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Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements by Kalah NIH andFDARequirements Cell-Based Commercializing Stem A uchincloss T herapies:

eeting September 2009 September Commer c ializing Stem Cell-Ba s ed T herapie : M eeting NIH and F DA R equirement

In March, President Obama signed an executive order lifting the Bush Administration restrictions on federal funding for human embryonic stem cell (HES) research. The possibility of new federal funding opportunities, in combination with more than a decade of scientific advances in both embryonic and adult stem cell research, signal that stem cell-based therapies (“SCBT”) could soon be available for patients in a clinical setting. For those wishing to commercialize such therapies, it will be important to ascertain how the U.S. Food and Drug Administration (“FDA”), which has regulatory authority over U.S. marketing of SCBT, will exercise this oversight.

This article is not intended to be an exhaustive dissertation on all laws and regulations pertaining to stem cell research, embryonic or otherwise.1 Rather, it discusses the controversial history of federal funding for stem cell research, and then focuses on regulations and guidelines likely to govern FDA approval of clinical applications of SCBT. It also discusses some of the recent recommendations included in the International Society for Stem Cell Research Guidelines in the context of U.S. application of those recommendations. NIH: Restrictions on Federal Funding for Human Embryonic Stem Cell Research

Federal funding for human embryonic stem cell research enjoys a long and storied history, reflecting the moral, ethical, and political sensitivities of theU .S. Advances in the early 1990s eventually led to isolation of the first human embryonic stem cells in 1998. Anticipating the resulting public unease from those who believed an embryo was a human life, Congress passed the Dickey-Wicker amendment (named after its sponsors) in 1996. The amendment, which has been enacted annually as part of the appropriations process since 1996, prohibits the use of federal funding for any experiment in which a human embryo is either created for research purposes or “destroyed, discarded, or knowingly subjected to risk of injury or death…”2 After passage of the amendment, an opinion from the Department of

1 This article also does not address laws that exist in a number of states prohibiting certain forms of human embryonic stem cell research, somatic cell nuclear transfer, and/or cloning. See e.g., Az. Rev. Stat. §§ 32-3212, 35-196.04, 36-112, 36-2302, 36-2303.

2 The Balanced Budget Down Payment Act, Pub. L. No. 104-99 § 104 (1996).

1 2 Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements provided fordonationoftheembryo. obtained for the donation of the embryo; and no financial inducements were embryo was no longer needed for these purposes; informed consent was EDT embryonic stem cells where: the derivation process was initiated prior to 9 p.m. policy, federal funds could be (and have been) used for research on human P under the Clinton T fund research onthestemcellsoncetheyhadbeenderivedwithprivatefunding. (because this would destroy the embryo and run afoul of the law); but that it would indicated that it would not fund efforts to derive stem cells from human embryos I including humanembryonicstem cellresearch, totheextentpermittedbylaw.” Id. the Director andconduct“responsible, humanstemcell oftheNIH,tosupport scientificallyworthy research, Fed. Reg.10668(Mar. 11,2009).IntheExecutiveOrder, the President permitstheSecretary HHS, through of no longerneededforthatpurpose.” embryos created byinvitro (IVF)forreproductive fertilization purposesandwere research “using only those human embryonic stem cells that were derived from NIH “because suchcellsare notahumanembryowithinthestatutorydefinition.” embryo research wouldnotapplytoresearch usingembryonicstemcells statutory language found that prohibiting the use of federal funds for human oftheGeneralCounselinterpretingHealth andumanServices(“HHS”)Office the 6 5 4 3 issue newguidelinestoimplementthefundingpolicy. signed ExecutiveOrder 13505revoking therestrictions anddirecting theNIHto President Bush’s untilMarch policywasineffect 9,2009,whenPresident Obama Ethically ResponsibleWays, 72Fed.Reg.34591(Jun.22,2007). http://stemcells.nih.gov/policy/2001policy.htm n accordance with the Letterfrom HHSGen.CounselHarrietRabbtoarold Varmus, Director, NIH(Jan.15,1999). NIH, GuidelinesforHumanStemCellResearch, 74 Fed. Executive Order 13505:RemovingBarrierstoResponsibleScientificResearch InvolvingHumanStemCells, 74 President BushStatement(Aug.9,2001),availableat he resident Bush took office and issued a new guidelines, which were finalized on July 7, 2009, the

