authorisations. All ATMPs are required to show safety and efficacy throughapprovedclinicalstudies.
MedicalDevices(EU)
In the EU, medical devices are defined as those products which do not achieve their principal intended action in or on the human body by pharmacological, immunological or metabolic means. Therefore, the European medical device directives principally apply to tissue repair scaffolds and biomaterials that perform a more structural function. Medical devices are classified based upon their risk and regulated under the medical device directive (93/42/EEC, as amended by 2007/47/EC in March2010).Inordertomarketanewmedicaldevice,itisrequiredtogo through the CE marking process whereby a technology assessment is carriedoutbyindependentnotifiedbodiesthattestthedevicetoensure thatitmeetstheEUrequirements.
CellandTissueBasedTherapies(US)
Viablecellandtissuebasedproductsmustfollowtheregulatoryroutefor human cells, tissues and cell and tissuebased products (HCT/Ps). If the product is minimally manipulated, intended for homologous/autologous use and not combined with a drug or device, it will be regulated under section361 of the public health service act. However, most products will not meet these strict criteria and will be regulated under section 351 of the Public Health Service Act. Under section 351, the HCT/P is subject to clinical assessment under an Investigational New Drug (IND) application before marketing approval can be granted via a Biologics License Application(BLA).
MedicalDevices(US)
510(k) premarket notification is a regulatory route for mediumrisk medicaldevicesthatshowsubstantialequivalence(SE)toapredicateClass II device that has been given marketing approval in the US since May 1976. SE is determined by the device’s intended use and technological characteristics,evidenceforwhichmustbesubmittedtotheFDA90days priortomarketing.The510(k)pathwayisusuallyreservedforscaffoldand
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biomaterialbased devices that perform a structural function. Premarket approval (PMA) is a regulatory route for Class III medical devices. This meansthattheyarenotsubstantiallyequivalent(NSE)toanexistingClass IIdeviceandposeasignificantrisktohumanhealthand/orprovidealife supporting/sustaining function. Therefore the device is subject to pre approval by the FDA to ensure that the device is both safe and effective which is demonstrated through the collection of clinical data under an InvestigationalDeviceExemption(IDE).AproductregulatedunderaPMA may often contain an active drug or biologic provided that this drug/biologicdoesnotprovidetheprimarytherapeuticeffect.
regulatoryuncertainty
A large proportion of the conformance requirements for cell and tissue basedproductsareborrowedfromthepharmaceuticalregulations(Figs1 & 2). As a result, they lack a number of key specific requirements that encumber their transposition into a form that can be used in the development of cell and tissuebased products. Although some specific legislation is provided in the HCT/P and ATMP regulations, many of the specific good manufacturing practice (GMP) and postmarketing regulations that are required to fully implement them have yet to be promulgated. This is especially detrimental given the requirement for GMPgrade material to be used in both clinical studies and the final commercialgrade product. In addition, there are currently no published international standards documents available to guide the testing and manufacture of ATMPs or HCT/Ps. These deficiencies increase the regulatoryburdenupondevelopersbylimitingtheirunderstandingofhow they must fulfil the requirements and creating uncertainty over their business practices and best use of resources. The medical device regulations are more clear cut in both the US and EU, provided that the device is not combined with a viable cell component. These combined products (EU) or combination products (US) have the additional complicationofhavingtofollowmultiplesetsofGMPregulationsatsome
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stageoftheprocess,eveniftheaimistoproducethetwocomponentsas asingleentity.considerationsandstrategiesforSMEs
