that in spite of the high visibility and great amount of controversy …around human embryonic stem cell research that you not put an extra layer of risk averseness or safety requirements on this research simply because the nature of the visibility or the controversy on the issue…I would plead that you do not, as scientists, allow external controversy in any way to interfere with your analysis.” – Amy Comstock Rick at April 10, 2008 CTGTAC hearing. Meeting minutes available at http://www.fda.gov/ohrms/dockets/ac/cber08.html#CellularTissueGeneTherapies, (last accessed July 21, 2008).

[5] Kessler, D., Halme, D., The New England Journal of Medicine, 355 (2006), pp. 1730-1735

[6] Ibid.

[7] 21 CFR Part 1271 “HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS”

[8] FDA – CBER – “Tissue Action Plan,” available at http://www.fda.gov/CbER/tissue/tissue.htm (last accessed July 18, 2008).

[9] FDA – CBER – “Concerning the Current Good Tissue Practice (cGTP) Final Rule,” available at http://www.fda.gov/CBER/rules/gtpq&a.htm (last accessed July 18, 2008).

[10] 21 CFR Part 1271 “HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS”

[11] Processes that entail more than “minimal manipulation” are defined as those “that alter the relevant biological characteristics of cells or tissues.” Common ways of creating, maintaining, and using cell lines, such as inducing multipotency of an adult cell or causing targeted differentiation of an embryonic stem cell line, would be considered processes that alter biological characteristics. According to 21 CFR 1271.3: “Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.”

[12] Kessler, D., Halme, D. (2006).

[13] 21 CFR 312.23(a)(8) DRUGS FOR HUMAN USE – Investigational New Drug Application.

[14] Donald W. Fink, Jr., Ph.D., Office of Cellular, Tissue and Gene Therapies, presentation, “Embryonic Stem Cell-based Therapies: US-FDA Regulatory Expectations” February 12, 2007, available at http://www.fda.gov/CbER/genetherapy/stemcell012907df.htm (last accessed July 23, 2008).

^[15] Xenotransplantation is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs, available at http://www.fda.gov/Cber/xap/xap.htm (last accessed July 23, 2008).

[16] Donald W. Fink, Jr., Ph.D., “Embryonic Stem Cell-based Therapies: US-FDA Regulatory Expectations.”

^[17] National Institutes of Health, “GUIDANCE FOR INVESTIGATORS AND INSTITUTIONAL REVIEW BOARDS REGARDING RESEARCH INVOLVING HUMAN EMBRYONIC STEM CELLS, GERM CELLS AND STEM CELL-DERIVED TEST ARTICLES,” NOT-OD-02-044 (April 10, 2002).

[18] Recombinant DNA Advisory Committee, “Recombinatant DNA and Gene Transfer,” available at http://www4.od.nih.gov/oba/rac/aboutrdagt.htm.

[19] National Institutes of Health, “NIH Human Embryonic Stem Cell Registry, available at http://stemcells.nih.gov/research/registry/.

[20] National Institutes of Health, “Frequently Asked Questions (FAQs): Funding Questions,” available at http://stemcells.nih.gov/info/faqs.asp#funding.

[21] Committee on Guidelines for Human Embryonic Stem Cell Research, Institute of Medicine, Guidelines for Human Embryonic Stem Cell Research (The National Academies Press, 2005), available at http://books.nap.edu/catalog.php?record_id=11278 (last accessed July 15, 2008).

[22] “To help ensure that these guidelines are taken seriously, stakeholders in hES cell research—sponsors, funding sources, research institutions, relevant oversight committees, professional societies, and scientific journals, as well as investigators— should develop policies and practices that are consistent with the principles inherent in these guidelines. Funding agencies, professional societies, journals, and institutional review panels can provide valuable community pressure and impose appropriate sanctions to ensure compliance. For example, ESCRO committees and IRBs should require evidence of compliance when protocols are reviewed for renewal funding agencies should assess compliance when reviewing applications for support, and journals should require that evidence of compliance accompanies publication of results,” from the Guidelines for Human Embryonic Stem Cell Research, 2005.

^[23] “An ESCRO committee should include independent representatives of the lay public as well as persons with expertise in developmental biology, stem cell research, molecular biology, assisted reproduction, and ethical and legal issues in hES cell research,” from the 2007 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research.

In response to the recent progress in adult stem cell science, many institutions have created committees that review research involving both embryonic and adult stem cells; sometimes titled Stem Cell Research Oversight (SCRO) committees.

[24] Guidelines for Human Embryonic Stem Cell Research (2005).

^[25] Personal communication with Anne Hiskes, PhD, Director of Research Ethics and Education for Stem Cell Research and Chair of the ESCRO; Associate Professor, Philosophy; The University of Connecticut. Dr. Hiskes performed a national survey in early 2007 of ESCRO committees that provided some initial data. Survey results are available at http://www.escro.uconn.edu/survey.html (last accessed July 23, 2008).

^[26] California requires research funded by California Institute for Regenerative Medicine (CIRM) to be reviewed by a ESCRO committee(s) established in accordance with the requirements of Code of California Regulations, title 17, section 100060, available at http://www.cirm.ca.gov/reg/default.asp. In Connecticut, an ESCRO must review “all research funded by the State of Connecticut Stem Cell Research Fund, including those that do not use human embryonic stem cells”; available at http://www.das.state.ct.us/rfpdoc/DPH06/bids/2007stemcellresearchgrant.pdf. New Jersey institutions must establish an ESCRO to receive funding. Additionally an ethics panel guided by the National Academy of Science’s 2005 Guidelines for Stem Cell Research and the New Jersey Human Stem Cell Research Act performs a review during the grant application process; available at http://www.state.nj.us/scitech/stemcell/grants/.

[27] Human Embryonic Stem Cell Research Advisory Committee, “Project Information,” available at http://www8.nationalacademies.org/cp/projectview.aspx?key=46992 (last accessed July 17, 2008).

[28] National Academies, “Stem Cells at the National Academies: Events” available at http://dels.nas.edu/bls/stemcells/events.shtml (last accessed July 17, 2008).

^[29] National Academies, “ESCRO Committee Listserv,” http://dels.nas.edu/bls/stemcells/escro-listserv.shtml (last accessed July 23, 2008).

^[30] More information available at: http://www.mscrf.org/index.cfm, http://www.masslifesciences.com/index.html, http://www.idph.state.il.us/irmi/index.html, http://www.state.nj.us/scitech/stemcell/grants/index.html, http://stemcell.ny.gov/grantee_requirements.htm, http://www.cirm.ca.gov/reg/default.asp, and http://www.das.state.ct.us/rfpdoc/DPH06/bids/2007stemcellresearchgrant.pdf.

^[31] See: National Conference of State Legislatures: http://www.ncsl.org/programs/health/Genetics/embfet.htm; International Society for Stem Cell Research: http://isscr.org/public/regions/states.cfm; Henry J. Kaiser Foundation, http://www.statehealthfacts.org.