NIH A ugust 9, 2001; the embryo was created for reproductive purposes; the published guidelines to implement this policy, but before applications A dministration guidelines were accepted and funded by the HH S opinion, the ; ExecutiveOrder 13435:Expanding Approved Stem Cell Lines in 6 Theseguidelinespreserve President Bush’s 4 http://usgovinfo.about.com/blwhrelease16.htm N R ational eg. 32170 (Jul. 7, 2009). HE S research policy. I nstitutes of NIH 5

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7 ’s role in in role ’s egulations, 21 C.F. 21 egulations, R DA , F , goes on to state that that state to on goes T ractice ractice P NIH he he T rder could be a signal to to signal a be could rder aboratory aboratory L O , including transferring or or transferring including , S research, but, by eliminating the the eliminating by but, research, S T ickey-Wicker amendment is in force force in is amendment ickey-Wicker SCs created from such embryos based on wide wide on based embryos such from created SCs ood ood D HE G HE

DA xecutive xecutive E n addition to the restrictions on federal funding for human human for funding federal on restrictions the to addition n I http://oba.od.nih.gov/oba/rac/guidelines_02/NIH_Gdlnes_ resident Clinton’s more expansive approach in in approach expansive more Clinton’s resident resident’s resident’s P P .S.C. § 2131 et seq.); F seq.); et 2131 § .S.C. U funding for stem cell research and new scientific advances advances scientific new and research cell stem for funding ct, 7 7 ct, A NIH s we move toward the clinical use of SCB of use clinical the toward move we s A he majority of these policies are applied to stem cell research much as they are applied to much as they are applied to stem cell research . The majority of these policies are received 49,000 comments to the draft guidelines, several of which argued that research on on research that argued which of several guidelines, draft the to comments 49,000 received nimal Welfare Welfare nimal NIH A he he T S research, and depending upon funding streams, could lead to exciting new new exciting to lead could streams, funding upon depending and research, S ew sources of of sources ew ug 9, 2001 date, adopt adopt date, 2001 9, ug he new guidelines should provide additional opportunities for federal funding for for funding federal for opportunities additional provide should guidelines new he Id. While this article does not focus in depth on preclinical or laboratory stem-cell based research, it is valuable to or laboratory stem-cell based research, While this article does not focus in depth on preclinical

