The stated mission of the California Institute for Regenerative Medicine (CIRM) is “to support and advance stem cell research and regenerative medicine under the highest ethical and medical standards for the discovery and development of cures, therapies, diagnostics and research technologies to relieve human suffering from chronic disease and injury” (CIRM, 2012a, p. 5, 2012b). The California Stem Cell Research and Cures Act establishes CIRM as an institute that will be responsible for disbursing the proceeds from the general obligation bonds issued by the state for the purpose of supporting stem cell research in California, emphasizing pluripotent stem cell and progenitor cell research and other vital medical technologies, for the development of life-saving regenerative medical treatments and cures.
The passage of Proposition 71 focused worldwide attention on regenerative medicine, and CIRM’s subsequent activities catapulted California into a position as an international hub of research and development in stem cell biology. This chapter first addresses CIRM’s strategic planning as it has evolved since the Institute’s inception. It then presents an analysis of the Institute’s grant management system, as well as the bioethics- and industry-related challenges that lie ahead for clinical applications of stem cell research. As discussed in Chapter 1, it was outside of the scope of the committee’s work to rigorously evaluate the details of CIRM’s scientific contributions, specific grant awards, or impact on the field of regenerative medicine. Rather, the committee examined CIRM’s overall scientific priorities and the quality of the processes instituted to guide its funding priorities and decisions. The final section provides the committee’s conclusions and
recommendations on the nature, scope, and accomplishments of CIRM’s scientific program.
This section begins by examining the impact of work resulting from CIRM’s research funding as guided by its initial (CIRM, 2006a) strategic goals. It then reviews the goals and funding model articulated in the 2012 strategic plan (CIRM, 2012a), considers the potential impact on the development of cures and therapies for chronic disease and injury, and presents the committee’s view of the potential benefit to CIRM of establishing independent guidance for the establishment of its evolving priorities.
The 2006 Strategic Plan
To fulfill CIRM’s mission, the Institute’s governing board, the Independent Citizens Oversight Committee (ICOC), adopted the first scientific strategic plan in December 2006. This plan served as the blueprint that guided the first 5 years of CIRM’s programs. The goals during this initial phase were to develop appropriate laboratory facilities for stem cell research, to fund basic research in stem cell biology, to invest in programs directly focused on research on a broad range of diseases, and to establish a long-term foundation for California leadership in stem cell research and development (CIRM, 2006a).
Because all of CIRM’s awards are made on a competitive basis in response to requests for applications (RFAs) issued by the Institute, a grant review process was instituted to evaluate proposals and make funding recommendations to the ICOC, which was responsible for final decisions (CIRM, 2012c). Operationally, CIRM developed RFAs, which were issued to the community after being approved by the ICOC. The initial RFAs were tied to objectives outlined in the 2006 strategic plan; those objectives were informed by a series of workshops convened by CIRM’s scientific staff and other interactions with the broader scientific community. Eventually, CIRM’s scientific staff, working under the direction of the chief scientific officer,1 prepared drafts of RFAs, which were then presented to the ICOC. The ICOC considered each RFA in terms of its overall priority and determined the maximum amount of funding that would be available for each of the approved initiatives. All ICOC-approved RFAs were then announced widely and posted on the CIRM website, and applicants were invited to submit proposals with a defined deadline (CIRM, 2012c).
1The title of chief scientific officer was later replaced by senior vice president for research and development.
During its early phase, CIRM issued a variety of RFAs. One of these was for the construction of research facilities to house investigators and promote their interaction in close proximity (CIRM, 2007a). Given the political climate at the time of CIRM’s authorization, there was concern that federal legislation would continue to preclude stem cell research in facilities constructed with federal dollars. Hence CIRM was authorized to spend up to 10 percent of its research budget on new facilities that could then operate independently of federal stem cell legislation. CIRM also focused heavily on developing the manpower necessary to sustain a long-term capacity in stem cell research and development in California. This objective was operationalized through a series of RFAs to support faculty recruitment, which resulted in both junior investigators and senior faculty being retained in and recruited to California (CIRM, 2007b). In addition, training grants were awarded that included programs for graduate and postgraduate trainees, as well as more innovative programs. An example of the latter is the Bridges Program, designed to encourage students at community colleges to enter the field of stem cell research and its clinical applications (CIRM, 2005, 2008a,b).
This early phase of CIRM also saw RFAs focused largely on the basic science of stem cells, as it was perceived that the fundamental understanding of these cells and their potential functions was still in its infancy (CIRM, 2006b, 2008c, 2009a, 2010a). Such basic research was viewed as a foundation for subsequent translational investigation. These RFAs were followed by RFAs focused on topical areas designed to address perceived roadblocks to the potential use of stem cells for therapy (e.g., an RFA on studying how to overcome the immune response to stem cells) (CIRM, 2009b), and to stimulate the development of new technologies (e.g., tools and technology grants) (CIRM, 2010b) or reagents (e.g., development of new cell lines) that were thought to be critical for the field’s further development (CIRM, 2007c).
Overall, the RFAs that were issued in the first few years of CIRM’s operations were concordant with the goals outlined in the original 2006 strategic plan. In this first crucial period of operations, CIRM funded—in a remarkably expeditious and thoughtful manner—more than $1.3 billion in awards to 59 institutions.2 The focus of these awards was fully consistent with CIRM’s stated mission and was important for building the infrastructure for stem cell investigation in California. CIRM allocated these funds in an open and competitive manner that was well informed by scientific expertise from outside California. Moreover, CIRM-supported programs have been responsive to scientific advances occurring outside of California.
One example of CIRM’s efforts to connect with research outside of
California is its collaborations with other centers of excellence in stem cell research located both within the United States and around the world. Collaborations with funding partners and stem cell researchers in Australia, Canada, Germany, Japan, Spain, the United Kingdom, the United States, and several other countries have attracted tens of millions of dollars in matching funds for initiatives in regenerative medicine elsewhere, which enhanced the work of CIRM investigators, and raised the Institute’s profile as a global leader in regenerative medicine (CIRM, 2011a). Similar collaborations with the National Institutes of Health (NIH), other stem cell organizations (e.g., in Maryland and New York; see Chapter 2), and foundations (e.g., the Juvenile Diabetes Foundation) have resulted in new levels of cooperation and funding in the field (CIRM, 2011b). Another potential benefit is access to external intellectual property that could be commercialized by California companies.
The committee understands that it is challenging to measure outcomes of these partnerships at this early stage and that it remains to be determined whether the benefits outweigh the cost of initiating, negotiating and managing them because of complex intellectual property (IP) and other policies. The committee is encouraged by CIRM’s recent launch of the External Innovation Initiative (created in response to a recommendation of the 2010 External Advisory Panel [EAP, 2010]), which enhances this collaborative program (CIRM, 2011c). However, through interviews with several external partners (including those in the United States and abroad), the committee learned that at least some of CIRM’s partners believe they have had insufficient input into the development of the Institute’s RFAs (IOM, 2012a,b,c). The committee appreciates this concern, because CIRM would be well served to take the fullest advantage of the special skills and opportunities these collaborators can provide to its joint ventures.3
Given the state of science in regenerative medicine, the 2006 5-year strategic plan, and CIRM’s 10-year funding horizon, the committee believes it made good sense to begin with investments in basic research; in physical infrastructure (especially given the matching funds that were required and mobilized by each institution awarded a major facilities grant and the requirement that construction be completed with a rapid timeline); in human capital (from young technicians to established researchers); and in collaborations with research partners from other centers of excellence worldwide. It is clear that in this initial period, CIRM substantially enhanced the position of California as one of the key international hubs of activity in regenerative medicine.
