Medicines for Children: Strategic Considerations Module 1 Strategic Planning in Regulatory Affairs TOPRA MSc in Regulatory Affairs Presented by Paolo Tomasi MD PhD, on 12 December 2014 Head of Paediatric Medicines European Medicines Agency London E14 5EU An agency of the European Union
Paediatric development is mandatory in the EU for new medicines Unless a product-specific waiver or a class waiver (for a class of medicinal products) is granted by EMA (waivers apply only for specific medical conditions) Deferrals can also be granted (studies in children can be initiated and/or completed after applying for marketing authorisation in other populations or conditions) 1
The EU Paediatric Regulation Regulation: Most powerful type of EU law Immediately applicable in all EU Member States 2
Why was there a need for a EU Paediatric Regulation? for = 3
EU Paediatric Regulation: obligations versus incentives Type of MP Obligation Incentive Comments New # medicinal product Paediatric Investigation Plan or Waiver 6 months extension of SPC (patent) * Necessary for validation of application On-patent and Paediatric Investigation 6 months extension When new indication or new authorized medicine Plan or Waiver of SPC (patent)* route or new pharmaceutical form: necessary for validation Orphandesignated medicine Paediatric Investigation Plan or Waiver 2 additional years of market exclusivity* In addition to 10 years Off-patent medicine None (voluntary PIP possible for PUMA) 10 years of data protection Research funds Paed. Use MA (PUMA) *if compliance with PIP, information, approval EU-wide # according to GMA concept, and not necessarily a new active substance
Rewards Reward is given for all PIPs correctly completed, but PIPs are always required (cfr. US PREA, where: obligation but no reward) -> if development is compliant with agreed PIP (compliance statement in MA); -> if results of studies included in Summary of PC + patient s leaflet; -> if product is authorised in all MSs (except for PUMA): Non-orphan products: 6-month extension of SPC (patent protection) [not when MAH applied for +1 market protection] Orphan medicinal products: + 2 additional years of market exclusivity PUMA: 8+2 years of data+market protection - Product-specific or class waiver does NOT trigger the reward - «negative» PIP results allow reward - Inconclusive studies in PIP do NOT trigger the reward
Differences EU (Paediatric Regulation) / USA (BPCA- PREA-FDASIA) US BPCA US PREA EU Development Optional Mandatory Mandatory (optional for off-patent) Instrument Written Request Paediatric Study Plan Paediatric Investigation Plan Waiver N/A 3 grounds 3 grounds Timing End of phase 2 End of phase 2 > End of phase 1 Reward 6-month exclusivity - Main: 6-month SPC extension (patent) New drugs Yes, with exclusivity Yes Yes Biologicals (most) Yes All All Orphan products Included Excluded Included Decision 6 FDA FDA EMA (not EC) Opinion: Paed. Committee
Slide 7 A7 taking the paediatric need into account Author, 06/09/2013
New Drug Development Process: US vs EU EC/EMA PIP (all inclusive) Required for Filing Preclinical Phas se Phase One Phase Three Phase Two PREA*/WR NDA Submissio on Marketing Appr roval Postmarketing Written Request FDA From Dianne Murphy, FDA
The role of EMA in paediatric medicines development 8 Medicines for children - strategic aspects
EMA works with own staff (scientific/administrative) + Scientific Committees (nominated by Member States/EC) All EMA Scientific Committees are involved with paediatric medicines: CHMP: authorises medicines for paediatric (and adult) use CHMP PRAC PRAC: monitors safety of paediatric (and adult) authorised medicines SAWP HMPC EMA Scientific and Administrative CAT: assesses advanced therapies for children (and adults) CAT PDCO Secretariat COMP: designates medicinal products as orphan drugs, for paediatric (and adult) use COMP HMPC: discusses herbal medicinal products for paediatric (and adult) use SAWP: provides scientific advice on medicines being developed for paediatric (and adult) use PDCO: agrees Paediatric Investigation Plans, Waivers, modifications of plans, checks 9 compliance with plans, advises other Committees / EC on paediatric uses
