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.
Consumers expect that a drug will do what it is supposed to do. If an animal drug is approved in the US, the user can be assured that a certain level of scrutiny has been applied. There is no guessing as to whether a drug will work or not. Users are provided scientific information, which establishes what can be expected from the drug.

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.
What this boils down to is: To test for effectiveness, the drug is used in the manner for which is to be used by the people who are likely to use in the environments that it is likely to be used.

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.
There are any number of pathways to prove effectiveness.

5. Studies These studies can come from Published studies Foreign studies
Validated model studies
The data must be scientifically valid. Empiric evidence is not enough to support approval of a drug.

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
*Following the identified principles should lay the groundwork for a successful study. In the end, the need is for drug sponsors to show that their proposed new animal drug is indeed safe and effective under the proposed conditions of use. The more work done upfront to assure success, the more likely the study will provide useful information.
*GCP defined as A standard for the design, conduct, monitoring, recording, auditing, analysis, and reporting of clinical studies. Adherence to the standard provides assurance that the data and reported results are complete, correct and accurate, that the welfare of the study animals and the safety of the study personnel involved in the study are ensured, and that the environment and the human and animal food chains are protected.
A study has a primary investigator, monitor, provides independent substantiation and inferential value, QA/QC; *protect human and animal food chain
*The study uses methods to assess animal response that are well defined and reliable

7. Types of Controls Placebo concurrent control
Untreated concurrent control
Active treatment concurrent control
Historical control
*The study uses a design that permits a valid comparison with one or more controls to provide a quantitative evaluation of drug effects.
*Briefly discuss the differences among them

8. Control Over Non-Traditional Studies
“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. Invited review: use of meta-analysis in animal health and reproduction: methods and applications. J Dairy Sci 2009;92:
*Meta analysis and systematic review ;funnel plots;
*The Cochrane collaboration (Cochrane
Collaboration, 2008) has been a long-standing,
rigorous, and innovative leader in developing methods
in the field
* We recommend, in
general, that the evidential base used in a meta-analysis
consist of randomized controlled clinical studies or
prospective cohort studies as these should provide the
most rigorous data
*Studies are chosen for meta-analysis based on inclusion
criteria;
clinically relevant questions
should be formulated, the systematic review should be carefully
planned as for any other research project with a detailed protocol,
eligibility criteria should be defined a priori, and search
procedures must be comprehensive to identify all relevant studies (Yuan)
STROBE (refer to Laura’s presentation)

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.
We look at the body of evidence as a whole. What can be gleaned from a study that has broad application to the general population of animals in which the drug will be used? Stop…..

10. Animal Drug Effectiveness Determined By
Independent Substantiation
The results obtained from a study are likely to be repeatable.
Study results would likely be similar among different investigators, when conducted under different environmental conditions or other circumstances.

11. US FDA Guiding Principles
21 CFR § (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