Drug vs medical device clinical trial applications - TOPRA

November Issue 200623European Focus FranceNew biomedical research legal framework in France:Drug vs medical device clinical trial applications – a comparisonChristelle Véchot, Regulatory Affairs Consultant andDavid Uguen, Senior Regulatory Affairs Consultant, MDS Pharma Services, FranceIntroductionDirective 2001/20/EC (the so-called Clinical Trial Directive) was adoptedby the European Parliament and the Council with the aim of harmonisingthe regulatory requirements of the Member States (MS) for the conductof clinical studies while emphasising the protection of subjects.Whereas this Directive was transposed into the national laws of most ofthe European Union (EU) MS in May 2004, in France, the transposed lawcame into effect only on August 27, 2006.One key aspect of the new French regulatory framework governingclinical studies is that it applies to all products administered to subjectswithin the scope of a clinical trial, ie, not only to medicinal products butalso to medical devices as well as to cosmetics, products used for tattoosand other products.The aim of this review is to present this new scheme, focusingspecifically on clinical trial applications (CTAs) for medicinal productsand medical devices. Where appropriate, noteworthy differencesbetween these two kinds of products are highlighted.Regulatory frameworkIn France, implementation of Directive 2001/20/EC was initiated withthe issue of Law N°2004-806 in August 2004, followed by DecreeN°2006-477, which was published on April 26, 2006. This Decreedefines the overall regulatory framework for the conduct ofbiomedical researches in France and applies not only to the testing ofdrugs but also of medical devices, cosmetics and other products.Table 1: Regulatory framework for drugs or medical devices clinical studies: published ordersOrder’s topicOrder’s reference (NOR)Format and content of the CTA dossier to be submitted to the AFSSAPSFormat and content of the CTA dossier to be submitted to the centralethics committeeDrugsSANP0622223ASANP0623844A*SANP0622225AMedical devicesSANP0623370ASANP0623371AFormat and content of the protocol SANP0622226A SANP0623372AFormat and content of the Investigator’s Brochure SANP0622120A SANP0623373AFormat and content of the declaration of adverse reactions and safety issues SANP0622224A SANP0623374AFormat and content of the declaration of serious adverse reactions SANP0621452A –Format and content of the safety report SANP0622181A SANP0623515AContent of requests for authorisation of substantial amendments SANP0622121A SANP0623514AFormat and content of the end of study declaration, final study report andstudy report synopsisSANP0622180ASANP0623516AData to be transferred into the EudraCT database by the AFSSAPS SANP0621680A –Content of labels SANP0622221A –CTA: Clinical Trial ApplicationAFSSAPS (French competent authority): Agence Française de Sécurité Sanitaire des Produits de Santé* order amending the previous order encoded SANP0622223AEuropean Focus continued …www.topra.org

November Issue 200625Table 2: Content of the administrative dossierItems in the administrative dossierInvestigational medicinalproductInvestigationalmedical deviceApplication letter* ✓ ✓Application form EudraCT form AFSSAPS formRegistration number EudraCT number AFSSAPS numberList of CAs within the Community to which the application has beensubmitted and nature of decisions, if available✓✓Power of attorney letter, if the applicant acts on behalf of the sponsor ✓ ✓Copy of any specific authorisations, if appropriate ✓ ✓Copy of any scientific advice, if any ✓ NRAuthorisation to submit third party’s data, if appropriate ✓ ✓Proof of payment of fees ✓ ✓* Template available on the AFSSAPS’s website - NR: not requestedThe above table shows that the contents of the administrative dossiers are very similar. One key difference comes from the fact that the EudraCTsystem applies to IMPs only. As a result, the EudraCT registration number and the EudraCT application form do not work for medical devices.However, AFSSAPS has put a similar system in place (allowing allocation of a specific number and use of a similar application form). Also, it is notrequested to include in the administrative dossier for an investigational medical device the minutes of previously received scientific advice.Part 2 – Biomedical research dossierHere again, the requirements are very similar for IMPs and medical devices (see Table 3).Table 3: Content of the biomedical research dossierItems in the biomedical research dossierInvestigationalmedicinal productInvestigational medicaldeviceProtocol ✓ ✓Protocol synopsis ✓ ✓Investigator’s Brochure or the SmPC 1 or the instructions for use 2Authorisation to use the Investigator’s Brochure, if it is the property of aThird Party✓✓Insurance certificate ✓ ✓Peer review of the trial, if any ✓ ✓Reference document to assess the unexpectedness of serious adverse events ✓ ✓SmPC: summary of products characteristics1 : when the medicinal product has been authorised in any EU Member State2 : when the medical device bears the CE markingWhenever the IMP or the investigational medical device has been granted a Marketing Authorisation or affixed the CE mark, the approvedSmPC or instructions for use may be submitted in replacement to the Investigator’s Brochure – providing that the product is used in the studywithin the approved conditions for use.www.topra.org