), Pub. L. No.Part 58; privacy rules under the Health Information and Portability Accountability Act (HIPAA InvolvingResearch under the NIH Guidelines for DNA research 104-191 (1996); and oversight of recombinant Recombinant DNA Molecules, available at lnk_2002z.pdf research. laboratory of forms other T HE the while Furthermore, advances. scientific the 2009, year fiscal for the door fiscal years, opening its position in subsequent to reconsider Congress funding. federal additional for briefly note several applicable regulations. regulations. applicable several note briefly (both HES and adult stem all stem cell research research, like other pre-clinical embryonic stem cell research, (e.g., the Public Health Service Act § 289d for animals in research may be subject to: protections cell research) the and additional sources of human stem cells (e.g., embryos created for research purposes or by somatic cell purposes or by for research of human stem cells (e.g., embryos created additional sources using the the NIH stated that “the Guidelines reflect In response, nuclear transfer) should be eligible for NIH funding. research of funding federal for support public broad stem cells proposed by the respondents involve complex ethical and scientific issues on which a similar similar a which on issues scientific and ethical of human pluripotent The use of additional sources and elsewhere. complex and diverse debate on the topic in Congress involve respondents the by proposed cells stem by parthenogenesis and SCNT entities created For example, the embryo-like consensus has not emerged. the health risk that has health and ethical implications, including women to donate oocytes, a procedure require Id. oocyte production.” needed to induce the course of hormonal treatments to the donor from 8 A focus the is which purposes, therapeutic for humans into cells stem implanting article. this of important used in humans becomes to understand. oversight of products 7 N SCB of applications clinical to closer us bring determining what projects are eligible for funding. funding. for eligible are projects what determining Stem Cell Therapies FDA: Oversight of Clinical precedent in permitting funding for certain certain for funding permitting in precedent stemusing human embryonic it will not fund research new guidelines, under the transfer, nuclear cell somatic “including sources, other from derived cells purposes.” for research parthenogenesis, and/or IVF embryos created 4 Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements at aninstitutionwhichhasagreed toabidebytheprovisions. also applies to research, whether or not funded by a government agency, performed approval andongoingmonitoringofthestudybyanInstitutionalReviewBoard (IRB). protections require informed consent of human participants in the research, as well as the novelandexperimentalaspectsofcellbased interventions.” reasonable therapeutic alternatives, the informed consent process must emphasize inthetrialwithstemcells;sincepatientsmayhave recourse participating to clinical researchers “provide the utmost clarity regarding the potential benefits of available athttp://www.hhs.gov/ohrp/humansubjects/guidance/stemcell.pdf Research InvolvingHumanEmbryonicStemCells,GermCellsandCell-DerivedTest (Mar. Articles 19,2002), H P Clinical Research: Human Subject Protections 14 13 12 11 10 9 T ethical calculation must also factor into the informed consent and participant, who must fully understand the permanency of therapy. the adverse effects. implantation of stem cell based therapies cannot be undone and could lead to lasting the product is permanent. For SCB oragency”whichhasadoptedtheCommonRule. department orotherwisesubjecttoregulation subjects conducted,supported byanyfederal specific scientificandethicalexpertise.” “human subjectsreview ofstemcell-basedclinicalprotocols mustenliststemcell- ohrp/humansubjects/guidance/basics.htm agencies havecodifiedtheprotections elsewhere intheCodeofFederalRegulations.Seealso (Dec. 3.2008),availableat A benefits. that the risks to subjects are minimized and are reasonable in relation to anticipated

T ffice forHumanResearch HHSOffice Protections, GuidanceforInvestigatorsandInstitutionalReviewBoards Regarding he pproval by an rotections for human subjects are outlined in the Federal 45 C.F. 45 C.F.R. §§46.101,46.111,46.116(2008). uman Subjects, or the “Common Id. atRecommendation3;seealso Recommendations 20and28. I he nternational Society for Stem Cell IR D I nternational Society for Stem Cell epartment of B, as well as consequences for obtaining informed consent from the study R . § 46.111 (2008). T 12 , this risk-benefit analysis could be particularly difficult, as transplantation of H IR ealth and T B can only be obtained if the his has implications for the risk-benefit calculation undertaken by http://www.isscr.org/clinical_trans/pdfs/ISSCRGLClinicalT H uman Services has codified the Common R U esearch, nlike other drugs which can be stopped at any time, . G R uidelines for the Clinical ule”, and apply to all research “involving human R 13 esearch (

I n addition, the IR B determines, among other things, I SSC T ranslation of Stem Cells, R R . ule at 45 C.F. ) recently recommended that I SSC rans.pdf P olicy for the 10 9

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H 16 ublic ublic P funds for for funds NIH would fall into this category, assuming assuming category, this into fall would http://www.hhs.gov/ohrp/humansubjects/guidance/ T nvestigators should carefully consider whether whether consider carefully should nvestigators I

http://www.fda.gov/downloads/BiologicsBloodVaccines/ 17 ost SCB ost M S guidelines indicate that if the investigator utilizes utilizes investigator the if that indicate guidelines S

