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FDA GASK Guidance: Regulatory reset or familiar echo?
A conversation between Lauren Black and Pramila Singh
A recent FDA GASK guidance has sparked discussions about its potential to reshape drug development. In this post, we delve into Generally Accepted Scientific Knowledge (GASK) in Applications for Drug and Biological Products: Nonclinical Information (May, 2023) and its potential impact on drug development. The FDA GASK guidance refers to the general knowledge we can tap from the literature and other public sources about existing, highly similar products and relevant information on biological activity and safety. Here, we look in on a conversation between Lauren Black, PhD, a former FDA drug reviewer, and Pramila Singh, PhD, DABT, a former EPA scientist, both part of Charles River’s Scientific Advisory Services. Together, they discuss the implications of the new FDA GASK guidance and consider the opportunities it opens up in drug development including taking the responsibility to reduce animal studies, when possible, by supporting more refined studies and study waivers, utilizing more in vitro systems for safety assessment, and changing how we construct regulatory submission packages.
Unpacking the GASK guidance: Does it represent a shift in the regulatory landscape?
The FDA GASK guidance is defined as "medical or scientific information that is generally accepted by experts qualified by scientific training and experience in the relevant field, including FDA experts." The guidance invites drug sponsors to consider submitting GASK to the FDA (CBER or CDER), instead of or in addition to conducting animal studies. Doing this would help avoid conducting redundant research on animals. Some examples where GASK can be helpful are with new drugs to old targets whose pathways are well understood; drugs whose actions are an incremental improvement on past drugs (like an old cancer drug attached to a targeting agent); or drugs that simulate endogenous molecules like hormones or enzymes. Reliance on GASK could replace some toxicity studies, for example, when reproductive toxicity or carcinogenicity risk can be addressed using a weight of evidence analysis of existing data, especially where the pathway has known liabilities, like with retinoid drugs and teratogenicity.
Expert Perspectives on GASK's Implications
Pramila suggested that while the FDA’s GASK guidance may be new, the EPA has historically accepted this approach for chemical and agrochemical products. She noted that the FDA’s GASK guidance together with the recent FDA Modernization Act 2.0, signed into law a year ago, opens the door for FDA to accept alternatives to animal testing including in vitro cell-based assays, 3D and organ-on-a-chip models, in addition to artificial intelligence (AI) and machine learning (ML) approaches.
Lauren sees the FDA’s GASK guidance as not truly “new”, but rather a modern acknowledgment that it can add translational insight. She also doubts that it is a coincidence that this guidance is coming out right after a move by Congress that clarifies that safety testing is not just about animal studies. Lauren points out, “The FDA has had regulations that allow study waivers for about 40 years1, so it bears some discussion why it’s taken so long for FDA to encourage this approach.” She emphasized the need for proactivity on both the CRO and the sponsor sides and highlighted that use of GASK could be vetted with the FDA before animal programs are designed for human trials. She often finds sponsors overlook this option to avoid excess studies but shouldn’t, especially when many prior products with similar quality attributes have accumulated a track record in animal and human evaluations.
Dialogue on FDA Versus EPA Approaches
Pramila and Lauren have seen differing approaches at the FDA and EPA regarding the use of GASK and alternative testing methods.
Lauren asked, “It’s a tall order to dismantle the ICH-driven infrastructure (13 safety guidelines with long lists of animal studies needed) for drugs. Why do you think it’s easier for EPA to use GASK?”
Pramila pointed out that EPA, driven by its mandate to safeguard the public and the environment from the tens of thousands of different chemicals, accepts “GASK” as a routine component of study waiver requests by chemical registrants. She also highlighted EPA's New Approach Methods (NAMS) initiative, aimed at developing and promoting alternative testing strategies as well as its own commitment to phase out mammalian toxicity studies by 2035.
Lauren acknowledged the FDA has been slow to encourage use of GASK guidance, primarily due to fact that drugs are designed to acutely alter the human body and they have far narrower safety margins compared to chemicals regulated by the EPA. This leaves a lot less room for uncertainties in risk assessments. She noted that the FDA is actively working to validate NAMs for drugs, but acknowledged the continued need for animal studies to ensure drug safety in humans.
Both agreed that it’s challenging to balance the need for protecting human health with the ethical concerns surrounding animal testing, but factoring in the use of GASK and alternative testing methods can reduce unnecessary animal testing while maintaining the high standards of safety testing.
A Glimpse of GASK's Potential: A Real-World Example
Lauren recounted from her experience at FDA, highlighting how reviewers have been employing GASK in the past (on a case-by-case basis) to assess risk without animals. As usual with “shortcuts”, the devil was in the details: a monoclonal antibody for a serious disease bound specifically to a receptor on patient cells, and activation of the receptor could be assessed directly using in vitro cellular proliferation. Further, the drug is only bound to a well-understood target on human cells, so animals could not be relied on for risk prediction. Since approving the IND required prediction of a safe doses for patients, she located published human trials with highly similar drugs and could see the close correlation between the in vitro responses and the patient responses with the older monoclonal. Additionally, there were minimal differences between the two drugs. In essence, she leveraged GASK (the literature on past clinical trials and the well understood target) to predict safe doses, along with in current vitro data of the two molecules side-by-side to confirm safe dose estimation. We see evidence that these types of decisions are being made today, on a case-by-case basis, especially when animals lack response to the highly targeted drug or overreact to the foreign nature of a biologic product. This type of multi-dimensional argument, based on multiple literature citations with drug analogs (agents with the same pharmacology makes it more likely that new products can be “platformed” off prior drug data.
Pramila added that there are ever more tools to help select better drugs, predict safety, and reduce reliance on animals. Data analytics and predictive modeling are reshaping nonclinical development, leveraging vast datasets from in vitro and in silico experiments to identify promising drug candidates based on high activity and reduced toxic risk. Predictive models using AI and ML can be designed to flag potential hazards in early development, guide targeted in vitro experiments, streamline later drug experiments, and save costly resources. Still, care must be taken when setting up these models because they will only function as well as the quality of their training data. However, when used responsibly and transparently, these tools could complement GASK and modernize drug development.
The Future of GASK: A Path of Humane and Efficient Drug Development
The routine use of GASK in testing of new drugs is still in its early stages, but it holds immense promise for revolutionizing drug development. As sponsors become more familiar with utilizing GASK starting at the pre-IND/scientific advice stage and as FDA reads good arguments and adapts to these approaches, we might see more FDA proactivity over time. The effective use of GASK will ultimately rely on the scientific and regulatory judgment of the developer. This places responsibility on the sponsor to research how their therapeutic product fits in with historical data, identify the critical knowledge gaps, and propose lean experiments to address them. Modern, alternative testing approaches are poised to significantly contribute to a new drug product’s safe and effective clinical use.
The FDA's GASK guidance is a positive step in addressing the ethical concerns surrounding animal testing and streamlining drug development. While challenges remain in its widespread implementation, more reliance on GASK will mark a promising shift toward even more humane, modern, and efficient approaches in drug development.
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Reference: 150 FR7493, Feb 22, 1985 and 52 FR 8831, Mar 19, 1987: 21 CFR, Chpt 1, Subpart D, Parts 314.90 and 312.10
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