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U.S. Department of Health and Human Services

Advisory Committees

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Pfizer Animal Health by Stephen Sutherland, D.V.M. and Tatty Hodge, D.V.M., M.S.

Dr. Stephen Sutherland

DR. SUTHERLAND:  I am happy to be here today, along with Dr. Tatty Hodge, representing Pfizer Animal Health, and we really look forward to sharing with you information about ProHeart 6 and to getting feedback from CVM as well as the VMAC panel regarding the ProHeart 6 RiskMAP.


So, who am I?  I am the Senior Director of Pfizer Animal Health’s Regulatory Affairs Group in Kalamazoo, Michigan.  I have a background in private practice and about 20 years of experience in research and development, primarily regulatory affairs.  I just say, as an aside, my most valuable experience comes from my dog, my cat, my chickens, my three children and a very smart wife.


So today, during my presentation, I hope to set the stage for Dr. Hodge’s presentation on the RiskMAP program, and then Dr. John Baker from CVM, his presentation on the data analysis from the RiskMAP.  So I am going to try to provide some context for those presentations. 

I will start with a brief historical perspective of how ProHeart 6 came to be within Pfizer, a little bit on the ProHeart 6 product itself, a quick overview of heartworm disease, and them Pfizer’s assessment of, and our commitment to, ProHeart 6, and then finally a little bit about Pfizer’s pharmacovigilance program that Dr. Hodge will go into extensive presentation on.


So, just to provide some context and explain why Pfizer Animal Health is at this meeting today when Fort Dodge was at the VMAC that occurred back in 2004-2005.

Well, in October of 2009, Pfizer, Incorporated acquired Wyeth.  Fort Dodge Animal Health is a Division of Wyeth, or was a division of Wyeth, because Wyeth no longer exists.  Pfizer Animal Health assumed ownership and regulatory responsibility for a variety of Fort Dodge Animal Health products, including ProHeart 6.  So that is what brings us here today at this meeting.


So what is ProHeart 6?  Well, basically, it is a parasite-killing drug from the macrocytic lactone family that is commonly used in animal health in a variety of products for dogs, cats, horses, cattle and sheep.  Other products, or other drugs, from this category include Ivermectin and Milbemycin and Selamectin.

Specifically, ProHeart 6 is a sustained, slow-release formulation of Moxidectin.  And this particular product is administered subcutaneously by the veterinarian.

The benefit of the product is that it provides six months of protection following that subcutaneous injection and it provides protection against heartworm disease.  A side benefit of it is that it also treats existing larva and adult hookworms infections.


So what is heartworm disease?  And this is the disease, of course, that ProHeart 6 prevents.  Heartworm disease is a serious and potential life-threatening infection in dogs.  The parasitic worms, when they achieve their adult stage, they live in the arteries and the lungs of the heart.  I want to say, too, that I really appreciate these pictures from the American Heartworm Society and the information that they have provided us.

Heartworm disease is transmitted by mosquitoes after taking a blood meal.  It is a -- fortunately, it is an easy disease to prevent, but a difficult and expensive disease to treat when the dogs have the established infections from the adult heartworms.

This particular parasite has increased in distribution over the years, primarily due to population mobility, people and their pets moving from one climate to another and bringing the disease into that region. 


This just illustrates the distribution of heartworm throughout the United States.  It has been reported in all 50 states.  It gives you some indication that the incidence of heartworm is higher in the warmer climates because those warmer climates are more conducive to the mosquito parasite.


So, how is heartworm disease prevented?  A little bit about that perspective of it. 

After a mosquito bites a dog and has the parasite in it, there is a window of life -- of opportunity within the life cycle to eliminate that parasite from the body so that it doesn’t progress to the next stage, into the heart and into the arteries of the heart and lung, and that is where the prevention of heartworm disease occurs. 

There are a variety of products that are safe, easy and inexpensive to treat heartworm at that life cycle, a susceptible life cycle stage, and these products include oral products, pills, topical products that are administered by putting on the skin, and both of those products are administered by pet owners.  

