On Friday, September 3, 2004, the FDA cited concerns about ProHeart 6 and issued a press release requesting the recall of the product.    Return to Making the Best Choices

 

Fort Dodge Animal Health

Division of Wyeth

Brent Standridge

Senior Vice President

North America Sales & Marketing

 

September 2004

 

Dear Doctor:

 

As you may be aware, on Friday, September 3, 2004, the FDA cited concerns about ProHeart 6 and issued a press release requesting the recall of the product.

 

Fort Dodge Animal Health has voluntarily complied with the U.S. Food and Drug Administration Center for Veterinary Medicine's request to temporarily cease marketing and recall ProHeart® 6 to the veterinarian level until the FDA's questions regarding safety are resolved. Fort Dodge Animal Health has also announced its strong support for FDA's formation of an independent Advisory Panel to review and evaluate safety data on ProHeart 6.

 

While Fort Dodge Animal Health is cooperating with FDA's request for a recall, we strongly disagree with the Agency's interpretation of the data and the conclusions that were drawn. Based on a thorough evaluation of FDA's data, and consultation with independent experts in veterinary medicine and epidemiology. Fort Dodge Animal Health remains extremely confident in the safety and efficacy of ProHeart 6.

 

The Company fully supports the initiation of the review process, and will work closely with FDA to provide the necessary information for the panel to make a fair and accurate assessment in a very timely manner. Our first and foremost concern is providing safe and effective products to ensure the health and well being of all pets.

 

It is important to note the voluntary recall of ProHeart 6 has no impact on any of Fort Dodge's other pharmaceutical or biological products. As a committed partner to veterinary practitioners, livestock producers and pet owners worldwide, Fort Dodge continues to make a difference in the future of animal health through innovative research and product development that addresses current and emerging animal health needs.

 

Formal recall information, with detailed instructions about return of product, will be sent to you. Until that time, we ask you to remove the product from your inventory and cease using it. We encourage you to call our Professional Services department at 1-800-533-8536 if you have additional questions, or to contact your Fort Dodge territory manager. Thank you for your prompt attention to this important information.

 

Sincerely,

 

Brent Standridge

Senior Vice President

North America Sales & Marketing

 

ProHeart 6 is generally well tolerated. A small percentage of dogs showed mild, transient swelling or itching at the injection site. While rare, digestive, neurological or hypersensitivity reactions may occur. For any additional questions, please call 1-800-477-1365.


 

information about THE voluntary recall OF proheart 6

 

response TO FDA concerns

In response to the concerns raised by the FDA, Fort Dodge Animal Health has compiled the following data, which we believe solidly support our claims of safety and efficacy. We are confident this information will help clarify this situation, and will help enable you to successfully address questions and concerns that may arise from pet owners.

 

FDA Concern

FDA has cited concern with the number of adverse reactions and deaths reported for ProHeart 6.

 

Fort Dodge Response

Potential adverse events reported to the FDA are unfiltered, meaning all reported potential events are submitted without regard to cause and effect. Cases subsequently determined not to be related to the product remain in the overall reporting numbers, and are used to draw medical conclusions that dramatically overstate the incidence of various conditions.

Since launch in 2001 through August 2004, the overall rate of reports for ProHeart 6 has been calculated at approximately 3 unfiltered reports for each 10,000 doses sold. Independent data from one of the most comprehensive databases available in the U.S. indicates a reporting rate of 4 reports per 10,000 doses actually administered to dogs. Considering the difference between "doses sold" to veterinarians and "doses administered," we believe this data to be representative of what is occurring in actual field use, and disagree with the FDA's assertion that there is significant "under reporting" with the product. Our belief is underscored by the fact that ProHeart 6 is administered only by veterinarians, and has received undue media and Internet attention, both of which increase the likelihood of event reporting.

 

Nonetheless, the breakdown of unfiltered reports is as follows (based on reports per 10,000 doses)

·        For allergic reactions, the number of unfiltered reports for May 02 - April 03 was 2.2 per 10,000 doses. From May 03 - April 04, that number was 0.85 per 10,000 doses.

·        For illness, the number of unfiltered reports for May 02 - April 03 was 2.1 per 10,000 doses. From May 03 - April 04, that number was 0.98 per 10,000 doses.

·        For death, the number of unfiltered reports for May 02 - April 03 was 0.4 per 10,000 doses. From May 03 - April 04, that number was 0.28 per 10,000 doses.

 

Noted in this document are examples of dogs included in the adverse event database. Despite medical evidence that reflects health issues not related to ProHeart 6, the cases are included in the analysis of the database and the subsequent conclusions.


 

FDA Concern

In the FDA news release, the Agency cited a concern with liver and abnormal bleeding issues.

 

Fort Dodge Response

Fort Dodge disagrees with the FDA's conclusions about the magnitude of these issues, as no consideration was given to the basic principle of epidemiology, which requires events be evaluated in the context of the population at risk.

Research by Bronson (Am J Vet Res, Vol. 43, No. 11, p.2057-2059, 1982) shows the mean age at death from hepatic necrosis as 4.9 years. The FDA's own data reflects the average age for liver signs, with relation to ProHeart 6 reports, as 4.5 years, which is in keeping with the baseline canine population in the U.S.

