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Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance
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Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance

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This presentation will address issues surrounding the development of a pediatric plan for PREA/PMDSIA compliance including: when to develop a pediatric plan, what age groups should be included, is a …

This presentation will address issues surrounding the development of a pediatric plan for PREA/PMDSIA compliance including: when to develop a pediatric plan, what age groups should be included, is a pediatric formulation necessary, timing of the pediatric studies, what information should be submitted to FDA, and when a waiver or deferral is appropriate.

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  • ExclusivitySection 505(A) of The Modernization Act1 enabled FDA to:Issue Written Requests for pediatric studies prior to approval of a NDA if FDA has determined that information related to the use of the drugs in the pediatric population may produce health benefits. Issue Written Requests to holders of approved applications for pediatric studies if it has determined that information related to the use of the drug in the pediatric population may produce health benefits.
  • Under 21 CFR 314.55(a), each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration must contain adequate pediatric data unless the requirement is DEFERRED (314.55(b)), WAIVED (314.55(c)), PARTIAL WAIVER orEXEMPTED (314.55(d) – Orphans
  • PKStudy EndpointsPharmacodynamicsSafety Vital Signs Incidence of AEs Co-morbidities Rescue regimens Adjunct medications Signs of withdrawal or toleranceS&EObjective of StudiesLoading, initial dosing, maintenance dosingExposure-response Relationships
  • Transcript

