FDA Definition of Generally Accepted Scientific Knowledge: Will It Reduce Animal Studies?
(Thursday, June 8, 2023)
In its ongoing efforts to show how sponsors of market approval applications can provide alternate data to reduce non-clinical studies, FDA released a guidance describing Generally Accepted Scientific Knowledge (GASK) which can be used in lieu of animal studies. In the process, FDA also highlighted how subjective this assessment can be, and how it would need a change in the FDA review process to be practically useful.
About 8 out of 10 new drugs products approved by the FDA are repurposed, reformulated, or otherwise modified previously approved drugs cleared for market via the 505(b)(2) pathway. The reference products for these “new” products have mostly been used in the US for many years, both per the label and off-label. FDA defines GASK as “medical or scientific information that is generally accepted by experts qualified by scientific training and experience in the relevant field, including FDA experts.” FDA further expands on the definition by stating that GASK is based on widely accepted scientific principles that are typically long-standing. In addition, FDA states that it may be possible to extrapolate GASK beyond the specific instances for which the information is available. FDA clarifies that the above concepts will rarely apply for standalone new drugs, only for 505(b)(2) products.
According to FDA’s own publications and the recent laws passed by the US Congress, animal studies must be minimized based on the principle of three R’s: Reduce, Refine, and Replace. However, in the absence of clear, binding, and independently enforced parameters, the issue of eliminating animal studies listed in other guidance documents comes down to individual FDA reviewer’s opinions. There is significant subjectivity about which aspect of toxicity of a 505(b)(2) drug is relevant to a given indication. There have been cases where sponsors were asked to conduct specialized non-clinical studies by FDA for 505(b)(2) applications despite extensive published peer-reviewed literature supporting the off-label use of a drug for which the new approval is being sought. This new guidance does not mean that it would prevent an FDA reviewer from continuing to ask for such animal studies.
There are many questions to which there are no simple answers. The phrase “Generally Accepted Scientific Knowledge” is itself quite subjective. Is “Generally Accepted” an average of medically accepted anecdotes because that’s what they are in real-world? Can a sponsor present evidence from a professional survey to make the claim “generally acceptable”? If there is a counter argument of the acceptability by a minority would FDA still accept the information? Would FDA overrule its internal reviewers if there is sufficient evidence from independent “experts qualified by scientific training and experience in the relevant field” for issues related to need for additional animal studies? The words “Scientific Knowledge” could also very subjective. In academic circles, peer reviewed publications and textbook references are sufficient to accept a piece of information to be scientific knowledge, but mostly not so for FDA regulators. There are numerous instances, where FDA reviewers pulled a minor publication to raise concerns about an otherwise widely accepted scientific fact, to force sponsors to conduct additional animal and even clinical studies.
Overall, time would tell if this guidance indicates an openness from FDA to consider alternate data or just a document to address political pressure FDA faces to show that it is reducing animal studies. There should be independent accountability of how this guidance led to reducing in animal studies for approval of 505(b)(2) products.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC