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Breakthrough Designation Opportunities Challenges AAPS 2014


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The 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) includes a provision that allows sponsors to request that their drug be designated as a "Breakthrough Therapy". This designation is primarily based on the early clinical finding of substantial efficacy in s serious medical need indication. A Breakthrough Therapy Designation provides fast track program advantages alongside a frequent FDA guidance on an efficient drug development program. The FDA also makes an organizational commitment to involve experienced reviewers and senior management in such guidance. This presentation provides an overview of Breakthrough Therapy Designation and discusses why CMC aspects can lag-behind clinical development and how this may be addressed.

The time has come to seriously work on leveraging End-of-Phase II for setting regulatory specifications.

Published in: Leadership & Management
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Breakthrough Designation Opportunities Challenges AAPS 2014

  1. 1. Expediting Drug Development via "Breakthrough Therapies" Designation – Challenges and Opportunities Ajaz S. Hussain, Ph.D. Insight Advice & Solutions LLC 11/3/2014 1
  2. 2. “Breakthrough Therapy” Breakthrough Therapy designation differs Early clinical data (substantial improvements in & unmet need) Accelerated review; early on in development A new expedited review program July 2012, The Food and Drug Administration Safety and Innovation Act (FDASIA) Several mechanisms (~ 20 years) to expedite approval Priority review, Accelerated approval and Fast-track status 11/3/2014 2
  3. 3. The program is designed to Leverage early consultation with senior FDA staff and reviewers Reduce uncertainty & risk Integrated multi- disciplinary review Thereby facilitating earlier approval 11/3/2014 3
  4. 4. Mechanism via FDASIA 11/3/2014 4 “FDA considers all relevant evidence and weighs the uncertainty against the severity of the disease to be treated and the lack of available therapy”
  5. 5. Expectation Impact Early launch (unmet need –early access & competitive advantage) Reduction in clinical development time and costs On drugs currently in early development; Application during IND, ideally no later than end-of-Phase 2 11/3/2014 5
  6. 6. Applications: Granted/Denied 11/3/2014 6 2012 2013 2014 1 31 28 1 52 47 CDER BREAKTHROUGH THERAPY APPLICATIONS 2012 2013 2014 0 1 6 0 10 16 CBER BREAKTHROUGH THERAPY APPLICATIONS
  7. 7. Designations Withdrawn after Granting or Rescinded? 2 CDER 0 CBER 11/3/2014 7 As of September 10, 2014
  8. 8. CDER Breakthrough Therapy Approvals BLA 125486 GAZYVA® (OBINUTUZUMAB), GENENTECH, INC, 11/1/2013 NDA 205552 IMBRUVICA® (IBRUTINIB), PHARMACYCLICS, INC, 11/13/2013 NDA 204671 SOVALDI® (SOFOSBUVIR), GILEAD SCIENCE, INC., 12/6/2013 NDA 203188 KALYDECO® (IVACAFTOR), VERTEX PHARMACEUTICALS, 02/22/2014 11/3/2014 8
  9. 9. CDER Breakthrough Therapy Approvals BLA 125326 (S-60) ARZERRA® (OFATUMUMAB), GSK, 04/17/2014 NDA 205755 ZYKADIA® (CERITINIB), NOVARTIS, 04/29/2014 NDA 206545 ZYDELIG® (IDELALISIB ), GILEAD SCIENCE, INC., 07/23/2014 NDA 205552 (S-1) IMBRUVICA® (IBRUTINIB ), PHARMACYCLICS INC, 07/28/2014 11/3/2014 9
  10. 10. CDER Breakthrough Therapy Approvals NDA 22291 (S-12) PROMACTA® (ELTROMBOPAG ), GSK, 08/28/2014 BLA 125514 KEYTRUDA® (PEMBROLIZUMAB), MERCK SHARP & DOHME , 09/04/2014 NDA 205834 HARVONI® (LEDIPASVIR/SOFOSBUVIR)GILEAD SCIENCE, INC., 10/10/2014 NDA 205832 OFEV® (NINTEDANIB ), BOEHRINGER INGELHEIM PHARMACEUTICALS, 10/15/2014 NDA 22535 ESBRIET®(PIRFENIDONE), INTERMUNE INC , 10/15/2014 11/3/2014 10
  11. 11. NDA 205552: IMBRUVICA® 11/3/2014 11
  12. 12. Regulatory History & Development Milestones: KALYDECO® (IVACAFTOR) 11/3/2014 12 allergydrugsadvisorycommittee/ucm420673.pdf
  13. 13. Novel plan I am rooting for their success! Continuous processing enables streamlined development for breakthrough therapies Presented at several conferences e.g., University of Heidelberg in October 2014 11/3/2014 13
  14. 14. Challenges CMC can lag behind clinical development” • Designation (should be) based on a reasonable confidence in ‘Exposure – Response’ data (CMC - Pharm-Tox - Clin. Pharm) Launch readiness planning (with the “end in mind”) • Date? Site (development, commercial,..), Process Validation, PAI,…(facility’s risk classification?) Development plan prioritized based on risk • Controls and Specifications -Continued assurance of the ‘Exposure – Response’ data considering the intended use? • Intended use and minimal practical shelf-life? 12 months of drug product stability data in commercial packaging? • Lifecycle considerations – before and after launch (e.g., process improvements) Leveraging FDASIA • Frequent and effective communication + regulatory flexibility 11/3/2014 14