3Each of CIRM’s collaborators outside of California must mobilize the resources necessary to support its own work.
Stimulation of Translational Research
In 2008, CIRM undertook a broadening of its portfolio of grants to stimulate progress toward its translational goals by issuing a call for planning awards to lay the foundation for a subsequent call for disease team research awards. The initial awards were designed to stimulate the planning of projects focused on the use of stem cells in the development of therapies (CIRM, 2007d). The Disease Team Research RFA followed in 2009 (CIRM, 2009c). The goal was to fund multidisciplinary teams that would engage in milestone-driven translational research for the development of stem cell–based therapies. The funded teams were to conduct research and plan for the regulatory activities necessary to support Investigational New Drug (IND) applications to the Food and Drug Administration (FDA), with the goal of eventually enabling or at least moving toward Phase 1/2 clinical trials. The Disease Team Research Awards have now emerged as fundamental to CIRM’s core ongoing mission. The following 14 disease team awards (totaling approximately $230 million) were made (CIRM, 2009d,e):
- Cedars-Sinai Medical Center: Autologous Cardiac-Derived Cells for Advanced Ischemic Cardiomyopathy
- Stanford University: Development of Therapeutic Antibodies Targeting Human Acute Myeloid Leukemia Stem Cells
- Stanford University: Embryonic-Derived Neural Stem Cells for Treatment of Motor Sequelae Following sub-Cortical Stroke
- Stanford University: iPS Cell-Based Treatment of Dystrophic Epidermolysis Bullosa
- The City of Hope: Stem Cell–Mediated Therapy for High-grade Glioma: Toward Phase I-II Clinical Trials
- The City of Hope: Zinc Finger Nuclease-Based Stem Cell Therapy for AIDS
- UCLA: HPSC–Based Therapy for HIV Disease Using RNAi to CCR5
- UCLA: Stem Cell Gene Therapy for Sickle Cell Disease
- UCLA: Therapeutic Opportunities to Target Tumor Initiating Cells in Solid Tumors
- UCSD: Development of Highly Active Anti-Leukemia Stem Cell Therapy
- UCSD: Stem Cell–Derived Astrocyte Precursor Transplants in Amyotrophic Lateral Sclerosis
- UCSF: Stem Cell–Mediated Oncocidal Gene Therapy of Glioblastoma
- USC: Stem Cell–Based Treatment Strategy for Age-Related Macular Degeneration
- ViaCyte Inc.: Cell Therapy for Diabetes
In 2011, approximately 18 months after disease team funding began, CIRM convened clinical development advisory panels to meet with each team to evaluate progress on the regulatory and scientific pathway toward clinically important products and/or services. Based both on the advisory panels’ input and internal deliberations under the guidance of CIRM’s president, the Institute decided to continue 12 projects with no change in goals. One project was recommended for continuation but with revisions to its original goals (Cedars-Sinai Medical Center Autologous Cardiac-Derived Cells for Advanced Ischemic Cardiomyopathy), and another project was terminated because it did not achieve appropriate milestones (UCSF Stem Cell–Mediated Oncocidal Gene Therapy of Glioblastoma) (CIRM, 2012d).
Deciding to tackle translation on a broad front was a critical strategic decision. Such an approach has advantages in an arena in which there is a great deal of uncertainty as to where the next important breakthrough might occur. It is not possible to say at this point whether the net cast by CIRM’s disease teams is too wide or too narrow. What is clear is that the resources ultimately required to bring any one of these initiatives to the bedside far exceed the resources available from CIRM. Therefore, the committee believes CIRM could make a significant contribution by expanding efforts dealing with regulatory and other challenges of cell-based therapies that are common across diseases. These efforts would diminish the remaining risk for private entities that would need to make the investments necessary to take a promising approach through clinical trials.
Also, as discussed later, CIRM has made other strategic decisions during this initial phase that have resulted in omitting certain important areas from its scientific program. Examples include the lack of RFAs addressing the study of ethical aspects of the clinical applications of potential stem cell therapies and incentives for academic institutions in California to collaborate with the private biotechnology and large pharmaceutical sectors early on in the process. These are important opportunities that fall squarely within the CIRM mandate but have not been pursued.
The 2012 Strategic Plan
In 2012, CIRM developed a new strategic plan outlining 10 goals that build on and extend those of the 2006 plan. The 2012 5-year plan increases the priority of projects clearly focused on moving toward clinical trials to produce evidence of therapeutic benefit and articulates the importance of developing partnerships with both industry and other centers for research in regenerative medicine (CIRM, 2012a). The key goals that, in part, reflect CIRM’s response to the EAP review of 2010 can be summarized as follows (EAP, 2010):
- Scientific—Accelerate stem cell science and its applications to human diseases and injuries to achieve transformative research discoveries.
- Clinical—Advance stem cell science to clinical trials for proof-of-concept stem cell therapies.
- Sustainability—Establish a platform that would enable other funding mechanisms to pursue CIRM’s mission upon expiration of Proposition 71 bond funding.
To guide its ongoing implementation of the 2012 plan, CIRM proposes forming a Clinical Advisory Panel that would include individuals with appropriate skill sets related to preclinical and clinical research, process development and manufacturing, regulatory standards, stem cell/disease-specific biology, disease-specific clinical expertise, and commercial relevance. In addition, CIRM is proposing to create an Industry Advisory Board with 8-10 internationally recognized expert members representing biotechnology, pharmaceutical, venture capital, and disease organizations (CIRM, 2012a). The goal is to advise CIRM on how to make its programs attractive to industry, identify research areas most appropriate for industry, identify CIRM-funded inventions that should be patented, create opportunities for follow-on funding for CIRM-funded research approaching clinical trials, assist CIRM in fostering industry-academic partnering opportunities, and identify and advance business models for regenerative medicine (CIRM, 2012a).
CIRM has $1.48 billion in funds yet to be awarded, of which $695 million is for programs already concept approved and $856 million for future, currently undefined programs (CIRM, 2012e). CIRM’s 2012 strategic plan reflects an intent to shift the relative allocation of funds among its five core target areas to favor translation and development as opposed to facilities, training, and basic research. Two possible scenarios have been outlined for allocating the uncommitted funds (see Table 4-1). In either scenario, funding for training and basic research is reduced relative to translational and development research, thereby impacting what has been an impressive record in providing manpower for stem cell research and developing basic concepts of stem cell biology.
As noted above, the 2012 goals and funding plan significantly shift CIRM’s focus toward projects believed to have the potential to move therapies toward and into the clinic. This shift is illustrated further by the July 26, 2012, announcement of an additional eight disease team awards totaling approximately $151 million (CIRM, 2012f). These teams are expected either to have filed a request to begin clinical trials or to have completed a Phase 1/2 clinical trial within 4 years:
- Cedars-Sinai Medical Center: Progenitor Cells Secreting GDNF for the Treatment of ALS
- Stanford University: A Monoclonal Antibody That Depletes Blood Stem Cells and Enables Chemotherapy Free Transplants
- Stanford University: Human Embryonic Stem Cell-Derived Cardiomyocytes for Patients with End Stage Heart Failure
- Stem Cells Inc.: Neural Stem Cell Transplantation for Chronic Cervical Spinal Cord Injury
- UC Davis: MSC engineered to produce BDNF for the treatment of Wheelock-Huntington’s disease
- UC Davis: Phase I Study of IM Injection of VEGF-Producing MSC for the Treatment of Critical Limb Ischemia
- UC Davis: Treatment of Osteoporosis with Endogenous Mesenchymal Stem Cells
- UCLA: Genetic Re-Programming of Stem Cells to Fight Cancer
This latest round of disease team awards brings the total funding for this program to roughly $360 million, and CIRM-supported late-stage research projects now address 37 different disease areas (CIRM, 2009d, 2012f). Exactly how CIRM will prioritize its distribution of remaining resources is a question of great importance.
