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Cell Stem Cell

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Developing a Case Study Model

for Successful Translation of Stem Cell Therapies
Alan Trounson,1,* Elona Baum,1 Don Gibbons,1 and Patricia Tekamp-Olson1
1California Institute for Regenerative Medicine, 210 King Street, San Francisco, CA 94107, USA

*Correspondence: [email protected]
DOI 10.1016/j.stem.2010.05.008

Cell therapies derived from pluripotent stem cells are entering the preclinical and early clinical development
phase, but eventual translation faces many challenges. We describe a new approach by California to form
global public-private ‘‘disease team’’ partnerships to enable new clinical opportunities to be evaluated in
the complex regulatory environment.

There are three key elements that must be search would be expected to reach the date therapy may be more productive in
present to ensure the clinical translation of clinic more quickly than pluripotential looking at new measures of risk. Also,
candidate stem cell therapies. The first stem cell treatments or even genetically since existing cell-based therapies,
two are obvious. There needs to be modified adult cells. Yet, with the field largely from bone marrow, have generally
adequate funding, and the therapies promising to significantly alter healthcare relied on academic-based clinical trials
need to be shown to be safe and effi- by delivering not just incremental and early roll-out, creating those partner-
cacious in accordance with regulatory improvements but potentially cures, this ships that include clinical staff at the
requirements. Third, and perhaps less is an area that warrants investment and, beginning can cut steps and time to
obvious, is in order to accelerate and even in these difficult economic times, a marketable product.
perhaps even succeed in demonstrating public financial support. A test case of this hypothesis is
safety and efficacy of these novel thera- With most funding sources pressuring now underway. In October 2009, the
pies, researchers need to work in multi- research to increase speed to the market California Institute for Regenerative Medi-
disciplinary, collaborative teams (U.S. at the same time the Food and Drug cine (CIRM) awarded 14 Disease Team
Department of Health and Human Administration (FDA) and other regulators Awards (CIRM, 2009), averaging over
Services, 2005). are showing caution with some new U.S. $16 million each, and involved
The opportunity for stem cell science to avenues to therapy, industry publications some level of academic-industry partner-
lead to therapeutic benefit is increasing as and conferences have started to discuss ships to achieve the team goal of filing an
evidenced by rapid advances and repro- the theory that the best way to increase Investigational New Drug (IND) applica-
ducible results in so many parts of the speed to market without increasing risk tion within 4 years to begin a clinical trial.
field from self-renewal and differentiation is via industry-industry collaboration and Four of the five awards for pluripotent-
to reprogramming pluripotentiality. There cooperation to solve the common preclin- derived therapies have industry participa-
are also challenges to realizing this oppor- ical chalenges in the precompetitive tion, as do three of the five genetically
tunity. The business climate is presently space (Brainloop, Inc., 2010; Cambridge manipulated adult stem cell therapies.
difficult, but it seems to be particularly Health Institute, 2010). We postulate that Two of the three targeting cancer stem
challenging for therapies originating from while this aspect of collaboration can cells have industry participants. In these
pluripotent stem cells or genetically help, a broader, more effective way to first awards, the grants were awarded
manipulated adult stem cells. Venture accelerate the path from research bench based on scientific merit and the potential
capital is increasingly risk-averse and to clinic is to foster academic-industry to achieve an IND filing. Hence, several
intolerant of waiting for long-term pay- collaborations that are structured in grants targeted the same disease. Given
outs. Product regulatory bodies are acting a manner that is more focused than these the probability of success for any of the
with caution, and insurers and healthcare relationships have been in the past. awards is far from assured, CIRM decided
payers have yet to determine whether Academic stem cell biologists and those not to restrict the awards programmati-
health-care reform will allow them to clinicians who will be responsible for cally on this occasion.
benefit from regenerative therapies that testing these treatments can answer
are likely to require many years to accrue questions that are blocking a particular Incentives for Translational
sufficient savings to cover upfront costs. path to the clinic and may be able to Research
Sustained funding will be critical take advantage of more favorable As Dr. Susan Desmond-Hellmann, Chan-
because the complex nature of the licensing and Material Transfer Agree- cellor of UCSF and former President of
delivery and monitoring of stem cell treat- ments (MTAs) offered to academia. Product Development at Genentech,
ments will result in an extended time A discussion on risk involving regulators, stated at CIRM’s recent grantee confer-
frame for development of many therapies. industry and academic team members, ence, ‘‘what matters to patients is not
Candidate small molecule and protein patient advocates, and clinicians who that these therapies get into a clinic, but
therapeutics arising from stem cell re- will be involved in delivery of the candi- rather that they ultimately get approved

