COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP)

Eurpean Medicines Agency Lndn, 20 Nvember 2008 Dc. Ref. EMEA/149995/2008 COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) GUIDELINE ON SAFETY AND EFFICACY FOLLOW-UP - RISK MANAGEMENT OF ADVANCED THERAPY MEDICINAL PRODUCTS DRAFTING GROUP DISCUSSION December 2007 t February 2008 DISCUSSION IN GTWP, CPWP, PHVWP February and March 2008 DISCUSSION AND ADOPTION OF THE DRAFT BY CHMP March and April 2008 RELEASE FOR PUBLIC CONSULTATION May 2008 END OF PUBLIC CONSULTATION (DEADLINE FOR COMMENTS) 15 August 2008 DRAFTING GROUP DISCUSSION ON COMMENTS August and September 2008 DISCUSSION OF COMMENTS IN GTWP, CPWP, PHVWP, AND PRESENTATION TO BWP September and Octber 2008 ADOPTION BY CHMP Nvember 2008 DATE FOR COMING INTO EFFECT 31 December 2008 7 Westferry Circus, Canary Wharf, Lndn, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 68 E-mail: mail@emea.eurpa.eu http://www.emea.eurpa.eu Eurpean Medicines Agency, 2008. Reprductin is authrised prvided the surce is acknwledged

EXECUTIVE SUMMARY Scientific prgress in cellular and mlecular bitechnlgy has led t the develpment f advanced therapy medicinal prducts, such as gene therapy, smatic cell therapy, and tissue engineering prducts. The Eurpean parliament and the Cuncil have issued Regulatin N 1394/2007 (hereafter referred as the Regulatin) that set up specific rules fr advanced therapy medicinal prducts (ATMPs). Article 14 (4) f the Regulatin requests the Eurpean Medicines Agency t draw up detailed guidelines relating t the pst authrisatin fllw-up f efficacy and adverse reactins, and risk management. T meet this requirement, this guideline has been prepared by the EMEA and its scientific cmmittees and wrking parties. It shuld be read and understd in cnjunctin with existing relevant guidelines, and prvides a basis fr the develpment f future detailed guidelines in the field. The scientific ratinale fr specific rules fr pharmacvigilance f advanced therapies is described as a list f main pints that shuld be cnsidered when preparing a risk management plan fr advanced therapy medicinal prducts (ATMP.) Safety and efficacy fllw-up systems frm part f the Risk management system and shuld be planned in the EU-Risk management plan (EU-RMP). Bth fllw up systems are defined as any systematic cllectin and cllatin f data that is designed in a way that enables learning abut safety and/r efficacy f an ATMP. It may include passive r active surveillance, bservatinal studies, r clinical trials. It is stressed that bth the efficacy and the safety fllw-up systems are nt a substitute fr the need fr adequate data t be available at the time f authrisatin t enable prper benefit-risk evaluatin. Tw dcuments that are part f a marketing authrisatin applicatin are directly affected by this guideline the EU Risk Management Plan (EU-RMP) and the Detailed Descriptin f the Pharmacvigilance System (DDPS). It may be necessary t intrduce additinal elements t the descriptin f the pharmacvigilance system t take accunt f the particular issues with ATMPs. In Part I f the EU-RMP, a new chapter fr ATMPs is intrduced within the sectin Additinal EU Requirements f the Safety Specificatins. Grups f risks that are mre targeted t ATMPs shuld be discussed there in an rder that fllws the prcurement in living dnrs, the prduct manufacturing, administratin, and fllw-up f patients. Part II f the RMP shall cntain a new discussin n the need f efficacy fllw-up. If the need is identified, details f an efficacy fllw-up plan shuld be submitted as Annex 9 f the RMP. The guideline als lists sme pints t be cnsidered fr efficacy pst-authrisatin studies, in particular sample size, use f data, reprting, chice f endpints and examples f events f particular interest. It is als acknwledged that supprt f electrnic exchange f pharmacvigilance infrmatin will need sme adjustments. It will be addressed with EudraVigilance stakehlders separately Cnsequences f nn-cmpliance with the agreed risk management plan include financial penalties and regulatry measures. These are utlined in the guideline as requested by stakehlders in the public cnsultatin. Fllw-up systems, risk management and traceability need prcessing f persnal data. Related data prtectin issues are therefre briefly discussed with fcus n legal situatin and feasibility. EMEA/149995/2008 EMEA 2008 Page 2/22

GUIDELINE ON SAFETY AND EFFICACY FOLLOW-UP - RISK MANAGEMENT OF ADVANCED THERAPY MEDICINAL PRODUCTS TABLE OF CONTENT 1. INTRODUCTION... 4 2. SCOPE OF THE GUIDELINE... 4 3. LEGAL BASIS... 5 4. DEFINITIONS... 5 5. COMMON RULES FOR POST-AUTHORISATION SURVEILLANCE OF MEDICINAL PRODUCTS... 7 6. SCIENTIFIC RATIONALE FOR SPECIFIC RULES FOR POST-AUTHORISATION SURVEILLANCE OF ADVANCED THERAPY MEDICINAL PRODUCTS... 7 6.1. SAFETY CONCERNS... 7 6.2. EFFICACY CONCERNS... 9 6.3. POINTS TO CONSIDER WHEN DESIGNING THE STUDIES... 10 6.3.1. Sample size fr fllw-up... 10 6.3.2. Dynamics f the disease and effects f the prduct... 10 6.3.3. Cnsideratins n clinical fllw-up... 10 6.3.4. Cnsideratins n safety fllw-up f living dnrs... 11 6.3.5. Safety fllw-up f clse cntacts and ffsprings... 11 7. ADDITIONAL REQUIREMENTS FOR THE PHARMACOVIGILANCE SYSTEM OF MARKETING AUTHORISATION HOLDERS... 12 8. ADDITIONAL REQUIREMENTS FOR THE RISK MANAGEMENT SYSTEM OF ADVANCED THERAPY MEDICINAL PRODUCTS... 13 8.1. SAFETY SPECIFICATIONS... 14 8.1.1. Additinal EU requirements... 14 8.2. SUMMARY OF SAFETY SPECIFICATIONS... 15 8.3. PHARMACOVIGILANCE PLAN (INCORPORATING SAFETY FOLLOW-UP)... 15 8.4. EVALUATION OF THE NEED FOR EFFICACY FOLLOW-UP... 16 8.5. RISK MINIMISATION PLAN... 16 8.5.1. Effectiveness f the risk minimisatin measures... 17 8.6. EFFICACY FOLLOW-UP PLAN (ANNEX 9 OF THE RMP)... 17 8.6.1. Scientific ratinale fr the efficacy fllw-up... 17 8.6.2. Overview f the study prtcls fr efficacy fllw-up... 17 8.6.3. Detailed prtcls f the efficacy fllw-up studies... 17 9. USE OF REGULATORY TOOLS IN POST-AUTHORISATION SURVEILLANCE OF THE ADVANCED THERAPY MEDICINAL PRODUCTS... 18 10. ELECTRONIC EXCHANGE OF PHARMACOVIGILANCE INFORMATION... 18 11. COMPLIANCE MONITORING... 19 12. PERSONAL DATA PROTECTION ISSUES... 19 APPENDIX I RELATED LEGISLATION AND GUIDELINES... 21 RELATED LEGISLATION... 21 RELEVANT GUIDELINES... 21 EMEA/149995/2008 EMEA 2008 Page 3/22

