FDA's New Regulatory Guidelines Pave the Way for Precision Immuno-Oncology Companion Diagnostics

In December 2017, the U.S. Food and Drug Administration (FDA)Proposed two initiatives for personalized diagnosis and treatmentThe new draft guidelines outline regulatory requirements for in vitro diagnostic devices in the development and clinical trials of targeted therapies based on molecular subtypes.

In the first draft guidance titled “Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease,” the FDA explores how to stratify patients by molecular subtypes for enrollment in clinical trials of targeted therapies, particularly when one or more molecular subtypes are relatively rare.

Furthermore, the draft outlines criteria for patient selection in clinical trials, summarization of results, assessment and labeling of benefits and risks, and refinement of the target population likely to benefit, thereby further clarifying and standardizing the clinical application of molecular diagnostics.

Many clinically defined diseases are driven by a spectrum of distinct molecular subtypes, some of which involve low-frequency mutations. The pathways in which these molecules reside are responsible for maintaining specific tumor characteristics; inhibiting these pathways can attenuate tumor growth and evolutionary capacity, thereby controlling cancer progression. Among patients with identical clinical presentations, heterogeneity in molecular subtyping may lead to varied responses to a given targeted therapy. Conversely, certain targeted therapies may be effective across multiple patient groups with different molecular subtypes.

In a statement, FDA Commissioner Scott Gottlieb noted, “New drugs are being developed specifically based on their profiles targeting these potential molecular subtypes. The same molecular stratification may underlie drivers across different disease phenotypes. When a drug targeting the same molecular subtype demonstrates efficacy in multiple distinct diseases, we need to establish new mechanisms that allow for the approval of such drugs for multiple indications.”

This inevitably brings to mind May 2017, when the FDA granted accelerated approval to Keytruda (pembrolizumab) for adult and pediatric patients with unresectable or metastatic solid tumors who had experienced disease progression following prior treatment. Pembrolizumab was the first anticancer drug approved by the FDA based on a biomarker rather than the tumor’s anatomical site of origin.

Pembrolizumab has established a substantial body of clinical trial data, which included 90 patients with colorectal cancer and 49 patients with 14 other types of cancer among the 149 participants. Several months later, the FDA issued a new letter, undoubtedly pointing to a new direction for the advancement of targeted drug development.

The second draft guidance, titled “Investigational IVD Devices Used in Clinical Investigations of Therapeutic Products,” is designed to assist sponsors and Institutional Review Boards (IRBs) in conducting risk assessments for investigational in vitro diagnostic (IVD) devices used in clinical investigations of therapeutic products.

For example, in new drug research, clinical trials often use investigational or unapproved IVDs to evaluate biomarkers and stratify populations; such imprecise assays can lead to erroneous stratification. Consequently, when a medical device manufacturer seeks to conduct a clinical evaluation of a device posing significant risk, it must obtain approval from the FDA or multiple Institutional Review Boards via an Investigational Device Exemption (IDE) application, thereby exempting certain regulatory provisions to facilitate the clinical trial of the medical device.

In his statement, Dr. Gottlieb specifically noted that the finalized draft guidance will clarify the regulatory pathway for investigational in vitro diagnostic (IVD) devices used in clinical trials of therapeutic products, but that trial results for novel targeted therapies will not be compromised if the diagnostic tests for specific biomarkers fail to meet regulatory standards. The draft aims to improve the approval efficiency for personalized medicines and diagnostic systems, enabling these initiatives to advance more rapidly in the right direction.

In November 2017, the FDA approved two novel sequencing-based devices: MSK-IMPACT™ and FoundationOne CDx (F1CDx). These two products cover 468 and 324 genes, respectively, enabling rapid and sensitive detection of gene mutations and genetic alterations across multiple genes in patient tumors through a single assay, thereby allowing for the simultaneous detection of multiple cancer biomarkers.

The domestic NGS genetic testing market is also exceptionally active. Yuheng Genetics, a leading enterprise in precision immuno-diagnosis and treatment in China, recently launched an NGS-based analytical product for 620 genes.

“Positioned as the ‘optimal companion for immunotherapy,’ this product is China’s first ctDNA panel designed to evaluate the efficacy of immune checkpoint inhibitors. It covers the most comprehensive set of genes associated with immunotherapy, including those linked to drug resistance, rapid disease progression, and DNA repair systems,” said Jin Ge, CEO of Yuheng Genetics. “Our focus extends beyond the precision of genetic testing; we aim to integrate clinical phenotype data and follow-up data on drug efficacy to facilitate the clinical translation of companion diagnostics for predicting treatment outcomes. We plan to achieve this goal through the ‘Ten-Thousand-Person Immune Ark Initiative,’ which also relies on favorable government policies. We eagerly anticipate the early introduction of new domestic policies.”