The other option is ProHeart 6, which again is an injectable product.  It is administered not by the owner but by the veterinarian, and it is given every 6 months and provides that 6 months of protection against the disease.  And as I said, these medications arrest the heartworm development before the adult heartworm can reach the lungs and cause the disease progression.


One of the problems related to heartworm treatment is that although heartworm preventatives are very effective when properly administered, if you miss a dose and you miss that window of opportunity in the life cycle to kill the parasite, it can increase the chances of the heartworm infection progressing. 

Compliance, then, is critical.  It is critical that the pet owner administer the product on a monthly basis.  And it is -- compliance is a problem in the sense that owners, just like us when we forget to take our own medicine, sometime we forget to administer products to our pets each month.  Some people also have difficulty in properly administering oral products or topical products.  And then, finally, products can be spit out by the dog or vomited and the owner doesn’t know that the dog has left -- has not gotten the dose. 

ProHeart 6 is administered via injection by the veterinarian, insuring 6 months of continuous protection against heartworm disease.  And we talked before a little bit about benefits and risks -- this is indeed a benefit of the product.


Now, turning to some background in terms of the events that have led up to this VMAC today.  FDA approved an NADA for ProHeart 6 in 2001.  The product was approved internationally in several countries, including Canada, Japan, European countries, Australia, as early as 2000.  It has been marketed in international markets continuously since introduction in 2000 and 2001, 2002.  Over 9,000,000 doses of ProHeart 6 have been utilized on a worldwide basis.

The product was voluntarily removed from the U.S. market in 2004 due to the field reports of adverse events and the concern over safety.


In the past few years, several key events have occurred with ProHeart 6.  Several manufacturing changes were made and approved by CVM.  Specifically, when the product was reintroduced, the specification of the Moxidectin active ingredient was revised to “no detectable residual solvents.”

Additionally, safety studies were performed to further evaluate the product, including an evaluation of the immuno-toxicity potential of residual solvents, given that the primary adverse event that is observed is allergy-related, and we wanted to study that in depth.


So, the product was reintroduced to the market based on the manufacturing changes that were made, the favorable international experience in terms of looking at all of that international experience data, and the low adverse event incidence that was recorded on a global basis. 

The product returned to the market under what we are talking about today, the Risk Minimization Action Plan, in June of 2008. 

That RiskMAP provided an excellent framework for the reintroduction of ProHeart 6 while allowing the characterization of the safety profile to be closely scrutinized while eliminating the interference of other factors such as concurrent vaccination or older, older dogs that had -- may have other problems that would confound your ability to figure out, was it the drug or was it some disease that an older animal had?

ProHeart 6 is the first and only product marketed under a RiskMAP.  The RiskMAP was modeled, as was just previously talked about, using RiskMAPs established for human products. 

When the RiskMAP was entered into, it was due for reevaluation in 1 -- after 1 year of RiskMAP.  We are currently in the 20th month of the RiskMAP, and we are continuing to follow very rigidly the RiskMAP framework that was put in place back in June of 2008. 

ProHeart continues to be provided.  You train veterinarians in accordance with the program, and as we stand here today, veterinarians are utilizing it. 


After acquiring ProHeart 6 as part of the Wyeth acquisition, Pfizer Animal Health performed a thorough assessment of ProHeart 6. 

It was very important for us to have confidence in the safety and efficacy of this product, so we conducted an extensive analysis of all the adverse events received for ProHeart during the first 18 months of the RiskMAP as well as all the other international related adverse event information that was available. 

We also looked at the safety information that was generated to approve -- to gain approval of the NADA as well as post-approval safety studies that were conducted. 

We also closely evaluated the effectiveness profile for the product. 

In the end, we decided to continue marketing of ProHeart 6 and support the RiskMAP process and the VMAC process, and we did that based upon a favorable evaluation of the safety and effectiveness profile, and, frankly, the unique product benefits -- the single injection providing 6 months of continuous heartworm protection over a 6-month period, insuring treatment compliance, which is a huge benefit, particularly in endemic regions.


