dr. med. klaus rose, m.d., m.s

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 1

34th EMWA Conference

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.net2

Why Pediatric Pharmaceutical Legislation? Official Objectives on EMA Website:

klaus.rose@klausrose.net3

• 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?

Why a Legislation on MfC?

- Klaus’ Tentative Answers -

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• 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

Progress in Clinical Pharmacology: Key PublicationKearns, 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

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Kearns et al, NEJM 2003

ADME In Children

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Iron Lungs For Children With Polio 1950ies

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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****

*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

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• In force since January 2007

• Combines mandatory development with reward

• Pediatric Investigation Plan (PIP) mandatory @ 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 klaus.rose@klausrose.net

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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

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Labels in the Past

Showcard 1918. 19. Jahrhundert

Source: www.wellcomecollection.org

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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 CompetitionFDA: Early dialogue recommended;

Ped Plan mandatory at submission

EU Pediatric Investigation Plan (PIP): mandatory at end of human PK

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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

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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

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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)

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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

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PDCO Oral Explanation: Room & Sitting

PDCO Members

PDCO Chairman

Industry Representatives

15 m

Industry Speaker

PIP Structure

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Part: Procedural Issues: Shift into application formPart B: Overall development of the drug & target diseasePart C: Product-specific waiversPart D: Pediatric Investigation Plan

D. 1 Proposed ped dev: indication, age grups, existing dataD. 2 Quality (CMC, technical staff) D. 3 Non-clinical aspectsD. 4 Clinical aspects: clinical strategy & individual studiesD. 5 Timeslines of proposesd measures

Part E: Applications for Deferrals Part F: Annexes

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

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PIP-related And Other Documentation

Pre-PIP•Briefing Book for advisory board meeting•Briefing book for scientific advice meetingPeri- & 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.

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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

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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 projects PedResearch Networks (EnprEMA), CROs

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.

•

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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

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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). 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

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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 15-19 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

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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

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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

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 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

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*Q Quality N-C Non Clinical C Clinical

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?

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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

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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

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Joint DIA/ EFGCP/ EMA Paediatric Forum 2012The EU paediatric regulation in its 6th year:

From Learning to Adapting

26 & 27 September 2012

London, UK Programme Committee:Gesine Bejeuhr, VfA (Association of Research-based Pharmaceutical Companies, Germany)Irja Lutsar, PDCO member for EstoniaCecile Ollivier, EMA, London, UKThorsten Olski, EMA, London, UKKlaus Rose, klausrose Consulting, SwitzerlandThomas Severin, Novartis, SwitzerlandOrganised

by :In partnership with :

JUST ANNOUNCED !

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.net35

Thank You For Your Attention!

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Back-Ups

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Released May 2010

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