Navigating Pediatric Regulations in the           United States and European Union                                        ...
Navigating Pediatric Regulations in the                    United States and European UnionDr. med. Klaus Rose, MD, MS, Ma...
Navigating Pediatric Regulations in the                       United States and European UnionWilliam Sietsema, PhD, Vice ...
INC Webinar on Pediatric Drug DevelopmentEU and U.S. Pediatric Pharma:Background and Update 2011         Dr. med. Klaus Ro...
Factors Contributing to PediatricPharmaceutical Legislation• Advancement of pharmaceutical treatment in adults• Progress o...
Official Objectives EU Pediatric Legislation• Facilitate development of availability of Medicines for Children (MfC) from ...
On-Label and Off-Label Drug Use• Drug labels did not exist before 1962• Legislation to prove safety and efficacy were intr...
Children and Clinical Trials• Scepticism towards clinical trials in 1960’s• Specific reluctance towards pediatric clinical...
Pediatric Legislation Began with Two U.S.Laws• Voluntary Pediatric Exclusivity (PE): BPCA* 2007 after first laws  1997 and...
EU Pediatric Regulation• In force since January 2007• Combines mandatory development                   with reward• Pediat...
Key PublicationKearns, 2003, NEJM• Absorption, distribution,  metabolization, excretion in  children are different from  a...
ADME in Children                                              Kearns et al,                                              N...
Regulatory and Scientific Challenge: EarlierInclusion of Children in Drug Development                       EU Pediatric I...
EU Pediatric Regulation, EMA Expectations• FDA started with looking for ‘some’ pediatric data• EMA wants, as far as possib...
Key People in the PIP Negotiation• EMA pediatric coordinator – focus on procedures, but …• PDCO rapporteur• PDCO peer revi...
A New Logic• Usually companies fight with authorities for recognition of additional  therapeutic benefit• In the PIP dialo...
Old and New Key Documents• EU Pediatric Regulation 2006 (in force 2007)• PIP guideline of the EU Commission 2008• Template...
EMA Ped Report 2011                      klaus.rose@klausrose.net   15
Key Points EMA Ped Report 2011 toEU Commission• Regulation created new tasks for EMA and EU states, with major impact on  ...
Interim Analysis• Pediatric clinical pharmacology has followed drug development  – a chaotic, market-driven process, somet...
Conclusions• Drug development can not ignore children any more• EMA wants early PIP with late registration dossier details...
Thank you for your attention!         klaus.rose@klausrose.net   19
INC Webinar on Pediatric Drug DevelopmentPediatric Investigational        Planning          William K. Sietsema, PhD      ...
Agenda Preparation of a Global Plan and Pediatric Definitions            EU Regulations and Procedures           U.S. Regu...
Preparation of a Global Planand Pediatric Definitions         © 2011 INC Research, LLC   3
Preparing a Global Pediatric Plan• Pediatric data is a requirement in the U.S. and EU• By end of Phase 2 should have solid...
Pediatric Definitions     Category             ICH E11 Definition                    FDA DefinitionIntrauterine           ...
EU Regulations andProcedures        © 2011 INC Research, LLC   6
Paediatric Committee• EU Paediatric Committee (PDCO) is the key expert committee• Involved in multiple aspects of research...
PDCO Duties• Evaluate and approve PIPs• Evaluate waivers and deferrals• Check PIP compliance (in all cases for Centralised...
EU Product Specific Waivers• Waivers only on three conditions:  – Likely to be ineffective or unsafe in part of paediatric...
EU Class Waivers• List of class waivers is on the EMA website: diseases that officially do not exist  in children• Class w...
EU Deferrals• When PIP is submitted, application can be made to defer the initiation or  completion of some or all of the ...
PIP Application Procedures• Regulation says initial submission should occur “early in clinical  development” … except in c...
PIP Evaluation Timeline                                                                    Applicant                      ...
EU Rewards• Additional six months on supplementary patent certificate, if:  – Compliance in agreed time frame with all mea...
