Effectiveness Evaluation for Therapeutic Drugs for Food Animals

1. Effectiveness Evaluation for Therapeutic Drugs for Food Animals Emily Smith, DVMOffice of New Animal Drug Evaluation (ONADE)Division of Therapeutic Drugs for Food Animals

2. What are therapeutic drugs? Drugs used in the diagnosis, cure, mitigation, treatment, or prevention of a disease or condition

3. Example Indications for Therapeutic Drugs for Food Animals Antimicrobials: “for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni in beef cattle.” Antiparasitic and Physiologic Drugs: “for the treatment and control of [specific internal and external parasites]” “for the control of pyrexia associated with acute bovine mastitis” Aquaculture Drugs: For the control of mortality in freshwater-reared coolwater finfish and channel catfish due to external columnaris disease associated with Flavobacterium columnare (Flexibacter columnaris).”

4. Purpose of the Effectiveness Evaluation • To demonstrate that the drug has the effect it claims to have for each of its intended uses and conditions of use • Obtain additional safety data under the conditions of use

5. What type of information is commonly used to demonstrate effectiveness for therapeutic drugs for food animals? • Validated model studies • Dose confirmation studies • Literature • Pharmacokinetic data

6. Validated Model Studies • Generally use challenge models or induced infection models • Used to demonstrate effectiveness when some aspect of the effectiveness study cannot be adequately represented or evaluated using field conditions. • Number of animals used will depend on the endpoint and the type of statistical analysis.

7. Validated Model Studies • Model validation includes the following: • The model shows that the study endpoints are clinically relevant and scientifically accepted; • The model shows that clinical disease induced in the model is as representative as is practical of natural infection in terms of morbidity levels and clinical presentation; • The model demonstrates that results are reproducible (i.e., by using different investigators and conducting the model at two or more sites); and, • If the model is being used to demonstrate effectiveness against a pathogen: the model should demonstrate or provide justification that the pathogen isolate used for challenge is representative of recent isolates from the region.

8. Dose Confirmation Studies • Type of study conducted will vary with the specific product • Usually conducted in multiple geographic locations • Small in vivo studies • commonly used for anthelmintics (worm count studies) • Field studies • commonly used as sole type of study for antimicrobials • generally includes conditions that mimic actual conditions of use (husbandry practices, stocking density, etc); generally take advantage of natural infection and/or disease

9. Use of Literature in the Effectiveness Evaluation • Increased reliance on literature if the reports contain the following information • Multiple studies by independent investigators with adequate study designs and consistent findings • Appropriate and objective endpoints • High level of detail • Systematic reviews may be useful

10. Scientific Principles for the Development of an Effectiveness Study • Protocols • Dosage selection • Drug Formulation • Treatment Groups • Animal Numbers • Study Site Selection • Animal Selection • Measurements and Observations • Minimizing bias • Adverse Event monitoring • Analysis

11. Protocols • Outlines objectives, design, methodology, organization, and analysis. • Good protocols are the foundation for conducting controlled studies • Helps to ensure consistency in study conduct between sites for multi-site studies

12. Dosage selection • The intended dose, drug concentration, route of administration, frequency of treatment, and duration of treatment should be determined. The same dosage should be used in all the studies performed to support the effectiveness of the therapeutic drug. • A dose range is acceptable. TAS is evaluated at the high end of the dose range. Effectiveness is evaluated at the low end of the dose range.

13. Drug Formulation • The formulation of the drug can impact the safety and/or effectiveness outcomes • Final formulation (e.g. intended marketed product) should be used • If final formulation is not used in the study, need to consider how to bridge data between formulations

14. Treatment Groups • For a single dose, treatment groups should include a group of animals treated with the intended dose of the therapeutic drug and an appropriate control group • If a dose range is used, treatment groups should include a group treated with the lowest dose in the range and an appropriate control group

15. Animal Numbers • Based on expected variation in response between experimental units, predetermined success criteria, and the desired statistical power • Sufficient numbers to accommodate loss during the study due to death or removal from the study • When pen, pasture, or cage is the experimental unit, the number of animals per pen, pasture, or cage should mimic common commercial practices for stocking density, taking research facility limitations into account

16. Study Site Selection • If a field study is performed, the study should be conducted in geographic areas representative of the species/class of animal and disease condition to enable valid inferences to the entire target animal population • Number of sites will impact statistical analysis

17. Animal Selection • Initial selection criteria may include species/class, age range, gender, and body weight range • Study inclusion criteria are specific to the disease condition being evaluated and the study endpoints

18. Measurements and Observations • May include such things as: • Physical examinations • Body weights • Feed and water consumption • General Health Observations • Disease specific scoring/assessments • Calibrate equipment used to collect data

19. Minimizing Bias • Extent and methods for masking • Identifying personnel that will be masked • Ensure study procedures do not compromise masking • How to handle situations when masking is compromised • Randomization methods

20. Adverse Event Monitoring • Establish in protocol how animals will be observed and how adverse events will be recorded • Establish criteria for animal removals • Consider masking • It is important to identify acceptable concomitant therapies before initiating the study

21. Appropriate Analysis • Identify and define variables • Clearly describe statistical methods • Include criteria for including and excluding data from analysis • Clear basis of study conclusion

22. General Guidance Addressing Effectiveness • CVM GFI #56 Protocol Development Guideline for Clinical Effectiveness and Target Animal Safety Trials • CVM GFI #85 VICH GL9 – Good Clinical Practices • CVM GFI #215 Target animal Safety and Effectiveness Protocol Development and Submission

23. Guidance specific to food animal therapeutic drugs • CVM GFI #49 Target Animal Safety and Drug Effectiveness Studies for Anti-Microbial Bovine Mastitis Products (Lactating and Non-Lactating Cow Products) • CVM GFI #217 Evaluation of the effectiveness of anticoccidial drugs for food-producing animals • CVM GFI #178 Design/Evaluation of Effectiveness Studies – Swine Respiratory Disease Claims

24. Guidance specific to food animal antiparasitic drugs • CVM GFI #90 VICH GL7- Effectiveness of Anthelmintics: General Recommendations • CVM GFI #95 VICH GL12 – Efficacy of Anthelmintics: Specific Recommendations for Bovines • CVM GFI #96 VICH GL13 – Efficacy of Anthelmintics: Specific Recommendations for Ovines • CVM GFI #97 VICH GL14 – Efficacy of Anthelmintics: Specific Recommendations for Caprines • CVM GFI #110 VICH GL16 – Specific Recommendations for Porcine • CVM GFI #114 VICH GL 21 – Specific Recommendations for Poultry – Gallus Gallus

25. Other Available Guidance Addressing Effectiveness • CVM GFI #123 Development of Data Supporting approval of NSAIDS for Use in Animals