Substantial Evidence of Drug Effectiveness

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Substantial Evidence of Drug Effectiveness

• Cindy L. Burnsteel, DVM
• Division of Therapeutic Drugs for Food Animals
• Center for Veterinary Medicine

March 7, 2002
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In order for a New Animal Drug to be approved

• FDA must find, among other things, that
• the product is safe and effective for its
• intended use.
• the methods, facilities and controls used for the
  manufacturing, processing and packaging of the
  drug are adequate to preserve its identity,
  strength, quality and purity.

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Substantial Evidence

• Statutory Standard for demonstrating
  Effectiveness
• Adequate and Well Controlled Studies
• Inferential Value
• Independent Substantiation

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Demonstrating Effectiveness

• Drug effectiveness is evaluated on the basis of
  the information submitted in the application and
  must provide substantial evidence that the the
  drug will have the effect it purports or is
  represented to have under the conditions of use
  prescribed, recommended, or suggested in the
  proposed labeling.

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Animal Drug Availability Act of 1996 (ADAA)

• Amended the Federal Food, Drug Cosmetic Act
  (FFDCA)

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Animal Drug Availability Act of 1996 (ADAA)

• Its purpose was to facilitate the approval of new
  animal drugs and medicated feeds by, among other
  things,
• further defining adequate and well-controlled
  (AWC) studies and substantial evidence (SE) of
  effectiveness
• modifying the approval process for certain
  combination new animal drug applications

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Definition of Substantial Evidence

• evidence consisting of one or more adequate
  and well-controlled studies (AWC), such as a
  study in a target species, study in laboratory
  animals, field study, bioequivalence study, or an
  in vitro study,

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Definition continued...

• conducted by experts qualified by
  scientific training and experience to evaluate
  the effectiveness of the drug involved, on the
  basis of which it could fairly and reasonably be
  concluded by such experts

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Definition continued...

• that the new animal drug will have the
  effect it purports or is represented to have
  under the conditions of use prescribed,
  recommended or suggested in the labeling or
  proposed labeling thereof

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Substantial Evidence

• Statutory Standard for demonstrating
  Effectiveness
• Adequate and Well Controlled Studies
• Inferential Value
• Independent Substantiation

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Substantial Evidence...

• Shall consist of a sufficient number of current
  AWC studies of sufficient quality and
  persuasiveness to permit qualified experts to
• Determine that the selected parameters and their
  measured responses reliably reflect
  effectiveness.
• Determine that the results are repeatable and
  valid inferences can be drawn to the target
  population.
• Conclude that the drug is effective for
  proposed claim at dose/dose range and associated
  conditions of use.

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Type of AWC Studies

• May include, but are not limited to
• published studies
• foreign studies
• validated, model studies
• studies conducted by or on behalf of the sponsor

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Flexibility Created by ADAA

• Before it was amended by ADAA, the FFDCA required
  investigations, i.e. a minimum of two studies,
  one of which had to be a field study.
• Now, there is more flexibility
• one AWC study may suffice
• a field study may not be required

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What Studies Are Needed to Demonstrate
Effectiveness?

• Case-by-case judgement dependent upon
• New entity
• Number of proposed claims
• Narrow or broad definition for each proposed
  claim
• Conditions of use for each proposed claim

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Substantial Evidence

• Statutory Standard for demonstrating
  Effectiveness
• Adequate and Well Controlled Studies
• Inferential Value
• Independent Substantiation

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Inferential Value

• Confidence with which Effectiveness data
• For a proposed claim
• Under the conditions tested
• Can be used to conclude the drug will be
  effective in the target population for the claim
  and associated conditions of use suggested in the
  proposed labeling

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Inferential Value

• Historically, CVM used geographic location as a
  way of referring to factors that affect the
  effectiveness of the new animal drug in the
  inferential space.
• These factors may interact with the drug effect
  to render the drug more or less effective at some
  locations than at others.
• These factors may have an impact on growth,
  production, or response to therapy.