In order to achieve commercial success, it is essential that all of the potentialregulatorypathwaysareunderstoodandconsideredbeforekey businessdecisionsaremade,astheregulatoryburdenisheavilylinkedto resource and will define the business model for the company (table 1). The requirement for clinical studies to support the majority of cell and tissuebased products requires a significant amount of investment and a thorough knowledge of the regulatory requirements. However, as indicated by the medical device pathways, regenerative products do not necessarily require clinical studies to gain marketing approval and this is thecertainlythecaseforthemajorityofproductsmarketedviathe510(k) PMNroute(table2). Table1.Regulatoryburdenandtimetomarketforcellanddevicebasedproducts Devicebased Cellbased Technology Noviablecellcomponent, largelystructuralfunction Viablecellcomponent,provides biologicaltherapeuticeffect
ApprovalRoute 510(k),PMA,CEMark INDBLA,ATMP
Regulatory Burden Lowtomedium,littleorno clinicaldatarequiredfor ClassIIandsomeClassIII Relativelyhigh,clinicaldata requiredformajorityofproducts Speedto Market Faster,23yearsforClassII and57yearsforPMA Slower,~1015years
This allows them to reach the market more quickly and provide a demonstratortoinvestorsandotherlargercompaniesthatthereisvalue in the technology and the business. Similarly, the CE marking process in the EU allows many devices, including some Class III devices, to be approved without the need for new clinical studies, as they can rely on existingclinicaldataprovidedthereisasignificantsimilaritybetweenthe newproductandthatusedtocollecttheoriginalclinicaldata.Inaddition,
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medicaldevicescanbeusedasaprecursortoamorecomplexbiological product with the initial device acting as a stepping stone to a more ambitious longterm product pipeline. For example, these products are oftensimplebiomaterialbasedproductsthat,whilsthavinglimitedclinical impactintheshortterm, mayprovideasuitablescaffoldforthedelivery andsupportofanATMP/HCT/Pinthelongterm. Table2.Exemplarproductswithregenerativemedicineapplications Regenerativemedicineapplication Regulatory pathway EUapproved products USapproved products EU US ClassII medical device Kerraglove(Ark Therapeutics) (ClassIIb) Actifuse (Apatech) Noninvasive woundhealing device Scaffold devicefor bone regeneration ClassIII medical device Chondromimetic (Orthomimetics) INFUSE (Medtronic) Osteochondral plugforkneejoint repair Bonegraftfor spinalrepair ATMP(EU) HCT/P(US) Chondrocelect (Tigenix) Carticel (Genzyme) Viableautologouscellulartherapy productsforcartilagerepair
In addition to utilising the device regulations, developers of ATMPs/HCT/Psshouldensurethattheyuseallavailablemeanstoenhance their chances of commercial success. For example, as the costs of development are likely to be high given the limited investment for regenerative medicine SMEs, product reimbursement may provide a significant barrier, especially as it is not tied in with regulatory approval. Therefore,clinicaltrialdesignandcostofgoodsshouldtakeintoaccount the requirements of the business, the regulator and those who will ultimately reimburse the product. This regulatory burden can also be shared by the strategic use of contract manufacturing and research organisationsthathavebothGMPfacilitiesandcapabilitiesthatcannotbe resourced “inhouse”. It should also be noted that the European MedicinesAgencyprovidesincentivesforSMEswithATMPssuchasa50% reductioninthemarketingapplicationfeeandafreecertificationservice forallrelevantqualityandnonclinicaldata.
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Medical Devices (2007/47/EC) ATMPs (EC 1394/2007)Class II (a/b) Class III
Full audit, Clinical data & technical file
Notified body assessment
EU 2001/20/EC Clinical trials directive EU 2003/94/EC GMP for medicinal products
EU 2006/17/EC
implementing 2004/23/EC Directive for the donation, procurement and testing of human tissues and cells
UK SI 1031 2004
Medicines for human use clinical trials regulations EU 2005/28/EC
GCP for medicinal products
Combined Products
Does the product contain viable cells?
Design dossier and ISO:13485 Yes No Medical Devices (2007/47/EC) ATMPs (EC 1394/2007)
Class II (a/b) Class III
Full audit, Clinical data & technical file
Notified body assessment
EU 2001/20/EC Clinical trials directive EU 2003/94/EC GMP for medicinal products
EU 2006/17/EC
implementing 2004/23/EC Directive for the donation, procurement and testing of human tissues and cells
UK SI 1031 2004
Medicines for human use clinical trials regulations EU 2005/28/EC
GCP for medicinal products
Combined Products
Does the product contain viable cells?
Design dossier and ISO:13485 Yes No Clinical trials required Clinical trials not required Requirements written for cell- based products Requirements written for pharmaceuticals Figure1.Regulatoryconformanceroutesforregenerativemedicineproductsin theEU