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for wide use in patients.’’ It is not getting searchers has dramatically incentivized Cell Consortium, the UK Medical Re-
into clinical trials that matters; it’s getting the research community. There are search Council, the Japanese Science
commercial approval for use in all patients a very large number of applications and Technology (JST) organization, the
that could benefit. This requires funding of submitted to CIRM in response to calls Chinese Ministry of Science and Tech-
the complete program from preclinical for applications, many with merit for nology, Spanish Ministry of Science and
translational studies to the safety and support. Innovation, German Ministry of Education
proof of concept of benefit to patients, and Research, and the U.S. State of Mary-
commonly referred to as Phase I and Global Collaborations Accelerate land and the New York Stem Cell Founda-
IIA/B clinical trials. There is very little fund- Research Benefits tion.
ing available from investment financing or Team research is effective in achieving Globalizing collaborations provides
pharmaceutical company support for this high impact developments because of opportunities for different communities
component of the development chain. its speed of producing innovative high to participate in the development of
It is necessary for private foundations quality data. This is true on a national a new area of research and to ensure
and public funding initiatives, such as scale and an international scale, but there that the priorities of these communities
NIH’s expenditures on Clinical and Trans- are relatively few funding bodies that are included in determining the direction
lation Science Centers, to fill the void left support international collaborations of the research. Consequently the
by the virtual exit of angel funders (inves- between multiple public and private emphasis on cancer stem cells is driven
tors interested for simply programmatic teams. The European Framework Pro- by both Californian and Canadian
reasons) and venture capital from the gramme and NIH have such collaborative researchers as a priority for their commu-
translational phases of stem cell research. initiatives, but they are limited in number nities. Certain diseases that may domi-
In the present difficult economic environ- and in the level of funding available for nate in one community may be less
ment, it is challenging to persuade translational research. While some coun- frequent in another but collaborative
government to contribute to funding tries have some private-public funding research tends to be inclusive of these
medical research despite the acknowl- mechanisms, they are still relatively rare needs. For example, the need for afford-
edged economic return of such invest- and don’t provide comprehensive funding able cures for diseases such as HIV/
ments because the benefits are long for the full translational process, particu- AIDS and malaria becomes evident
term and budget shortfalls are acute larly for stem cell research. One partial when global health priorities are consid-
(Murphy and Topel, 2003; Health exception is seen in Spain, in the form of ered.
Economics Research Group, 2008). The the Andalusian Initiative for Advanced
long-term benefits for the economy and Therapies (Cuende and Izeta, 2010, this Regulatory Approval: Drugs
for health require funding that is reliably issue). Klein and Trounson have argued and Biologics versus Cell Therapies
sustained for decades. This enables the that state or international bond funded While CIRM’s funding of the translational
discovery process to mature and the initiatives for such purposes can be phases of the research pipeline will
translational phase to support proof of a very effective approach to stimulate provide the critical financial support
concept. Few public agencies adequately these arrangements with little direct influ- needed to meet the first condition laid
support the translation phase, and even ence on public debt repayments before out above for success in this field, the
those that do require multiple grant appli- substantial economic returns are gener- second element, proving safety and effi-
cation rounds to enable a new product, ated (Klein and Trounson, 2010). They cacy, will be more challenging. Unlike for
such as stem cells, to reach a mature argue returns to California on the bond biologics and small molecules, the regu-
stage attractive for private investment. sales are likely to be substantial as debt latory pathway for stem cell-derived ther-
CIRM has decided to invest signifi- repayments are offset for 5 years in the apeutics is not well defined and, hence,
cantly in preclinical and clinical research capital raising, and taxation benefits not well understood. While the biologic
with grants of up to U.S. $25 million for accrue as buildings are erected and and small molecule industries benefit
pluripotent-derived stem cell candidate academic and biotechnology compo- from a well-defined regulatory pathway
clinical trials, up to U.S. $20 million for nents expand. Clinical trials have already and commonly accepted best practices
each ‘‘Disease Team’’ research award been initiated with potentially large for preclinical safety testing, product
and up to U.S. $6 million each for ‘‘Early savings on the state’s healthcare budget characterization, and measures of purity
Translational’’ research awards. These expected. and potency, the same cannot be said
awards are large enough to support CIRM has taken a very proactive role in for product development for the stem
multiple phases of preclinical-clinical creating international collaborative agree- cell industry. Certainly, there are
development through a single grant appli- ments to cofund stem cell research. a number of autologous stem cell thera-
cation and have been supplemented with These agreements enable scientists to pies in clinical trial as well as some allo-
additional funding by collaborative fund- jointly submit research team applications genic adult cell therapies, but pluripotent
ing partners in other nations and, in for review by CIRM’s international review and genetically manipulated stem cell
some instances, further leveraged by panels (excludes Californian reviewers) therapies are experiencing significant
funds from the grantee. and the collaborating national or state delays in entering into the clinic (Plagnol
The size of the grants available and the review panels if necessary. The agree- et al., 2009). While it may be argued
potential to collaborate within California ments include the State of Victoria, that companies need to address signifi-
and with overseas and interstate re- Australia, the Canadian Cancer Stem cant concerns of the regulators, the