18 HH n addition, stem-cell based products are almost certain certain almost are products based stem-cell addition, n I S-conducted or supported research that does not involve living living involve not does that research supported or S-conducted . HH grant money would certainly be subject to the Common Common the to subject be certainly would money grant S laboratory research, research, laboratory S , 62 62 , to Regulation of Cellular and Tissue Based Products Approach R. § 1271.10 (2009); FDA, Proposed 21 C.F. rticles “containing or consisting of human cells or tissues that are intended for for intended are that tissues or cells human of consisting or “containing rticles R. § 1271.3(d) (2009); see 42 U.S.C. § 264. 21 C.F. rotections, Guidance for Investigators Protections, R. § 46.102(f) (2008); see also HHS Office for Human Research 45 C.F. Id. is generally required on unused embryos embryo donors for research Id. Note also that informed consent from ar. 4, 1997), available at Fed. Reg. 9721 (Mar. GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM062601.pdf subject to FDA regulations. 18 19 15 16 17 whether human subject protections apply to laboratory research on human human on research laboratory to apply protections subject human whether difficult (and may become to answer question is a more stem cell lines embryonic of opening the with issue prominent more a IND Requirements A are or transfer into a human recipient” implantation, transplantation, infusion ( products” tissue-based and cellular and tissues, cells, “human considered Clinical Research: HCT/P Regulations and FDA FDA and Regulations HCT/P Research: Clinical Clinical research to test a stem cell based therapy in humans which is funded by by funded is which humans in therapy based cell stem a test to research Clinical NIH general, humans or identifiable private information is not considered human subject subject human considered not is information private identifiable or humans subject protections. and is thus not subject to human research, the product is intended to be transplanted into the recipient patient as part of the the of part as patient recipient the into transplanted be to intended is product the intervention. therapeutic the under products biological as regulated be to “are highly processed, are used for other than their normal function, are combined combined are function, normal their than other for used are processed, highly “are metabolic purposes.” used for are with non-tissue components, or their stem cell laboratory research is subject to the Common Rule. is subject to the Common their stem cell laboratory research research on human cell lines where the donor may be identified would be subject subject be would identified be may donor the where lines cell human on research to the Common Rule provisions. and Institutional Review Boards Regarding Research Involving Human Embryonic Stem Cells, Germ Cells and Stemand Cells Cells, Germ Stem Embryonic Human Involving Research Regarding Boards Review Institutional and 19, 2002), available at Articles (Mar. Cell-Derived Test stemcell.pdf laws in all states, usually at the time of embryo donation. by state property HE be cannot donor(s) the of identify the which from lines cell established already cell those using animals in research and research ascertained, then in vitro readily by not governed is therefore and subject research human lines is not considered IRB oversight. or regulations human subject protection 6 Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements conduct humanclinicaltrialswiththeproduct. submit an submitting data to support marketing approval of the therapy, the sponsor must M showing thebiologicissafe,pure, andpotent. contrast to the as abiologicalproduct undersection351ofthePublicHealthServiceAct.In normal function,” most SCB Depending onhowFDAconstrues“highlyprocessed” or“usedforotherthantheir For biological products, the sponsor must submit a Biologics sponsor to demonstrate that the product is safe and effective for its intended use. transfer of communicable diseases; premarket approval provisions require the Rule requirements. human subjectprotections andIRBregulations, inadditiontoapplicableCommon required by the F diseases, the risk of which could be passed on to the recipient. required by the F infectious diseases. screening for genetic diseases, as appropriate, in addition to screening for T manufacturer of spread of communicable diseases. screening andtesting 26 25 24 23 22 21 20 the cellortissuedonor.” 21C.F.R. §1271.10(e). processing, storage, labeling, packaging, or distribution of any human cell or tissue, and the screening or testing of in accordance withallotherapplicableregulatory requirements. Id. responsible fortheinitialandcontinuingreview andapproval oftheclinicalstudy; and(3)toconducttheinvestigation (2)thatanIRBwillbe (1) nottobeginclinicalinvestigations untilanINDcoveringtheinvestigationsisineffect; regulations. therapies which are implanted into humans will need to comply with the Any institutionorcompanywhichengagesinaclinicaltrialofstemcellbased 21C.F. 1271.10(2009). R. Part 21C.F. CandD(2009). 1271,Subparts R. Part he 21 C.F. 50(2009);21C.F.R. Part 56(2009). R. Part 21 C.F. 42 U.S.C.§262etseq.(2009);21C.F.R. §§610.10,610.11,610.13,600.3 (2009). ISSCR Guidelinesatecommendation4;see21C.F.R. §1271.85. A oreover, if the stem cell product is considered a biological product, even before ccording to the regulations, “manufacturer” means, but is not limited to, “any or all steps in the recovery, H C R T . P / art 312 (2009). P I nvestigational regulations are intended to prevent the introduction, transmission, or 22 With SCB H H DA DA C C T 26 T / , it may also become important to screen the donor for genetic 23

