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

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

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

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.

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

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

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

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

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

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.

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.

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

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

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

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

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

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

Summary