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Support & Concerns about FDA's Recent Actions on Diagnostics

DiGiulio, Sarah

doi: 10.1097/01.COT.0000455773.26810.ea


In July the U.S. Food and Drug Administration issued a “final guidance” about companion diagnostics used to detect certain gene-based cancers (OT 9/10/14 issue). The agency also released a statement notifying Congress of its intention to propose a plan for risk-based oversight for laboratory-developed tests that are designed, manufactured, and used within a single laboratory.

While many of the major cancer organizations agreed that the actions are a step in the right direction for personalized medicine, others had concerns. For example, the American Medical Association released a statement attributed to AMA Board Chair Barbara L. McAneny, MD, that the FDA proposal “adds an additional layer of regulatory requirements which may result in patients losing access to timely life-saving diagnostic services and hinder advancements in the practice of medicine.”

Asked to elaborate several weeks later for this article, though, the AMA declined to comment further.

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The National Comprehensive Cancer Network did not release an official statement, but the Vice-Chair of the NCCN Guidelines Panel for Occult Primary, Charles Handorf, MD, PhD, Professor and Chair of Pathology at the University of Tennessee Health Science Center, said in an interview, “Nobody likes to have to adhere to more rules when you're in the business of trying to get something to market quickly, but it's a good thing to have that organization—something that's been lacking until now.”

Molecular medicine opens exciting possibilities for physicians who treat cancers of unknown primary, he said. “Genomic tests can reveal what pathways may be available to be treated in a particular tumor. You're not as worried then about what the primary was. You care about—do you have drugs that can treat the pathway that can affect this particular tumor no matter what its primary was?”

He acknowledged that there is a concern that a new set of regulations will introduce stumbling blocks into the process of getting a new drug or test to market. But development of these tests is speeding up—“and sometimes in a way that is disorganized.”



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The guidance on companion diagnostics is intended to assist sponsors who are planning to develop a drug—either existing or novel—that would require the use of a companion diagnostic, as well as those planning to develop companion diagnostics.

“We hope to encourage interest in the area of personalized medicine and provide greater clarity to companies seeking to develop companion diagnostics with their targeted treatments,” Jeff Shuren, MD, JD, Director of the FDA's Center for Devices and Radiological Health, said during a news briefing. “[The final guidance] provides companies with important information that will help them more efficiently develop therapies that target specific patients.”

The guidance: clarifies when companion diagnostics and corresponding therapeutics should be approved contemporaneously by the FDA; and provides information for industry and FDA staff on possible premarket regulatory pathways and FDA's regulatory enforcement policy. The document is available as a pdf on the FDA site at

Additionally, Shuren explained, although the FDA has historically exercised enforcement discretion over laboratory-developed tests (i.e., generally did not enforce the applicable regulatory requirements since the tests were considered to be lower risk and used on only a limited basis), now that the tests are being used more broadly (sometimes without clinical studies to support their use) and sometimes competing with tests that are FDA-approved, there are instances where using a laboratory-developed test (LDT) may put patients at unnecessary and avoidable risk.

“We have reports of faulty LDTs that have led to misdiagnosis—leading to failure to treat or wrong treatment for patients,” he said.

“Back when we first were implementing the program in 1976, these were relatively simple tests that were being used by the local lab for the local patient population to meet their needs and a lot of times for rare diseases... We're now seeing these tests made available to a nationwide audience.”



FDA oversight of LDTs would provide premarket evaluation of tests and assurance of clinical validity where appropriate, as well as post-market monitoring of serious adverse events, Shuren explained. The framework is risk-based, meaning it would continue to leave some LDTs under enforcement discretion with respect to premarket review and good manufacturing practices requirements.

There are concerns from academic medical labs who say they make tests to address unmet needs because there are no FDA-approved tests, Shuren noted. “We understand the value of and need for these types of tests. We believe our draft oversight framework, which is based on risk to the patient—and not whether tests are made by a sole manufacturer or a single laboratory—provides the flexibility necessary to address the regulatory uncertainty without losing the diagnostic innovation critical to public health.”

