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Dr. med. Klaus Rose, M.D., M.S.

34th EMWA Conference. Challenges of Pediatric Drug Development & Impact of Pediatric Legislation (Plenary Lecture). Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development & More klausrose Consulting klaus.rose@klausrose.net. Conclusions. No easy black or white conclusions.

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Dr. med. Klaus Rose, M.D., M.S.

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  1. 34th EMWA Conference Challenges of Pediatric Drug Development & Impact of Pediatric Legislation (Plenary Lecture) Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development & Moreklausrose Consultingklaus.rose@klausrose.net

  2. Conclusions • No easy black or white conclusions. • No more drug development without considering children • Increases cost & complexity of drug development • EMA/PDCO: nice vision; limited interest in economic reality; bureaucratic procedures; not all needed PIP skills are science • Invested resources could be used better – as is mostly the outcome of complex decision making • Reviews 2013/18: opposing proposals will be made • Costs/ benefit is difficult to quantify due to confidentiality • Law drives child research in some areas; road block in others • There will be some future clinical benefit for children • It will ensure more work for many groups including medical writers. Background understanding remains essential klaus.rose@klausrose.net

  3. WhyPediatricPharmaceuticalLegislation? Official Objectives on EMA Website: • FacilitatedevelopmentofavailabilityofMedicinesforChildren (MfC) frombirth to < 18y • EnsurethatMfC‘sare of high quality, ethicallyresearched, andauthorisedappropriately • Improveavailabilityofinformation on the use of MfC • Q: Would such a program have made sense 1950? klaus.rose@klausrose.net

  4. Benefitofpharmaceuticaltreatment in adults • Scientific progress in clinicalpharmacology, pediatricclinicalpharmacology & pediatricmedicine • General high interest in health • Obviouswealthof Big Pharma • Big Pharma’sreputation • Politicians’ preference: spendsomebodyelse’smoney Why a Legislation on MfC? - Klaus’ Tentative Answers - klaus.rose@klausrose.net

  5. Progress in Clinical Pharmacology: Key Publication Kearns, 2003, NEJM • Absorption, distribution, metabolization, excretion in childrenare different fromadults • Maturationis not linear and not in parallel • Variabilitymuchhigher • Drugs in childrenoftenunderdosed / overdosed klaus.rose@klausrose.net

  6. ADME In Children Kearns et al, NEJM 2003 klaus.rose@klausrose.net

  7. Iron Lungs ForChildrenWith Polio 1950ies

  8. Modern Drug Labels Are Relatively New In History. Pediatric Legislation Started With Two US Laws • US legislation 1962 enforced proof of efficacy for claims. Use in children mostly off-label since then. • Voluntary Pediatric Exclusivity (PE): FDAMA 1997, named* 2007. Biologics & Orphans excluded. • Mandatory ped development: PREA*** 2003. All age groups. Biologics included. Same indication as in adults only. • Re-authorized Sept 2007 as FDAAA**** • Pediatriclegislationresulted in multiple pediatricresearch on patenteddrugs. Seen asmajorsuccessby FDA *FDAMA FDA Modernisation Act *BPCA Best Pharmaceuticals for Children Act **PREA Pediatric Research Equity Act ***FDAAA FDA Amendment Acts klaus.rose@klausrose.net

  9. EU Pediatric Regulation • In force sinceJanuary 2007 • Combines mandatorydevelopmentwithreward • Pediatric Investigation Plan (PIP) mandatory@ of human PK • PIP must cover all age groups • PedCommittee (PDCO) assessesPIPs, waivers & deferrals • Reward of six months SPC*prolongation • EMA will not validatesubmissionwithoutagreed PIP • PDCO members + alternates (66) represent EU states+CHMP • EMA team: 20 pediatriccoordinators • *SPC Supplementary Protection Certificate klaus.rose@klausrose.net

  10. Drugs Were Developed For Children Before 1997 – Where There Was A Market • Vaccines: children • Lung Surfactant: pretermnewborns • Growth hormone: Dornase-alfa (pulmozyme): CysticFibrosis • Iboprufen: painrelief in adults; arterialduct in newborns • Antibiotics • Cough & coldmedication: not alwaysbeneficial klaus.rose@klausrose.net

  11. Labels in thePast Showcard 1918. 19. Jahrhundert Source: www.wellcomecollection.org klaus.rose@klausrose.net

  12. Regulatory & Scientific Challenge: Earlier Inclusion of Children In Drug Development EU Pediatric Investigation Plan (PIP): mandatoryat end of human PK Basic Research Entry into Man Proof of Concept (PoC) Phase II+III Registration 1st Country Patent-protected Market Patent Expiry  Generic Competition FDA: Early dialoguerecommended; Ped Plan mandatoryatsubmission klaus.rose@klausrose.net

  13. Waivers & Deferrals • Waiversaregivenfor all childrenorspecificagegroups • Age classificationbased on ICH E 11 • Waiversonlyifdrugisprobablyineffective/ unsafe; disease not in children; nosignificanttherapeuticbenefit • Deferralallowscompanytoperformpediatricmeasures (studies, technicaldevelopment etc.) later • Onlyconcretemeasurescanbedeferred