MAA Requirements• From July 2008 all MAAs for products not already approved in the EU must  include one or a combination o...
Obligation to Market• When agreed PIP has led to authorisation of a paediatric indication, the MAH  is obliged to market t...
Other EU Issues• Enforcement  – EU commission on request from the EMA can impose financial penalties on a    company for f...
U.S. Regulations andProcedures        © 2011 INC Research, LLC   18
Overview of U.S. Process• Two U.S. regulations, one voluntary (BPCA) and one mandatory (PREA)• Must submit a pediatric pla...
Written Request• Within the voluntary BPCA legislation• Drafted by Sponsor as a “proposed pediatric study request” (PPSR, ...
Deferrals• May be granted for all or for specific pediatric classifications  – If product use is primarily in adults  – If...
Waivers• Full versus partial waiver• Waivers may be granted for:  – Lack of feasibility to conduct trials in certain pedia...
Pediatric Review Committee (PeRC)• Established by the most recent PDUFA legislation (September 2007)• Greater transparency...
PeRC Responsibilities• Review all written requests before issuance• May review studies submitted in a response to a writte...
PeRC Membership• PeRC includes employees of FDA, including representatives from CDER, CBER,  and the Office of the Commiss...
Pediatric Advisory Committee• Reviews all pediatric AE reports• Ensures pediatric information included in labels• Particip...
Summary• U.S. and EU both have well defined pediatric regulations  – Requirement for pediatric data  – Reward with additio...
References• Grylack L. Pediatric Drug Development: Focus on U.S. Regulatory Issues. Focus March 2008, pages  27-31• Klimek...
Questions and Discussion        © 2011 INC Research, LLC   29
Navigating Pediatric Regulations in the United States and European Union
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Navigating Pediatric Regulations in the United States and European Union

  1. 1. Navigating Pediatric Regulations in the  United States and European Union Kathy Bohannon, Principal Strategist, Pediatrics INC Research Dr. med. Klaus Rose, MD, MS, Managing Director, klausrose Consulting William Sietsema, PhD, Vice President, Regulatory Consulting & Submissions, INC Research Adjunct Professor of Pharmaceutical Sciences University of Cincinnati College of PharmacyCopyright © 2010 Honeycomb Xtalks Inc.
  2. 2. Navigating Pediatric Regulations in the  United States and European UnionDr. med. Klaus Rose, MD, MS, Managing Director, klausrose Consulting Dr. Rose is Managing Director of klausrose Consulting, Basel, Switzerland. He qualified 1986 in medicine in Berlin after studying Latin languages and psychology. He completed postgraduate clinical training in General Medicine in Germany and England and joined pharmaceutical industry in 1991. He held various positions in R&D and medical affairs culminating in the position of Global Head Pediatrics Novartis in 2001 - 2005 and then Global Head Pediatrics Roche 2005 - 2009. From 2010 until March 2011 he was Principal Consultant with Granzer Regulatory Affairs, Munich, Germany. Dr. Rose is a frequent speaker on international conferences on pediatric drug development and publishes on this theme on a regular base. The second edition of “Guide to Paediatric Drug Development and Clinical Research“, co- edited with Professor van den Anker, was released May 2010. Married with two daughters, his private interests include Mediterranean cooking, wine, gardening, Latin languages, and classical guitar. Copyright © 2010 Honeycomb Xtalks Inc.
