FDA Hears Proposals on Codevelopment of Companion Diagnostics for Breakthrough Therapies


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A companion diagnostic developed for use with a drug that has received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) should automatically be eligible for priority review, according to an expert panel that presented this proposal and four others to the FDA in early September (see related link).

With members representing cancer centers, industry, and the National Cancer Institute, the panel presented a report suggesting ways to modify FDA’s standard review procedures specifically for in vitro diagnostics associated with Breakthrough Therapies, the FDA’s newest pathway for expedited approval.

Burgeoning Field

The five proposals and FDA’s consideration of them are among the latest developments in the burgeoning field of companion diagnostics, the tests designed to show whether a patient can benefit from a specific targeted therapy. Companion diagnostics have come to the fore, especially in oncology, with the increasing number of molecular targeted therapies. In the 12 months following Congressional approval of the Breakthrough Therapy designation in July 2012, the FDA received 82 applications for the designation, most of them for targeted drugs.

A major issue in the field is now codevelopment of a drug and its companion diagnostic to ensure that they can be evaluated and cleared for use in the clinic at the same time.

Codevelopment is “probably the biggest development in the in vitro diagnostics world in the past few years,” said FDA’s Elizabeth Mansfield, PhD, Director of the Personalized Medicine Staff at the Center for Devices and Radiological Health. Responding to the five proposals at a public forum in September, convened by Friends of Cancer Research, she said “we know the questions. We don’t have all the answers.”

Key Recommendation

First and foremost, the panel recommended that a companion diagnostic be closely linked to its associated Breakthrough Therapy, making it automatically eligible for priority review and, importantly, receiving the same intensive guidance from FDA’s senior management.

Dr. Mansfield said that she believed this administrative section of the proposal would be “relatively easy to do.” The Breakthrough Therapy designation was not accompanied by recommendations on the diagnostic side, she said, “but we do have processes” related to codevelopment. She added that a draft guidance on codevelopment—for companion diagnostics associated with any targeted drug, not only those with the breakthrough designation—will be published soon.

Mike Pacanowski, PharmD, FDA’s Associate Director for Genomics and Targeted Therapy, Office of Clinical Pharmacology, noted that timing is key to successful codevelopment. The biggest issue, he said, is early development of biomarkers by sponsors so that they can be reviewed along with the Breakthrough Therapy. “When developed later, it takes more planning to accommodate them,” he said.

Analysis and Production Issues

The panel’s third and fourth proposals outlined modifications to the usual FDA requirements for analytic studies and for quality systems and manufacturing processes and software.

On the analytic side, for instance, one current requirement is that full specificity studies be included in the premarket approval. The recommendation is that FDA consider limiting the number of substances to be tested for cross-reactivity, endogenous interferences, effect of pharmaceuticals, or a human anti-mouse antibody (HAMA) effect (for immunoassays only).

Consideration would be based on risk, on a case-by-case basis. The sponsor would present data to justify modifications during presubmission discussions, supplying the agency with a study plan for the specificity studies, any reduced requirements, and any mitigations.

On the production side, one proposed modification would allow an abbreviated description of a manufacturing system in place of a full description, based on whether the sponsor had an approved or pending premarket approval that contained the same or highly similar information.

Similarly, instead of a full description of quality systems, the FDA could consider an abbreviated description if the sponsor had an approved or pending premarket approval that contained essentially the same information, according to another proposed modification.

In general, Dr. Mansfield said, these risk-based modifications are reasonable. “Choosing what data can wait makes sense,” she said.

However, she added that it may be difficult to implement the proposals related to quality systems—procedures to ensure that the process of manufacturing a diagnostic test, when repeated, results in the same response. “The biggest challenge is not from the analysis and review sides but from quality systems,” she said. “That’s the biggest hurdle.”

Investigational Device Exception

The fifth proposal would allow additional laboratories, not part of the clinical trial, to conduct testing immediately upon approval of the companion diagnostic, rather than waiting several weeks for verification and approval as under current regulations. This would be done through a Continued Access investigational device exception supplement.

Currently a diagnostic can be shipped at any time to other laboratories, but cannot be used except for validation purposes until FDA approval is received.

Dr. Mansfield said the agency has been considering an investigational device exception supplement. “We have struggled with this,” she said, “but it is not solidified yet; we’re hoping to be able to do it.”

Asked whether any of the five proposals might need legislation to implement, both FDA officials said probably not. “I think there’s a lot we can do with our current authority,” said Dr. Mansfield. “We’re looking at whether we could take it further with legislation.” ■

Disclosure: Dr. Mansfield reported no potential conflicts of interest.


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At a forum convened by Friends of Cancer Research in September 2013, a panel of experts presented five proposals outlining how sponsors and FDA may be able to improve and expedite the process for the codevelopment and review of a companion diagnostic designed for use with a drug that has received...


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