1. INTRODUCTION Scientific prgress in cellular and mlecular bitechnlgy has led t the develpment f advanced therapies, such as gene therapy, smatic cell therapy, and tissue engineering. Because f the nvelty, cmplexity and technical specificity f advanced therapy medicinal prducts, specially tailred and harmnised rules are needed t guarantee a high level f health prtectin, as well as t harmnise and facilitate market access, fster cmpetitiveness and prvide legal certainty. The Eurpean parliament and the Cuncil have issued Regulatin N 1394/2007 (hereafter referred as the Regulatin) that sets up specific rules fr advanced therapy medicinal prducts (ATMPs). It regulates thse ATMPs which are intended t be placed n the market in the Eurpean Ecnmic Area, and that are within the scpe f Directive 2001/83/EC as amended, i.e. prducts that are either prepared industrially r manufactured by a methd invlving an industrial prcess. In its Chapter 5 the Regulatin details pst-authrisatin requirements. Article 14 (4) specifically requests the Eurpean Medicines Agency t draw up detailed guidelines relating t the pst authrisatin fllw-up f efficacy and adverse reactins, and risk management. In rder t meet this request, the EMEA is issuing this guideline t cmplement the existing relevant guidelines. It shuld als prvide a basis fr the develpment f future detailed guidelines in the field. This guideline cncerns an area where knwledge is fast evlving and there is limited experience. Marketing authrisatin applicants and hlders are encuraged t apply fr scientific advice frm the EMEA as early as pssible t prevent unnecessary mistakes in develpment and delays in the regulatry prcess. The guideline prvisins are f verarching" character, which means that they describe a framewrk f regulatry requirements applicable t all ATMPs. Specific prvisins fr gene therapy, cell therapy and tissue engineering prducts cntinue t be included in prduct type specific guidelines. In the freseeable future, it is expected that with grwing experience and establishment f the Cmmittee n Advanced Therapies (CAT), there will ften be a need t update the guidelines cncerning ATMPs. Therefre, users f this guideline shuld always check whether a newer guideline has been published which further specifies the issues discussed belw. It needs t be highlighted that the cncept fr generatin f lng-term data in pst-authrisatin phase is nt a substitute fr the need fr efficacy and safety data at the time f marketing authrisatin applicatin. Quality, safety and efficacy data are required as the basis fr apprval and shuld be sufficient t enable a prper benefit-risk evaluatin. Any lack f such data and the intentin t generate pst-authrisatin data shuld be fully justified at the time f marketing authrisatin applicatin. Due t the nvelty f these prducts, applicants are encuraged t seek scientific advice frm the EMEA als in respect f risk management plans. T ensure ptimal assessment prcesses, regulatry authrities are encuraged t use multidisciplinary teams fr assessment f risk management plans, particularly when the plan cntains efficacy fllwup activities. 2. SCOPE OF THE GUIDELINE The Regulatin defines ATMPs as gene therapy medicinal prducts, smatic cell therapy medicinal prducts and tissue engineered prducts. This guideline fcuses n unique characteristics f ATMPs as further detailed in the Chapter 6 - Scientific Ratinale. Its applicability is restricted t ATMPs. This guideline describes specific aspects f pharmacvigilance, risk management planning, safety and efficacy fllw-up f authrised ATMPs, as well as sme aspects f clinical fllw-up f patients treated with such prducts. The target audience includes in particular marketing authrisatin hlders, cmpetent authrities fr medicinal prducts, and health care prviders, irrespective whether f cmmercial r nn-cmmercial character. EMEA/149995/2008 EMEA 2008 Page 4/22

It shuld be highlighted that the specific aspects described in this guideline frm nly a part f the infrmatin necessary fr a benefit-risk analysis. Therefre, a full benefit-risk discussin is nt in the scpe f this guideline. Fllw-up f subjects in interventinal clinical trials with ATMPs is nt directly in the scpe f this guideline. Nevertheless, it is appreciated that sme subjects f such clinical trials will require very lng r even life-lng fllw-up. Therefre, when designing a pst-authrisatin patients' fllw-up system, it is always necessary t take int accunt any existing requirements and guidelines fr fllw-up f subjects in clinical trials, as well as the fllw-up system that was, r still is, in place fr subjects f clinical trials with the particular ATMP. The text f this dcument is based n existing pharmacvigilance and efficacy guidelines cllected in The Rules Gverning Medicinal Prducts in the Eurpean Unin which set up cmmn rules. Thse rules are hereafter nt repeated, r nly a summary is prvided when necessary. Readers are encuraged t fllw the references t get the full infrmatin. Fr specific rules, this guideline cnsidered in particular existing cncepts and guidelines published, r drafted, by the EMEA, CHMP and its wrking parties in areas f gene therapy, cell therapy and tissue engineering, as well as pharmacvigilance and risk management. Figure 1 Scpe f the guideline Medicinal prducts (MP) MP in scpe f Directive 2001/83/EC Advanced therapy MP (ATMP) Gene therapy MP Medical devices Smatic cell therapy MP Cmbined ATMP Tissue engineered prduct 3. LEGAL BASIS Regulatin (EC) N 1394/2007 f the Eurpean Parliament and f the Cuncil n advanced therapy medicinal prducts intrduces additinal prvisins t thse laid dwn in Directive 2001/83/EC and Regulatin (EC) 726/2004. Article 14 (4) f Regulatin (EC) N 1394/2007 specifically requests the Eurpean Medicines Agency t draw up detailed guidelines relating t the pst authrisatin fllwup f efficacy and adverse reactins, and risk management. The EMEA issues this guideline t meet this request and t cmplement existing guidelines in the area. All relevant legislatin and guidelines have been included in Appendix I f this guideline in rder t enable regular update f these references withut a need fr an update f the main text f this guideline. 4. DEFINITIONS This guideline wrks with definitins used in related legislatin and guidelines, and adds sme new nes. Fr ease f reference, the fllwing definitins are used in this dcument: Pharmacvigilance Pharmacvigilance is defined by the Wrld Health Organisatin as the science and activities relating t the detectin, assessment, understanding and preventin f adverse effects r any ther drug-related prblem. EMEA/149995/2008 EMEA 2008 Page 5/22