  3. 3. Navigating Pediatric Regulations in the  United States and European UnionWilliam Sietsema, PhD, Vice President, Regulatory Consulting & Submissions, INC Research& Adjunct Professor of Pharmaceutical Sciences University of Cincinnati College of Pharmacy Dr. Sietsema is VP, Global Regulatory Consulting and Submissions at INC Research and Adjunct Professor of Pharmaceutical Sciences at the University of Cincinnati, College of Pharmacy. He has 26 years experience in the pharmaceutical industry. During his fifteen years with INC Research (formerly known as Kendle), he has brought leadership to several initiatives in the fields of inflammation, skeletal disease, analgesia, gastrointestinal disease, and womens health. He played a pivotal role in the rapid development of Pharmacias Celebrex, which transited from beginning of Phase 2 to NDA approval in less than three years. Ethics of pediatric research have been a particular interest of his and he has given lectures and sat on discussion panels for this topic. He received his BA, magna cum laude, in Chemistry from the University of Colorado, Boulder in 1977 and his PhD in biochemistry from the University of Wisconsin, Madison in 1982. He is the author of more than 35 journal articles, several book chapters, and more than 50 presentations and posters and is an inventor on four patents. He has published four books, He is on the editorial boards for Regulatory Affairs Professional Society Focus magazine and Scrip Clinical Research. He was recently recognized by R&D Directions as one of the top 20 clinical research scientists. Copyright © 2010 Honeycomb Xtalks Inc.
  4. 4. INC Webinar on Pediatric Drug DevelopmentEU and U.S. Pediatric Pharma:Background and Update 2011 Dr. med. Klaus Rose, M.D., M.S. klausrose Consulting Nov. 8, 2011 klaus.rose@klausrose.net
  5. 5. Factors Contributing to PediatricPharmaceutical Legislation• Advancement of pharmaceutical treatment in adults• Progress of clinical pharmacology, pediatric clinical pharmacology and pediatric medicine• Visible wealth of big pharma• Behaviour of big pharma• Public finances• Politicians’ priorities klaus.rose@klausrose.net 2
  6. 6. Official Objectives EU Pediatric Legislation• 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 klaus.rose@klausrose.net 3
  7. 7. On-Label and Off-Label Drug Use• Drug labels did not exist before 1962• Legislation to prove safety and efficacy were introduced in the wake of two tragedies: – Sulfonilamide elixir 1937 – Thalidomide 1962• Kefauver-Harris amendments 1962 introduced manufacturers’ obligation to prove efficacy of drugs by adequate trials• Was the beginning of modern regulatory trials• Only since then off-label use of drugs is possible klaus.rose@klausrose.net 4
  8. 8. Children and Clinical Trials• Scepticism towards clinical trials in 1960’s• Specific reluctance towards pediatric clinical trials• Companies introduced ‘pediatric disclaimers’• Term coined by H Shirkey: children therapeutic orphans• Pediatric dose often ½ [babies ¼], formulas or tabels• Regulatory authorities, academic pediatrics, academic clinical pharmacology and others lobbied long behind the curtains klaus.rose@klausrose.net 5
  9. 9. Pediatric Legislation Began with Two U.S.Laws• Voluntary Pediatric Exclusivity (PE): BPCA* 2007 after first laws 1997 and 2002. Biologics excluded• Mandatory pediatric development: PREA** 2003. All age groups. Biologics included. Applies to 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 *BPCA Best Pharmaceuticals for Children Act **PREA Pediatric Research Equity Act ***FDAAA FDA Amendment Acts klaus.rose@klausrose.net 6
  10. 10. EU Pediatric Regulation• In force since January 2007• Combines mandatory development with reward• Pediatric Investigation Plan (PIP) mandatory @ of human PK• PIP must cover all age groups• Pediatric Committee (PDCO) assesses PIPs, waivers abd deferrals• Reward of six months SPC* prolongation• EMA will not validate submission without agreed PIP• PDCO members + alternates (2 x 35) represent EU states, CHMP, professional pediatric societies, patients• EMA team: 20 pediatric coordinators *SPC Supplementary Protection Certificate klaus.rose@klausrose.net 7
  11. 11. 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 klaus.rose@klausrose.net 8
  12. 12. ADME in Children Kearns et al, NEJM 2003 © 2011 INC Research, LLC 9
