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Planning your Paediatric Investigation Plan (PIP) Submission in Europe
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Planning your Paediatric Investigation Plan (PIP) Submission in Europe

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During this presentation, Dr. Susan Bhatti, an experienced regulatory affairs professional, shared best practices and experiences learned from submitting PIPs. This included a brief review of the......

During this presentation, Dr. Susan Bhatti, an experienced regulatory affairs professional, shared best practices and experiences learned from submitting PIPs. This included a brief review of the pediatric regulation requirements, insight for interacting with PDCO, and an overview of the PIP submission including procedures, timelines, structure and compliance.

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  • 1. 2 0 11 P E D I AT R I C C L I N I C A L R E S E A R C H W E B I N A R SERIES Planning your Paediatric Investigation Plan (PIP) Submission in EuropeMarch 16, 2011 Presented by Susan Bhatti, Ph.D.
  • 2. Susan Bhatti, Ph.D.  Director International Regulatory Affairs  Based in Germany  15+ years of regulatory experience  Expertise includes Paediatric Investigation Plans (PIPs) and pediatric strategies for product development2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 3. Paediatric Regulation Requirements3  Submission of an approved PIP is mandatory for: – Marketing authorisation applications for new substances – New indications for patent protected authorised products  Without a PIP, the application for marketing authorisation will not be validated in EU  PIP has to be approved by the EMA Paediatric Committee (PDCO) or a waiver or deferral has to be granted  PIP defines the clinical studies to be conducted in 2011 children PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 4. Paediatric Regulation Requirements4  The PIP is the document upon which the development of a medicinal product for the treatment of a defined condition in the various paediatric age groups is based  Should include details of timing of studies and the measures proposed to show quality, safety and efficacy of the product in children  PIP should cover all subsets of the paediatric population, existing and new indications, different pharmaceutical forms and routes of administration 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 5. Paediatric Committee (PDCO)5  Established in July 2007  Members are appointed for 3 years (renewable)  33 members – 5 CHMP members – One expert from each of the 22 Member States not already represented by a CHMP member – 3 representatives of patients’ associations – 3 health care professional representatives  Nearly all of the current PDCO members are paediatricians 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 6. Timing of PDCO Consultation6 CTA according Paediatric CTA CT to PIP MAA studies defined in A deferral Marketing Phase Preclinical Phase 2 Phase 3 Authorisati Post Approval 1 on 1 PIP Compliance PIP Ammendments or Deferral or Waiver 5 CHMP members Opinio 22 member states Pediatric Committee n 3 patient organisation professionals 3 healthcare professionals 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 7. PIP Structure7 Part A: Administrative and product information ← intelligent pdf file Part B: Overall development of the product  Information on the target disease/condition  information on the product/mode of action  Significant therapeutic benefit/therapeutic needs Scientific Part C: Applications for product specific waivers document (Word + pdf) Part D: Overall strategy for development in children 50 pages < if possible  Existing data in adults and children  Details of proposed studies (ongoing or future)  Proposed timelines Part E: Applications for deferrals Part F: Annexes (References) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 8. Part A Administrative and Product Information8 Electronic Application  Choice of Article 7, 8 or 30  General information  Information about completed, ongoing and proposed studies  Intelligent pdf file containing all data (reusable) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 9. Part B Overall Development9 B.1 Similarities and differences:  Similarities and differences of the condition between populations (to include info on prevalence/incidence in children)  Summary of pharmacology (to include structure, absorption, metabolism, PK, PD, elimination) B.2 Current methods of diagnosis, prevention or treatment in paediatric populations  How does your product differ from existing options available to treat the indication in children? B.3 Significant therapeutic benefit/fulfilment of therapeutic needs  Is there a need for a new product to treat this condition and is your product likely to satisfy this need? 