1. EMEA current thinking on Conditional Marketing Authorization Oncologic Drug Advisory Committee Meeting 8 November 2005 Francesco Pignatti, MD The European Medicines Agency (EMEA) London - United Kingdom

2. 2 The New Medicines Legislation Types of approval (Normal, Exceptional, Conditional) Conditional marketing authorization Draft implementing regulation Guidelines and external consultation pending Assessment of obligations and compliance Models for conditional authorization Under discussion Contents

3. 3 The New Medicines Legislation l New regulation governing the EMEA and the Centralized Procedure u Procedure gives access to 27 countries in Europe (25 EU + Norway and Iceland) u Mandatory for new treatments of cancer, AIDS, neurodegenerative disorders, diabetes l Marketing authorisation u Objective criteria of quality, safety efficacy – Economic considerations, comparative efficacy remain excluded (Member State responsibility) u Normal, Exceptional circumstances, Conditional (new)

4. 4 Initial Data Requirements v. Phase IV studies l Normal u Comprehensive data to assess risk-benefit balance – In general, randomized active and placebo-controlled trials required u Phase IV: “Follow-up” studies of (dose-response), therapeutic use l Exceptional circumstances u Comprehensive data cannot be provided (because of specific circumstances: rarity, medical ethics, state of scientific knowledge) u Phase IV: “Specific obligations” to inform about the safe and effective use (normally not possible to assemble full data package) – Specific safety procedures l Conditional Marketing Authorization u Can demonstrate positive benefit risk balance, based on preliminary evidence from an ultimately comprehensive development u Phase IV: “Specific obligations” to provide the missing data (intended to become a “normal” marketing authorisation)

5. 5 Conditional Marketing Authorization Article 14(7) “Following consultation with the applicant, an authorisation may be granted subject to certain specific obligations, to be reviewed annually by the Agency … such authorisation shall be valid for one year [instead of 5], on a renewable basis.” Note: Implementing regulation and guidelines pending

6. 6 Conditional Marketing Authorization Scope and Conditions (based on draft legislation) l Scope and conditions u Orphan drugs, emergency threats, serious, chronic, life-threatening conditions u Public health interest, fulfil an unmet medical need u Applicant must demonstrate “presumed positive benefit/risk” of the product based on scientific evidence and pending completion of further studies (“specific obligations”) – Strict criteria to be established u Quality and non-clinical safety data package should be complete

7. 7 Assessment of obligations and compliance l Obligations and timeframes made publicly available l Clear information to patients and health professionals on the conditional nature of the authorization l Authorisation valid for 1 year, renewable u Assess compliance with timeframe for obligations u Retain, modify obligations, or consider benefit-risk established u If holder does not apply for renewal, authorization ceases to be valid on expiry date l Suspend, revoke, withdraw or vary authorisation if a product is viewed as harmful or as lacking therapeutic efficacy l Financial penalties on the holders of marketing authorizations if they fail to observe obligations (draft regulation)

8. 8 Conditional v. Exceptional Conditional MA Exceptional circumstances Granted before all data are available Comprehensive data cannot be provided (e.g., too rare) Authorization valid for one year (renewable) Annual reassessment of the risk- benefit balance Obligations: Further clinical studies to verify benefit/risk balance Obligations: Specific procedures in particular concerning safety Data package: Initial + Obligations = Normal Data package: Initial + Obligations < Normal Approved under exceptional circumstances: MabCampath (alemtuzumab), Foscan (temoporfin), Glivec (imatinib), Onsenal (celecoxib), Taxotere (docetaxel), Trisenox (arsenic trioxide), Velcade (bortezomib), Zevalin (ibritumomab tiuxetan)

9. 9 What studies as commitments? l Studies (ongoing or new) to confirm that benefit-risk balance is positive u Clarify any outstanding questions on the quality, safety, efficacy, pharmacovigilance l Pharmacology, Dose-Response, Therapeutic use u Refine understanding of B/R (ICH E8) l Therapeutic confirmatory trials u Randomized controlled trials (RCT, Phase III) u Essential to demonstrate efficacy (ICH E9) u Generally not feasible as commitment in approved indication (ethical concerns)

10. 10 What models for conditional authorization? l Frequently discussed models Basis for approval Confirmation Short-term “Soft endpoint” Long-term “Hard endpoint” Interim analysis of RCT Further analysis “Selective approval” (small effect in broad indication) Identify responders (restrict indication) Biomarker Exploratory (Phase II single- arm or randomized) Clinical outcome Randomized controlled trial (Phase III in the same or related indication)

11. 11 Lack of adequate RCT most important objection for rejection CPMP opinions September 1997 to July 2002 (N=170). Competing risks analysis. Aronsson, DIA, 2003

12. 12 Common reasons for rejection l Negative trials u Claims based on exploratory subgroup analysis u Non-inferiority (switch) but control arm not- established u A posteriori defined non-inferiority margins l Marginal activity, safety issues l Lack of randomized control trial u No appropriate historical control u No dramatic activity

13. 13 Interim analysis with further confirmation l Planned interim analysis of efficacy aiming for early rejection of null hypothesis l Methodological issues u Need to define appropriate stopping rules u Balance early stopping and study maturity, generalizability l Obligation: confirmatory analysis when more events available u Confirm effect in larger data set, secondary endpoints u Handling of unblinding and cross-over

14. 14 “Selective approval” l Roberts, T. G., Jr. and B. A. Chabner (2004). “Beyond fast track for drug approvals.” N Engl J Med 351(5): 501-5. l Approve conditionally in target indication (typically, low proportion of responders) l A possible model for targeted therapies? l Role of commitments u Studies to identify patients most likely to benefit  restrict indication u Studies in special populations  change product information

15. 15 What models for conditional authorization? ModelIssues (Biomarkers, Single- arm  RCT) Assumptions on surrogacy Results of single-arm trials are the most problematic to interpret  high risk of rejection RCT after approval not feasible  risk of remaining conditional indefinitely Soft endpoint  Hard endpoint Clinical relevance of effect on soft endpoints not always easy to define Interim analysis  Further analysis Methodological issues to be addressed carefully Selective approval Promising, experience lacking

16. 16 The Role of Scientific Advice l Scientific advice early during development u Address planning of submission of (conditional) marketing authorisation u Parallel advice from FDA and EMEA l If high expectation of benefit u Randomize as early as possible, may use Phase II/III design u Pre-specify interim analysis and early stopping for efficacy, use adequate endpoints (ICH E8, ICH E9) u External control only if effect dramatic and outcome highly predictable (ICH E10)

17. 17 Conclusions l Conditional approval implementing legislation, guidance and consultation still pending, discussion on appropriate models ongoing l Need to balance clinical data requirements at the time of authorization v. medical need and value of treatment l What models of conditional approval? u Randomized controlled trials – Phase IV data to confirm effect on other endpoints, more mature data, study therapeutic use and select responders u Single-arm studies and other exploratory approaches are the, most problematic – High risk of rejection, confirmation difficult l Distinguish situations where it will never be possible to assemble full dossier (“exceptional circumstances”) l Scientific advice early during the development

18. 18 Acknowledgements EMEA Co-ordinators B. Aronsson F. Pignatti EMEA/CHMP Sponsors E. Abadie K. Broich J. Borvendég A. Saint-Raymond EMEA Implementation Group H. Boone H. Janssen A. North E. Pelfrene N. Seigneuret V. Stamouli S. Vanlievendael