The EMA and its Paediatric Committee (PDCO) EMA: European Medicines Agency Staff: 25-26 (Scientific Administrators and Assistants). Work and (usually) live in London, UK PDCO: Paediatric Committee External experts from all EU 1 expert + 1 alternate from each EU member state 3 representatives (+ alt.) for healthcare professions 3 patient representatives (+ alt.) (parents) Meetings in London every month for 2.5 days Procedures at PDCO: 10 Evaluation team (1 staff, 1 PDCO Rapporteur, 1 PDCO peer-reviewer)
Small increase in total PIP + waiver + modification procedures in the last years These are procedures, not products 11 The EMA's role in paediatric medicines
PIPs, waivers and deferrals 12 Medicines for children - strategic aspects
Paediatric Investigation Plan Basis for development and authorisation of a medicinal product for all paediatric population subsets Includes details of the timing and the measures proposed, to demonstrate: Quality Safety Efficacy To be agreed upon and/or amended by the PDCO Binding on company compliance check (but modifications possible, at the company s request) 13 Marketing Authorisation Criteria
Paediatric Investigation Plan Contained in a PDCO Opinion with key elements Timelines for start and completion of each study Opinions cover a condition (relevant for both adult and paed development), within which one paediatric indication is selected for development. Formulation (quality) 14 Non-clinical studies Toxicology Carcinogenicity Genotox Juvenile animal studies Paed clinical trials PK PK/PD Tolerability, safety Efficacy and safety Extrapolation studies Including modelling and simulation Other measures Registries
When is a PIP necessary? Pharmaceutical companies need to produce data from paediatric studies, done in accordance with an agreed PIP: 15 When applying for a new marketing authorisation; in case of an already authorised and patented product, when applying for a new indication / route / dosage form (but not for new strengths, presentations, etc.) Alternatively, they need a total waiver (for applicable condition[s], in all paediatric subsets), or a deferral. If total waiver: no PIP If deferral[s]: deferral implies a PIP; a deferral is for initiating or completing a study / measure, NOT for agreeing the PIP!
When is a PIP or waiver not required? Off-patent products already authorised in the EU (authorised products that do not have a valid Supplementary Protection Certificate (SPC) or a valid patent that qualifies for it.) New medicinal products that belong to some specific groups (legal basis): Traditional herbal medicinal products Homeopathic products Generic products Hybrid products* Biosimilar products When there is a class-waiver: For a class of products in a condition *a PIP can optionally be agreed for future PUMA application
Waivers: Three types: total (product-specific) waiver for all paediatric subsets (in one or more specific condition[s]) partial waiver: one and more subset(s), indication(s), but there is a PIP! Class waiver: for a class of medicinal products in a condition Legal grounds: Lack of efficacy and safety Disease or condition occurring only in adults population Lack of significant therapeutic benefit
Deferral(s): Instrument to avoid delaying marketing authorisation in adults. Deferred means: Marketing Authorisation Application for adults is possible before completion of one or more studies/measures in the PIP Given by study/measure (cfr. US PREA: total deferral) For initiation and/or completion of study/measure: completion of a clinical trial may be deferred, but initiation may not be! Completion dates established in any case 18
Lag time between planned MAA date and agreed PIP completion date examples of long deferrals Application Number Substance(s) PIP completion Lag (years) date EMEA-000145-PIP01- denosumab Juvenile idiopathic arthritis 31/12/2034 26 07 EMEA-001098-PIP01-10 Lorcaserin Obesity 31/12/2026 15 EMEA-000157-PIP01- belatacept Renal transplantation 31/12/2021 13 07 EMEA-000063-PIP01- Laropiprant / Nicotinic Familial hypercholesterolemia 31/03/2019 12 07 Acid EMEA-001100-PIP01- Anacetrapib Hypercholesterolemia 31/12/2028 12 10 EMEA-000927-PIP01-10 Linaclotide Functional constipation 31/03/2023 12 EMEA-000737-PIP02-11 Afamelanotide Erythropoietic protoporphyria 30/06/2022 11 EMEA-001123-PIP01-11 Odanacatib Osteoporosis 30/09/2023 11 EMEA-000237-PIP01-08 Azilsartan medoxomil Hypertension 31/12/2020 11 19 EMEA-000601-PIP01-09 Pazopanib Rhabodomyosarcoma, Ewing, soft tissue sarcomas 30/09/2021 11
