Abstract
“Master protocol” phase III national trials that simultaneously test multiple agents were among proposals designed to streamline drug trial and approval processes that were discussed at the fifth annual Conference on Clinical Cancer Research.
Running clinical trials for novel cancer therapies is complicated, expensive, slow, and often inefficient. But “master protocol” phase III national registration trials that simultaneously test multiple agents could streamline clinical research and drug approvals, a panel of oncologists and other cancer experts suggested at the fifth annual Conference on Clinical Cancer Research in Washington, DC, on November 14.
With genetic screening rapidly becoming a routine part of treatment, lung cancer represents a good prototype, the panelists said, for a nationwide, multiarm, multibiomarker, multidrug phase III trial aimed to allow approval from the U.S. Food and Drug Administration (FDA) of new therapeutics along with biomarker-driven companion diagnostic tests.
Before use in the trial, experimental drugs would have shown activity in a patient group that could be identified by a validated biomarker test, the panelists noted. After tumor and biomarker screening at intake, patients in the master protocol trial would be directed to an arm of the trial based on their tumor subtype.
Ideally, enough targeted drugs would be used in the trial to increase the odds that “any given patient coming in the door would be a candidate for one of the treatments,” said panelist Eric Rubin, MD, vice president of clinical research oncology at Merck in Whitehouse Station, NJ. The master protocol approach could allow a single control group to be associated with multiple trial arms, significantly dropping the number of patients required and thereby increasing efficiency.
Compared with traditional studies, this approach also might offer more consistency in screening, reduce screening failure rates, and boost consistency of drug testing, proponents said.
Hosted by the Friends of Cancer Research and the Engelberg Center for Health Care Reform at Brookings Institution in Washington, DC, and supported by the American Association for Cancer Research in Philadelphia, the American Society of Clinical Oncology (ASCO) in Alexandria, VA, and Susan G. Komen for the Cure, in Dallas, TX, the conference also featured discussions of ways to expedite other clinical and regulatory processes.
One expert panel discussed setting standards that would qualify as “breakthroughs” under recent legislation. The breakthrough designation is intended for therapies that have a compelling scientific mode of action and show substantial promise in early studies for diseases with few or no good systemic treatment options.
The real issue in the breakthrough designation is what happens afterwards, commented Janet Woodcock, director of the FDA's Center for Drug Evaluation. The goal, she said, is “making sure the trials are the most parsimonious trials you could do and still get you the information you need in a timely manner.”
During her keynote address, Woodcock said the agency is currently piloting studies to clarify the benefit–risk framework for new drugs from a patient's point of view and raised the following questions: “What are people burdened with from their disease, and how much risk would they tolerate to have those burdens relieved?”
A separate expert panel explored whether standards should be reassessed for what meets the accelerated approval designation, which is intended for drugs that treat serious diseases for which there is an “unmet medical need.” That standard arguably could apply to all cancers, the panelists said.
Although the accelerated approval process has drawn criticism, “in oncology, accelerated approval has largely been quite successful,” said Richard Schilsky, chief of hematology–oncology at the University of Chicago Medical Center and incoming chief medical officer for ASCO. “This pathway has enabled drugs to become available on average about 4.7 years before there was actual verification of clinical benefit in postmarketing studies.”
However, during a question-and-answer period, Richard Pazdur, MD, director of the FDA Office of Hematology and Oncology Products, commented that in some cases the postmarketing studies took 10 or more years to complete, with some of these studies eventually showing that the drug is not as effective as originally thought.
Noting the FDA's May 2012 release of draft guidance for pathologic complete response as a surrogate trial endpoint for accelerated approvals in localized breast cancer, the panelists recommended further work in developing additional surrogate endpoints, such as FDG–PET imaging. They also called for increased use of the accelerated approval process in earlier disease settings, not just in heavily pretreated patients.
The annual Conference on Clinical Cancer Research brings together leaders in cancer drug development from federal agencies, academic research, and industry to discuss ways to improve the development and regulation of cancer therapies.
