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

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Perspectives on Licensing Vaccines by the Animal Rule

Mary Kate Hart, Ph.D.

Director, Nonclinical Research

DynPort Vaccine Company LLC, A CSC Company

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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

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Vaccine Development by DVC: Perspectives and Considerations

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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

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Perspectives on Biodefense Vaccines

• Developing vaccines for biodefense– What are we building?

– What are the customer’s requirements?

– What are the risks?

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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.

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What are the requirements?

• 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)

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.

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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.

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

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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)

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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

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Development Timeline – Traditional Approach

R&DPre-

Clinical Phase 1 Phase 2 Phase 3

FDA Approval

To the Market

Clinical Studies

6.5YEARS 7

TOTAL: 15 years

1.5

IND BLA

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Development Timeline – Animal Rule Approach

R&DPre-

Clinical

Phase 1 Phase 2 Phase 3 FDA

Approval To the Market

TOTAL: Unknown

IND BLA

Animal Rule – Efficacy Studies

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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

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DVC’s Approach to Meeting the Animal Rule Requirements

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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

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Balance: Manufacturing Development, Animal Model Development and the Human Response

Justify why human trials are not feasible or ethical; justify appropriateness of selected animal models

GDP/GLP

CGMP

GCP

Correlate of Protective Immunity

Bridge to human response; support selection of human effective dose

Demonstrate manufacturing consistency – effective change control

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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

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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

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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

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Phase 1Emphasis 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 2Scientific Evaluation – Purified bulk and FDP

characterization– Assay development– Increased stability– Continued formulation

development– Product

characterization– Change Control– Reference standard– Quality

Phase 3Control and Validation– Process optimized– Process and assay

Validation– Specifications– Consistency Lot

production– Quality

Development of a Manufacturing Process

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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

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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

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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

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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

Development of Animal Models

Pre- Clinical

Phase 1 Phase 2 Phase 3

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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

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Addressing the Requirements

Animal Rule Requirements Study Design

Understand the disease• Lethal dose for 50% of animals (LD50);

natural history (pathophysiology)

Demonstrate efficacy in more than one species which react as humans would with similar endpoint (e.g., survival)

• Test article administration combined with an active challenge

• Evaluate immune response• Establish assay to be used as correlate• Breakthrough of protection

Select effective human dosage

• Establish vaccination regimen that induces immune response similar to that observed in the clinic. Demonstrate efficacy in challenge study

• Evaluate dosage in clinical trials

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Bridging the Immune Response – Vaccine Example

Efficacy Study Clinical Study

Immunology Assay

Vaccination Vaccination

NHP Sample Human Sample

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DVC Clinical Efforts

R&DPre-

Clinical

Phase 1 Phase 2 Phase 3 FDA

Approval To the Market

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Animal Rule – Efficacy Studies

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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.

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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

Documents

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