At the request of the Food and Drug Administration, Fort Dodge Animal Health voluntarily ceased production of ProHeart 6, and recalled all ProHeart 6 that had been distributed to veterinarians until the FDA's concerns about the drug's safety are resolved.
The FDA issued a statement about the recall on Sept. 3. The agency said it had received more than 5,000 reports of adverse events—including some deaths. The agency is encouraging Fort Dodge to continue its research into the cause of the adverse events and is convening an independent scientific advisory committee to evaluate the available data.
The FDA is asking veterinarians not to administer this product to dogs until further notice and to advise their clients on alternative heartworm preventives.
In a press release issued Sept. 3, Fort Dodge officials said they stand behind the safety of ProHeart 6, and questioned the methods the FDA has used to evaluate the adverse event reports.
"While Fort Dodge Animal Health is cooperating with the FDA's request for a recall, we have concerns about how the agency interpreted these complex data," according to a statement from the company. "As such, the company fully supports the initiation of this review process, and will work closely with the FDA to provide any necessary information for the panel to make a fair and accurate assessment of these data. We look forward to working with the panel and remain confident in the safety and efficacy of ProHeart 6."
Product safety questioned
The Food and Drug Administration approved ProHeart 6, the first injectable heartworm preventive, in June 2001. The product provides six months of protection with one injection by a veterinarian, and is an alternative to oral and topical heartworm preventives, which clients must administer monthly.
Over the course of the past three years, however, the FDA has received 5,913 adverse events reports about the drug from veterinarians and dog owners. According to the FDA, many of these reports involved life-threatening events, such as anaphylaxis, convulsions, hematopoetic disorders, and hepatopathies—about 616 reports involved deaths. The FDA has also evaluated a number of reports involving neurologic problems and cardiac signs.
The company has made three label revisions, added a client information sheet, and issued two "Dear Doctor" letters, at the request of the FDA, over the same time period.
Dr. Stephen F. Sundlof, the director of the FDA Center for Veterinary Medicine, said that this is the first time in his 10 years as director that the center has requested a product recall because of adverse event reports.
He explained that it is not unusual to receive unexpected adverse events reports for a new drug when it is first put on the market, because no matter how large or well-conducted the preapproval clinical trials are, they can never fully capture every segment of the population.
But after millions of doses of a new drug are administered, the agency and the company are usually able to identify populations that may be sensitive to the drug, and make adjustments to the label to prevent adverse events. In the case of ProHeart 6, however, the agency and the company have not been able to pinpoint and correct any problems that may exist.
"Despite (our and the company's efforts), we have continued to see a high number of adverse events," Dr. Sundlof said. "The thing that was more troubling for us was that the severity of the events was unchanged or going up. We felt that until we have a better understanding of why we were seeing these severe adverse drug reactions, it was prudent to remove the drug from veterinary use."
Company questions FDA methods
Dr. Rami Cobb, the vice president of pharmaceutical research and development at Fort Dodge, said the company disagrees with the FDA's interpretation of the adverse event reports.
The FDA's process relies on voluntary adverse event reports from veterinarians and pet owners. These reports can be submitted to the company or directly to the FDA. The company is required to submit all the reports they receive, unfiltered, to the FDA. Then, the agency's surveillance veterinarians analyze the reports to determine whether the drug could have caused the clinical signs described in the report and use a scale to rate how probable it is that the sign was caused by the drug. They use a variety of criteria including the timing of the signs, possible overdoses, alternate explanations for the signs, and whether the clinical signs described have previously been associated with the drug. They may also make follow-up calls to veterinarians or pet owners.
At press time, the FDA had received 5,913 unfiltered adverse event reports on ProHeart 6; the agency concluded that 5,480 of those reports contained at least one clinical sign that was possibly, probably, or definitely caused by ProHeart 6. Of the 21,258 clinical signs that were assessed in the reports, 19,179 were deemed by the FDA to be possibly, probably, or definitely associated with ProHeart 6.
"There's a lot of effort that goes into each report," Dr. Sundlof said. "We have a lot of experience in doing this, and we have highly qualified veterinarians who do this on a continuous basis and have the perspective of looking at this across the spectrum of all the drugs that we've approved."
A special report by the FDA on pages 533-536 of the Aug. 15 issue of JAVMA explains the process.
Dr. Cobb said the company has also evaluated the reports and has come to a different conclusion on some of them.
"We take every death and injury very seriously," Dr. Cobb said. She explained that the company files unfiltered reports to the FDA and does follow up investigations and testing on the reports of adverse events they and the FDA receive.
"We know definitively that some of the cases the FDA is reporting are not related to the use of the drug," she said.
Additionally, the company contends that the incidence of death and disease seen with the use of ProHeart 6 is at or below the normal incidence of death and disease expected for the U.S. dog population.
Dr. Sundlof said that it's not valid to compare the FDA's findings with background incidence in the U.S. population of dogs.
"It's just not a valid comparison," he said. "We don't evaluate adverse events in comparison to the background occurrence of those events, and the reason is those events are culled."
Both sides are looking to the independent scientific advisory committee to clear up any concerns about the way the FDA has evaluated the safety of this drug.
"Pet owners look to their family veterinarian for guidance in making sound decisions about pet health care," said Dr. Bruce W. Little, the executive vice president of the AVMA. "Veterinarians look to the FDA and pharmaceutical industry for quality products that are safe and effective. It is important to all parties that regulatory agencies fairly evaluate product information, using science-based processes to make proper decisions. The AVMA is examining how it can assist in the process to serve the best interests of the patient."