Risk Management System Defined in the Regulatin EC/1901/2006 and in the Vlume 9A as a set f pharmacvigilance activities and interventins designed t identify, characterise, prevent r minimise risks relating t medicinal prducts, and the assessment f the effectiveness f thse interventins. EU -Risk Management Plan A dcument that describes a Risk Management System, which is specific t a particular prduct abbreviated as EU-RMP. (Vlume 9A) Risk Minimisatin Defined as a set f activities used t reduce the prbability f an adverse reactin ccurring r its severity shuld it ccur. (Vlume 9A) Reprt fllw-up A part f rutine pharmacvigilance that is aimed at btaining further relevant infrmatin abut an adverse drug reactin case frm the reprting health care prfessinal. If a targeted reprt fllw-up is put in place fr a specific prduct (i.e. using pre-defined prduct specific questinnaires), then it is cnsidered t be an additinal pharmacvigilance activity. (CIOMS V, Vlume 9A) Traceability The ability t trace each individual unit f an ATMP frm the dnr and /r surce material t the patient and vice versa. (Fr mre details see the separate guideline) Active surveillance Active surveillance, in cntrast t passive surveillance, seeks t ascertain cmpletely the number f adverse events via a cntinuus pre-rganized prcess. An example f active surveillance is the fllw-up f patients treated with a particular drug thrugh a risk management prgram. Patients wh fill a prescriptin fr this drug may be asked t cmplete a brief survey frm and give permissin fr later cntact. In general, it is mre feasible t get cmprehensive data n individual adverse event reprts thrugh an active surveillance system than thrugh a passive reprting system. (Vlume 9A) In additin, fr the purpse f this guideline, the fllwing definitins apply: Passive surveillance A surveillance cnducted by a methd that relies n the cllectin f unslicited initial safety infrmatin. The mtivatin f persns prviding the infrmatin is nt specifically encuraged by the passive surveillance. Examples f a passive surveillance include spntaneus reprting scheme, literature mnitring, and Internet searches. (based n Vlume 9A) Clinical fllw-up A fllw-up f individual patients cnducted by healthcare prfessinals. It includes preventin, screening, mnitring, diagnsis and treatment f diseases, injuries, cmplicatins, adverse reactins and medical errrs. Safety fllw-up Any systematic cllectin and cllatin f data that is designed in a way that enables learning abut the safety f a medicinal prduct. It may include passive r active surveillance, bservatinal studies, r clinical trials. Efficacy fllw-up Any systematic cllectin and cllatin f data that is designed in a way that enables learning abut the efficacy r effectiveness f a medicinal prduct. It may include passive r active surveillance, bservatinal studies, r clinical trials. EMEA/149995/2008 EMEA 2008 Page 6/22

Living dnrs Dnrs alive at the time f dnatin. Fr the purpse f this guideline this term des nt include autlgus dnatins. Cnditining f a patient Any medical prcedure used t prepare the patient fr the applicatin f the prduct. Examples include immunsuppressin, destructin f the patient s bne marrw, use f hrmnes fr stimulatin r inhibitin f certain physilgical functins etc. Clse cntact A clse cntact is a persn wh had prlnged, frequent, r intense cntact with the patient treated with the prduct in questin. This term usually includes peple living in the same husehld, but depending n the nature f the risk in questin, it may als include treating healthcare prfessinals, relatives, friends, clleagues at wrk etc. 5. COMMON RULES FOR POST-AUTHORISATION SURVEILLANCE OF MEDICINAL PRODUCTS The rules fr pst-authrisatin surveillance (pharmacvigilance) f medicinal prducts fr human use apply t all advanced therapy medicinal prducts. These rules are set up in the legislatin, and detailed guidelines are cllected in Vlume 9A f the Rules gverning medicinal prducts in the Eurpean Unin. The Cmmunity system f Pharmacvigilance directly cncerns health care prfessinals, marketing authrisatin hlders, natinal cmpetent authrities fr medicinal prducts, the Eurpean Medicines Agency and the Eurpean Cmmissin. Sme additinal pharmacvigilance bligatins are impsed by natinal law, and may cncern healthcare prviders, distributrs, pharmacies, spnsrs f clinical trials, nn-cmmercial investigatrs, and ethics cmmittees. The main stakehlder grups are patients, healthcare prfessinals, academia, the pharmaceutical industry and gvernments. Any specific rules described in this guideline are set up in additin t the cmmn rules. It is f utmst imprtance that the users f this guideline read it in cnjunctin with the legislatin and guidelines detailing cmmn rules fr pst-authrisatin surveillance f medicinal prducts. 6. SCIENTIFIC RATIONALE FOR SPECIFIC RULES FOR POST-AUTHORISATION SURVEILLANCE OF ADVANCED THERAPY MEDICINAL PRODUCTS 6.1. Safety cncerns Advanced therapy medicinal prducts prvide new pssibilities fr restring, crrecting r mdifying physilgical functins, r making a diagnsis. At the same time, because f their nvelty, cmplexity and technical specificity, they may bring alng new, unexplred risks t public health and t individual patients. The specific rules described in this guideline shuld facilitate early detectin f such risks and prvide a framewrk fr effective mitigatin f their cnsequences t public health r t individual patients. When preparing a risk management plan fr a particular advanced therapy medicinal prduct, cmprehensive scientific cnsideratin shuld be given t the imprtant identified r ptential risks, and t the imprtant missing infrmatin. The need fr flexibility and fr a significant deal f creativity is recgnised in this wrk. Fr this purpse, the fllwing cmprehensive list f pssible risks might be helpful. EMEA/149995/2008 EMEA 2008 Page 7/22

Users f this list shuld be aware that it shuld nt serve as a prescriptive checklist, but rather as a stimulus fr further cnsideratins. Althugh nt all f the risks listed belw are unique t ATMPs, they represent the mst relevant nes t be cnsidered. They are listed in the usual chrnlgical rder f the prduct manufacturing, handling, applicatin and clinical fllw-up: Risks t living dnrs, fr instance: Risks t living dnrs related t their cnditining prir t prcurement (immunsuppressin, cyttxic agents, grwth factrs etc.) Risks t living dnrs related t surgical/medical prcedures used during r fllwing prcurement, irrespective whether the tissue was cllected r nt Risks t patients related t quality characteristics f the prduct, in particular: Species f rigin and characteristics f cells (and related bdy fluids, bimaterials, bimlecules) that are used during manufacturing, and the safety testing perfrmed. Characteristics f vectrs fr gene therapy medicinal prducts Bilgically active substances used in manufacturing (e.g. enzymes, antibdies, cytkines, sera, grwth factrs, antibitics) Quality assurance and characteristics f the finished prduct in terms f defined cmpsitin, stability, bilgical activity, and purity with reference t nnphysilgic prteins and fragments theref. Risk related t transmissible diseases (viral, bacterial, parasitical infectins and infestatins, but als malignant disease and thers) Risks t patients related t the strage and distributin f the prduct, fr instance: Risks related t preservatin, freezing and thawing Risks f breaking the cld chain r ther type f cntrlled temperature cnditins Risks related t stability f the prduct Risks t patients related t administratin prcedures, fr instance: Bilgically active substances used in preparatin f the prduct prir t administratin (e.g. enzymes, antibdies, cytkines, sera, grwth factrs, antibitics) Risks related t cnditining f the patient Risks f related medical r surgical prcedures (such as anaesthesia, infusin, transfusin, implantatin, transplantatin r ther applicatin methd,...) Risks related t clinical fllw-up (immunsuppressin as c-medicatin r as necessary fr treatment f cmplicatins, diagnstic prcedures, hspitalisatin ) Risks related t mistakes r vilatins f the standard prcedures fr administratin f the prduct (e.g. different administratin prcedures used by different healthcare establishments/healthcare prfessinals resulting in differing results) Risks related t interactin f the prduct and the patient, fr instance: Unwanted immungenicity and its cnsequences (including anaphylaxis, graft versus hst disease, graft rejectin, hypersensitivity reactins, immune deficiencies, ) Risks related t bth intended and unintended genetic mdificatin f the patient s cells (apptsis, change f functin, alteratin f grwth and/r differentiatin, malignancy) Early and late cnsequences f hming, grafting, differentiatin, migratin and prliferatin EMEA/149995/2008 EMEA 2008 Page 8/22

Risks related t infectin with vectrs used in gene therapy medicinal prducts (type f vectr, target cells, persistence, ptential fr latency and reactivatin, ptential fr integratin f genetic material int the hst genme, prlnged expressin f the transgene, altered expressin f the hst s genes) Risks related t scafflds, matrices and bimaterials (bidegradatin, mechanical factrs ) Risks related t persistence f the prduct in the patient, fr instance: Availability f rescue prcedures r antidtes and their risks Late cmplicatins, particularly malignancies and autimmunity Cnsideratins n the ptential impact f previus, cncmitant, r future therapies typical fr the diagnsis r treatment f the respective disease n the prduct, r vice versa impact f the prduct n thse ther therapies (e.g., an immunglbulin treatment later in life culd impact n expressin f the intrduced gene by antibdy interactin ) Risks related t re-administratin, fr instance: Immune reactins - anaphylaxis, neutralising antibdies Risks related t repeated surgical r administratin prcedures Risks t clse cntacts, fr instance: Based n the envirnmental risk assessment, virus shedding and its cnsequences Specific parent-child risks, fr instance: Risk f germ line integratin f transgene, r ther genetic transfrmatin f the germ line Fetal transmissin (f vectrs, bilgically active substances, cells, infectius agents ) Transmammary expsure f children in lactating wmen (t vectrs, bilgically active substances, cells, infectius agents ) 6.2. Efficacy cncerns Given the nature f advanced therapy medicinal prducts and the characteristics f the diseases they are intended t treat, nly limited efficacy data may be available at the end f pre-authrisatin clinical trials (slw dynamics f the disease and effects f the treatment, rare disease ). Therefre, full efficacy assessment may need several years f fllw-up. As a cnsequence, there might be situatins that require the efficacy prfile t be further studied in a real-life setting, i.e. in the pstauthrisatin phase. Relevant examples might include: Many f the ATMPs incrprate living rganisms. Efficacy f these ATMPs is subject t their changing characteristics after their administratin t patient ver lng perids f time (mnths, years, decades). This may result in an increase (e.g. verexpressin f a gene f interest) r decrease f efficacy, and the cnsequences fr the patient may nt be fully established during the curse f pre-authrisatin clinical trials. Likewise, the cnsequences f lss f efficacy f an ATMP n the disease curse and future treatment ptins might nt be fully established. Pre-existing immunity f the recipient t the vectr and its change with ptential repeat administratins at later stages (individual fr each patient) can in itself alter the clinical curse f efficacy and safety, and als add t hetergeneity in the patient grup; therefre, pst-authrisatin fllw-up might be necessary. The time needed fr the new tissue t be fully functinal will depend upn the prduct and may be cunted in years. In such a situatin prf f cncept and a psitive clinical utcme in clinical trials using acceptable surrgate methds fr efficacy might be sufficient fr the evidence f efficacy required fr granting a marketing authrisatin. Nevertheless, the EMEA/149995/2008 EMEA 2008 Page 9/22

efficacy prfile, including clinical endpints, might need t be cnfirmed in pst-authrisatin phase. In sme cases, the use f ATMPs is expected t be a nce in a life-time treatment. Sustainability f efficacy ver time is a questin that can nly be answered by lng-term efficacy fllw-up. The frm and length f such fllw-up will depend n characteristics f the prduct. Efficacy f many ATMPs is ntably highly dependent n the quality f the administratin prcedure, including cnditining f the patient, surgery and clinical fllw-up. This may differ significantly between a cntrlled pre-authrisatin clinical trial setting, and pstauthrisatin nrmal healthcare, as well as between varius healthcare establishments. These issues may be captured and addressed nly via gd pst-authrisatin efficacy fllw-up system. Cell therapy prducts with limited life-time may require an efficacy fllw-up system that mnitrs dynamics f efficacy. This will help t determine the need f re-applicatin f the prduct and t generate infrmatin that will apprpriately reflect the perids f required reapplicatin in clinical practice. 6.3. Pints t cnsider when designing the studies T cnsider all the pints relevant fr designing the clinical trials and bservatinal studies is utside the scpe f this guideline. In this chapter, nly a selectin f issues is highlighted, based n the experience s far with the kind f prblems encuntered by develpers f advanced therapies as discussed by EMEA scientific cmmittees and the Innvatin Task Frce. A Marketing Authrisatin Applicant/Hlder shuld always cnsult existing clinical guidelines, particularly thse published in Vlume 3 f the Rules Gverning Medicinal Prducts in the Eurpean Unin. Fr ATMPs in general, it is likely that at the time f marketing authrisatin there will be cntinuing fllw-up f subjects f pre-authrisatin clinical trials. This shuld be always taken int accunt when designing further pst-authrisatin studies. 6.3.1. Sample size fr fllw-up The legislatin des nt give clear guidance n whether the required safety and efficacy fllw-up shuld be applicable t all recipients f an ATMP. Based n the epidemilgy f the target ppulatin (disease), anticipated frequency f risks and chsen endpints fr safety r efficacy fllw-up, sample size may incrprate all expsed patients r a defined subset. When a subset f expsed patients is used, scientific justificatin shuld be prvided. A subset is nrmally nt acceptable fr rphan drugs. Sample size calculatins shuld cnsider the high ptential fr drp-uts ver the years f fllw-up. It may be apprpriate t request scientific advice fr this purpse frm the EMEA. 6.3.2. Dynamics f the disease and effects f the prduct Detectin f early cmplicatins (infectius diseases, cmplicatins linked t the related surgical prcedures) and late cmplicatins (malignant diseases, emerging diseases...) are likely t need different appraches. Mrever, they need t be cnsidered in cnjunctin with the pssible gradual increase r decrease f efficacy f the administered prduct ver time. Design f the studies needs t take int accunt such dynamics, and gd medical practice that may require specific timing f prcedures, treatment adjustments, and labratry investigatins t be tailred fr individual patients. 6.3.3. Cnsideratins n clinical fllw-up Recmmended clinical fllw-up in the frm f particular labratry and clinical investigatins fr patients treated with the particular prduct must be described in the SPC and PIL. These EMEA/149995/2008 EMEA 2008 Page 10/22

