FDA’s Publication Highlights How to Use/Not Use Precedent Information
(Thursday, September 23, 2021)
In almost 2 out of 5 cases where the efficacy data submitted in support of a market approval application was borderline (i.e., not clearly conclusive), FDA used its discretion to approve products, citing no clear public reasoning for its decision. Many times, it was done differently than FDA’s own previous decisions about similar applications. The definition of “approvable,” varied based on the reviewers assigned, nature of the disease, and unmet therapeutic need. FDA never cites previous approvals or rejections as precedent for its current decisions based on its dogma that “all products are unique so what applies for one, may not apply to the next, even if unobvious to those outside FDA”. A report on a study funded by FDA stated that “the FDA has no mechanism to find or tradition to cite similar cases when weighing evidence for approvals, resulting in standalone, bespoke decisions.” The publication, although seemingly critical of the FDA, drops some very valuable nuggets of information that all applicants should consider. First and most importantly, such FDA discretion is particularly true for new chemical entities intended to treat life-threatening diseases and unmet therapeutic needs. Products intending to treat life-threatening diseases with few or no good treatment options are the cases where most of FDA’s controversial decisions reside. If a product meets this criteria, the sponsor should focus less on the precedent information (which may or may not exist) but convince FDA on the merits of their own applications in the context of the dire circumstances surrounding the disease. CEOs of companies who could convince FDA that some treatment (a.k.a. “hope to patients”) is better than no treatment have been much more successful than those that kept arguing over a controversial endpoint or less robust efficacy data. Second, it is very critical to eliminate common FDA concerns about the efficacy data. Almost one-fifth of applications that went through multiple review cycles did so because of questions about the efficacy data. The most common concerns for efficacy data are the choice of the end points, the clinical meaningfulness of the observed effect or inconsistent results across multiple studies. All of these should be addressed at the End-of-Phase-2 or not later than the pre-NDA stage, prior to submitting the market approval application. Third, the above two strategies are applicable to the first product intended for life-threatening diseases with an unmet therapeutic need. Subsequent products, after the first approval, may not see the same flexibility in FDA’s decisions. Developers trying to follow the first products that got approved with deficient data should try to justify how their product is still critically needed and hence should be granted FDA’s blessing despite some deficits in the data. Arguing with the FDA to provide the same flexibility merely based on the first decision may not work. FDA’s decisions are not like those of the courts where one decision becomes a precedent for all subsequent ones. FDA’s decisions have rarely been successfully challenged for being arbitrary or unpredictable, and its reviewers get to set the approval requirements for each individual application based on their current perceptions of the need of the treatment, with no apparent consideration to what they did for other applications. It was suggested in the report that FDA should set up a searchable database of precedent-setting decisions and then treat them like established policies just like case law. A database of FDA’s decisions already exists in the approval packages published on FDA’s website. FDA cannot agree to treat previous decisions as binding policies for its future decisions due to the regulatory flexibility it needs to make hard decisions that it deems necessary to protect patients. For now, we must live by the existing rules and policies. You got lemons, make lemonade.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC