breakthrough designation opportunities challenges aaps 2014

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

mailto:[email protected]

“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


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


Mechanism via FDASIA


“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


Applications: Granted/Denied


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Designations Withdrawn after

Granting or Rescinded?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


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



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



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


NDA 205552: IMBRUVICA®


http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000CrossR.pdf

Regulatory History & Development

Milestones: KALYDECO® (IVACAFTOR)


http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/pulmonary- allergydrugsadvisorycommittee/ucm420673.pdf

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


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


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)


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



Critical Clinical Questions Critical Pharmaceutical

Questions

TPP QTPP

Commercial Technical Regulatory

Clinical Program Design & Plans

Questions, Assumptions, Precision;

Sequence & Decisions


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)


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


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


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


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)


Acknowledgment

• Philippe Cini and Felicia Stallings

– The Question Based Development

approach was developed and

implemented in collaboration with Tunnell

Consulting


breakthrough designation opportunities challenges aaps 2014

Leadership & Management