Transcript EU & US Regulatory Requirements For Pediatric

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
[email protected]
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Conclusions
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•
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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
[email protected]
2
Why Pediatric Pharmaceutical Legislation?
Official Objectives on EMA Website:
• 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?
[email protected]
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Why a Legislation on MfC?
- Klaus’ Tentative Answers • 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
[email protected]
4
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
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ADME In Children
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Kearns et al, NEJM
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2003
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
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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****
• Pediatric legislation resulted in multiple pediatric research
on patented drugs. Seen as major success by FDA
*FDAMA FDA Modernisation Act *BPCA Best Pharmaceuticals for Children Act
**PREA Pediatric Research Equity Act ***FDAAA FDA Amendment Acts
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EU Pediatric Regulation
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In force since January 2007
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Combines mandatory development
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Pediatric Investigation Plan (PIP) mandatory @ of human PK
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PIP must cover all age groups
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Ped Committee (PDCO) assesses PIPs, waivers & deferrals
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Reward of six months SPC* prolongation
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EMA will not validate submission without agreed PIP
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PDCO members + alternates (66) represent EU states+CHMP
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EMA team: 20 pediatric coordinators
with reward
*SPC Supplementary Protection Certificate
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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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10
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
Basic Research
EU Pediatric Investigation Plan (PIP):
mandatory at end of human PK
Entry into Man
Proof of Concept (PoC)
Phase II+III
Registration 1st
Country
Patent-protected
Market
FDA: Early dialogue recommended;
Ped Plan mandatory at submission
Patent Expiry  Generic
Competition
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[email protected]
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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14
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
15 m
PDCO
Chairman
Industry Speaker
PDCO Members
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[email protected]
Industry
Representatives
PIP Structure
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
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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
[email protected]
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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.
[email protected]
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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
3
CROs, medical writers,
(general) & write PIP (EU)
regulatory/ pediatric
consultants, medical
writers
3. Design individual projects, e.g. clinical PedResearch Networks
studies, preclinical test batteries,
(EnprEMA); reg/ ped
technical formulation development etc 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.
•
[email protected]
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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_deci
sion/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_deci
sion/WC500107411.pdf
[email protected]
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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=7
3453&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=1
16583&pageIndex=0&doclang=EN&mode=doc&dir=&occ=first&part=
1&cid=234507
[email protected]
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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
[email protected]
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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
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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
*Q Quality
N-C Non Clinical
C Clinical
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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
[email protected]
32
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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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
Programme Committee:
Gesine Bejeuhr, VfA (Association of Researchbased 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 :
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
[email protected]
35
Thank You For
Your Attention!
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36
Back-Ups
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Released May 2010
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