Animal Rule Information
Overview | Related Guidances | Approvals | Compliance program for nonclinical labs | Data standards | Qualification Program | Animal Rule links | Resources
Overview
Before a medical product can be approved by FDA, the sponsor must prove efficacy—that the product works. In some cases, such as developing medical countermeasures (MCMs) for potential bioterror threats, human challenge studies (exposing people to the threat agent) would not be ethical and human efficacy studies after an accidental or hostile exposure to the threat agent have not been feasible.
In these cases, FDA may grant approval based on well-controlled animal studies, when the results of those studies establish that the drug or biological product is reasonably likely to produce clinical benefit in humans. The product sponsor must still demonstrate the product’s safety in humans.
Animal Rule Summary
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:
- There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product;
- 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;
- The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and
- 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.
Animal Rule-Related Guidances
FDA has issued the following guidances for industry to help sponsors and other stakeholders understand FDA’s current thinking on developing products under these regulations:
- The overarching Animal Rule guidance
- Product Development Under the Animal Rule (October 2015)
- Indication-specific Animal Rule-related guidances
FDA has also issued the following draft guidance for industry that, when finalized, will represent the FDA’s current thinking on this topic:
Establishing Early and Ongoing Communication with FDA
FDA strongly encourages sponsors proposing to develop products under the Animal Rule to establish early and ongoing communications with FDA. Sponsors should consult FDA’s draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products (September 2023) regarding the process and expectations for formal meetings whether the meetings will be conducted as in person face-to-face meetings, virtual face-to-face meetings (video conference), teleconference, or as written response only. This draft guidance, when finalized, will represent the FDA’s current thinking on the topics covered.
Animal Rule Approvals
Products approved under the Animal Rule are listed under the relevant chemical, biological, radiological, or nuclear substance-induced disease or condition with the Animal Rule-approved indication and use, approval date, and approving Center.
| PYRIDOSTIGMINE BROMIDE (pyridostigmine bromide tablet (30mg)) – For prophylaxis against the lethal effects of soman nerve agent poisoning – approved on February 5, 2003 (CDER). | Publicly available approval information |
| CYANOKIT (hydroxocobalamin injection, powder, lyophilized, for solution) – For the treatment of known or suspected cyanide poisoning – approved on December 15, 2006 (CDER). | Publicly available approval information |
| ([Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) – (Equine)] sterile solution for injection) – For the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and pediatric patients – approved on March 22, 2013 (CBER). | Publicly available approval information |
| RAXIBACUMAB (raxibacumab injection) – For the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs; also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate – approved on December 14, 2012 (CDER). | Publicly available approval information |
| ANTHRASIL ([Anthrax Immune Globulin Intravenous (Human)] sterile solution for infusion) – For the treatment of inhalational anthrax in adult and pediatric patients in combination with appropriate antibacterial drugs – approved on March 24, 2015 (CBER). | Publicly available approval information |
| BioThrax ((Anthrax Vaccine Adsorbed) suspension for intramuscular or subcutaneous injection) – For the treatment of adult and pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs; also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate – approved on December 14, 2012 (CDER). | Publicly available approval information |
| ANTHIM (obiltoxaximab injection) – Indicated in adult and pediatric patients for treatment of inhalational anthrax due to B. anthracis in combination with appropriate antibacterial drugs and, for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate – approved on March 18, 2016 (CDER). | Publicly available approval information |
| CYFENDUS ((Anthrax Vaccine Adsorbed, Adjuvanted) suspension for intramuscular injection) – For post-exposure prophylaxis of disease following suspected or confirmed exposure to Bacillus anthracis in persons 18 through 65 years of age when administered in conjunction with recommended antibacterial drugs – approved on July 20, 2023 (CBER). | Publicly available approval information |
| LEVAQUIN (levofloxacin tablet, levofloxacin injection, levofloxacin oral solution) – For treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients, 6 months of age and older – approved on April 27, 2012 (CDER). | Publicly available approval information |
| CIPRO (ciprofloxacin hydrochloride tablet and ciprofloxacin hydrochloride oral suspension) and CIPRO IV (ciprofloxacin for intravenous infusion) – For treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients from birth to 17 years of age – approved on February 2, 2015 (CDER). | Only approval letter and product label publicly available |
