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					                                                          "State of the Industry" Regarding Animal Model Development and Using the Animal Rule for Licensure
                                                                                                                                                                                                    Doris Snow, Ph.D.1,2
                                                                                                                                                                                        1Vaccines Subgroup of Alliance for Biosecurity
                                                                                                                                                                               2DynPort Vaccine Company LLC, A CSC Company, Frederick, MD



                                                                           Introduction                                                                                         Figure 1 Product Development Timelines for Traditional vs. Animal Rule Licensure Pathways                                                                                                                   Figure 8 Potential Difficulties with Overall Product Development                                                                          Table 2 Technology Readiness Level (TRL) Status
Licensure using animal models poses the risk that the products may not work as intended in humans, thus efficacy testing using the Animal Rule presents a more                                                                                                                                                                                                                                                                                                                                                                                    Animal Models       Overall Product
                                                                                                                                                                                       Traditional Approach                                                                                                                                                                                                                                                                                                                             TRL
complicated path to licensure than the more traditional route of efficacy testing in humans. It is particularly challenging to develop and refine relevant animal                                                                                                       TOTAL: 15 years                                                                                                                                Funding
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   Criteria Only       Development
models that mimic human disease, to demonstrate vaccine efficacy and amelioration of disease using animal challenge models and to bridge the animal responses                                                                                                               7                                             1.5                                                                         Clinical Study Planning
                                                                                                                                                                                          YEARS                 6.5                                                                                                                                                                                                                                                                                                                       1            0.0%                0.0%
to human immune responses to predict clinical benefit. The Animal Model Working Group of the Alliance and its Vaccines Subgroup initiate regular dialogue                                                                            IND                                                                          BLA
                                                                                                                                                                                                                                                                                                                                                                                             CRO/CMO Project Management
between industry, academia and government on means to accelerate development of acceptable animal models to support advanced development of products                                                                                                                                                                                                                                                                                                                                                                                      2            0.0%                0.0%
under the Animal Rule. What is the current understanding of the "State of the Industry" in regards to animal model development? What is the current status of                                                                                                                                                                                                                                 Nonclinical Safety Study Design
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          3            8.3%                8.3%
animal model development for medical countermeasures? What are industry’s most pressing concerns? What models are working and are considered well-                                                                                                    Phase 1                   Phase 2             Phase 3
                                                                                                                                                                                                                                                                                                                                                                                              Regulatory/Quality Interactions
characterized by the scientific community? What models are not working? These and other challenging questions have been assessed via a confidential survey of                                                             Pre-                                                                                                   FDA                                                                                                                                                                                                      4            8.3%                8.3%
                                                                                                                                                                                             R&D                                                                                                                                                                 Phase 4
                                                                                                                                                                                                                          Clinical                                                                                              Approval                                                          Animal Model Development
industry (Alliance and non-Alliance companies), CROs and academic research centers. The survey was conducted anonymously online in the fall of 2009.                                                                                                      Animal Rule – Nonclinical Efficacy Studies                                                                                                                                                                                                                                      5            8.3%                0.0%
                                                                                                                                                                                                                                                                                                                                                                                                            Process Validation
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          6            8.3%               25.0%
                                                                                                                                                                                                                                                                                                                                                                                                           Assay Development
                                                                                                                                                                                                                                                                        TOTAL: Unknown                                                                                                                                                                                                                                                    7           50.0%               25.0%
                                                             The Alliance for Biosecurity                                                                                              Animal Rule Approach:                                                                                                                                                                                       Manufacturing "At-Scale"
                                                                                                                                                                                       Traditional Requirements and
                                                                                                                                                                                                                                                                                                                                                                                                                                                                    Funding                                                               8           16.7%               33.3%
The Alliance for Biosecurity works to promote a stronger, more effective partnership between government and the BioPharma industry to better develop critically                                                                                                                                                                                                                                                             Available Analytical and Immunological Tools to
                                                                                                                                                                                       Additional Nonclinical Studies                                                                                                                                                                                                          0.0%         10.0%         20.0%
                                                                                                                                                                                                                                                                                                                                                                                                                                  Interpret Data from Animal Models     30.0%      40.0%     50.0%    60.0%   70.0%       80.0%           9            0.0%                0.0%
needed medical countermeasures. The Alliance also seeks to usher in a new era in the prevention and treatment of severe infectious diseases that present global                                                                                                                                                                                                                                                                      Interpreting Regulatory Requirements
                                                                                                                                                                                                                                     IND                                                                        BLA
security challenges. This new era will be characterized by the capacity to rapidly develop, produce and stockpile medical countermeasures for the country.                                                                                                                                                                                                                                                                      Insufficient Experience in Designing Models                                           Major Problem

Members of the Alliance are striving to create a long-term national security vision for achieving and sustaining defenses against a range of current and future                                                                                                                                                                                                                             Figure 9 Potential Difficulties withofAnimal Space
                                                                                                                                                                                                                                                                                                                                                                                                                          Availability Biosafety Lab Model Development
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      Manageable
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      Not a Problem    Figure 10 Sufficient Regulatory Guidance?
