• No tags were found...


Human Tissue and Stem CellTherapies: Revolutionary New Therapiesthat Face Increasing FDA Scrutinyby Chad A. Landmon and Tara R. RahembaAs the scientific community embarks into the brave newworld of cell therapy and tissue engineering, numeroushuman tissue- and stem cell-based products are beingdeveloped for various therapeutic uses. While these productshave traditionally been viewed as exempt from FDA’s premarketingapproval requirements, FDA is beginning to takea hard look at many of these therapies. FDA’s recent enforcementaction against Regenerative Sciences (Regenerative) islikely a harbinger of increased FDA scrutiny of tissue- andstem cell-based therapies. It is imperative that companies andresearchers in this dynamic industry take a proactive approachto ensure compliance with the complicated FDA regulatoryregime and to stave off any FDA enforcement actions.FDA’s Tiered Approach toCell and Tissue RegulationFDA defines human cells, tissues or cellular- or tissue-basedproducts (HCT/Ps) as “articles containing or consisting ofhuman cells or tissues that are intended for implantation,transplantation, infusion, or transfer into a human recipient.” 1Examples of HCT/Ps include bone, ligament, skin, heart valve,cornea, hematopoietic stem cells derived from peripheral andMr. Landmonis a Partner in the Hartford andWashington, D.C. offices of Axinn,Veltrop & Harkrider LLP, where hechairs the FDA Practice Group.Ms. Rahembais an Associate in the Hartford,CT office of Axinn, Veltrop &Harkrider LLP.16 Up d a t e September/October

Enforcementcord blood, manipulated autologouschondrocytes, epithelial cells on a syntheticmatrix and reproductive tissues. 2Examples of items that FDA does notconsider to be HCT/Ps include vascularizedhuman organs for transplantationand cells, tissues and organs that are derivedfrom animals other than humans. 3FDA’s HCT/P regulations, codified in21 C.F.R. § 1271, were promulgated onJanuary 19, 2001 under the authority ofSection 361 of the Public Health Service(PHS) Act. 4 In promulgating the regulationsgoverning HCT/Ps, FDA recognizedthe need to balance its responsibility toprotect the public health with the public’sinterest in FDA not unduly impairing thedevelopment and use of cutting-edge tissue-and stem cell-based therapies.FDA explained that its primary goalwas “the improved protection of thepublic health without the imposition ofunnecessary restrictions on research,development, or the availability of newproducts.” 5 With this goal in mind, FDAattempted to develop a regulatory structurein which the degree of regulatoryscrutiny afforded different types of HCT/Ps is commensurate with the potentialrisks that such therapies present.In adjusting the scope of FDAoversight according to the potentialrisks associated with each particulartherapy, FDA reasoned that “minimallyprocessed tissues transplanted fromone person to another for their normalstructural functions would be subject toinfectious disease screening and testingand to requirements for good handlingprocedures [for HCT/Ps], but would notneed FDA premarket review or marketingapproval.” 6 FDA codified this in21 C.F.R. § 1271.10(a): “An HCT/P isregulated solely under section 361 of thePHS Act and the regulations in this partif it meets all of the following criteria: (1)The HCT/P is minimally manipulated;(2) The HCT/P is intended for homologoususe only, as reflected by the labeling,advertising, or other indications of themanufacturer’s objective intent; (3) Themanufacture of the HCT/P does not involvethe combination of the cell or tissuecomponent with a drug or device . . . ; and(4) Either: (i) The HCT/P does not have asystemic effect and is not dependent uponthe metabolic activity of living cells forits primary function; or (ii) The HCT/Phas a systemic effect or is dependent uponthe metabolic activity of living cells for itsprimary function, and: (a) Is for autologoususe; (b) Is for allogeneic use in a firstdegreeor second-degree blood relative; or(c) Is for reproductive use.” 7Although HCT/Ps meeting therequirements of Section 1271.10(a) arenot subject to premarketing approval requirementsunder the FDCA or the PHSAct, FDA still has the authority to inspectthese HCT/P facilities to ensure that theyare in compliance with HCT/P handlingand processing requirements. FDA is alsoempowered to take actions with respectto these HCT/Ps including ordering theretention, recall or destruction of suchproducts in order to prevent the transmissionof communicable diseases. 