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Animal Rule Summary

Final Guidance for Industry: Product Development Under the Animal Rule (PDF, 574 KB)

On May 31, 2002, FDA published the regulations commonly known as the Animal Rule, which are found at 21 CFR 314 subpart I for drugs and 21 CFR 601 subpart H for biological products. These regulations provide a regulatory pathway for the approval of drugs and biological products when human efficacy studies are not ethical or feasible. The Animal Rule can be used only in limited circumstances. It applies only to drugs and biological products that are intended to ameliorate or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear (CBRN) substances when it has not been feasible to study the product’s effectiveness in field trials after accidental or hostile exposures to a CBRN substance and it would not be ethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic CBRN substance, and when the investigational product cannot be approved for the proposed indication through other existing regulatory pathways. The product’s safety must still be demonstrated in humans.

The Animal Rule allows FDA to use the results from adequate and well-controlled animal efficacy studies conducted in carefully vetted animal models of the human disease or condition of interest to provide the evidence of effectiveness needed for marketing approval when the results of those animal studies establish that the drug or biological product is reasonably likely to produce clinical benefit in humans.

The Animal Rule states:

FDA will rely on the evidence from studies in animals to provide substantial evidence of the effectiveness of these products only when:

  1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;
  2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;
  3. The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and
  4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans.

The Animal Rule also allows FDA to consider other data available to the Agency, including human data, when assessing the sufficiency of animal data.

The approval of products under the Animal Rule is subject to three requirements. The first is for postmarketing studies to verify and describe the product’s clinical benefit and to assess its safety when the product is used as indicated when such studies are feasible and ethical. A plan or approach to conducting such studies must be included in the marketing application. The second is for approval with restrictions to ensure safe use, if needed. The third is for information to be provided in the labeling to patient recipients that explains that for ethical or feasibility reasons, the product’s approval under this regulation was based on efficacy studies conducted in animals alone. This labeling must also include all the other relevant information required by FDA at the time of approval (including the product’s indication(s), directions for use (dosage and administration), contraindications, a description of any reasonably foreseeable risks, adverse reactions, anticipated benefits, drug interactions) and the labeling must be provided to the patient recipients before administration or dispensing of the product for the indication approved under the Animal Rule, if possible.

Products approved under the Animal Rule are subject to postmarketing recordkeeping and safety reporting applicable to all approved drug and biological products. The Animal Rule also includes information on withdrawal procedures, submission of promotional materials, and termination of certain requirements.

For more detailed information, refer to regulations at 21 CFR 314 subpart I for drugs and 21 CFR 601 subpart H for biological products. Also refer to FDA’s guidance for industry Product Development Under the Animal Rule (October 2015) and the indication-specific Animal Rule-related guidances listed on the Animal Rule Information webpage. These guidances address a broader scope of issues for product development under the Animal Rule, reflecting accumulated experience with the regulations, and provide additional scientific and regulatory information to support a better understanding of the specific expectations for animal data intended to support approval under the Animal Rule.

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