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Investigational cell therapy products—including those derived from stem and pro-genitor cells—hold great promise for address-ing unmet medical needs but also present challenges related to product characteriza-tion, safety testing, and clinical trial design(Fig. 1). T e U.S. Food and Drug Administra-tion (FDA) adapts to the changing landscape of this evolving f eld by applying f exible reg-ulatory standards that balance benef ts and risks to those who take part in clinical trials. In this Focus, we describe the FDA’s process for facilitating the development of safe and ef ective cell therapy products and highlight the importance of information sharing and transparency in the regulatory decision-making process.

DEVELOPING SAFE CELL THERAPY PRODUCTSFDA’s primary objectives in the oversight of clinical trials involv-ing cell therapy products are to (i) assure the safety and rights of trial participants and (ii) ensure that the quality of the scientif c evidence is adequate to permit an evaluation of the product’s ef ec-tiveness and safety. In regulating cell therapy products, FDA takes into account the scientif c and medical information currently available and complements inter-nal expertise by engaging outside scientif c and clinical experts, the patient community, and other stakeholders through various mechanisms, including sci-entif c workshops and advisory committees. To ensure that the public has an opportunity to participate at these meetings, time is allot-ted for public comments.

When FDA proposes a new regula-tion, input from stakeholders and the pub-lic is solicited through a formal notice and comment process that provides a pathway through which all interested parties can sup-ply written input to FDA (1). By following such an approach, FDA’s Center for Biolog-ics Evaluation and Research (CBER) hopes to facilitate free exchange of ideas and infor-mation among all interested parties, which is of particular importance when developing regulatory policy in a new f eld of research. To promote maximum transparency of the regulatory decision-making process, all rel-evant regulations and guidance documents are available online or through other public-

ly accessible means (2). FDA staf members also conduct intramural research to inves-tigate the fate and function of transplanted cells and to improve cell product testing strategies. Outcomes from intramural re-search assist FDA’s decision-making pro-cess in the evaluation of cell therapy prod-ucts. FDA staf members are also involved in clinical trial design research to improve strategies for clinical evaluation of the safety and ef cacy of cell therapy products.

In the United States, clinical trials of all

cell therapy products that require licensure, but have not yet been approved, must be performed under an Investigational New Drug (IND) application (3) with oversight from CBER (for example, see Fig. 1). INDs are reviewed by FDA scientists with exper-tise in product chemistry, manufacturing, and controls (CMC) as well as preclini-cal testing and clinical trial design for cell therapeutics. Prospective IND applicants are encouraged to communicate early with FDA regarding their product development program through informal interactions and formal pre-IND meetings. During this early engagement, prospective IND applicants and FDA scientists discuss both general and specif c issues regarding overall product de-velopment strategy and ways to ensure that suf cient information is generated to justify the initiation of a clinical trial.

CMC CONSIDERATIONST roughout clinical development, the most important CMC review issue for cell therapy products is the administration of a safe prod-uct to the subject. T us, meticulous attention must be paid both to the source of the cells and to preventing the introduction of micro-

organisms during the manufac-turing process.

Microbiological safety is most ef ectively implemented through source control, which includes qualif cation of the cell or tissue donor and control of all materi-als used in manufacture. As a minimum requirement, donors of living cell s must be screened and tested for relevant communi-cable disease agents and diseases (4). All materials used in product manufacturing must be qualif ed by certif cation from the vendor, tested by the end user, or both in order to ensure that they are free of adventitious agents (microor-ganisms introduced unintention-

ally) and are otherwise of suitable quality for their intended use. Because of potential exposure to animal viruses, product compo-nents derived from animal material present additional qualif cation concerns. Further, in the United States, human cells or tissues intended for human administration that come into direct contact with live nonhu-man animal cells during product manu-facture are considered xenotransplantation products, warranting additional microbio-logical testing (5).