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20 C P regulations which are intended to prevent contamination or mong other things, the gain, the informed consent process and ongoing to comply with good tissue practices, including donor T and toregister withFDAandlistallHCT/Pmanufactured. T / , in addition to screening for infectious diseases as N P ew regulations, the T will likely also be subject to F D rug ( A IND ccordingly, these regulations require the IND ) application to F application must include a commitment from the sponsor: I SSC 25 24 Such research is subject to F

R specifically recommends DA DA for clearance to premarket approval L icense A lthough not A pplication IR H C B T

/ P DA 21

Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements 7

. DA C1 C1 . his is is his T

to to 27 . . 31 T DA GRNOP eron process process eron G , submitted by by submitted , his may signal the the signal may his T IND

30 .S. regulatory process. process. regulatory .S. U underwent extensive F extensive underwent , and the interaction interaction the and , ugust 18 to allow F allow to 18 ugust IND DA A lthough the the lthough A

, for example, specifically specifically example, for , .S. struggles with how to define and and define to how with struggles .S. R 28 U his could help repair spinal injuries due to torn or or torn to due injuries spinal repair help could his SSC T I for a human clinical trial using the the using trial clinical human a for C1 to assess the safety of the therapy in in therapy the of safety the assess to C1 f allowed to move forward, the the forward, move to allowed f he he I IND

T eron has announced that it will continue to to continue will it that announced has eron l http://www.geron.com/grnopc1clearance/grnopc1-pr.htm 29 G GRNOP trial of of trial I recommendations in shaping the the shaping in recommendations R cleared the first first the cleared his approaches “comparative effectiveness research” and and research” effectiveness “comparative approaches his T also recommends that “clinical research should compare new new compare should research “clinical that recommends also ’s oversight of other medical products and will presumably be be presumably will and products medical other of oversight ’s

