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1
Introduction and Context
On November 2, 2004, Proposition 711 (The California Stem Cell Research and Cures Act,
reproduced in Appendix C) was adopted by the voters of California. Its purpose was to provide
substantial state support for a comprehensive in-state stem cell research program or, more
broadly speaking, to make a significant investment in biomedical research within the field of
regenerative medicine in California. Proposition 71 also amended the state constitution to
provide freedom to conduct pluripotent and progenitor stem cell research and established a
distinctive model of both governance and long-term finance for this publicly financed activity in
biomedical research.2 In 2005, the California Institute for Regenerative Medicine (CIRM),
charged by Proposition 71 with determining the most effective means of distributing $3 billion in
state funds for stem cell research over at least 10 years, was created and began its operations.
CIRM’s principal aims were to accelerate certain critical aspects of the science of regenerative
medicine, emphasizing pluripotent stem cell and progenitor cell research and other vital medical
technologies, and its translation into the treatment of a spectrum of currently intractable human
diseases. In addition, CIRM sought to establish California as one of the world’s principal hubs
in this area of biomedicine.3 Under the terms of Proposition 71, the Institute was to be governed
by an Independent Citizens Oversight Committee (ICOC).
In both its formation and its ongoing operations, CIRM has sought advice from a wide range
of sources and has been the subject of a series of external evaluations. During the initial
campaign for Proposition 71, the California Research and Cures Coalition, comprising the
principal advocates for Proposition 71, consulted from time to time with the National Academy
of Sciences (NAS) and the Institute of Medicine (IOM), as well as others, as they designed the
proposition’s details. Once established, CIRM again consulted the NAS and IOM for help in
establishing the initial set of ethical guidelines for its research program (IOM, 2005). In addition,
a number of studies have been commissioned to assess the potential economic impact of CIRM’s
activities. One such study, by the Analysis Group (Baker and Deal, 2004), preceded the
1
California Stem Cell Research and Cures Initiative, Proposition 71 (2004) (codified at California Health and Safety
Codes § 125291.10-125291.85).
2
In September 2002, California had enacted a law to permit research involving human embryonic stem cells.
California Health and Safety Codes § 123440, 24185, 12115-7, 125300-320.
3
Operations were delayed for more than a year by various legal challenges to Proposition 71, but the courts of
California ruled decisively against these challenges. During this delay, CIRM initiated its operations through
financing provided by private philanthropy and a loan from the State of California.
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1-1
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1-2 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
Institute’s establishment, and two others (an update by the Analysis Group [Baker and Deal,
2008] and an independent study by Jose Alberro [2011]) were completed more recently. In 2009,
California’s Little Hoover Commission, responding to a suggestion by two California legislators,
undertook an evaluation of CIRM’s governance structure, its conflict of interest policies, and its
responsibilities in the area of accountability.4 The Commission issued a report suggesting some
significant changes in these areas, only a few of which CIRM adopted (LHC, 2009).5 In addition,
every 2 years, as required by California law, CIRM must report on the quality of its system of
internal control. In 2012, as required under Senate Bill (SB) 10646 (2010, also reproduced in
Appendix D), which amended certain provisions of Proposition 71, CIRM underwent an
independent performance review aimed at evaluating its administrative procedures and its
compliance with various responsibilities as laid out in both Proposition 71 and SB 1064 (Moss
Adams, LLP, 2012). Finally, in 2010 CIRM convened a broad-based External Advisory Panel
(EAP) comprising a distinguished international group of scientists, industry representatives, and
global health leaders to assess the broad nature of CIRM’s scientific program and future plans
(EAP, 2010). The EAP’s report encouraged CIRM to continue its programs, but with a sharper
emphasis on moving research in regenerative medicine toward clinical applications. Reports
resulting from these various reviews have in general been highly positive, although, as noted
above, the Little Hoover Commission made a series of recommendations, some echoed in the
recent performance review (Moss Adams, LLP, 2012), regarding more efficient/effective
governance and administration.
STATEMENT OF TASK AND STUDY APPROACH
In 2010, as CIRM approached the midpoint of its 10-year state funding horizon, it asked the
IOM to provide an independent assessment of the process through which it was established and
of its programmatic and scientific scope, organizational and management systems, funding
model, and intellectual property policies. The IOM Committee on a Review of the California
Institute for Regenerative Medicine, comprising experts in developmental biology, stem cell
research, research administration, bioethics, economics, business administration, finance,
program evaluation, intellectual property, consumer perspectives, and policy, was assembled in
2011 to critically review the Institute and produce a report containing recommendations for ways
in which it could improve its performance. The committee’s statement of task is presented in
Box 1-1.
4
The Little Hoover Commission is an independent state oversight agency whose mission is to investigate state
government operations with the aim of promoting efficiency, economy, and improved service. The Commission
selects its own agenda in deciding which government operations it wishes to study.
5
CIRM’S response to the Little Hoover Commission’s report (CIRM, 2012).
6
California Legislature (Sen. Bill No. 1064), approved by Governor September 30, 2010. Filed with Secretary of
State September 30, 2010.
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INTRODUCTION AND CONTEXT 1-3
BOX 1-1
Statement of Task
The California Institute for Regenerative Medicine (CIRM) asked the Institute of Medicine
(IOM) to convene a committee to produce a report providing an independent assessment of
CIRM’s programs, operations, strategies, and performance since 2005. Specifically, the
committee was charged with addressing the following questions:
CIRM’s initial processes—What can be learned from the history and process of
building consensus in the public and scientific communities to support the inception
and work of CIRM?
CIRM’s programmatic and scientific scope—Does CIRM have the portfolio of
projects and grant opportunities necessary to meet its scientific goals? How can CIRM
improve upon its existing array of programs? What additional programs and initiatives
are recommended to meet its goals? What impacts have been seen from international
agreements? Does CIRM’s scientific strategic plan address the range of relevant
issues in regenerative medicine within CIRM’s mandated scope of work?
CIRM’s organizational and management systems—Are the internal organizational
and management systems (in particular the board and working group structures and
operations, the peer review system, the conflict of interest guidelines, and the grants
management system) effective in working toward the institute’s scientific goals? Are
the systems that are in place scientifically and ethically valid and rigorous? Do they
achieve the level of transparency and the level of stakeholder and scientific
community involvement needed to meet the institute’s public responsibilities and
scientific goals?
CIRM’s funding model—Has the funding model for CIRM had an impact on the work
of the institute? What are the advantages of CIRM’s model for covering long-term
costs of medical research? Could aspects of this funding model serve as a paradigm
for other states or countries? What has been the economic impact of CIRM’s research
and facilities awards and grants?
CIRM’s intellectual property policies—What are the strengths and weaknesses of
CIRM’s policy for sharing revenue generated by intellectual property? How does this
model compare to the model governing federally-supported research?
The principal objective of this review was to ensure that all aspects of CIRM’s operations are
functioning at peak performance. The committee was asked to provide recommendations
regarding short-, medium-, and long-term actions that could improve the performance of
CIRM.
The committee used several methods for data collection. First, it held five meetings and
hosted three public meetings (one in Washington, DC, and two in California) to gather
information on topics related to the study charge and to hear stakeholder perspectives on the
operations of CIRM. The committee also received an extensive set of documents from CIRM
describing its history, structure, operations, and policies; reviewed previous reports, detailed
above, evaluating various aspects of the Institute; and gathered information through several
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1-4 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
questionnaires.7 In addition, committee members visited three institutions that receive CIRM
funding for facilities, research, and training to review some of the facilities funded by CIRM, to
speak with both CIRM-funded investigators and the leaders of these institutions, and to learn
firsthand about the CIRM-funded work being conducted.8 The study methods are described more
fully in Appendix A.
The purpose of this report is to present the committee’s assessment of CIRM’s organization,
policies, and performance. The committee’s findings, conclusions, and recommendations are
intended to address particular aspects of CIRM’s operations and to assist the Institute in its future
planning. Additional audiences for the report include other entities that fund biomedical research,
policy makers, researchers, and the public.
It is important to be clear that this committee was not asked to assess the wisdom of the
California voters in passing Proposition 71. However, many of the detailed provisions of
Proposition 71 directly impact aspects of CIRM’s operations that the committee was asked to
evaluate in its statement of task. For example, Proposition 71 details certain aspects of CIRM’s
management and governance structure, as well as its funding model. The committee was not
charged with rigorously evaluating the details of CIRM’s scientific contributions, specific grant
awards, or its impact on the field of regenerative medicine; however, the committee did examine
CIRM’s overall scientific priorities and the quality of the processes instituted to guide its funding
priorities and decisions. In summary, the conclusions expressed throughout this report address
some of the unique aspects of CIRM’s beginnings, its governance structure, its policies, and its
ongoing efforts. The report considers the vitality and success of the important dimensions of the
Institute’s activities and presents the committee’s assessment of whether this is a useful model
for others to consider. Finally, the report is intended to help CIRM consider the best path forward
as it works to meet its obligations to the citizens of California and the field of regenerative
medicine. The remainder of this chapter briefly reviews the character and potential of stem cell
research and the controversy that provides the historical context for the creation of CIRM.