recmmendatins shuld always take int accunt existing general guidelines fr clinical fllw-up f patients treated with ATMP in bth the clinical trial setting and pst-authrisatin setting (see Appendix I). Safety and efficacy studies shuld use usual clinical practice fr fllw-up whenever pssible t limit additinal prcedures and interventins. This shuld enable wider use f bservatinal designs fr studies in pst-authrisatin where suitable fr generating r testing a particular hypthesis. 6.3.4. Cnsideratins n safety fllw-up f living dnrs It is acknwledged that fllw-up f living dnrs f tissues, cells r bld is a legal respnsibility f tissue establishments r bld establishments. Nevertheless, when the ATMP in questin requires dnatin frm living dnrs fr its prductin, the MAH f such ATMP shuld take int accunt the risks identified fr dnrs and design its pharmacvigilance plan in such a way that guarantee a data exchange with the establishment perfrming the prcurement. The aim is t make sure that prductin f the prduct des nt bring undue risk t living dnrs, and als t ensure that in the event that an infectius disease with a lng latency emerges in the dnr, the receivers may get apprpriate screening and treatment (using the traceability system). The particular design and length f such fllw-up shuld be decided n a case by case basis, and needs t be prprtinate t the nature f the prcurement prcedure, identified and ptential risks t dnrs and health characteristics f dnrs. As with the majrity f pharmacvigilance bligatins, this activity may be utsurced t anther legal entity based n a written agreement. As a minimum, the agreement shall specify the data t be cllected and prcedures fr data exchange, quality assurance f the system, length f the fllw-up f dnrs, and respnsible persns n bth sides. It is expected that traceability data may be used fr facilitatin f such fllw-up. 6.3.5. Safety fllw-up f clse cntacts and ffsprings When a need fr safety fllw-up f clse cntacts and ffspring is identified, feasibility is an imprtant feature in the design f such a study. Scientific advice frm the EMEA is strngly recmmended. Figure 2 MAH s systems f pst-authrisatin surveillance f ATMPs and their descriptin in the marketing authrisatin applicatin dssier Marketing Authrisatin Hlder Traceability System Pharmacvigilance Pharmacvigilance System Risk Management System Mdule 3 Detailed Descriptin f the Pharmacvigilance System (1.8.1) Risk Management Plan (1.8.2) Efficacy fllw-up system Efficacy Fllwup Plan (Annex 9 f the RMP) EMEA/149995/2008 EMEA 2008 Page 11/22

7. ADDITIONAL REQUIREMENTS FOR THE PHARMACOVIGILANCE SYSTEM OF MARKETING AUTHORISATION HOLDERS As a part f the applicatin fr marketing authrisatin f a medicinal prduct, the applicant is requested t prvide a detailed descriptin f its pharmacvigilance system. This is further detailed in the Guideline n mnitring f cmpliance with pharmacvigilance regulatry bligatins and pharmacvigilance inspectins in Vlume 9A. Article 14(1) f the Regulatin requests the applicant t detail, in the marketing authrisatin applicatin, the measures envisaged t ensure the fllw-up f efficacy f advanced therapy medicinal prducts and f adverse reactins theret. This bligatin shall be fulfilled by: 1. Descriptin f additinal pharmacvigilance activities and the efficacy fllw-up system in the Risk management plan that is submitted in Mdule 1.8.2 f the CTD. 2. Descriptin f the elements f the pharmacvigilance system necessary t supprt such additinal pharmacvigilance and efficacy fllw-up activities. This shuld be included in the Detailed Descriptin f the Pharmacvigilance System that is submitted in Mdule 1.8.1 f the CTD. In additin, the pharmacvigilance system f ATMP marketing authrisatin hlders shuld include, where applicable: Prcedures fr data exchange with ther vigilance systems as applicable based n the nature f the prducts f the marketing authrisatin hlder/applicant (fr example tissues and cells vigilance, haemvigilance, and vigilance f medical devices see the legislatin references in the Appendix I). Whenever pssible, the data exchange shuld be perfrmed electrnically. Prcedures fr fllw-up f reprted ADRs that aim at btaining at least minimum infrmatin as required fr bilgical medicinal prducts, i.e. including prduct name and batch number. Databases r ther recrd systems capable f recrd linkage with traceability data f the same MAH (fr instance via the batch number). EMEA/149995/2008 EMEA 2008 Page 12/22

Table 1 Examples f additinal elements t be described in the DDPS Additinal pharmacvigilance activity (in the Mdule 1.8.2 Risk Management Plan) Safety fllw-up - registry study with use f traceability data Active surveillance - Sentinel sites fr bth safety and efficacy fllwup Elements f the pharmacvigilance system (in the Mdule 1.8.1 Detailed Descriptin f the Pharmacvigilance System) Infrastructure t supprt the registry study Recrd linkage between pharmacvigilance and traceability databases and/r ther recrd systems used fr the registry study Infrastructure t supprt fulfilment f the active surveillance prtcl Supprt t the relevant disease registries where suitable Availability and qualificatin f staff invlved in a review f medical recrds r interviews with patients and/r physicians Prcedures fr nging risk-benefit evaluatin Efficacy fllw-up based n bservatinal study/studies Supprt f bservatinal studies with efficacy endpints Prcedures fr nging risk-benefit assessment, including cperatin between parts f the cmpany invlved in clinical research, pharmacvigilance, and regulatry and medical affairs The marketing authrisatin hlders/applicants may utsurce sme f the pharmacvigilance activities t ther legal entities. Mre infrmatin may be fund in Vlume 9A. 8. ADDITIONAL REQUIREMENTS FOR THE RISK MANAGEMENT SYSTEM OF ADVANCED THERAPY MEDICINAL PRODUCTS Accrding t Article 14 (2), the Eurpean Cmmissin, n the advice f the EMEA shall require as part f the marketing authrisatin that a risk management system is set up and specific pstmarketing studies are carried ut. Bth f these requirements shuld be met by a submissin f the EU-Risk Management Plan as per the Guideline n Risk Management Systems fr Medicinal Prducts fr Human Use (incrprated in Vlume 9A). Currently, all medicinal prducts with new active substances submitted via centralised authrisatin prcedure must prvide a descriptin f the risk management system, unless therwise justified. It is expected that fr majrity f ATMPs a risk management system including specific pst-authrisatin studies will be requested. Because f the wide range f prducts cvered by this guideline, the nvelty and high speed f develpment in this area, applicants are encuraged t seek scientific advice fr Risk Management Planning frm the EMEA. Figure 3 The basic risk management cycle Risk Identificatin Evaluatin f Effectiveness f Risk Minimisatin Risk Assessment Risk Minimisatin EMEA/149995/2008 EMEA 2008 Page 13/22

