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FDA Releases Draft Guidelines to Clarify Regulatory Framework Supporting Precision Medicine

NEW YORK (GenomeWeb) – The US Food and Drug Administration released two draft guidances on Friday outlining the regulatory requirements for molecularly guided personalized treatments and investigational in vitro diagnostics that identify those molecular changes in patients in clinical trials. 

In the draft guidance, entitled "Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease," the FDA discusses how sponsors can group patients with different molecular alterations in clinical trials, and evaluate the benefits and risks of drugs particularly when the molecular markers driving the disease are rare in the population. 

"The FDA needs to clarify and expand an existing pathway that allows innovators to develop products based on the molecular markers that the drug targets, rather than the more traditional approach to drug development, where new medicines were developed based on the disease phenotype that they targeted," Commissioner Scott Gottlieb said in a statement accompanying the release of this guidance. "In many cases, science is revealing that the driver of disease is really a molecular change in the body."

Based on clinical evidence that the immunotherapy Keytruda (pembrolizumab) was shrinking tumors in a variety of cancers that were hypermutated, the FDA for the first time this year approved this drug for a pan-cancer, tissue-agnostic indication. Specifically, a patient with any kind of unresectable or advanced solid tumor found to have high microsatellite instability or deficiencies in mismatch repair could receive Keytruda. 

In the draft guidance, the agency told sponsors interested in developing these types of drugs to use analytically validated assays to identify the markers of interest in patients and enroll them in clinical trials. In studying Keytruda's pan-cancer indication, researchers drew on data from a number of small studies, as well as a basket trial enrolling patients with various solid tumors. Patients were enrolled in the studies based on their MSI-H and dMMR status based on testing via PCR and immunohistochemistry. 

"The FDA recognizes that the clinical trial assay method may limit who is eligible for clinical trials," the agency said. "Ideally, clinical trial assays should be designed to detect all possible molecular alterations that comprise the group that is expected to respond (e.g., as detected through next-generation sequencing)."

The agency acknowledged in the draft guidance that the molecular markers may be particularly rare in certain disease settings, and as such the FDA may expand or narrow the indication of the drug in the post-market setting based on data from registries or traditional controlled trials. The public has 60 days to comment on this draft document.

The FDA also simultaneously released another draft guidance, entitled "Investigation IVD Used in Clinical Investigations of Therapeutic Products," expressing concern that sponsors and investigational review boards many not appreciate that investigational IVDs used in clinical trials can pose significant risk to patients by affecting important aspects of the treatment they are receiving with in the study. In fact, the FDA is worried that sponsors and IRBs may not even understand that "many IVDs used as a critical part of therapeutic product trials are investigational," and as such require an investigational device exemption (IDE) in order to be used in the study. 

Two years ago, researchers involved in federally funded projects looking at the impact of sequencing healthy and sick newborns were surprised to find out that they needed IDEs before using next-generation sequencing approaches in these studies. 

In the draft guidance, the FDA outlined the concepts sponsors and IRBs should use to evaluate these risks of investigational IVDs in drug trials, and what they should submit as part of an IDE application.

"When final, this draft guidance will clarify the appropriate regulatory pathway for investigational IVDs used in clinical trials for therapeutic products, which is significant so that trial results for a novel targeted therapy are not undermined just because the diagnostic test to determine a specific biomarker did not meet appropriate regulatory criteria," Gottlieb said in a statement. "The aim is to make the process for developing more targeted “drug and diagnostics systems” more efficient and to simplify the proper development of these approaches."

The public has 90 days to comment on this document.