  13. 13. Regulatory and Scientific Challenge: EarlierInclusion of Children in Drug Development EU Pediatric Investigation Plan (PIP): Basic Research 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; Patent Expiry Generic Ped Plan mandatory at submission Competition klaus.rose@klausrose.net 10
  14. 14. 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 klaus.rose@klausrose.net 11
  15. 15. 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 klaus.rose@klausrose.net 12
  16. 16. A New Logic• Usually companies fight with authorities for recognition of additional therapeutic benefit• In the PIP dialogue, PDCO will assume potential high therapeutic benefit and will insist on extensive development program in all age groups• If you think the disease is not relevant/not existing in a certain age groups, you must prove so klaus.rose@klausrose.net 13
  17. 17. Old and New Key Documents• EU Pediatric Regulation 2006 (in force 2007)• PIP guideline of the EU Commission 2008• Template for the PDCO Summary Report• Procedural PIP Q&As @ EMA ped website (24)• EMA Report to the EU Commission spring 2011• Publications by EMA members, e.g. Olski T et al.: Three years of paediatric regulation in the EU, Eur J Clin Pharmacol (2011) 67:245–252 klaus.rose@klausrose.net 14
  18. 18. EMA Ped Report 2011 klaus.rose@klausrose.net 15
  19. 19. Key Points EMA Ped Report 2011 toEU Commission• Regulation created new tasks for EMA and EU states, with major impact on resources of EMA and National Competent Authorities (1.3 Overview of implementation)• EMA estimates 3-5 future modifications per agreed PIP (2.2)3.0 Conclusion – Development in children now part of drug development in adults – Large number of pediatric developments deferred – Granted SPC extensions still limited, growing. No PUMA so far – Regulation is stimulating pediatric research – Delayed submissions: missed opportunity for early dialogue – Financial penalties not yet available – Contributed to non-EU initiatives, e.g. Ped Medicines Regulatory Network, coordinated by WHO klaus.rose@klausrose.net 16
  20. 20. Interim Analysis• Pediatric clinical pharmacology has followed drug development – a chaotic, market-driven process, sometimes successful —• Children should indeed participate. First pragmatic FDA steps.• Pharmaceutical industry could have been smarter in U.S. and EU• Compared to EU budgets assigned to tobacco subsidies (€ 1Billion until 2010!), EU budgets for ped research are tiny• EU pediatric regulation is the attempt to impose the logic of public health to drug development for a special population• A machinery squeezes resources into research projects that sometimes are reasonable klaus.rose@klausrose.net 17
  21. 21. Conclusions• Drug development can not ignore children any more• EMA wants early PIP with late registration dossier details• EMA estimate: 3–5 modifications per agreed PIP• Within this framework: draft PIP, negotiate, convince PDCO• Worst mistake: time pressure, resulting in bad commitments• To ignore pediatrics will block EU submission• Compliance can prolong patent ½ year in EU and U.S.• Way forward for companies: do your homework in time, negotiate a PIP that serves patients and lets company survive klaus.rose@klausrose.net 18
  22. 22. Thank you for your attention! klaus.rose@klausrose.net 19
  23. 23. INC Webinar on Pediatric Drug DevelopmentPediatric Investigational Planning William K. Sietsema, PhD Nov. 8, 2011
  24. 24. Agenda Preparation of a Global Plan and Pediatric Definitions EU Regulations and Procedures U.S. Regulations and Procedures Questions and Discussion © 2011 INC Research, LLC 2
  25. 25. Preparation of a Global Planand Pediatric Definitions © 2011 INC Research, LLC 3
  26. 26. Preparing a Global Pediatric Plan• Pediatric data is a requirement in the U.S. and EU• By end of Phase 2 should have solidified a basic strategy for pediatric data• Consider U.S. and EU requirements• Design pediatric program which addresses requirements efficiently• Write a draft plan• Submit to PDCO in EU around beginning of Phase 2• Submit to FDA at EOP2 meeting• Revise plan based on feedback and finalize with PDCO• With FDA, pediatric plan becomes a review issue during NDA review © 2011 INC Research, LLC 4
  27. 27. Pediatric Definitions Category ICH E11 Definition FDA DefinitionIntrauterine Not defined Conception to BirthPreterm newborn Not defined but less than 36 weeks ofinfants acknowledged as different gestationTerm newborn Birth to 27 days Birth up to 1 monthinfants (neonatal)Infants and toddlers 28 days to 23 months 1 month up to 2 yearsChildren 2 to 11 years 2 years up to 12 yearsAdolescents 12 to 16-18 years 12 years up to 16 years (depending on region) © 2011 INC Research, LLC 5
