Understanding the Animal Rule in Drug Approval Process
The Animal Rule addresses the approval of new drugs when human efficacy studies are not possible. It serves as a surrogate for human studies, requiring well-controlled animal testing to predict clinical benefits in humans. Safety must still be demonstrated in human trials, and the rule can be bypassed if approval standards are met elsewhere. The pathophysiological mechanism of toxicity and the efficacy of the test product must be well understood and demonstrated across relevant animal species.
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J.E. Estep, DVM, PhD Senior Program Manager Battelle Memorial Institute 29 January 2009 29 January 2009
History What is The Animal Rule Essential Elements of an Animal Model as a Test System Discussion
Issue: Licensing of CBRN medical products (prophylactics, therapeutics) when normal clinical trails are not possible requires alternative approaches for efficacy demonstration
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 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
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
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
Reasonably well-understood pathophysiological mechanism of the toxicity of the substance (agent) and its prevention/reduction by the test product Effect is demonstrated in more than one animal species expected to react with a response predictive of human 2 Animal Rule * * 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
Animal study outcome is clearly related to the desired benefit in human Reduced morbidity/mortality Data on pharmacokinetics/dynamics of the product in animals and humans allows selection of an effective dose in humans
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
Predict the outcome of controls following challenged route, dose, and strain of the infectious agent or chemical Preparation & characterization of the infectious agent or chemical material must be standardized, consistent, reproducible Challenge material is a critical reagent 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
All studies subject to this Rule must be conducted in accordance with preexisting requirements under the Good Laboratory Practices (21 CFR 58) regulations Adherence to Animal Welfare Act (7 U.S.C. 2131) required 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
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
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 Safety must still be demonstrated in human subjects enrolled in Phase I, II & III clinical trials 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 The purpose of the Animal Rule is to develop a product for use in humans, not animals
From product concept through advanced development, everyone should consider the applicability and requirements of the Animal Rule Design studies on a critical path to support the product development goal licensure Develop integrated research plans which account for all aspects of the licensing needs Studies require Good Laboratory Practice (GLP) Compliance Validation of all critical assays is expected
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
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
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)
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 Natural history of the disease Pathophysiologic comparable to humans Time course of disease Manifestations of disease (signs, symptoms) Pathology Outcome (death, recovery)
Trigger for Intervention Characterization of medical intervention Type of material Mechanism of action Activity (in vitro and in vivo) how does it intervene Pharmacokinetics/Pharmacodynamics Interactions with other medical products
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
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
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)
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
Timing of intervention Route of administration Dose or dose regimen
Agent characterization Host susceptibility and natural history Compared to human disease Intervention what and when How does the product affect outcome Animal test design Endpoints Timing of endpoints measuring drive intervention Route of administration agent Dosing route and regimen
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
John Wade, DVM, PhD, Personal communication and prior presentations materials Mark J. Abdy, DVM, PhD - Clarification of the Regulatory Position Regarding Animal Studies to bring Vaccines to Licensure, 2006 Many: Scientists, Battelle and other companies, NIAID Program Officers, FDA through meetings and discussions
