Separating the Hype from the Hyperbole Surrounding FDORA’s Alternatives to Animal Testing under the FD&C Act

February 3, 2023By Mark A. Tobolowsky & Charles G. Raver

Amongst the many provisions that Congress included in the recent Food and Drug Omnibus Reform Act (“FDORA”) were two subtle changes – one change to the Federal Food, Drug, & Cosmetic Act’s (“FD&C Act”) requirements for advancing an investigational new drug into clinical trials and another change to the Public Health Service Act’s (“PHS Act”) (as amended by the Biologics Price Competition and Innovation Act of 2009) requirements for developing a biosimilar biological product. (For more on FDORA’s other provisions, see HPM’s complete summary here).  Since 1962, the FD&C Act has authorized FDA to require that sponsors of clinical trials submit data from “preclinical tests (including tests on animals)” in order to demonstrate that their drug is safe enough to advance to testing in humans.  FDORA’s change to that key phrase (“preclinical tests…”) has been touted by some as anything but subtle and that it represents a monumental shift in what FDA is empowered to require of sponsors. While this hype may be warranted in some respects—a 60-year old legal provision has now been amended to acknowledge that the science of drug development is advancing—the change is mostly symbolic and is likely to take many years before we see it have a measurable impact.  In effect, the revisions to the FD&C Act and the PHS Act are designed to encourage the use of alternatives to animal testing not eliminate animal testing in drug development.

As noted above, Section 3209 of FDORA amends the statutory language regarding the criteria to obtain an IND.  Previously, the law stated that FDA could condition the opening of an IND upon the submission of reports of “preclinical tests (including tests on animals) . . . adequate to justify the proposed clinical testing.”  21 U.S.C. § 355(i)(1)(A).  FDORA replaces the term “preclinical tests (including tests on animals)” with a newly defined term “nonclinical tests.”  FDORA § 3209(a)(1).  The law defines this term to mean “a test conducted in vitro, in silico, or in chemico, or a nonhuman in vivo test that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug.”  FDORA § 3209(a)(2).  The definition goes on to list potential options for such tests: cell-based assays, organ chips and microphysiological systems, computer modeling, other nonhuman or human biology-based test methods such as bioprinting, as well as animal tests.

As to biosimilars, FDORA amends the statutory language regarding criteria for the demonstration of biosimilarity for a 351(k) biologic.  Previously, the law stated that the demonstration of biosimilarity could be based on data derived from:

(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;

(bb) animal studies (including the assessment of toxicity); and

(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product.

42 U.S.C. § 262(k)(2)(A)(i)(I).

FDORA replaces the language in (bb) regarding animal studies with “an assessment of toxicity (which may rely on, or consist of, a study or studies described in item (aa) or (cc).”  FDORA § 3209(b).

While these changes to the IND and the biosimilarity provisions represent real changes to the words governing FDA’s authority under the FD&C Act, we think it is worth asking just how measurable and immediate an impact they will have on day-to-day decision-making of the FDA and its review staff.   The pre-existing statutory language did not require animal testing. Rather, the provisions did, and still do, leave it up to FDA’s discretion what methods and tests are most appropriate under the circumstances.  In both contexts, FDORA amends the language to more explicitly allow for alternatives to animal testing but does not mandate the acceptance of any of these alternatives.

In our experience, FDA is inherently an empirically driven body of scientists, physicians, and policy-makers. It will likely take time to supplant decades of reliance upon existing animal testing methods used to investigate drug pharmacology and toxicology. Alternative methods will require significant research investment to demonstrate their utility for a particular context of use and inform regulatory decision-making.

However, there are signs that FDA is receptive from a policy perspective to alternative methods.  The 2017 Predictive Toxicology Roadmap laid out some of the FDA’s thinking around the need for new toxicology methods driven in part by a desire to find alternatives to animal testing.  In 2019, FDA formed an agency-wide Alternative Methods Working Group indicating that it viewed the applicable scope of alternative methods to go beyond just toxicology research.  More recently still, FDA requested $5 million in its FY 2023 budget request to support the New Alternatives Method Program to “replace, reduce and refine animal testing (the 3Rs), and improve predictivity of nonclinical testing.”  As FDA notes in its budget request, “FDA cannot develop and implement alternative methods alone, so through this initiative FDA will expand qualification processes, provide clear guidelines to external stakeholders developing alternative methods, and fill information gaps with applied research to advance new policy and guidance development.”

Ultimately, regardless of any changes made by FDORA, it will be up to the science surrounding new alternative methods, and FDA’s acceptance of the evidence base to support them, to demonstrate the suitability of these alternative tests as replacements for animal testing. In our experience, FDA review divisions will engage with sponsors about their plans to implement novel methods in their development programs but have yet to let them replace traditional animal testing in a measurable way. To us, some of the hype regarding the changes FDORA made to the law regarding animal testing may be overselling the law’s impact. Meaningful change in this arena will require the investment of time and resources to achieve the scientific advancement it promises.