In January, the Food and Drug Administration's Veterinary Medicine Advisory Committee and consultants heard presentations by the FDA Center for Veterinary Medicine and Fort Dodge Animal Health on the safety of ProHeart 6 (sustained release injectable moxidectin). This past September, Fort Dodge voluntarily issued a recall and ceased production of the drug, until FDA concerns about safety could be resolved. The advisory committee failed to reach consensus.

The VMAC deliberated over two questions. First, based on the presentations and information provided, is ProHeart 6 safe for use in dogs? Second, if there are remaining safety concerns with ProHeart 6, what additional avenues of research could be explored to mitigate and/or prevent the adverse events? Before voting, the committee heard from a number of presenters.

Background
Dr. Lynn Post, director of the FDA-CVM Division of Surveillance, and Dr. Margarita Brown, a veterinary medical officer with the FDA-CVM, explained the agency's method for analyzing animal drug adverse event reports, and discussed the ProHeart 6 experience.

Several veterinarians with practice experience review adverse event reports. Most reports come to the FDA from manufacturers, which are mandated by the FDA to furnish the voluntary reports of veterinarians and animal owners. Some reports come directly to the FDA from the public. The FDA employees assign points to six components and use an algorithm to interpret whether events are remotely, possibly, probably, or definitely drug-related. The components are previous experience with the drug, alternative explanations of the events, timing of events, any evidence of overdose, whether the problem disappears after withdrawal of the drug, and whether the problem reappears when the drug is reintroduced.

On the basis of the number of reports judged to be possibly related, the FDA concluded that the number of deaths associated with ProHeart 6 was greater than with other heartworm preventives, relative to the market shares of the products. The FDA also believed that ProHeart 6 was associated with a greater number of certain organ system events and allergic reactions. Despite three label changes, the CVM had continued to receive a large number of serious adverse drug event reports. The FDA expressed concern with the timing of reports coinciding with peak serum concentrations of the drug.

With this information in hand, and considering that ProHeart 6 is used in a preventive fashion and alternatives exist, the FDA asked Fort Dodge for the recall. The FDA is of the opinion that a higher standard for safety of preventive drugs should exist as compared with therapeutic drugs.

The debate
Dr. Rami Cobb, vice president of pharmaceutical research and development for Fort Dodge, reviewed the safety data that had been used by the FDA to approve the drug in 2001. Dr. Cobb explained the extensive toxicology database for the active ingredient moxidectin, and the data review and continued marketing of ProHeart drugs in other countries.

Dr. David Hustead, senior director of international technical and regulatory affairs at Fort Dodge, focused on the company's analysis of adverse event reports. He described a method approved by the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products. The company used the total number of adverse reports divided by doses of drug sold to achieve a reporting rate. Differentiating reporting rate from incidence, Dr. Hustead indicated that a reporting rate is a useful tool, so long as one is aware of its limitation. Dr. Hustead explained that the firm retained independent experts, and that they and the company concluded that most adverse events were not causally related to ProHeart 6 and reflect the normal range of diseases occurring in the dog population. Fort Dodge Animal Health concluded that ProHeart 6 is a safe and effective product for prevention of heartworm disease.

Dr. Larry Glickman, a professor of epidemiology and environmental medicine at the Purdue University School of Veterinary Medicine, also came to the conclusion that there was no scientific rationale for the continued withdrawal of ProHeart 6 from the market. His evidence came from an unpublished, controlled epidemiologic study that evaluated more than seven million dog encounters at Banfield, The Pet Hospital from 42 states. The study examined the safety profiles of ProHeart 6, which provides six months of protection, and two monthly heartworm preventives in dogs. Because exposure to the drug was known and could serve as a denominator against which adverse event reports are considered, the study was the only source of incidence data. His conclusion was that the safety profile of ProHeart 6 was favorable compared with those of the two monthly heartworm preventives.

Consideration
As the advisory committee and consultants individually considered the question of safety posed to them, it appeared that participants were not operating under a common definition of "safe." Several members wrestled with their own interpretation of the term, as well as what clients might expect, including zero tolerance for risk. Narrower interpretations of safe were generally accompanied by requests for more information.

The VMAC grappled with the data and issues, including how concomitant administration with vaccination may confuse interpretation of the associated adverse event reports following office visits. Some participants pointed out that the risks of an adverse event associated with the drug, while such an event may be severe, appear to be small and, by some accounts, similar to those of other approved drugs widely used for the same purpose. Some pondered the concept of the safety standard for a preventive medication being higher than that for a disease treatment. The lack of risk/benefit information further complicated the evaluation. What is the risk of adverse reaction to the product, compared with the benefit of heartworm prevention, particularly since the sustained-release nature of the product eliminates possible infections caused by poor compliance with monthly dosing?

Many committee members and consultants agreed that the epidemiologic data from Banfield, The Pet Hospital were compelling.

In the end, eight participants did not declare the drug safe and indicated that they needed more information. Seven participants voted that the drug was safe.

Future outlook
Because a clear signal had not emerged from the advisory committee, Dr. Stephen Sundlof, director of the FDA-CVM, said that the FDA would take the comments back to the agency for additional discussion.

Dr. John Gay, as epidemiology representative to the AVMA Council on Biologic and Therapeutic Agents, stated during the public comment period that there is room for improvement in the federal process for collecting, analyzing, and responding to adverse event reports. He emphasized that a strong system would reduce two general types of errors in the areas of sensitivity and specificity. Improving system sensitivity would provide early, clear detection of associations between particular drugs and adverse effects in segments of the patient population. Improving system specificity would reduce the problems with spurious associations between particular drugs and adverse events in animals' lives. Both are required to maintain the profession's confidence in the drugs that veterinarians use, the availability of safe and effective drugs, and clients' confidence in their veterinarians, Dr. Gay said.

At press time, the FDA had not made any further decisions about ProHeart 6.

For more information, including copies of presentations made at the meeting, visit www.fda.gov/cvm/index/vmac/VMACWinter2005.htm.