Presentation is loading. Please wait.

Presentation is loading. Please wait.

Challenges of Pediatric Drug Development & Impact of Pediatric Legislation (Plenary Lecture) Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development.

Similar presentations


Presentation on theme: "Challenges of Pediatric Drug Development & Impact of Pediatric Legislation (Plenary Lecture) Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development."— Presentation transcript:

1 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 1 34th EMWA Conference

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 2

3 Why Pediatric Pharmaceutical Legislation? Official Objectives on EMA Website: 3 Facilitate development of availability of Medicines for Children (MfC) from birth to < 18y Ensure that MfC‘s are of high quality, ethically researched, and authorised appropriately Improve availability of information on the use of MfC Q: Would such a program have made sense 1950?

4 Why a Legislation on MfC? - Klaus’ Tentative Answers - 4 Benefit of pharmaceutical treatment in adults Scientific progress in clinical pharmacology, pediatric clinical pharmacology & pediatric medicine General high interest in health Obvious wealth of Big Pharma Big Pharma’s reputation Politicians’ preference: spend somebody else’s money

5 Progress in Clinical Pharmacology: Key Publication Kearns, 2003, NEJM Absorption, distribution, metabolization, excretion in children are different from adults Maturation is not linear and not in parallel Variability much higher Drugs in children often underdosed / overdosed

6 Kearns et al, NEJM 2003 ADME In Children

7 Iron Lungs For Children With Polio 1950ies 7

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* Biologics & Orphans excluded. Mandatory ped development: PREA*** All age groups. Biologics included. Same indication as in adults only. Re-authorized Sept 2007 as FDAAA**** *FDAMA FDA Modernisation Act * BPCA Best Pharmaceuticals for Children Act **PREA Pediatric Research Equity Act ***FDAAA FDA Amendment Acts Pediatric legislation resulted in multiple pediatric research on patented drugs. Seen as major success by FDA 8

9 In force since January 2007 Combines mandatory development with reward Pediatric Investigation Plan (PIP) of human PK PIP must cover all age groups Ped Committee (PDCO) assesses PIPs, waivers & deferrals Reward of six months SPC* prolongation EMA will not validate submission without agreed PIP PDCO members + alternates (66) represent EU states+CHMP EMA team: 20 pediatric coordinators EU Pediatric Regulation * SPC Supplementary Protection Certificate 9

10 Drugs Were Developed For Children Before 1997 – Where There Was A Market Vaccines: children Lung Surfactant: preterm newborns Growth hormone: Dornase-alfa (pulmozyme): Cystic Fibrosis Iboprufen: pain relief in adults; arterial duct in newborns Antibiotics Cough & cold medication: not always beneficial 10

11 Labels in the Past Showcard Jahrhundert Source: 11

12 Regulatory & Scientific Challenge: Earlier Inclusion of Children In Drug Development Entry into Man Proof of Concept (PoC) Patent-protected Market Registration 1st Country Phase II+III Basic Research Patent Expiry  Generic Competition FDA: Early dialogue recommended; Ped Plan mandatory at submission EU Pediatric Investigation Plan (PIP): mandatory at end of human PK 12

13 Waivers & Deferrals Waivers are given for all children or specific age groups Age classification based on ICH E 11 Waivers only if drug is probably ineffective/ unsafe; disease not in children; no significant therapeutic benefit Deferral allows company to perform pediatric measures (studies, technical development etc.) later Only concrete measures can be deferred - 13

14 PIP: When? Should be submitted in time Better not too early, and never too late Too early: potential added workload, need for later modification Too late: can block submission  There is no perfect recommendation 14

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) 15

16 Key People In The PIP Negotiation EMA pediatric coordinator – focus on procedures, but … PDCO rapporteur PDCO peer reviewer Pre-submission meeting (TC) possible since spring 2011 Whatever you discuss, final decision by PDCO only 16

17 17

18 18 PDCO Oral Explanation: Room & Sitting PDCO Members PDCO Chairman Industry Representatives 15 m Industry Speaker

19 PIP Structure 19 Part: Procedural Issues:  Shift into application form Part B:Overall development of the drug & target disease Part C:Product-specific waivers Part D:Pediatric Investigation Plan D. 1 Proposed ped dev: indication, age grups, existing data D. 2 Quality (CMC, technical staff) D. 3 Non-clinical aspects D. 4 Clinical aspects: clinical strategy & individual studies D. 5 Timeslines of proposesd measures Part E: Applications for Deferrals Part F: Annexes

