Perspectives on Licensing Vaccines by the Animal Rule

1. Perspectives on Licensing Vaccines by the Animal Rule Mary Kate Hart, Ph.D. Director, Nonclinical Research DynPort Vaccine Company LLC, A CSC Company

2. Overview • Vaccine development by DynPort Vaccine Company LLC (DVC): perspectives and considerations • The Animal Rule: what it is and what it is not • DVC’s approach to meeting the Animal Rule requirements

3. Vaccine Development by DVC: Perspectives and Considerations

4. Bona fides • DVC has been engaged in advanced development of biodefense products since 1998. • Product portfolio includes: • Live bacterial vaccine (tularemia) • Live viral vaccines (Venezuelan equine encephalitis virus; Cell Culture Smallpox Vaccine) • Inactivated viral vaccines (seasonal and pandemic influenza with Baxter) • Recombinant peptide vaccines (plague, anthrax, botulinum neurotoxin) • Plasma-derived biotherapeutics (BioScavenger with Baxter) • Therapeutic immunoglobulin (Vaccinia immune globulin) • Customers include Department of Defense, National Institutes of Allergy and Infectious Diseases and Department of Health and Human Services • Licensed one of the first biodefense-specific products

5. Perspectives on Biodefense Vaccines • Developing vaccines for biodefense • What are we building? • What are the customer’s requirements? • What are the risks?

6. What are we building? • The most important criterion: build with the end in sight. • Proof-of-Concept does not ensure a viable product. • Product developers need clear requirements: • What is an acceptable level of protection? • What is the final indication? • What is the final format expected to be? (Single-dose, multi-dose, filled syringes, something else?) • What is a “licensable” product? • Product plan should not radically change over time: • Product development plans must be flexible, but cannot be anarchistic. Government customer may require forward planning (4-5 years) to ensure funding is available. • Animal Rule provides many daunting challenges, and approach to compliance should be set early.

7. We need to know: Nature and identity of threat Level of protection required Onset vs. duration of protection Administration strategy Storage conditions Initial delivery amount Ongoing requirements Regulatory strategy Because: Specificity of the response Nonclinical and clinical study design Administration and testing paradigm Clinical strategy Formulation, stability and format Manufacturing strategy Manufacturing strategy Overall program design (licensed vs. unlicensed) What are the requirements? Deviations from the plan always result in significant cost and schedule ramifications. A clear plan for development of the product is necessary in advance, and modifications should be made only when absolutely necessary.

8. Risk Management is Crucial to Success • Murphy’s Law is first, last and always the operating principle. • Development of biodefense medical countermeasures is inherently a high-risk enterprise: • Lack of prior art (make it up as you go). • Compliance with the Animal Rule: new licensure strategy. • The product may not work as expected. • Logistics of countermeasure use still being worked out.

9. The Animal Rule: What it is and What it is Not

10. FDA Animal Rule • Allows for approval of vaccines in which efficacy testing in humans is unethical • Is not a shortcut to approval, or applicable to products that can be licensed by other approaches • Need to understand pathophysiology of the disease • Use dosages scaled to reproduce the human response • Well-controlled animal studies will provide data that are likely to predict a benefit in humans • Demonstrate effect in two species • nonhuman primates [NHPs] • Rodents • Additional considerations available in Concept Paper (e.g., use of well-characterized materials)

11. Animal Rule Challenges • Meet the traditional licensure requirements AND • Design proof-of-concept studies • Demonstrate relevance of animal model • Model considerations; small and large animal models desired • Provide rationale for use of Animal Rule • Define protection • Good Documentation Practices essential • Design of Animal Rule studies • Determine correlate that predicts clinical benefit • Support selection of human dosage • Good Laboratory Practices required • Efficacy demonstrated in animals • Bridge from animals to human response to predict clinical benefit

12. Development Timeline – Traditional Approach IND BLA R&D Pre- Clinical Phase 1 Phase 2 Phase 3 FDA Approval To the Market Clinical Studies YEARS 6.5 7 1.5 TOTAL: 15 years

13. Development Timeline – Animal Rule Approach IND BLA R&D Pre- Clinical Phase 1 Phase 2 Phase 3 To the Market FDA Approval Animal Rule – Efficacy Studies TOTAL: Unknown

14. Animal Rule-Based Vaccine Development • Pathway to Licensure is a “work in progress” • Uncertain requirements from a regulatory standpoint • Conservative approaches in determining what is acceptable • There are NO licensed vaccines that demonstrate efficacy by the Animal Rule • Detailed planning essential due to government funding restrictions • Changes in protocols affect schedule/cost and can result in major delays • NHP availability • Facility expertise and availability

15. DVC’s Approach to Meeting the Animal Rule Requirements

16. DVC Vaccine Program Technical Approach • Expertise and coordination between technical areas: • Science: technical oversight and integration • Quality: oversight of product and clinical studies • Regulatory: FDA communications, strategy for licensure • Manufacturing: material for clinical and nonclinical studies • Nonclinical: animal studies (safety, immunogenicity, efficacy) • Clinical: Phase 1,2,3 safety and immunogenicity trials

17. CGMP Justify why human trials are not feasible or ethical; justify appropriateness of selected animal models Demonstrate manufacturing consistency – effective change control Correlate of Protective Immunity Bridge to human response; support selection of human effective dose GDP/GLP GCP Balance: Manufacturing Development, Animal Model Development and the Human Response

