FAQs: FDA Animal Rule
DVC is an industry leader in navigating requirements of the Animal Rule, which provides an FDA licensure pathway for candidate vaccines that cannot meet the requirements of traditional licensure because human efficacy studies are not ethical or feasible. DVC provides answers to frequently asked questions about the Animal Rule, based on our experience and the latest industry guidance.
Frequently Asked Questions
Q: What is the Animal Rule?
A: The Animal Rule (21 CFR 314 Subpart I or 601 Subpart H, and draft Guidance for Industry January 2009: Animal Models-Essential Elements to Address Efficacy Under the Animal Rule PDF) is a pathway for candidate vaccines that cannot meet the requirements of traditional licensure because human efficacy studies are not possible for ethical reasons or because field studies to assess efficacy are not feasible. Sponsors must demonstrate that the tested product is likely to clinically benefit humans by:
- Selecting appropriate animal models and study endpoints and obtaining concurrence from the FDA on the choice of animal models.
- Understanding the pathophysiology of the disease and the immune responses involved in protection and conducting studies in the selected species using CGMP-produced material.
- Developing and validating assays that are indicators of protection and which link human and animal immune responses.
- Demonstrating that the appropriate type and level of immune response is induced in humans receiving the vaccine candidate in a manner that permits selection of an effective human dose.
Q: Why aren't studies to demonstrate safety and efficacy routinely conducted in animals, rather than in human clinical trials?
A: Animal responses to vaccines are not always predictive of the human responses and regulations require that both safety and efficacy be demonstrated in humans unless human efficacy studies are not ethical or feasible. However, candidate vaccines are tested in animals for toxicity prior to being tested in the clinic regardless of the licensure pathway.
Q: May Sponsors choose to use the Animal Rule path to licensure over more traditional pathways?
A: No, the FDA will only consider vaccine licensure under the Animal Rule (21 CFR 314 Subpart I or 601 Subpart H) when human efficacy studies are not possible for ethical reasons or because field studies to assess efficacy are not feasible. If licensure is feasible by field trials or by using the Accelerated Approval regulations (21 CFR 314 Subpart H or 21 CFR 601 Subpart X), the Animal Rule would not be pursued.
Q: What are the differences between developing products using traditional licensure pathways and the Animal Rule?
A: The major difference is that the Animal Rule allows efficacy to be demonstrated in animals rather than people. All other requirements for traditional licensure still apply. Phase 1, 2 and 3 clinical studies are still required to demonstrate safety and immunogenicity and to establish a link between the pivotal animal and human studies to predict clinical benefit.
Q: How does a Sponsor know what animal model to use?
A: Sponsors may select models based on historic use and a body of available information on the model or their own nonclinical studies; however it is necessary to obtain FDA concurrence that the models are suitable for the intended label indication. The FDA will examine the data submitted by a Sponsor on a case-by-case basis.
There have been government agency-sponsored workshops focused on animal model development at which the components of acceptable animal models and challenge strategies were discussed, including:
- Anthrax Vaccines: Efficacy Testing and Surrogate Markers of Immunity Workshop, April 23, 2002 (PDF transcript, 275 KB)
- Public Workshop on Animal Models and Correlates of Protection for Plague Vaccines, October 13, 2004 (PDF transcript, 594 KB)
- Public Workshop: Anthrax Vaccines: Bridging Correlates of Protection in Animals to Immunogenicity in Humans, November 8, 2007 (PDF transcript, 869 KB)
Q: What types of animal studies must be conducted to meet the requirements of the Animal Rule?
A: Natural history studies or studies that evaluate the pathophysiology of disease and vaccine efficacy studies must be conducted using well-characterized challenge material. Pivotal nonclinical studies must be conducted using Good Laboratory Practices. The immune responses induced by vaccination, principally the measured aspect(s) of the immune response that correlate with protection from disease following exposure to a challenge agent, must be demonstrated to be similar to those induced in humans to serve as a bridge between species. The bridge will be used to predict clinical benefit and to select an effective human vaccine dosage.
Q: Is the Animal Rule a more rapid approach to licensure than more traditional pathways?
A: No. All traditional licensure requirements must still be fulfilled including conducting nonclinical safety studies, demonstrating control of manufacturing processes, establishing lot release criteria, completing assay validation, providing regulatory submissions to the FDA and conducting Phase 1, 2 and 3 clinical trials under CGMP, GLP and GCP guidelines as appropriate.
In addition, nonclinical studies will be required to demonstrate that the hallmarks of human disease occur in the animal models selected and are ameliorated by vaccination, that immune responses evaluated in the animals are similar to those induced in the clinic and that immune responses between animals and humans can be bridged in a manner that predicts clinical benefit and supports selection of an effective dose. No vaccines have been licensed using the Animal Rule to date so the impact of the additional nonclinical studies on product development timelines has not been assessed.
Q: Is the Animal Rule less expensive than the more traditional route to licensure?
A: No. The Animal Rule is unlikely to result in cost savings over traditional licensure routes, since all other licensure requirements still apply. Additional nonclinical testing requirements may result in additional costs over traditional licensure paths. The Animal Rule is neither a shortcut nor a cheaper alternative to licensure.
Q: What products have been licensed using the Animal Rule?
A: The FDA Center for Drugs Evaluation and Research (CDER) has approved two products to date using the Animal Rule (source). The products are Cyanokit®, for the treatment of known or suspected cyanide poisoning and pyridostigmine bromide, to increase survival after exposure to the nerve agent Soman. Pyridostigmine bromide is approved only for combat use by U.S. military personnel. To date, no vaccines have been approved under the Animal Rule.
Learn more about the Animal Rule in 21 CFR 314 Subpart I or 601 Subpart H, and Draft Guidance for Industry January 2009: Animal Models-Essential Elements to Address Efficacy Under the Animal Rule (PDF).
Learn more about DVC's work toward licensing plague and botulinum neurotoxin vaccines under the Animal Rule in this case study presentation (324 KB, PDF).
Contact us to learn more about how DVC can assist your program with Animal Rule requirements.