8During the rulemaking process, FDAreceived several comments asserting thatFDA was proposing to regulate the practiceof medicine. FDA responded by clarifyingits intentions, stating that it is “notattempting to govern practitioners’ use ofHCT/P’s, but rather to ensure that HCT/P’sthat would be used by practitioners in theirtreatment of patients are in compliancewith applicable regulations . . . .” 9The Critical Question:Is It An HCT/P Only?It undoubtedly can be quite challengingfor a researcher or company tonavigate the criteria set forth by FDAin Section 1271.10(a). In the course ofits notice-and-comment rulemaking,however, FDA provided some definitionsand examples to help guide innovatorsand sponsors of a new HCT/P throughthe regulatory framework.The first criterion that makes an HCT/Peligible for regulation under only thePHS Act requires that the HCT/P be onlyminimally manipulated. 10 Whether HCT/Ps are “minimally manipulated” withinthe meaning of Section 1271.10(a)(1)depends in part on whether the HCT/P isa “structural tissue” or a “cell or nonstructuraltissue,” although this structuralnonstructuraldistinction is not defined inthe regulations.If the HCT/P is a “structural tissue,” itis deemed “minimally manipulated” if theprocessing it undergoes “does not alter theoriginal relevant characteristics of the tissuerelating to the tissue’s utility for reconstruction,repair, or replacement.” 11 If theHCT/P is a “nonstructural tissue or a cell,”“minimal manipulation” simply meansthat the tissue or cell is processed in a way“that does not alter the relevant biologicalcharacteristics” of the material. 12Several comments submitted duringFDA’s rulemaking process asserted thatthe term “minimal manipulation” isvague and open to subjective interpretationand should therefore be eliminatedfrom the regulations. FDA decided,however, to maintain this language because,in FDA’s view, “it serves as a validindicator of those HCT/P’s that presentfewer risks and that are most appropriatelyregulated solely under section 361of the PHS Act and part 271 (so long asother criteria are also met).” 13FDA indicated that processes such ascentrifugation, sterilization by ethyleneoxide treatment or irradiation, cell separation,lyophilization and cryopreservationare considered to be “minimalFDLISeptember/October 2010 Up d a t e 17

Enforcementmanipulation” within the meaning ofSection 1271.10(a)(1). 14 FDA also specificallystated, however, that the expansionof mesenchymal cells in culture or theuse of growth factors to expand umbilicalcord blood cells does not constitute“minimal manipulation.” 15The second criterion under Section1271.10(a)(2) to avoid premarketingapproval requires that the HCT/P be intendedfor homologous use only, accordingto product labeling, advertising andother indications of the manufacturer’sintent. As with the minimal manipulationrequirement, several comments submittedduring rulemaking suggested thishomologous use criterion be eliminatedbecause it is vague and susceptible tosubjective interpretation. Again, however,FDA maintained the language becauseFDA “consider[s] nonhomologous use tobe a meaningful indicator that regulationsolely under section 361 of the PHS Act isnot sufficient.” 16FDA defines “homologous use” as“the replacement or supplementationof a recipient’s cells or tissues with anHCT/P that performs the same basicfunction or functions in the recipient asin the donor.” 17 FDA clarified that evenif a structural tissue is used in a differentlocation in the recipient’s body than fromwhere it was retrieved from the donor,that might still constitute a homologoususe of the HCT/P if the HCT/P performsthe same function in the recipient as itdid in the donor. 18 Significantly, FDApointed out that the homologous usecriterion is determined with respectto how the manufacturer intended theHCT/P to be used. FDA explained that itdecided to focus on the objective intent ofthe HCT/P manufacturer rather than onthe intent of the practitioner who uses theHCT/P because it believed such an “approachwill lead to more efficient use of[FDA’s] resources.” 