By: Anita Nelsen, Senior Director and Head, Genomic Medicine Services and Partha Roy, Ph.D., Vice President, Technical, PAREXEL International
Precision medicine, sometimes called personalized medicine, leverages one or more biomarkers, often genetic or genomic in nature, to guide therapy decisions; the biomarkers are indicators of how the drug will be metabolized in the body, who is mostly likely to benefit or who may be at risk of side effects. Many of the precision medicines available today are in oncology where targeted therapies are developed to act on a cancer with specific molecular alterations, or a range of alterations, that cause or contribute to the disease. A diagnostic test(s) is used to stratify patients within a clinically-defined disease according to their molecular characteristics and likelihood of response to treatment.
Rare functional variants occur at a low frequency across the genome and may alter gene function. Modern DNA sequencing technologies, such as Next Generation Sequencing or NGS, have made it cost-effective to rapidly conduct whole exome or whole genome sequencing enabling the detection of these low-frequency variants. The application of these technologies is increasingly being extended into the clinic, making it possible to leverage low frequency genetic variation to inform disease diagnosis and treatment decisions. By nature, these low frequency molecular alterations occur so rarely that it is neither feasible nor practical to enroll sufficient patients into clinical trials to correlate a particular rare molecular alteration with pharmacological efficacy of a targeted therapy.
Under the Precision Medicine Initiative, the FDA seeks to develop a framework to enable the flexible review of innovative new therapies and the molecular tests that help ensure the right treatment for each patient. In December 2017, the FDA published a draft guidance that outlines their recommendations for grouping patients with different molecular alterations into clinical trials and for evaluating the benefit-risk profile of targeted therapies within a clinically defined disease where the molecular profile includes multiple low-frequency alterations. Specifically, the draft guidance document provides detailed recommendations on the types of evidence, including computational, experimental, and clinical, that can demonstrate patients with different molecular alterations are likely to experience similar pharmacological response and are thereby appropriate to group into clinical trials. Additionally, the draft guidance describes considerations for drug labeling and lifecycle strategies further refine the population post initial approval.
PAREXEL’s Consulting and Biomarker and Genomic Medicine teams can provide key advice to companies developing molecularly targeted therapies. Our subject matter expertise helps drug developers to select the right genomic technology for their program, identify the right patient population and navigate the innovative and rapidly evolving regulatory framework for precision medicines.