Transcript Animal Rule

J.E. Estep, DVM, PhD
Senior Program Manager
Battelle Memorial Institute
29 January 2009
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History
What is “The Animal Rule”
Essential Elements of an Animal Model as a Test
System
Discussion
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Issue:
◦ Licensing of CBRN medical products (prophylactics, therapeutics)
when normal clinical trails are not possible requires alternative
approaches for efficacy demonstration
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Solution – 21 CFR 314.600 & 21 CFR 601.90 – “Animal Rule”
Approval of Drugs and Biological Products (Vaccines, Therapeutics)
When Human Efficacy Studies Are Neither Ethical or Feasible
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Request For Comments:
Proposed Rule:
Final Rule:
Regulations:
62 FR 40996 (July 31, 1997)
64 FR 53960 (Oct 5, 1999)
67 FR 37988 (May 31, 2002)**
21 CFR § 601.90-95 (Biologicals)
21 CFR § 314.600-650 (Pharmaceuticals)
◦ Guidance for Industry: Animal Models – Essential Elements to Address Efficacy
Under the Animal Rule (January 2009) – DRAFT (recommendations)
** = significant change
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Important points
◦ Animal rule concerns the approval of new drug or
biological products when human efficacy studies are
neither ethical nor feasible
◦ Testing under the Animal Rule is a surrogate for human
efficacy/clinical studies
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The Rule does not apply if product approval can be
based on standards described elsewhere in U.S. FDA
regulations
Safety must still be demonstrated in human subjects
enrolled in conventional clinical trials – Phases I-III
FDA may approve a product for which …
◦ Human safety has been established, and;
◦ “Animal Rule” requirements are met – based on adequate and
well-controlled animal studies, the results of which establish that
the product is reasonably likely to provide clinical benefit when
administered in humans
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Reasonably well-understood pathophysiological mechanism
of the toxicity of the substance (agent) and its
prevention/reduction by the test product
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Effect is demonstrated in more than one animal species
expected to react with a response predictive of human
◦ ”2 Animal Rule” *
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* the effect can be demonstrated in a single animal species if there is a
sufficiently well-characterized animal model for predicting the response in
humans; nowhere in the Rule is “Two Animal” stated
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Animal study outcome is clearly related to the
desired benefit in human
◦ Reduced morbidity/mortality
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Data on pharmacokinetics/dynamics of the
product in animals and humans allows selection
of an effective dose in humans
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If these tenets are met then it is reasonable to
expect the effectiveness of the product in animals
to be a reliable indicator of its effectiveness in
human
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Predict the outcome of controls following challenged
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Preparation & characterization of the infectious
agent or chemical material must be standardized,
consistent, reproducible
◦ route, dose, and strain of the infectious agent or chemical
◦ Challenge material is a “critical reagent”
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Use optimized/validated assays to monitor the
response and bridge data to humans
Non-validated assays may be useful and acceptable
Pivotal studies conducted under the FDA GLPs
guidelines
Have a prospective statistical plan in place
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All studies subject to this Rule must be conducted in
accordance with preexisting requirements under the
Good Laboratory Practices (21 CFR § 58)
regulations
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Adherence to Animal Welfare Act (7 U.S.C. 2131)
required
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GLP expected for the definitive/pivotal animal
studies – not necessary for the pilot studies. Also, if
you want to describe an animal study in the label
(package insert), then it should comply with GLP
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The word “Validated” is not mentioned in the regulatory language of
the Rule. The Rule uses the phrase - “adequate and well controlled
animal studies.”