SC DA hase hase R I 32 P DA will also be a useful regulatory model for subsequent SCB subsequent for model regulatory useful a be also will SSC to address the agency’s concerns, and is hopeful it will be able to to able be will it hopeful is and concerns, agency’s the address to I DA IND eron eron G eron Corporation, was placed on “clinical hold” on on hold” “clinical on placed was Corporation, eron owever, the the owever, Id. ISSCR Guidelines at Recommendation 8. Id. at Recommendations 25 and 26. ccording to press releases, the initial 21,000 page page 21,000 initial the releases, press to ccording s such, it will be crucial for peer companies to closely monitor the the monitor closely to companies peer for crucial be will it such, s he he ISSCR at Recommendation 28. Release (Jan. 23, 2009), available at Press Geron 7 Release (Aug. 18, 2009), available at http://www.geron.com/media/pressview.aspx?id=118 Press Geron n January 2009, F 2009, January n 30 31 32 27 28 29 I repeatedly the ISSCR repeatedly therapies – for stem cell based will be critical oversight benefits and risks all of comprehension participants’ study ensuring that emphasizes “assessed be would ideally, and, trial, clinical the of phase each at done be should of obtaining consent.” during the time or an oral quiz a written test through stem cell therapy. of human embryonic product could prove more difficult to undertake, as the the as undertake, to difficult more prove could trial will yield important scientific information regarding the safety and efficacy of the of efficacy and safety the regarding information scientific important yield will trial product. T A review, which was in partR guidelines. influenced by the ISSC review, review additional animal study data, data, study animal additional review injury. spinal cord patients with acute work with F with work the with proceed G C1 is “a collection of oligodendrocyte precursor cells (OPC) that will be injected into the precursor GRNOPC1 is “a collection of oligodendrocyte to Geron, According neurons. spinal to form hopes that the injected OPCs will eventually mature injuries.” Geron of patients with spinal cord spinal cord surrounds that sheath protective the myelin, damaged myelin (though it will not help patient whose injuries are due to torn or severed spinal neurons). Id. spinal neurons). due to torn or severed damaged myelin (though it will not help patient whose injuries are recommends that “the level of regulation and oversight should be proportional to to proportional be should oversight and regulation of level “the that recommends and intended use.” of risk raised by the particular cell product the degree between the agency and the sponsor. sponsor. the and agency the between importance of the the of importance A F by required data of quantity and type the assess to stem cell-based therapies against the best medical therapy currently available to the the best medical therapy currently stem cell-based therapies against local population.” consistent with F with consistent adopted by the FDA. H 8 Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements with theFDA between the agency and the sponsor after submission of the sponsors of used by pharmaceutical and biotech companies and could be particularly useful to Guidances/ucm070951.pdf (Oct. 2007),availableat would be needed to support theINDapplication. would beneededtosupport submission of the Finally, Geron Corporationutilizedthe“pre-IND” process toengagewithFDAprior will dosoisnotclear. explicitly consider such factors into the approval decision, though how the agency discuss the ethical implications of stem cell based therapies, and may even definable measure. terms ofpatientoutcomes,qualitylife,safetyprofile orsomeother studies demonstratingthatthenewproduct isbetterthanexistingtherapiesin enforcement ofsocialjusticeconsiderationsbyappropriate agencies.” evaluation procedures; foropendiscussionsaboutethicalissues;(c) (b)opportunity advocates in public discussions, committee representation, and oversight board their evaluations. international) must explicitly include the consideration of social justice principles into I process for human subjects who participate in stem cell based clinical research, the I superiority dataforSCBTisanopenquestion. 34 37 36 35 fund suchresearch. 33 fda.gov/AboutFDA/WhatWeDo/FDAT ), June 9, 2009. by SenatorsMaxBaucus(D-MT)andKentConradND),June9,2009. Engl JMed.7;360(19):1927-9(ay2009);S.1213,Patient-Centered OutcomesResearch Actof2009,introduced Researchto determinecoveragedecisions).Seee.g.,J.Avorn,DebateaboutFundingComparative-Effectiveness , N research, andpermissibleusesforinformationgeneratedbysuchresearch (e.g.,whetheritmaybeusedbypayors of appropriate and varied patient populations),employed (literature reviews, head-to-headrandomizedcontrolled clinicaltrials,inclusionofcostasafactor, sampling what federal (or non-federal) agency or entity should oversee such SSC n addition to the ethical considerations which factor into the informed consent

Geron Press Release,supra note29. NoticeofT

See FDA,Draft Guidance for Industry Antibacterial Drug Products: Use of Noninferiority Studies to Support Approval ISSCR Guidelinesatecommendation35. T he debate on comparative effectiveness research (C R recommends that “regulatory and oversight agencies (local, national and ransparency T ’s recent transparency initiative IND s for stem cell based therapies, in addition to frequent interaction M http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ IND 34 echanisms include (a) involvement of community and patient 33 . ask Force PublicMeeting,74Fed.Reg.26712(Jun.3,2009);seealso Whether the F

and to work with the agency to discuss what information T hat being said, the F ransparencyT DA askForce/default.htm will require comparative effectiveness or ER ) in the 36 DA , F increasingly requests superiority U DA .S. has focused on the methodology to be 37

may convene public meetings to T he pre- . IND IND process is routinely .

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Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements 9

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40 REM S for for S DAAA ay 20, 208), 208), 20, ay M REM ct (F ct A S would likely likely would S uide or patient patient or uide may require a require may S for approved approved for S G may require a require may DA has exercised its its exercised has REM DA REM , F , S applied to all SCB all to applied S DA T he he , F , T mendments mendments has also imposed a a imposed also has ost ost A REM edication edication M