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burn rate of capital while waiting for addi- opment are very costly, not only to the manner. These academic-industry part-
tional data and approval to proceed funder but potentially to the patient. There nerships could provide ongoing benefit
makes survival particularly difficult for is clearly a potential symbiotic relation- in future steps as well. It is anticipated
any corporate entity with limited financial ship between academic research talent that, like bone marrow and organ trans-
flexibility (McKernan et al., 2010, this and the know-how of the biotechnology plantation, many new cell therapies are
issue). While the FDA is not insensitive industry. In fact, it is difficult for one to likely to be delivered in tertiary clinical
to the situation, many unknowns remain make major advances without the other settings that will involve academic and
in this new field that can delay approvals, in the present relative absence of signifi- community clinicians and networked
despite the best intentions of all parties. cant venture capital. stem cell clinics that may be partnered
The US federal government has taken The depth of research resources in the with companies supplying specific
steps to address the issue. The FDA is in university sector and the considerable reagents and cell products.
active discussion with industry, in part infrastructure there is of immense value
through the Regenerative Medicine Con- to biotechnology companies that have Public-Private Partnerships for
sortium, which was convened by CIRM limited capital. The companies, in turn, Translation Established by CIRM
and has a mix of industry and academic can keep academic scientists focused Funding
participants. FDA Commissioner Mar- on the critical developments needed for In the area of human embryonic stem cells
garet Hamburg’s emphasis in regulatory regulatory filing. Hence, merging the (hESCs), the studies on dry macular
science may ultimately provide more tools resources provided by companies and degeneration at the University of
and regulatory certainty to the field. Like- academic research institutions can create Southern California, University of Califor-
wise, NIH has declared its intention to the ideal team. nia (UC) Santa Barbara, and University
work with the FDA as well. CIRM has implemented an active team College London are further enhanced
There are concerns that the relative management approach for its multidisci- through collaboration with the company
ease of obtaining regulatory approval for plinary Disease Teams. The approach is Geron and the Center for Applied Tech-
clinical studies for transient cell therapies, based on best practices following discus- nology Development (CATD) at City of
such as those based on autologous bone sion with individuals whose expertise and Hope, which serves as a national
marrow implantations for a wide variety of relevant experience derives from academic biologics manufacturing re-
disorders without solid scientific ratio- academia, the biotechnology and phar- source. Geron and CATD provide cell
nale, may be counterproductive for regu- maceutical industries, and from private banks, cGMP manufacturing, and exper-
latory support of regenerative therapies foundations (CIRM, 2007). tise for regulatory requirements. A study
involving pluripotent stem cell derivatives. Challenges to translational research on ESCs derivatives for treatment of
Others see these as a logical order for the teams include maintaining focus, en- stroke at Stanford University has a collab-
relative risk versus benefit. suring that the scope of the research con- oration with Progenitor Cell Therapy,
ducted best addresses the project goal, a company that provides the expertise in
Developing a Symbiotic Team and maintaining good communication product and assay development and
Approach among team members and with funders. cGMP manufacturing for the therapeutic
In the absence of well-defined regulatory For Disease Team projects, each team is candidate. This team is also working
requirements for the development and required to have a project team leader(s) with SRI whose expertise in toxicological
approval of pluripotential and genetically and a project manager with development testing and their successful record in
manipulated stem cell therapeutics, it is experience to ensure team direction, medical product development are major
necessary to have sufficient innovative focus, energy, and communication. Prior assets. Progenitor Cell Therapy will also
expertise on the team to address the to the start of funding, to further facilitate be participating in the development and
concerns of regulators. The knowledge successful project outcomes, each manufacture of neural stem cells on
base for new developments in stem cell team, together with CIRM, develops behalf of a team at UC San Francisco in
biology generally resides in the academic mutually agreed upon timelines for key support of their efforts to leverage the
research community and in biotechnology project activities and determines mile- homing ability of these cells to deliver
companies with a substantial research stones that reflect critical measures of drugs to treat glioblastoma. The team
capacity or those well connected to project progress and go/no go decision from UC San Diego and the Salk Institute
academic research groups. The points. These, in conjunction with an are working with Life Technologies Inc. for
academic community is, however, gener- activity based budget, help teams to the scale-up, differentiation, and purifica-
ally less well prepared for the highly regu- refine project plans to ensure that all tion of ESCs to astrocyte precursors and
lated aspects of product development, necessary research is conducted, and cGMP manufacturing for treatment of
particularly those relating to toxicological that the time and funding allowed for the Amyotrophic Lateral Sclerosis (ALS). For
testing, consistency, and source of conduct of the research activities are diabetes, the company ViaCyte Inc. has
product as required for cGMP (current sufficient and reasonable. several associations with academia,
Good Manufacturing Practices) manu- The response of the Disease Team including a critical collaboration on
facturing, etc. Academic scientists are, investigators to the new funding format immune modulation with UC San Fran-
in many instances, less familiar with the opportunity has been exceptional, given cisco.
timeline and milestone demands of that academics are rarely organized in For genetically modified adult stem
industry, where delays in product devel- such a targeted and highly focused cells, the team at the City of Hope that

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