    • 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 RSERIES Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance Presented by Charlene Sanders, M.D.,Feb. 16, 2011 F.A.A.P.
    • 2. Charlene Sanders, M.D.  Vice President, Global Regulatory Affairs and Pediatric Strategic Consulting  15+ years of regulatory and medical affairs experience – Regulatory portfolio includes NDA approvals for 15 programs which incorporated pediatric protocol design, pediatric clinical study development, PREA discussions and/or pediatric related safety issues  25+ years of clinical patient care management experience  Trained in pediatrics and completed post-doctoral2011 PEDIATRICspecialty fellowship training in critical care pediatrics CLINICAL RESEARCH WEBINAR SERIES
    • 3. The Challenge: Pediatric Written Requests (WR) “Divide each difficulty into as many parts as is feasible and necessary to resolve it.” - Rene Descartes2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 4. The Idea of Reward: Exclusivity2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 5. Pediatric Exclusivity - 6 months5 Section 505A Modernization FDA can request Act allows the FDA to make 1) A new formulation for 1) Written request prior to target population approval or post- approval 2) FDA can ask for 2) FDA must update The List anything The Rule FDA Authority Pediatric assessments for: Approved drugs Indication Dosage 1) that have substantial use in form kids or 2) meaningful Route Dosage regimen therapeutic benefit that if use Safety Effectiveness in children without adequate Subpopulations Pharma or labeling could pose a risk biologics 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 6. Pediatric Research Equity Act (PREA) Renewed 20076  Authorizes FDA to require pediatric studies or clinical trials of marketed drugs that are not adequately labeled for children after other opportunities to obtain such studies or clinical trials on a voluntary basis have been exhausted  Where exclusivity is not an option, PREA opens the door for Written Requests in post- marketing phases of drugs, biologics, and devices where applicable 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 7. FDA Authority – Now Expansive7 FDA has the authority to require pediatric studies on a product for the approved indications:  IF SUBSTANTIAL USE in the pediatric population OR  MEANINGFUL THERAPEUTIC BENEFIT - AND the absence of adequate labeling could pose significant risk (see 21 CFR 201.23(a)) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 8. PREA Realities: How To Handle A Written Request8 A PREA generated requirement for pediatric studies or clinical trials may be waived if:  Necessary studies or clinical trials in children are impossible  Strong evidence suggesting it will not be effective or safe in children  Does not represent a meaningful therapeutic benefit over existing therapies for children  Not likely to be used in a substantial number of children Some studies or clinical trials may also be deferred 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 9. PREA Realities: Applicability & Feasibility9 Written Requests and the MESSSI Test M eaningful therapy for kids E ffective S mall numbers, subpopulation, substantial use S afety S cientific sense I mpossible 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 10. PREA and FDA Authority: Time and Response10 FDA has authority to:  Set a clock for needed studies to be submitted  Mandate a response from sponsors and set the timing of that response 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 11. Time and Terms11  Deferral: the Pediatric Rule states that FDA may approve an application for use in adults SUBJECT TO THE REQUIREMENT that the applicant submits the required assessments WITHIN A SPECIFIED TIME  Waiver and Exemption: removes the requirement to conduct pediatric studies (and the "clock") with respect to the particular supplement or application  Partial Waiver: a waiver granted only for studies 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 12. Time and Time Bending12  Deferrals have clocks  Waivers and Exemptions are not bound to clocks Each Division makes its own decision as to what products, etc. will be granted waivers/deferrals/exemptions 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 13. A MESSSI Example: Applicability and Feasibility13  FDA requires a sponsor to conduct pediatric studies even if the disease only occurs in certain pediatric subpopulations  FDA requires a sponsor to conduct pediatric studies even if only a small number of children are affected if the information would provide a meaningful therapeutic benefit in pediatric patients  FDA should issue a partial waiver for the age groups in which the disease does not occur  The sponsor tries to conduct a study in the affected population but cannot complete the study, perhaps due to a very small number of patients in which the disease occurs, FDA may issue a waiver 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 14. Carrot on a Stick Reminder14 An inadequate study that meets the terms of a Written Request (FDAMA) may still earn pediatric exclusivity 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 15. Formulations15 Can FDA ask for a new formulation under the pediatric rule and/or in a Written Request that is tied to exclusivity? YES! Under the rule, FDA not only can ask but can require a new formulation if it is needed in a pediatric age group that will use the drug 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 16. Rationale for Pediatric Formulation16  FDA can request a sponsor to conduct studies in all relevant pediatric populations  As such, a sponsor will not be able to satisfy such a Written Request unless it completes studies in all relevant populations  To complete such studies, a sponsor may need to develop a new formulation 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 17. Case Study: ABC Pharma Applying the MESSSI Rule Written Request includes the following:  Pharmacokinetic Studies  Safety and Efficacy (Clinical) Studies  Drug Information  Statistical Information  Labeling  Format  Timeframe for Submission2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 