26RegulatoryRapporteurPart 3 – Technical dossierThe content of the technical dossier for an IMP (so-called IMP dossier,“IMPD”) or a medical device should include different sectionssummarising the quality, the non-clinical and the clinical data (whererelevant) and include a benefit/risk assessment.Obviously, the content of the quality, non-clinical and clinical sectionswill differ significantly between both product types and thereforecannot be compared. Nonetheless, guidance on the content of thetechnical dossier of specific products has been released and is brieflysummarized here.Case of medical devices containing an active substance“Where the biomedical research implies the use of a medical devicecontaining an active substance, which – when used separately – islikely to be considered as a medicinal product, the technical dossiershould be completed by information regarding this active substance”.Pursuant to this requirement, the technical dossier should includequality, non-clinical and clinical data – in particular local pharmacokineticand local effects data – on the active substance used, completed by ascientific rationale justifying its addition to the medical device.It is interesting to note that, where the active substance has alreadybeen authorised as part of a medicinal product in the EU, the qualitysection related to this substance may be limited to the SmPCtogether with a statement from its manufacturer specifying that it isstrictly identical to the one contained in the authorised medicinalproduct – and described in the quality part of the approved MarketingAuthorisation dossier. In that case, the non-clinical and clinical datashould demonstrate that the efficacy/safety ratio remains unalteredwhen compared to the usual utilisation of the medicinal product.On the contrary, when the medical device contains an “unauthorisedactive substance”, the data to be provided on the active substance aresimilar to the ones which need to be included in the so-called “full IMPD”.Table 4 details the data to be provided as part of each of the threesections of the “active substance technical dossier” depending on itsauthorisation status.

November Issue 200627Table 4: “Active substance technical dossier” requirements (for a medical device)Technical dossier part Authorised active substance Unauthorised active substanceQuality Manufacturer statement Summary data on the pharmaceutical, chemical andbiological qualityNon-clinical and clinical Unaltered benefit/risk ratio Local pharmacokinetic and local effects data in particularAdditional SmPC –(Prepared from Order N°SANP0623370A, article 3)Abridged technical dossierIn certain circumstances (see Table 5 and Table 6), an abridged technical dossier for IMPs and medical devices can be submitted to the AFSSAPS.The general principle is that whenever the IMP or the medical device is already “known” to the AFSSAPS or another EU competent authority,the submission of an abridged technical dossier is permitted.Table 5: Simplified technical dossier for IMPs (simplified IMPD)CircumstancesSimplified IMPD contentQuality Data Non-clinical Data Clinical DataThe IMP has a MA in any EU Member State, USA or Japan, or isauthorised for a compassionate use in France, and is used in the trial:– within the conditions of the SmPC SmPC SmPC SmPC– outside the conditions of the SmPC SmPC Yes YesThe IMP has no MA in any EU Member State but:– another pharmaceutical form or strength of the IMP has a MA inany EU Member State and the IMP is supplied by the MAH– the drug substance is part of a product with a MarketingAuthorisation in a MS and is supplied from the same manufacturerSmPC Yes YesSmPC Yes YesThe sponsor has already submitted a CTA for this IMP to theAFSSAPS and– new data are available since CTA New Data New Data New Data– the IMP is used in the trial outside the conditions stated in theprevious CTANo Yes YesThe IMPD was submitted as part of a previous CTA submitted by athird party who authorised the sponsor to refer to the previousCTA and– new data are available since CTA New Data New Data New Data– the IMP is used in the trial outside the conditions stated in theprevious CTANo Yes YesThe IMP is a placebo P+A No NoBut if the excipients are identical to the IMP and if it is not a sterile No No NoformIMP: Investigational Medicinal Product; IMPD: Investigational Medicinal Product Dossier; MA: Marketing Authorisation; MAH: Marketing Authorisation Holder;CTA: Clinical Trial Application. (Prepared from Order N°SANP0622223A, article 4)www.topra.org