  14. PIP: When? • Shouldbesubmitted in time • Better not tooearly, andnevertoolate • Tooearly: potential addedworkload, needforlatermodification • Toolate: can block submission • Thereisnoperfectrecommendation klaus.rose@klausrose.net

  15. Dialogue Partners • Decisions: PDCO • Dialogue: EMA Pediatric coordinator; PDCO rapporteur + peer reviewer • Procedure usually 275 days, rarely less, can be much more • Dialogue primarily with EMA coordinator; clarification TCs with coordinator, PDCO rapporteur & peer reviewer • F2F with PDCO at the end of procedure only (Oral Explanation) klaus.rose@klausrose.net

  16. Key People In The PIP Negotiation • EMA pediatriccoordinator – focus on procedures, but … • PDCO rapporteur • PDCO peerreviewer • Pre-submission meeting (TC) possiblesince spring 2011 • Whateveryoudiscuss, final decisionby PDCO only klaus.rose@klausrose.net

  17. PDCO Oral Explanation: Room & Sitting 15 m PDCO Chairman Industry Speaker PDCO Members Industry Representatives klaus.rose@klausrose.net

  18. PIP Structure Part: ProceduralIssues:  Shiftintoapplication form Part B: Overall developmentofthedrug & targetdisease Part C: Product-specificwaivers Part D: Pediatric Investigation Plan D. 1 Proposedpeddev: indication, agegrups, existingdata D. 2 Quality (CMC, technicalstaff) D. 3 Non-clinicalaspects D. 4 Clinical aspects: clinicalstrategy & individual studies D. 5 Timeslinesofproposesdmeasures Part E: ApplicationsforDeferrals Part F: Annexes

  19. EU PediatricRegulation, EMA Expectations • FDA startedwithlookingfor ‘some‘ pediatricdata • EMA wants, asfaraspossible, fullpediatricindication(s) • Want thenecessarydataassoonaspossibleformarketeddrugsandasearlyaspossiblefornewdrugs • Expecteachcompanytobeknowledgeable + uptodate • EMEA / PDCO style: have a mission; science-driven; tough • Somerequestscanbeperceivedasexaggerated • A lotofproceduralguidance on the EMA website, including 26 procedural Q&As klaus.rose@klausrose.net

  20. PIP-related And Other Documentation Pre-PIP • Briefing Book for advisory board meeting • Briefing book for scientific advice meeting Peri- & Post-PIP • Request for PIP modification • Request for compliance check • Request for complete waiver Operational in clinical trials • Protocol writing • Informed consent adults & children • Clinical summary, etc. klaus.rose@klausrose.net

  21. PIP Decisions: Keywords on EMA Website • 19 areas – eachrequires 5 yearspostgraduatetraining, • PIPs deal withthepediatriccounterpartnewbornstoadolescents • Not easy toavoidconfusion klaus.rose@klausrose.net

  22. Levels OfExternal Support In Pediatric Drug Development

  23. Case Study Coronary Artery Disease (CAD) • Nykomed requested a full waiver for a diagnostic agent for coronary artery disease (CAD), a disease listed on the class waiver list • EMA: condition is “Visualisation of myocardial perfusion for diagnostic purposes”. Myocardial perfusion deficits exists in children (congenital heart defects, coronary anomalies, cardiomyopathies) • Negative opinion 2008 • Applicant took EMA to EU Court of Justice; 1st instance backed EMA • US originator company negotiated a new PIP with EMA, agreed 2011 • Nykomed continued law suit . EU General Court backed EMA 2011: otherwise it would be too easy for companies to circumvent pediatric development. klaus.rose@klausrose.net

  24. EMA Decisions • EMA decision of 28 November 2008 on the application for product specific waiver for perflubutane EMEA-000194-PIP01-08 in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council as amended. http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500005753.pdf • EMA decision of 18 May 2011 on the agreement of a paediatric investigation plan and on the granting of a deferral and on the granting of a waiver for perflubutane (EMEA-000194-PIP03-10) http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC500107411.pdf klaus.rose@klausrose.net

  25. EU Court of Justice Decisions • Order of the President of the Court of First Instance of 24 April 2009 – NycomedDanmark v EMEA (Case T-52/09 R). http://curia.europa.eu/juris/document/document.jsf?text=&docid=73453&pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1&cid=327397 • Judgment Of The General Court (Third Chamber) 14 December 2011. http://curia.europa.eu/juris/document/document.jsf?text=&docid=116583&pageIndex=0&doclang=EN&mode=doc&dir=&occ=first&part=1&cid=234507 klaus.rose@klausrose.net

  26. EU Court of Justice - Consequences • Havestrengthenedconsiderably legal EMA/PDCO position • For a new PIP, companiesnowknow minimal requirements • Examplerules: • Don’tpropose a waiverbecausethediseaseis rare • Knowthegrayzonebetween rare & ultra-rare: juvenile melanomawith 1.7/100’000 in 15-19 y oldsispediatricdisease; ovariancancer in the same agegroupwith 1.4/100’000 is not • Never arguethat a requestedmeasureistoo expensive klaus.rose@klausrose.net