R E G U L AT O R Y S C I E N C E

FDA Oversight of Cell Therapy Clinical TrialsPatrick Au,* Deborah A. Hursh, Agnes Lim, Malcolm C. Moos Jr., Steven S. Oh, Bruce S. Schneider, Celia M. Witten

Authors are listed alphabetically. *Corresponding author. E-mail: pakwai.au@fda.hhs.gov

Of ce of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD 20852, USA.

The U. S. Food and Drug Administration applies regulatory f exibility to balance benef ts and risks to subjects in cell-therapy clinical trials.

Fig. 1. Historical trends. Shown are the numbers of FDA IND submis-sions for investigational cell therapy products from 2003 to 2011.

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It is crucial to identify product attributes that will reliably predict safety and ef ective-ness. T is can be a formidable challenge, especially for stem cell–derived products, which may undergo further dif erentiation at the time of administration into human subjects or subsequently. To arrive at a pre-dictive set of tests, one must explore a wide variety of product characteristics such as morphology, synthesis and release of bio-active factors, gene expression prof les, and other attributes indicative of cell identity or viability. T ese investigations should be ini-tiated during the early stages of product de-velopment (that is, before and during phase 1 and 2 clinical trials). Once appropriate attributes and tests are conceived, product developers need to conf rm the ability of the manufacturing process to yield a consistent f nal product with the desired characteris-tics. In 2008, FDA amended current good manufacturing practices (cGMP) regula-tions (6) to exempt most investigational phase 1 drugs from complying fully with the cGMP regulations. In an accompanying guidance (6), FDA provides recommenda-tions on approaches to comply with the basic concept of cGMP for this early-phase material. As product development proceeds, the manufacturing process should be re-f ned, culminating with full cGMP compli-ance at the time of licensure.

As with other biological products subject to FDA’s biologics regulations, licensed cell therapy products need to be tested for safety, identity, purity, and potency (7). In contrast, during the investigational phase, which includes all phases of clinical trials before marketing authorization, FDA requires suf-f cient information “to assure the proper identif cation, quality, purity, and strength of the investigational drug” (7). CBER has f exibility in determining which tests are appropriate to meet the regulatory require-ments for these products. T e regulations also require that an identity test be designed to ensure that the investigational product is identical to what is described on its label and can be distinguished from other prod-ucts manufactured in the same laboratory (7). CBER expects implementation of an identity test for early clinical trials to ensure that the participant receives the intended product. All phases of clinical investigation require purity testing, which encompasses sterility and the absence of endotoxins or other undesired components. Other aspects of establishing a purity/impurities prof le present challenges in early phases of devel-

opment when product characterization data are of en limited. Although the f nal prod-uct may not be a homogeneous population of identical cells, it is important to minimize the percentage of cells with undesired char-acteristics (for example, undif erentiated or misdif erentiated cells) in the f nal product. At a minimum, the various cell populations should be characterized to the extent fea-sible and should be as consistent as possible between preparations.

As for all licensed biologics, a measure-ment of potency is required. Potency is de-f ned by FDA biologics regulations as “the specif c ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to ef ect a given result” (8). Development of meaning-ful and relevant potency assays for cell ther-apy products necessitates extensive product characterization. Measures of potency may be demonstrated using in vitro and/or in vivo tests, as appropriate. T is topic is dis-cussed in detail in FDA’s guidance on po-tency tests for cell and gene therapy prod-ucts (8).

PHARMACOLOGY AND TOXICOLOGYPreclinical pharmacology and toxicology studies are conducted to characterize the safety prof le of a cell therapy product before its administration to clinical trial partici-pants. T e complex nature of these investi-gational products precludes the application of a traditional toxicology program; the design of the preclinical studies is therefore formulated on a case-by-case approach. T e selection of animal species, animal models, product delivery systems, study duration, and study end points (biochemical, func-tional, and morphological) will depend on the known biological attributes of the prod-uct, the anticipated mechanism of action of the product, the target disease population, and the proposed clinical trial design.