| AVELOX (moxifloxacin hydrochloride tablet) and AVELOX IV (moxifloxacin injection) – For adult patients for the treatment of plague, including pneumonic and septicemic plague, due to susceptible isolates of Yersinia pestis and prophylaxis of plague in adult patients – approved on May 8, 2015 (CDER). | Only approval letter and product label publicly available |
| TPOXX (tecovirimat capsule, for oral use) – – For the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg – approved on July 13, 2018 (CDER).#1 Patient population expanded to adult and pediatric patients weighing at least 3 kg – approved on May 18, 2022 (CDER).#2 | Publicly available approval information for #1 and #3, for #2, only approval letter and product label publicly available |
| TPOXX (tecovirimat injection, for intravenous use) – For the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 3 kg – approved on May 18, 2022.#3 | |
| TEMBEXA (brincidofovir oral suspension and brincidofovir tablets) – – For the treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates – approved on June 4, 2021 (CDER). | Publicly available approval information |
| NEUPOGEN (filgrastim injection) – To increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) – approved on March 30, 2015 (CDER). | Only approval letter and product label publicly available |
| NEULASTA (pegfilgrastim injection) – To increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome) – approved on November 13, 2015 (CDER). | Publicly available approval information |
| LEUKINE (sargramostim (solution) injection and sargramostim (lyophilized powder) for injection) – To increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]) – approved on March 29, 2018 (CDER). | Publicly available approval information |
| LEUKINE (sargramostim (solution) injection and sargramostim (lyophilized powder) for injection) – To increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]) – approved on March 29, 2018 (CDER). | Only approval letter and product label publicly available |
Compliance Program for the Inspection of Nonclinical Laboratories Conducting Animal Rule-Specific Studies
On April 1, 2019, FDA posted a Compliance Program for the Inspection of Nonclinical Laboratories Conducting Animal Rule-Specific Studies (CP 7348.007) (PDF, 173 KB) on its Bioresearch Monitoring Program (BIMO) Compliance Programs web page.
This compliance program provides instructions for the inspection of nonclinical laboratories conducting the Animal Rule-specific studies (i.e., the natural history studies that define the animal model in which the efficacy of an investigational drug or biological product will be tested, the adequate and well-controlled animal efficacy studies intended to provide the primary evidence of effectiveness to support marketing approval of the product, and the pharmacokinetic and/or pharmacodynamic studies in animals used to select a dose and regimen in humans).
Inspections of these studies are conducted to verify, to the extent practicable, the quality and integrity of the data contained in the final reports of the Animal Rule-specific studies submitted to FDA.
The following two recorded presentations were part of a July 19-20, 2022, virtual workshop Office of Study Integrity and Surveillance (OSIS) Workshop 2022: CDER Inspections of Good Laboratory Practice, Animal Rule, and Bioavailability/Bioequivalence Study Sites
- “Animal Rule Compliance Program” (at time stamp 1:04:00)
- “Animal Rule Case Study”
Data Standards for Animal Rule Studies
FDA worked with the Clinical Data Interchange Standards Consortium (CDISC) to develop electronic data standards for the natural history and efficacy studies conducted in animals that support Animal Rule applications. The Standard for Exchange of Nonclinical Data (SEND) Implementation Guide-Animal Rule v1.0 (SENDIG-AR v1.0) was published by CDISC on September 17, 2019, and FDA’s support for these data standards began on March 15, 2020.
SEND data sets are required in Animal Rule submissions to the Center for Drug Evaluation and Research (CDER) for studies initiated after March 15, 2022, for new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs) and for studies initiated after March 15, 2023, for certain investigational new drug applications (INDs).
SEND data sets are required in Animal Rule submissions to the Center for Biologics Evaluation and Research (CBER) for studies initiated after March 15, 2027, for NDAs, ANDAs, certain BLAs, and certain INDs.
Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), at least 24 months after the issuance of a final guidance document in which the U.S. Food and Drug Administration (FDA or the Agency) has specified the electronic format for submitting certain submission types to the Agency, such content must be submitted electronically and in the format specified by FDA. FDA’s guidance for industry Providing Regulatory Submissions in Electronic Format — Standardized Study Data (December 2014 [original]; October 2020 [revision 1]; June 2021 [revision 2]) implements and describes these electronic submission requirements under section 745A(a) of the FD&C Act for clinical and nonclinical study data, specifies the types of submissions to which these requirements apply, and specifies timetables for the implementation of the requirements.
