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.
Fort Dodge Animal
Health
Division of Wyeth
Brent Standridge
Senior Vice President
North America Sales & Marketing
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 Adminse 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.
Fort Dodge Animal
Health
Division of Wyeth
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 dogs 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 rate
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.
FREQUENTLY ASKED QUESTIONS
To answer some of your questions and those raised by your clients, Fort Dodge has drafted the
following information for your reference. If you have questions not covered in this document or
you would like to discuss any issues further, please contact our Professional Services department
at 1-800-533-8536.
1. What is the current situation with ProHeart 6?
Fort Dodge Animal Health has announced it will voluntarily comply with the U.S. Food and Drug
Administration Center for Veterinary Medicine’s request to temporarily cease marketing and
recall ProHeart 6 from the veterinary level until the FDA’s questions regarding safety are
resolved. Fort Dodge Animal Health 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. 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 of these
data. We look forward to working with the panel and remain confident in the safety and efficacy
of ProHeart 6.
2. Was Fort Dodge required to comply with the FDA’s request to voluntarily recall
ProHeart 6?
While the announcement indicates this is a voluntary recall, it is important to understand the FDA
was going to issue a press release that was very severe in its wording. It was our judgment that this
would have put veterinarians in a very undesirable position with their clients. While not a perfect
solution, we have chosen to pursue the expert Advisory Panel as the best means of reversing this
FDA’s decision.
3. Why did Fort Dodge not contact veterinarians in advance about the voluntary recall?
Fort Dodge specifically requested the FDA hold its news release until the company could contact
its customers and communicate to them the voluntary recall of ProHeart 6. Fort Dodge felt
strongly that to allow the media to drive the communication of this information would be
extremely detrimental to veterinarians, as well as pet owners. The FDA refused our request.
Unfortunately, we could not respond to the FDA’s position until they issued their press release,
which occurred after 4:30 p.m. Eastern Time on Friday, 03 September 2004. We sincerely regret
that the timing of this process was such that we were unable to alert our customers in a more
timely manner. While dissemination of information to the media can be instantaneous and farreaching,
providing immediate information to tens of thousands veterinarians across the country
proves significantly more difficult.
We have posted these materials on the Veterinary Information Network, as well as
www.proheart6dvm.com, for your convenience. If you have further questions, please call our
Professional Services department at 1-800-533-8536.
Fort Dodge Animal Health has consistently communicated with veterinarians about issues relevant
to the animal healthcare industry, including ProHeart 6. Effective communication with our
constituencies has been and continues to be a priority for Fort Dodge.
4. If ProHeart 6 has already been voluntarily recalled, why is an independent advisory
committee being convened?
While Fort Dodge has agreed to voluntarily recall ProHeart 6 from the market, we continue to be
confident in the safety and efficacy of the product. We disagree with the FDA’s interpretation of
the data and the conclusions that have been drawn, and feel strongly the data need to be
thoroughly reviewed and evaluated by an independent committee of experts from the animal
health/veterinary industry. Fort Dodge is pushing for an immediate selection of the committee and
review of the data.
5. Does Fort Dodge plan to reintroduce the product at a later time?
Fort Dodge Animal Health will make all reasonable efforts to resolve the current concerns and
reintroduce ProHeart 6. The Company is committed to working with the FDA to address its
concerns and to take the necessary actions to make ProHeart 6 available to veterinarians and dog
owners throughout the U.S.
6. What should dog owners do if they have used ProHeart 6 for their dog(s)?
Fort Dodge remains confident in the safety and efficacy of ProHeart 6. Pet owners with concerns
should contact their veterinarian or they may call Fort Dodge’s Professional Services department
at 1-800-533-8536. Veterinarians with questions regarding specific patients should call Fort
Dodge Professional Services for further discussion.
7. What should I do if a pet owner feels his/her dog has had a reaction to ProHeart 6?
Veterinarians or pet owners with concerns may call our Professional Services department at
1-800-533-8536.
8. If ProHeart 6 is not available, what should dog owners’ use?
While ProHeart 6 is unavailable, we urge dog owners to consult with their veterinarians to discuss
alternative preventatives.
9. How has the Internet impacted ProHeart 6?
During the past year, misinformation about ProHeart 6 has spread rapidly via the Internet. While
the Internet can be a valuable source of information, it is also full of opinion and conjecture
presented as fact. Unfortunately, it is often difficult to tell the difference between the two. Fort
Dodge strongly encourages interested individuals to fully investigate websites and verify the
accuracy of information presented on those sites. Fort Dodge consistently reminds pet owners that
the best resource for information is the veterinarian. Not only can a veterinarian review the data
concerning ProHeart 6, but he/she can also evaluate the health needs of the animal and determine
the most appropriate heartworm prevention program.