Assessment f the effectiveness f the risk management system, as well as the results f any newly finished studies shuld be regularly included in the Peridic Safety Update Reprts (PSUR) and regular updates f the EU-RMP as per Vlume 9A. It is recgnised that sme f the parts f the Guideline n Risk Management System fr Medicinal Prducts fr Human Use (in Vlume 9A) might nt be suitable fr a particular ATMP. In such a case, the unsuitable part f the EU RMP template may be mitted subject t scientific justificatin. Nevertheless, where an analgy exists between the terminlgies f chemical drugs, bilgics and advanced therapy medicinal prducts, this shuld be used. Fr example pharmaclgical class effects may be presented as effects knwn t be cmmn fr certain types f vectrs, cells, tissues, scafflds r matrices. The cntent and extent f the EU-Risk Management Plan must be prprtinate t the risks f the particular prduct. It shuld nt simply cpy ther parts f the dssier submitted fr the marketing authrisatin applicatin. Infrmatin prvided in the EU-RMP, and particularly in its Safety Specificatin shuld be presented in a summary fashin. The aim is t prvide sufficient infrmatin within the EU-RMP t enable a decisin making n whether additinal risk minimisatin activities are needed, and whether the rutine nes are apprpriate. It is a plan fr the identificatin and management f safety cncerns and needs t be drafted in a way that allws fr quick rientatin t the imprtant safety issues and their management. Regulatin (EC) 1394/2007 set up a transitinal perid fr ATMPs which were legally n the Cmmunity market in accrdance with natinal r Cmmunity legislatin n 30 December 2008 t cmply with this Regulatin. When submitting RMP fr these prducts, it is expected that the pstauthrisatin experience will be included in the safety specificatins. Fr practical reasns, efficacy fllw-up shuld als use the same reprting systems t cmpetent authrities. Management f the efficacy fllw-up shuld use existing tls, i.e. the EU-Risk Management Plan. At the same time, it shuld be made clear that psitive efficacy data are nt t be reprted n an expedited basis. The EU-Risk Management Plan shuld detail bth the safety and efficacy fllw-up activities. T ensure that safety and efficacy data are cmparable in their quality and scientific rbustness, efficacy fllw-up systems shuld use the same infrastructure that exists fr safety fllw-up whenever feasible. Study prtcls and detailed descriptin f ther activities fr efficacy fllw-up shuld be submitted as Annex 9 f the RMP. This is t ensure cnsistency with the safety surveillance, and t facilitate prper assessment by efficacy, safety, and pharmacvigilance assessrs. Peridic Safety Update Reprts (PSURs) and their assessment reprts shuld discuss nging cumulative efficacy and safety data. A specific new chapter in the PSUR assessment reprt might be intrduced fr this purpse. This chapter shuld als discuss safety data relating t dnrs and clse cntacts. In additin t the requirements fr risk management systems detailed in Vlume 9A, the pints belw shall be included in the RMP f an ATMP. 8.1. Safety specificatins 8.1.1. Additinal EU requirements Specific risks f advanced therapy medicinal prduct A new sectin under Additinal EU Requirements shuld cnsider specific risks f ATMPs, taking int accunt the pints mentined abve in Chapter 6 Scientific ratinale fr specific rules fr pstauthrisatin surveillance f ATMPs. This sectin shuld prvide an pprtunity t discuss risks that wuld nt fit int ther parts f the safety specificatins in the EU-RMP. The discussin shall be structured in the fllwing rder: EMEA/149995/2008 EMEA 2008 Page 14/22

a. Flw-Chart f the lgistics f the therapy (fr instance, harvesting, transprt, cntrls, manipulatin, cnditining, administratin, clinical fllw-up ) b. Risks t living dnrs (where applicable) c. Risks t patients in relatin t quality characteristics, strage and distributin f the prduct d. Risks t patients related t administratin prcedures e. Risks related t interactin f the prduct and the patient f. Risks related t scafflds, matrices and bimaterials g. Risks related t persistence f the prduct in the patient h. Risks t healthcare prfessinals, care givers, ffspring and ther clse cntacts with the prduct r its cmpnents, r with patients, presented in a summary fashin and based n the envirnmental risk assessment 8.2. Summary f safety specificatins Fr many ATMPs, the fllwing examples are likely t represent imprtant safety cncerns: Transmissin f infectius agens t the patient and t clse cntacts Graft dysfunctin and/r rejectin Inductin f autimmunity r immungenic reactins Inductin f malignancies Impssibility f discntinuing r remval f the prduct Ptential f the vectr fr latency and reactivatin, integratin f genetic material int hst genme, prlnged expressin f the transgene, altered expressin f the hst s genes, ptential fr germline integratin 8.3. Pharmacvigilance plan (incrprating safety fllw-up) In additin t rutine pharmacvigilance, additinal pharmacvigilance activities may be intrduced t characterise further identified risks, detect early ptential risks and cmplement missing infrmatin. Fr ATMPs the Pharmacvigilance plan shuld cnsider: Any specific aspects f rutine pharmacvigilance if applicable, e.g. any adjustment f spntaneus reprting, targeted reprts fllw-up/investigatin, use f reprts frm patients/caregivers, specific methdlgy fr signal detectin, additinal chapters f PSURs etc. Active surveillance shuld ften be put in place, particularly when the ATMP is expected t be used in a few centres f excellence that culd serve as sentinel sites. It is expected that fr ATMPs, a specific clinical fllw-up including labratry investigatins will becme a part f nrmal practice described in the Summary f Prduct Characteristics (SPC). Nn-interventinal pst-authrisatin safety studies shuld be designed in a way that maximises the use f data frm these nrmal practice labratry investigatins. Any nging cmpassinate use and fllw-up f patients expsed t the prduct in clinical trials needs t be described and shuld serve as a basis fr the develpment f lng-term surveillance/pst-authrisatin safety studies. The length and frm f safety fllw-up shuld be set up accrding t existing guidelines, and n a case by case basis. Use f traceability data fr surveillance purpses (e.g. an established registry f batches f prducts distributed t a particular centre and its recrd linkage t the pharmacvigilance database f reprts received frm that centre.) EMEA/149995/2008 EMEA 2008 Page 15/22

Measures prpsed t ensure essential safety fllw-up f patients even if the MAH ceased t exist (e.g., link t risk minimisatin patient alert cards infrming a treating physician abut essentials f clinical fllw-up, websites with further infrmatin ). 8.4. Evaluatin f the need fr efficacy fllw-up This new chapter shuld be incrprated in PART II f the EU Risk Management Plan. It shuld discuss the scientific need fr efficacy fllw-up. Sme examples f the ratinale fr such a need are listed in chapter 6.2 abve. Fr efficacy fllw-up, the system that is r will be established fr safety fllw-up shuld be used as much as pssible t save resurces and increase the mtivatin f healthcare prfessinals that is the key t success f any such system. It shuld be highlighted that lss f efficacy r less than expected efficacy f a medicinal prduct used in life-threatening diseases is cnsidered t be a safety issue (see Vlume 9A). Therefre, fr this kind f cncern, safety fllw-up alne might be apprpriate. The establishment f efficacy fllw-up shuld nly be cnsidered in situatins which require further study f the prduct s efficacy prfile in the pst-authrisatin phase, and when it is inapprpriate t use the safety fllw-up alne fr this purpse. The efficacy fllw-up needs t be designed fr a particular prduct-disease cmbinatin. Therefre, the discussin f the need fr it shuld als be structured accrding t the indicatins and varius ways f use f the prduct. When a need fr efficacy fllw-up is identified in this discussin, the Annex 9 described in the chapter 8.6 belw shuld be prduced and attached t the EU-RMP. 8.5. Risk minimisatin plan Based n the existing tls and feasible appraches t risk minimisatin, the fllwing shuld be cnsidered t reduce particular risks: Limitatin f the use f the prduct t adequately trained and experienced clinicians nly, pssibly including a cntrlled distributin system t specialised (accredited) centres nly. Selectin and accreditatin f centres by marketing authrisatin hlder and/r member states authrities, pssibly in cperatin with an apprpriate medical rganisatin might als be part f the risk minimisatin plan. Specific risk cmmunicatin (patient alert cards; patient ID cards; risk cmmunicatin cmpnents f the educatinal prgrams; infrmed cnsent frms; prtcls and mechanisms ensuring that any recipients wh have received treatment prir t the age f cnsent r in need f infrmatin at a later stage will receive risk cmmunicatin; guidance fr recipients n hw t cmmunicate risks t clse cntacts and ffspring where they culd be at risk...) Intrductin f barriers t errrs (design f the prduct, crss checks, duble patient identificatin, secnd pinins, dedicated teams ). Sme f these may be implemented by MAH alne (prduct design), sme needs c-peratin f healthcare establishments. When a need is identified, requirement t implement these barriers may be part f the accreditatin f healthcare establishments fr the use f the prduct. Training f healthcare prfessinals in respect f prcurement, strage, handling, administratin, clinical fllw-up, and their prtectin based n the envirnmental risk assessment Educatin f supprt persnnel, family and caregivers fr instance indicative symptms f imprtant identified r ptential adverse reactins, clinical fllw-up prcedures, prtectin based n the envirnmental risk assessment etc. EMEA/149995/2008 EMEA 2008 Page 16/22

