FDA Has Drug Evidence Flexibility: Califf, Staff
FDA already has the regulatory flexibility it needs to make drug decisions based on evidence from a variety of sources, according to former FDA commissioner Robert Califf and four other agency staffers, writing in an online Nature article that was submitted while Califf was still in office. The article says that agency efforts to close the gap between the scientific evidence generated on medical products during clinical trials to support their approval or clearance and the evidence need to inform their optimal use in real-world environments, “have been clouded by widely held views that current regulatory structures cannot accommodate a modern robust and diverse evidence base, and that these regulatory structures are predicated on narrowly targeted premarket evaluations of medical products. We regard both of these views as misperceptions that need to be corrected.”
The authors explain that FDA considers the totality of evidence when evaluating the safety and effectiveness of new drugs. “This phrase reflects the nature of drug development, with each successive piece of evidence building on prior data to provide the quantity and quality of evidence needed to adequately assess risks and benefits,” they say. “Data from a study are always assessed within the context of other available data, never in isolation, and data from different studies are considered based on the reliability of a given study result. Another element of flexibility includes the ability to use an understanding of the therapy, the disease, treatment alternatives, and patient preferences to make discrete decisions about marketing and labeling with full recognition that the evidence bases for the disease and for alternative therapies are always changing.”
The article suggests that recognizing that the evidence needed to support regulatory approval or clearance and the evidence needed to inform treatment decisions are both part of a single continuum creates a powerful direct incentive for manufacturers and/or study sponsors to appropriately evaluate the benefits and risks of a product in real-world conditions and among the groups of patients likely to be treated once the product is marketed.
The authors say they recognize the challenge in achieving the cultural shift to a new direction given the sensitivity to the maintenance of perceived or real standards. They say the current paradigm is heavily weighted towards systems that focus on elements needed for precise answers to narrow questions, and FDA is just beginning to grapple with defining quality in ways that allow it to accurately characterize product performance in real-world settings that include diverse and varied patient populations and practice patterns. “However,” they conclude, “we believe that routinely integrating these separate worlds into a continuum that progressively demonstrates that a therapy can be used safely and efficaciously, but pivots as quickly as possible to producing evidence to accurately inform a clinical use, will yield a comprehensive understanding of how to use medical products in practice — an understanding that can be incorporated into product labeling. This could also facilitate wider market access for products whose benefits are shown to outweigh risks, while simultaneously enabling ineffective or dangerous uses to be identified and avoided.”