CHARACTER AND POTENTIAL OF STEM CELL RESEARCH
Research on stem cells remains an important area of biomedical research because of its
anticipated potential to yield new and more effective treatments for a wide variety of diseases.
Stem cells have the critical characteristic that they can self-renew and also differentiate into a
variety of specialized cell types (NIH, 2010; The National Academies, 2009). There are two
major types of stem cells—adult and embryonic. Adult stem cells, sometimes referred to as
“tissue-specific” or “somatic,” generally are thought to have more limited developmental
potential—for example, giving rise only to cells within a particular tissue or organ. Human
embryonic stem (hES) cells are pluripotent cells derived from the inner cells of the 3- to 5-day-
old embryo (the blastocyst), which give rise to the entire body of the human organism (Thomson
et al., 1998) and retain the potential to differentiate into almost all types of cells (ISSCR, 2011).
More recently, scientists have been able to reprogram differentiated adult cells into cells that
closely resemble hES cells (Takahashi and Yamanaka, 2006; Takahashi et al., 2007); however,
the full therapeutic and scientific potential of these induced pluripotent stem (iPS) cells requires
7
The committee wishes to acknowledge the assistance of CIRM staff in expeditiously assembling a great deal of
information for this study.
8
The institutions visited were the University of California, San Francisco; Stanford University; and the University of
California, Davis.
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INTRODUCTION AND CONTEXT 1-5
continued exploration (Robinton and Daley, 2012). Both hES and iPS cells are often referred to
as pluripotent stem cells because they have, in principle, the capability to give rise to all adult
tissues.
The ability of these different types of stem cells to self-renew and differentiate into more
mature cell types is the foundation of the regenerative medicine field, providing hope for
repairing or supplementing a patient’s damaged tissue (Robinton and Daley, 2012). Furthermore,
stem cell therapy, if successfully developed, could potentially treat diseases, such as Parkinson’s
disease, type 1 diabetes, and spinal cord injury, for which current forms of therapy are less than
adequate, and although even more challenging, could potentially be used in treatment of other
serious diseases that historically have had poor outcomes, such as Alzheimer’s disease, stroke,
and some types of cancer. Another use of stem cells is to help test and develop new drugs
(Grskovic et al., 2011). Since pluripotent stem cells can differentiate into a variety of
differentiated cell types, drug testing can be performed on these cells before clinical trials are
conducted on human subjects, making it possible to test the drugs’ effectiveness and adverse
effects more efficiently, particularly in patient-specific stem cell lines (Yu and Thomson, 2010).
Pluripotent stem cells (both hES and iPS) derived from patients with specific diseases have also
proved useful in studying disease pathogenesis. This has been clearly demonstrated for “cell-
autonomous” diseases such as long QT syndrome, in which cardiomyocytes differentiated from
patient-specific pluripotent stem cells display the abnormal electrophysiologic phenotype
characteristic of the disease. Regenerative medicine can be defined as the process of creating
living, functional tissues to repair or replace tissue or organ function lost due to age, disease,
damage, or congenital defects. This can be done through a variety of approaches including the
replacement of tissue function with synthetic constructs (artificial organs) an using cellular
therapies such as stem cells or genetically modified cells to generate new tissues and organs
(ESF, 2012).
THE STEM CELL CONTROVERSY
Since the derivation of hES cells involves the destruction of human embryos, the scientific
community and others immediately recognized that the use of these cells raises important ethical
questions regarding the moral status of the embryo; whether research that involves the
destruction of embryos is morally acceptable; and if so, whether such research should be funded
by federal or state governments. Given the continuing and sharply different perspectives on these
key ethical issues, the controversy regarding the appropriateness of public funding for research
that requires creating and/or using hES cells has remained unresolved. The tension between this
unsettled ethical controversy and the perceived potential of this new area of biomedical research
is reflected in the fact that Presidents Clinton, George W. Bush, and Obama all found it
necessary to clarify their differing views on these matters by issuing a series of policy guidelines
governing the provision of federal funds for research that involves creating and/or using hES
cells.9
9
See National Institute of Health Guidelines for Research Using Human Pluripotent Stem Cells (65 Fed. Reg.,
51976-51981 [2000]) for the Clinton Administration’s policy; Address to the Nation on Stem Cell Research from
Crawford, Texas (37 Weekly Comp. Pres. Doc. 1149 [August 9, 2001]) for the Bush Administration’s policy; and
Removing Barriers to Responsible Scientific Research Involving Human Stem Cells (74 Fed. Reg. 10667 [2009]),
and National Institute of Health Guidelines for Human Stem Cell Research Notice (74 Fed. Reg. 32170 [2009]) for
the Obama Administration’s policy.
