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FDA Issues Draft Precision Medicine Trial Guidance

Scott Gottlieb

Scott Gottlieb, FDA Commissioner, in November 2017 (A. Kotok)

15 December 2017. The U.S. Food and Drug Administration issued draft regulatory guidance on clinical trials for new treatments that target genetic mutations rather than disease states. The agency also released a companion document for comment on diagnostic tests that determine a patient’s status for taking part in clinical studies of therapies based on genomic factors.

FDA’s guidance aims to clarify the evidence required by developers to submit for review of therapies that address mutations linked to diseases. This approach to treatments is sometimes called precision medicine, since the therapies address the underlying genomic factors affecting  production of proteins that result in a disease rather than the state of the disease itself. Some disorders may be caused by various genomic alterations, which would limit the potential impact of a single molecular-targeted therapy. On the other hand, a specific mutation may be associated with different diseases, which the document says it addresses as well.

In the document, issued for public comment, FDA proposes that strategies for grouping clinical trial participants be based on evidence supporting the mechanisms of the experimental therapies targeting the genetic alterations. New treatments would need to show how their properties affect individuals with the particular mutations, compared to persons without that alteration. At the same time, clinical studies may group participants with different genomic compositions, if there are reasons to believe people with this collection of properties would respond similarly to the treatments.

The agency says it gives priority to evidence produced in clinical studies, but is open to other types of evidence. Clinical trials remain the gold standard, but FDA would be willing to accept results from preclinical lab models, such as animal tests, as well as computational studies and results from tests of similar drugs. Lab tests for determining the presence of specific mutations, and thus participation in a trial, need to be validated, and if possible test for all possible qualifying mutations, such as with high-throughput genomic sequencing. A second draft document issued today focuses on these lab tests.

Because a new therapy clinically tested for specific mutations may still be applicable to other genetic properties, FDA says it will give applicants leeway in generalizing its evidence based on results of tests other than clinical trials, and consider the totality of evidence in weighing its benefits and risks. The document also outlines a rule-making approach for labeling and description of genetically-targeted therapies, as well as criteria for expanding or narrowing the therapy’s target population.

The second document proposes a regulatory strategy for in vitro diagnostics, lab tests that detect biomarkers or other criteria to determine participation in clinical trials for precision medicine therapies. These diagnostics test for genetic or molecular properties, using specimen samples, such as blood or urine. If the test is already approved by FDA for the purposes covered in the trial, then it’s not considered investigational and the proposed guidance would not apply.

In cases where these in vitro diagnostics are new or used for a purpose other than previously approved, then FDA says the tests are covered by its investigational device exemption rules for medical devices used in clinical trials. Those rules rank medical devices according to risk: significant risk, non-significant risk, or exempt. Devices — diagnostics in this case — are exempt if they are non-invasive, take samples without posing risks to individuals, do not introduce energy into a person, and have results that are confirmed by another test or procedure.

Tests with significant risks are those that require invasive procedures, such as an implant, or have consequences that can affect the health, safety, or welfare of the individual. Examples given in the document include tests where false positives can result in persons receiving drugs that cause unnecessary adverse effects. Invasive procedures to collect samples, such as surgical biopsies, are also included. The guidance says diagnostics that do not pose these health or safety risks, but still do not meet the criteria for exemption, are considered non-significant risk devices and do not need to be cleared in advance by FDA. However, if the clinical study reveals unforeseen significant risks from the tests, FDA may stop the trial and require approval of the diagnostic before the study can resume.

Scott Gottlieb, FDA’s Commissioner, says in an agency statement today that new guidance is needed for these tests, “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.” Gottleib adds, “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.”

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