TABLE 4-1 Scenarios for Allocating Uncommitted Funds
|Target Area||Funded, 2006-2012 (Millions of $)||Concept Approved $695 million (Millions of $)||Future Scenario 1 $856 million (Millions of $)||Future Scenario 2 $857 million (Millions of $)|
SOURCE: Research Funding Strategy: ICOC Board Meeting (March 21, 2012), agenda item #9 (CIRM, 2012e).
An important aspect of CIRM’s organization is how program staff manages pre- and post-award mechanisms. The committee recognizes the magnitude of CIRM’s successful effort to develop a grant management infrastructure within a remarkably short period of time following passage of the legislation authorizing its creation. CIRM developed a structure for conceptualizing RFAs, soliciting applications, evaluating proposals, and then managing grant awards. Given the complexity of this endeavor and the legislated limitation on staff size (initially no greater than 50 full-time equivalents), the overall success of the grant management infrastructure is impressive.
CIRM staff are available to potential applicants to discuss ideas and to answer questions about published RFAs and the conformity of a particular proposal to the goals of announced programs. From responses to a questionnaire submitted to the committee by the California stem cell scientific community,4 it appears that views on discussions of this type vary, with some individuals being highly appreciative of these preliminary discussions and others finding the CIRM staff less accessible (IOM, 2012d). The committee agrees that having a system for communicating with potential applicants early in the process is important, in particular to ensure that neither applicants nor CIRM staff are spending large amounts of time writing or assessing proposals that are not in keeping with the goals of any particular RFA. The committee also suggests that CIRM continue making its scientific staff available to potential applicants and working with this constituency to maximize the effectiveness of this aspect of the grant submission process.
CIRM staff recognized that the number of applications that would potentially be received for a given RFA could overwhelm the Institute’s ability to review each rigorously for scientific merit. Accordingly, during its early years, CIRM restricted the number of applications that would be accepted from any one institution in response to a particular RFA. The reasoning was that doing so would limit the overall number of applications, making the review process manageable while guaranteeing that applications would represent the scientific communities at a wide range of California institutions. This was especially important given that CIRM’s enabling legislation limited administrative expenditures, requiring that the process for grant-making decisions be streamlined. However, there was considerable pushback from potential grantees, because it was thought that some individuals, in particular junior investigators or those new to stem cell biology, were at a disadvantage in competing with colleagues at their home
4See Appendix B for a summary of the questionnaire responses.
institutions for the right to submit a proposal and hence had limited access to possible CIRM support.
To address this concern while keeping the number of proposals sent for full review manageable, CIRM established a pre-application procedure and eliminated the restriction on the number of applications that could be submitted from any single institution (CIRM, 2011d). The preapplication procedure is similar to a process used by a number of private foundations that provide support for biomedical research. Applicants are asked to provide a shortened version of their proposal through the CIRM website. CIRM staff evaluate these shortened proposals to ensure that they are in keeping with the RFA. Those deemed responsive to the RFA are then sent to three outside reviewers, who are also provided the RFA. Each reviewer is asked to evaluate the pre-application, indicating whether it should definitely, possibly, or definitely not be invited as a full proposal. Additionally, each reviewer is asked to identify proposals that are among the two to three best in the group being evaluated by that reviewer (each reviewer typically is given 10-25 pre-applications to consider). No written critique is requested of the evaluators. Using these initial external evaluations, CIRM staff determine which applicants will be invited to submit full proposals. Once invited, proposals must be based on the pre-application proposal that was submitted. There is no appeal process for pre-applications that are not invited for a full proposal submission (CIRM, 2011e).
After the pre-application process was piloted, applicants, reviewers, CIRM staff, and the ICOC board members were surveyed regarding its acceptability (CIRM, 2011e). As might be expected, applicants often expressed frustration that there was no feedback on why their pre-application was not selected to move forward. Additionally, in responses to the committee’s questionnaire,5 some principal investigators raised concern about whether a short proposal contains sufficient detail for an informed review (IOM, 2012d). On balance, however, there appeared to be overwhelming support for the pre-application process, especially in comparison with the previous model whereby there was a limit on the number of applications that could be submitted from any single institution (CIRM, 2011e). The committee agrees that, despite its limitations, the current pre-application procedure opens up the opportunity for CIRM funding to a broader cohort of investigators and is, in principle, an appropriate process. The committee recognizes the tension between providing applicants as much information as possible and not overburdening reviewers, and it suggests that CIRM consider ways of offering applicants more information on the shortcomings perceived in pre-applications that were not selected for further consideration.
5See Appendix B for a summary of the questionnaire responses.
The Scientific and Medical Research Funding Working Group, designated in most CIRM materials as the Grants Working Group (GWG), is the entity charged with reviewing scientific proposals and making recommendations to the ICOC with respect to those that should be funded. The GWG is appointed by the ICOC and consists of 23 members, including the chair of the ICOC, 7 of the 10 ICOC patient advocates, and 15 non-California scientists known for their expertise in stem cell biology (CIRM, 2009f, 2012g). The 15 scientists are selected based on the particulars of the individual RFAs and are drawn from a pool of more than 150 individuals chosen by CIRM as highly qualified to review proposals. Participation of these experts, none of whom, as non-Californians, is eligible for CIRM funding and stand to gain directly from CIRM, is instrumental in providing the rigorous scientific review required for making funding decisions. The success that CIRM has had in commissioning outstanding review committees for each of its RFAs is a testament both to the Institute’s stature in the eyes of the stem cell community and the willingness of stem cell scientists outside of California to contribute their time and effort to facilitate the work of their California colleagues
Full proposals received by CIRM by the RFA deadline are entered into the CIRM database, and all GWG members assigned to this review cycle declare any conflicts of interest with any of the applications (CIRM, 2009g). Any GWG member in conflict for a particular application is recused during discussions, scoring, and final voting. The GWG members are then assigned applications for which no conflict exists based on their unique expertise. Typically, three external scientists review each application. The GWG can call on additional specialist reviewers as needed if its own expertise is insufficient to evaluate the science in any individual application adequately. Prior to the GWG’s face-to-face meeting, each reviewer and ad hoc specialist submits a scientific score (1-100, with 100 being best) and a written critique for each assigned application. A meeting of the GWG is then announced on the CIRM website. This meeting starts with a session open to the public, during which GWG business is conducted. The GWG then meets in closed session for a two-stage review of the applications (CIRM, 2011g).
The first stage of the review is scientific in nature, led by the chair of the GWG (an external scientist member appointed to this role by the ICOC). The assigned reviewers declare their scores for the application being discussed and briefly summarize the basis for their recommendations. This is followed by full discussion of the application by GWG members, ending with the assigned reviewers suggesting revised scores based on the discussion. Each scientific member of the GWG not in conflict with that application then submits a final scientific score. Although ad hoc specialist reviewers can suggest scores in their written evaluations and, if present, during the discussion, only GWG members can submit a final score.
