prop · GY0344 · 2010-12-21 00:00:00 — (10)The evaluation of advanced therapy medicinal products often requires very specific expertise, which goes beyond the traditional pharmaceutical field and covers areas bor- dering on other sectors such as biotechnology and medi- cal devices. For this reason, it is appropriate to create, within the Agency, a , which should be responsible for preparing a draft opinion onthequality,safetyandefficacyofeachadvancedtherapy medicinalproductforfinalapprovalbytheAgencysCom- mittee for for Human Use. In addition, should be con- sulted for the evaluation of any other medicinal product which requires specific expertise falling within its area of competence. (11)should the best available expertise on advanced therapy medicinal productsintheCommunity.ThecompositionoftheCom- mittee for Advanced Therapies should ensure appropriate coverage of the scientific areas relevant to advanced (1) OJL136,30.4.2004,p.1.RegulationasamendedbyRegulation(EC) No 1901/2006. therapies,includinggenetherapy,celltherapy,tissueengi- neering, devices, pharmacovigilance and ethics. Patient associations and clinicians with scientific experi- ence of advanced therapy medicinal products should also be represented. (12)To ensure scientific consistency and the efficiency of the system, the Agency should ensure the coordination between other Committees, advisory groups and working parties, notably for Human Use, , and the Scientific Advice Working Party. (13)Advancedtherapymedicinalproductsshouldbesubjectto the same regulatory principles as other types of biotech- nology medicinal products. However, technical require- ments, in particular the type and amount of quality, pre- clinical and clinical data necessary to demonstrate the quality, safety and efficacy of the product, may be highly specific.Whilethoserequirementsarealreadylaiddownin AnnexItoDirective2001/83/ECforgenetherapymedici- nal products and somatic cell therapy medicinal products, they need to be established for tissue engineered products. Thisshouldbedonethroughaprocedurethatprovidesfor sufficientflexibility,soastoeasilyaccommodatetherapid evolution of science and technology. (14)Directive 2004/23/EC of Parliament and of the Council (2) sets standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. This Regulation should not derogate from the basic principles laid down in Directive 2004/23/EC, but should supple- ment them with additional requirements, where appropri- ate. Where an advanced therapy medicinal product contains human cells or tissues, Directive 2004/23/EC should apply only as far as donation, procurement and testingareconcerned,sincethefurtheraspectsarecovered by this Regulation. (15)As regards the donation of human cells or tissues, prin- ciples such as the anonymity of both donor and recipient, altruism of the donor and solidarity between donor and recipient should be respected. As a matter of principle, human cells or tissues contained in advanced therapy medicinal products should be procured from voluntary and unpaid donation. Member States should be urged to take all necessary steps to encourage a strong public and non-profit sector involvement in the procurement of humancellsortissues,asvoluntaryandunpaidcellandtis- sue donations may contribute to high safety standards for cells and tissues and therefore to the protection of human health. (2) OJ L 102, , p. L 324/123 (16)Clinical trials on advanced therapy medicinal products should be conducted in accordance with the overarching principlesandtheethicalrequirementslaiddowninDirec- tive 2001/20/EC of Parliament and of the Councilof4April2001ontheapproximationofthelaws, regulations and administrative provisions of the Member Statesrelatingtotheimplementationofgoodclinicalprac- tice in the conduct of clinical trials on medicinal products for human use (1). However, Commission Directive 2005/28/EC of laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufactur- ing or importation of such products (2) should be adapted bylayingdownrulestailoredtofullytakeintoaccountthe specific technical characteristics of advanced therapy medicinal products. (17)The manufacture of advanced therapy medicinal products shouldbeincompliancewiththeprinciplesofgoodmanu- facturing practice, as set out in Commission Directive 2003/94/ECof8October2003layingdowntheprinciples and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use (3), and adapted, where necessary, to reflect the specific nature of those products. Furthermore, guidelines specific to advanced therapy medicinal products should be drawn up, so as to properly reflecttheparticularnatureoftheirmanufacturingprocess. (18)Advanced therapy medicinal products may incorporate devices or implantable devices. Those devices should meet the essential requirements laid down in Council Directive 93/42/EEC of 14 1993 concerning devices (4) and Council Directive 90/385/EECof20June1990ontheapproximationofthe laws of the Member States relating to implantable devices (5), respectively, in order to ensure an appropriate level of quality and safety. The results of the assessmentofthemedicaldevicepartortheactiveimplant- able device part by a notified body in accordance with those Directives should be recognised by the Agency in the evaluation of a combined advanced therapy medici- nal product carried out under this Regulation. (19)The requirements in Directive 2001/83/EC as regards the summaryofproductcharacteristics,labellingandthepack- age leaflet should be adapted to the technical specificities of advanced therapy medicinal products by laying down (1) OJ L 121, , p. Directive as amended by Regulation (EC) No 1901/2006. (2) OJ L 91, , p. (3) OJ L 262, 14.10.2003, p. (4) OJ L 169, , p. Directive as last amended by Directive 2007/47/ECoftheEuropeanParliamentandoftheCouncil(OJL247, 21.9.2007, p. (5) OJ L 189, 20.7.1990, p. Directive as last amended by Directive 2007/47/EC. specific rules on those products. These rules should com- ply fully with the patients right to know the origin of any cellsortissuesusedinthepreparationofadvancedtherapy medicinal products, while respecting donor anonymity. (20)Follow-up of efficacy and adverse reactions is a crucial aspect of the regulation of advanced therapy medicinal products. The applicant should therefore detail in its mar- keting authorisation application whether measures are envisaged to ensure such follow-up and, if so, what those measures are. Where justified on public health grounds, the holder of the marketing authorisation should also be requiredtoputinplaceasuitableriskmanagementsystem to address risks related to advanced therapy medicinal products. (21)TheoperationofthisRegulationrequirestheestablishment of guidelines to be drawn up either by the Agency or by the Commission. Open consultation with all interested parties, in particular authorities and the industry, should be carried out in order to allow a pooling ofthelimitedexpertiseinthisareaandensureproportion- ality. The guidelines on good clinical practice and good manufacturing practice should be laid down as soon as possible, preferably during the first year after entry into forceandbeforethedateofapplicationofthisRegulation. (22)A system allowing complete traceability of the patient as well as of the product and its starting materials is essential tomonitorthesafetyofadvancedtherapymedicinalprod- ucts. The and maintenance of that system should be done in such a way as to ensure coherence and compatibility with traceability requirements laid down in Directive 2004/23/EC in respect of human tissues and cells, and in Directive 2002/98/EC of Parlia- ment and of 2003 setting stan- dards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components (6). The traceability system should also respect the provisions laid down in Directive 95/46/EC of Parliament and of ber 1995 on the protection of individuals with regard to the processing of personal data and the free movement of such data (7). (23)As science evolves very rapidly in this field, undertakings developing advanced therapy medicinal products should be enabled to request scientific advice from the Agency, including advice on post-authorisation activities. As an incentive, the fee for that scientific advice should be kept ataminimallevelforsmallandmedium-sizedenterprises, and should also be reduced for other applicants. (6) OJ L 33, , p. (7) OJL281,23.11.1995,p.31.DirectiveasamendedbyRegulation(EC) No 1882/2003 (OJ L 284, 31.10.2003, p. L 324/124 (24)TheAgencyshouldbeempoweredtogivescientificrecom- mendations on whether a given product based on genes, cells or tissues meets the scientific criteria which define advanced therapy medicinal products, in order to address, as early as possible, questions of borderline with other areas such as cosmetics or devices, which may arise as science develops. , with its unique expertise, should have a promi- nent role in the provision of such advice. (25)Studies necessary to demonstrate the quality and non- clinical safety of advanced therapy medicinal products are often carried out by small and