FDA Companion Diagnostic Road Map Critical Tool, Clarity Sought

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By Jeannie Baumann

Oct. 20 — Industry groups generally hailed the FDA’s proposed road map for developing companion diagnostics but questioned the feasibility of avoiding their use for clinical trial prescreening.

The Food and Drug Administration’s draft guidance, Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product, drew 15 online comments, primarily from drug and device companies or their trade groups. The draft guidance directs industry sponsors through the process of developing a drug or biologic with a companion device so the agency can approve both at the same time. Companion in vitro diagnostics (IVDs) are considered a critical tool to advance the White House priority of precision medicine.

“Personalized medicine is an emerging field that uses diagnostic tools to identify specific biological markers, often genetic, that help determine which medical treatments and procedures will work best for each patient,” Amy M. Miller, executive vice president of the Personalized Medicine Coalition, wrote in her Oct. 14 comment letter. “By combining this information with an individual’s medical records, circumstances, and values, personalized medicine allows doctors and patients to develop targeted treatment and prevention plans.”

The FDA released the draft guidance in July; comments were due Oct. 13 10 LSLR, 7/22/16 . The draft guidance is part of a suite of FDA guidances on companion diagnostics, including one issued in 2014 and two out this summer on next-generation sequencing tests.

More Companion IVDs on Horizon

Lakshman Ramamurthy, global regulatory lead for cancer genomic company Foundation Medicine, said in an Oct. 13 letter that nearly a third of the FDA’s new drug approvals are personalized medicines.

Pharmaceutical Research and Manufacturers of America’s Kristin Dolinski, the group’s director of science and regulatory advocacy, said Oct. 13 in her letter that 29 drugs and biologics have been approved with a companion IVD. Many biopharmaceutical companies are actively developing numerous other products that will require a companion IVD, she added.

“Therefore, it is critical that both biopharmaceutical and diagnostic sponsors have a clear and predictable pathway for the development and regulatory review of such products,” Dilonski said.

Both the American Association for Cancer Research and AstraZeneca praised what they described as a flexible regulatory approach in the draft guidance.“Ultimately, the key to speeding safe and effective therapies to patients will be a flexible regulatory framework,” the AACR’s Oct. 6 letter said.

Every letter asked for greater clarity in specific areas or suggested the FDA include more examples. Khatereh Calleja, senior vice president of technology and regulatory affairs for the diagnostics trade group AdvaMedDx, a division of the the Advanced Medical Technology Association, said it would be particularly helpful to have examples of products intended to be covered by the guidance.

“In that vein, we suggest the scope of the guidance be more clearly outlined as not to create indiscriminate application to other diagnostic tests. This will avoid confusion among sponsors not otherwise meeting the definition under the guidance,” Calleja wrote in AdvaMed’s Oct. 13 letter. “Care should be taken to avoid vague or overly broad provisions or footnotes and ensure that the guidance is not misapplied to other technologies (e.g., clinical decision support software or any diagnostic used to monitor blood concentrations of a certain analyte to gauge how well a therapy is working).”

The Biotechnology Innovation Organization noted future companion devices may be medical mobile applications and wearable technologies rather than IVDs. “BIO believes that it would be beneficial for FDA to provide recommendations on similarities and differences between IVDs and other types of medical devices,” the trade group’s Oct. 13 letter said.

Clinical Trial Prescreening

Almost every letter mentioned the FDA’s resistance to the use of tests developed to inform treatment decisions as a tool to prescreen patients for clinical trials.

Under the section titled Prescreening for Eligibility for Therapeutic Product Clinical Trials, the FDA said “there is often no assurance that these tests (referred to as local tests) are standardized or interchangeable.” The FDA also expressed concerns about potential study bias because the clinical trial population wouldn’t represent the population that would be selected by the IVD companion diagnostic in real-world testing.

“Thus, planning to enroll subjects into a trial based on confirmation of a local test result is strongly discouraged,” the draft guidance said.

Sponsors could educate clinical trial sites on sending forward specimens from all potential enrollees for testing with the trial test, rather than forwarding just those specimens from subjects that are identified based on a prescreening test, as one way of mitigating sample bias, the FDA document said.

“By testing all samples from the intent-to-diagnose (ITD) population, the IVD sponsor can determine the true performance of the IVD, as well as assure that the therapeutic product clinical trial is not compromised by a trial population that is skewed toward a non-representative population,” the draft guidance said.

Hard to Avoid

But a number of comment letters questioned how realistic it was to avoid prescreening.

Janet Jenkins-Showalter, head of U.S. regulatory policy for Genentech, a member of the Roche Group, recommended the FDA indicate a reasonable number of the ITD samples are tested instead of requiring testing for all ITD samples.

“We understand and agree with the Agency’s concerns regarding biasing the ITD population based on prescreening,” Jenkins-Showalter wrote in her Oct. 13 letter. “However, as a practical matter, given that these studies are performed primarily to match patients to a specific treatment, it may not be possible to always test all samples from the ITD population.”

Brian Abbott, senior regional director of global regulatory affairs, patient safety and quality assurance for AstraZeneca, asked what approaches the FDA recommends to address potential selection bias adequately when prescreening with a local test is unavoidable.

“We understand that the Agency is strongly discouraging [enrollment] of subjects into a trial based on confirmation of a local test result,” Abbott said.

PhRMA Concerns

Dolinski of PhRMA said it’s unlikely investigators will send samples from all tested subjects if an approved companion diagnostic is already commercially available for a similar therapeutic product. With the use of next-generation sequencing, the drug industry trade group said, investigators will increasingly have test results before the start of the trial.

“PhRMA is concerned with the FDA’s overall recommendation to avoid prescreening and believes that sponsors should be allowed to enroll subjects into a trial based on confirmation of a local test result on a case-by-case basis, where there is reasonable assurance that the local test is reliable,” Dolinski wrote.

Charles E. Hill, president of the Association for Molecular Pathology, took issue with the FDA’s position that there is no assessment of local tests. Hill said, the Clinical Laboratory Improvement Amendments program at the Centers for Medicare & Medicaid Services, state level requirements and third-party reviewers are “readily verifying” the local tests are “both accurate and precise.” “[S]tandards developed through collaborative efforts between professional organizations and various government entities, which could include FDA, would provide laboratories with the ability to ensure that agreed upon thresholds for analytical validity were met without the need for burdensome and costly FDA premarket review,” Hill wrote in his Oct. 13 letter.

To contact the reporter on this story: Jeannie Baumann in Washington at jbaumann@bna.com

To contact the editor responsible for this story: Randy Kubetin at rkubetin@bna.com

For More Information

The draft guidance is available at http://src.bna.com/jwn.

The Regulations.gov docket with the comment letters is available at http://bit.ly/2eGYYcJ.

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