Animal Models and Regulatory Considerations

1. Animal Models and Regulatory Considerations Rosemary Roberts, MD, FAAP Director, Office of Counter-Terrorism and Emergency Coordination, CDER ASM Biodefense and Emerging Diseases Research Meeting February 26, 2012

3. Presentation Objectives • Historical overview • The Animal Rule – Requirements • Animal Rule and Challenges • Sufficiently well-characterized • Animal Model Qualification Program • Resources

4. Historical Overview • Animal Rule – published May 2002 • Draft Guidance – published January 2009 Animal Models – Essential Elements to Address Efficacy Under the Animal Rule • Draft Guidance – published October 2010 Qualification Process for Drug Development Tools • Drug Development Tool: Animal Model Qualification Program – initiated June 2011 • Drug Development Tool Website – posted December 2011

5. The Animal Rule – Requirements • The pathophysiological mechanism of the toxicity of the agent, and the mechanism by which the product prevents or substantially reduces that toxicity, must be reasonably well-understood. • 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.

6. The Animal Rule – Requirements • The animal study endpoint is clearly related to the desired benefit in humans • Enhancement of survival • Prevention of major morbidity • Pharmacokinetic and pharmacodynamic data or other relevant data to allow selection of an effective dose in humans • Reasonable to expect the effectiveness of the product in animal to be a reliable indicator of its effectiveness in humans

7. Animal Rule and Challenges • Animal Rule • Scope – clinical trials infeasible or unethical • Defines terms • “Sufficiently well-characterized” • “Reasonably likely” • Natural history of disease/condition; pathophysiologic comparability • Fidelity of the animal model to the human disease/condition • Lack of relevant human data

8. Sufficiently Well-characterized • “meaning the model has been adequately evaluated for its responsiveness”* • Odds are that will need animal model in more than one species. • Prior human experience with the product supportive of use of a single animal model in one animal species. • Model is reproducible. *FR Notice 67:37989

9. Animal Rule and Challenges • Number of species • How many species? • Which species? • Is a single species adequate? • Must one species always be a non-human primate? • Animal models • Lack of publicly available animal models • Product-independent models Qualification of Animal Models

10. Drug Development Tools (DDT)Background • Concept: if a DDT is a qualified and analytically valid measurement, it can be relied upon to have a specific use and interpretable meaning in drug development; qualified DDT will be publicly available. • Regulatory implication: Industry (developers) can rely on using the DDT for the qualified purpose during drug development. • Voluntary program • Three qualification programs for DDTs: • Biomarkers • Clinical Outcome Assessments • Animal Models - piloting the first submission • CBER and CDER joint program

11. What is Qualification? Qualification is a conclusion that within the stated context of use, the results of assessment with a Drug Development Tool have met evidentiary standards and can be relied upon to have a specific interpretation and application in drug development and regulatory decision-making as long as:   • There are no serious study flaws (e.g., unverifiable data, improper performance of the assays); • There are no attempts to apply the DDT outside the qualified context of use; and • There are no new and conflicting scientific facts not known at the time the qualification was determined.

12. What is Context of Use? • For animal models, the context of use statement may be extensive, it should detail how the model is to be used in drug development, and it should specify details necessary to replicate the model. These details include, but are not be limited to: • characterization of the animals to be used, This includes but is not limited to species, age, gender, screening assays, and exclusion criteria; • characterization and preparation of the challenge agent; • procedural information regarding exposure; and • identification of endpoints and treatment triggers.

13. DDT Qualification Program Goals • Support stakeholders who are trying to establish an acceptable Drug Development Tool. • Provide an organized structure and process for interactions in a consistent and responsive manner. • For animal models, a goal is to reduce use of resources and animals, and ultimately, decrease development time for medical countermeasures.

14. DDT Qualification Program: A New Pathway FDA Consultation & Advice Phase Planning Phase FDA Review Phase Greater Efficiency Letter of Intent (LOI), Briefing Document DDT Available Publicly  Methods & Results Sharing  Dossier Submission; FDA Review 

15. Planning Phase • Submitter provides LOI to CDER or CBER. • Evaluation of request by program team. • Interdisciplinary team (qualification review team) assembled within CDER and other components of FDA as appropriate (e.g., CBER rep).

16. Consultation and Advice Phase • Information gathering and data assessment steps involving interactions, including face-to- face meetings, between the qualification review team (QRT) and the submitter. • Advancement to the next step (review phase) is based on agreement between the submitter and QRT.

17. FDA Review Phase • The review phase is entered when the data are thought to be sufficiently complete and adequate. • The QRT performs full review of the complete data package and renders a qualification recommendation.

18. Qualification Decision • In CDER (CBER), a Regulatory Briefing and discussion are held with Office Directors. Comments and discussion on the QRT recommendation. • Final sign-off is by the Center Director. • Submitter receives a qualification decision by letter. • The decision that the animal model is qualified will be made publically available. The availability of the qualified DDT will be announced in the Federal Register.

19. Resources • Draft Guidance for Industry - Animal Models – Essential Elements to Address Efficacy Under the Animal Rule, published 1/2009 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078923.pdf • Draft Guidance to Industry - Qualification Process for Drug Development Tools, published 10/2010 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm121568.htm • Drug Development Tools (DDT) Qualification Program, posted 12/2011 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/default.htm

20. Animal Model Qualification Contacts • For Drugs - Contact Rosemary Roberts, M.D Center for Drug Evaluation and Research Email:rosemary.roberts@fda.hhs.gov Phone:(301) 796-2210 • For Vaccines – Contact Cynthia Kelley, MS Center for Biologics Evaluation and Research Email:  Cynthia.Kelley@fda.hhs.govPhone: (301) 827-0636