Principles of New Animal Drug Effectiveness: An Overview

1. Principles of New Animal Drug Effectiveness: An Overview Linda M. Wilmot, DVM, MS Director Division of Production Drugs

2. Why do we test for animal drug effectiveness? • So that qualified experts can fairly and reasonably conclude that a new animal drug will have the effect it purports to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling. • Affords end users the ability to anticipate likely responses.

3. How do we establish effectiveness? • Adequate and well-controlled studies, the purpose of which is to distinguish the effect of the drug from other influences such as spontaneous change in the course of disease and biased observation. • A further purpose of an adequate and well-controlled field study is to observe the new animal drug’s effects under conditions which closely approximate the conditions under which the new animal drug will be applied or administered.

4. Evidence of Effectiveness: Where Does it Come From? • Study in the target species • Study in laboratory animals • Field study • Bioequivalence study • In vitro study On the other hand, the body of evidence to support effectiveness may be a patchwork of one or more of these studies.

5. Studies These studies can come from • Published studies • Foreign studies • Validated model studies

6. Overarching Scientific Principles • Appropriate study design (e.g., animal types, numbers, randomization scheme, minimizing bias) • Study provides a valid comparison with control to provide quantitative evaluation of drug effects • Appropriate study conduct and monitoring, and reporting (e.g., recording of raw data and other information, auditing study) • Appropriate data analysis • Accurate report reflective of data findings

7. Types of Controls • Placebo concurrent control • Untreated concurrent control • Active treatment concurrent control • Historical control

8. “Key characteristics of a systematic review are a clearly stated set of objectives with predefined eligibility criteria for studies; an explicit, reproducible methodology; a systematic search that attempts to identify all studies that meet the eligibility criteria; an assessment of the validity of the findings of the included studies (e.g., through the assessment of risk of bias); and a systematic presentation and synthesis of the attributes and findings from the studies used.”* *Lean, J, Rabiee, AR, Duffield, TF, et al. Invitedreview: use of meta-analysis in animal health and reproduction: methods and applications. J Dairy Sci 2009;92:3545-65. Control Over Non-Traditional Studies

9. Animal Drug Effectiveness Determined By Inferential value Confidence with which the data relating to effectiveness of a new animal drug for an intended use under the conditions tested can be used to conclude that the new animal drug will be effective in the target animal population for the intended use and associated conditions of use suggested in the labeling.

10. Animal Drug Effectiveness Determined By Independent Substantiation The results obtained from a study are likely to be repeatable.

11. US FDA Guiding Principles • 21 CFR §514.117 (Adequate and well-controlled studies) • 21 CFR §514.4 (Substantial Evidence) • Guidance for Industry #85: Good Guidance Practice (VICH GL9)

12. Take Home Messages • Effectiveness determination is important to the end user of the animal drug in assuring that it will do as intended (economic importance for food animals and intrinsic importance for companion animals). • Well thought out and executed studies are likely to provide scientifically valid results. • Effectiveness of animal drugs may be determined by several different types of studies. • The body of evidence supporting effectiveness must assure that the animal drug will do as the label indicates it will.

13. Additional Videos on Effectiveness • Effectiveness Evaluation for Production Drugs • Effectiveness Evaluations for Therapeutic Drugs for Food Animals • Effectiveness Evaluation for Therapeutic Drugs for Non-Food Animals