The final scientific score is the arithmetic mean of the reviewers’ scores. If there is a wide divergence in scores with a sizable proportion (greater than 35 percent) of the GWG being in disagreement with the majority view, a minority report is forwarded to the ICOC along with the final score (CIRM, 2011g).
The next stage is the programmatic review, chaired by one of the patient advocate members of the GWG appointed to this position by the ICOC (CIRM, 2011g). The purpose of this review is to evaluate all of the applications taking into account not only their scientific scores but also the overall purpose of the RFA, with the goal of segregating the applications into three tiers—recommended, provisionally recommended, or not recommended for funding. This process has two steps. First, a histogram of the scores of all of the applications is generated. Of note, at this stage the applications are deidentified, and only the scores are revealed. The GWG examines this histogram and identifies natural breaks to divide the applications into the three tiers based on their scores. Next, the applications are identified so that the scientific score (and tier) of each is made known. GWG members (except those with conflicts, who leave the room) begin a discussion to determine whether any of the applications should be moved from one tier to another in an effort to achieve a balanced portfolio representing a spectrum of priority disease areas, scientific approaches, innovation, and so forth. For an application to be moved from one tier to another, a majority vote of the GWG is required; all members of the GWG not in conflict (scientists and patient advocates) participate in this vote. Once the GWG is satisfied with the final ranking of proposals, a final vote is taken, and the rank order is proposed to the ICOC for approval. For each application, in addition to its final ranking, the scientific score voted by the scientists on the GWG is provided to the ICOC (CIRM, 2011g; IOM, 2012e).
The ICOC makes funding decisions at a meeting scheduled and publicized in advance. As with other ICOC agenda items, deliberations on the funding of applications begin in a session that is open to the public. ICOC board members in conflict with any particular application are recused from both this public discussion and any subsequent private deliberations. Prior to the ICOC meeting, summary information about each application is available on the CIRM website, including how that particular application ranked relative to the others and its tier designation. Applications are redacted, however, to remove information that would identify applicants or institutions. Individual applicants are aware of how their proposal scored and how likely it is to be funded, and they have the opportunity to make an “extraordinary petition” to the ICOC. Any ICOC board member may request that the petition be heard. In such cases, petitioners are invited to the ICOC meeting to explain why they believe the assigned score and priority ranking are not appropriate. The ICOC takes this information into
consideration as it deliberates about the final ranking of applications. If it is necessary to discuss proprietary information, then the ICOC may meet in closed session before a final vote is taken on which applications will be funded. As a result of its private and public deliberations, the ICOC may move applications from one tier to another before taking a final vote, after which applicants are notified about funding decisions. Examination of ICOC records indicates that the shifting of applications from one tier to another does occur. For example, as of October 22, 2012, 62 extraordinary petitions were heard by the ICOC, of which 20 (32 percent) were successfully funded (CIRM, 2012h). Although most of this shifting is between adjacent tiers, there have been cases in which applications have been moved from tier 3 to tier 1 (CIRM, 2011g; IOM, 2012e); this has occurred with applications for major programs with large budgets. As discussed in greater detail below, the committee is troubled by the extraordinary petition mechanism and suggests that this practice be eliminated. The committee recognizes that CIRM has recently initiated a self-study regarding all aspects of extraordinary petitions.
Bioethics is part of the portfolio of issues that range across the entire spectrum of projects moving toward the clinic. As stated above, CIRM describes its mission in the 2012 strategic plan as supporting and advancing stem cell research and regenerative medicine under the highest ethical and medical standards. To achieve this mission, CIRM has proposed as one of its main goals advancing stem cell research to clinical trials to establish evidence of therapeutic benefit to patients. The most important milestone toward this goal is achieving clinical proof of concept for new therapies within the next 5 years (CIRM, 2012a). This is an ambitious goal, and CIRM acknowledges the importance of fostering a new regulatory path for stem cell therapies.
Current NIH standards for informed consent and human subjects research do not address specific challenges related to clinical trials involving complex stem cell–based biologic products. Unlike drugs and many medical devices, transplanted progenitor cells have the potential to integrate and proliferate within their human recipient and as a result may be difficult to remove if necessary. Transplanted cells can last for the lifetime of the recipient and cause deleterious effects that are difficult to ameliorate. In light of the complexity and novelty of new stem cell–based biologics—many of which may not be directly analogous to local, well-characterized donor tissue transplants or drug therapies—all stem cell–based clinical trials research raises crucial ethical concerns. Given the nature of stem cell–based therapies, safety and clinical proof-of-principle studies are likely to involve
patient research subjects. Thus, there is an immediate need for researchers and regulators to define reasonable risks, appropriate study endpoints, appropriate experimental comparators, standards for long-term follow-up of research subjects, and other aspects of ethical clinical trial design, in addition to formulating practical ways to minimize the threat of therapeutic misconception in patient research volunteers.
CIRM projected in its 2006 strategic plan that $25.5 million should be spent over the 10-year span of CIRM funding on Stem Cell Research and Society: Implications and Impact. These funds were meant to span three aspects of CIRM’s mission: (1) laying the foundation, (2) preparing for the clinic, and (3) clinical research (CIRM 2006 Strategic Plan) (CIRM, 2006a). To date, however, very little CIRM funding has been spent in the area of Stem Cell Research and Society. Most of CIRM’s ethics and public policy spending has focused on intramural funding for public outreach and education and the internal development of technical, instrumental, and procedural policy frameworks for basic stem cell research, including, for example, CIRM policies on oocyte donation for stem cell derivation. To its credit, CIRM has spent much time developing its own regulations for basic CIRM-funded stem cell research, regulations that are harmonious with the current NIH policies for stem cell line registration and eligibility for federal funding. These CIRM regulations were not imposed on California stem cell researchers and institutions, but were developed organically through consultations with these groups. The result of this interactive process was that scientists and institutions were encouraged to help establish and comply with oversight of stem cell research.
Furthermore, the Scientific and Medical Accountability Standards Working Group (Standards Working Group) recently drafted CIRM-specific guidelines for the reporting of incidental findings by secondary researchers using induced pluripotent stem (iPS) cell lines derived from living donors. The Standards Working Group also recently provided model-informed consent documents for iPS cell research in conjunction with CIRM’s new RFA for iPS cell derivation and banking (CIRM, 2012i). These efforts were the culmination of several Standards Working Group meetings and workshops involving bioethics experts and researchers outside of CIRM. Although the committee applauds CIRM and the Standards Working Group for taking the initiative to address these important emerging issues in the ethical conduct of human stem cell research, the drafting of sample consent forms for iPS cell research and banking could have been aided greatly by empirical studies examining the most effective ways to bolster patient-informed consent during the consent interview process—studies the Standards Working Group did not sponsor or utilize. Such efforts at policy development should continue in other areas of stem cell science supported through CIRM funding.
Proposition 71 clearly states as one of its key objectives: “Benefit the California economy by creating projects, jobs, and therapies that will generate millions of dollars in new tax revenues in our state … [and] advance the biotech industry in California to world leadership, as an economic engine for California’s future.”6Chapter 2 includes a discussion of the challenges entailed at present in assessing the long-term economic benefits of CIRM’s investment in stem cell research. One aspect of this issue is CIRM’s engagement with the biotechnology and pharmaceutical industry in California.
California is already home to a vibrant biotechnology community with more than 2,240 companies, estimated revenues of $114 billion, and approximately $2.6 billion in venture capital investment in 2010 (CHI, 2011). In that same year, an estimated 50 percent of all venture capital investment in the United States went to companies in California, with life sciences being the sector receiving the largest tranche of funds. Although venture capital investment in California returned to 2003 levels in 2010 (approximately $8 billion), its overall level has been relatively stable during CIRM’s lifetime ($8-$15 billion) (CHI, 2011).
Regenerative medicine is still an emerging industry, so leading companies in the field are at a relatively early stage, representing a small fraction of the total number of biotechnology companies in California. Indeed, given how much research and development remains to be done before the risks attendant to the successful commercialization of a cell-based product can be adequately characterized, investments in the field of regenerative medicine will likely remain modest in scale in the short term. Nevertheless, the well-developed entrepreneurial ecosystem in California represents a unique potential asset in moving discoveries in regenerative medicine to the bedside.
Through the halfway point in its existence, CIRM has engaged industry in a number of ways. Four representatives of commercial life science entities sit on the ICOC, and individuals with industry experience serve on the GWG. CIRM also supports the Alliance for Regenerative Medicine (ARM), a multistakeholder advocacy organization that promotes legislative, regulatory, and reimbursement initiatives in regenerative medicine; CIRM and ARM co-organize an annual meeting in La Jolla, California (Stem Cell Meeting on the Mesa) touted as the industry’s premier investor and partnering forum and recognized nationally as bridging academia, industry, and investors. With input from industry, CIRM has adopted detailed intellectual property, profit sharing, and access plan policies (see Chapter 5) governing
6California Stem Cell Research and Cures Initiative, Proposition 71 (2004) (codified at California Health and Safety Codes § 125291.10-125291.85).
the commercialization of discoveries supported by CIRM funding. Most important, for-profit entities can receive direct support from CIRM to advance their product pipelines in the form of either grants or loans. The loan vehicle was adopted specifically to “supplement [CIRM’s] grant funding by offering research loans to for-profit organizations” (CIRM, 2011f, p. 1). These loans are awarded in two forms—product-backed (forgiveness) or company-backed—both subject to various terms and conditions (including warrant coverage) and payable within up to 10 years (CIRM, 2011f). Approximately 15 for-profit entities have received CIRM grants and loans, totaling around $80 million, covering a broad spectrum of research and development topics: basic research, translation, tools and technologies, disease teams, and clinical trials. CIRM also supports the supply side of the regenerative medicine industry by requiring that 70 percent of supplies used for CIRM-funded research be procured from California companies on a good faith effort basis.
CIRM’s 2012 strategic plan emphasizes the need to attract both risk capital and support from the biotechnology and pharmaceutical industries to take CIRM-funded Phase 2 candidates through clinical validation. This emphasis was endorsed by the 2010 External Advisory Panel, which recommended that CIRM strengthen its engagement of industry and proposed a number of initiatives to that end. CIRM’s president has acknowledged this need by stating that “industry will and should have a role in providing stem cell therapies … they provide the focus, manufacturing, quality control programs, pharmacokinetic data, and substantive capacity in preclinical investigational new drug (IND)—enabling research” (Trounson et al., 2012, p. 1). However, CIRM’s relatively small investment in industry projects (roughly 6 percent of its total budget) and the notable absence of industry on most disease teams was cited by participants in the committee’s industry forum and in interviews with external medical and industry experts as examples of the failure of CIRM’s translational/development RFAs to place appropriate emphasis on what is needed to enable regulatory approval for stem cell–based therapies (CIRM, 2008d, 2010c,d,e, 2011h; IOM, 2012f).
This section presents the committee’s conclusions and recommendations with respect to the nature, scope, and accomplishments of CIRM’s scientific program in the areas of strategic planning, grant management, bioethics, and industry engagement.
Regarding CIRM’s 2012 Strategic Plan, although the committee supports the Institute’s intent to establish advisory boards, it recommends that one Scientific Advisory Board (SAB) be established, comprising individuals with expertise in the scientific, clinical, ethical, industry, and regulatory aspects of stem cell biology. The members should be appointed by and report to the CIRM president. A single SAB, as opposed to multiple advisory boards as currently proposed, would serve as a mechanism for providing cohesive, integrated, and longitudinal advice to the president regarding strategic priorities, which is lacking in the current CIRM organizational structure. The committee believes such an external board would be invaluable in vetting ideas for new RFAs, suggesting RFAs that would not otherwise have been considered, and helping CIRM maintain an appropriate balance in its research portfolio. The SAB could form subcommittees, provided the necessary expertise was available on the SAB. The SAB could supplement its subcommittees on an ad hoc basis whenever additional external expertise is determined to be useful. Input from such an external board is essential to help CIRM make fundamental decisions on efforts to deal with challenges that cut across particular diseases, on which discoveries should progress toward the clinic, and on how best to engage industry partners in developing new therapies. The SAB’s reports and the president’s response to these reports should be delivered to the ICOC and discussed in sessions open to the public.
The committee affirms the need for translational studies, as laboratory experiments or preclinical models cannot accurately predict the consequences and complications of a therapeutic intervention in humans. The 2012 strategic plan calls for proof-of-principle animal models for more than 10 diseases (Goal IV) and for 10 therapies in Phase 1 or 2 clinical trials in at least five different therapeutic areas based on stem cell research (Goal VIII) (CIRM, 2012a). As noted earlier, these ambitious goals reflect a shift in the emphasis of CIRM’s funding from basic and preclinical research to the generation of new treatments for patients. Depending on one’s perspective, this change may reflect a thoughtful progression from basic to more applied research or a rush to translation. Striking the proper balance in research across the portfolio of basic, translational, and clinical studies will require CIRM to solicit broad input in executing its strategic plan. The committee believes the proposed SAB could serve an invaluable role in this process.
Recommendation 4-1.7Establish a Scientific Advisory Board. CIRM should establish a single Scientific Advisory Board comprising individuals with expertise in the scientific, clinical, ethical, industry, and regulatory aspects of stem cell biology and cell-based therapies. A single Scientific Advisory Board, as opposed to multiple advisory boards as proposed in the 2012 strategic plan, would provide cohesive, longitudinal, and integrated advice to the president regarding strategic priorities, which is lacking in the current CIRM organizational structure. The majority of the members of the Scientific Advisory Board should be external to California, appointed by and reporting to the CIRM president. Such an external board would be invaluable in vetting ideas for new RFAs, suggesting RFAs that otherwise would not have been considered, and helping CIRM maintain an appropriate balance in its research portfolio. Input from this board would help CIRM make fundamental decisions about dealing with challenges that cut across particular diseases, decide which discoveries should progress toward the clinic, and determine how best to engage industry partners in developing new therapies. The board’s reports and the president’s response to those reports should be delivered to the ICOC and discussed in sessions open to the public.