  27. EMA Assessment – 2 Key Documents: • Olski T, Lampus S, Gherarducci G, Saint Raymond S: Three years of paediatric regulation in the European Union. Eur J Clin Pharmacol (2011) 67:245–252 • Report to the European Commission On companies and products that have benefited from any of the rewards and incentives in the Paediatric Regulation and on the companies that have failed to comply with any of the obligations in this Regulation, covering the year 2010. 3rd May 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/05/WC500106262.pdf klaus.rose@klausrose.net

  28. EMA-EFPIA Info Day 2011: EFPIA Conclusions* • Impact on R&D and resources • Additional PDCO requests on submitted PIPs • PIP withdrawals/ abandoned programs: wasted resources • PIP regulatory procedure is resource intensive • Initial submission plus downstream modifications • To be considered in context • Pediatric trials are more expensive than adults • R&D budgets are defined • Global project viability may be at greater risk by increase of costs *www.efpia.org

  29. Epilepsy Example: PIP Indications* • Brivaracetam PIP 2011 Studies for the indications: • Pediatric Epilepsy Syndromes 0 Q, 3 N-C, 4 C • NeonatalSeizures0 Q, 3 N-C, 4 C • Epilepsywith partial onsetseizures0 Q, 3 N-C, 1 C • Idiopathic Generalized Epilepsy with Primary Generalized Tonic Clonic Seizures 0 Q, 3 N-C, 1 C • Retigabine PIP 2011 • Epilepsy with partial onset seizures 4 Q, 1 N-C, 8 C • Lennox-Gastaut Syndrom 4 Q, 1 N-C, 6 C • Perampanel PIP 2010 • Treatment-resistant epilepsies (localisation-related or generalised epilepsies and age-related epilepsy syndromes) 1 Q, 1 N-C, 8 C *Q Quality N-C Non Clinical C Clinical klaus.rose@klausrose.net

  30. Thoughts • US pediatriclegislation was introducedwhenpharmaindustrypeaked in size, output & productivity (orhadpasseditzenith) • EU: 10 years later: • Changed framework of drug development: Output down and requirements up • Silent assumptions: Flow of new products & budgets are unlimited, pushing drugdevelopersis noble & justified • Desire: anticipateanyfuturepediatricuse ASAP • As individuals, PDCO members /EMA coordinatorsare fair • But we talk aboutstructuresherethatincludemisconceptions, groupdynamics & politics • Nobody isagainstpediatriclegislation – isthatgoodorbad? klaus.rose@klausrose.net

  31. More Throughts • Epilepsy PIPs discourage further R&D. • Companies in late development had to comply • Others will avoid areas of heavy PDCO requests • Light at The End of The Tunnel? • EMA report 2011 emphasizes need for penalties • EMA admits request for too many details and works on reducing them • Revision of ped regulation in 2018 • Different sides will propose different modifications klaus.rose@klausrose.net

  32. Better Medicines for Children or Better Use of Adult Medicines in Children? • EU & US pediatricpharmaceuticallegislationtriestoclose a gap - in theuseofexistingadultdrugs in children • Therearefewcompaniesthatdevelopdrugsforchildren • Such an industrycouldexist. Childrendon’tvoteorpay. Adultswouldhavetodecidetospendmoreforchildren • Therearemany rare diseases – but somebody must pay • Today, not even a strawfacilitatingintakeofantibioticsisreimbursed in Germany – formulation was abandoned • Twoissues: (1) Additional pediatricrequestsfor adult drugs, (2) ‘bettermedicinesforchildren’ - withmanymeanings klaus.rose@klausrose.net

  33. Programme Committee: Gesine Bejeuhr, VfA (Association of Research-based Pharmaceutical Companies, Germany) Irja Lutsar, PDCO member for Estonia Cecile Ollivier, EMA, London, UK Thorsten Olski, EMA, London, UK Klaus Rose, klausrose Consulting, Switzerland Thomas Severin, Novartis, Switzerland JUST ANNOUNCED ! Joint DIA/ EFGCP/ EMA Paediatric Forum 2012 The EU paediatric regulation in its 6th year: From Learning to Adapting 26 & 27 September 2012 London, UK Organised by : In partnership with : For further information, please visit www.efgcp.eu

  34. Conclusions • No easy black or white conclusions. • No more drug development without considering children • Increases cost & complexity of drug development • EMA/PDCO: nice vision; limited interest in economic reality; bureaucratic procedures; not all needed PIP skills are science • Invested resources could be used better – as is mostly the outcome of complex decision making • Reviews 2013/18: opposing proposals will be made • Costs/ benefit is difficult to quantify due to confidentiality • Law drives child research in some areas; road block in others • There will be some future clinical benefit for children • It will ensure more work for many groups including medical writers. Background understanding remains essential klaus.rose@klausrose.net

  35. ThankYouForYour Attention! klaus.rose@klausrose.net

  36. Back-Ups klaus.rose@klausrose.net

  37. klaus.rose@klausrose.net

  38. Released May 2010 klaus.rose@klausrose.net

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