  28. 28. EU Regulations andProcedures © 2011 INC Research, LLC 6
  29. 29. Paediatric Committee• EU Paediatric Committee (PDCO) is the key expert committee• Involved in multiple aspects of research development and authorisation and use of medicines in children• Part of EMA infrastructure, but most PDCO members do not report to EMA rather to EU national regulatory authorities, or are independent clinicians• Comprises in principal 35 members – Five CHMP members/alternates – One member from each Member State (except those from CHMP) – Three from healthcare professionals – Three from patient associations• As there are member + alternate for each position and these two often alternate physical PDCO participation, the applicant has to deal with a body of almost 70 people (EU + Norway + Iceland; some positions are always vacant) © 2011 INC Research, LLC 7
  30. 30. PDCO Duties• Evaluate and approve PIPs• Evaluate waivers and deferrals• Check PIP compliance (in all cases for Centralised procedures)• ad hoc assessments of paediatric Q, S, or E at request of CHMP or National Competent Authority• Prepare inventory of paediatric medicines in use, therapeutic needs and priorities for research for three year horizon © 2011 INC Research, LLC 8
  31. 31. EU Product Specific Waivers• Waivers only on three conditions: – Likely to be ineffective or unsafe in part of paediatric population – Disease only occurs in adult populations – Does not represent significant therapeutic benefit over existing treatments• Waiver can be issued for all or part of the paediatric population – One or more indication – Or a combination of the above• Time frame for a product specific waiver is 60 days• Waivers not allowed for – Small populations – Geographical dispersion – Studies not practical or formulation efforts failed © 2011 INC Research, LLC 9
  32. 32. EU Class Waivers• List of class waivers is on the EMA website: diseases that officially do not exist in children• Class waivers can be revoked, i.e., the decision that a certain disease does not exist in childhood is reversed• Examples: – Melanoma – Peri-and postmenopausal symptoms and diseases• If a class waiver is revoked, companies have a 36 months grace period to submit a registration without a PIP• After these 36 months, no registration without a PIP © 2011 INC Research, LLC 10
  33. 33. EU Deferrals• When PIP is submitted, application can be made to defer the initiation or completion of some or all of the measures it proposes• Legitimate reasons for deferral: – Grounds of public health, scientific or technical grounds – When it is more appropriate to conduct studies in adults before children – When studies in children will take longer• Forecast of when studies in paediatric population will start and complete must be given• Annual progress reports must be provided © 2011 INC Research, LLC 11
  34. 34. PIP Application Procedures• Regulation says initial submission should occur “early in clinical development” … except in certain justified cases not later than completion of human PK studies• Is interpreted by EMA as end of Phase 1• This is in contrast to FDA for which a paediatric plan may not be negotiated until the product is being reviewed for approval in adults• PIP can in theory be approved in around 180 days• PIP procedure starts only after validation of submitted PIP document• Time period between PIP submission and start of procedure is 30 days• Deadline for requests of clarification during this period is usually 48 hours• Procedure will take longer in case of longer clock stop or if applicant asks for re-examination• You should allow at least a year for your PIP negotiation © 2011 INC Research, LLC 12
  35. 35. PIP Evaluation Timeline Applicant Applicant Day 30 Day 60 Day 90 Draft Summary Summary Draft Opinion report for Report & for information EMEALetter ofLetter of PIP PIP information Request for Re-submission Re-submission Opinion to Approved Approved Submission Day 61 Applicant PIP Intent Intent Submission modification Day 61 PIP Oral Explanation? 30 Days Clock Stop 10 Days + 30 Days Clock Stop (approx. 3 months) (approx. 3 months) If no re- examination request, opinion = definitive. EMEA have 10 days Day 1 Day 30 Day 60 Updated Day 90 Day 120 to adopt decision Validation 1st 1st Summary 2nd 3rd & Summary presentation discussion Report discussion discussion Publication on Report at PDCO at PDCO at PDCO at PDCO website follows… to PDCO EMEA EMEA PDCO PDCO EMEA EMEA © 2011 INC Research, LLC 13
  36. 36. EU Rewards• Additional six months on supplementary patent certificate, if: – Compliance in agreed time frame with all measures included and approved in PIP – Product is protected by a patent or supplementary patent certificate – Product is authorised in all member states – Relevant info on results are included in SmPC – Reward can be granted even if outcome is negative – An alternative to the six month patent extension is an additional 12 months data exclusivity but not both• Additional two years market exclusivity on top of the 10 years for designated orphan drugs, provided PIP compliance is established © 2011 INC Research, LLC 14
  37. 37. MAA Requirements• From July 2008 all MAAs for products not already approved in the EU must include one or a combination of: – Results of paediatric studies and details of all information collected in compliance with an agreed PIP – An EMA product-specific waiver – An EMA class/indication-specific waiver (from list) – An EMA deferral letter• The above must cover all subsets of the paediatric population• Requirements are similar for line extensions, for which paediatric plans must cover all existing indications © 2011 INC Research, LLC 15
  38. 38. Obligation to Market• When agreed PIP has led to authorisation of a paediatric indication, the MAH is obliged to market the product accordingly within two years• To obtain the supplementary patent certificate, it must be marketed throughout the EU• If the MAH decides to discontinue commercialisation – The MA shall be transferred, or – A third party shall be allowed to use the pharmaceutical, preclinical and clinical documentation contained in the file © 2011 INC Research, LLC 16
  39. 39. Other EU Issues• Enforcement – EU commission on request from the EMA can impose financial penalties on a company for failure to comply – This could include failure to complete the studies in a PIP – However, execution rules have not been implemented so far, so for the moment these penalties do not exist – EMA would, however, desire them as explained in the 2011 report to the EU commission• Free scientific advice is provided for study designs, pharmacovigilance, and risk management plans• EudraCT database is being adapted to better accommodate paediatric data• EMA will make public a list of companies that have benefited from reward or have failed to comply © 2011 INC Research, LLC 17
  40. 40. U.S. Regulations andProcedures © 2011 INC Research, LLC 18
  41. 41. Overview of U.S. Process• Two U.S. regulations, one voluntary (BPCA) and one mandatory (PREA)• Must submit a pediatric plan at adult submission to comply with PREA• Can negotiate a voluntary written request to get pediatric exclusivity (PE)• For PE, Sponsor sends a “proposed pediatric study request” (PPSR) to FDA• FDA reviews request and makes modifications• FDA issues document back to sponsor as a “written request” (WR)• Sponsor agrees to written request and conducts studies according to it• Studies are reported to FDA within agreed time frame• FDA reviews studies for pediatric exclusivity (180 days)• If conducted as agreed, FDA grants pediatric exclusivity which begins when other exclusivities expire• Data incorporated into label, regardless of outcome – May suggest indication, dosage, etc. by pediatric classification – May indicate that product not safe in various pediatric classifications © 2011 INC Research, LLC 19
  42. 42. Written Request• Within the voluntary BPCA legislation• Drafted by Sponsor as a “proposed pediatric study request” (PPSR, must go beyond PREA requirements)• Template available on FDA web site• Modified and issued by FDA as a “written request”• Focus on establishing right dose and understanding pharmacokinetics in various pediatric indications• Specifies: – Indications (approved and unapproved) – Types of studies to be performed – Number of patients and treatment arms – Safety and efficacy measures to be employed – Age groups to be studied• May include nonclinical studies and development of new formulations• Sponsors must respond to “written request” within 180 days © 2011 INC Research, LLC 20
