9/20/2011. Impact of EU Paediatric Regulation on drug development and Marketing authorisations Industry experience

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1 Impact of EU Paediatric Regulation on drug development and Marketing authorisations Industry experience Judith Creba Head EU Liaison and Policy, DRA Novartis Pharma AG, Switzerland Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to, Inc. ( DIA ), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved., DIA and DIA logo are registered trademarks or trademarks of Inc. All other trademarks are the property of their respective owners. 2 Agenda Introduction Industry experiences with Paediatric Legislation: EFPIA survey on the the impact of the paediatric regulation on Marketing Authorisation Holders (Jan June 2010) Conclusion/ recommendations Acknowledgements EFPIA for permission to use the data from the survey EFPIA Paediatric Working Group 3 1

2 Implementation of the EU Paediatric Regulation Progress Continuous effort for paediatric drug development PIP and waivers situation (PDCO report August 2011) Total PIP/waiver applications 1087 Total of agreed PIP/waiver 683 Positive opinion on PIPs 475 Positive opinion on Full waiver 208 Negative opinion on PIP/waiver 27 Indications covered by PIP/waiver applications 1516 Positive opinion on compliance check 25 Positive opinion on modification PIPs 259 Increased paediatric information Article 45 and Article 46 assessments ( ) EMA CMD(h) Art.45 Number of products submitted Outcome Update of the SmPC for 6 products 44 products completed the assessment Art.46 Number of studies submitted 60 N/A Outcome Update of SmPC for 19 cases 4 Industry Experience EFPIA survey on the the impact of the paediatric regulation on Marketing Authorisation Holders (Jan June 2010) 5 EFPIA survey on impact of Paediatric regulation (Jan 2007 Jun 2010) Objective - to assess the impact of the first 3.5 years of implementation of the paediatric regulation on marketing authorization holders (Jan 2007 June 2010) Extensive survey of 61 questions covering all aspects relating to PIP application/outcomes and the impact on company drug development and resources. Very good response rate - 34 companies including large and small firms Data from 316 PIPs/partial waivers analysed Legal basis - 53% Art 7, 46% Art 8, 1% Art 30 12% Orphan products 4% paediatric indications only, 96% paedaitric development as part of ongoing adult programme 6 2

3 Timing of PIP/Waiver submissions and outcomes 7 Timing for submission of Art.7 PIP/waiver to EMA (information received on N=146 out of 168 submitted PIPs) majority of PIP/waiver applications were submitted to EMA following the proof of concept (PoC) or confirmation of the adult dose 8 Timing and outcomes of Art.7 PIP/waiver applications (information received on N=146 out of 168 submitted PIPs) PIP agreed unchanged or with minor modifications PIP agreed with major modifications PIP agreed with suggestion to come back for later discussion in a "Modification of agreed PIP" procedure PIP refused (negative PDCO opinion) PIP withdrawn 50% 47% 18% 15% 15% 2% 4% 4% 12% 4% 20% 50% 12% 39% 24% 18% 18% 40% 31% 58% 19% Before first human dose in adults End of Phase 1 in adults Following confirmation Following completion of After starting paediatric of adult dose or proof of confirmatory clinical trials concept, but before the trials in adults, but start of paediatric trials before the start of paediatric trials n=2 n=17 n=49 n=52 n=26 9 3

4 Key findings on the timing and outcome of PIP submissions Submission timings for Paediatric Investigation Plans vary Majority of PIPS were submitted following proof of concept or confirmation of adult dose Submission of PIP before PoC resulted in high rate of withdrawal Companies obtaining agreement on PIP submitted after PoC, are still requested to come back for later discussion in a modification process A high proportion of PIPs agreed with major modifications regardless of the submission timing 10 Withdrawals and Modification to agreed PIPs 11 Outcomes and withdrawal of PIP/waiver applications n= = 28% of submitted PIPs n=98 n= PIPs Full waiver requests Confirmations of class waivers Agreed Ongoing Withdrawn Negative EMA decision 12 4