18. Sample Letter18 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 19. Do the Math19 #Amendments to a Written Request = #Negotiations …You do not usually get what you deserve (or expect), you get what you negotiate… “In the spirit of PREA” 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 20. Pediatric Studies Apply the MESSSI Rule20 Pharmacokinetics Studies Efficacy and Safety Studies  Open label, dose escalation  Objective of studies  PK profile for different ages  Numbers of patients and age  Appropriate dosages for groups different age groups  Powered to 80% to detect  Numbers of patients (evenly statistically significant distributed sex/age) difference in primary endpoints  Inclusion/exclusion criteria  Inclusion/exclusion criteria  Study endpoints  Patient study discontinuation  Study endpoints criteria  Data Safety Monitoring Board 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 21. Age Categories21  ≥ 28 weeks to ≤ 1 month  1 month to < 6 months  6 months to < 12 months  12 months to < 24 months  2 years to < 6 years  6 years to ≤ 16 years 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 22. Pediatric Studies Apply the MESSSI Rule22 Drug Information Statistical Information Requirements  Dosage forms  Non-powered trials -  Route(s) of administration descriptive statistics  Regimen  SAP for efficacy trials  Drug-safety concerns  Demographic data  Descriptive analysis of safety data Format Labeling  Full study reports  Draft labeling  Ethnic and racial representation analysis  Study Data Tabulation (SDTM)  Clinical Data Interchange Standards Consortium (CDISC) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 23. Timeframe23 Reports of the above studies must be submitted to the Agency on or before XXX, in order to possibly qualify for pediatric exclusivity extension under Section 505A of the Act. Please keep in mind that Pediatric Exclusivity attaches only to existing patent protection of exclusivity that has not expired at the time you submit your reports of the studies in response to this Written Request.  Response to Written Request within 180 days!!  Don’t agree, then, in the spirit of PREA – Amend!!  Agree – must sign WR and give a start date 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 24. Housekeeping24 Pediatric Protocol submitted for Pediatric to the IND Exclusivity Study Proposed Written Agreement for to the NDA/PMA Pediatric Studies to the approved NDA labeled “Pediatric Completed Pediatric Exclusivity Study Reports Determination Requested” 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 25. Proposed Changes = Negotiations25 If you wish to discuss ANY amendments to this Written Request, submit proposed changes and the reasons for the proposed changes to your NDA XX- XXX. Clearly mark submissions of proposed changes to this request “PROPOSED CHANGES IN WRITTEN REQUEST FOR PEDIATRIC STUDIES” in large font, bolded type at the beginning of the cover letter of the submission. We will notify you in writing if we agree to any changes to this Written Request. Carpe Diem! Or in this case, seize the opportunity!! 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 26. Advice on Device Pediatric Medical Device Safety & Improvement Act 2007 (PMDSIA)2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 27. Advice on Device27 Increased Tracking of Pediatric Device Approvals  # and types, approval times PMAs/HDEs Pediatric Device Contact Point  NIH designates an office to help innovators access existing funding for pediatric device development Pediatric Advisory Committee Review  FDA’s Pediatric Advisory Committee to monitor pediatric devices and make recommendations for improving their availability and safety 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 28. Advice on Device28 Authority to Require Post-market Surveillance  For devices that are expected to have significant use in pediatric populations, allows FDA to require a manufacturer to conduct post-market surveillance for any class II or class III device Post-market Studies as Condition of Approval  For a devices that are expected to have significant use in pediatric populations, allows FDA to require post-market studies as a condition of approval 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 29. Summary: Take Home Message WR has been issued  use the MESSSI test:  Break down components of WR  Submit proposal to amend WR  “In the spirit of PREA”- Negotiate feasibility/applicability  Don’t finalize/sign WR until all points addressed/amended Have a pediatric plan early in development2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 30. References: FDA Amendments Act of 200730 (FDAAA)  FDAAA - Title IV: Pediatric Research Equity Act of 2007 (PREA) and Title V: Best (PDF)  PREA Retrospective Review (PDF)  Internal Review Committee - Memorandum Establishing Pediatric Review Committee (PDF)  Medical, Statistical, and Clinical Pharmacology Reviews of Pediatric Studies Conducted under Section 505A and 505B of the Federal Food, Drug, and Cosmetic Act (the Act), as amended by the FDA Amendments Act of 2007 (FDAAA)  New Pediatric Information in Labeling - Searchable (PDF)  Breakdown of FDAAA Completed Pediatric Studies  Pediatric Study Characteristics - Searchable (PDF) 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 31. Upcoming Webinars31 Register at www.premier-research.com/webinars ▪ Planning your Paediatric Investigation Plan (PIP) Submission in Europe 16 March at 10:00 am ET Speaker: Susan Bhatti, Ph.D. ▪ Guidelines for Effective and Appropriate Pediatric Assent and Parental Permission 13 April at 11:00 am ET Speakers: Angi Robinson and Elizabeth Jay, RN, MA ▪ Pediatric Considerations beyond Assent 11 May at11:00 am ET Speakers: Krista Armstrong, Ph.D. and Patricia Molloy, M.D. 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    • 32. Questions? Charlene Sanders, M.D. Vice President, Global Regulatory Affairs and Pediatric Strategic Consulting Centre Square West 1500 Market Street, Suite 3500 Philadelphia, PA 19102 Telephone: 215.282.5476 charlene.sanders@premier-research.com2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

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