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FDA Commissioner Announces New Clinical Trial Modernization Steps

Eastman, Peggy

doi: 10.1097/01.COT.0000544334.53216.3f
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The FDA Commissioner Scott Gottlieb, MD, told attendees at a policy summit sponsored by the National Comprehensive Cancer Network (NCCN) that the agency is taking specific, new steps to modernize the clinical trials process.

Speaking during a keynote address at the National Press Club in Washington, D.C., he said FDA's Center for Drug Evaluation and Research will, for the first time, soon publish an online list of the surrogate endpoints that were the primary basis of approval or licensure of a drug or biological for both accelerated and traditional FDA approvals.

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Surrogate Endpoints

While overall survival is considered the gold standard in drug approvals, Gottlieb said the time has come because of advances in understanding tumor biology to approve drugs based on surrogate endpoints in distinct tumor types from trial data, endpoints such as minimal residual disease, progression-free survival, objective response, or complete response.

“Standard of care for a number of cancers now includes FDA products approved using earlier endpoints like progression-free survival, cytogenic response, or pathological complete response,” noted Gottlieb.

“We believe this list will help to address some of the questions that've been raised about how we apply surrogates to make a given regulatory decision,” he continued. “We'll also be taking steps to provide more guidance to drug developers on these novel approaches. This includes how to design trials based on a biomarker as a novel surrogate endpoint.”

Gottlieb said drug sponsors will now be able to request meetings with FDA staff earlier in the drug development process. “Innovators can use these meetings to discuss the use of a biomarker as a surrogate endpoint in clinical contexts where that marker was never used as the primary basis for approval.”

Critics of FDA drug approvals based on surrogate endpoints rather than traditional endpoints are worried that such a strategy may “introduce uncertainty about the final clinical benefit,” said Gottlieb. “[However,] there was a growing recognition that these traditional endpoints were based on a previous era of highly toxic chemotherapies. They were standards designed for an era that no longer exists.... To justify the significant toxicity of these drugs, the ability to extend survival was considered the only appropriate trade-off.” He added, “In some cases, for instance in rare cancers, there are simply not enough patients to power a trial to measure overall survival.”

Gottlieb noted that, in today's new era, “If we were only approving drugs for serious and life-threatening diseases based on an overall survival benefit, and then denying patients the ability to crossover to the experimental arms in confirmatory trials, we would literally be asking patients to die so that we could achieve a lower ‘p’ value.

“If outdated regulations delay or derail the development of innovative, safe, and effective products, patients suffer.”

Asked by Oncology Times if he is concerned about validation of surrogate endpoints used in clinical trials, Gottlieb said some surrogate endpoints have been validated, and some go on to be used in confirmatory studies. He also noted that some surrogate endpoints have been correlated with a survival benefit.

“We're in early days now” of looking at therapeutic benefits differently, said the FDA Commissioner, noting that sometimes preventing disease progression is an important clinical goal. “If you can keep a patient stable with less toxicity, that's a substantial clinical benefit.”

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Technological Innovation

Gottlieb said the FDA is also collaborating with NCI to develop digital biomarkers for measuring cancer pain, quality of life, functional status, and cognitive function “using biometric sensors, computer vision, and voice recognition technologies.

“Digital biomarkers and algorithms can replace highly variable surveys or ‘snapshot’ clinician assessments done during clinical trials,” he noted. “These approaches often don't capture the day-to-day burden of cancer and the treatment-related toxicities.”

In order to take advantage of technological innovation, Gottlieb said the FDA is also “testing new diagnostic imaging artificial intelligence frameworks to support more objective and less-volatile assessments of tumor response to treatment.” For example, he said, it may be possible “to use annotated radiology images to train artificial intelligence algorithms to deliver a more objective, holistic estimate of tumor response by scanning very large numbers of radiology images.... Using these approaches, we could generate a standardized measure of tumor dynamics based on a patient's entire tumor burden.”

Gottlieb said the agency also wants to “make sure that the data tools exist to fully support the kinds of clinical trial approaches that we're embracing.” And that means “building out more capacity to use real-world data, especially in the post-market setting, to continue to evaluate the long-term safety and benefits of new treatments.” He said such data tools could help the FDA develop “virtual control arms” based on standard of care in different tumor types (thus sparing patients in control arms from potential toxicities when the disease history is already well-known), and these tools could also reduce the cost and time to run high-quality oncology trials.