Consistent with the requirements of the Food and Drug Administration Safety and Innovation Act of 2012, the FDA notified Congress that the agency intends to issue a draft guidance on the proposed framework for LDTs (that letter is also published online, at, and will publish the draft guidance within 60 days of the notification. A public comment period will follow, as well as a public meeting for stakeholders to provide input, before the guidance is finalized.

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The American Association for Cancer Research issued a policy statement in September in support of the FDA actions regarding regulation of laboratory-developed tests.

In an email interview, AACR's Immediate Past President, Charles L. Sawyers, MD, who co-authored the statement, explained: “Regulatory standards should evolve alongside the latest scientific evidence to inform policy. To ensure patient safety while simultaneously encouraging innovation, we need a single regulatory standard and path to market for diagnostic tests, especially high-risk tests.”

Sawyers, a Howard Hughes Medical Institute Investigator and Chair of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, testified before Congress—representing AACR—to voice support of the FDA actions: “Targeted therapies are already standard of care for many cancer patients. Gene sequencing will soon be a routine part of cancer care, and hundreds of thousands—if not millions—of patients will be impacted by this sophisticated and complicated technology,” he said. “Too much is at stake to compromise on the regulatory standards that govern diagnostic tests, which is why this is an issue of urgent concern for us.”

Asked if he thought the recent framework proposed by the FDA went far enough to regulate LDTs, Sawyers said that AACR looks forward to submitting comments when the formal docket opens and participating in public meetings to answer that question and finalize the guidance.

AACR had also released a statement in August immediately following the FDA's announcement of the steps regarding diagnostic testing, which applauded the guidance on companion diagnostics and the proposal for regulatory oversight of LDTs: “Both are key steps to protecting our nation's health and advancing personalized medicine,” the statement said.

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The American Society of Clinical Oncology did not release a statement on the FDA decision at the time it was announced, but in an interview Chief Medical Officer Richard Schilsky, MD, FACP, FASCO, said the organization is currently reviewing the FDA notice to Congress to determine if the society will submit comments during the public comment period.



He said that considering the extent of advances in precision therapy, oncology treatment is increasingly dependent on having reliable tests—“both to determine which therapy is most appropriate for which patient, and also to some extent to determine which patient is most likely to be able to tolerate [that therapy] without unacceptable side effects.

“Regarding these kinds of high-risk tests, a bad test is just as dangerous as a bad drug,” he added. “We all want innovation for our patients. But we also want to make sure that the products that are in the marketplace that are used by our patients are safe and effective.”

He pointed to trastuzumab, a human epidermal growth factor (HER2)-targeting therapy approved for the treatment of patients with HER2-positive breast cancer, as an example to illustrate the importance of accurate diagnostics: “If the HER2 test is inaccurate, either there's a risk that a woman who has HER2-negative breast cancer gets the drug needlessly and is therefore exposed to the toxicity of that treatment. Or the flip side is that a woman who has HER2-positive breast cancer would not get the drug that could potentially be a life-saving medicine. The test becomes every bit as important as the drug.”



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The stakes are now higher, Christopher W. Hansen, President of the American Cancer Society Cancer Action Network (ACS CAN)—ACS's nonprofit, nonpartisan advocacy affiliate—said in a statement: “While early LDTs were relatively simple, low-risk tests and technological advances have created the need for more complete regulation of such tests that provide information that can lead to a specific course of treatment. ... LDTs are becoming more numerous, more complex, and have the potential to have a bigger impact on health care decisions.”

Mark Fleury, PhD, ACS CAN's Policy Principal, added in an interview that critical to the success of the new framework will be its implementation, especially with regards to FDA's planned oversight exemptions for tests for unmet medical needs.

“There may need to be some adjustment as this framework comes into effect, and FDA should be willing to adjust implementation as needed to ensure it doesn't dampen enthusiasm for diagnostic development or have negative impacts on patients,” he said.

© 2014 by Lippincott Williams & Wilkins, Inc.
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