The US Food and Drug Administration (FDA) on Friday published two new draft guidance documents that seek to support the development of treatments that address underlying genetic mutations that often cause or contribute to diseases, and another discussing how to determine if an in vitro diagnostic (IVD) device used in a study must undergo its own FDA review, distinct from a drug study.
"New drugs are being developed based solely on their ability to target these underlying molecular subtypes," FDA Commissioner Scott Gottlieb explained in a statement. "Moreover, this same molecular change may be present as the driving factor of many different disease phenotypes. When drugs successfully target these molecular mistakes to reverse the effects of different diseases, we need a development pathway that allows the new drug to pursue approval in each of these novel settings on the basis of the molecular marker that the drug targets. In the setting of oncology, this is often referred to as tissue agnostic drug development."
Earlier this year, FDA for the first time approved a tissue-agnostic treatment – Merck’s Keytruda (pembrolizumab) – based on a common biomarker rather than the location in the body where the tumor originated. These two draft guidance documents could help more companies take the route that Merck took to approval.
Low Frequency Molecular Subsets
One of the draft guidances offers help for companies developing certain targeted therapies on the basis of targeting a molecular subtype that is common across different phenotypes, rather than solely on an individual disease.
The guidance focuses on the type and quantity of evidence that can demonstrate efficacy across these molecular subsets within a disease, particularly when one or more subsets occur at a low frequency. The 8-page document features FDA’s current recommendations on how to group patients with different genetic mutations for eligibility in clinical trials and approaches to evaluating the benefits and risks of targeted therapies within a clinically defined disease, where some molecular alterations may occur at low frequencies.
"For the purpose of this guidance, low-frequency molecular alterations are those that occur at frequencies low enough that enrolling a sufficient number of patients to conduct a clinical trial limited to the specific molecular alteration of interest is not feasible or practical," FDA says.
The draft offers sections on how to identify patients for inclusion in clinical trials, what kind of findings can be generizable, benefit and risk determination and labeling, and refining the target population after initial approval.
In addition, FDA released a draft guidance intended to aid sponsors and institutional review boards (IRBs) in making determinations about the risks of investigational IVDs used in therapeutic product studies.
The guideline is intended to streamline the decision-making process, FDA says, and provides information on definitions and concepts for assessing investigational IVD risks; the roles and responsibilities of sponsors and IRBs in complying with investigational device exemption (IDE) requirements; and FDA’s recommendations and requirements for submitting significant risk investigational IVD information in an IDE application.
"FDA is concerned that sponsors (including sponsor-investigators) and IRBs may not understand that many IVDs used as a critical part of therapeutic product trials are investigational," the draft says.
Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease Guidance for Industry
Investigational IVDs Used in Clinical Investigations of Therapeutic Products: Draft Guidance for Industry, Food and Drug Administration Staff, Sponsors, and Institutional Review Boards