medium-sized enterprises. Asanincentivetoconductthosestudies,asystemofevalu- ation and certification of the resulting data by the Agency, independentlyofanymarketingauthorisationapplication, shouldbeintroduced.Eventhoughthecertificationwould notbelegallybinding,thissystemshouldalsoaimatfacili- tating the evaluation of any future application for clinical trialsandmarketingauthorisationapplicationbasedonthe same data. (26)Inordertotakeintoaccountscientificandtechnicaldevel- opments,theCommissionshouldbeempoweredtoadopt any necessary changes regarding the technical require- ments for applications for marketing authorisation of advanced therapy medicinal products, the summary of product characteristics, labelling, and the package leaflet. The Commission should ensure that relevant information on envisaged measures is made available to interested par- ties without delay. (27)Provisionsshouldbelaiddowntoreportontheimplemen- tation of this Regulation after experience has been gained, with a particular attention to the different types of advanced therapy medicinal products authorised. (28)The opinions of concerning tissue engineer- ing and that of Group on Ethics in Science and have been taken into account, as well as international experience in this field. (29)The measures necessary for the implementation of this Regulation should be adopted in accordance with Council Decision 1999/468/EC of 28 1999 laying down the procedures for the exercise of implementing powers con- ferred on the Commission (1). (30)In particular, the Commission should be empowered to adopt amendments to Annexes I to IV to this Regulation andtoAnnexItoDirective2001/83/EC.Sincethosemea- suresareofgeneralscopeandaredesignedtoamendnon- essential elements of this Regulation and of Directive 2001/83/EC,theymustbeadoptedinaccordancewiththe (1) OJ L 184, , p. Decision as amended by Decision 2006/512/EC (OJ L 200, 22.7.2006, p. regulatory procedure with scrutiny provided for in Article 5a of Decision 1999/468/EC. Those measures are essential for the proper operation of the whole regulatory framework and should therefore be adopted as soon as possible. (31)Directive 2001/83/EC and Regulation (EC) No 726/2004 should therefore be amended accordingly, SUBJECT MATTER AND DEFINITIONS This Regulation lays down specific rules concerning the authori- sation, supervision and pharmacovigilance of advanced therapy medicinal products. InadditiontothedefinitionslaiddowninArticle1ofDirec- tive 2001/83/EC and in Article 3, points (a) to (l) and (o) to (q) of Directive 2004/23/EC, the following definitions shall apply for the purposes of this Regulation: (a)Advanced therapy medicinal product means any of the fol- lowing medicinal products for human use: a gene therapy medicinal product as defined in Part IV of to Directive 2001/83/EC, a somatic cell therapy medicinal product as defined in Part IV of to Directive 2001/83/EC, a tissue engineered product as defined in point (b). (b)Tissue engineered product means a product that: contains or consists of engineered cells or tissues, and is presented as having properties for, or is used in or administered to human beings with a view to regenerat- ing, repairing or replacing a human tissue. A tissue engineered product may contain cells or tissues of human or animal origin, or both. The cells or tissues may be viable or non-viable. It may also contain additional sub- stances, such as cellular products, bio-molecules, bio- materials, chemical substances, scaffolds or matrices. L 324/125 Products containing or consisting exclusively of non-viable human or animal cells and/or tissues, which do not contain anyviablecellsortissuesandwhichdonotactprincipallyby pharmacological, immunological or metabolic action, shall be excluded from this definition. (c)Cells or tissues shall be considered engineered if they fulfil at least one of the following conditions: the cells or tissues have been subject to substantial manipulation, so that biological characteristics, physi- ological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved. The manipulations listed in , in par- ticular, shall not be considered as substantial manipulations, the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donor. (d)Combined advanced therapy medicinal product means an advanced therapy medicinal product that fulfils the follow- ing conditions: it must incorporate, as an integral part of the product, one or more devices within the meaning of Article 1(2)(a) of Directive 93/42/EEC or one or more implantable devices within the meaning of Article 1(2)(c) of Directive 90/385/EEC, and its cellular or tissue part must contain viable cells or tis- sues, or its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to. 2.Where a product contains viable cells or tissues, the phar- macological, immunological or metabolic action of those cells or tissues shall be considered as the principal mode of action of the product. 3.An advanced therapy medicinal product containing both autologous (emanating from the patient himself) and allogeneic (coming from another human being) cells or tissues shall be con- sidered to be for allogeneic use. 4.A product which may fall within the definition of a tissue engineered product and within the definition of a somatic cell therapy medicinal product shall be considered as a tissue engi- neered product. 5.A product which may fall within the definition of: a somatic cell therapy medicinal product or a tissue engi- neered product, and a gene therapy medicinal product, shall be considered as a gene therapy medicinal product. Donation, procurement and testing Where an advanced therapy medicinal product contains human cells or tissues, the donation, procurement and testing of those cells or tissues shall be made in accordance with Directive 2004/23/EC. 1.The rules set out in Article 6(7) and Article 9(4) and (6) of Directive2001/20/ECinrespectofgenetherapyandsomaticcell therapy medicinal products shall apply to tissue engineered products. 2.TheCommissionshall,afterconsultingtheAgency,drawup detailed guidelines on good clinical practice specific to advanced therapy medicinal products. The Commission shall, after consulting the Agency, draw up guidelinesinlinewiththeprinciplesofgoodmanufacturingprac- tice and specific to advanced therapy medicinal products. Issues specific to devices 1.Amedicaldevicewhichformspartofacombinedadvanced therapy medicinal product shall meet the essential requirements laid down in to Directive 93/42/EEC. 2.Anactiveimplantablemedicaldevicewhichformspartofa combined advanced therapy medicinal product shall meet the essential requirements laid down in 1 to Directive 90/385/EEC. Specific requirements for advanced therapy medicinal products containing devices InadditiontotherequirementslaiddowninArticle6(1)ofRegu- lation(EC)No726/2004,applicationsfortheauthorisationofan advanced therapy medicinal product containing devices, bio-materials, scaffolds or matrices shall include a description of thephysicalcharacteristicsandperformanceoftheproductanda description of the product design methods, in accordance with to Directive 2001/83/EC. L 324/126 TheCommitteeforMedicinalProductsforHumanUseshall consult on any scientific assessment of advanced therapy medicinal products necessary to draw up the scientific opinions referred to in Article 5(2) and (3) of Regulation (EC) No 726/2004. shall also be consulted in the event of re-examination of the opinion pursuant to Article 9(2) of Regulation (EC) No 726/2004. 2.When preparing a draft opinion for final approval by for Human Use, the Commit- tee for Advanced Therapies shall endeavour to reach a scientific consensus. If such consensus cannot be reached, shall adopt the position of the majority of its members. The draft opinion shall mention the divergent positions and the grounds on which they are based. 3.The draft opinion given by for for Human Use in a timely mannersoastoensurethatthedeadlinelaiddowninArticle6(3) or Article 9(2) of Regulation (EC) No 726/2004 can be met. 4.Where the scientific opinion on an advanced therapy medicinal product drawn up by for Human Use under Article 5(2) and (3) of Regulation (EC) No 726/2004 is not in accordance with the draft opinion of , for Human Use shall annex to its opinion a detailed explanation of the scientific grounds for the differences. 5.TheAgencyshalldrawupspecificproceduresfortheappli- cation of paragraphs 1 to 4. Combined advanced therapy medicinal products 1.Where a combined advanced therapy medicinal product is concerned, the whole product shall be subject to final evaluation by the Agency. 2.The application for a marketing authorisation for a com- binedadvancedtherapymedicinalproductshallincludeevidence of conformity with the essential requirements referred to in Article 6. 