5 Timing for withdrawals of PIP/waiver applications (n=90) 45% 40% 39% 35% 33% 30% 25% 20% 15% 17% 10% 11% 5% 0% Day 1 60 During clock stop Day Day 120 EMA Decision 13 Key findings for withdrawals High percentage of withdrawals is of concern Majority of the withdrawals occurred after Day 60 PDCO review (during clock-stop or between D61-120) Main reasons for PIP withdrawals (n=90): termination or reconsideration of the development that was unrelated to the PIP (33%) divergent positions between the applicant and the PDCO (21%) need for additional time for applicants to consider requests by PDCO (11%) studies or key binding elements requested by the PDCO being considered unfeasible (7%) cost of the pediatric programme (6%) or the inability to achieve the reward in the remaining time (13%) Main reasons for withdrawals of Full waiver request (n=17): PDCO identified a medical need for a pediatric population in the development programme (41%) Reasons unrelated tp paediatric development (e.g adult development stopped (29%) 14 Modification to agreed PIPs (N=82 out of 169 agreed PIPs) Almost half of agreed PIPs in survey have been modified One fifth of agreed PIPs in survey have been modified at least twice (n=33) High proportion of requested changes are fully accepted by PDCO % of agreed PIPs (n=169) that have been modified 29% 20% Although companies are submitting PIP applications after Proof of Concept, over half of the agreed PIPs in survey have been modified Maintenance of agreed PIPs is resource intensive 0% 10% 20% 30% 40% 50% Only 1 modification/pip At least 2 modifications/pip 15 5

6 Content and Scope of PIPs 16 Consistency between adult and paediatric indications in submitted PIPs/waiver (n=414) 300 PIP/waiver applications Companies usually align the PIP/waiver indications with the targeted adult indications indications consistent with the intended adult indication(s) indications not consistent with the intended adult indications, but were covered by the intended adult condition(s) indications not covered by the intended adult conditions Detailed target indication language difficult at a point when this is not clear in the development path. 17 PDCO requests for different development program than initially proposed by companies (n=316 PIPs submitted) Additional program/studies requested by PDCO Additional paediatric subsets 27% Additional efficacy studies (including efficacy studies with 21% Additional formulations 18% Additional Non clinical studies Additional PK/PD studies Additional paediatric indications within the intended adult Additional Safety studies Additional dosage forms Others (e.g. juvenile tox studies, longterm maintenace Additional paediatric indications outside the intended adult Additional "dose finding" studies 14% 14% 13% 12% 12% 10% 9% 8% 18 6

7 Key findings on content and scope of PIPs Additional PDCO requests are routinely received on company PIP proposals Requests include additional programmes and studies High proportion of PDCO requests impact on study feasibility and incur unplanned costs in development 19 Some other findings Interaction with EMA and PDCO Interactions with EMA usually work well. Clarification TC following receipt of request for modification is particularly valued However, the interactions with PDCO during the procedures could improve Compliance check Companies reported 100% of positive opinion on partial check (n = 34) However, 2 negative opinions on full compliance check were reported (2/20), although EMA reported one case. This may indicate that 1 company was able to remedy the issues and reach positive compliance Survey did not reveal any specific issues to date 20 Interaction with EMA and FDA Global paediatric development program 21 7

8 FDA/EMA requests for changes to identical paediatric development program proposals (N=27 from EMA, N=18 from FDA) Yes Not yet known No Not reported FDA requested additional/different development than agreed with PDCO/EMA PDCO requested additional/different development than agreed with FDA 22 Key findings on interaction with EMA and FDA Companies carry-out global development and strive for alignment of paediatric development programmes between US and EU Companies may opt to submit Paediatric plans in parallel to EMA and FDA to facilitate Inter-Agency discussion Higher rate of requests from PDCO for changes to FDA-agreed paediatric plans Possible reflects early experiences with the EU Regulation, but need for continued monitoring 23 Impact of paediatric i regulation on drug development and MAs 24 8

9 Impact of paediatric regulation on drug development (n=34) 70% 60% 65% 59% 50% 40% 30% 20% 10% 0% 44% 24% 21% 15% 15% 9% 9% 6% 6% 3% 3% 0% 0% My company considers pediatric The introduction of the EU pediatric The introduction of the development an integral part of the Regulation has led to an earlier requirement for submission of a PIP overall development of a product discussion of pediatric development has led to earlier discussion of within my company for new pediatric development with products regulators for new products Strongly agree Agree Neither agree nor disagree Disagree Strongly disagree 25 Impact on development in adults Has the development in adults of any of your company's products been delayed or abandoned in expectation of or as a consequence of additional costs and requirements associated with paediatric development? 7 7 The objectives of the paediatric regulation should be achieved without... delaying the authorisation of medicinal products for other age populations Yes, for new indications/extensions to existing products Yes, for NCEs/NBEs No 26 Postponement of submission of a Marketing Authorization application, or a variation, for a new adult indication due to requirements of the paediatric Regulation (N=159) 139 (=87%) of 159 MAAs or variations for a new adult indication were not postponed due to requirements of the paediatric regulation. However, 19 MAAs or variations were postponed Due to divergence between EMA/PDCO and company Due to intrinsic length of the PIP/waiver procedure Due to non validation of MAA/Type II variation due to formalistic interpretation of PIP scope by EMA Due to too late submission of PIP/waiver application by applicant Due to intrinsic length of the Compliance Check procedure Other reasons

10 Key findings on the impact on drug development and Marketing Authorisations Companies have integrated paediatric development into the overall development of a product Early discussion within company and with regulators However In 14 cases, the development in adults had been delayed or abandoned in expectation, or as a consequence, of additional cost and requirements associated with the paediatric regulation (7 cases for NCEs/NMEs and 7 cases for new indications) 19 marketing authorisation applications or variations experienced a delay due to requirements of the EU Paediatric Regulation (out of 159 regulatory applications) 28 Key findings on the impact on drug development and company resources Impact on company resources: Paediatric Regulation has had a significant impact on R&D and regulatory resources - Actual management of regulatory procedure is resource intensive - Additional PDCO requests routinely received on company PIP proposals - Withdrawal of PIPs/abandoned development programmes results in wasted resource 29 Overall impact of the Paediatric Regulation to June Applications for PIPs/partial Applications for Any paediatric PIPs/partial waiver requests modification to information waiver agreed an agreed PIP added to SmPCs submitted submitted based on agreed PIP Positive Full compliance check Pediatric SPC extensions indications requested approved based on studies in agreed PIPs 30 10

11 Overall impact of the Paediatric Regulation to June Art.45 procedures initiated 54 finalised Of finalised procedures, 25 (46%) have resulted in revised product information Impact of finalised Art.45 procedures safety updates in PI new paediatric use (indication and/or dosing) deletion of a paediatric indication from PI No impact on PI? 13% 0% 33% 54% 0% 10% 20% 30% 40% 50% 60% 31 Conclusions and Recommendations 32 Conclusions First survey of industry experience with Paediatric Regulation gathering extensive information from 34 companies on 316 PIPs Some beneficial results realised for paediatric patients: 22 SmPCs with updated paediatric information based on agreed PIPs, including 10 paediatric indications Article 45: 25 procedures resulted in revised SmPCs Industry has embedded paediatric development in its development process

12 Conclusions Paediatric Regulation has impacted R&D productivity significant impact on R&D resources some development programmes (including adult programmes) have been negatively impacted Some companies are beginning to realise the incentives Signals in survey highlight some areas for future work 34 Proposals for improvement PIP process Day 90 of procedure- Allow clock-stop, allow optional interactive discussion with PDCO Allow clock-stop during the PIP modification procedure Facilitate more direct discussions between PDCO Rapporteur(s) and sponsors where required Guidance Definition of condition vs indication for the scope of the PIP Publish available data and regulatory guidance related to epidemiology for known disease areas in order to avoid duplication Facilitation of discussions between regulatory experts, academia, learned society and the pharmaceutical industry - building consensus on most appropriate paediatric plan in disease areas, balancing unmet or critical paediatric needs and current practical/feasibility limitations 35 Proposals for improvement Medium-long term measures An initial PIP should generally be submitted and discussed with regulators once Proof of Concept in adults is established/reached Limit the initial PIP to "high-level" information and agree paediatric needs, target indication, target population Include commitment to return to the PDCO with detailed study design proposals before pediatric studies are started Limit the scope of mandatory paediatric development to the corresponding adult indication and defined critical unmet medical needs 36 12

13 Thank You! Basel, Switzerland 37 PDCO request for changes to clinical study design that impacted feasibility to conduct studies (n=316 PIPs submitted) PDCO request for changes to the study design impacting on feasibility Request to include specific procedures in the protocol that presented practical or logistical challenges (e.g. specific monitoring or sample collection procedures) 24% Additional patients (leading to enrolment rates that would not allow meeting the agreed completion date or that would make the conduct of the study unfeasible) 24% Others (e.g. request for DSMB or request related to ethical aspects...) 11% 38 13