19 FDA also noted thatit intended to interpret “nonhomologous”narrowly. Examples of nonhomologoususes include the use of amniotic membranein the eye and the use of cartilagein the bladder. 20In order to potentially be relieved ofpremarketing approval obligations underthe PHSA or FDCA, Section 1271.10(a)(3) further requires that the HCT/P notbe combined with a drug or a device,except for a sterilizing, preserving orstorage agent, and only as long as theagent does not raise new clinical safetyconcerns with respect to the HCT/P. 21FDA’s rationale behind this criterion isthat “[t]he addition of a drug or a deviceto the cell or tissue component of anHCT/P may ordinarily be expected toadd a therapeutic effect and may alsoraise safety concerns.” 22 Therefore, theaddition of such a component to anHCT/P makes it no longer appropriate toregulate the HCT/P solely under Section361 of the PHS Act.Examples of agents that can be combinedwith the HCT/P without subjectingthe product to premarketing approvalrequirements are cryoprotectants (suchas dimethyl sulfoxide), chemicals used forsterilization (such as ethylene oxide) andstorage solutions. 23 If, however, such agentsalso have a therapeutic effect in addition totheir other functions as cryoprotectants,sterilizers or storage agents, the additionof such agents takes the HCT/P outside thepurview of Section 1271.10(a). 24The last criterion of Section 1271.10(a)that must be met in order to escape additionalregulatory oversight requiresthat the HCT/P have no systemic effectand not depend on the metabolic activityof living cells for its primary function.If it does, the HCT/P must be eitherfor autologous use (i.e., implantationinto the same patient from which it wasretrieved), for allogeneic (i.e., non-autologous)use in a first- or second-degree25, 26blood relative or for reproductive use.In promulgating the HCT/P regulations,FDA recognized that the field ofHCT/Ps is relatively immature and that,as technology continues to develop,some HCT/P-associated risks might bedemonstrated to be rarer or less severethan initially thought. For example, withrespect to the “minimally manipulated”requirement of Section 1271.10(a)(1), FDAstated that “the subsequent accumulationof clinical data and experience abouta particular process may demonstratethat it does not alter the original relevantcharacteristics of the cells or tissue, andthe agency will consider this informationin determining whether a procedureshould be considered minimal as opposedto more-than-minimal manipulation.” 27FDA has already changed its stance onthe degree of manipulation involved inpreparing certain demineralized bone(DMB) products due to the availabilityof further data. 28 FDA previouslyconsidered DMB products to be morethan minimally manipulated. Afterreconsideration and a review of furtherdata, however, FDA determined that therelevant characteristics of bone specimensare not altered by processing thespecimens into DMB products. FDAtherefore concluded that such productsdo in fact meet the criterion set forth inSection 1271.10(a)(1). 29FDA and RegenerativeOne of the therapies that has recentlypopped up on FDA’s radar is the RegenexxProcedure, which was developed byRegenerative, a company formed in 2006as an outgrowth of the medical practicesof two physicians. In the Regenexx Procedure,a bone marrow sample is takenfrom the back of a patient’s hip and bloodsamples are also taken from the patient’s18 Up d a t e September/October

Enforcementarm. Both samples are sent to a laboratorywhere stem cells are isolated fromthe bone marrow and grown in vitrofor about five weeks using the naturalgrowth factors from the patient’s bloodsample. The expanded stem cells are thenimplanted into the injured area of thepatient, such as the patient’s knee, hip orrotator cuff. There, the stem cells purportedlybegin to repair the injured area.In early 2009, FDA inspected Regenerative’sfacilities pursuant to Section 361 ofthe PHS Act. At the close of the inspection,FDA provided Regenerative with aForm 483, which classified Regenerativeas a drug manufacturer. As a result ofthis classification, the Form also identifieda number of deficiencies at Regenerativedue to the company’s failure to complywith regulatory requirements that areonly pertinent to drug manufacturers.Such requirements include