On March 11, 2020, FDA published a Federal Register notice that announced that FDA’s support of the Clinical Data Interchange Standards Consortium (CDISC) for Study Data Tabulation Model version 1.8 (SDTM v1.8), and CDISC Standard for Exchange of Nonclinical Data Implementation Guide—Animal Rule version 1.0 (SENDIG–AR v1.0) began on March 15, 2020. That document also announced that these new standards would be required in submissions for studies that start after March 15, 2022. That document omitted the 36-month implementation period for certain INDs as required by FDA’s guidance for industry Providing Regulatory Submissions in Electronic Format--Standardized Study Data. On June 10, 2021, FDA published a Federal Register notice that corrected that error and clarified that that these new standards would be required for studies initiated after March 15, 2022, for new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs) and for studies initiated after March 15, 2023, for certain investigational new drug applications (INDs) submitted to the Center for Drug Evaluation and Research (CDER) for products being developed under the regulations commonly known as the Animal Rule (see 21 CFR 314.600-650 for drugs and 21 CFR 601.90-95 for biological products). Currently, only CDER will require the use of these Animal Rule data standards (i.e., SDTM v1.8 and SENDIG-AR v1.0).
Specifically, Standard Exchange for Nonclinical Data (SEND) datasets are required for any nonclinical natural history or efficacy study initiated after March 15, 2022, for NDAs, ANDAs, and BLAs and for any nonclinical natural history or efficacy study initiated after March 15, 2023, for certain INDs that are submitted to CDER and for which the CDER review division expects a full tabulation of data (i.e., line listings of the results for each individual animal) to support detailed review. Although not required, FDA also recommends that sponsors submit SEND datasets for such studies that were initiated before March 15, 2022, and March 15, 2023, as applicable. In addition, FDA recommends SEND datasets for such studies that are submitted to pre-INDs and FDA’s Animal Model Qualification Program.
Application-specific questions about which natural history and efficacy studies should include full tabulations of data and datasets should be discussed with the appropriate CDER review division as early as possible during product development. Questions about natural history studies that will be submitted to an animal model qualification package should be discussed with the Animal Model Qualification Program (contact CDERAnimalModelQualification@fda.hhs.gov).
Additional information about data standards is available at FDA’s Study Data Standards Resources web page. For additional information on how FDA interprets and intends to implement the electronic submission requirements of section 745A(a) of the FD&C Act, see FDA’s guidance for industry Providing Regulatory Submissions in Electronic Format – Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (December 2014). For general data standards inquiries for CDER, contact cder-edata@fda.hhs.gov.
For further information about FDA’s expectations for the reports of nonclinical natural history and efficacy studies submitted to support Animal Rule applications (exclusive of the data standards) see section IV.D of FDA’s guidance for industry Product Development Under the Animal Rule (October 2015).
Animal Model Qualification Program
CDER and CBER created the Animal Model Qualification Program (AMQP) to support the development of product-independent animal models that can be used for testing the efficacy of multiple investigational products that must be developed under the Animal Rule. A key impetus for the development of the AMQP was the desire to reduce redundancy in animal model development. This program also provides an avenue to obtain FDA subject matter feedback on early animal model development. Qualified animal models are made publicly available and can be referenced for use in regulatory applications. Seeking qualification of an animal model through the AMQP is voluntary. The use of a qualified model is not required for approval of an investigational product under the Animal Rule. Further information can be found in section III.D of FDA’s guidance for industry Product Development Under the Animal Rule.
Animal Rule Related Links
- Federal Register Notice: New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible; Final Rule
- 21 CFR 314 Subpart I – Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible
- 21 CFR 601 Subpart H – Approval of Biological Products When Human Efficacy Studies Are Not Ethical or Feasible
- Animal Rule Approvals (CDER)
Resources For You
FDA works closely with U.S. government partners to build and sustain the MCM programs necessary to effectively respond to public health emergencies and to support the unique needs of U.S. military personnel.
- Administration for Strategic Preparedness and Response (ASPR)
- Center for the Biomedical Advanced Research and Development Authority (BARDA)
- National Institute of Allergy and Infectious Diseases (NIAID)
- Centers for Disease Control (CDC) Emergency Preparedness and Response
- U.S. Department of Defense (DoD) U.S. Army Medical Research and Development Command
Contact Info: ORES@fda.hhs.gov