Animal Rule Information

Overview | For product sponsors | Compliance program for nonclinical labs | Data standards | Animal Rule links | Product approval information

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 or 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 biologic product is reasonably likely to produce clinical benefit in humans. The product sponsor must still demonstrate the product’s safety in humans.

For product sponsors

FDA strongly encourages MCM sponsors to establish early and ongoing communications with FDA. 

The Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) added a new section 565(d) of the FD&C Act to require that FDA establish a procedure for a sponsor or applicant developing “a countermeasure for which human efficacy studies are not ethical or practicable, and that has an approved investigational new drug application or investigational device exemption” (IND and IDE, respectively) to request and receive two meetings with FDA – one meeting to discuss “proposed animal model development activities” and a second meeting prior to initiating pivotal animal studies. More MCM-related counterterrorism legislation

Drug products and biologics

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

FDA intends to rely on its existing procedures for arranging formal meetings with sponsors and applicants to enable them to request and receive the meetings provided in section 565(d).  Thus, sponsors or applicants developing drug products should consult the following resources for detailed information about the process and expectations for meetings about product development under the Animal Rule, in addition to the guidance linked above:

1. Guidance for Industry - Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products (PDF, 156 KB) (December 2017)
2. FDA’s Drug Development Tools Qualification Programs

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.

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).

Learn about requirements for data standards for Animal Rule submissions to CDER

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 Rule links

• October 28, 2015: Federal Register notice: Product Development Under the Animal Rule; Guidance for Industry
• February 2016: Draft Guidance for Industry - Anthrax: Developing Antibacterial Drugs for Prophylaxis of Inhalational Anthrax (PDF, 116 KB)
• Webcast recording: Product Development Under the Animal Rule - Revised Draft Guidance for Industry (June 3, 2014)
• Activities to Encourage Development, Qualification, and Use of Animal Models
• Animal Rule Summary
• 21 CFR 314.600 (drugs)
• 21 CFR 601.90 (biological products)
• Animal Model Qualification Program
• Animal Model Qualification: Frequently Asked Questions
• Drug Development Tools (DDTs)
• Countering Bioterrorism Questions and Answers from CBER

Product approval information

• May 18, 2022: FDA approved an intravenous (IV) formulation (PDF, 565 KB) of TPOXX (tecovirimat) to treat smallpox
• June 4, 2021: FDA approved Tembexa (brincidofovir) to treat smallpox
• January 28, 2021: FDA approved a treatment to increase survival in adults and pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [HS-ARS]). For more information about this treatment, please see the NPLATE (romiplostim) product label (PDF, 684 KB).
• July 13, 2018: FDA approves the first drug with an indication for treatment of smallpox (TPOXX (tecovirimat))
• March 29, 2018: FDA approves Leukine for treatment of Acute Radiation Syndrome, adding to the country's available treatments in the event of radiological or nuclear emergency
• March 18, 2016: FDA approves new treatment for inhalation anthrax (Anthim) [ARCHIVED]
• November 23, 2015: FDA approves vaccine for use after known or suspected anthrax exposure (BioThrax) [ARCHIVED]
• November 13, 2015: FDA approves new indication for use of Neulasta (pegfilgrastim) to treat adult and pediatric patients at risk of developing myelosuppression after a radiological/nuclear incident
• May 8, 2015: FDA approves additional antibacterial treatment for plague (Avelox) [ARCHIVED]
• March 30, 2015: FDA approves Neupogen for treatment of patients with radiation-induced myelosuppression following a radiological/nuclear incident
• March 25, 2015: FDA approves treatment for inhalation anthrax (Anthrasil, Anthrax Immune Globulin Intravenous (Human)) [ARCHIVED]
• February 2, 2015: Ciprofloxacin - supplemental NDA approved to add indication for treatment and prophylaxis of plague due to Yersinia pestis in adults and pediatric patients
• March 22, 2013: FDA approves first Botulism Antitoxin for use in neutralizing all seven known botulinum nerve toxin serotypes [ARCHIVED]
• December 14, 2012: FDA approves raxibacumab to treat inhalational anthrax [ARCHIVED]
• April 27, 2012: FDA approves new antibacterial treatment for plague (levofloxacin) [ARCHIVED]
• December 15, 2006: FDA approves drug to treat cyanide poisoning (Cyanokit) [ARCHIVED]
• February 5, 2003: FDA approves pyridostigmine bromide as pretreatment against nerve gas [ARCHIVED]

Related links

• Animal Rule Approvals (CDER)
• Draft guidance for industry: Acute Radiation Syndrome: Developing Drugs for Prevention and Treatment (April 2023; submit comments by July 19, 2023)