Perspectives on the Animal Rule What is the Animal Rule? The Basics

1. Perspectives on the Animal RuleWhat is the Animal Rule?The Basics J.E. Estep, DVM, PhD Senior Program Manager Battelle Memorial Institute 29 January 2009

2. Outline • History • What is “The Animal Rule” • Essential Elements of an Animal Model as a Test System • Discussion

3. Background • Issue: • Licensing of CBRN medical products (prophylactics, therapeutics) when normal clinical trails are not possible requires alternative approaches for efficacy demonstration

4. History / Background • Solution – 21 CFR 314.600 & 21 CFR 601.90 – “Animal Rule” Approval of Drugs and Biological Products (Vaccines, Therapeutics) When Human Efficacy Studies Are Neither Ethical or Feasible • Request For Comments: 62 FR 40996 (July 31, 1997) • Proposed Rule: 64 FR 53960 (Oct 5, 1999) • Final Rule: 67 FR 37988 (May 31, 2002)** • Regulations: 21 CFR § 601.90-95 (Biologicals) 21 CFR § 314.600-650 (Pharmaceuticals) • Guidance for Industry: Animal Models – Essential Elements to Address Efficacy Under the Animal Rule(January 2009) – DRAFT (recommendations) ** = significant change

5. U.S. FDA Animal Rule • Important points • Animal rule concerns the approval of new drug or biological products when human efficacy studies are neither ethical nor feasible • Testing under the Animal Rule is a surrogate for human efficacy/clinical studies

6. U.S. FDA Animal Rule • The Rule does not apply if product approval can be based on standards described elsewhere in U.S. FDA regulations • Safety must still be demonstrated in human subjects enrolled in conventional clinical trials – Phases I-III • FDA may approve a product for which … • Human safety has been established, and; • “Animal Rule” requirements are met – based on adequate and well-controlled animal studies, the results of which establish that the product is reasonably likely to provide clinical benefit when administered in humans

7. U.S. FDA Animal Rule – Tenets • Reasonably well-understood pathophysiological mechanism of the toxicity of the substance (agent) and its prevention/reduction by the test product • Effect is demonstrated in more than one animal species expected to react with a response predictive of human • ”2 Animal Rule” * • * the effect can be demonstrated in a single animal species if there is a sufficiently well-characterized animal model for predicting the response in humans; nowhere in the Rule is “Two Animal” stated

8. U.S. FDA Animal Rule - Tenets • Animal study outcome is clearly related to the desired benefit in human • Reduced morbidity/mortality • Data on pharmacokinetics/dynamics of the product in animals and humans allows selection of an effective dose in humans

9. U.S. FDA Animal Rule • If these tenets are met then it is reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its effectiveness in human

10. Final, Definitive AnimalEfficacy Studies • Predict the outcome of controls following challenged • route, dose, and strain of the infectious agent or chemical • Preparation & characterization of the infectious agent or chemical material must be standardized, consistent, reproducible • Challenge material is a “critical reagent” • Use optimized/validated assays to monitor the response and bridge data to humans • Non-validated assays may be useful and acceptable • Pivotal studies conducted under the FDA GLPs guidelines • Have a prospective statistical plan in place

11. GLP & AWA Requirements • All studies subject to this Rule must be conducted in accordance with preexisting requirements under the Good Laboratory Practices (21 CFR § 58) regulations • Adherence to Animal Welfare Act (7 U.S.C. 2131) required • GLP expected for the definitive/pivotal animal studies – not necessary for the pilot studies. Also, if you want to describe an animal study in the label (package insert), then it should comply with GLP

12. “Validation” Under Animal Rule • The word “Validated” is not mentioned in the regulatory language of the Rule. The Rule uses the phrase - “adequate and well controlled animal studies.” • Animals are complex biological systems that will have individual animal variation (e.g. they are not a 96-well plate, cell culture, an instrument, etc.) -- ?? validated animal model • Studies must be reproducible and predicative for infected / intoxicated negative controls • Use validated assays • Standardized instruments and procedures • Techniques or methods should be sensitive enough to make make comparisons on studies and between species • Comparable results from a given type/dose/route of challenge • Comparable results if study conducted at different location

13. Potential Misunderstandings • The Rule does not apply if product approval can be based on standards described elsewhere in FDA's regulations – normal human trials can be done • Safety must still be demonstrated in human subjects enrolled in Phase I, II & III clinical trials • The Rule is not an Accelerated or Fast-Track approval and is not a short-cut to approval, in fact, it may take longer • Two products licensed under the Animal Rule today, but many more on the very near horizon • Seven years in all that we have been using this rule • The purpose of the “Animal Rule” is to develop a product for use in humans, not animals