                                                                                                                                                                                                                                                                                                                                                                                                                              Availability of Critical Reagents for Challenge
biothreats. Much can and should be done by public and private partners in advance of a bioterrorist attack or natural pandemic to minimize illness and death, as                                                                                                                                                                                                                                                                           Within Animal Studies

well as catastrophic social, economic and political disruption.                                                                                                                                                                                                                                                                                                                                                                Product Availability to use in Animal Studies                                                             70.00%
                                                                                                                                                                                                  1, 2,                    3, 4, 5                    6                          7                    8                                                          9                                                                     Funding
                                                                                                                                                                                                                                                                                                                                                                                                                                                                            0.0%     20.0%    40.0%   60.0%   80.0%
                                                                                                                                                                                                                                                                                                                                                                                             Available Analytical and Immunological Tools to
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         60.00%
Sample Alliance activities include:                                                                                                                                                                                                                                                                                                                                                                Interpret Data from Animal Models
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         50.00%
• Educating members of Congress and other government stakeholders about biosecurity and drug development issues                                                                                                                                                                                                                                                                                       Interpreting Regulatory Requirements
                                                                                                                                                                                                                                 HHS Technology Readiness Levels for Medical Countermeasures Products                                                                                                                                                                                                                                    40.00%
• Promoting the goals of the Biomedical Advanced Research and Development Authority (BARDA) within HHS                                                                                                                                                                                                                                                                                                                                                                                                           Major Problem
                                                                                                                                                                                                                                                                                                                                                                                                 Insufficient Experience in Designing Models
• Publishing in Nature Biotechnology an article about the challenges of animal model development under the FDA’s Animal Efficacy Rule and presenting                                                                                                                                                                                                                                                                                                                                                             Manageable              30.00%
                                                                                                                                                                           Figure 2 Funding Sources                                              Figure 3 Phase of Clinical Development                                               Figure 4 Overall Program Goal                                       Availability of Biosafety Lab Space
  proposed solutions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             Not a Problem
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         20.00%
                                                                                                                                                                            100.0%                                                                                                                                                              Basic/Academic
• Pursuing a public-private collaboration on animal model development issues                                                                                                                                                                      80.0%                                                                                            Research                                    Availability of Critical Reagents for Challenge
                                                                                                                                                                             90.0%                                                                                                                                                                    7%                                                    Within Animal Studies                                                                                                        10.00%
  – Members of the Alliance and experts from NIAID, USAMRIID, DTRA and BARDA have been working together to develop a joint database of natural                               80.0%
                                                                                                                                                                                                                                                  70.0%
                                                                                                                                                                                                                                                                                                                                                                                                Product Availability to use in Animal Studies                                                                                             0.00%
    history and control data for Animal Models relevant to therapeutic countermeasures. The purpose of the database is to share data, increase scientific                    70.0%                                                                60.0%
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        Yes                 No
    understanding, accelerate development of needed countermeasures and decrease overall use of animals.                                                                     60.0%                                                                50.0%                                                                                        Toxicology and         Licensure/Marketing                                                        0.0%              20.0%           40.0%      60.0%      80.0%
• Providing venues for stakeholder dialogue about key biosecurity policy issues                                                                                              50.0%                                                   Product X    40.0%
                                                                                                                                                                                                                                                                                                                         Phase 1             Immunology (only
                                                                                                                                                                                                                                                                                                                                              through Phase 1)
                                                                                                                                                                                                                                                                                                                                                                           Approval
                                                                                                                                                                                                                                                                                                                                                                              27%

• Developing and presenting consensus policy proposals to government                                                                                                         40.0%                                                                                                                                                                  17%
                                                                                                                                                                                                                                     Product Y                                                                           Phase 2
                                                                                                                                                                             30.0%                                                   Product Z
                                                                                                                                                                                                                                                  30.0%
                                                                                                                                                                                                                                                                                                                         Phase 3
       MEMBERS        Bavarian Nordic                            Emergent BioSolutions                           Pfizer Inc.
                                                                                                                                                                             20.0%                                                                20.0%                                                                                       Availability for
                                                                                                                                                                                                                                                                                                                                              Emergency Use            Strategic National
                                                                                                                                                                                                                                                                                                                                                                                                                                            Moving Forward - Facilitating Animal Model Development
                                                                                                                                                                             10.0%                                                                                                                                                            Authorization                Stockpile
                      Cangene Corporation                                                                         PharmAthene
                                                                                                                                                                                                                                                  10.0%                                                                                                                      25%
                                                                  Hematech, Inc., a subsidiary of Kyowa Kirin
                                                                                                                                                                                                                                                                                                                                                   24%
                                                                                                                                                                             0.0%                                                                                                                                                                                                           What Can Industry Do?
                      DOR BioPharma, Inc.                                                                         SIGA Technologies
                                                                                                                                                                                     Government     Private    Venture    Academic                 0.0%
                                                                  Human Genome Sciences, Inc.                                                                                        Contracts     Grants     Capital     Grants                                                                                                                                                           • More transparency and cooperation, less secrecy and scientific egotism about what models are best
                                                                                                                                                                                                                                                                Product X            Product Y      Product Z
                      DynPort Vaccine Company LLC, A             NanoViricides, Inc.                             Unither Virology LLC, a subsidiary of United                                                                                                                                                                                                                            • Work with the animal model CRO and allow interaction between the CRO, sponsor and regulator agencies. Some industry partners are better than
                       CSC Company                                                                                  Therapeutics                                             *Companies were requested to provide details on product development on up to 3 products (e.g., X, Y and Z)                                                                                                       others
                      Elusys Therapeutics, Inc.                                                                                                                                                                                                                                                                                                                                            • Encourage publication of data for government funded development (e.g., participation in public meetings and sharing of data)
                                                                                                                                                                           Figure 5 Intended Market                                                                                                    Figure 6 Funding Secured                                                             • Coordinate efforts to support natural history studies and development of a database to house natural history data that is accessible to those working to
     ASSOCIATE        Battelle Biomedical Research Center           Southern Research Institute                                                                                                                                                                                                                                                                                             development countermeasures
      MEMBERS         Lovelace Respiratory Research Institute                                                                                                                                                                                                                                            60.0%
                                                                                                                                                                                           Africa                                                                                                                                                                                           • To avoid duplication, discuss with other agencies animal model development
                                                                                                                                                                                                                                                                                                          50.0%                                                                             • Free exchange of information with other agencies
                                                                                                                                                                             Australia-Indonesia                                                                                                                                                                                            • Consistency of study designs so that comparison across studies can be done
Table 1 Alliance Survey Response Summary                                                                                                                                                                                                                                                                  40.0%
                                                                                                                                                                                      Asia-Pacific                                                                                                                                                                                          • Develop a database to share natural history, and ideally safety and efficacy information
             Question                                                                            Details                                                                                                                                                              Government & Public Market                                                                           Product X
                                                                                                                                                                                                                                                                                                          30.0%                                                                             • Provide necessary skill sets to support regulatory approval process
                                                                                                                                                                                     Middle East                                                                      Public Market                                                                                        Product Y
                                       The survey was distributed to 23 industry organizations, 4 CROs/CMOs and 13 academic organizations (including RCEs)
                                                                                                                                                                                                                                                                                                          20.0%
                                       and 3 US government entities. Of the 12 completed surveys, 9 were from industry, 1 was from academia and 2 were from                     Western Europe
                                                                                                                                                                                                                                                                      Government Market                                                                                    Product Z        What Can the Government Do?