  43. 43. Deferrals• May be granted for all or for specific pediatric classifications – If product use is primarily in adults – If studies in children are planned or under way but could not be completed within same time frame as adults• Applicant must submit: – Certification of the grounds for deferral – Description of the planned studies – Evidence that the studies are being conducted or will be conducted with some diligence and at earliest possible time• Status of deferred studies must be reported in each Annual Report to the NDA and will be made public © 2011 INC Research, LLC 21
  44. 44. Waivers• Full versus partial waiver• Waivers may be granted for: – Lack of feasibility to conduct trials in certain pediatric classifications – Low probability that the product would be safe or effective in selected pediatric classifications – New therapy does not represent meaningful therapeutic benefit over existing therapies AND not likely to be used in substantial number of pediatric patients – Inability to produce an appropriate formulation (but must demonstrate infeasibility; supporting data will be made public) © 2011 INC Research, LLC 22
  45. 45. Pediatric Review Committee (PeRC)• Established by the most recent PDUFA legislation (September 2007)• Greater transparency – most things now made public © 2011 INC Research, LLC 23
  46. 46. PeRC Responsibilities• Review all written requests before issuance• May review studies submitted in a response to a written request to make recommendation on exclusivity determinations (previously only the reviewing division made this determination)• Provide consultation to reviewing divisions on all pediatric plans and assessments prior to approval of an application or supplement for which a Pediatric assessment is required• Provide review of all deferrals and waivers from the requirement to submit pediatric assessments• Provide recommendations to reviewing divisions as to whether a supplement [with pediatric data] will be considered for priority review• Provide consultation on tracking and making available to the public certain information about pediatric studies and labeling changes Woodcock J. Establishment of the Pediatric Review Committee. 10/23/07. http://www.fda.gov/cder/Pediatric/Pediatric_Review_Committee_Establishment_Memo.pdf © 2011 INC Research, LLC 24
  47. 47. PeRC Membership• PeRC includes employees of FDA, including representatives from CDER, CBER, and the Office of the Commissioner• Expertise will include: – Pediatrics (including from Office of Pediatric Therapeutics) – Clinical Pharmacology – Statistics – Chemistry – Legal issues – Pediatric ethics – Appropriate expertise pertaining to the product under review (e.g., expertise in child and adolescent psychiatry) – Other individuals as designated by the Secretary Woodcock J. Establishment of the Pediatric Review Committee. 10/23/07. http://www.fda.gov/cder/Pediatric/Pediatric_Review_Committee_Establishment_Memo.pdf © 2011 INC Research, LLC 25
  48. 48. Pediatric Advisory Committee• Reviews all pediatric AE reports• Ensures pediatric information included in labels• Participates in labeling dispute resolution• Provides advice and recommendations when requested © 2011 INC Research, LLC 26
  49. 49. Summary• U.S. and EU both have well defined pediatric regulations – Requirement for pediatric data – Reward with additional exclusivity or patent extension• U.S. legislation FDAAA (BPCA + PREA) up for re-authorisation in 2012• EU legislation will see 1st review 2013 and 2nd in 2018• While it is not easy to develop a global pediatric plan, this should be the goal for any development program• Recommend developing a global pediatric plan according to EU timelines and designing studies so as to avoid duplication• Approach FDA early and act diplomatically if division is not enthusiastic in the beginning © 2011 INC Research, LLC 27
  50. 50. References• Grylack L. Pediatric Drug Development: Focus on U.S. Regulatory Issues. Focus March 2008, pages 27-31• Klimek J. U.S. Pediatric Developments. Focus March 2008, pages 32-35• Erickson M and Bateman M, The Paediatric Regulation in The Fundamentals of EU Regulatory Affairs 4th Edn RAPS 2008, Ch 24 pp 261-267 ISBN0-9787006-1-9• http://www.fda.gov/cder/pediatric/• http://www.emea.europa.eu/htms/human/paediatrics/introduction• Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004• Regulation (EC) No 1902/2006 of the European Parliament and of the Council of 20 December 2006 amending Regulation 1901/2006 on medicinal products for paediatric use• ICH E11 Clinical investigation of medicinal products in the paediatric population (CPMP/ICH/2711/99) © 2011 INC Research, LLC 28
  51. 51. Questions and Discussion © 2011 INC Research, LLC 29

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