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Affordable Care Act

In other news from the policy summit, NCCN released results from a survey of NCI-designated cancer centers on the topic of their experience with Affordable Care Act (ACA) exchange marketplace insurance coverage plans. The survey was conducted for NCCN from December 2017 through January 2018 by Avalere Health. Of the 29 responding cancer centers across 21 states and Washington, D.C., 25 were only in the exchange network for some, not all, of the ACA plans available in their state. Two more were excluded from all of their state's exchanges.

Basically, the majority of cancer centers surveyed were out of network for some or all of the health exchange carriers in their state. The percentage of centers that were excluded despite attempting to be in the network rose slightly from 2017 to 2018. Some 44 percent of cancer center respondents in 2018 said their main reason for being out of network was the low reimbursement rates. Some 40 percent of respondents also expressed uncertainty about insurers remaining part of health insurance exchanges.

In presenting the survey data, NCCN Director of Policy Alyssa Schatz, MSW, said the results raise concerns about narrow, restrictive networks for consumers. She said the results show that thorough consumer education efforts are needed to make sure “people who purchase health insurance plans on an exchange fully understand any limitations when they sign up.” She noted that, if consumers sign up for a plan with lower health insurance premiums, they need to understand that this could restrict the sites where they are eligible to be treated, or lead to higher out-of-pocket costs in the future.

Agreeing was Kavita Patel, MD, MS, Associate Chief Medical Officer and Medicare Director at Johns Hopkins Medicine, Sibley Hospital in Washington, D.C., and a nonresident Senior Fellow at the Brookings Institution. Patel, who serves on the national Physician-Focused Payment Model Technical Advisory Committee, noted that consumers tend to gravitate toward lower-cost health insurance plans that look attractive to them. But when they are diagnosed with cancer, she said, patients often say, “Wait a minute,” because they may not receive the care they want and expect.

A number of speakers at the policy summit expressed concern that patients with cancer may not be getting top-quality care due to narrow networks. “The mismatches in care are becoming apparent,” said Joseph Alvarnas, MD, Vice President of Government Affairs and Senior Medical Director for Employer Strategy at City of Hope Comprehensive Cancer Center in Duarte, Calif. He said many of the exchange networks have less and less breadth of experience and expertise “to deliver the kind of care patients need. There is an impact to this lack of expertise.”

“If you're diagnosed with cancer, tell me if you want to put up with these narrow networks,” commented Elizabeth Franklin, LGSW, ACSW, Executive Director of the Cancer Policy Institute at the Cancer Support Community, the largest direct provider of social and emotional support services for cancer patients and their families nationwide. She agreed with Schatz that patients need much more education on health plans, noting that many patients do not understand what a deductible is or what a co-pay is.

Health care providers are “very frustrated” by the fragmentation of care generated by narrow networks, said John Cox, DO, MBA, Medical Director of Oncology Services at the University of Texas Southwestern's Parkland Health and Hospital System in Dallas, where he leads that institution's participation in the Oncology Care Model of the Center for Medicare and Medicaid Services. He noted that in some cases patients have to travel all over the county to obtain high-quality care.

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Cancer Policy

The NCCN summit featured Congressional Reps. Mark DeSaulnier (D-CA) and Ted Poe (R-TX), both of whom are cancer survivors, in a session on cancer policy.

“This is a quality-of-life issue; it's a bipartisan issue,” stressed Poe. On some things “we're pretty dysfunctional right now,” said DeSaulnier of Congress. “But on this we're about solving problems. Cancer should be a perfect example of that.” Both agreed that any new health insurance reform efforts should protect people with pre-existing conditions such as cancer.

Poe and DeSaulnier recently introduced the bipartisan Cancer Care Planning and Communications Act, H.R. 5160 (CCPC) in the U.S. House of Representatives, where they are Co-Chairs of the Congressional Cancer Survivors Caucus. The act would encourage the development of a personalized care plan for Medicare beneficiaries diagnosed with cancer.

According to the National Coalition for Cancer Survivorship (NCCS), which strongly supports this act, most cancer patients still do not receive a written plan that fully explains their diagnosis, prognosis, treatments, and expected symptoms, thus putting them at a disadvantage and leaving them without clear direction. “Communication is vital,” said Poe of the act.

The NCCS recently sponsored its annual Cancer Policy and Advocacy Team Symposium and Hill Day on Capitol Hill in Washington. More than 70 survivors, caregivers, and providers spent 2 days in educational sessions about cancer policy and advocating for passage of the CCPC Act with members of Congress. The act gained four Congressional co-sponsors at the event and NCCN expects more to sign on.

Peggy Eastman is a contributing writer.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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