Based on unfiltered reports with some reference to hematologic signs/autoimmune signs, the incidence rate for ProHeart 6 is 0.0025 percent or one in approximately 31,000 doses. Again, Bronson reported that one percent of all deaths in dogs were due to hemolytic anemia. Even with unfiltered reporting numbers, ProHeart 6 is well below the baseline of disease for the U.S. canine population.

 

FDA Concern

In a presentation to Fort Dodge, FDA cited unusual cardiac complications as a concern with ProHeart 6.

 

Fort Dodge Response

Based on the unfiltered data, the frequency of total "cardiac" reports is 0.2 reports per 10,000 doses. In the U.S. canine population, there is an underlying incidence of heart disease in dogs, and a higher prevalence is recognized in boxers than in the general canine population. The FDA has stated finding "atypical heart problems" in boxers because of cases with no macroscopic dilation. Boxers, in fact, have a genetic predisposition to cardiomyopathy. Two distinct types are recognized. One has macroscopic dilated findings, while the other does not (Gough and Thomas, Breed Disposition to Disease in Dogs and Cats, ISBN 1-4051-0748-0)

 

FDA Concern

The FDA has cited cancer as a concern for ProHeart 6 and has stated a "suspicious timing of cancer, four to 30 days" and in young dogs.

 

Fort Dodge Response

In our opinion and those of experts we have consulted, the timing suggested by the FDA (4 to 30 days post administration) is not biologically feasible. And the data reflects the age of dogs included in the reporting numbers is less than the rate of cancer seen in the general canine population (Cancer Incidence in Dogs Survey, 1952-1963, and Cohen et al., Cancer Research, 34:2859-2868, 1974).

It is estimated that almost half of all pets over the age of 10 will develop cancer (Cancer in Dogs and Cats, Brakke Consulting, 2002). While cancer is more common in older dogs, it does occur in young ones, as well. In the unfiltered reports for ProHeart 6, the rate of cancer is 0.07 reports per 10,000 doses. Nearly 77% of these cases are in dogs older than six years. The Veterinary Cancer Registry shows 75% of does with cancer are seven years or older.


 

Cohen, et al. (Cohen, et al.. Cancer Research, Epidemiological Analysis of the Most Prevalent Sites and Types of Canine Neoplasia Observed in a Veterinary Hospital, 34: 2859-2868) reported 2,499 cancer cases in 60,000 dogs presented to veterinary hospitals over a 12-year period. The rat (of prevalence was 4.2%. The unfiltered ProHeart 6 database shows 122 reports out of 18.2 million doses (through April 2004) with a diagnosis of cancer, which is considerably lower than that seen in the general canine population. In addition, the wide range of cancer seen in the unfiltered ProHeart 6 reports is reflective of the range of normally occurring cancers seen in the general canine population.

 

An example of a dog included in the cancer category for ProHeart 6 is as follows:

The dog, a 10.5-year-old Yorkie with a known sensitivity to ivermectin (lethargy and vomiting), was treated with ProHeart 6. Approximately four months later, the dog presented with anorexia, ataxia and lethargy. Initial diagnostic evaluation revealed bilateral luxating patellas. The dog was also thought to have a possible liver problem or a tumor, but the owner initially declined medical treatment and a further diagnostic evaluation. A referral veterinary ophthalmologist later examined this dog for a vision problem. While the veterinarian could not make an initial definitive diagnosis he did note that if this problem were pharmaceutically related, he would expect the problem to be symmetric, not asymmetric as exhibited by this dog.

 

Eight months after the injection, the dog was diagnosed with lymphoma in its right eye. The veterinary ophthalmologist noted he has seen this same problem in a number of dogs that had not been administered ProHeart 6. Evidence of glaucoma was found in the other eye. Approximately one month later, the dog was euthanized at the owner's request because of the dog's difficulties. Two veterinarians told the owner that the lymphoma most likely spread to other parts of this dog's body. The referral veterinarian suggested a necropsy be performed; the owner declined.

Despite the evaluations of the attending veterinarians, FDA has assigned the following signs in this dog as being "probably related to the drug." - Anorexia, Depression/Lethargy, Neoplasm, Weight Loss, WBC High/Blood Problem, Ataxia, Circling, Blindness, Hyphaema and Eye/Eyelid Lesion.

 

Lymphoma is a common cancer in dogs, with a reported incidence of 11.4 cases per 10,000 dogs per year (Morris & Dobson, ISBN, 0-632-05282-1).

 

FDA Concern

In a presentation to Fort Dodge, the FDA cited a concern with the efficacy rate for ProHeart 6.

 

Fort Dodge Response

Based on unfiltered reports, the efficacy rate for ProHeart 6 continues to be solid - 99.997%.

 

FDA Concern

The FDA has cited a concern with unfiltered reports of anaphylaxis for ProHeart 6

.

Fort Dodge Response

Unfortunately, almost any drug can trigger an allergic reaction. After ProHeart 6 was launched and anaphylaxis was observed, labeling changes were instituted promptly to describe the post-launch experience.

 

The rate of anaphylactic reactions has decreased from 2.2 per 10,000 doses in May 02-April 03 to 0.85 per 10,000 doses in May 03-April 04. In addition, there has also been a decrease in the "illness" category of reports from 2.1 per 10,000 doses to 0.98 per 10,000 doses, which supports the premise that many of the illnesses reported (vomiting, diarrhea) were allergy related.