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4
Nature, Scope, and Accomplishments of the
CIRM Scientific Program
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 its 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.
STRATEGIC PLANNING
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.
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4-2 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
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).
Since 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).
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).
1
The title of chief scientific office was later replaced by senior vice president for research and development.
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-3
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 the United States, Canada, Germany, the United Kingdom, Australia, Spain,
Japan, 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 New York and Maryland; 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 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, as 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.
2
See http://www.cirm.ca.gov/InstitutionList.
3
Each of CIRM’s collaborators outside of California must mobilize the resources necessary to support its own work.
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4-4 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
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 the 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
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-5
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
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4-6 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
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.
TABLE 4-1 Scenarios for Allocating Uncommitted Funds
Concept
Funded, Approved Future Scenario 1 Future Scenario 2
2006-2012 $695 million $856 million $857 million
Target Area (millions of $) (millions of $) (millions of $) (millions of $)
Facilities/Core 332.2 30.0 0 25.0
Resources
Training/Career 295.6 122.5 0 60.0
Dev.
Basic Research 252.6 80.0 135.0 105.0
Translational 173.6 100.0 195.0 160.0
Research
Development 226.6 317.0 506.0 486.0
Research
SOURCE: Research Funding Strategy: ICOC Board Meeting (March 21,2012), agenda Item #9 (CIRM, 2012e).
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.
UC Davis MSC engineered to produce BDNF for the treatment of Wheelock-
Huntington’s disease
UCLA Genetic re-programming of stem cells to fight cancer
UC Davis Treatment of osteoporosis with endogenous mesenchymal stem cells
UC Davis Phase I study of IM injection of VEGF-producing MSC for the treatment of
critical limb ischemia
Stem Cells Inc. Neural stem cell transplantation for chronic cervical spinal cord injury
Stanford University Human embryonic stem cell-derived cardiomyocytes for patients
with end stage heart failure
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
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-7
This latest round of disease team awards brings the total funding for this program to roughly
$360 million, and CIRM-supported late-state 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.
GRANT REVIEW AND FUNDING PROCESS
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 by the committee to 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, as 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 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
4
See Appendix B for a summary of the questionnaire responses.
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4-8 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
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 preapplication, 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
questionnaire5, 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 preapplication 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 suggests that CIRM consider ways of offering applicants more
information on the shortcomings perceived in preapplications that were not selected for further
consideration.
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, are 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 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
5
See Appendix B for a summary of the questionnaire responses.
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-9
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 have the opportunity to make an “extraordinary petition” to the ICOC. Any ICOC
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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, 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). While 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
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
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-11
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.
INDUSTRY ENGAGEMENT
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.”6 Chapter 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
6
California Stem Cell Research and Cures Initiative, Proposition 71 (2004) (codified at California Health and Safety
Codes § 125291.10-125291.85).
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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 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 FDA
to overcoming regulatory hurdles and facilitating 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
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-15
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 since 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.
Grant Review
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 members of the GWG. 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
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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 preapplication 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, members of the ICOC (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 composition of the ICOC, 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 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
8
See Nature 486: 169-171 (June 14, 2012).
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-17
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 4-2.9 Restructure 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:
9
CIRM may need to work with the state legislature in order to fully implement this recommendation.
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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.
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, be 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.
Bioethics
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
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-19
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 through 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
10
Proposition 71, 125290.35, b1 and b2.
11
Proposition 71, 125290.55 b2 and b5.
12
The 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.
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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 4-3.13 Fund 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.
Industry Engagement
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.
13
In the committee’s view, this recommendation can be carried out by CIRM without legislative action.
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-21
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 4-4.14 Enhance 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.
14
CIRM may need to work with the state legislature in order to fully implement this recommendation.
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CIRM. 2010a. RFA 10-04: CIRM basic biology awards III. http://www.cirm.ca.gov/RFA_10-04
(accessed August 27, 2012).
CIRM. 2010b. RFA 10-02: CIRM tools and technology awards II. http://www.cirm.ca.gov/RFA_10-02
(accessed August 27, 2012).