The 22 funded disease teams represent translational efforts in diverse disease areas. The committee and solicited experts note that the approaches of several of the disease teams do not fit neatly into what is generally considered stem cell research; rather, they are extensions of more conventional therapeutic strategies not tied to CIRM’s basic stem cell research portfolio. This observation is not meant as a criticism of the validity of these efforts or the quality of these disease teams or as denial of the importance of developing these technologies to counter these illnesses. Rather, the focus of these disease teams likely reflects the immaturity of the stem cell field with respect to the development of novel translational opportunities. Particular diseases or injuries will vary greatly in the point at which they are poised for translation. Given pressure for CIRM to show progress in disease applications within its limited time frame, the rapid transition to the disease teams and the stated goals of the 2012 strategic plan are understandable. Based on the consensus of both academic and industrial stem cell experts who provided comments, however, the committee believes the translational goals enumerated in the 2012 strategic plan are unrealistic in light of both the lengthy time frame generally required for the development of new therapies and the high failure rate of clinical trials at Phase 1 or 2. Instead of focusing
7In the committee’s view, this recommendation can be carried out by CIRM without legislative action.
on purely quantitative measures, such as numbers of trials and diseases, the committee suggests that CIRM also devote considerable attention to fundamental biological mechanisms that ultimately determine the success or failure of a specific disease intervention and the careful design of translational studies to make them maximally informative even in the absence of any demonstrable clinical benefit. Furthermore, a concerted effort focused on working with the Food and Drug Administration (FDA) to overcome regulatory hurdles and facilitate approval pathways for cell-based therapies agnostic to any particular disease would benefit the entire field, and its broad portfolio of programs places CIRM in an excellent position to undertake such an effort.
Historical precedents provide a perspective on the pace of clinical translation. Initial efforts in bone marrow transplantation, the most widely used and validated stem cell therapy, began in the late 1950s and were uniformly unsuccessful except in the setting of transplants between monozygotic twins. Subsequently, it took more than 20 years of studies in patients before the efficacy of allogeneic stem cell transplantation in various disease contexts was established. The high failure rate in early transplant experiments in patients would challenge contemporary regulatory and approval pathways for new therapies. Experience has been similar in the field of gene therapy, in which it has taken more than 20 years for clinical success; the field suffered significant setbacks from adverse events in early clinical trials.
CIRM’s 2012 strategic plan also outlines the proposed creation of new alpha stem cell clinics. This effort is in part a response to “stem cell tourism,” whereby people suffering from diverse conditions travel to clinics with unproven and potentially harmful therapies. The goal of the creation of alpha stem cell clinics is to establish a stem cell therapy clinical infrastructure with the requisite scientific, technical, and medical expertise, combined with operational efficiencies, to foster clinical trials, to evaluate and establish safe and effective therapies, and to develop and maintain the delivery of therapies approved by the FDA or other regulatory agencies (CIRM, 2012a; Trounson et al., 2012). Patients accessing these clinics would range from those with no therapeutic options seeking counseling or experimental treatment to those seeking standard-of-care treatment that would be paid for by their insurance.
The development of alpha stem cell clinics is anticipated to occur in a staged manner. Initially, the clinics would provide counseling to patients on therapeutic options, as well as information regarding emerging trials and technology. A goal is to provide clinical trial capacity for those studies moving toward IND registration, establishing proven therapies with benefits exceeding those of the alternative treatments presently available, and therefore allowing patients the possibility of a broader range of treatments. The alpha stem cell clinics are envisioned to provide a venue for
participation of industry, along with experts from academic medical centers (Trounson et al., 2012).
The committee agrees that the alpha stem cell clinic concept is important and holds great potential for bringing new therapies to the people of California in a setting where these therapies can be evaluated rigorously for safety and efficacy. However, the committee believes this step requires more careful planning. These facilities, providing a site for clinical trials of stem cell therapies, would house multidisciplinary activities, cell production capabilities, and trained personnel in a setting attractive to industry involvement. When fully developed, these clinics might resemble Clinical Translational Research Centers (CTRCs), NIH-supported facilities located at academic medical centers throughout California and the United States. CTRCs, coupled with NIH’s Clinical and Translational Science Awards (CTSAs), provide an infrastructure for the training of personnel as well as resources for state-of-the-art patient-oriented research. The alpha stem cell clinics could be integrated into the existing clinical investigation infrastructure at academic medical centers so as to avoid duplication of facilities and personnel at a time of strained resources. The more CIRM utilizes and partners with facilities in academic medical centers, the more wisely it can deploy its remaining, precious resources.
The plans developed by CIRM also should ensure that these clinics adhere to strict ethical and professional standards. The committee appreciates that CIRM itself has identified some of the potential concerns. In a recent article (Trounson et al., 2012), CIRM’s president cites some of the ethical challenges facing this proposal (including, for example, the need for qualified medical and clinical expertise, long-term patient monitoring, and regulatory and institutional oversight). It is also imperative that a management plan for addressing the possibility of therapeutic misconception be formulated and operationalized for all CIRM-funded alpha stem cell clinics, especially because patient populations would be served across a spectrum of clinical services ranging from the clinically accepted to the highly experimental. For example, the use of patient advisors who were independent of the clinical research or treatment team might help facilitate the voluntary and informed consent of patients contemplating either treatment or research participation at an alpha stem cell clinic.
CIRM’s credibility requires that the grant review process be expert, transparent, and fair. The committee focused its assessment on the process of awarding grants, not post-award management. The committee appreciates that creation of a mechanism for soliciting and evaluating applications over a broad portfolio was a difficult task. It is particularly notable that
CIRM has engaged a cadre of outstanding stem cell scientists from outside of California to serve as peer reviewers, both as ad hoc reviewers and as GWG members. The committee also acknowledges the importance of having patient advocates participate in the grant-making process; as discussed below, however, the committee believes the process adopted by CIRM may not be the most appropriate. CIRM’s efforts to engage investigators as they prepare applications are laudable, but it appears that the scientific community has differing perceptions of the success of these efforts. Formalizing this process and making clearer to the community what role CIRM staff can play during the preparation of applications would be beneficial. The committee agrees that the pre-application process is a practical solution to avoid overwhelming the GWG; however, CIRM should consider ways to provide more information to applicants who are not invited to submit full proposals.
As discussed in detail in Chapter 3, the committee has considerable concern regarding the management versus oversight roles of the ICOC, a particularly cogent issue with respect to the grant-making process. Under the current structure, ICOC members (both as participants in the GWG and through deliberations of the ICOC itself) have considerable influence at all levels with respect to which grants are funded. Given the ICOC composition, which includes individuals with vested interests in what disease areas are supported by grants and others who represent institutions that stand to gain greatly from grant-making decisions, it is not surprising that, even if no actions have been based on these interests, many in the community believe that irreconcilable conflicts exist. The committee believes these inherent and perceived conflicts diminish the credibility of the ICOC and thus decrease the potential for CIRM to be effective as a transparent, impartial body. Recent controversy surrounding the Cancer Prevention and Research Institute of Texas grants process illustrates the importance of rigorous scientific review free from inherent or perceived conflict and the consequences when these boundaries appear to be breached.8 The committee therefore strongly recommends that CIRM restructure the application review and grant-funding processes to separate oversight and strategic planning from day-to-day operations. The ICOC should remain responsible for performing oversight and articulating an overall strategic plan and for approving and determining the allocation of funds for each RFA before it is announced. Going forward, however, all aspects of application review, funding recommendations, and grant administration should be the sole responsibility of the CIRM scientific staff, reporting to the president. While the ICOC should remain responsible for ultimate approval of grants, it should not be empowered to act on individual applications. The committee
8See Nature 486:169-171 (June 14, 2012).
believes these structural changes would eliminate many concerns related to conflicts while also placing the review and funding processes in the hands of those individuals, both scientists and patient advocates, best equipped to make these decisions.
The committee deliberated on the best way to operationalize these structural changes and decided that RFAs should continue to be developed through the CIRM scientific staff (and, as noted above, with input from an SAB appointed by the president) and that the ICOC should provide final approval and funding amounts for each grant. At the same time, the GWG should be reconstituted to exclude any members of the ICOC. The group should continue to include scientists outside of California with expertise in stem cell science and regenerative medicine, with ad hoc scientific reviewers continuing to participate as needed, still as nonvoting members. The committee also believes it is important for patient advocates to continue to be involved in the application review process, in addition to their participation in the ICOC and its decisions about which RFAs to announce and the level of funding for each. However, the committee believes patient advocates participating in the GWG should not be ICOC board members; instead, the ICOC should appoint up to seven patient advocates to participate in any GWG meeting, drawing on a panel of appropriate individuals from inside and outside of California. The committee believes further that the patient advocates should be encouraged to continue to participate in the discussions of proposals and to lead the programmatic phase of the review. Neither the system for assigning scientific scores nor the tiering of applications following the discussion of programmatic fit need be altered. This step would actually increase the role of patient advocates with those sitting on the ICOC being involved in deciding which RFAs should be issued as well as the overall level of funding for each major initiative, and another independent group of patient advocates involved in programmatic ranking of proposals that have been scientifically reviewed. Finally, CIRM scientific staff should be present at all GWG meetings, not to serve as voting members but to provide information about CIRM processes and procedures and to clarify aspects of the RFA as necessary. The committee agrees that GWG meetings must remain closed whenever specific applications are discussed.
The committee recommends that after the GWG has completed its work, the CIRM scientific staff, under the direction of the senior vice president for research and development, should examine the rank order of applications that emerged from the GWG meeting to determine whether, for programmatic reasons, reordering of the applications is necessary. If this is the case, the senior vice president for research and development should meet with the CIRM scientific staff to adjust the rank order of applications, with an explanation being provided for any that have been moved relative
to the score voted by the GWG. Once this proposed final slate has been determined, applicants should be notified of their scores, given copies of the critiques, and informed about the likelihood that they will be funded. Applicants should then have a 10-day period within which to inform the CIRM scientific staff if they believe there are conflicts or factual errors in the reviews that may have impacted their score and they wish to appeal the decision. In this case, the CIRM scientific staff, in consultation with members of the GWG, should review the appeal and recommend to the senior vice president for research and development whether the rank order of that particular application should change. The senior vice president for research and development and the president should then decide on a final slate of proposals, taking into consideration any appeals made by applicants. This slate should then be provided to the ICOC for a vote “yes” or “no” on the entire slate. Should the ICOC vote down the slate of proposals, this would be communicated immediately to the CIRM scientific staff along with a justification for the vote. The CIRM scientific staff would consider this justification and propose a revised slate of grants for approval at the next ICOC meeting. Under no circumstances, however, would the ICOC be empowered to evaluate individual applications or move applications from one tier to another. Additionally, although applicants could, at the discretion of the ICOC, present their views on funding decisions at open ICOC meetings, there should be no mechanism for the ICOC to change funding decisions based on such petitions.
Recommendation 4-2.9Restructure the Grant Review and Funding Process. CIRM should restructure the grant review and funding process to separate oversight and strategic planning from day-to-day operations. The ICOC should remain responsible for oversight and articulation of an overall strategic plan. However, grant management, funding recommendations, and grant administration should be the responsibility of the CIRM scientific staff, reporting to the president. This restructuring would help mitigate concerns related to conflicts of interest and would also put the review and funding process in the hands of those best equipped to make those decisions. The committee recommends the following specific structural changes:
- Development and approval of RFAs—CIRM scientific staff, with input from the Scientific Advisory Board, should develop RFAs. The ICOC should provide final approval and funding amounts for each RFA.
9CIRM may need to work with the state legislature in order to fully implement this recommendation.
- Composition of the Grants Working Group—To ensure separation of oversight and operations, the ICOC board chair should not be a member of the Grants Working Group. Similarly, patient advocates participating in the Grants Working Group should not be ICOC board members.
- Reordering of rankings by CIRM staff—After the Grants Working Group has completed its rankings, the CIRM scientific staff, under the direction of the senior vice president for research and development, should examine those rankings and determine whether, for programmatic reasons, proposals need to be reordered. If so, the senior vice president for research and development should meet with the CIRM executive leadership to adjust the rank order of applications; any reordering should be accompanied by an explanation. The CIRM president should then create a final slate of applications recommended for funding.
- Notification of applicants—Once the proposed final slate has been determined, applicants should be notified of their scores, given copies of the critiques, and notified of the likelihood that they will be funded. Applicants should then have a 10-day period during which they can inform the CIRM scientific staff if they believe factual errors in the reviews may have impacted their score and wish to appeal the decision.
- Final decisions—The senior vice president for research and development and the president should then decide on a final slate of proposals to submit to the ICOC for a “yes” or “no” vote on the entire slate. The ICOC should not be empowered to evaluate individual applications or move applications from one tier to another. This process would also eliminate the use of extraordinary petitions.
Given the speedy timeline and the scientific and regulatory complexities entailed in the goal of bringing stem cell research to clinical trials within the next 5 years, the committee recommends that CIRM sponsor projects and offer new grant opportunities aimed specifically at identifying and addressing ethical and regulatory issues surrounding stem cell–based clinical trials research. CIRM should use the information resulting from these initiatives to strengthen its ethical standards for human subjects research. Expanding CIRM’s portfolio of projects and grant opportunities in this manner is consistent with (indeed, even mandated by) Proposition 71. According to Proposition 71, the ICOC was to begin CIRM funding for stem cell
research by initially adopting ethical standards based on the NIH standards for informed consent and human subjects research that were in place as of January 1, 2003. After initially adopting these NIH standards for ethical research, the ICOC was to add further requirements so as to adopt the highest standards for informed consent and human subjects research.10
Given CIRM’s stated goal in the 2012 strategic plan of initiating clinical trials research, the ICOC needs to adopt additional ethical standards and expectations specific to stem cell research for all its funded human trials. Doing so would help ensure that CIRM remains true to its mission of advancing stem cell research and regenerative medicine under the highest ethical and medical standards. To this end, CIRM should offer additional programs and initiatives within its research portfolio. In the short term, the Standards Working Group should convene with federal regulators, research ethics experts, and clinicians outside CIRM to identify and discuss the ethical and regulatory challenges entailed in stem cell–based clinical trials. One of the key outcomes of this initial discussion should be the identification of strategically important areas for RFAs in ethics for which California research ethicists and social scientists could apply.
While the Standards Working Group created and operationalized many rigorous ethical standards for basic stem cell research during CIRM’s early years, it has not been equally productive of late in formulating CIRM policies for the ethical conduct of human clinical trials research. The Standards Working Group should be encouraged and empowered to focus on this unmet need. According to Proposition 71, the Standards Working Group shall “recommend to the ICOC standards for all medical, socioeconomic, and financial aspects of clinical trials and therapy delivered to patients, including, among others, standards for … clinical efforts for the appropriate treatment of human subjects in medical research.” Furthermore, the Standards Working Group is to advise the ICOC and other working groups on relevant ethical and regulatory issues on an ongoing basis.11 CIRM could make a major contribution to regenerative medicine and advance stem cell research by issuing a series of RFAs aimed at advancing understanding of what constitutes an ethical human subjects research policy in the area of stem cell research. The ultimate purpose of these RFAs should be to enhance the Standards Working Group’s ability to draft recommendations to the ICOC.12 The ethical issues facing stem cell–based clinical trials must be addressed not only through careful deliberations during
10Proposition 71, 125290.35, b1 and b2.
