Clinical trial sponsors and the clinical research organizations (CROs) supporting them have more clarity from the U.S. Federal Food & Drug Administration (FDA) on how to better select trial participants and design precision-based clinical trials for targeted therapies.
New direction is contained in two new agency draft guidance documents recently published by the agency. They are:
- Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease Guidance for Industry
- Investigational IVDs Used in Clinical Investigations of Therapeutic Products
The guidance, when finalized, is intended to support safe, accelerated development of precision medicine-based treatments. It comes as the agency works to implement the federal 21st Century Cures Act, a law empowering the FDA to construct a more modern scientific and regulatory framework that can support the swift medical advances researchers are making in gene therapy, regenerative medicine, and precision medicine.
“Across multiple fields of science, we stand at an inflection point in medicine – where new technology is creating foundational opportunities to treat and cure disease in ways that weren’t possible just a short time ago,” FDA Commissioner Scott Gottlieb, M.D., said in December. “By proposing streamlined approaches for our colleagues in the research and development communities, the FDA hopes to enable more efficient access to safe and effective, novel targeted therapies for the patients who need them.”
Taken together the two nonbinding draft guidance documents – which remain open to comment by the scientific research and medical communities before becoming final – outline the FDA’s current thinking on:
- the FDA’s current recommendations on how to group patients with different molecular alterations for eligibility in precision medicine-based clinical trials
- general approaches to evaluating the benefits and risks of targeted therapies within a clinically defined disease where some molecular alterations may occur at low frequencies
- the roles and responsibilities of clinical trial sponsors and institutional review boards (IRBs) in complying with investigational device exemption (IDE) requirements in precision medicine research
- how to properly submit significant risk investigational in vitro diagnostic (IVD) information in an IDE application
Advancement in oncology treatment is at the core of these updates. Before this year, the FDA approved cancer treatments based on where in the body the cancer started — in the kidney, lung, or breast, etc. In May, that all changed when the FDA granted accelerated approval to Merck’s Keytruda (pembrolizumab), the first time the agency approved a tumor-agnostic drug cancer treatment based on a common tumor biomarker instead of by the location in the body where the tumor originated.
The accelerated approval of Keytruda was supported by data researchers drew from several small studies and a “basket trial” with five uncontrolled, single-arm clinical trials that enrolled patients having various solid tumors with MSI-H or dMMR cancers. This relatively new, but increasingly popular precision-medicine trial type, test the effect of one drug on a single mutation in a variety of tumor types, at the same time. Research has shown such trials have the potential to use fewer patients to power valid results at a more modest cost while greatly increasing the number of patients who are eligible to receive certain drugs relative to other trials designs.
The latest FDA draft guidance further shows the agency’s support of such new innovative trial designs and clarifies the rules around their use.
“Certain targeted therapies may be effective in multiple groups of patients who have different underlying molecular alterations,” the FDA’s draft guidance states. In clinical trials, “the FDA will accept grouping patients with different molecular alterations if it is reasonable to expect that the grouped patients will have similar pharmacological responses based on a strong scientific rationale. The rationale for grouping patients can be based on computational (e.g., in silico), experimental (e.g., in vitro or animal experiments), or clinical evidence.”
FDA Commissioner Gottlieb said in an accompanying statement that the agency determined the pace of current medical innovation requires it to clarify development guidelines and routinely allow for the development of new therapies based on the molecular markers that a drug targets, rather than the more traditional approach to drug development, where new medicines were developed based on the disease phenotype that they targeted.
The FDA also issued separate, related guidance on the use of in vitro diagnostic (IVD) devices to detect and measure biomarkers and other individual characteristics of disease. Precision medicine, also known as personalized medicine, relies on the use of vitro diagnostic (IVD), including companion diagnostic (CDx) devices, to detect and measure biomarkers and other individual characteristics of disease or other conditions to help direct patient treatment.
The FDA found that an increasing number of clinical investigations into potential therapies are using investigational IVDs, including CDx, to guide the management of clinical trial participants. Such diagnostics are gaining considerable importance in the effective treatment of patients, especially in oncology, but also other conditions.
“The information generated by the use of investigational IVDs in therapeutic product trials may affect important aspects of treatment for the enrolled subjects and, by doing so, directly influence the types of therapeutic products or therapeutic management strategies the subjects may be exposed to during the study,” the draft guidance document states. “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.”
Dr. Gottlieb said that the agency is now providing “those running clinical trials with a clear framework to reference when determining if an in vitro diagnostic (IVD) device used in a therapeutic product study must undergo its own FDA review, distinct from the drug being studied.” In the past, misunderstandings about IVD/CDx development and use have led to delays and added cost in certain research trials.
The development and use of precision, targeted therapies is expanding rapidly. In years past, critics have argued the FDA’s actions have lagged, its words in supporting the development and approval of such therapies. The FDA is showing this is no longer the case by laying out clearer regulatory direction on clinical trials in this area, and taking other tangible actions, to better guide and support sponsors and CROs in the larger-scale, yet safe, development of precision medicines that hold such great promise for so many.