8.5.1. Effectiveness f the risk minimisatin measures Specific tls t measure effectiveness f risk minimisatin via bjective metrics (systems f measurement and assessment f such measurement) shuld always accmpany any risk minimisatin activity. Examples f such metrics fr particular risk minimisatin activity may include: If an educatinal plan is in place, test f the knwledge and skills f the target audience that shuld have been imprved by the particular educatinal plan shuld be cnducted and evaluated n regular basis. If barriers t errrs are intrduced (e.g. prduct design), active surveillance f errrs may serve as metrics f the barriers effectiveness. If a cntrlled distributin is implemented, traceability data may be used t evaluate the real pathways f the prduct t patients. 8.6. Efficacy fllw-up plan (Annex 9 f the RMP) This Annex shuld describe details f the efficacy fllw-up when a need fr it is identified in Part II f the RMP. The fllwing structure is recmmended fr this dcument: 8.6.1. Scientific ratinale fr the efficacy fllw-up Based n the evaluatin f the need fr efficacy fllw-up, the ratinale fr the chsen design f the system shuld be discussed in this chapter. Any nging cmpassinate use and fllw-up f patients expsed t the prduct in clinical trials needs t be described and shuld serve as a basis fr the develpment f lng term efficacy studies. The length and frm f efficacy fllw-up shuld be set accrding t existing guidelines, and n a case by case basis. 8.6.2. Overview f the study prtcls fr efficacy fllw-up It is recmmended t use the table belw t keep cnsistency with the frmat f the tables used fr safety fllw-up in the Pharmacvigilance plan. Table 2 Template fr the verview f the study prtcls fr efficacy fllw-up Study Prtcl versin Prtcl status Planned date fr submissin f interim data Planned date fr submissin f final data 8.6.3. Detailed prtcls f the efficacy fllw-up studies All the prtcls listed in the verview table abve shuld be included. When prtcls are nt ready at the time f submissin, at least their drafts (utlines) shuld be incrprated. The pst authrisatin studies may use bth interventinal and bservatinal designs. In additin t the pints listed in 6.2 and 6.3 abve, the fllwing shuld be taken int accunt when drafting the prtcls: Existing guidelines n efficacy studies shuld be fllwed when applicable. Design f any pst-authrisatin bservatinal study shuld build n existing r recmmended clinical fllw-up f patients. Wider spectrum f endpint(s) shuld be cnsidered reflecting real life effectiveness (clinical mnitring, labratry mnitring, and bimarkers). Surrgates shuld nt be used unless necessary. EMEA/149995/2008 EMEA 2008 Page 17/22

Reasns fr drp uts, and cases f re-administratin r re-initiatin f therapy shuld be f particular interest fr efficacy fllw-up. Lng-term efficacy studies shuld nrmally be f cmparative design. The chice f cmparatr r lack theref shuld be justified. It is acknwledged that changes in the standard f care ver time may influence the cnduct f such studies. This shuld be discussed with regulatrs n regular basis as part f relevant reprts (e.g. in PSUR, Annual Safety Reprts, updates f the EU-RMP). 9. USE OF REGULATORY TOOLS IN POST-AUTHORISATION SURVEILLANCE OF THE ADVANCED THERAPY MEDICINAL PRODUCTS There are number f tls available fr management f varius pst-authrisatin cmmitments fr prducts authrised via centralised prcedure. These include letters f cmmitments; fllw-up measures; cnditinal apprvals r apprvals under exceptinal circumstances with specific bligatins and their annual re-assessments; and there are number f reprting bligatins t (expedited and peridic reprts, EU-RMP updates, varius special reprts requested by regulatrs, sunset clause reprting etc.) Use f these tls is cvered by cmmn rules fr medicinal prducts. All f these tls have their apprpriate use and their effective cmbinatin shuld ensure high quality f pst-authrisatin benefit-risk management f the prduct. Bth regulatrs and marketing authrisatin hlders shuld ensure cnsistency in use f these varius tls. This cnsistency between sft and hard (legally enfrceable) regulatin in the area f pst-authrisatin surveillance may be illustrated by the fllwing figure: Figure 4 Illustratin f the need fr cnsistency in (parallel) use f varius tls in the pst-authrisatin surveillance f ATMPs. Hard regulatin Sft regulatin Cmmissin Decisin Apprved Risk Management Plan Pharmacvigilance Plan Annex 9 Efficacy Fllw-up Plan Letter f Cmmitment Specific Obligatins S & E Fllw-up Measures S & E 10. ELECTRONIC EXCHANGE OF PHARMACOVIGILANCE INFORMATION It is recgnised that the length f sme data fields set up by the ICH E2B (M) fr Individual Case Safety Reprt, and cnsequently the length f sme fields in the EudraVigilance Medicinal Prduct Dictinary (EVMPD) might nt be sufficient fr the needs f Advanced Therapy Medicinal Prducts. At the same time, a need fr additinal fields needs t be cnsidered. It is acknwledged that business rules and validatin prcedures f the authrities need t ensure that ICSRs f ATMPs can clearly be EMEA/149995/2008 EMEA 2008 Page 18/22

