What Does the Future Hold for the Animal Rule? Examining FDAs Final Guidance

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The author reviews FDA's final Animal Rule guidance.

Thirteen years after FDA issued regulations that have become known as the “Animal Rule,” the agency issued final guidance in October 2015 aimed at clarifying its expectations for sponsors seeking approval of drugs or biologic products based on efficacy data solely from animal studies.   The issuance of this guidance provides an opportunity to revisit the purposes of this infrequently used regulation and to assess the extent to which it has achieved Congress’ goal of fostering the development of medical countermeasures to bioterrorism.

The Animal Rule was first proposed by FDA in 1999, in the wake of controversial decisions by the agency to authorize the use of certain countermeasures by the Department of Defense (DOD) to protect troops against chemical and biological agents, including anthrax, that were believed to be part of Saddam Hussein’s arsenal. Although FDA’s decision was ultimately upheld by a federal appeals court (1), the agency faced criticism in some quarters for allowing DOD to administer agents to troops that had not been approved for such use.

The Animal Rule was intended to reduce barriers to the approval of preventive and therapeutic treatments for chemical, biological, radiological, and nuclear (CBRN) substances. FDA finalized the Animal Rule on May 31, 2002, after being expressly directed to do so by Congress pursuant to the Public Health Security and Bioterrorism Preparedness Response Act of 2002. 

The Animal Rule and drug development
The Animal Rule permits the approval of new drugs and biological products intended to reduce or prevent serious or life-threatening conditions based on efficacy data obtained solely from studies in animals in situations if it would be unethical or infeasible to conduct such studies in humans. The animal efficacy data must establish that the product is “reasonably likely” to produce clinical benefit in humans.

The Animal Rule thus effectively exempts such drugs from the statutory requirement that drugs be approved based on “substantial evidence,” defined as “evidence consisting of adequate and well-controlled investigations, including clinical investigations … on the basis of which it could fairly and responsibly be concluded … that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling …” (2).   

The Animal Rule applies only to new drugs for which it would be unethical to expose healthy human volunteers to a lethal or permanently disabling toxic CBRN substance and for which field trials to study the product’s effectiveness after an accidental or hostile exposure would be infeasible.  Furthermore, the regulation specifies four criteria that must be met in order for FDA to rely solely on animal-efficacy data: a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the proposed product; demonstration of efficacy in more than one species expected to react with a response predictive for humans, unless FDA determines that a single animal species is sufficiently predictive of human response; an animal study endpoint that is clearly related to the desired benefit in humans; and the availability of pharmacokinetic/pharmacodynamics data that permit selection of an effective dose in humans.

The Animal Rule does not exempt sponsors from the requirement to establish the safety of the product in humans. Additionally, the quid pro quo for relaxation of pre-approval statutory obligations is that drugs approved under the Animal Rule may be subject to postmarketing studies, where feasible, as well as restrictions on distribution and use and additional recordkeeping, reporting, and labeling requirements.

Between 2002 and 2009, FDA approved only two drugs under the Animal Rule. First, in 2003 FDA approved pyridostigmine bromide (PB) for use as a pretreatment for exposure to the nerve gas Soman. The drug had previously been approved, at a different dose, to treat the neuromuscular disorder myasthenia gravis. Prior to issuing the Animal Rule, FDA had allowed DOD to administer PB to troops during the first Gulf War and had granted a waiver of informed consent for the off-label use of the product. Second, in 2006, FDA approved hydroxycobalamin, a vitamin-B-related compound, which was already approved for treatment of vitamin B12 deficiency, for treatment of cyanide poisoning. Thus, both of these early approvals were for new indications of compounds with which FDA already had substantial experience.

Concerns about the practical difficulties for sponsors in effectively employing the Animal Rule for new drug and biological product approval led the Alliance for Biosecurity, a coalition of academic and industry entities, in 2007 to call on FDA to do a better job of implementing its regulations. Specifically, the Alliance recommended that FDA decide on acceptable animal models and testing methods for specific disease threats, and that the agency develop a consistent interpretation of the Animal Rule internally.

FDA guidance on the Animal Rule
FDA first issued draft guidance interpreting the Animal Rule in 2009 (3). The approximately two dozen comments submitted to FDA generally reflected support for the objectives of the rule, while several expressed frustration with FDA’s failure to provide sufficiently specific guidance to enable sponsors to take advantage of it in practice. Some commenters requested that FDA provide more specific guidance regarding selection of animal models and extrapolation of animal data to humans, and questioned the need for data from more than one animal species in all cases. Some commenters also requested that FDA provide enhanced interaction with sponsors on an accelerated basis, given the potentially-exigent circumstances that could arise when dealing with rapidly emerging threats from bioterrorism or naturally-occurring infectious disease outbreak.

FDA did not issue a revised draft guidance until 2014, which garnered only a few comments. In the intervening years, the agency approved three products under the Animal Rule: for plague, anthrax, and botulinum toxin (4).