PIP/waiver agreement procedure 20 Medicines for children - strategic aspects
Simplified workflow of the PIP/waiver application Application (pharma company) Validation (EMA staff) Assessment (EMA staff + PDCO members) Opinion (PDCO) 21 Decision (EMA)
When should the PIP be requested? Non-clin Phase 1 Phase 2 Phase 3 Post approval MA Paediatric Investigation Plan (PIP Amendments) Paediatric Committee (PDCO) Compliance check
Overview PIP procedure 1 st discussion PDCO Day 30 2 nd discussion PDCO + OE Day 60 Stop Clock Start ~ 3 Clock months Day 61 Update Sum Report 60 days 60 days Adoption of Opinion Day 1 After Validation, Sum Report EMA Adoption of Opinion, OR List of Issues 3 rd discussion PDCO Day 90 OE OE= oral explanation
How to prepare the perfect application For a PIP or a waiver 24 Medicines for children - strategic aspects
How to use existing resources efficiently to ensure a successful PIP/waiver procedure and paediatric development Scientific Advice PDCO Applicant early! Optimal outcome PDCO Scientific Advice free Come early, come often! 25
1 - What to do first Read the basics do the homework! Paediatric Regulation Revised EC Guideline on Format and Content of PIP applications (September 2014) EMA Procedural Advice (Q&A format): revised version December 2014 Other documents/guidelines: 26 standard PIPs scientific guidelines, policy on the scope of the condition, other Q&As )
EMA decisions on Paediatric Investigation Plans Contains information on paediatric trials agreed between EMA and company (+dosage form and non-clinical studies) From 2014: Summary of PDCO evaluation of the PIP/ waiver application 27
Paediatric clinical trials in EU-CTR All clinical trials and of other trials submitted to National Authorities (protocol-related information) Third countries trials linked to a PIP Results from 2014 Global search in WHO-ICTRP 28
Presentations and conclusions from Expert Meetings / Workshops at EMA Repeat interaction with experts to design better Paediatric Investigation Plans 29
2 - Have clear in mind where you want to go Don t forget that the PIP application needs to be: 1. a stand-alone document. Don t put essential information into appendices! 2. well written, self-explanatory and with a good storyline. Count on spending at least 3 months on the PIP 30drafting process.
3 Decide on the role / amount of extrapolation: complete vs. partial extrapolation anything less than 2 fully powered confirmatory trials is extrapolation? partial extrapolation is highly prevalent, but often unacknowledged. Examples: 31 One-sided vs. two-sided significance tests and/or higher p values allowed in specific situations Bayesian methods One confirmatory study only No confirmatory study (orphan conditions) Registration after failed superiority vs placebo (but superiority vs active comparator demonstrated!) A9
Slide 32 A9 will this be understood by your audience (regulatory folks)? Author, 06/09/2013
European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) Network of research networks EU and extra-eu EMA implementing strategy of the European network Stimulation of quality research in EU Annual workshop, meeting with industry 32
Global development FDA-EMA interactions (and HC, PMDA, TGA ) 33 Medicines for children - strategic aspects
Paediatric Type 2 Diabetes Areas of agreement Age group for study 10 to less than 18 years 10 to less than 18 years Study population Treatment naïve and non-naïve and stratify by background therapy Primary endpoint HbA1c Total study duration 1 year Timing During or after adult Phase 3
Paediatric Type 2 Diabetes partially unresolved: duration of studies Duration of placebo-controlled period and timing for measurement of primary EP EMA guideline 12 weeks if HbA1c >8.5% (but exceptions possible, e.g. for long half-life products) 24 weeks if HbA1c <8.5% FDA 24 weeks provided baseline HbA1c not dangerously high, glycemic monitoring is adequate and strict glycemic rescue criteria are implemented Conclusion: Different time point for primary efficacy assessment and different approaches in modulating hyperglycemic risk
Hypertension: Age Resolution Indication: Essential and secondary HTN PIP already agreed from 6 months -FDA only asked for 1year and above because additional interim data had been received from animal studies which supported conservative approach - No need to ask for changes: just include patients from 1 year of age! 36
Conclusions 37
Coordination of various EMA activities / Scientific Committees has been key to achieve better paediatric plans: Paediatric Committee (PDCO) Scientific Advice Working Party (SAWP) Authorising Committee (CHMP) Pharmacovigilance Committee (PRAC) Committee for Advanced Therapies (CAT)... More good quality research, leading to more information on medicines for children, and more (good) medicines authorised for children 38
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Thank you for your attention Further information http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/gene ral_content_000023.jsp&mid=wc0b01ac05800240cd European Medicines Agency 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact Follow us on @EMA_News
Backup slides 41 Medicines for children - strategic aspects
Weblinks Annual EMA Report to the European Commission, May 2013: http://ec.europa.eu/health/files/paediatrics/2012_report_paed_regulation.pdf Proceedings from Expert groups at EMA: http://tinyurl.com/paedexpgroups EMA decisions on PIPs and waivers: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_sea rch.jsp&mid=wc0b01ac058001d129 EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ EnprEMA: http://www.ema.europa.eu/ema/index.jsp?curl=pages/partners_and_networks/g eneral/general_content_000303.jsp&mid=wc0b01ac05801df74a 42
Paediatric clinical trials are increasing! % of CTs including children (of all studies in EudraCT) Vaccine studies excluded Data from: 43 The EMA's role in paediatric medicines Number of children to be included in CT is increasing
A significant number of PIPs are not completed in time (or at all) 44 Data from EMA annual reports to the EC
Will all Paediatric Investigation Plans be completed? Completion of studies under PREA obligations chemicals (USA / FDA) biologicals completed 22% not completed / delayed 54% completed 46% not completed / delayed 78% 45 Source: AAP as cited in Nature (doi:10.1038/nature.2012.10132)
Will all Paediatric Investigation Plans be completed? Completion of studies under BPCA written request (optional, but 80% suggested by applicant) 46 Source: IOM report on Safe and Effective Medicines for Children: Pediatric Studies Conducted Under BPCA and PREA
Annual Reports on deferred measures Only applies to authorised products (not before MA) 47 The EMA's role in paediatric medicines
Problems reported in Annual Reports 48 The EMA's role in paediatric medicines
Attrition rate (new medicinal products) 49 J Arrowsmith, Nature Drug Dev, 11:17, 2012
Compliance is confirmed at the first attempt in > 96% of cases And all negative compliance check became positive (after modification of the agreed PIP no major violations) Data at 25/09/14 Applicants are compliant, EMA is flexible 50 The EMA's role in paediatric medicines
EMA FDA concordance for waiver requests (products evaluated by both Agencies) FDA asked for a few more PIPs for single AS products FDA asks for more PIPs for FDC 51 The EMA's role in paediatric medicines Egger G and Tomasi P, 2014, unpublished data
Data protection vs. reward 0 orphans 8 10 11 12 years Market exclusivity: all products - vs. generic - vs. similar 0 8 10 11 years Data protection: - vs. generic only Paediatric reward: 0 10 20 years Qualifying patent (20 years) Possible 2 year extension of ME for off-patent orphan drugs which complete a PIP 2 years market protection : - Data available - MAA for generic receivable - MA for generic cannot be granted until expiration of the total 10 years 1 year possible extension of market protection: - new indication in first 8 years + s.b. - OTC switch - WEU: complicated! SPC (variable) Reward (6 m.) Incompatible with extension of ME or MP There has to be a SPC (SPC is prolonged, not patent)