separated/distinguished frm ICSRs f ther types f medicinal prducts. EMEA address this issue with EudraVigilance system stakehlders and keep the users infrmed via the EudraVigilance website. Natinal regulatry authrities will then address the cnsequences fr their electrnic reprting systems with their stakehlders. 11. COMPLIANCE MONITORING EMEA and natinal regulatry authrities fr medicinal prducts are required by law t mnitr cmpliance with pharmacvigilance bligatins. This is ensured by varius internal prcesses, and by cnduct f pharmacvigilance inspectins. Mre details can be fund in Vlume 9A. EMEA must infrm Eurpean Cmmissin abut nn-cmpliance, including nn-cmpliance with risk management plans (art. 14(3) f the Cmmissin Regulatin 1394/2007). Eurpean Cmmissin may impse financial penalties fr infringement f certain MAH s bligatins accrding t Cmmissin Regulatin N 658/2007. In additin, if benefit-risk f the prduct is fund t be cmprmised, the marketing authrisatin may be suspended. 12. PERSONAL DATA PROTECTION ISSUES Fllw-up systems, risk minimisatin plans and traceability systems naturally require access t persnal data. The Directive 95/46/EC f the Eurpean Parliament and f the Cuncil f 24 Octber 1995 n the prtectin f individuals with regard t the prcessing f persnal data and f the free mvement f such data includes prvisin t enable the systems described in this guideline t perate. The Directive 95/46/EC prhibits prcessing persnal data cncerning health, except in particular circumstances: 1. Explicit cnsent f the data subject (except where the laws f the Member State prvide therwise); r 2. When the prcessing is necessary t prtect the vital interests f the data subject, where the data subject is physically r legally incapable f giving his cnsent; 3. When the data are prcessed fr the scpe f preventive medicine, medical diagnsis, when the prcessing is necessary fr the prvisin f care r treatment r the management f health-care services, and where thse data are prcessed by a health prfessinal subject under natinal law r rules established by natinal cmpetent bdies t the bligatin f prfessinal secrecy r by anther persn als subject t an equivalent bligatin f secrecy; r 4. The directive als fresees the pssibility fr the Member States fr reasns f substantial public interest lay dwn exemptins in additin t the abve. This may be dne either by natinal law r by decisin f the supervisry authrity. The Regulatin (EC) 1349/2007 is directly applicable in all Member States and self executing. Its requirements in article 14 (Pst-authrisatin fllw-up f efficacy and adverse reactins, and risk management), and in article 15 (Traceability), represents supremacy clause which prevails n any single prvisin at natinal level with regard t the prtectin f persnal data, while respecting prvisins f the Directive 95/46/EC. Fundamental principle n the lawful prcessing f persnal data prvided fr by the Directive 95/46/EC must be respected any prcessing f persnal data must be lawful and fair t the individuals cncerned; in particular, the data must be adequate, relevant and nt excessive in relatin t the purpses fr which they are prcessed; such purpses must be explicit and legitimate and must be determined at the time f cllectin f the data; the purpses f prcessing further t cllectin shall nt be incmpatible with the purpses as they were riginally specified. Based n this legal situatin, there shuld nt be any legal bstacle t establish apprpriate safety and efficacy fllw-up system and risk management system fr advanced therapy medicinal prducts. These systems are in public interest, they are legally required, they are necessary fr the prvisin f care r treatment, they shuld be prcessed by (health) prfessinals subject t prfessinal secrecy, and spnsred by MAH. EMEA/149995/2008 EMEA 2008 Page 19/22

The MAH needs t fllw the principles f lawful prcessing, e.g. t strictly limit the access t the data t staff that are bliged by prfessinal secrecy, use f the data nly fr the purpse these data were cllected etc. Any ther use f the data (e.g., fr marketing) wuld be unlawful. There are als endless pssibilities fr varius utsurcing and cntractual mdels that respect the data privacy legislatin. It is recgnised that these systems might be expensive, but feasible, and certainly pssible frm the legal pint f view. EMEA/149995/2008 EMEA 2008 Page 20/22

APPENDIX I RELATED LEGISLATION AND GUIDELINES Related legislatin Directive 2001/83/EC n the Cmmunity cde relating t medicinal prducts fr human use and Regulatin (EC) N 726/2004 fr Cmmunity prcedures fr the authrisatin and supervisin f medicinal prducts fr human and veterinary use and establishing a Eurpean Medicines Agency Annex I f the Directive 2001/83/EC, particularly Part IV Advanced Therapy Medicinal Prducts. Directive 2004/23/EC and daughter Directive 2006/86/EC n setting standards f quality and safety fr the dnatin, prcurement, testing, prcessing, preservatin, strage and distributin f human tissues and cells Directive 2002/98/EC setting standards f quality and safety fr the cllectin, testing, prcessing, strage and distributin f human bld and bld cmpnents and daughter directives 2005/61/EC as regards traceability requirements and ntificatin f serius adverse reactins and events and 2005/62/EC as regards Cmmunity standards and specificatins relating t a quality system fr bld establishments Directive 2001/20/EC n the apprximatin f the laws, regulatins and administrative prvisins f the Member States relating t the implementatin f gd clinical practice in the cnduct f clinical trials n medicinal prducts fr human use Directive 2007/47/EC amending Directive 90/385/EC n the apprximatin f the laws f the Member States relating t active implantable medical devices and 93/42/EEC cncerning medical devices Relevant guidelines The Rules gverning medicinal prducts in the Eurpean Unin, in particular Clinical efficacy and safety guidelines in Vlume 3 Pharmacvigilance guidelines in Vlume 9A Please, see in particular the CHMP Guideline n Risk Management Systems (EMEA/CHMP/96268/2005) and its annexes which include the template fr the Risk Management Plan (http://www.emea.eurpa.eu/pdfs/human/euleg/19263206en.pdf). Guidelines n Clinical trials in Vlume 10 Guidelines with additinal prvisins fr advanced therapy medicinal prducts: CPMP/BWP/3088/99: Nte fr guidance n the quality, preclinical and clinical aspects f gene transfer medicinal prducts EMEA/CHMP/GTWP/125491/2006: Guideline n scientific requirements fr the envirnmental risk assessment f gene therapy medicinal prducts CPMP/BWP/41450/98 Pints t cnsider n human smatic cell therapy CPMP/1199/02 Pints t cnsider n xengeneic cell therapy medicinal prducts EMEA/CHMP/GTWP/405681/2006: Cncept paper n the develpment f a guideline n the quality, preclinical and clinical aspects f medicinal prducts cntaining genetically mdified cells. EMEA/149995/2008 EMEA 2008 Page 21/22

EMEA/CHMP/410869/2006 Guideline n human cell-based medicinal prducts CHMP/GTWP/60436/07 Guideline n fllw-up f patients administered with gene therapy medicinal prducts (Released fr Cnsultatin May 2008) ICH Cnsideratins General Principles t Address the Risk f Inadvertent Germline Integratin f Gene Therapy Vectrs (2006) Draft under CHMP/CPWP discussin: Guidance n the pst-marketing surveillance fr cell-based medicinal prducts Draft under CHMP/CPWP discussin: Guideline n xengeneic cell therapy medicinal prducts. Expected Eurpean Cmmissin Guideline n traceability f advanced therapy medicinal prducts Draft under develpment Gd Clinical Practice n clinical trials with advanced therapy medicinal prducts Fr cmbinatin medicinal prducts, als cnsider guidelines fr medical devices MedDEV, in particular MedDEV 2.12/1 rev.5 n medical devices vigilance system Further useful infrmatin can be fund n the websites f Eurpean Cmmissin DG Enterprise (http://ec.eurpa.eu/enterprise/pharmaceuticals.htm) and EMEA (www.emea.eurpa.eu). EMEA/149995/2008 EMEA 2008 Page 22/22