◦ Animals are complex biological systems that will have individual
animal variation (e.g. they are not a 96-well plate, cell culture, an
instrument, etc.) -- ?? validated animal model
Studies must be reproducible and predicative for infected /
intoxicated negative controls
◦ Use validated assays
◦ Standardized instruments and procedures
◦ Techniques or methods should be sensitive enough to make
make comparisons on studies and between species
◦ Comparable results from a given type/dose/route of challenge
◦ Comparable results if study conducted at different location
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The Rule does not apply if product approval can be based on
standards described elsewhere in FDA's regulations – normal
human trials can be done
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Safety must still be demonstrated in human subjects enrolled
in Phase I, II & III clinical trials
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The Rule is not an Accelerated or Fast-Track approval and is
not a short-cut to approval, in fact, it may take longer
◦ Two products licensed under the Animal Rule today, but many more on
the very near horizon
◦ Seven years in all that we have been using this rule
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The purpose of the “Animal Rule” is to develop a product for
use in humans, not animals
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From product concept through advanced
development, everyone should consider the
applicability and requirements of the Animal Rule
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Design studies on a critical path to support the
product development goal – licensure
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Develop integrated research plans which account
for all aspects of the licensing needs
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Studies require Good Laboratory Practice (GLP)
Compliance
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Validation of all critical assays is expected
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Animal Model - Selection Criteria
◦ Species
◦ Pathogenesis
◦ Endpoints of Study
◦ Manipulations Required
◦ Cost
Challenge System
◦ Vaccine / Therapeutic Dose
◦ Delivery of Agent
◦ Strain or Form of Agent
◦ Challenge Dose
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Characterization of the Agent (CBRN)
◦ Etiologic agent same as that caused disease in
humans
 Surrogates can be acceptable
 Monkey pox
◦ Pathogenic Determinants
 How does the agent cause the pathology
 Toxin production of a bacteria
 Target and disrupt a target organ
 This should be the same in both humans and the
animal species
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Characterization of the Agent – continued
◦ Route of Exposure should be same as the treat to
humans
 Inhalation, oral, etc
◦ Quantification of Exposure
 Reliable and reproducible challenge dose
 Show scalable relationship between dose and outcome
(especially in humans)
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Host susceptibility and response
◦ Animal species chosen should be susceptible to the
agent – seems obvious but requires consideration
of the dose compared to the human dose must be
discussed
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Natural history of the disease
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Pathophysiologic comparable to humans
Time course of disease
Manifestations of disease (signs, symptoms)
Pathology
Outcome (death, recovery)
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Trigger for Intervention
Characterization of medical intervention
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Type of material
Mechanism of action
Activity (in vitro and in vivo) – how does it intervene
Pharmacokinetics/Pharmacodynamics
Interactions with other medical products
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Endpoints
◦ Ultimate key to success is the study endpoints
◦ You need to measure something, otherwise you
cannot make a comparison to humans or
characterize the pathogenesis and/or pathology
◦ Common endpoint in our business is ,but we need
drill down to the pathogenesis to understand how
that developed
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Endpoints of Study
◦ Survival / Lethality (ultimate goal, but good not enough)
◦ Non-Lethal Pathology or Clinical Observations
 Pneumonia
 Fever
 Emesis
 Hematology (white blood cell shift reflecting infection)
 Clinical Chemistries (i.e., Liver Function Tests)
◦ Bacteremia / Viremia
◦ Immunomodulation Assessments
 Antibody Production
 T / B Cell Stimulation
 Reagent Availability and Correlation in Humans
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Manipulations Required
◦ Pulmonary Radiographs
 Larger Animal Model
◦ Blood Draw Volume
 Limits Based on Body Weight
 Cellular Component Assessment Require Larger Volumes
◦ Constant Physiological Monitoring Vs Clinical Observations
 Telemetry vs Chaired/Restraint Manipulation
◦ Exposure Route
 Inhalation (Head-Only, Nose-Only, Whole-Body)
 Parenteral
 Oral
 Dermal (percutaneous)
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Pathogenesis
◦ Similarity to human disease process
 SEB - causes emesis and fever in humans and monkeys
 Lethal at higher doses (~1,000 X emesis dose)
 Anthrax - widened mediastinum in humans and monkeys
 Q-Fever - pneumonia in humans and monkeys
 Botulinum - flaccid paralysis in virtually all species
 Classical Nerve Agents
◦ Not an absolute criteria
 Tuberculosis
 Rabbit / Pulmonary Tubercles
 Mouse and guinea pig usually other forms
 VEE – mouse is a lethal model
 Sulfur Mustard – no good animal vessication model
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Timing of intervention
Route of administration
Dose or dose regimen
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Agent characterization
Host susceptibility and natural history
◦ Compared to human disease
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Intervention – what and when
How does the product affect outcome
Animal test design
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Endpoints
Timing of endpoints measuring drive intervention
Route of administration agent
Dosing – route and regimen
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Involve FDA early and in every step of the
product develop program
Never start and pivotal animal challenge
study without getting comments from FDA
When you talk to FDA on the animal test
program – have animal model experienced
scientists on board – FDA expects details on
the plan
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John Wade, DVM, PhD, Personal communication and
prior presentations materials
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Mark J. Abdy, DVM, PhD - “Clarification of the
Regulatory Position Regarding Animal Studies to bring
Vaccines to Licensure,” 2006
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Many: Scientists, Battelle and other companies, NIAID
Program Officers, FDA through meetings and
discussions