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Proceedings: Accelerating Stem Cell Treatments forPatients: The Value of Networks and Collaboration

GEOFFREY P. LOMAX, JOHN ADAMS, CATRIONA JAMIESON, JOHN ZAIA, MARIA T. MILLAN

California Institute for Regenerative Medicine, San Francisco, California, USA

INTRODUCTION

Since the early pioneering cell-based therapeu-tic experiences with bone marrow, cord bloodand peripheral blood stem cells, embryonicstem cell-derived cells, and gene-modified celltherapeutics, the pipeline for stem cell-basedtherapeutics entering clinical trials has grownconsiderably [1]. TheCalifornia Institute for Re-generative Medicine (CIRM) has funded morethan 90 developmental-stage programs with12 accepted investigational new drug applica-tions [2]. This growing pipeline has importantoperational implications for the developmentof stem cell research-derived therapeutics.Specifically, the prospect of pipeline growthcreates an opportunity to develop sustainableclinical capacity dedicated to treating patientswith stem cell-related medicines.In early 2015, CIRM launched the Alpha Clin-

ics Network, which is designed to catalyze thedevelopment of specialized clinical capacity inCalifornia [3]. The clinics are centers of excel-lence that will maintain the clinical and regula-tory expertise needed to deliver what, in manycases, will be first-in-human clinical trials andthat will also have trained personnel, state-of-the-art facilities, stem cell trial counseling, patient carecoordination, and long-term follow-up capacity [4].The Alpha Clinics Network is anchored by

three lead programs at (a) City of Hope Na-tionalMedical Center, (b) theUniversity of Cal-ifornia San Diego, and (c) the University ofCalifornia Los Angeles and Irvine collaborativeprogram. The network is designed to be a plat-form for rigorous clinical testing of stem celltherapies. Each Alpha Clinic is located withinthe host institution as a fully integrated unitthat is enabled to leverage the infrastructureand assets of the institution’s medical centerto support stem cell clinical trials. The AlphaClinics were selected, in part, because theybring a variety of unique assets to the network.Extensive CIRM funding for this initiative is de-signed to allow the clinics to leverage their in-stitutional assets so they may be developed

and adapted to address the unique needs ofstem cell clinical trials.

GENERAL CONSIDERATIONS

Asnewtrialsenter thenetwork, there isanoppor-tunity to develop core infrastructure to supporta variety of stem cell research-informed thera-peutic approaches targeting a diverse array ofindications. The experience gained from theseprojects, and others, will provide further insightsinto a variety of issues related to the clinical test-ing and delivery of stem cell therapies. Havinga platform dedicated to these therapeutic activi-ties creates the opportunity for continuous-looplearning and development of quality systems.CIRM believes such a platform can facilitate theentry of patient treatments into clinical practiceand, ultimately, into commercial success.Each of the network sites will maintain core

infrastructure necessary to support clinical tri-als emerging from its institutional pipeline oroutside sponsors. The network will also sharebest practices and accelerating and added-value resources (AAVRs) while aggregatingexperiences and data that would inform howbest to support future trials and activities withstem cell therapeutics. As available, the AlphaClinics Network would adapt and refine otheroperational efficiency resources of existingresearch networks. Pipeline development is akey component of the Alpha Clinics program.Consequently, an early focus of planning is toidentify ways in which the network can providevalue to outside sponsors.

ACCELERATING AND ADDED-VALUE RESOURCES

The value of a network may be measured in itsability to achieve greater or more efficientresults than the member organizations wouldif they were acting independently [5].There are numerous examples of clinical net-

works forming to address a particular disease in-dication (e.g., cancer) or therapeutic approach(e.g., gene therapy). Networks enhance the de-velopment of patient therapies by leveraging

CIRM was established in Novem-ber 2004 with the passage ofProposition 71, the CaliforniaStem Cell Research and Cures Act.The statewide ballot measure,which provided $3 billion in fund-ing for stem cell research at Cali-fornia universities and researchinstitutions, was overwhelminglyapproved by voters, and called forthe establishment of an entity tomake grants and provide loans forstem cell research.

The Proceedings of the CaliforniaStem Cell Agency is a monthlyseries of commentaries, articles,interviews, webinars, forums, andconcise reviews on a wide range oftopics in regenerative medicine.

Correspondence: Geoffrey P.Lomax, Dr.P.H., California Institutefor Regenerative Medicine, 210King Street, Third Floor, SanFrancisco, California 94107, USA.Telephone: 415-396-9134; E-Mail:glomax@cirm.ca.gov

ReceivedMay 4, 2015; accepted forpublication May 20, 2015.