  15. 15. Global Development More often development is not just for patients in the USA • IDP should incorporate programs for expedited review and approval in other regions such as EU and Japan For example • European scientific advice, experienced assessors, and adopted through CHMP • MHRA’s ‘Innovation Office’ • MHRA has dedicated product life cycle assessment teams (PLATs) 11/3/2014 15
  16. 16. Time crunch… Extraordinary emphasis is needed on ensuring effective cross-functional communication, alignment and synergy This then extends to regulatory communications which will be frequent and critical to leverage FDASIA opportunities Questions, Assumptions, Precision; Sequence & Decisions 11/3/2014 16
  17. 17. 11/3/2014 17 Critical Clinical Questions Critical Pharmaceutical Questions TPP QTPP Commercial Technical Regulatory Clinical Program Design & Plans
  18. 18. Questions, Assumptions, Precision; Sequence & Decisions 11/3/2014 18 Target Product Profile & QTPP Set of questions to inform cross functional team review, deliberations and decisions Functional plans and activities to efficiently deliver materials, information/guidance and evidence to answer questions posed by cross functional team Approved product & package insert
  19. 19. Questions guiding development project management QbR: Clinical Pharmacology & Biopharmaceutics QbR: Generic CMC to CMC (evolving) Practical implementation of QbD Methodology Office of Pharmaceutical Quality - “one voice” Clinical relevance & failure modes; clinical specifications (TPP – QTPP) Linking CMC, Pharm. Tox., Clin. Pharm, & Clinical Controls and Specifications -Continued assurance of the ‘Exposure – Response’ data considering the intended use Specifications @ End of Phase II Intended use and minimal practical shelf- life? 12 months of drug product stability data in commercial packaging? Development –to- Process Qualification, Validation; PAI & facility risk classification Lifecycle considerations – before and after launch (e.g., process improvements) 11/3/2014 19
  20. 20. Critical considerations Before the designation of ‘Breakthrough Therapy’ • Understanding the level of uncertainty • In CMC, Pharm-Tox, Clin Pharm data underpinning the clinical data supporting the application • Note: Early clinical data – is the basis of ‘Breakthrough Therapy’ Designation After receiving the designation of ‘Breakthrough Therapy’ • Effective execution of an Integrated Development Plan • Reduce uncertainty (mitigating risk of clinical failure), • Secure quality and supply of clinical trial materials • Leveraging the FDASIA opportunities 11/3/2014 20 Integrated Development Plan: A new approach to process development and commercial launch. Application during IND, ideally no later than end-of-Phase 2 + Priority Review (~8 month) IDP
  21. 21. Integrated Development Plan • For example; conventional analytics & process vs novel analytics and continuous process Contemporary to Novel • What data provides reasonable assurance that ‘exposure – response’ will not be not compromised? What assumptions are acceptable at what stages of development? …. ‘Integrative thinking’, alignment within, CRO,CMO • Progressively measurable reduction in uncertainty, with every meeting with FDA, securing the launch date with successful PAI Effectively leverage the FDASIA opportunity 11/3/2014 21
  22. 22. Developing a IDP •Leveraging the regulatory intent based on process understanding •Methodology; underpinning Question based Review (QbR) •Specification agreed before pivotal clinical trial PAT & Quality by Design •Cross-disciplinary efforts for identifying a mitigating risk and leveraging opportunities •Linking quality, patients and how product is to be used Integrative thinking •Questions, Assumptions, Precision •Sequence & Decisions •Communication with FDA •Project Management System Question based Development 11/3/2014 22
  23. 23. Summary Breakthrough Therapy designation based on early clinical data CMC can be on the critical path; contemporary and novel process Effective, structured communication (internal and with regulators) is a key success factor Consider structuring cross-functional communication via questions, assumptions and level of precision needed (at various stages) 11/3/2014 23
  24. 24. Acknowledgment • Philippe Cini and Felicia Stallings – The Question Based Development approach was developed and implemented in collaboration with Tunnell Consulting 11/3/2014 24