November 16, 2018
In keeping with the goals of reducing, replacing, and/or refining the use of animals in research, the U.S. Food and Drug Administration today released for public comment proposed research to validate an alternative approach for bioequivalence studies for certain animal drugs. The FDA expects that the availability of this alternative approach will provide animal drug sponsors with a scientifically sound method to demonstrate bioequivalence of certain drugs that does not require that dogs be euthanized as part of the study.
The proposed study involves collection of blood samples from dogs, which is minimally invasive, after they have received oral tablets of two commonly used, generally well-tolerated medicines. The dogs taking part will be retired for adoption at the study conclusion.
To ensure that an animal drug is safe and effective, the FDA must understand how a drug behaves in an animal’s body. As part of generating these data, animal drug sponsors perform bioequivalence studies, which are studies that compare pharmaceutical products (i.e., an original approved product and proposed generic version) to see if they are similar enough to link the safety and effectiveness of one drug to another.
The goal of the proposed study is to compare the bioequivalence of tablets containing both locally and systemically acting drugs. Drugs that act locally are not absorbed into an animal’s blood stream, while systemically acting drugs are absorbed into the blood stream. For antiparasitic drugs that act locally within the gastrointestinal tract, this has historically required data gathered from terminal studies, meaning the animals were euthanized.
The alternative approach described in the FDA’s study will mitigate the need for terminal, artificial infection clinical endpoint bioequivalence studies. In this study, none of the dogs will be artificially infected, and every effort will be made to ensure their health from the time that they arrive at the test facilities until they are retired for adoption as pets.
The proposed study will measure the bioequivalence of the approved antiparasitic drugs ivermectin and praziquantel by in vitro dissolution compared to blood levels that indicate how the drug is dissolving in the body (also known as blood-level pharmacokinetics), with the goal of validating these laboratory-based alternative (i.e., surrogate) endpoints. Ivermectin is used in dogs to treat heartworm, a potentially fatal infection. Praziquantel treats tapeworms, an internal parasite that lives primarily in the gastrointestinal tract but can form cysts in liver and other organs.
If the collected data support the study hypothesis, the resulting data will be made publicly available. Animal drug sponsors may use these data to aid in the design of in vitro studies used as an alternative to bioequivalence trials using animal subjects. Sponsors perform these studies to demonstrate that their oral canine drug containing both locally and systemically acting drugs dissolves in the dog at a rate and extent equivalent to that of the original, or pioneer, approved product. We anticipate, therefore, that dogs will no longer need to be used for bioequivalence studies for these types of drugs.
For at least two months before the study begins, FDA's animal care staff will work with the dogs to socialize them and acclimate them to being handled. The dogs will also receive regular veterinary care, including vaccinations and preventive care, so that they remain happy, well socialized and healthy.
The FDA is accepting public comments on the study protocol beginning on November 16, 2018. To electronically submit comments to the docket, visit www.regulations.gov and type FDA-2018-N-3345 in the search box. For assistance in submitting electronic comments, please see Regulations.gov Help.
To submit comments to the docket by mail, use the following address. Be sure to include docket number FDA-2018-N-3345 on each page of your written comments.
Dockets Management Staff
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
Comments will be accepted at any time, but should be submitted no later than January 15, 2019 to ensure that the FDA takes the information into consideration before making further decisions on this issue.
For more information:
- Concept Paper: Alternative Methods for Evaluating Locally Acting, Non-systemically Absorbed Drugs in Canine Disintegrating or Chewable, Single Layer Combination Drug Products
- Statement by FDA Commissioner Scott Gottlieb, M.D., on efforts to reduce animal testing through a study aimed at eliminating the use of dogs in certain trials
For questions, Contact CVM.