T e invasive routes of administration and presumed permanence in vivo, as well as the potential for (i) inf ammatory reac-tions in target and nontarget tissues, (ii) host immune response to the product, (iii) dif erentiation to undesired cell and tissue types, and (iv) unregulated or dysregu-lated cell proliferation (that is, tumor for-mation), raise safety concerns about cell therapy products. T erefore, the conduct of preclinical studies to provide support for a reasonable expectation of clinical benef t is

important. Well designed proof-of-concept (POC) studies in appropriate animal mod-els of disease or injury can provide a level of conf dence that the scientif c rationale for initial human studies is suf ciently sound to justify the risks of product administration. In addition, POC studies help to determine a pharmacologically ef ective dose range and dosing regimen, optimize the route and timing of product administration relative to disease progression, and elucidate the in vivo outcome of the administered cells (9). Addressing these questions will help to in-form clinical trial design.

In order to complement POC studies in def ning the risk-benef t prof le of a cell therapy product, toxicology studies are con-ducted to identify, characterize, and quan-tify potential local and systemic adverse ef-fects resulting from the cell therapy product itself and the product administration proce-dure. In many instances, assessment of the toxicology parameters can also be addressed in the POC studies. Data generated from toxicology studies should help def ne a po-tentially safe dose range, as well as identify safety signals that may be useful in develop-ing an appropriate clinical monitoring plan.

T e preclinical testing paradigm for each cell therapy product can dif er in complexity, scope, and design; thus, early communica-tion with CBER staf is strongly encouraged. T ese interactions help to accelerate the translation of research and to ensure consid-eration of the 3Rs—ref nement, reduction, and replacement—of animal use (10).

CLINICAL TRIAL DESIGNFDA oversight of the safety of cell therapy products in clinical trials includes consid-eration of the nature of the product and the proposed anatomical site and method of product administration. Early-phase tri-als of cell therapy products dif er markedly from typical phase 1 small-molecule drug trials because of the substantial dif erences between the two product types. In contrast to most drugs, cell therapy products are administered without terminal steriliza-tion; furthermore, af er administration the anatomical distribution, duration of action, and product life span are of en uncertain. For example, unchecked cell proliferation, as opposed to exponential decay of drug concentrations, is a possibility for some cell therapy products. In addition, dose deter-minations are far less precise for cell therapy products than for small-molecule drugs. T e possibility of immune rejection or other

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unanticipated immunological responses must also be addressed. T e anatomical sites of administration (for example, intra-cranial, intraspinal, or intracardiac) pro-posed for many cell therapy products may pose additional safety risks arising from the surgical procedures, the vulnerabilities of the sites themselves, and subsequent acces-sibility of the sites in the event of medical necessity, including the need for product removal. Given these considerations, it is important that sponsors provide suf cient preclinical safety data and rationale to sup-port the initial starting dose and dose esca-lation scheme proposed in the clinical study protocol. Finally, the risks of investigational cell therapy products, including administra-tion procedures and concomitant medica-tions, are generally too great to permit the study in healthy volunteers. T erefore, un-like many phase 1 drug trials, participants in trials for a cell therapy product have the targeted disease, which is of en serious or life-threatening. Such individuals may re-quire ongoing treatments and medications, which have the potential to interact with the cellular product.

Safety monitoring procedures employed during clinical trials of cell therapy prod-ucts should be based on potential product-specif c adverse outcomes that may emerge over a protracted period. Cell therapy products may consist of heterogeneous cell populations and may exhibit a variety of properties that ref ect the specif c cell mix-ture, including the capacity for proliferation, further dif erentiation, migration, and func-tional physiological or pathological integra-tion into target tissues. Monitoring methods in early-phase trials should be chosen af er considering the full capabilities of existing

technologies and analytical tools applied over appropriate periods, in order to provide adequate safety assessment and to measure potential therapeutic benef ts or pharmaco-dynamic actions of the cell product. T e du-ration of long-term follow-up will depend on the nature of the product and the specif c disease indication. T ere is a great need for the development of biomarkers of safety and ef cacy to characterize the ef ects of such products in trial participants. Furthermore, improvement in cell tracking techniques, especially those based on noninvasive im-aging modalities that can be used clinically, would aid in safety monitoring and advance the understanding of the clinical ef ects of this product class.

