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New FDA ‘Breakthrough’ Designation Aims to Speed Cancer Drug Approvals

Eastman, Peggy

doi: 10.1097/01.COT.0000425688.25867.04


WASHINGTON, DC—New breakthrough drug legislation enacted into law last July gives the Food and Drug Administration an important tool to move promising drugs from bench to bedside for cancer patients. That was the consensus of speakers at a clinical cancer research conference here hosted by Friends of Cancer Research (FOCR) and the Engelberg Center for Health Care Reform at Brookings.

At the meeting, which was supported by the American Society of Clinical Oncology, the American Association for Cancer Research, and Susan G. Komen for the Cure, S. Percy Ivy, MD, Associate Chief in the National Cancer Institute's Investigational Drug Branch, said the designation will be important for “exceptional new drugs that have the potential to change the way a disease is treated.”

Added panelist Wendy Selig, MS, President and CEO of the Melanoma Research Alliance, “I think having this kind of designation can really help patients. Late-stage cancer patients don't have time to wait for a lengthy process.” Asked by OT for comment, AACR CEO Margaret Foti, PhD, said, “We're hopeful. On the one hand, we need to do something. But at the same time we don't want to do harm.”

Keynote speaker Sen. Michael Bennet (D-CO), one of the sponsors of the new law, hailed its passage as a major accomplishment, especially since it was passed “at the height of one of the most dysfunctional Congresses in our history,” and six months before passage few people thought it would make it into law. Bennet said the legislation gives FDA “far more tools when a drug has promise early on.”

The FDA—which is currently writing a guidance document on criteria for the designation—already had three approaches to expedited drug development: accelerated approval; fast-track designation; and priority review. But the new law—which was included in the 2012 re-authorization of the Prescription Drug User Fee Act (PDUFA)—offers some potentially time-saving advantages, said panelist Robert Temple, MD, Deputy Center Director for Clinical Science in the FDA's Center for Drug Evaluation and Research.

“I think it does represent an important change,” he said. And while the concept of faster drug approval is not new, the legislative mandate for the breakthrough drug designation “makes us think collectively in a systematic way about this. We are going to be held accountable—that is a change. Fast-track didn't quite do that.”

Temple noted that as drug development becomes more genetically oriented based on molecular biology, there may be more and more cases where individual cancer patients have dramatic responses early on. So, drug sponsors will likely be increasingly asking, “When can early data make a convincing case that the drug is wonderful?”

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Difference between Breakthrough & Fast-Track Designations

Asked by OT for more clarification on how the breakthrough designation differs from the fast-track designation, Temple said the fast-track approach has an intent to treat a broad range of serious diseases and the “potential to fill an unmet medical need,” which can be based on preclinical data, while the breakthrough category is intended to treat serious or life-threatening diseases and shows early clinical evidence of “substantial improvement over existing therapies.”

For example, a new breakthrough-designated drug under study might target a molecular driver of a specific cancer in humans, analogous to ALK for a subset of lung cancer patients.

Asked when FDA's guidance document on criteria for the new breakthrough designation might be finished, Richard Pazdur, MD, Director of FDA's Office of Hematology and Oncology New Products, Office of New Drugs, said the legislative due date is 2014, but “We intend to be faster than that.”

Regarding the review process, he emphasized that it will be stringently regulated, whether a drug in the breakthrough category is the subject of an Oncologic Drugs Advisory Committee public hearing or not. The ODAC meetings are “lots and lots of work,” and not every promising new drug can be scrutinized publicly in an ODAC meeting,” he said.“We have to be judicious in our use of taxpayer dollars.”

Sandra Horning, MD, Senior Vice President and Global Head of Clinical Development for Hematology/Oncology Product Development at Genentech, said that one of the major benefits of the breakthrough drug designation is that it calls for earlier and more frequent communication between a drug sponsor and the FDA during the drug development process. “Real-time communication” between the drug sponsor and FDA could certainly be a boon to expedited development,” she said. “Expedited development is really equal to interactive communication.”

As part of this process, data for an Investigational New Drug Application (IND) or Biologics License Application (BLA) are submitted as they are accumulated (rather than in one large final package), thus shortening the review time for the drug.

One important issue for industry, several speakers noted, is how manufacturers can gear up to produce enough of a breakthrough-designated drug if and when it is approved by FDA. “You have to scale up the [manufacturing] process chemically; it can be very difficult,” said Janet Woodcook, MD, Director of FDA's Center for Drug Development and Research. She noted that in the past there were poignant situations where groups had lotteries to determine which patients received a new drug developed under expedited review, and no one wants to see that happen again.

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NCI's ‘Exceptional Cases’ Initiative

Speakers also discussed other ways of moving promising cancer drugs to patients faster. NCI Director and keynote speaker Harold Varmus, MD, described NCI's new “exceptional cases” initiative, which is designed to go from phenotype to genotype in investigating unusual anecdotes of marked patient response and rare responders in otherwise unsuccessful cancer clinical trials.

This initiative will screen cancerous tumors to find “actionable mutations” that might lead to improved treatment, he said. “Much of what we do these days fits under the rubric of precision medicine,” and as such, development of new cancer therapies is leading to novel questions for investigators to study, such as why some cancers can be treated successfully and others seem to have “undruggable” molecules.

What is known from The Cancer Genome Atlas (TCGA) at NCI, he noted, is that mutations in cancer tend to aggregate in pathways and networks.

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Improving Accelerated Approval

Also discussed at the meeting was how to improve FDA's accelerated approval process, which grants conditional approval using a surrogate endpoint (such as tumor shrinkage) from a Phase II or interim Phase III trial (subject to confirmatory trials with hard clinical endpoints).

“In oncology I think most of us would agree that accelerated approval has been quite successful,” said Richard L. Schilsky, MD, Chief of Hematology/Oncology in the Department of Medicine and Deputy Director of the University of Chicago Comprehensive Cancer Center. But he noted that accelerated approval has come under increasing scrutiny, with some charging that FDA is too lax when it comes to post-marketing studies and others stating that FDA is too strict with its approval criteria.

“We've been looking at situations where accelerated approval can be used for earlier stage disease,” said Schilsky, soon to be ASCO's Chief Medical Officer. “One problem is that there is a real lack of surrogate endpoints for accelerated approval. We propose to broaden the definition of ‘unmet medical need.’ Unmet medical need occurs in any non-curative setting.”

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Disease-Specific Master Trial Protocol

Finally, panelists discussed improving the clinical trial process to speed new drugs to cancer patients via the design of a disease-specific master trial protocol.

Speakers described a prototype for non-small cell lung cancer: a Phase III master protocol multi-drug registration trial run by a neutral third party. In this trial, the biomarker for each compound tested must have been previously validated analytically. This master trial protocol would build on existing innovative clinical trial designs such as BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) and I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) for breast cancer.

© 2012 Lippincott Williams & Wilkins, Inc.
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