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Inferential Value

• Factors to be considered
• Animal Management (husbandry, standards of
  veterinary care, vaccination programs,
  biosecurity, disease control, expertise of animal
  caretakers)
• Animal Characteristics (genetics, breeds, gender,
  age, weight, class of animal and health status)
• Nutritional regimes

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Inferential Value

• Factors to be considered (contd)
• Disease Characteristics (seasonality, genetic
  variation, species, strains, virulence, and drug
  resistance of the pathogen or parasite)
• Environmental conditions (climatic conditions,
  housing, stocking densities, sanitation level)

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Inferential Value

• Locations chosen should
• permit generalization of study findings to the
  target population
• be in major areas of production or endemic
  disease areas.
• Utility of data may be time dependent

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Substantial Evidence

• Statutory Standard for demonstrating
  Effectiveness
• Adequate and Well Controlled Studies
• Inferential Value
• Independent Substantiation

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Independent Substantiation

• Goal is to reduce the likelihood that an
  experimental finding is the result of
• unanticipated, undetected, or systematic bias
• chance
• fraudulent conduct/reporting of studies
• In other words, the likelihood that the results
  obtained are likely to be repeatable.

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Independent Substantiation

• Generally, independent substantiation is achieved
  by conducting multiple adequate and
  well-controlled studies that corroborate the
  results of one another.
• A single AWC study may be sufficient to provide
  independent substantiation if it has certain
  characteristics.

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Study characteristics

• Although no one of the following characteristics
  is necessarily determinative, the presence of one
  or more in a study makes it more likely that a
  single study could provide independent
  substantiation.

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Study characteristics

• a multi-location study in which no single study
  site provides an unusually large fraction of the
  target animals and no single investigator or site
  is disproportionately responsible for the effects
  seen
• a study with sufficiently large and broad
  entrance criteria such that significant effects
  are found across key subsets

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Study characteristics

• a study with multiple, prospectively identified
  endpoints, each of which represents a different
  effect and where more than one endpoint shows
  statistical evidence of an effect
• a study which provides highly reliable and
  statistically strong evidence of effectiveness.

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Top Market Hog Production States ( of total
hogs)
9.6
26.4
4.8
5.3
7.2
5.0
16.2
4.1
78.6
USDA, Dec. 2001 52,564,000 market hogs
http//usda.mannlib.cornell.edu/reports/nassr/live
stock/php-bb/2001
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Factors Affecting Swine Production

• Animal genetics
• Management practices
• Environmental conditions
• Dietary differences

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Animal Genetics

• High lean vs traditional or lower lean
• High lean
• Predominant lines- PIC, Dekalb, Newsham
• Low lean
• Older lines of genetics
• Traditional crossbred programs
• Stress susceptibility (stress gene)
• Differences between lines

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Management Practices

• Age at weaning/slaughter
• Breeding programs (AI vs. natural)
• Vaccination program
• Disease control program
• Intensity of individual animal care
• Employee expertise/Labor force
• All In - All Out vs. Gradual progression

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Environmental Conditions

• Climatic factors (temperature and humidity)
• House flooring (full slats, half-slats, solid
  concrete, dirt)
• House type (environmentally controlled,
  curtain-sided, open-front, etc.)
• Stocking densities
• Cleanliness and waste removal (pit system, dry
  manure, etc.)

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Dietary Differences

• Dietary ingredients
• Energy sources (corn, wheat, milo, etc.)
• Protein sources (SBM, FM, CSM, etc.)
• Use of crystalline amino acids
• Dietary preparation
• Fineness of feed grind, pelleting, etc.
• Number of dietary changes
• Sex-separate feeding

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Substantial Evidence

• Consists of one or more current AWC studies,
  conducted by qualified experts, that are of
  sufficient quality and persuasiveness to allow
  qualified experts to conclude the drug is
  effective for each intended use and associated
  conditions of use suggested in the labeling

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Acknowledgements

• Center Veterinary Medicine Staff