©AlphaMed Press1066-5099/2015/$20.00/0

STEM CELLS TRANSLATIONAL MEDICINE www.StemCellsTM.com ©AlphaMed Press 2015

VIEWS

participant assets. The National Cancer Institute’s Clinical TrialsNetwork, for example, focusesonavarietyofoperational efficien-cies across clinical activities. Stem cell therapies and regenerativemedicine are ripe for a network approach; the therapeutic pipe-line is robust but unique clinical challenges remain.This concept of network synergy is a fundamental organizing

principle for the Alpha Clinics. Each program has identified spe-cific resources and expertise that it brings to the network. Theseare termed “accelerating and added-value resources.”

Key Focus Areas

The network currently has three primary focus areas for acceler-ating and added-value resources.

Operational Efficiencies

This category of AAVRs encompasses operational considerationsspanning practical aspects of clinical care and business aspectsof fiscal sustainability. An area of clinical focus, for example, ison nursing acuity. A key question to be addressed is, “What isthe optimal staffing of clinical trails based on well-defined compe-tencies?”Nursing acuity is critical for serving patients as effectivelyas possible.The network focus on business sustainability is designed to

consider the areas in which cell-based therapies provide valuein health care. The Affordable Care Act is the major U.S. healthpolicy addressing and rewarding value delivery in care. For cell-based therapies to be successful, their comparative effectivenessagainst the standard of care must bemeasured. Currently, value-based metrics for stem cell therapies are limited. This AAVR willfocus on developing quality and valuemetrics for cell-based ther-apies to support effectiveness evaluation. Aggregating this expe-rience and collecting data are critical in discussions with third-party payers and enabling a data-driven approach to modelingthe best health care delivery model for stem cell therapies.

Shared Resources

This category of AAVRs is designed to leverage assets alreadyexisting at the network sites. Multisite clinical data repositoriesenable patient information to be aggregated and queried for co-hort discovery. The network, for example, can facilitate access tothe University of California Research Exchange (UC ReX), repre-senting approximately 13.6million patient records [6]. Althoughthe patient population is substantial, there is a need to developqueries to identify key patient attributes depending on a pro-posed clinical trial.The network aims to develop the capacity to accrue patients at

multiple clinical sites. To ensure timely and comprehensive enroll-ment, institutional reviewboard reliance agreements are beingde-veloped to allow one review of record for a specific trial. Adoptingbest practices for precontract activities, shared model contracts,and standardized approaches to accessing critical hospital servicesand ancillary support should improve efficiencies and acceleratetimelines.

Knowledge Efficiencies and Outreach

This category of AAVRs is designed to capture an experiencegained across a variety of preclinical and clinical research activi-ties. By addressing knowledge gaps, the network aims to acceler-ate therapeutic pipeline development. The regulatory landscapefor clinical trials with novel stem cell-based therapeutics, for

example, is in a state of dynamic flux and is being constantlyshaped by interactions between the developers and the regula-tory bodies. Pooling knowledge, data, and experience from stemcell clinical networks would be critical for informing regulatoryprocesses and policy. Experience gained from the expandingpipeline of stem cell therapies delivered across clinical sites willstrengthen the evidence base and, in turn, should improve reg-ulatory efficiency.With all these resources and assets in place, the Alpha Clinics

Network would provide access to credible high-quality clinicaltrials and associated information to patients and the public. Inaddition, the network would provide experienced and efficientclinical trial sites for corporate or academic sponsors developingstem cell therapies.

CIRM 2.0 READY

The Alpha Clinics Network is one component of a larger effort byCIRMtoaccelerate development of stemcell treatments. In 2015,CIRM transformed business operations to more efficiently meetpatient care needs, as reflected in a new operational plan calledCIRM 2.0. This plan was designed to place added emphasis onspeed, partnerships, and patients [7]. The processmakes it easierfor companies and academic researchers with promising clinicaltrials to partner with CIRM to obtain the requisite support tolaunch effective trials. One key aspect of the CIRM 2.0 ClinicalStage program is that it provides frequent and predictable fund-ing opportunities. CIRM, for example, accepts proposals for com-pletion of phase I, II, or III clinical trials on amonthly basis [8]. Thusthe Alpha Clinic Network platform and CIRM 2.0 funding oppor-tunities create a powerful synergy designed to accelerate stemcell treatments.A major objective of the Alpha Clinic Network is to support

the efficient conduct of a robust pipeline of stem cell clinicaltrials. The combination of the clinical capacity provided by thenetwork and funding support from CIRM is designed to servethe primary CIRM 2.0 objective: accelerating stem cell treatmentsfor patients with unmet medical needs. The network is open fornational and international collaborations, and CIRM 2.0 cansupport sponsors seeking to bring trials to California regard-less of the location of their corporate headquarters to ensurethat stem cell therapies for a plethora of degenerative disorderscome to clinical fruition.

