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FDA Guidances Elucidate Agency's Regulatory Thinking on Precision Oncology Drug Development

NEW YORK (GenomeWeb) – The US Food and Drug Administration this week released two guidances outlining regulatory frameworks for sponsors developing molecularly-informed oncology therapies.

The agency issued a draft document on the regulatory considerations for incorporating minimal residual disease (MRD) measurements into development programs for blood cancer drugs. In patients with hematologic malignancies, MRD is a metric for gauging how many cancer cells remain in their bone marrow after treatment, which can be indicative of their response to drugs and the extent of their remission. 

After holding workshops with stakeholders and noting inconsistencies in MRD data in marketing applications, the agency decided it needed to weigh in on the use of this biomarker in regulatory submissions, according to FDA Commissioner Scott Gottlieb.

In the draft guidance, the agency states that drugmakers can use patients' MRD status in studies to diagnose disease, as a prognostic factor associated with disease relapse, as a predictive marker associated with treatment response, as a surrogate measure of drug efficacy, or as a way of monitoring disease progression.

Specifically, in order to use MRD as a new surrogate endpoint in investigational new drug, new drug, or biologics applications, sponsors have to either submit evidence to formally qualify the biomarker or meet with the FDA's drug or biologics centers to present data supporting the proposed use of the biomarker. "With either approach, the strength of evidence to support surrogacy depends on 1) the biological plausibility of the relationship, 2) the demonstration in epidemiological studies of the prognostic value of the surrogate endpoint for the clinical outcome, and 3) evidence from clinical trials that treatment effects on the surrogate endpoint correspond to effects on the clinical outcome," the agency said in the guidance.

In the guidance, the agency also outlines considerations for including meta-analysis data to validate MRD as a surrogate endpoint; discusses the importance of including information in submissions about patients who could not be measured for MRD in clinical trials; and provides specific guidelines when applying the marker in the context of different types of leukemias and multiple myeloma.

In the latest guidance, the FDA notes that four types of tests are generally used to measure MRD — multiparametric flow cytometry, NGS, quantitative reverse-transcription PCR of specific gene fusions, and allele-specific oligonucleotide PCR. However, the agency states that it is technology-agnostic as long as the sponsor prespecifies the components of the platform and analytically validates it in the context it's being used.

"Additionally, the sensitivity of the MRD assay should be at least 10-fold below the clinical decision-making threshold," the agency states. "For example, if MRD positive or negative is defined as detection of greater or less than 1x10-5 cells, respectively, then the assay should be optimized and validated to have an analytical sensitivity of at least 1x10-6."

The FDA recently authorized Adaptive Biotechnologies' ClonoSeq next-generation sequencing test for measuring MRD at low levels. Gottlieb highlighted this latest authorization in a statement, adding that the application of MRD as a biomarker has "the potential to expedite product development." 

The FDA also finalized a guidance, entitled "Developing Targeted Therapies in Low-Frequency Molecular Subsets," in which the agency lays out its thinking on the development program for drugs indicated for molecular changes driving different cancers, instead of being indicated for a specific organ site affected by cancer. The agency approved Keytruda (pembrolizumab) last year for such a pan-cancer, tissue-agnostic indication, for patients with any kind of unresectable or advanced solid tumor with high microsatellite instability or deficiencies in mismatch repair. 

The agency issued a draft of this guidance last year. 

Gottlieb noted that innovative clinical trial designs will be needed to advance similar tissue-agnostic, molecularly-defined drug indications, such as master protocol studies that allow the safety and efficacy of multiple drugs to be investigated at once. "Today's guidance documents are part of the FDA's science-based mission to modernize clinical trials and advance the development of safe and effective drugs and biologics for the American public," he said in a statement.