June 27, 2024, Covington Alert

On June 25, 2024, the Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) announced that it has finalized Guidance for Industry (GFI) #276, Effectiveness of Anthelmintics: Specific Recommendations for Products Proposed for the Prevention of Heartworm Disease in Dogs (Final Guidance). The Final Guidance replaces CVM’s draft guidance issued in November 2022. While CVM’s core recommendations remain the same, the Final Guidance clarifies the discussion and recommendations related to geographic locations from which Dirofilaria immitis (D. immitis) larvae used in trials should be sourced, laboratory dose confirmation studies, and field effectiveness studies for products intended to prevent heartworm disease. CVM’s stated overarching goal in making the revisions is to better align GFI #276 with current technology and veterinary epidemiology, including available diagnostic methodology. Drug sponsors who deviate from these recommendations are encouraged to discuss the deviations with CVM.

Background

On May 24, 2018, FDA published a Federal Register Notice requesting public input on possible alternative approaches for evaluating the effectiveness of heartworm disease prevention products for dogs. On its webpage announcing the final guidance, FDA explained that it asked for public input because of reports of lack of effectiveness and certain limitations of the effectiveness studies conducted to support product approval. FDA’s then-current recommendation for demonstrating the effectiveness of a new animal drug intended to prevent heartworm disease was for sponsors to conduct two laboratory dose confirmation studies and one multi-site field effectiveness study under the principles of Good Clinical Practice. FDA specifically requested input on the population level effectiveness endpoint, exposure to infective D. immitis larvae in field studies, outcome assessment in field studies, and laboratory study designs.

As we previously reported, FDA published a draft guidance in November 2022 (Draft Guidance) that provided specific recommendations for laboratory dose confirmation studies and multi-site field effectiveness studies. FDA received eight comments on the Draft Guidance. Less than two years later, on June 25, 2024, FDA published its Final Guidance with amendments aimed at providing additional information to assist animal drug sponsors interested in pursuing approval of new animal drugs for the prevention of heartworm disease.

Key Revisions Made in the Final Guidance

Laboratory Dose Confirmation Studies

The Final Guidance retains CVM’s earlier recommendation that sponsors should conduct two induced laboratory dose confirmation studies when evaluating the effectiveness of heartworm disease prevention products for dogs. Sponsors should conduct each of these studies at different laboratory facilities, with different independent investigators, and using recent isolates of D. immitis from two separate geographic locations in the United States. CVM clarifies in the Final Guidance that using isolates from two separate geographic locations increases the likelihood that the isolated organisms represent distinct populations.

In the Draft Guidance, CVM noted that sponsors may characterize such isolates for susceptibility “against FDA approved products at the approved dosages” before conducting laboratory dose confirmation studies. CVM refines its position in the Final Guidance. Sponsors may still characterize isolates for susceptibility before conducting laboratory dose confirmation studies; however, sponsors should perform such characterization in accordance with the principles stated in GFI #90 (VICH GL7 regarding field isolate characterization).

CVM’s recommendations with respect to sample size, pre-existing heartworm infection, and assessment of effectiveness generally and in laboratory dose confirmation studies remain largely unchanged from the Draft Guidance.

Field Effectiveness Studies

In the Final Guidance, CVM maintains its prior recommendation that sponsors should conduct one field effectiveness study when evaluating the effectiveness of heartworm disease prevention products for dogs. The field effectiveness study should be a multi-site study conducted with investigators in various geographic regions of the continental United States where endemic heartworm disease exists. The Final Guidance features three substantive changes from the Draft Guidance with respect to field effectiveness studies.

First, in the Draft Guidance, CVM stated that an individual dog is considered a “success” if it does not test heartworm antigen- or microfilaria-positive up to and including 240 days after first dose administration. Under the Final Guidance, a dog is considered a success if it does not test heartworm antigen- or microfilaria-positive up to and including Day 120. Dogs testing positive between Day 120 and Day 240 “should be evaluated on a case-by-case basis.”

Second, CVM clarifies in the Final Guidance that its recommendation to include an active control group in a field effectiveness study is not just to minimize bias in data collection; it is also to “facilitate randomization and masking.” Masking is intended to minimize the potential biases resulting from differences in management, treatment, or assessment of subjects, or interpretation of results, that could arise as a result of subject or investigator knowledge of the assigned treatment.

Third, the Final Guidance provides that the active control group should contain no fewer than 50 animals. CVM’s recommendations with respect to study duration, enrollment, location of study sites, and pharmacokinetic evaluation of field effectiveness studies mimic those in the Draft Guidance. 

If you have any questions concerning the material discussed in this client alert, please contact the members of our Food, Drugs, and Devices practice.

Photo of Deepti Kulkarni Deepti Kulkarni

Drawing from over a decade of experience working in both FDA’s Office of Chief Counsel and private practice, Deepti Kulkarni provides strategic advice to clients on a wide range of complex matters involving FDA and USDA regulatory oversight. She has played a key…

Drawing from over a decade of experience working in both FDA’s Office of Chief Counsel and private practice, Deepti Kulkarni provides strategic advice to clients on a wide range of complex matters involving FDA and USDA regulatory oversight. She has played a key role in the development and implementation of the regulatory frameworks for alternative proteins as well as bioengineered food and agriculture products.

Deepti advises companies developing and marketing animal products, foods, dietary supplements, and cosmetics at nearly every step of the product lifecycle. She also counsels clients on potential crises, such as product recalls, import refusals, and other regulatory actions.

Deepti previously served as an Associate Chief Counsel in the FDA’s Office of Chief Counsel. While at FDA, she counseled various components of FDA and HHS on a broad scope of issues related to animal products, foods, dietary supplements, and cosmetics, as well as cross-product matters involving imports and exports, advisory committees, and constitutional issues. Deepti received several awards during her time at the FDA, including the FDA Award of Merit (FDA’s highest award), Commissioner’s Special Recognition Award, and the CFSAN Director’s Special Citation Award.

Photo of Alicia Lee Alicia Lee

Alicia Lee is an associate in the firm’s Food, Drug, and Device Practice Group. She advises food and biotechnology companies on a wide range of regulatory and compliance matters.

Emily Statham
Emily Statham is an associate in the firm’s Washington, DC office, where she is a member of the Food, Drug, and Device and Life Sciences Transactions Practice Groups. She advises pharmaceutical, biotechnology, and medical device companies on a variety of regulatory, compliance, and
Emily Statham is an associate in the firm’s Washington, DC office, where she is a member of the Food, Drug, and Device and Life Sciences Transactions Practice Groups. She advises pharmaceutical, biotechnology, and medical device companies on a variety of regulatory, compliance, and transactional issues.