FURTHER CONSIDERATIONS

The success of individual AAVRs is predicated on building theevidence base with clinical and economic metrics and rigorouslyanalyzing the cumulative clinical trial data to advance patientcare.Patient carecoverageanalysis, forexample,wouldbe informedby shared experience with stem cell clinical trials and would cre-ate efficiencies in obtaining patient coverage, would promotepatient access to these trials, and would provide a collectivedata set to support discussions with third-party payers andorganizations for future coverage models. Uniform quality sys-tems and data sets by which to evaluate performance metricsand cost analysis would be possible within the network. Draw-ing on these types of experience and data sets in early stage tri-als is critical to inform and promote downstream commercialdevelopment.

CIRM Alpha Clinics: Accelerating Treatments

©AlphaMed Press 2015 STEM CELLS TRANSLATIONAL MEDICINE

Network partners see the need for systematic and comprehen-sive data analysis designed to address safety, efficacy, and regu-latory and economic considerations. Currently, the capacity toaggregate data across sites does not restwithin any of the individ-ual Alpha Clinics. CIRM will consider the role of a data coordinat-ing, processing, and reporting center to address this gap. Poolingknowledge, data, and experience from stem cell clinical networkswould be critical for informing regulatory processes and policy,butmost important, it will informpatients about stem cell clinicaltrial-related progress. Experience gained from the expandingpipeline of stem cell therapies delivered across clinical sites willstrengthen the evidence base and, in turn, should improve regu-latory efficiency. In addition, a networkwould allow sharing of ex-pertise for local, national, and international collaborators; studysponsors; other academic and charitable funding organizations;institutional review boards; and data safety monitoring boardsfor stem cell clinical trials.

ACKNOWLEDGMENTS

The CIRMAlpha Clinics Network steering committee is composedof John S. Adams, M.D., Distinguished Professor, Orthopedic Sur-gery, Medicine and Molecular, Cell, and Developmental Biology,

Associate Director, University of California Los Angeles (UCLA)Clinical and Translational Science Institute, Assistant Dean forTranslational Research, Program Director, CIRM Alpha Clinic atUCLA-University of California Irvine Consortium—UCLA; CatrionaJamieson,M.D., Ph.D., Associate Professor ofMedicine, Chief, Di-vision of Regenerative Medicine, Deputy Director, Sanford StemCell Clinical Center, Program Director, CIRM Alpha Clinic at Uni-versity of California (UC) San Diego, Co-Leader, Hematologic Ma-lignancies Program, Moores Cancer Center—UC San Diego; JohnA. Zaia, M.D., Director, Center for Gene Therapy, Aaron D. andEdith Miller Chair for Gene Therapy, Program Director, CIRMAlpha Clinic at City of Hope, Hematologic Diseases and StemCell Transplantation Institute—City of Hope; and Maria T. Millan,M.D., Director, Medical Affairs and Stem Cell Projects andCenters—CIRM.

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

G.P.L. has uncompensated employment with CIRM. J.A. and J.Z.have compensated research funding fromCIRM. C.J. has compen-sated research funding through the Alpha Clinics Award. Theother author indicated no potential conflicts of interest.

REFERENCES

1 Promise and potential. Available at: http://alliancerm.org/promise-and-potential. AccessedMay 1, 2015.2 Funding clinical trials. Available at: https://

www.cirm.ca.gov/our-progress/funding-clinical-trials. Accessed May 1, 2015.3 About Alpha Clinics. Available at: https://

www.cirm.ca.gov/patients/alpha-clinics-network/about. Accessed May 1, 2015.

4 Trounson A, DeWitt ND, Feigal EG. The Al-pha Stem Cell Clinic: a model for evaluating anddelivering stem cell-based therapies. STEM CELLSTRANSLATIONAL MEDICINE 2012;1:9–14.5 Conteh C, Greitens TJ, Jesuit DK et al.,

editors. Governance and Public Management:Strategic Foundations for Volatile Times. London,U.K.: Routledge; 2014.6 UC ReX: University of California Research

eXchange. Available at: http://www.ucrex.org.Accessed May 4, 2015.

7 Funding opportunities. Available at: https://www.cirm.ca.gov/our-funding/requests-applications. Accessed April 30, 2015.

8 Partneringopportunity for clinical trial stageprojects: PA 15-02. Available at: https://www.cirm.ca.gov/sites/default/files/PA1502_123114_R1.pdf. Accessed May 18, 2015.

T ommunitUniting Researchers & Resources: he STEM CELLS Journal Online C yUniting Researchers & Resources:The STEM CELLS Journal Online Community

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Lomax, Adams, Jamieson et al.

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