1 Considerations for Licensure of Next Generation Smallpox Vaccines Timothy Nelle, PhD Team Leader, Division of Vaccines and Related Applications Office of Vaccines Research & Review Center for Biologics Evaluation & Research September 16, 2011

2 Outline  Define “next generation” smallpox vaccines  Regulatory considerations for licensure  Review the tenets of Animal Rule  Challenges for licensure under the Animal Rule  Possible approaches

3 ‘Generations’ of Smallpox Vaccines  First Generation (no longer manufactured) :  Dryvax, Wetvax, Elstree-RVIM, and others  Live vaccinia virus  Propagated on the flanks of animals (calf, sheep, etc.)  Considered the “Gold Standard” for protection against smallpox  Associated with rare, serious adverse reactions  More recently, high rate of myopericarditis (Dryvax)  Second Generation:  ACAM2000 (US Licensed), Elstree-BN  Virus strains derived from First Generation Vaccines  Cell-Culture based production  Modern standards for safety, potency, purity, efficacy, GMP, etc  May have serious adverse reaction profile similar to previous vaccines  Although no clinical efficacy study (i.e., smallpox is eradicated), licensure via demonstration of non-inferiority to Dryvax

4 Next ‘Generations’ of Smallpox Vaccines  Third Generation (currently in advanced development) :  MVA, LC16M8, NYVAC, and others  Attenuated vaccinia virus  Cell-culture derived  Expected to have better safety profile  Efficacy in preventing smallpox is unknown  Fourth Generation (currently in early development) :  Protein subunit, DNA, recombinant virus-vectored vaccines, etc

5 Regulatory Considerations for Licensure  Efficacy cannot be assessed in “field trials”  “Take” probably cannot be used as an endpoint as new vaccines produce either no take or modified take  Licensure likely to be based on the “Animal Rule” The use of the actual pathogen (variola) in definitive animal studies is problematic  A licensed vaccine (ACAM2000), is available What role should it play in evaluation of next generation smallpox vaccines, if any?

6 The “Animal Rule” “New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible” Federal Register 67: , 2002 Allows animal efficacy data to be used as a basis for approval, when human efficacy studies are not ethical or feasible to conduct

7 Animal Rule Approval Regulation (21 CFR ) FDA may grant marketing approval of a product, for which safety has been established in humans, based on adequate and well-controlled animal studies, the results of which establish that the product “is reasonably likely to provide clinical benefit in humans”.

8 Animal Rule Criteria  FDA will rely on animal efficacy data only where: 1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention or substantial reduction by the product 2. 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

9 Animal Rule Criteria 3. The animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity 4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information in animals and humans allows selection of an effective dose in humans  (For vaccines, the vaccine dose given to humans should elicit an immune response in humans comparable to the immune response achieved in animals that were protected by the vaccine)

10 Challenges for Licensing Smallpox Vaccines via Animal Rule  The use of the actual pathogen (variola) in definitive animal studies is problematic  The protective mechanisms are not known and the relative roles and contributions to protection of various types of immune responses are not completely understood  Smallpox vaccines elicit humoral and cellular immune responses  Data from animal models suggest both neutralizing antibody and cell-mediated responses are important  Selection of animal model… made on a case-by-case basis Animal Model development will be discussed during Session II today….

11 Challenges for Licensing Smallpox Vaccines via Animal Rule  How should animal protection data be “bridged” to humans?  Choice of immunological parameter to use as a “bridge”  Significant involvement in mechanism of protection  Species-independent (Humans vs Animals)  Plaque Reduction Neutralization Test may be a candidate Other candidates, e.g. CMI-based, should be evaluated  Identification of a correlate of protection not a licensure requirement

12 Possible Approaches to Licensure under the Animal Rule  Anthrax PEP model  Including non-inferiority to ACAM2000

13 Anthrax Animal Rule Approach Post-exposure Prophylaxis (PEP) Indication (Discussed in detail during VRBPAC Meeting, November 16, 2010)

14 Estimate Protective Antibody Levels in Animals Determine the relationship between antibody levels and survival

15 Clinical Trials Determine the population distribution of antibody titers in the human study population

16 Extrapolating Protective Antibody Levels  Link data sets using an antibody bridge  Extrapolate animal protection data to humans  Assess whether the vaccine is reasonably likely to provide clinical benefit

17 Major Differences Between Anthrax PEP and Smallpox that Affect Approach to Animal Rule  Anthrax animal models use anthrax  Current smallpox models do not use actual agent (i.e., variola)  Known protective mechanism for anthrax  Antibodies alone to a single antigen (Protective Antigen (PA)), in the absence of other facets of the immune system, can provide protection  Therefore, antibodies to PA would be an appropriate immune marker to link animal protection data to human efficacy  Protective mechanism for smallpox vaccine unclear  No single protective antigen for smallpox  Appropriate immune marker for bridging to be determined…  A licensed smallpox vaccine (ACAM2000) is available…

18 Should demonstration of non-inferiority to ACAM2000 in animals and/or clinical trials be required for licensure???

19 Incorporating Non-Inferiority to ACAM2000 in an Animal Rule Approach  Each Pivotal Animal Study would contain separate arms ACAM2000 and the investigational vaccine  Endpoints:  Survival from Challenge and Immunogenicity (PRNT) For PRNT, Choice of virus for neutralization is important  Pivotal Human Study may include an ACAM2000 arm*  One approach to studies that include ACAM2000 would be limited to ‘at risk’ populations, such as the military  Endpoints:  Immunogenicity (e.g. PRNT) to allow bridging to pivotal animal studies  Non-inferiority of immunogenicity to ACAM2000 (only if included in study)  Human Safety Studies still required for licensure

20 Should licensure of future smallpox vaccines be based on non-inferiority to ACAM2000?  Dryvax no longer available  ACAM2000 induces high neutralizing antibody titers  Over 90% of subjects had titers greater than 1:32* (* value that might be protective based on historical published record.)  …but induces lower neutralizing antibody titers than Dryvax  Non-inferiority endpoint narrowly missed in vaccinia-naïve population  Basing licensure of future vaccines on non-inferiority to ACAM2000 would allow further decrease in the level of acceptable neutralizing antibody titers  (i.e., “Regulatory Down-Creep”)

21 ACAM2000 : Neutralizing Antibody  Non-inferiority endpoint narrowly missed in primary vaccination, met in previously vaccinated subjects

22 Acknowledgment  Jerry Weir  Drusilla Burns  Cynthia Kelley  Rakesh Pandey  Wellington Sun  Marion Gruber