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1-6 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
It is also important to recall that the controversy over federal funding of research using
human embryos or aborted fetuses predates these more recent developments in stem cell
research. Embryo research was, for example, the focus of considerable controversy in the mid-
1990s, which led to the Dickey-Wicker Amendment of 1995 forbidding the expenditure of
federal funds for research that created or harmed human embryos. Indeed, as early as the 1960s,
scientists were already experimenting with the use of aborted human fetal tissue in an effort to
understand human development (e.g., August et al., 1968; IOM, 1994; NIH, 1994). As a matter
of policy, however, no federal funding was available for research using human embryos during
the administrations of Presidents Regan and George H.W. Bush.
This moratorium on federally funded research using human fetal tissue was lifted, with
certain restrictions, relatively early in the administration of President Clinton.10 Very soon
thereafter, however, President Clinton further clarified his views to ensure that federal funds
would not be used for research involving the destruction of human embryos.11 After Thomson
and colleagues (1998) had demonstrated the possibility of creating and sustaining hES cell lines,
the Clinton Administration, through the National Institutes of Health (NIH), issued guidelines in
2000 for grants funding hES cell research. No federal funding was to be allowed for the creation
of new hES cell lines, and in fact, no grants for research with hES cells were issued before the
end of the Clinton Administration.12
The administration of George W. Bush took an immediate interest in this controversy, and on
August 9, 2001, the President announced that federal funds would be available only for work
with hES cell lines that had been developed prior to that date.13 The impact of this new policy
was widely debated in the scholarly and disease advocacy communities.14 In fact, because NIH
was unable to take the lead in this area, the National Academies convened a committee to draft
voluntary guidelines for hES cell research (NRC and IOM, 2005).
In March 2009, shortly after taking office, President Obama issued an executive order
allowing NIH support for hES cell research to the extent permitted by law. Executive Order
13505—Removing Barriers to Responsible Scientific Research Involving Human Stem Cells—
states that the Secretary of Health and Human Services, through the director of NIH, “may
support and conduct responsible, scientifically worthy human stem cell research, including
human embryonic stem cell (hESC) research, to the extent permitted by law”15 Recognizing the
controversial ethical issues involved, the new guidelines, issued in July 2009, contain provisions
designed to ensure informed consent from donors, address potential conflicts of interest, and
limit federal funding to research on hES cell lines derived from embryos originally created for
reproductive purposes. Specifically, the guidelines state that, to be eligible for federal funding,
hES cell lines must be created from embryos that were produced for reproductive purposes and
10
National Institute of Health Revitalization Act of 1993, Public Law 103-43, 107 Stat. 122 (1993), 42 U.S.C. § 201.
11
Statement on the Federal Funding of Research on Human Embryos, 30 Weekly Comp. Pres. Doc. 2459 (December
2, 1994).
12
National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells (65 Fed. Reg., 51976-
51981 [2000]).
13
Address to the Nation on Stem Cell Research from Crawford, Texas, 37 Weekly Comp. Pres. Doc. 1149 (August 9,
2001).
14
Approximately 1 month after the President’s announcement, an NAS report and an unpublished NIH analysis both
stated that additional hES cell lines would have to be available to federally funded researchers to fulfill the promise
of research announced in 2001 (NRC, 2002). In addition, several studies have examined the geographic distribution
of publications in the field (e.g., Levine, 2008; Owen-Smith and McCormick, 2006).
15
Removing Barriers to Responsible Scientific Research Involving Human Stem Cells (74 Fed. Reg. 10667 [2009]).
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INTRODUCTION AND CONTEXT 1-7
are no longer needed for that purpose, that the embryos used to produce the lines must be
donated by individuals who sought reproductive treatment and who have given voluntary consent
for the embryos to be used for research purposes, and that no payments—cash or in kind—must
be offered for the donated embryos. NIH also established a stem cell working group to formulate
recommendations for the NIH Advisory Committee to present to the director regarding the
acceptability of lines that predate the new guidelines. With the new guidelines in place, 178 hES
cell lines have been approved by NIH as being eligible for federal funding (as of August 30,
2012).
In August 2009, a suit was filed in United States District Court to block the Department of
Health and Human Services (HHS) from implementing the new guidelines on the grounds that
they were in violation of the Dickey-Wicker Amendment.16 In August 2010, the court ruled in
favor of the plaintiffs and issued a preliminary injunction ordering HHS to cease funding
research using hES cells. The Obama Administration appealed this decision to the U.S. Court of
Appeals for the District of Columbia Circuit, which resulted, in September 2010, in a
preliminary stay of the injunction and then, in April 2011, its reversal. Following this decision, in
July 2011, the underlying case was decided in District Court in favor of the Obama
Administration. This ruling has been appealed to the U.S. Court of Appeals for the District of
Columbia, and as of this writing, a final decision is being awaited.
