Conditional Approval of Potassium Bromide for Dogs—An Innovative Approach
“Daisy,” an 8-year-old, female spayed Dalmatian with a history of idiopathic epilepsy, and her owner are in Exam Room 1. The owner says that Daisy’s having frequent seizures, even on daily phenobarbital therapy. What’s the next step to control the dog’s seizures? Likely, it’s adding potassium bromide.
For many years, both potassium bromide (KBr) and phenobarbital (PB) have been used in human and veterinary medicine as anti-seizure medications. Despite both drugs’ long history of common use, neither is fully approved by FDA to control seizures in people or animals. However, in January 2021, FDA conditionally approved KBroVet-CA1 (potassium bromide chewable tablets) to control seizures in dogs with idiopathic epilepsy. The drug is a halide salt, and when the salt passes through neuronal channels, it hyperpolarizes neuronal membranes and stabilizes the neurons. This stabilization reduces the likelihood of a seizure.
Conditional approval allows a drug company to legally sell an animal drug before collecting all necessary effectiveness data, but after proving it is safe and likely to be effective. Conditional approval doesn’t reduce the requirements for approval. It simply allows the drug company to legally sell the drug for a limited period while completing the effectiveness requirement.
The initial conditional approval is valid for one year with the potential for four annual renewals. During this time, the drug company must show active progress toward collecting the remaining effectiveness data needed for full approval. The drug company must get the drug fully approved by FDA within five years of the initial conditional approval, or it will no longer be in effect—the company would have to stop marketing the drug because it would be considered an unapproved animal drug.
Before 2018, conditional approval was limited to drugs for minor species (all animals that are not one of the seven major species: horses, dogs, cats, cattle, pigs, turkeys, and chickens) or for diseases in a major species that occur infrequently or in limited geographic areas and in only a small number of animals each year. Ferrets and fish are examples of minor species. A drug to treat osteosarcoma in dogs is an example of a drug for a disease in a major species that occurs infrequently and in only a small number of animals each year.
In 2018, Congress granted FDA the authority to expand conditional approval to include animal drugs intended for use in a major species that address a serious or life-threatening disease or condition, or an unmet animal or human health need, but demonstrating effectiveness would require complex or particularly difficult studies. KBroVet-CA1 was the first conditional approval granted under this expanded authority, and it met the criteria because no other animal drug is currently approved to control seizures in dogs with idiopathic epilepsy, which is a serious and potentially life-threatening condition affecting about 5% of the canine population.
Part of the conditional approval of KBroVet-CA1 was based on FDA’s literature review of the safety of potassium bromide in dogs, which was published in March 2012 in the Journal of the American Veterinary Medical Association. The comprehensive review covered more than 50 years of published literature on the use of potassium bromide in dogs. By evaluating 111 references that provided safety data, FDA “identified a considerable body of pharmacological, primary, and supportive evidence regarding the in vivo safety of KBr” in dogs.
Traditional Safety Studies
As part of the approval process for an animal drug, a drug company traditionally would conduct laboratory-based studies to collect safety information on the drug. These studies would evaluate the clinical and pathological changes in four groups of healthy laboratory dogs. Each group would receive 0, 1, 3, or 5 times the therapeutic dose of the drug. The results would provide detailed individual data, but might miss subtle adverse signs or those signs that occur after long-term use of the drug.
While traditional, laboratory-based safety studies remain the gold standard for evaluating the safety of an animal drug before approval, they may not be the only way for a drug company to prove a drug’s safety.
A review of published literature, such as the one done by FDA for potassium bromide, is an example of an innovative approach to potentially show the safety of a drug for a particular use. Literature reviews may be especially helpful to establish the safety of an animal drug that has a long history of use and many literature references, like KBr.
The vast amount of literature on KBr in dogs gave FDA “a volume and variety of evidence that far exceeded the data traditionally available to determine the safety of new animal drugs.” Client-owned pets provided much of the safety data in the literature. These pets had idiopathic epilepsy and were treated with KBr, PB, or both “under conditions of clinical use,” meaning in real-world settings. While the data collected on each animal were less detailed than in a traditional safety study, the reports by the pet owners often included information that may be missed in a laboratory setting. Also, the pet owners’ reports offered a look at the long-term effects of potassium bromide in a large number of animals. Chronic drug effects are often not detected in a short-term clinical trial involving only a small, select group of dogs.
The manufacturer of KBroVet-CA1 used the safety data from FDA’s literature review to help establish the safety of KBr in dogs. This was an innovative approach that allowed the company to establish the drug’s safety without performing animal studies and supported FDA’s commitment to reduce, replace, and refine the use of animals in research.
What’s next for Potassium Bromide?
With the conditional approval of KBroVet-CA1, veterinarians are assured that the drug is safe and likely to be effective, manufactured according to the same standards as full approval, and adequately labeled and packaged. A future full approval of either KBroVet-CA1 or another KBr product will provide veterinarians with even more assurance that the drug is safe and effective to control seizures in dogs, properly manufactured, and adequately labeled and packaged.
Resources for You
- A Systematic Review of the Safety of Potassium Bromide in Dogs (JAVMA, Vol 240, No. 6, March 15, 2012) (PDF - 670KB)
- Freedom of Information Summary for KBroVet-CA1 (potassium bromide chewable tablets), Application Number 141-544