Challenges of Pediatric Drug Development

1
Challenges of Pediatric Drug Development
Impact of Pediatric Legislation
(Plenary Lecture)
34th EMWA Conference

Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug
Development Moreklausrose Consultingklaus.rose
_at_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

3

• Why Pediatric Pharmaceutical Legislation?
  Official Objectives on EMA Website

• Facilitate development of availability of
  Medicines for Children (MfC) from birth to lt 18y
• Ensure that MfCs 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 -

• 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 Pharmas reputation
• Politicians preference spend somebody elses
  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
ADME In Children
Kearns et al, NEJM 2003
7
Iron Lungs For Children With 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

• 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
9
EU Pediatric Regulation

• In force since January 2007
• Combines mandatory development with
  reward
• Pediatric Investigation Plan (PIP) mandatory _at_ 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
  statesCHMP
• EMA team 20 pediatric coordinators

SPC Supplementary Protection Certificate
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

11

• Labels in the Past
• Showcard 1918.
• 
  19. Jahrhundert
• Source www.wellcomecollection.org

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

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

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)

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

17
(No Transcript)
18
PDCO Oral Explanation Room Sitting
15 m
PDCO Chairman
Industry Speaker
PDCO Members
Industry Representatives
19
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
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 QAs

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.

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

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 projects PedResearch 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 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.

25
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_libra
  ry/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_libra
  ry/PIP_decision/WC500107411.pdf

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). http//curia.europa.eu/juri
  s/document/document.jsf?textdocid73453pageInde
  x0doclangENmodelstdiroccfirstpart1cid
  327397
• Judgment Of The General Court (Third Chamber) 14
  December 2011. http//curia.europa.eu/juris/docume
  nt/document.jsf?textdocid116583pageIndex0doc
  langENmodedocdiroccfirstpart1cid234507
  

27
EU Court of Justice - Consequences

• Have strengthened considerably legal EMA/PDCO
  position
• For a new PIP, companies now know minimal
  requirements
• Example rules
• Dont propose a waiver because the disease is
  rare
• Know the gray zone between rare ultra-rare
  juvenile melanoma with 1.7/100000 in 15-19 y
  olds is pediatric disease ovarian cancer in the
  same age group with 1.4/100000 is not
• Never argue that a requested measure is too
  expensive

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)
  67245252
• 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/documen
  t_library/Report/2011/05/WC500106262.pdf

29
EMA-EFPIA Info Day 2011 EFPIA Conclusions

• Impact on RD 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
• RD 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 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-relat
  ed or generalised epilepsies and age-related
  epilepsy syndromes) 1 Q, 1 N-C, 8 C

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?

32
More Throughts

• Epilepsy PIPs discourage further RD.
• 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

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 dont 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

34
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
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

36
Thank You For Your Attention!
37
Back-Ups
38
(No Transcript)
39
Released May 2010