The 50-page final guidance was issued on Oct. 28, 2015. Responding to commenters’ concerns about the lack of specificity on an appropriate animal model, the final guidance devotes more than 20 pages to this issue. In particular, the guidance sets forth the “essential elements” of an animal model and provides design considerations for adequate and well-controlled animal efficacy studies. The guidance also devotes a section to considerations for the development of preventive vaccines and cellular and gene therapies under the animal rule.

Although a detailed review of the final guidance is beyond the scope of this article, the following highlights some of its more salient features (5):

  • Scope: Although the historical impetus for the Animal Rule was concern about bioterrorism-related CBRN exposures, the final guidance clarifies that products to address threats to individuals’ health from “accidental exposure (e.g., emerging infectious pathogens, snake venom, industrial chemicals” would also be eligible provided that human efficacy studies are not ethical and field trials to study effectiveness of the drug are not feasible, and the specified four criteria are met.

  • Determining feasibility: The guidance notes that, while it generally not difficult to determine  whether deliberate exposure studies in humans would be ethical, determining that it is not feasible to conduct human field trials may be more complicated, given the many changing, and not necessarily predictable, variables including incidence rate, geographical location of outbreaks, and the conditions of and resources available in such locations  The guidance advises that sponsors should provide FDA with a “clear rationale” to support using the Animal Rule before proceeding with drug development.

  • “Essential elements” of an animal model and animal efficacy study protocol:  The guidance sets forth the “essential elements,” or key criteria for the selection of an animal model. Some of these elements relate to the disease-causing agent, including the characteristics of the agent and the natural history of the disease or condition, while others relate to the investigational drug, including its mechanism of action and dose selection. The guidance includes a checklist that provides a list of the data elements that should be considered when developing an animal model. Similarly, the guidance addresses, and includes a checklist summarizing, the essential elements that sponsors should include in adequate and well-controlled animal efficacy study protocols.

  • Number of animal species required: The guidance states that the number of animal species necessary to support drug approval will depend on the nature and clinical significance of any differences between the animal models and humans with regard to the “essential elements.” The guidance advises sponsors to demonstrate that each animal model reflects key aspects of the pathophysiology of the human disease or condition and that the response in each animal model will likely predict human response. The guidance states that efficacy will generally need to be demonstrated in two or more animal species.  Use of single species will be permitted only where the species represents a sufficiently well-characterized animal model for predicting human response, and prior FDA review and agreement on the body of evidence supporting the adequacy of the model will be required.

  • Need for frequent and ongoing engagement: The guidance cautions that developing the requisite body of evidence to support approval using the Animal Rule is a “complex and iterative process.” The guidance therefore recommends that sponsors engage in “early and ongoing communications” with the agency, and also suggests that sponsors seek input from public health officials and/or the military about the potential need for, and operational use of, the product at issue. Finally, the guidance notes that protocols for animal efficacy studies intended to provide primary evidence of effectiveness are eligible for special protocol assessment, which is a means for FDA formally to indicate agreement with a sponsor’s choice of efficacy endpoints.

Judged solely by the number of products approved pursuant to the Animal Rule, it is fair to say that the impact of the rule on the availability of CBRN countermeasures has been modest. In the first decade of the Animal Rule’s existence, it was used on only two occasions, and only for products that already were approved for other indications. The uptick in Animal-Rule-based approvals beginning in 2012 (with the most recent approval, for a treatment of Yersinia pestis, the bacterial pathogen responsible for the Black Death, occurring in May 2015) may signal FDA’s growing appreciation of the real threats to the US population from infectious disease outbreaks regardless of where and how they originate, as the devastating 2015 Ebola outbreak in Africa made all too clear. 

To be sure, there are many legitimate scientific challenges to be surmounted when seeking to establish efficacy based solely on animal models, and in some cases an appropriate animal model may simply not be available. However, a threshold requirement to expeditiously and efficiently expanding the number of products available in the case of intentional or accidental exposure is having a government regulator that appreciates the stakes involved and is willing to engage with industry to use the available regulatory tools to their maximum potential. The final guidance appears to take important steps towards achieving that goal.  

1. Doe v. Sullivan, 938 F. 2d 1370 - Court of Appeals, Dist. of Columbia Circuit 1991, https://scholar.google.com/scholar_case?case=3446658551224574023&q=Doe+v.+Sullivan,+938+F.+2d+1370&hl=en&as_sdt=2006&as_vis=1

2. Federal Food, Drug, and Cosmetics Act, 21 U.S.C. § 355(d).

3. FDA, Guidance for Industry: Animal Models-Essential Elements to Address Efficacy Under the Animal Rule (January 2009).

4. FDA, Guidance for Industry: Product Development Under the Animal Rule (Draft) (May 2014).

5. FDA, Guidance for Industry: Product Development Under the Animal Rule (October 2015).

About the Author
Gail Hannah Javitt, JD, is MPH of Counsel at DLA Piper, LLC (US).