European Paediatric Initiative Experience in Oncology - PowerPoint PPT Presentation

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European Paediatric Initiative Experience in Oncology

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  1. European Paediatric InitiativeExperience in Oncology Dr Agnès Saint Raymond & Dr Ralf Herold Scientific Advice, Paediatrics and Orphan Drugs Sector European Medicines Agency, EMEA FDA April 16 2008

  2. Objectives of the Regulation • Improve the health of children • Increase high quality, ethical research into medicines for children • Increase availability of authorised medicines for children • Increase information on medicines • Achieve the above • Without unnecessary studies in children • Without delaying authorisation for adults

  3. Main pillars • Creation of a Paediatric Committee • Measures for new/patented drugs • Measures for off-patent drugs • Paediatric Investigation Plans • Many other measures (information and transparency)

  4. Main pillars • Creation of a Paediatric Committee • Expert Committee • Mix of Academics and Agencies employees, including paediatric oncologists • Meeting monthly at EMEA • Scientific decisions • Measures for new/patented drugs • Measures for off-patent drugs • Paediatric Investigation Plans • Many other measures (information and transparency)

  5. Paediatric Committee 1 elected Chair 5 members from Approval Committee (CHMP) 22 representatives from other Member States 3 Patients/families’ representatives* 3 Health Professionals representatives* *still to be appointed

  6. Main pillars • Creation of a Paediatric Committee • Measures for new/patented drugs • Measures for off-patent drugs • Paediatric Investigation Plans • Many other measures (information and transparency)

  7. New drugs before approval • Obligation to submit results of agreed Paediatric Investigation Plan (PIP) • At time of Marketing Authorisation Application, OR Deferral of studies, OR Waiver of development • Reward: 6-month extension of the patent • Conditions: • compliance with PIP • results in product information • approval in all Member States

  8. On-Patent marketed Drugs • Obligation to submit results of agreed Paediatric Investigation Plan (PIP) • When applying for new indication, new route of administration, and/or new formulation • OR deferral of studies, OR waiver • Reward: 6-month extension of the patent • Conditions: • compliance with PIP • results in product information • approval in all Member States

  9. Orphan drugs • Among orphan drugs, 15-20% are for diseases only affecting children, 55% for diseases affecting both adult and children* • Orphan drugs receive 10 years of market exclusivity in EU • Orphan drugs must submit a Paediatric Investigation Plan • Orphan drugs can get 2 additional years of exclusivity when they comply with PIP * EU orphan designation data

  10. Off-patentdrugs Paediatric Use Marketing Authorisation (PUMA) • Optional • Covers Paediatric Indication and Formulation • Need for agreed Paediatric Investigation Plan • Need for compliance and results in Product information • Incentive: Data protection of 10 years (as for new products in EU)

  11. Main pillars • Creation of a Paediatric Committee • Measures for new/patented drugs • Measures for off-patent drugs • Paediatric Investigation Plans • Many other measures (information and transparency)

  12. Paediatric Investigation Plan (PIP) • Paediatric Investigation Plan proposed by company • By end of phase 1 for new products • Plan is discussed, modified, and agreed/refused by Paediatric Committee • Followed by EMEA Decision • Binding on company

  13. Paediatric Investigation Plans • Define necessary data on Quality, Safety and Efficacy for use in the paediatric population (0 – 18 years) • No explicit link with adult indication • Specify development timelines, including deferral of studies • Define age-appropriate formulation • Results according to agreed plan serves as basis for approval

  14. PIP Waivers/Deferrals On request from applicant or initiative of Paediatric Committee, for all or part of the paediatric population: • Waiver of development for ‘classes’ of indications, or for a specific product • Deferral of initiation of studies and/or completion Development is most often a combination of a plan with deferrals and waivers (population subset)

  15. Life cycle of a Paediatric Investigation Plan PIP MA Non-clin Phase 1 Phase 2 Phase 3 Post Approval 1 Compliance Modifications Paediatric Committee

  16. Life cycle of a Paediatric Investigation Plan PIP MA With deferral Non-clin Phase 1 Phase 2 Phase 3 Post Approval 1 Modifications Compliance Paediatric Committee

  17. Applications and Indications • Each PIP corresponds to an active substance (or a combination) from a company • Each PIP usually covers more than one indication (e.g. high grade glioma and neuroblastoma)

  18. PIP and Waivers Applications • August 2007 – April 2008: • All Indications: 326 • PIP/Waiver applications: 178 • Authorised products: 30 % Update 3/18/2008

  19. PIP Therapeutic areas (%) • CNS 6 • Cardiovascular 10 • Oncology 14 • Anti-infectives 10 • Endocrinology / metabolism 21 • Immunology / vaccines 11 • Other 28

  20. Oncology PIPs* • Active substances • Total 18 • New: 9 • Authorised: 9 • Cytotoxic / established / conventional: 9 • Non-cytotoxic / innovative: 6 • Supportive (antiemetics, growth factors) 3 • Written requests: 8 * Exclude full Waivers Update 3/18/2008

  21. Oncology PIPs* • Number of conditions / indications in oncology (15 active substances): • Total: 52 • Adult condition only 24 • Paediatric condition only 26 • Front line-treatment 11 • Relapse treatment 15 • Adult and paediatric 2 * Excludes full waivers

  22. Class Waivers • Published: • Oropharyngeal epithelial cancer • Lung cancer (small cell and non-small cell) • Basal cell carcinoma • Breast carcinoma • Ovarian carcinoma • Endometrial carcinoma • Prostate carcinoma • Hairy cell leukaemia • Multiple myeloma

  23. Issues with PIPs/Waivers in paediatric oncology • Low incidence for condition but exists • Definition of condition • Wider name = extended scope • Lower age range for studies: • Glioma, neuroblastoma, rhabdomyosarcoma • Which is the appropriate cut-off: 0 – 6 mo – 1 – 2 - 3 years? • Which minimal age for relapse / refractory disease?

  24. Oncology PIPs • Paediatric trials for 15 active substances: • Completed 17 • Proposed, ongoing 6 • Total per active substance ~ 1.5 • Collaborative paediatric oncology group ~ 6 • Proposed and planned trials • Phase 1/2 4 • Phase 2 single arm 10 • Phase 3 4 • Combination therapy studies 8 • Additional to Written Requests (n=3) 2

  25. Paediatric condition/indication • Rhabdomyosarcoma 3 • Non-RMS soft tissue sarcomas 2 • Ewing sarcoma 2 • Neuroblastoma 3 • High-grade glioma (HGG) 5 • Brainstem HGG 1 • Leukaemia 2 • Lymphoma 2 • Carcinoma 2 • Melanoma 2 • ‘Any solid tumours’ 3 • First-line treatment 10 • Treatment of relapse or refractory disease 9

  26. More Issues • No corresponding development in adults (no proof-of-concept) • Neonates: waiver very often requested • Non-clinical data : highly variable level of details • Models of paediatric tumours? • Study design choice • Studies deferred not described: Lack of overall strategy

  27. Main pillars • Creation of a Paediatric Committee • Measures for new/patented drugs • Measures for off-patent drugs • Paediatric Investigation Plans • Many other measures (information and transparency)

  28. Transparency measures PUBLIC ACCESS to: • Decisions on Paediatric Investigation Plans • Summary of content • Timelines • Results in Product Information • Publication of Assessment Reports (public outcome of evaluation)

  29. Transparency measures PUBLIC ACCESS to EU Database of all clinical trials (called EudraCT): • protocol-related information • results-related information • All trials with at least a study site in EU • All those performed outside EU if included in a Paediatric Investigation Plan

  30. Other measures • Establishment of an EMEA network of paediatric research networks (in particular paediatric oncology groups e.g. SIOP, ITCC) • Inventory of all paediatric uses of medicines in Member States • To help define ‘paediatric needs’ for future Paediatric Investigation Plans

  31. Public funding for studies on off-patent drugs Off-patent drugs on EMEA Priority List of about 60 drugs • EU funding (Framework Programme) ~ 20-30 million Euros available in 2007 • 5 projects funded • New call for proposals in July 2008

  32. TAKE HOME MESSAGES • Successful implementation • Paediatric oncology as a model: • Consider Mechanism of action/Target of a drug rather than Adult indication • Lack of Proof of concept in adults/ in children • Lack of models of paediatric tumours • Age groups to be included in trials • Weak level of evidence proposed • Collaborative approach highly needed

  33. CHMP: Committee for Human Medicinal Products (EMEA ‘approval’ Committee) • CT: Clinical Trial(s) EMEA: European Medicines Agency (ww.emea.europa.eu) • EU: European Union • EUDRACT: European Database of Clinical Trials European Commission (pharmacos.europa.eu) • GCP: Good Clinical Practice • ICH: International Conference on Harmonization • MA: Marketing Authorisation (Drug Approval) • MS: Member State • PIP: Paediatric Investigation Plan • PUMA: Paediatric Use Marketing Authorisation