CVM Issues Draft Guidance on Effectiveness Evaluation of Heartworm Disease Prevention Products for Dogs

This week, the United States Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) issued Draft Guidance for Industry No. 276, “Effectiveness of Anthelmintics: Specific Recommendations for Products Proposed for the Prevention of Heartworm Disease in Dogs” (Draft Guidance). The Draft Guidance is intended for animal drug sponsors interested in pursuing approval of new animal drugs for the prevention of heartworm disease caused by Dirofilaria immitis in dogs, and provides recommendations for demonstrating the effectiveness of such investigational drugs.

Background

Under CVM regulations, a new animal drug application (NADA) must include, among other things, “evidence to establish safety and effectiveness” and may be refused “unless it includes substantial evidence of the effectiveness of the new animal drug.” 21 C.F.R. § 514.1(b)(8). Within this context, “substantial evidence” generally requires “a sufficient number of current adequate and well-controlled studies of sufficient quality and persuasiveness to permit qualified experts:

• To determine that the parameters selected for measurement and the measured responses reliably reflect the effectiveness of the new animal drug;
• To determine that the results obtained are likely to be repeatable, and that valid inferences can be drawn to the target animal population; and
• To conclude that the new animal drug is effective for the intended use at the dose or dose range and associated conditions of use prescribed, recommended, or suggested in the proposed labeling.” Id. § 514.4(b)(3).

CVM has been evaluating its current thinking regarding the design of these studies, and on May 24, 2018, published a Federal Register Notice requesting public input on possible alternative approaches for evaluating the effectiveness of heartworm disease prevention products for dogs.[1] In the 2018 Notice, CVM explained that the current recommended approach to demonstrating “substantial evidence of effectiveness” for heartworm disease prevention products for dogs is for the sponsor to conduct two laboratory dose confirmation studies and one multi-site field safety and effectiveness study under the principles outlined in Guidance for Industry #85 (Veterinary International Conference on Harmonization (VICH) GL9), “Good Clinical Practice.”

Noting potential strengths and limitations of these recommended studies, CVM sought comments on questions relating to the population level effectiveness endpoint, exposure to infective D. immitis larvae in field studies, outcome assessment in field studies, and laboratory study designs.

Draft Guidance

The Draft Guidance provides specific recommendations, with respect to the recommended approach of conducting two laboratory dose confirmation studies and one field effectiveness study, to evaluate the effectiveness of investigational drugs intended for the prevention of heartworm disease in dogs. CVM notes that its recommendations relating to design study elements for laboratory dose confirmation studies are based on the assumption that the field effectiveness study will be conducted in accordance with the recommendations for that study.

Recommendations for laboratory dose confirmation studies. The laboratory dose confirmation studies are experimentally-induced infection studies intended to confirm effectiveness of the investigational new animal drug under laboratory conditions. The Draft Guidance provides recommendations regarding the following elements in designing and assessing the effectiveness of the studies:

• Number of studies.
• Geographic considerations for obtaining D. immitis isolates.
• Number of dogs per investigational group.
• Number of infective D. immitis larvae used to induce infection.
• Testing for pre-existing heartworm infection.
• Assessment of effectiveness, including parasite counts and criteria to demonstrate effectiveness.
• Pilot study considerations.
• Pharmacokinetic evaluation.

Of particular note is that, for the criteria to demonstrate effectiveness, the Draft Guidance specifies a minimum of 99.5% effectiveness, representing a departure from CVM’s previous 100% efficacy standard for approval of drugs intended for the prevention of heartworm disease.

Recommendations for field effectiveness study. The field effectiveness study evaluates the use of the investigational new animal drug in client-owned dogs across various geographical regions of the continental United States with endemic heartworm disease. For this study, the Draft Guidance provides recommendations regarding the following:

• Study duration.
• Timing of enrollment (to maximize the likelihood of exposure to mosquitos that carry D. immitis).
• Location of study sites.
• Testing for pre-existing heartworm infection.
• Assessment of effectiveness.
• Control group.
• Minimum number of evaluable cases.
• Pharmacokinetic evaluation.

As the Draft Guidance is intended to provide additional detail to elements of study design and interpretation under the recommendations outlined in VICH guidance documents, CVM notes that the Draft Guidance, if finalized, should be read in conjunction with Guidance for Industry (GFI) #90 (VICH GL7), “Effectiveness of Anthelmintics: General Requirements,” and GFI #111 (VICH GL19), “Effectiveness of Anthelmintics: Specific Recommendations for Canines.”

What Can You Do?

Interested stakeholders can submit comments on the draft guidance at www.regulations.gov, Docket FDA-2022-D-2899. The comment deadline is January 30, 2023.

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