DA M DAAA 38 F 39 V postmarket safety study, pursuant pursuant study, safety postmarket V I nder F nder owever, the F the owever, U H class-wide class-wide . . hase hase A may heavily utilize its postmarket, the FDA may heavily utilize dministration dministration P A uide. uide. DAAA G rug rug D uide, and perhaps even certain restrictions on the the on restrictions certain even perhaps and uide, Drugs/DrugSafety/InformationbyDrugClass/ http://www.fda.gov/ G edication edication may require a a require may M DA edication edication S, F S, M approval of a stem cell based therapy for clinical use, unexpected unexpected use, clinical for therapy based cell stem a of approval REM , to ensure “the benefits of the drug outweigh the risks of the drug,” drug,” the of risks the outweigh drug the of benefits “the ensure to , . n the 2007 Food and and Food 2007 the n DA I lthough still years in the future, to manage ongoing safety concerns concerns safety ongoing manage to future, the in years still lthough A m Announcements/2008/ucm116899.ht Press NewsEvents/Newsroom/ http://www.fda.gov/ DAAA .S.C. § 355-l. 355-l. § .S.C. U S for any single approved stem cell based therapy. therapy. based cell stem approved single any for S was given two new authorities which may be particularly relevant to stem cell cell stem to relevant particularly be may which authorities new two given was nder F nder ven after F after ven , 74 Fed. Fed. FDA, Risk Evaluation and Mitigation Strategies for Certain74 Opioid Drugs, Notice of Public Meeting, codified codified Food and Drug Administration Amendments Act of 2007, Pub. Law 110-85 § 901 (Sept. 27, 2007), ( Bowel Function Following Surgery to Help Restore Entereg Release, FDA Approves FDA Press DA n addition to to addition n available at 40 38 39 based therapies, assuming such therapies are approved as biological products. approved assuming such therapies are based therapies, U ( itigation StrategyREMS), which must be a Risk Evaluation and M FDA may require a include may and intervals, specific at reassessed F and providers; healthcare to outreach for plan communication a insert, package drug. on distribution or use of the even restrictions authorities. authorities. Post-Market SurveillancePost-Market E the uses population patient diverse more a as emerge still may events adverse product. T clinical uses of SCB to approved related drugs include only the timetable for assessment and the less burdensome burdensome less the and assessment for timetable the only include drugs a as such requirements, the example, For drug. the of use and distribution restrict to authority ucm163647.htm pr. 20, 2009); see also Reg. 17967 (Apr. 21 21 at ntereg restricts the drug to inpatient use only and requires that hospitals be the drug to inpatient use only and requires restricts Entereg the product. dispensing specially certified before on an entire class of drugs, opioids, which could include restrictions on use. could include restrictions class of drugs, opioids, which on an entire postmarket safety study for a new drug or biologic based on “appropriate scientific postmarket safety study for a new drug or biologic based on “appropriate to the authority for such outlined in F in outlined such for authority the to the long term safety concerns and relative novelty of SCB of novelty relative and concerns safety term long the REM a least at include the administer may who on restrictions (e.g., therapy the of use or distribution settings). healthcare what in and therapy in perhaps though possible, also is basis, case-by-case a on determined than rather distant future. the more I 10 Commercializing Stem Cell-Based Therapies: Meeting NIH and FDA Requirements postmarket safetystudyisrequired, butthesponsordoesnotcompletetrial. enforcement mechanismbypermittingimpositionofcivilmonetarypenaltiesifa M postmarket surveillance are not sufficient to manage and detect adverse events. such arisk. drug, or to identify an unexpected serious risk if data indicate there is potential for data” toevaluateaknownriskoftheproduct, assessasignalofseriousriskthe 42 41 SCB to being cleared for clinical studies of a SCB With the availability of new federal money for Conclusion authorities will be necessary. Close monitoring of products, what modifications to these authorities will be required, and whether new important to assess how F stem cell research and are looking ahead to eventual F be informative, both from a scientific and regulatory perspective. implement theISSCRrecommendations. important to examine the for the trial is available). not sufficient to detect safety concerns (and provided a sufficient patient population determines, based on the particular product, that other postmarket authorities are T Id. 21U.S.C.§355(o)(3). he F oreover, although F T s are F DA could elect to require a post-market safety study for a SCB 41 DA

T -approved for clinical indications. For those who engage in clinical he trial may only be required if adverse event reporting and active DA has long requested I SSC DA will apply current authorities to stem cell based R

G uidelines to assess whether and how F T P HE , we are inching toward the day when hase S research, and the first G I eron Corporation’s V studies, F DA approval, it will be DAAA I t will also be T includes a new , if the agency GRNOP DA IND should close C1 will 42

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