14. Animal Rule Important Highlights • From product concept through advanced development, everyone should consider the applicability and requirements of the Animal Rule • Design studies on a critical path to support the product development goal – licensure • Develop integrated research plans which account for all aspects of the licensing needs • Studies require Good Laboratory Practice (GLP) Compliance • Validation of all critical assays is expected

15. Essential Data Elements of an Animal Model • Animal Model - Selection Criteria • Species • Pathogenesis • Endpoints of Study • Manipulations Required • Cost • Challenge System • Vaccine / Therapeutic Dose • Delivery of Agent • Strain or Form of Agent • Challenge Dose

16. Essential Data Elements of an Animal Model • Characterization of the Agent (CBRN) • Etiologic agent same as that caused disease in humans • Surrogates can be acceptable • Monkey pox • Pathogenic Determinants • How does the agent cause the pathology • Toxin production of a bacteria • Target and disrupt a target organ • This should be the same in both humans and the animal species

17. Essential Data Elements of an Animal Model • Characterization of the Agent – continued • Route of Exposure should be same as the treat to humans • Inhalation, oral, etc • Quantification of Exposure • Reliable and reproducible challenge dose • Show scalable relationship between dose and outcome (especially in humans)

18. Essential Data Elements of an Animal Model • Host susceptibility and response • Animal species chosen should be susceptible to the agent – seems obvious but requires consideration of the dose compared to the human dose must be discussed • Natural history of the disease • Pathophysiologic comparable to humans • Time course of disease • Manifestations of disease (signs, symptoms) • Pathology • Outcome (death, recovery)

19. Essential Data Elements of an Animal Model • Trigger for Intervention • Characterization of medical intervention • Type of material • Mechanism of action • Activity (in vitro and in vivo) – how does it intervene • Pharmacokinetics/Pharmacodynamics • Interactions with other medical products

20. Design Considerations for Animal Efficacy Studies • Endpoints • Ultimate key to success is the study endpoints • You need to measure something, otherwise you cannot make a comparison to humans or characterize the pathogenesis and/or pathology • Common endpoint in our business is ,but we need drill down to the pathogenesis to understand how that developed

21. Animal Species Selection • Endpoints of Study • Survival / Lethality (ultimate goal, but good not enough) • Non-Lethal Pathology or Clinical Observations • Pneumonia • Fever • Emesis • Hematology (white blood cell shift reflecting infection) • Clinical Chemistries (i.e., Liver Function Tests) • Bacteremia / Viremia • Immunomodulation Assessments • Antibody Production • T / B Cell Stimulation • Reagent Availability and Correlation in Humans

22. Animal Species Selection • Manipulations Required • Pulmonary Radiographs • Larger Animal Model • Blood Draw Volume • Limits Based on Body Weight • Cellular Component Assessment Require Larger Volumes • Constant Physiological Monitoring Vs Clinical Observations • Telemetry vs Chaired/Restraint Manipulation • Exposure Route • Inhalation (Head-Only, Nose-Only, Whole-Body) • Parenteral • Oral • Dermal (percutaneous)

23. Animal Species Selection • Pathogenesis • Similarity to human disease process • SEB - causes emesis and fever in humans and monkeys • Lethal at higher doses (~1,000 X emesis dose) • Anthrax - widened mediastinum in humans and monkeys • Q-Fever - pneumonia in humans and monkeys • Botulinum - flaccid paralysis in virtually all species • Classical Nerve Agents • Not an absolute criteria • Tuberculosis • Rabbit / Pulmonary Tubercles • Mouse and guinea pig usually other forms • VEE – mouse is a lethal model • Sulfur Mustard – no good animal vessication model

24. Design Considerations for Animal Efficacy Studies • Timing of intervention • Route of administration • Dose or dose regimen

25. Summary of Data Packet • Agent characterization • Host susceptibility and natural history • Compared to human disease • Intervention – what and when • How does the product affect outcome • Animal test design • Endpoints • Timing of endpoints measuring drive intervention • Route of administration agent • Dosing – route and regimen

26. One Last Point - Important • Involve FDA early and in every step of the product develop program • Never start and pivotal animal challenge study without getting comments from FDA • When you talk to FDA on the animal test program – have animal model experienced scientists on board – FDA expects details on the plan

27. Acknowledgements • John Wade, DVM, PhD, Personal communication and prior presentations materials • Mark J. Abdy, DVM, PhD - “Clarification of the Regulatory Position Regarding Animal Studies to bring Vaccines to Licensure,”2006 • Many: Scientists, Battelle and other companies, NIAID Program Officers, FDA through meetings and discussions