breakthrough designation opportunities challenges aaps 2014
DESCRIPTION
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.TRANSCRIPT
Expediting Drug Development via
"Breakthrough Therapies" Designation –
Challenges and Opportunities
Ajaz S. Hussain, Ph.D.
Insight Advice & Solutions LLC
11/3/2014 [email protected] 1
“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
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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
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Mechanism via FDASIA
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“FDA considers all relevant evidence and weighs the uncertainty against the severity
of the disease to be treated and the lack of available therapy”
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
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Applications: Granted/Denied
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2012 2013 2014
1
31 28
1
5247
CDER BREAKTHROUGH THERAPY APPLICATIONS
2012 2013 2014
0 1
6
0
10
16
CBER BREAKTHROUGH THERAPY APPLICATIONS
Designations Withdrawn after
Granting or Rescinded?
2CDER
0CBER
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As of September 10, 2014
CDER Breakthrough Therapy Approvals
BLA 125486GAZYVA® (OBINUTUZUMAB), GENENTECH, INC, 11/1/2013
NDA 205552IMBRUVICA® (IBRUTINIB), PHARMACYCLICS, INC, 11/13/2013
NDA 204671SOVALDI® (SOFOSBUVIR), GILEAD SCIENCE, INC., 12/6/2013
NDA 203188KALYDECO® (IVACAFTOR), VERTEX PHARMACEUTICALS, 02/22/2014
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CDER Breakthrough Therapy Approvals
BLA 125326 (S-60)
ARZERRA® (OFATUMUMAB), GSK, 04/17/2014
NDA 205755 ZYKADIA® (CERITINIB), NOVARTIS, 04/29/2014
NDA 206545ZYDELIG® (IDELALISIB ), GILEAD SCIENCE, INC., 07/23/2014
NDA 205552 (S-1)
IMBRUVICA® (IBRUTINIB ), PHARMACYCLICS INC, 07/28/2014
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CDER Breakthrough Therapy Approvals
NDA 22291 (S-12)
PROMACTA® (ELTROMBOPAG ), GSK, 08/28/2014
BLA 125514KEYTRUDA® (PEMBROLIZUMAB), MERCK SHARP & DOHME , 09/04/2014
NDA 205834HARVONI® (LEDIPASVIR/SOFOSBUVIR)GILEAD SCIENCE, INC., 10/10/2014
NDA 205832OFEV® (NINTEDANIB ), BOEHRINGER INGELHEIM PHARMACEUTICALS, 10/15/2014
NDA 22535ESBRIET®(PIRFENIDONE), INTERMUNE INC , 10/15/2014
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NDA 205552: IMBRUVICA®
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http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000CrossR.pdf
Regulatory History & Development
Milestones: KALYDECO® (IVACAFTOR)
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http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/pulmonary- allergydrugsadvisorycommittee/ucm420673.pdf
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
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ChallengesCMC 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
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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)
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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
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Critical Clinical Questions Critical Pharmaceutical
Questions
TPP QTPP
Commercial Technical Regulatory
Clinical Program Design & Plans
Questions, Assumptions, Precision;
Sequence & Decisions
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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
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)
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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
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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
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
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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
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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)
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Acknowledgment
• Philippe Cini and Felicia Stallings
– The Question Based Development
approach was developed and
implemented in collaboration with Tunnell
Consulting
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