Effectiveness Evaluation for Therapeutic Drugs for Non-Food Animals

1. Effectiveness Evaluation for Therapeutic Drugs for Non-Food Animals Christopher Loss, DVM Division of Therapeutic Drugs for Non-Food Animals Office of New Animal Drug Evaluation USFDA Center for Veterinary Medicine

2. Non-Food Animals • Non-food (companion) animals • Dogs • Cats • Horses (in US considered a non-food animal) • Ferrets • Laboratory animals (rodents, primates) • Excludes any animal that is commonly used for food

3. Indications • Therapeutic drugs are drugs used in the diagnosis, cure, mitigation, treatment, or prevention of a disease or condition • Companion animal drugs include a wide range of therapeutic indications. Examples include: • Treatment, control, or prevention of internal and external parasites • Control of pain associated with osteoarthritis or post-operative pain (analgesics) • Treatment of infections (antimicrobials) • systemic and topical

4. Indications • Indication examples (continued): • Induction and maintenance of anesthesia • Preanesthetics to general anesthesia • Reduction of hyperglycemia and hyperglycemia-associated clinical signs in diabetes mellitus • Management of cardiac disease • Treatment of otitis externa • Treatment of mast cell tumors (specific cancers) • Etc.

5. Purpose of Effectiveness Evaluation • To evaluate the indication(s) proposed for the new animal drug under expected conditions of use • Provide information for product labeling that is helpful to the user of the drug • Key component in risk:benefit assessment • This assessment is critical to approval decision

6. General Approach to Effectiveness • Basic understanding of the drug • Pilot studies (or literature) to determine dose • Intended dose, drug concentration, route of administration, frequency of treatment, and duration of treatment • Larger studies to establish effectiveness • Field effectiveness study in target population • Laboratory effectiveness studies • The regulatory approach should be open to considering new methods to appropriately address new technologies and indications

7. Types of Studies/Data to Establish Effectiveness • Clinical studies • Field study in client-owned animals to evaluate the safety and effectiveness of the drug for the proposed indication in the target population • Laboratory effectiveness studies • Pharmacokinetic studies • Weight of evidence approach • Utilize all available information to address the specific risk questions

8. Key Characteristics of Field Study Design • Study should be well-controlled • Protocol • Ensures the study is conducted consistently between sites • Study objectives should be clearly stated • Control group – placebo, active, historical • Methods to control bias • Masking • Multi-centered • Randomized

9. Key Characteristics of Field Study Design (continued) • Study should be appropriately powered • Include appropriate statistical analysis • Include enough animals to infer results to population • Animal removal or death should be taken into account • Study should evaluate drug in target population • Enrollment criteria (inclusion/exclusion) appropriate to define and select target population

10. Endpoint Selection and Effectiveness Criteria • Endpoints should be measurable, objective (if possible), and clinically relevant to the disease/condition in the proposed indication • Effectiveness/success criteria should be predefined in the protocol • Success may include statistical significance compared to control group, achievement of predefined percent success criteria, etc. • Secondary endpoints can be included to support label statements or explore other parameters of interest • Potential endpoints may include: • Clinical/veterinary assessment, owner assessment, scoring system, objective variable (such as change in laboratory value), etc.

11. Other Important Considerations for Field Studies • Field studies allow for evaluation of safety in the target population under conditions of use • Adverse events – incidence and severity • Measurements and Observations • Physical examinations • Clinical pathology • Body weight • Owner diaries • Etc.

12. Other Important Considerations for Field Studies (continued) • Consider user safety issues during the investigational use of the drug, especially for topical formulations and drugs with human safety concerns • Assess risks and means to control risks to user • Owner consent forms for field studies • Describe risks to animal and the user • Describe expectations of study

13. Other Important Considerations for Field Studies (continued) • Extended-use field studies • Assess safety in the target population • Allow animals to continue on the drug • Should use final market formulation • Final study report • Accurate and well organized

14. Label Language • Language relevant to the administration of a safe and effective dose for the product determined in the effectiveness and safety studies • Final labeling developed after all data to support the approval has been reviewed

15. Relevant International Guidelines • VICH GL9 - Good Clinical Practices • For specific classes of drugs: • VICH GL7 - Effectiveness of Anthelmintics: General Recommendations • VICH GL15 - Specific Recommendations for Equine • VICH GL19- Specific Recommendations for Canine • VICH GL20 - Specific Recommendations for Feline

16. Relevant CVM Guidances • For protocol development and data submission: • CVM GFI #56 Protocol Development Guideline for Clinical Effectiveness and Target Animal Safety Trials • CVM GFI #104 Content and Format of Effectiveness and Target Animal Safety Technical Sections and Final Study Reports For Submission • CVM GFI #215 Target Animal Safety and Effectiveness Protocol Development and Submission

17. Relevant CVM Guidances (continued) • For specific classes of drugs: • CVM GFI #38 Guideline for Effectiveness Evaluation of Topical/Otic Animal Drugs • CVM GFI #123 Development of Data Supporting Approval of NSAIDS for Use in Animals • CVM GFI #192 Anesthetics for Companion Animals

18. Summary