 Who Participated?                                                                                                                                                                                                                                                                                                                                                                          • Interact directly with the CRO during animal model development
                                       CRO/CMOs. Six incomplete surveys were provided but not included in the summary. As additional surveys are                                                                                                                                                          10.0%
                                       completed the Alliance will update survey results on the Alliance website.                                                                US and Canada                                                                                                                                                                                              • Provide more funding in early development with allowance for reasonable timelines in government contracts, understanding that studies need to be
                                                                                                                                                                                                                                                                                                          0.0%
                                                                                                                                                                                                                                                                                                                                                                                              repeated or refined
 What is the Primary Focus of the                                                                                                                                                                   0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0%                                                                  Phase 1     Phase 2    Phase 3 Licensure
                                       The organizations focus on therapeutic development (9), vaccine development (8) and environmental protection (1).                                                                                                                                                                                                                                    • Make available data from government master files
 Organizations?                                                                                                                                                                                                                                                                                                                                                                             • Provide transparency and more rapid availability of natural history data
                                                                                                                                                                                                                                                                                                                                                                                            • Fund support for an accessible database to house natural history data
 What is the Purpose of Animal
                                       All of the respondents indicate that the purpose of animal model development within the organization is intended to                                                    What is the Single Most Difficult Challenge in Developing Animal Models?                                                                                                      • Provide for more efficient and enhanced communication among the stakeholder agencies within government (e.g., NIAID/BARDA/FDA/DoD)
                                       demonstrate efficacy under the Animal Rule. Animal models are also being developed for toxicity testing (75%), proof of                                                                                                                                                                                                                              • Allow for free exchange of information between governmental agencies as well as industry
 Model Development Within                                                                                                                                              •    Ensuring that the model will meet regulatory needs for EUA/stockpiling/FDA licensure
                                       concept studies (75%), development of correlates of protection (8.3%) and evaluation of non-traditional threats and                                                                                                                                                                                                                                  • Improve the funding structure; with the structure of funding (limit of five years in many cases), it is not possible to conduct many model development
 Organizations?                                                                                                                                                        •    Time and money required to develop models for an area (e.g., Acute Radiation Syndrome) where there are no models that have been tested with the FDA
                                       neglected tropical diseases (8.3%) .                                                                                                                                                                                                                                                                                                                   and refinement studies in two species and also complete pivotal studies in two species
                                                                                                                                                                       •    Continued expansion of Animal Rule compliance expectations - not clearly defined
                                                                                                                                                                                                                                                                                                                                                                                            • Direct funding in terms of R&D contracts to industry to develop animal models before funding approved for licensure
                                       Biological threats are being evaluated by 91.7% of respondents (9/9 category A and 3/9 category A, B and C).                    •    Bridging animal data to clinical data
 What Category Threats Are Being                                                                                                                                                                                                                                                                                                                                                            • Obtain more expertise within the various agencies (immunology and investment in BSL-3 and BSL-4 facilities)
                                       Radiological and nuclear threats (33.3%), chemical defense countermeasures (33.3% ) and emerging diseases (58.3%) are           •    Accessibility to natural history data generated under government sponsorship
 Evaluated?                                                                                                                                                                                                                                                                                                                                                                                 • Obtain agreement with FDA on what models will support labeling, then develop and publish them
                                       being evaluated by respondents. Neglected tropical diseases are also being studied (8.3%).                                      •    Developing and evaluating therapeutic models with respect to challenge dose, route, pathogenesis, and clinical course in reflecting human clinical scenario
                                                                                                                                                                                                                                                                                                                                                                                            • Make supporting assays available
                                                                                                                                                                       •    Developing combination therapy models and showing added benefit is even a greater challenge
                                       More than 54% of the respondents use a combination of in-house and contract laboratories to perform work associated                                                                                                                                                                                                                                  • Provide more funding opportunities to support further development and to increase infrastructure to support the nonhuman primate model
                                                                                                                                                                       •    Clear feedback from FDA on their requirements
                                       with licensing products using the Animal Rule whereas 36% solely use CROs. GLP compliance varies based on the type
 Are Laboratories GLP-Compliant?                                                                                                                                       •    Conducting efficacy/safety studies that will be acceptable to support FDA licensure on a limited budget, with technical constraints (BSL3, assay readiness)                                                     What Areas Are in Need of Regulatory Guidance?
                                       of study as described: assays (75%), animal model development (58.3%), proof of concept studies (66.7%) and pivotal
                                                                                                                                                                       •    Obtaining experienced people                                                                                                                                                                                    • Provide more product specific guidance
                                       animal studies (75%).
                                                                                                                                                                       •    Ability to acquire funding to support costly animal studies                                                                                                                                                     • Provide clarity without requiring companies to come in for meetings (pre-IND, NDA)
 How Many INDs Related to the                                                                                                                                                                                                                                                                                                                                                               • Consider that animal models cannot be developed as black box human surrogates. For example, ICU expectations for humans can not be extrapolated
                                       The respondents in total have filed 14 INDs. The products are in Phase 1 and 2 development.
