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Clinical Trials: Addressing

Challenges Through Global

Expertise and Best Practices

Andrew Robertson, Ph.D., JD

BIO Latin America

Sept. 11, 2014

Perspectives from the U.S.

• Main Focus:

– What are promising strategies to expedite development and approval of safe, important medicines?

• Agenda

– FDA Expedited Development/Approval Pathways

• Fast Track

• Breakthrough Designation

• Accelerated Approval

• Priority Review

– New Approaches to Clinical Trial Design

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Background

• FDA has a longstanding goal to facilitate and expedite development and review of new drugs to address unmet medical need for serious conditions

• History of FDA Programs Prior to 2012

– 1998 – 21 CFR part 312, subpart E: earlier attention to drugs for serious and life-threatening conditions; recognizing risk/benefit balance may differ

– 1992 – Accelerated Approval: based on surrogate endpoint

– 1992 – Priority Review: faster review for drugs with potential to provide significant improvement in safety and effectiveness

– 1997 – Fast Track: to further expedite development & review

FDA Safety and Innovation Act 2012

• Reinforced FDA’s commitment to expedited development

• Provided additional flexibility and clarity to Accelerated Approval pathway

• Created “Breakthrough Therapy” designation

• Required FDA to issue draft guidances on expedited programs June 2013

FDA Guidance Details 4 Expedited Programs

• Fast track designation

• Breakthrough therapy designation

• Accelerated approval

• Priority review designation

• Key Definitions:

– Serious Condition

• a disease or condition associated with morbidity that has substantial impact on day-to-day functioning […] a matter of clinical judgment.

– Unmet medical Need

• An unmet medical need is a condition whose treatment or diagnosis is not addressed adequately by available therapy.

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Fast Track Designation

• Purpose: to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need..

• Criteria:

– Drug must be intended to treat a serious condition.

– Drug must fulfill an unmet medical need

• Is there an available therapy?

• If so, does the new treatment have the promise to significantly improve outcomes?

– Clinical data not needed to address unmet medical need

• Features:

– Actions to expedite development and review

• Frequent sponsor/Agency interactions

• Rolling review

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Breakthrough Therapy Designation

• Purpose: to expedite the development and review of drugs that are intended to treat a serious condition [and demonstrates] substantial improvement over available therapy on a clinically significant endpoint(s).

• Criteria

– Serious condition

– Preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on one or more clinically significant endpoints

• Features

– Frequent Sponsor/Agency Interactions

– Eligibility for Rolling Review and Priority Review

– Stronger Organizational Commitment and Development Guidance

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Breakthrough Therapy Designations

• Since 2012:

– FDA received 213 BT designation requests

– FDA granted 61 BT designations, denied 161 (~28% success)

– FDA approved 9 drug applications that were BT*

8 * Friends of Cancer Research

Breakthrough Therapy - Testimony

This program has been embraced by FDA and Industry

• "FDA and industry march to the beat of the same drummer during the development and review of Breakthrough products.“

– Sandra Horning (CMO, Genentech)

• "Receiving Breakthrough Designation allowed Imbruvica to be approved a year earlier than was expected.“

– Urte Gayko (VP, Pharmacyclics)

• "Getting drugs to patients who need them is why many people choose to work at the FDA. […] We are driving towards cures.“

– Janet Woodcock (Director of CDER, FDA)

• "Breakthrough has changed the culture at FDA…”

– Ellen Sigal (Chair and Founder, Friends of Cancer Research)

Breakthrough Therapy - Challenges

• Manufacturing / CMC -- can we match pace with the accelerated timeline?

• Eligibility – can we develop clearer criteria for which products would be eligible for Breakthrough?

• Funding – can the FDA maintain the resource commitment associated with Breakthrough Designation?

• Bureaucracy – are current legislative requirements, separate from Breakthrough, becoming bottlenecks?

• Benefit – What is the actual benefit to companies? To patients?

Accelerated Approval Pathway

• Purpose

– FDA can base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.

• Benefit

– Allows for approval of drug based on surrogate endpoints that are reasonably likely to predict clinical benefit

• Criteria

– Serious condition

– Meaningful advantage over available therapies

– Demonstrated effect on either:

• Surrogate endpoint thought to predict clinical benefit

• Intermediate clinical endpoint reasonably likely to predict clinical benefit

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Accelerated Approval

• Sponsor Requirements

– Submission of copies of promotional materials for review prior to use

– Required post-approval trials to verify and describe the anticipated clinical benefit

– Subject to expedited withdrawal

• Challenges

– Ensuring follow-up in relevant patient populations

• Are companies following through?

• Should we think of new populations?

– Choice of surrogate endpoint

• Does it reasonably predict outcomes? Is it overly restrictive?

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Priority Review Designation

• Purpose:

• Dedicate resources to products that would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

• Criteria:

– Demonstrates potential to be a significant improvement in safety or effectiveness and/or

– Proposes a labeling change pursuant to a report on a pediatric study under BPCA

• Features

– Marketing application reviewed in 6 months (compared to 10 months for standard review)

– Includes some special criteria which qualify products; e.g. qualified infectious disease products, priority review vouchers

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Advances in Clinical Trial Design

• FDA has issued multiple guidances looking to new clinical trial design

– Enrichment Strategies

– Adaptive Designs

– Bayesian Statistics for Devices

• Benefits

– Reduce Cost (!)

– Smaller patient enrollments

FDA is receptive of new, statistically valid approaches

Advances in Clinical Trial Design – 2.0

• Collaborative Trials and “Master Protocols” – Lung-MAP (Lung Cancer MP)

– I-SPY, I-SPY 2 (Breast Cancer)

Summary

• The US Congress has legislated several strategies to improve drug development and approval

• The FDA has implemented these strategies to great effect, and industry has adopted them actively

• New approaches to further streamline drug development are emerging, through the FDA, industry partnerships, and other organizations.