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 10. Part C Product Specific Waivers10  Possible lack of efficacy or lack of safety in children “Likely to be ineffective or unsafe” (NOT lack of data)  Disease or condition does not occur in some or all paediatric age groups  Lack of significant therapeutic benefit Over existing treatments As clinical studies are not feasible (e.g. extreme rarity) Paediatric needs already covered  Proposed clinical studies cannot be expected to be of significant therapeutic benefit to or fulfil a therapeutic need of the paediatric population (for example, because sufficient data are already available as studies have been conducted) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 11. Part D Paediatric Investigation Plan11 D.1 Existing Data/Overall Strategy Proposed for the Paediatric Development  D.1.a: Paediatric Investigation Plan indication  D.1.b: Selected paediatric subset(s)  D.1.c: Information on the existing quality, non-clinical and clinical data, including existing data in adults and completed studies in children D.2 Quality Aspects  D.2.a: Strategy in relation to quality aspects  D.2.b: Outline of each of the planned and/or ongoing studies and steps in the pharmaceutical development 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 12. Part D Paediatric Investigation Plan12 D.3 Non-clinical Aspects  D.3.a: Strategy in relation to non-clinical aspects  D.3.b: Overall Summary Table of non-clinical studies  D.3.c: Synopsis/outline of protocol of each of the planned and/or ongoing non-clinical studies D.4 Clinical Aspects  D.4.a: Strategy in relation to clinical aspects  D.4.b: Overall Summary Table of clinical studies  D.4.c: Synopsis/outline of protocol of each of the planned and/or ongoing clinical studies D.5 Timeline of Measures in the Paediatric Development Plan 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 13. Part E Deferrals13  Article 7 (and 8) requires submission of “the results of all studies performed and details of all information collected in compliance with an agreed paediatric investigation plan”  A deferral only means that the MAA is validated prior to completion of the studies listed in the PIP and so there is no need to submit the results yet  Deferrals can be requested for all paediatric studies or for certain subsets of the paediatric population and always have to be JUSTIFIED  NOTE: There MUST be an agreed PIP; only the agreed measures can be deferred 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 14. Part E Grounds for Deferrals14 PIP Guideline:  Conduct studies in adults prior to initiating studies in the paediatric population  Studies in the paediatric population will take longer to conduct than studies in adults  Additional nonclinical data are considered necessary  Major quality problems prevent development of the relevant formulation(s) If an unmet medical need is identified then PDCO can request shortening of the deferral timeline or deny deferral due to the need for availability of the product in children 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 15. Part F Annexes15  References (published literature)  Investigator’s brochure, protocol synopsis (if available)  Previous opinions and decisions from other authorities (EU Member States, FDA…)  Scientific advice  Product information (for an authorised product) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 16. PIP Submission Timelines for validation16 Day -60 Day -30 Day -90 Rapp/ PR PIP Letter of Day 0 designati Applicatio Intent on n Preparation Validation Start Preparation of EMA Summary Report 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 17. Overview of PIP Procedure17 APPLICATION max 30 days VALIDATION & Summary Report Day 1 Day 30 1st Discussion PDCO Possible teleconference ↓ Day 60 2nd Discussion PDCO List of Issues Update No issues d Clock stop PIP 3 months PDCO Opinion 3rd Discussion PDCO Updated Summary Day 120 Day 90 Report Possible oral Day 61 Explanation 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 18. How is a PIP Assessed?18 EMA staff (Scientific Administrators)  The Paediatric Coordinator of the procedure acts as the interface between companies and PDCO  Perform regulatory checks (validation)  Writes and comments on the draft version of the Summary Report  Participates in the PDCO meeting  Writes PDCO documents (i.e. requests for modification, opinions)  Assists and initiate the preparation of scientific and 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES regulatory procedural advice
  • 19. How is a PIP Assessed?19 PDCO members  Members and Alternates share the work  Designated Rapporteur and Peer Reviewer both review and comment on the Summary Report, (Day 30) then present to PDCO (Day 60)  Other Members comment on it during and after discussion (verbally or in writing)  Achieve consensus or vote if necessary  Experts invited if necessary  Teleconference with applicant may be requested  Oral Explanation meetings possible 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 20. PIP Procedure Key to Success20 Establish a close cooperation with EMA coordinator  Consider that major changes can occur between Day 30 and Day 60 Summary Report  Major issues are difficult to clarify during the procedure – New indications/age groups etc. are required – Requested switch from full waiver to PIP (if a waiver is refused, the PIP procedure has to be started again from the beginning)  Important issues should be clarified prior to Day 61(difficult to solve major issues between Day 61 and 120, even with a face to face