Substantial Evidence of Drug Effectiveness

Substantial Evidence of Drug Effectiveness Cindy L. Burnsteel, DVM Division of Therapeutic Drugs for Food Animals Center for Veterinary Medicine March 7, 2002

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.

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

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.

Animal Drug Availability Act of 1996 (ADAA) Amended the Federal Food, Drug & Cosmetic Act (FFDCA)

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

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, …”

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 …”

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…”

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.

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

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

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

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

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.

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

Inferential Value • Factors to be considered (cont’d): • 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)

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

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.

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.

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.

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

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.

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/livestock/php-bb/2001

Factors Affecting Swine Production • Animal genetics • Management practices • Environmental conditions • Dietary differences

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

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

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.)

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

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

Acknowledgements Center Veterinary Medicine Staff

Substantial Evidence of Drug Effectiveness