 Animal Rule Are Represented?                                                                                                                                              Figure 7 Integration of Development Processes                                                                                                                                                                      to a NHP animal model
                                                                                                                                                                                                                                                                                                                                                                                            • Provide guidance related to antibiotics in anthrax therapeutic models
                                                              What is the Animal Rule?                                                                                                                                    Nonclinical Studies
                                                                                                                                                                                                                                                                          Nonclinical Studies                           Nonclinical Studies
                                                                                                                                                                                                                                                                                                                                                                                            • Provide guidance on combination therapy requirement
                                                                                                                                                                                                                                                                          Prevalidation, FDA                           GLP Pivotal efficacy,
                                                                                                                                                                                                                      Model Development, proof-of-                      discussions on models,                     reproductive toxicity, bridge                                            • Provide guidance on the set dose or route of administration established for concurrent therapy
• An opportunity to license unique products that would otherwise remain in regulatory limbo with no clear pathway for approval.                                                                                        concept, nonclinical safety,
                                                                                                                                                                                                                       develop regulatory strategy
                                                                                                                                                                                                                                                                       effect of change control,
                                                                                                                                                                                                                                                                       studies to support pivotal
                                                                                                                                                                                                                                                                                                                      immunologic data from
                                                                                                                                                                                                                                                                                                                        nonclinical/clinical,
                                                                                                                                                                                                                                                                                                                                                                                            • Provide guidance on drug-drug interactions
• The FDA will consider the animal data to support licensure of a product only when the following conditions are met:                                                                                                                                                        GLP efficacy                              validation as feasible                                               • Provide understanding of the immunological correlates, especially when these may move away from the established neutralizing antibody mechanism
  1) The pathophysiological mechanism of toxicity and the prevention or substantial reduction of this toxicity by the vaccine are reasonably well understood in                                                                                                                                                                                                                             • Provide guidance on how to address safety concerns of drug administration in sick animals
      the animal models.                                                                                                                                                                                                                                                                                                                                                                    • Offer guidance on the requirements for studying combination therapies (e.g., How many concomitant drugs to test; or drug interaction (PK) only or
  2) The effect is demonstrated in a single sufficiently well-characterized animal model for predicting the response in humans, or independent substantiation of                                                                                                           Manufacturing                                                                                                      added benefit?)
                                                                                                                                                                                                                                                                                                                         Manufacturing
      the effect in multiple animal species.                                                                                                                                                                                 Manufacturing                                  Evaluation:                               Control and validation,                                               • Clinical relevance of animal models: triggers-to-treat, exposure levels, age of animals?
                                                                                                                                                                                                                                                                          characterization,
  3) The animal study endpoint clearly relates to the desired benefit in humans.                                                                                                                                         Emphasis on safety, assay
                                                                                                                                                                                                                             development                                formulation, assays,
                                                                                                                                                                                                                                                                                                                        consistency lots,
                                                                                                                                                                                                                                                                                                                          specifications
                                                                                                                                                                                                                                                                                                                                                                                            • Provide guidance on how best to link drug exposure with efficacy and human dose
  4) The kinetics and pharmacodynamics of the product in animals and humans allows for selection of an effective human dose.                                                                                                                                               change control

• Sponsors are expected to demonstrate that the effect of the product in animals is reasonably likely to predict clinical benefit in humans.
• Animal Rule approval is subject to requirements (e.g., post-marketing studies, restrictions on use, specialized information package for recipients and termination                                                                                                                                                                                                                                                                                Alliance for Biosecurity  1500 K Street, NW  Washington DC 20005
  of requirements).                                                                                                                                                                                                                                                                                                                                                                                                                            Contact: Anita Cicero, Alliance Secretariat  202-230-5163  anita.cicero@dbr.com
• Nonclinical studies adhere to the Animal Welfare Act (7 U.S.C. 2131 et.seq.).                                                                                                                                                    Clinical                                     Clinical                                     Clinical                                                                                                                                  http://www.allianceforbiosecurity.org
                                                                                                                                                                                                                             Phase 1 safety and                       Phase 2 immunogenicity and                   Phase 3 expanded safety and
                                                                                                                                                                                                                                                                                                                         immunogenicity
                                                                                                                                                                                                                         evaluate immune responses                     continue safety evaluation
                                                            What the Animal Rule is Not!                                                                                                                                                                                                                                                                                                                                                                                                              References
• Does not apply to products when approval can be based on a demonstration of efficacy as described in other regulations such as 21 CFR 601.41                                                                                                                                                                                                                                              • 21 CFR 601.91 Subpart H, ―Approval of Biological Products When Human Efficacy Studies Are Not Ethical or Feasible‖
• Does not address evaluation of safety as safety must be demonstrated in human volunteers in clinical trials (i.e., Phase 1, 2 and 3).                                                                                                                                                                                                                                                     • Draft FDA Guidance (2009): "Animal Models — Essential Elements to Address Efficacy Under the Animal Rule"
• Does not equal a short cut to approval.
                                                                                                                                                                                                                                                          Regulatory Affairs and Quality                                                                                                    • Grönvall et al. The FDA animal efficacy rule and biodefense. Nat. Biotech. 2007 Oct; 25: 1084-1087.

				
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