meeting) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 21. PIP Procedure Key to Success21 Before Day 61 Teleconference with EMA coordinator, Rapporteur, Peer Reviewer and external experts  Discuss draft response (submitted previously together with questions)  If high risk exists for PIP/Waiver refusal: exclude “critical” conditions (re-submit separately) Day 90 - 120: Meeting/Teleconference Final PDCO position and issues communicated to the applicant  Last chance for clarification in oral explanation  No submission of additional or modified documents possible 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 22. Outcome The PDCO Opinion22 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 23. Compliance Check23 A compliance check is performed to verify that all the measures agreed in a PIP and reflected in the EMA decision have been conducted in accordance with the decision, including the agreed timelines 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 24. PIP Compliance Check Key Points24 Comparison of the key binding elements in the Opinion with:  The full clinical study report(s)  All measures are checked  Can be partial (i.e. in case of a deferral only those measures are checked that should have already been completed before the MAA submission) If non-compliance is found then the MAA will not be validated! Solution: Request a PIP modification in a timely manner 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 25. PIP Compliance Check Key Points25 To avoid delays: compliance check should be initiated by applicant prior to submission (30 or 60 day procedure) once final clinical trial report is available NOTE: Request to modify agreed PIP may be needed prior to compliance check (60 days + 2 months to notify intent)  Keep paediatric trials off the critical path (timely PIP, deferral)  Regular monitoring of compliance to avoid surprises  Detailed advance planning of submission - identify potential delays to allow anticipatory actions  Discuss time-critical steps (and solutions) during pre- submission meeting 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 26. Compliance Check!26 Every word matters! ✓ Definition of condition ✓ Details of waivers ✓ PIP indication ✓ Lists applicable age subsets 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 27. Compliance Check!27 ✓ Specifies formulation ✓ Table of all studies/measures ✓ Overall timelines ✘Not published: Details of individual studies/measures (however, most will be available on EudraCT) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 28. PIP Modifications28 Modifications are always possible if there are difficulties with the PIP implementation i.e. the original plan is either unworkable or is no longer appropriate  Preferably prospective  Multiple modifications possible  60-day procedure - same EMA coordinator/Rapporteur/Peer Reviewer  New waivers/deferrals can also be requested  New opinion/decision supersedes original Changes have to be justified and should not be perceived to gradually erode the original PIP requirements 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 29. PIP Modifications29  Application has similar structure to the original PIP application but it is a Word document  PIP modifications required during product development should be submitted in a TIMELY manner!  Remember – the majority of PIPs will have to be modified at least once! 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 30. Take Home Messages  Paediatric Investigation Plan is a requirement for all new medicinal products (new substances and indications)  It needs careful preparation and it takes nearly a year to obtain a PDCO opinion, which is then binding  A PIP will probably have to be modified at least once prior to the marketing authorisation submission  Keep your paediatric trials off the critical submission path2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 31. Information on PIP Requirements31  EMA Paediatrics website: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/ge neral/general_content_000023.jsp&murl=menus/regulations/regulat ions.jsp&mid=WC0b01ac05800240cd&jsenabled=true  EU Commission Guideline on Format and Content of applications for PIPs/waivers/deferrals: http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2008:2 43:0001:0012:EN:PDF  Scientific guidelines and procedural advice on the EMA website: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/do cument_listing/document_listing_000293.jsp&murl=menus/regulatio ns/regulations.jsp&mid=WC0b01ac0580025b91#section1 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 32. Upcoming Webinars32 Register at www.premier-research.com/webinars ▪ Guidelines for Effective and Appropriate Pediatric Assent and Parental Permission 13 April at 11:00 am EDT Speakers: Angi Robinson and Elizabeth Jay, RN, MA ▪ Pediatric Considerations beyond Assent 11 May at11:00 am EDT Speakers: Krista Armstrong, Ph.D. and Patricia Molloy, M.D. 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
  • 33. Questions? Dr. Susan Bhatti Director International Regulatory Affairs Birkenweg 14 D-64295 Darmstadt Germany Telephone: +49 (6151) 8280-310 susan.bhatti@premier-research.com2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES