PharmaTherapeutics Pharmaceutical Sciences

Industry Perspective on Small Molecule

Breakthrough Therapies

FDA / PQRI Conference Sept 16-17, 2014

Susan Berlam

Pfizer Global CMC

Overview

Introduction

What does it mean to CMC?

Challenges

Opportunities

Summary

Introduction

BTD – What is it?

FDASIA Section 902

A breakthrough therapy is a drug:

Intended alone or in combination with one or more

other drugs to treat a serious or life threatening

disease or condition and

Preliminary clinical evidence indicates that the drug

may demonstrate substantial improvement over

existing therapies on one or more clinically significant

endpoints, such as substantial treatment effects

observed early in clinical development.

Introduction – BTD Benefits

Intended to expedite the development and review of drugs for serious and life threatening conditions

Conveys all the fast track program features

More intensive FDA guidance on an efficient drug development program

Engage more senior members of FDA

Eligibility for rolling submission and priority review

BTD– What does it mean to the Sponsor?

To Clinical and

the Business To CMC…

BTD– What does it mean for CMC?

Years of development - shaved off

Critical years where product experience & process understanding is gained

Fundamental expectations don’t change with BTD!

Commercializable dosage form upon approval

Same quality as a fully developed product

Safe

Efficacious

Perform as intended and consistently

Quality manufacturing

Available when needed

BTD – What does it mean to CMC?

We’re filing earlier and going through review faster !

Filing NDA based on Phase 2 data (~2 years ahead of a traditional NDA based on Phase 3 data)

Priority Review (8 month) period (Often shorter)

This presents significant challenges to the development team due to the reduced time

Can be further complicated by expectations for simultaneous submissions in other markets (EU, Japan, Emerging Markets)

BTD – CMC Challenges

BTD – CMC Challenges

Availability of Data

Establishing meaningful and practical specifications

Developing robust manufacturing processes

Launch site: R&D vs Commercial

Pre-Approval Inspection (PAI) readiness

High clinical demands

Product lifecycle planning

Agency Interaction

CMC Challenges

Data and Experience

CMC Challenges – Data & Experience

Experimental studies prioritized based on risk assessments

Process and method optimization prioritized based on risk

“Nice to have” takes a back seat

Dosage Form / Formulation Optimization

Explored ranges may be truncated

Stability data

Will you have 12 months of stability?

Is rolling submission an option?

What is the minimal practical shelf-life?

CMC Challenges – Data & Experience

Data / Experience to establish meaningful and practical specifications

Limited data may mean tighter specs

Opportunity to consider wider specs based on overall risk?

Utilize the flexibility provided in ICH S9 when setting specifications?

Opportunity - Provisional specifications?

CMC Challenges – Data & Experience (cont’d)

Experience to develop robust manufacturing process

Commercial site experience?

Likely end up with narrow process descriptions and higher regulatory commitments

Opportunity - leverage Comparability Protocols

CMC Challenges

Launch and PAI

CMC Challenges – Launch & PAI

Launch readiness

Sponsor and Agency expectation for launch date

Importation concerns, timelines, PLAIR (Pre-Launch Activities Importation Requests)

Concurrent validation? - to allow for the release of each batch on its own merits

Launch site: R&D vs Commercial

Is your R&D site equipped to manage a “Commercial” product?

Are the Quality Systems suitable for commercial launch? Global launch?

PAI readiness

Agency interested in PAI as soon as possible

Sometimes prior to filing?

Site readiness challenged while planning for quick approval and launch

Opportunity – site inspection history?

CMC Challenges

Clinical Demand & Lifecycle

CMC Challenges – Clinical Demand & Lifecycle

Potential for high clinical demands

BTD brings ideas out of the woodwork!

Increase in Compassionate Use and IIR studies

Supply challenges (clinical vs commercial product)

Lifecycle Planning

Likely have list of process improvements that require post-approval

Challenge to manage these while other markets are being filed

Potential for sites to have to manage numerous forms of the same product

Inventory planning nightmare!

CMC Challenges

Agency Interaction

CMC Challenges – Agency Interaction

Meaningful & timely discussions with FDA under accelerated timelines

Agency adherence to procedural timelines prohibits timely discussion

Development decisions can’t wait 60-90+ days

Meaningful FDA feedback requires meaningful Sponsor input

“it’s a review issue” not always helpful

Experience has shown –

Closer to submission, FDA interactions & responsiveness improves, but procedural timelines don’t change

During review, willing to interact more frequently as Information Requests are issued

PDUFA V – Mid-cycle Review Meeting – how does that work with BTD

Prepare, Prepare, Prepare for very short timelines for Information Requests

Opportunity: Direct and real time communication?

Opportunities

Open Communication – Meaningful and timely

Meaningful Feedback

Comparability Protocols

Provisional Specifications

PAI - Site Inspection History

Summary

Patient benefit is clear

CMC challenges are numerous and varied

Opportunities are available

More regulatory collaboration needed to focus on the right risks

Meaningful and timely Agency communication

Breakthrough Therapy

Thank You !