CIRM. 2010c. RFA 10-01: CIRM early translational II research awards.
http://www.cirm.ca.gov/RFA_10-01 (accessed August 29, 2012).
CIRM. 2010d. RFA 10-03: CIRM targeted clinical development awards.
http://www.cirm.ca.gov/RFA_10-03 (accessed August 29, 2012).
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NATURE, SCOPE, AND ACCOMPLISHMENTS OF THE CIRM SCIENTIFIC PROGRAM 4-23
CIRM. 2010e. RFA 10-05: CIRM disease team therapy development awards.
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CIRM. 2011a.* Collaborations_CIRM CFPs as of Nov 2011. CIRM’s response to IOM’s data request:
list of international organizations/companies that work with CIRM (dated December 2, 2011)
(accessed October 19, 2012).
CIRM. 2011b.* Collaborations info re. CFPs productivity evaluation. CIRM’s response to IOM’s data
request: provide data about all collaborations from 2006 to the present including origination of the
collaboration, nature of the collaboration, how the collaboration was funded and monies spent, how
the collaboration was managed (dated December 2, 2011) (accessed October 19, 2012).
CIRM. 2011c. CIRM approves $27 million for initiatives to accelerate promising stem cell research
projects. http://www.cirm.ca.gov/PressRelease_2011-12-08 (accessed August 27, 2012).
CIRM. 2011d.* GWG review process for CIRM pre-applications. CIRM’s response to IOM’s data
Request: Documentation describing the peer review process (dated December 19, 2011) (accessed
October 19, 2012).
CIRM. 2011e.* Report on CIRM’s trial pre-application process. CIRM’s response to IOM’s data request:
Documentation describing the peer review process (dated December 19, 2011) (accessed October 19,
2012).
CIRM. 2011f. CIRM loan administration policy.
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CIRM. 2011g.* CIRM review process. CIRM’s responses to IOM’s data request: Documentation
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CIRM. 2011h. RFA 11-02: CIRM early translational III research awards.
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early-translational-awards-iii (accessed August 29, 2012).
CIRM. 2012a. Strategic plan update: Accelerating the opportunity for cures.
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19, 2012).
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CIRM. 2012f. Stem cell agency commits $150 million to develop new therapies.
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CIRM. 2012g.* The response from the Grants Working Group (GWG) represents the scientific GWG
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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) (accessed
November 12, 2012)
CIRM. 2012i. RFA 12-03: CIRM hiPSC derivation award. http://www.cirm.ca.gov/RFA/rfa-12-03-cirm-
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EAP (External Advisory Panel). 2010. Report of the External Advisory Panel.
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2012).
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4-24 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
IOM (Institute of Medicine). 2012a.* Conversation with former director of Cancer Stem Cell Consortium
in Canada. Institute of Medicine Committee on Review of California Institute for Regenerative
Medicine open call on June 7, 2012. (accessed October 19, 2012).
IOM. 2012b.* Conversation with Director of the NIH Intramural Center for Regenerative Medicine.
Institute of Medicine Committee on Review of California Institute for Regenerative Medicine open
call on June 8, 2012. (accessed October 19, 2012).
IOM. 2012c.* Conversation with CIRM’s international partners in Germany. Institute of Medicine
Committee on Review of California Institute for Regenerative Medicine open call on July 5, 2012.
(accessed October 19, 2012).
IOM. 2012d.* Questionnaire for CIRM principal investigators. Institute of Medicine Committee on
Review of California Institute for Regenerative Medicine Online Questionnaire launched on February
8, 2012. (accessed October 19, 2012)
IOM. 2012e.* Conversation with CIRM’s ICOC member regarding the review process. Institute of
Medicine Committee on Review of California Institute for Regenerative Medicine open call on June
28, 2012. (accessed October 19, 2012)
IOM. 2012f.* Roundtable discussion of CIRM’s scientific impact. IOM Committee on Review of CIRM
Subcommittee Meeting with Boston Stem Cell Scientists on June 26, 2012, Boston, MA. Washington,
DC: The National Academies Press.
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 asterisk (*) are public access files. To access those documents, please contact The
National Academies’ Public Access Records Office at (202)334-3543 or paro@nas.edu.
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