11Proposition 71, 125290.55, b2 and b5.
12The committee’s recommendations regarding governance (Chapter 3) suggest that the Standards Working Group would report directly to the senior vice president for research and development.
CIRM-sponsored workshops but also through the collection and analysis of important empirical information using rigorous social scientific methodologies. Ethics and policy studies would help support CIRM’s commitment to advancing stem cell research under the highest ethical standards. By providing extramural funding for ethics and policy work conducted by researchers outside the organization, CIRM could fulfill an important aspect of its mission in an independent manner, drawing on the expertise of others working in the ethics of human subjects research.
Furthermore, CIRM should commit financial resources to support training programs for stem cell bioethicists and research regulators. These bioethics training programs should be similar to CIRM’s training programs for basic scientists but would focus on bioethics capacity building at CIRM-supported research institutions and stem cell alpha clinics throughout the state. CIRM-sponsored bioethics training programs would help address emerging ethical challenges associated with moving stem cell therapies to the clinic.
In summary, the committee strongly recommends that CIRM fund primary research projects on the ethical, social, and legal dimensions of stem cell research and enable bioethics training programs at institutions that have invested heavily in such research. It is difficult for researchers to find appropriate funding for stem cell–specific ethics and policy work, and filling this funding gap is well within CIRM’s budget. Other ethical aspects of stem cell research need attention besides ethical issues in stem cell–based clinical trials. These areas include (but are not limited to) the legal and ethical rights of somatic cell donors in iPS cell research, the appropriate use of stored tissues for stem cell research, and the use of pediatric and other somatic cell donors with diminished decision-making capacity.
Recommendation 4-3.13Fund Research and Training on Ethical and Regulatory Issues. CIRM should sponsor training programs and workshops and offer new grant opportunities aimed specifically at identifying and addressing ethical and regulatory issues surrounding stem cell–based clinical trials research. CIRM should use the information resulting from these initiatives, together with current knowledge, to strengthen its ethical standards for CIRM-funded human subjects research based on sound empirical and theoretical grounds.
13In the committee’s view, this recommendation can be carried out by CIRM without legislative action.
Because large industry investments will be required to carry CIRM’s most promising new therapies through clinical trials and to the bedside, enhanced industry representation in the Institute’s work is needed in a number of ways. The committee recommends additional industry representation on the ICOC, the SAB, the Standards Working Group, and the GWG to leverage industry’s expertise and resources. Investors in and representatives of biotechnology and pharmaceutical companies should play an explicit role in formulating RFAs, adjudicating awards, and setting strategic directions. This role will be particularly important as CIRM focuses on product development, manufacturing, regulatory approval, and clinical translation. Industry expertise on these issues and the rigor demonstrated by venture capitalists in reviewing commercial opportunities must carry the same weight as the input and oversight already afforded to academicians and patient advocates.
The committee encourages CIRM to create industry-specific RFAs and examine how to integrate industry participation as a highly weighted success criterion for its translational/developmental RFAs. In addition, the committee suggests that investors, entrepreneurs, and companies be solicited for proposals on how to deliver therapies anticipated from the work of the disease teams to the clinic for trials and, ultimately, to their target patient populations. Some of these therapies will require new tools and devices, others large-scale manufacturing, and still others unique business models. The committee believes the best source for these solutions is industry.
The committee notes that CIRM has created a technology transfer fund to support the patenting of CIRM-generated intellectual property. CIRM should be proactive in exploring ways to enhance company creation and outlicensing of its portfolio of patents. It should investigate the creation of financing vehicle(s) to stimulate investment in emerging and existing regenerative medicine companies by engaging the investment community in California, one of the most sophisticated venture capital communities in the world.
CIRM has created an exemplary training program and seeded a pipeline of intellectual property and translational projects that are primed for industry involvement, outside funding, and unique therapy delivery mechanisms. The proposed alpha stem cell clinics offer an intriguing solution to the delivery of therapies, but CIRM must also engage industry to
find equally innovative mechanisms for addressing product development, regulatory, manufacturing, and distribution gaps in its pipeline.
Recommendation 4-4.14Enhance Industry Representation in Key Aspects of CIRM Organization. Industry representation on the ICOC, the Scientific Advisory Board, the Standards Working Group, and the Grants Working Group should be enhanced to leverage industry’s expertise and resources in product development, manufacturing, and regulatory approval in support of the ultimate goal of bringing therapies to patients.
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14CIRM may need to work with the state legislature in order to fully implement this recommendation.
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CIRM. 2012f. Stem cell agency commits $150 million to develop new therapies. http://www.cirm.ca.gov/PressRelease_2012-07-26 (accessed August 28, 2012).
CIRM. 2012g.*The response from the Grants Working Group (GWG) represents the scientific GWG members only. CIRM’s response to IOM’s data request: Questions for working groups (dated May 29, 2012) (accessed October 19, 2012).
CIRM. 2012h.* Update of details of extraordinary petitions. CIRM’s response to IOM’s data request: Details of extraordinary petitions. How many were there, how many were successful, in what tier were they before the petition was made, who are the investigators. (dated October 22, 2012).
CIRM. 2012i. RFA 12-03: CIRM hiPSC derivation award. http://www.cirm.ca.gov/RFA/rfa-12-03-cirm-hipsc-derivation-award (accessed August 28, 2012).
EAP (External Advisory Panel). 2010. Report of the External Advisory Panel. http://www.cirm.ca.gov/files/PDFs/Administrative/CIRM-EAP_Report.pdf (accessed September 4, 2012).
IOM (Institute of Medicine). 2012a.*Conversation with former director of Cancer Stem Cell Consortium in Canada. Institute of Medicine Committee on a Review of the California Institute for Regenerative Medicine open call on June 7, 2012.
IOM. 2012b.*Conversation with Director of the NIH Intramural Center for Regenerative Medicine. Institute of Medicine Committee on a Review of the California Institute for Regenerative Medicine open call on June 8, 2012.
IOM. 2012c.*Conversation with CIRM’s international partners in Germany. IInstitute of Medicine Committee on a Review of the California Institute for Regenerative Medicine open call on July 5, 2012.
IOM. 2012d.*Questionnaire for CIRM principal investigators. Institute of Medicine Committee on a Review of the California Institute for Regenerative Medicine Online Questionnaire launched on February 8, 2012.
IOM. 2012e.*Conversation with CIRM’s ICOC member regarding the review process. Institute of Medicine Committee on a Review of the California Institute for Regenerative Medicine open call on June 28, 2012.
IOM. 2012f.*Roundtable discussion of CIRM’s scientific impact. IOM Committee on a Review of the California Institute for Regenerative Medicine Subcommittee Meeting with Boston Stem Cell Scientists on June 26, 2012, Boston, MA.
Trounson, A., N. D. Natalie, and G. F. Ellen. 2012. The Alpha Stem Cell Clinic: A model for evaluating and delivering stem cell-based therapies. Stem Cells Translational Medicine 1:9-14.
References with an asterisk (*) are public access files. To access those documents, please contact The National Academies’ Public Access Records Office at (202)334-3543 or email@example.com.