premarketingapproval requirements, such as thesubmission of an Investigational NewDrug Application or a Biologics LicenseApplication, which are applicable to drugand biologic products, respectively.Regenerative disputes FDA’s classificationof the Regenexx Procedure as themanufacture of a drug. Regenerativealleges that its procedure is more appropriatelycharacterized as “practicingmedicine,” which FDA is not authorizedto regulate. Because it is not manufacturinga drug, Regenerative contends thatits procedure should not be subject topremarketing approval requirements.In June, Regenerative filed suit againstFDA in the U.S. District Court for theDistrict of Columbia, seeking declaratoryrelief that FDA does not have the authorityto regulate Regenerative’s practice ofmedicine and that Regenerative is not adrug manufacturer. Regenerative alsosought to enjoin FDA from seeking aninjunction against Regenerative becausesuch an injunction would “ruin Regenerative’sbusiness and cause it to incurmassive civil liability.” 30In response to Regenerative’s Complaint,FDA asserted that the mesenchymalstem cells used in the RegenexxProcedure qualify as HCT/Ps underFDA’s regulations. 31 FDA explained,however, that “HCT/Ps are not subjectto additional statutory requirements,such as biologics license application(BLA) or investigational new drug (IND)requirements, only if all the criteria in 21C.F.R. § 1271.10(a) are met. If any of thecriteria are not met, HCT/Ps are regulatedby FDA not only under the PHSAct, but also under the [Food, Drug, andCosmetic Act (FDCA)] as devices, drugs,and/or biological products.” 32FDA suggested that the mesenchymalstem cells used in the Regenexx Procedureare neither “minimally manipulated”nor “intended for homologous useonly” and therefore do not meet all of thecriteria of 21 C.F.R. § 1271.10(a). 33 As aresult, FDA contended that the RegenexxProcedure is subject to premarketing approvalrequirements under the FDCA.In August, just before this article wentto press, FDA put its foot down withRegenerative. The U.S. Department ofJustice (DOJ) filed a Complaint on behalfof FDA in the U.S. District Court for theDistrict of Columbia against Regenerativealleging, inter alia, that Regenerative’scultured cell product is not exemptfrom regulation under the FDCA. 34 TheDOJ also sought an injunction againstRegenerative, and Regenerative agreedto stay its previously-filed action andto cease production of its cultured cellproduct while the suit brought by theDOJ is pending. 35Be Prepared For FDAAs more researchers and companiesventure into the developing field of tissue-and stem cell-based products, valuablelessons can be learned from the predicamentin which Regenerative now findsitself. Before embarking on developinga new clinical therapy, researchers andcompanies should be sure to correctlyassess how their HCT/Ps will be characterizedby FDA and which regulatoryrequirements will apply to their products.It is likely that FDA’s enforcementactions against Regenerative spell justthe beginning of increased regulatoryscrutiny over these therapies. As celltherapy and tissue engineering applicationscontinue to develop at lightningspeed, promising new human tissue- andstem cell-based treatments will abound.Companies need to be cognizant of theapplicable regulatory requirements andaddress any issues proactively, before agiven therapy hits the market.For those unable to decipher wheretheir HCT/P fits in with the regulations,particularly with respect to whether theHCT/P meets the minimal manipulationand homologous use criteria of Section1271.10(a), FDA permits individuals torequest an opinion from FDA’s TissueReference Group. Because of this provisionfor such a proactive approach, FDAmakes clear that individuals who areuncertain as to whether their productsmeet all of the criteria under Section1271.10(a) and choose to neverthelessproceed without seeking clarification“assume the risk” that they might fail tocomply with appropriate premarketingand labeling requirements. 36 Planningahead to ensure compliance with all ofthe applicable regulations from the startwill allow developers of new HCT/Ps toescape the FDA scrutiny that Regenerativenow faces.FDLI1 21 C.F.R. § 1271.3(d)(2).2 Id.3 Id.FDLISeptember/October 2010 Up d a t e 19

More magazines by this user
Similar magazines