Last, at all stages in the regulatory pro-cess, FDA encourages open and transpar-ent communication among participants in the cell therapy f eld—academic and com-mercial researchers, patient interest groups, funding agencies, and regulators—to help facilitate the development of safe and ef ec-tive cell-based therapies.

REFERENCES AND NOTES 1. Making your voice heard at FDA; http://www.fda.gov/

RegulatoryInformation/Dockets/Comments/default.htm. 2. Cellular and gene therapy guidance documents; http://

www.fda.gov/BiologicsBloodVaccines/GuidanceCom-plianceRegulatoryInformation/Guidances/Cellularand-GeneTherapy/default.htm.

3. D. A. Kessler, J. P. Siegel, P. D. Noguchi, K. C. Zoon, K. L. Feiden, J. Woodcock, Regulation of somatic-cell therapy and gene therapy by the food and drug administration. N. Engl. J. Med. 329, 1169–1173 (1993).

4. Donors of living cells, U.S. Code title 21, section 1271 subpart C; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1271.

5. FDA guidance for industry: Source animal, product, preclinical, and clinical issues concerning the use of xenotransplantation products in humans; http://www.fda.gov/BiologicsBloodVaccines/GuidanceCompliance

RegulatoryInformation/Guidances/Xenotransplanta-tion/ucm074354.htm.

6. Current GMP, U.S. Code title 21, section 210; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=210; GMP for early-phase cell products, U. S. Code title 21, section 211; http://www.accessdata.fda.gov/scr ipts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=211; Guidance for industry: Current Good Manufacturing Practice for phase 1 investi-gational drugs; http://www.fda.gov/downloads/Drugs/G u i d a n c e Co m p l i a n c e R e g u l a t o r y I n fo r m a t i o n /Guidances/UCM070273.

7. Licensed cell therapy testing of product safety, identity, purity, and potency, U.S. Code title 21, section 610 sub-part B; http://www.accessdata.fda.gov/scripts/cdrh/cf-docs/cfCFR/CFRSearch.cfm?CFRPart=610&showFR=1&subpartNode=21:7.0.1.1.5.2; Investigational phase test-ing to assure proper identifi cation, quality, purity, and strength, U.S. Code title 21, section 312.23(a)(7); http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=312.23; Identity testing; U.S. Code title 21, section 610.14; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=610.14.

8. Potency: U.S. Code title 21, section 600.3(s); http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=600.3; U.S. Code title 21, section 610.10; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=610.10; Guidance for industry: Potency tests for cellular and gene therapy products; http://www.fda.gov/downloads/Bio logicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/CellularandGeneTherapy/UCM243392.pdf.

9. A. M. Bailey, Balancing tissue and tumor formation inregenerative medicine. Sci. Transl. Med. 4, 147fs28 (2012).

10. R. Robinson, 3Rs of animal testing for regenerative medi-cine products. Sci. Transl. Med. 3, 112fs11 (2011).

Acknowledgments: We are indebted to our colleagues in the Offi ce of Cellular, Tissue and Gene Therapies—in particular M. Serabian, R. K. Puri, W. Bryan, K. Benton, S. Bauer, and D. Fink Jr.—for important contributions. Funding: None. Competing inter-ests: The authors declare that they have no competing interests.

Citation: P. Au, D. A. Hursh, A. Lim, M. C. Moos Jr., S. S. Oh, B. S. Schneider, C. M. Witten, FDA oversight of cell therapy clinical trials. Sci. Transl. Med. 4, 149fs31 (2012).

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FDA Oversight of Cell Therapy Clinical TrialsPatrick Au, Deborah A. Hursh, Agnes Lim, Malcolm C. Moos, Jr., Steven S. Oh, Bruce S. Schneider and Celia M. Witten

DOI: 10.1126/scitranslmed.3004131, 149fs31149fs31.4Sci Transl Med

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