Thus the last decade and a half has seen continuing uncertainty regarding the federal
government’s willingness to fund research using hES cells—an ongoing disappointment to those
scientists and other citizens who believe the nation is foregoing a highly promising opportunity
to relieve human suffering. Given that the federal government has traditionally been the largest
source of funding for biomedical research outside of industry and the largest funder of basic
research, it appeared to some that the United States was foregoing an important opportunity to be
a pioneer in developing the basic research necessary to produce critical new clinical applications.
Within industry itself, the uncertainty surrounding both state and federal policies on this research
also has produced some hesitancy to enter this research arena. It was in this context that a broad
group of California-based scientists, leaders in California higher education, disease advocates,
and others mounted the Proposition 71 initiative.
Since the early years of this century, when the campaign for CIRM was energetically under
way, a great deal of progress has been made in stem cell research. In particular, the increased
ability to reprogram adult cells has made the field of regenerative medicine somewhat less
dependent on hES cells, a development that is fully reflected both in CIRM’s programs and the
field of regenerative medicine worldwide. Indeed, this is one of the key factors that CIRM has
considered in updating its strategic plan. These issues are discussed more fully in Chapter 4.
ORGANIZATION OF THIS REPORT
The remainder of this report presents the results of the committee’s response to its statement
of task (Box 1-1), including its findings, conclusions, and recommendations; Table 1-1 shows
where in the report each element of the statement of task is addressed. Chapter 2 provides an
overview of the process by which CIRM was created and the committee’s assessment of what
can be learned from this history, as well as the impact of the Institute’s funding model and
whether it might serve as a model for other states or countries. This chapter also provides, for
16
Sherely et al. v. Sebelius et al., 686 F. Supp. 2d 1 (D.D.C. 2009).
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1-8 THE CALIFORNIA INSTITUTE FOR REGENERATIVE MEDICINE
comparative purposes, a review of analogous efforts by other states. Chapter 3 assesses the
effectiveness of CIRM’s governance structure, including issues of conflict of interest. Chapter 4
evaluates CIRM’s scientific and programmatic scope and how the organization can improve its
processes and programs to better meet its goals. Finally, Chapter 5 provides an assessment of
CIRM’s intellectual property policies.
The committee’s findings are presented throughout these chapters; each chapter ends with the
committee’s conclusions and recommendations on the respective topic. It is important to note
that CIRM is in a constant state of transition in various aspects of its work as it adapts to its own
experience, to rapid scientific developments in regenerative medicine, to some public concerns,
and to its own concerns regarding its longer-term financial condition. This assessment is as
current as the committee could make it, but inevitably some further changes in response to these
various influences are under way even as the committee completes this report.
TABLE 1-1 Elements of the Study Charge and Chapters Where They Are Addressed
Element of Charge Chapter
CIRM’s initial processes—What can be learned from the history and process 2
of building consensus in the public and scientific communities to support the
inception and work of CIRM?
CIRM’s programmatic and scientific scope—Does CIRM have the portfolio 4
of projects and grant opportunities necessary to meet its scientific goals? How
can CIRM improve upon its existing array of programs? What additional
programs and initiatives are recommended to meet its goals? What impacts
have been seen from international agreements? Does CIRM’s scientific
strategic plan address the range of relevant issues in regenerative medicine
within CIRM’s mandated scope of work?
CIRM’s organizational and management systems—Are the internal 3
organizational and management systems (in particular the board and working
group structures and operations, the peer review system, the conflict of interest
guidelines, and the grants management system) effective in working toward the
institute’s scientific goals? Are the systems that are in place scientifically and
ethically valid and rigorous? Do they achieve the level of transparency and the
level of stakeholder and scientific community involvement needed to meet the
institute’s public responsibilities and scientific goals?
CIRM’s funding model—Has the funding model for CIRM had an impact on 2
the work of the institute? What are the advantages of CIRM’s model for
covering long-term costs of medical research? Could aspects of this funding
model serve as a paradigm for other states or countries? What has been the
economic impact of CIRM’s research and facilities awards and grants?
CIRM’s intellectual property policies—What are the strengths and 5
weaknesses of CIRM’s policy for sharing revenue generated by intellectual
property? How does this model compare to the model governing federally-
supported research?
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INTRODUCTION AND CONTEXT 1-9
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