3.The application for a marketing authorisation for a com- bined advanced therapy medicinal product shall include, where available,theresultsoftheassessmentbyanotifiedbodyinaccor- dance with Directive 93/42/EEC or Directive 90/385/EEC of the device part or implantable device part. shall recognise the results of that assessment in its evaluation of the medicinal product concerned. may request the relevant notified body to transmit any information related to the results of its assessment. The noti- fied body shall transmit the information within a period of one month. If the application does not include the results of the assessment, theAgencyshallseekanopinionontheconformityofthedevice part with to Directive 93/42/EEC or 1 to Direc- tive 90/385/EEC from a notified body identified in conjunction withtheapplicant,unlesstheCommitteeforAdvancedTherapies advised by its experts for devices decides that involve- ment of a notified body is not required. SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING Summary of product characteristics By way of derogation from Article 11 of Directive 2001/83/EC, the summary of the product characteristics for advanced therapy medicinal products shall contain the information listed in to this Regulation, in the order indicated therein. Labelling of outer/immediate packaging By way of derogation from Articles 54 and 55(1) of Directive 2001/83/EC, the particulars listed in to this Regulation shall appear on the outer packaging of advanced therapy medici- nalproductsor,wherethereisnoouterpackaging,ontheimme- diate packaging. In addition to the particulars mentioned in Article 55(2) and (3) of Directive 2001/83/EC, the following particulars shall appear on the immediate packaging of advanced therapy medicinal products: (a)the unique donation and product codes, as referred to in Article 8(2) of Directive 2004/23/EC; (b)in the case of advanced therapy medicinal products for autologous use, the unique patient identifier and the state- ment For autologous use only. L 324/127 1.By way of derogation from Article 59(1) of Directive 2001/83/EC, the package leaflet for an advanced therapy medici- nal product shall be drawn up in accordance with the summary ofproductcharacteristicsandshallincludetheinformationlisted in to this Regulation, in the order indicated therein. 2.The package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use. Post-authorisation follow-up of efficacy and adverse reactions, and risk management 1.In addition to the requirements for pharmacovigilance laid down in Articles 21 to 29 of Regulation (EC) No 726/2004, the applicant shall detail, in the marketing authorisation application, the measures envisaged to ensure the follow-up of efficacy of advanced therapy medicinal products and of adverse reactions thereto. 2.Where there is particular cause for concern, the Commis- sionshall,ontheadviceoftheAgency,requireaspartofthemar- keting authorisation that a risk management system designed to identify, characterise, prevent or minimise risks related to advanced therapy medicinal products, including an evaluation of the effectiveness of that system, be set up, or that specific post- marketing studies be carried out by the holder of the marketing authorisation and submitted for review to the Agency. In addition, the Agency may request submission of additional reports evaluating the effectiveness of any risk management sys- tem and the results of any such studies performed. Evaluation of the effectiveness of any risk management system and the results of any studies performed shall be included in the periodicsafetyupdatereportsreferredtoinArticle24(3)ofRegu- lation (EC) No 726/2004. 3.The Agency shall forthwith inform the Commission if it finds that the marketing authorisation holder has failed to com- ply with the requirements referred to in paragraph 2. 4.TheAgencyshalldrawupdetailedguidelinesrelatingtothe application of paragraphs 1, 2 and 3. 5.If serious adverse events or reactions occur in relation to a combined advanced therapy medicinal product, the Agency shall inform the relevant national competent authorities respon- sible for implementing Directives 90/385/EEC, 93/42/EEC and 2004/23/EC. 1.The holder of a marketing authorisation for an advanced therapy medicinal product shall establish and maintain a system ensuring that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourc- ing, manufacturing, packaging, storage, transport and delivery to the hospital, institution or private practice where the product is used. 2.The hospital, institution or private practice where the advanced therapy medicinal product is used shall establish and maintain a system for patient and product traceability. That sys- tem shall contain sufficient detail to allow linking of each prod- uct to the patient who received it and vice versa.