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

Effectiveness Evaluation for Therapeutic Drugs for

Food Animals

Drugs used in the diagnosis, cure, mitigation, treatment, or prevention of a disease or condition

What are therapeutic drugs?

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).”

Example Indications for Therapeutic Drugs for Food Animals

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

Purpose of the Effectiveness Evaluation

Validated model studies

Dose confirmation studies

Literature

Pharmacokinetic data

What type of information is commonly used to demonstrate

effectiveness for therapeutic drugs for food animals?

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.

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.

Validated Model Studies

Type of study conducted will vary with the specific productUsually conducted in multiple geographic locationsSmall 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

Dose Confirmation Studies

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

Use of Literature in the Effectiveness Evaluation

ProtocolsDosage selectionDrug FormulationTreatment GroupsAnimal NumbersStudy Site SelectionAnimal SelectionMeasurements and ObservationsMinimizing biasAdverse Event monitoringAnalysis

Scientific Principles for the Development of an Effectiveness

Study

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

Protocols

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.

Dosage selection

The formulation of the drug can impact the safety and/or effectiveness outcomesFinal 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

Drug Formulation

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

Treatment Groups

Based on expected variation in response between experimental units, predetermined success criteria, and the desired statistical powerSufficient numbers to accommodate loss during the study due to death or removal from the studyWhen 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

Animal Numbers

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 populationNumber of sites will impact statistical analysis

Study Site Selection

Initial selection criteria may include species/class, age range, gender, and body weight rangeStudy inclusion criteria are specific to the disease condition being evaluated and the study endpoints

Animal Selection

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

Measurements and Observations

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

compromisedRandomization methods

Minimizing Bias

Establish in protocol how animals will be observed and how adverse events will be recordedEstablish criteria for animal removalsConsider maskingIt is important to identify acceptable concomitant therapies before initiating the study

Adverse Event Monitoring

Identify and define variables Clearly describe statistical methodsInclude criteria for including and excluding data from analysisClear basis of study conclusion

Appropriate Analysis

CVM GFI #56 Protocol Development Guideline for Clinical Effectiveness and Target Animal Safety TrialsCVM GFI #85 VICH GL9 – Good Clinical PracticesCVM GFI #215 Target animal Safety and Effectiveness Protocol Development and Submission

General Guidance Addressing Effectiveness

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 animalsCVM GFI #178 Design/Evaluation of Effectiveness Studies – Swine Respiratory Disease Claims

Guidance specific to food animal therapeutic 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

Guidance specific to food animal antiparasitic drugs

CVM GFI #123 Development of Data Supporting approval of NSAIDS for Use in Animals

Other Available Guidance Addressing Effectiveness