20 EU Pediatric Regulation, EMA Expectations FDA started with looking for ‘some‘ pediatric data EMA wants, as far as possible, full pediatric indication(s) Want the necessary data as soon as possible for marketed drugs and as early as possible for new drugs Expect each company to be knowledgeable + up to date EMEA / PDCO style: have a mission; science-driven; tough Some requests can be perceived as exaggerated A lot of procedural guidance on the EMA website, including 26 procedural Q&As 20

21 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. 21

22 PIP Decisions: Keywords on EMA Website 19 areas – each requires 5 years postgraduate training, PIPs deal with the pediatric counterpart newborns to adolescents Not easy to avoid confusion 22

23 Levels Of External Support In Pediatric Drug Development 1 Strategic level: Reflect potential use in children [same, similar, different from adult use]. Advise on pediatric epidemiology and mechanism of disease in different age groups Clinical specialists, consultants, 2 Designing pediatric development plan (general) & write PIP (EU) CROs, medical writers, regulatory/ pediatric consultants, medical writers 3 3. Design individual projects, e.g. clinical studies, preclinical test batteries, technical formulation development etc PedResearch Networks (EnprEMA); reg/ ped consultants, CROs 4 Execute individual projectsPedResearch Networks (EnprEMA), CROs

24 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; 1 st 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. 24

25 EMA Decisions EMA decision of 28 November 2008 on the application for product specific waiver for perflubutane EMEA PIP01-08 in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council as amended. sion/WC pdf sion/WC 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 PIP03-10) sion/WC pdf sion/WC pdf 25

26 EU Court of Justice Decisions Order of the President of the Court of First Instance of 24 April 2009 – Nycomed Danmark v EMEA (Case T-52/09 R) &pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1& cid= &pageIndex=0&doclang=EN&mode=lst&dir=&occ=first&part=1& cid= Judgment Of The General Court (Third Chamber) 14 December &pageIndex=0&doclang=EN&mode=doc&dir=&occ=first&part= 1&cid= &pageIndex=0&doclang=EN&mode=doc&dir=&occ=first&part= 1&cid=

27 EU Court of Justice - Consequences Have strengthened considerably legal EMA/PDCO position For a new PIP, companies now know minimal requirements Example rules: Don’t propose a waiver because the disease is rare Know the gray zone between rare & ultra-rare: juvenile melanoma with 1.7/100’000 in y olds is pediatric disease; ovarian cancer in the same age group with 1.4/100’000 is not Never argue that a requested measure is too expensive 27

28 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 rd May /05/WC pdf 2011/05/WC pdf 28

29 29 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

30 Epilepsy Example: PIP Indications* Brivaracetam PIP 2011 Studies for the indications: -Pediatric Epilepsy Syndromes 0 Q, 3 N-C, 4 C -Neonatal Seizures 0 Q, 3 N-C, 4 C -Epilepsy with partial onset seizures 0 Q, 3 N-C, 1 C -Idiopathic Generalized Epilepsy with Primary Generalized Tonic Clonic Seizures 0 Q, 3 N-C, 1 C Retigabine PIP Epilepsy with partial onset seizures 4 Q, 1 N-C, 8 C -Lennox-Gastaut Syndrom 4 Q, 1 N-C, 6 C Perampanel PIP Treatment-resistant epilepsies (localisation-related or generalised epilepsies and age-related epilepsy syndromes) 1 Q, 1 N-C, 8 C 30 *Q Quality N-C Non Clinical C Clinical

31 Thoughts US pediatric legislation was introduced when pharma industry peaked in size, output & productivity (or had passed it zenith) EU: 10 years later: -Changed framework of drug development: Output down and requirements up -Silent assumptions: Flow of new products & budgets are unlimited, pushing drug developers is noble & justified -Desire: anticipate any future pediatric use ASAP As individuals, PDCO members /EMA coordinators are fair But we talk about structures here that include misconceptions, group dynamics & politics Nobody is against pediatric legislation – is that good or bad? 31

32 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 32

33 Better Medicines for Children or Better Use of Adult Medicines in Children? EU & US pediatric pharmaceutical legislation tries to close a gap - in the use of existing adult drugs in children There are few companies that develop drugs for children Such an industry could exist. Children don’t vote or pay. Adults would have to decide to spend more for children There are many rare diseases – but somebody must pay Today, not even a straw facilitating intake of antibiotics is reimbursed in Germany – formulation was abandoned Two issues: (1) Additional pediatric requests for adult drugs, (2) ‘better medicines for children’ - with many meanings 33

34 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 For further information, please visit 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 Organised by :In partnership with : JUST ANNOUNCED !

35 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 35

36 Thank You For Your Attention! 36

37 Back-Ups 37

38

39 Released May 2010


Download ppt "Challenges of Pediatric Drug Development & Impact of Pediatric Legislation (Plenary Lecture) Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development."

Similar presentations


Ads by Google