18. DVC Program Technical Approach • Science: technical oversight and integration • Quality: oversight of product and clinical studies • Regulatory: FDA communications, strategy for licensure • Manufacturing: material for clinical and nonclinical studies • Nonclinical: animal studies (safety, immunogenicity, efficacy) • Clinical: Phase 1,2,3 safety and immunogenicity trials

19. Regulatory FDA Interactions Pre-IND meeting IND submitted with all development plans included Type C meetings Discussion of aspects of technical development plan Study designs provided for comment prior to conducting the study Timing of interactions is critical: Too soon: insufficient detail to receive specific comments Too late: cost and schedule impacts due to FDA comments

20. FDA Communication • Close FDA communication is vital; no vaccine has yet been licensed under the Animal Rule • Workshops • Working groups • Formal meetings • Review of strategy • Review of study protocols

21. Science: technical oversight and integration • Quality: oversight of product and clinical studies • Regulatory: FDA communications, strategy for licensure • Manufacturing: material for clinical and nonclinical studies • Nonclinical: animal studies (safety, immunogenicity, efficacy) • Clinical: Phase 1,2,3 safety and immunogenicity trials DVC Program Technical Approach

22. Development of a Manufacturing Process • Phase 1 • Emphasis on Safety • Source characterization • Raw materials traced and qualified • Characterization of purified bulk and FDP • Testing /clearance of Impurities • Description of manufacturing • Assay development • Formulation • Quality • Phase 3 • Control and Validation • Process optimized • Process and assay Validation • Specifications • Consistency Lot production • Quality • Phase 2 • Scientific Evaluation • Purified bulk and FDP characterization • Assay development • Increased stability • Continued formulation development • Product characterization • Change Control • Reference standard • Quality

23. DVC Program Technical Approach • Science: technical oversight and integration • Quality: oversight of product and clinical studies • Regulatory:FDA communications, strategy for licensure • Manufacturing: material for clinical and nonclinical studies • Nonclinical: animal studies (safety, immunogenicity, efficacy) • Clinical: Phase 1,2,3 safety and immunogenicity trials

24. Critical Issues • What is the intended label indication? • How does disease in the animal model compare to human disease? Are sufficient hallmarks covered? • Demonstrating correlate of protective immunity in animals, including humans • Is the mechanism of protection clearly defined? • Are functional in vitro assays available? • Is the challenge material characterized and have the route and dosage been determined? • Breakthrough of protection? • How is protection defined? • Are there multiple subtypes to consider? • Statistical considerations? • May need multiple animal models to satisfy Animal Rule requirements

25. Nonclinical Strategy for Vaccines Demonstrate Safety (Tox studies) Model selection: Animal studies must demonstrate that the vaccine is likely to clinically benefit humans. Enable selection of a protective dosage for humans. Identify a marker of immunity that predicts protection and can be measured in both animals and humans. Mechanism of protection: is it known? Pivotal animal studies Demonstrate efficacy Bridge immune responses to human immune responses

26. Considerations for Animal Model Selection • Species • Susceptibility to pathogen by the route of exposure intended for the label indication • Similarity to human response • Display similar characteristics to human disease and pathogenesis • Immune response • Endpoints of study • Manipulations required • Cost • Facility space and required biosafety containment level • Availability of sufficient animals

27. Development of Animal Models Pre- Clinical Phase 1 Phase 2 Phase 3 • Emphasis on development • The studies often use research-grade products • Proof-of-concept studies • Develop and present a regulatory strategy • Nonclinical safety studies • Scientific evaluation, • prevalidation studies • FDA communication on animal model design • Animal studies to support design of pivotal studies • Change control (how do manufacturing changes affect product performance in animal models) • Control and validation • Facility, process and assay validation complete • Demonstrate efficacy in animal models (GLP) • Collect supportive data from clinical study • Reproductive toxicity

28. Proof-of-Concept Studies • Good Documentation Practices • Identification and development of relevant animal models • Preferably more than one animal species • Animal study endpoint is clearly related to the desired benefit in humans • Route of administration • Adjuvant requirement • Formulation optimization • Dose and schedule requirements • Animal data supports effective dose in humans • Immunological Response • Development of assays to detect response

29. Addressing the Requirements

30. Bridging the Immune Response – Vaccine Example Vaccination Vaccination Efficacy Study Clinical Study Human Sample NHP Sample Immunology Assay

31. DVC Program Technical Approach • Science: technical oversight and integration • Quality: oversight of product and clinical studies • Regulatory: FDA communications, strategy for licensure • Manufacturing: material for clinical and nonclinical studies • Nonclinical: animal studies (safety, immunogenicity, efficacy) • Clinical: Phase 1,2,3 safety and immunogenicity trials

32. DVC Clinical Efforts IND BLA R&D Pre- Clinical Phase 1 Phase 2 To the Market Phase 3 FDA Approval Animal Rule – Efficacy Studies

33. Conclusions • The Animal Rule is a last-resort approach to vaccine licensure, with unique challenges and no exceptions to the licensure requirements under other regulations. • The challenges may be met with careful planning and coordination of technical activities. • No vaccines have been licensed to date using this new regulatory approach. This adds risk to a program. • Licensure under the Animal Rule will increase the program’s cost and likely extend the time to licensure. • FDA communication is essential for success.

34. Acknowledgments • Chemical Biological Medical System-Joint Vaccine Acquisition Program (CBMS-JVAP), Department of Defense (DoD) Contract DAMD 17-98-C-8024 • National Institute Of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Contract No. N01-AI-50041