We remain committed to all the -- we assume all the responsibilities and we are completely committed to the -- what has been previously committed to under the RiskMAP, and working through the process, and we look forward to the recommendations of the VMAC panel and working with the Center for Veterinary Medicine to develop a Modified Risk Mitigation Plan that is not only acceptable to veterinarians and pet owners but insures the safe and effective use of ProHeart 6 in pets.


We are very proud at Pfizer that we have a comprehensive pharmacovigilance program that Dr. Tatty Hodge will talk about.  In fact, Tatty just spent the last two days at a pharmacovigilance meeting with the Center and other parties. 

We have a comprehensive program for the collection, verification, evaluation, reporting of potential adverse effects for all products, and regardless of whether or not we determine that the product is associated with the adverse event, we report every adverse event that is reported to us for analysis. 

Calls are received by trained veterinarians, animal health care technicians, using a toll-free number system.  The complaint calls are recorded using the validated PV-Works software.  Reports are submitted to the regulatory agents routinely, generally on a weekly basis. 

Reports are received from veterinarians, pet owners and published literature.  Anything that could be deemed an adverse event potentially associated with the product, including ProHeart 6, is recorded and submitted. 

We are continually in the process of monitoring the benefits versus the risk of products, and if we see trends, we will work closely with the Center for Veterinary Medicine to make label changes to reflect those risks.


So, I am pleased to introduce Dr. Tatty Hodge.

Tatty is the Director of our Global Pharmacovigilance Group.  She has extensive experience in the pharmacovigilance arena and she is a pioneer in the pharmacovigilance -- the PV-Works area as well as, you know, improving the processes for documenting adverse events and analyzing those events, and has been really a partner, I think, with the Center for Veterinary Medicine in that regard. 

So I am pleased to introduce Dr. Tatty Hodge.



Dr. Tatty Hodge

DR. HODGE:  Thanks, Steve.  Just a little bit about myself.  I have worked for Pfizer for 10 years in pharmacovigilance, not my whole life, though, and prior to that I was a small animal practitioner with extensive experience with exotic and wildlife medicine and disaster relief and humane investigation.


I am going to be going over the components of the ProHeart RiskMAP.  I am leaving out the “6” because it makes me stutter.  But we are going to talk about the revised label, the educational program for veterinarians and owners, how we distribute the product to veterinarians, and a little bit about our pharmacovigilance system and how we monitor the events, and our communication with CVM.


As far as the product label -- and you all know from previous training and also previous presentations that the label is really the cornerstone for risk minimization.  It is not the only one, however, because as we know in practice, a lot of people don’t read or haven’t been instructed in the use, the proper use, of the label.  But the label nonetheless provides instructions for the indication for use and the dosage and administration. 

In addition, there are sections on the precautions and warnings, and in the case of ProHeart 6, the revised label contains warnings about “Do not administer within 1 month of vaccinations,” talks about observing the dogs for any toxicity to the product, as well as a warning not to use in sick, debilitated, underweight dogs or those experiencing weight loss.

It also goes through -- there are also additions as far as adverse events that had been observed prior to the voluntary withdrawal.  Those have been included on the revised label.


The comprehensive educational program, this to me really is the cornerstone of the program and what makes it so successful in safe use.  This is the educational program for the veterinarian.  And it started with a “Dear Doctor” letter, and the Dear Doctor letter really outlined the educational program, announced the re-launch of the product, told the veterinarians where to go, what website to use, and how to get registered as a user. 

The web-based training talked about the conditions of ProHeart use under the RiskMAP, described the label and the information sheet, and gave a lot of safety information on that web training as far as how to use the product safely.  It also listed and explained the adverse events that had been seen previously.


Additional information.  There are 2 Pfizer-sponsored websites.  1 is for veterinarians and one is for pet owners.  And there is also a toll-free number available if veterinarians or pet owners suspect an adverse event. 

You heard from Steve that we acquired Fort Dodge in October last year.  And then in the middle of December, through a transition plan, we took over the calls for all of the Fort Dodge legacy products. 

So currently, the 800 number does ring into Pfizer, and that number is staffed from 9:00 a.m. to 8:00 p.m. to allow for colleagues on the West Coast, and it is staffed by licensed technicians and veterinarians and they answer both inquiries and they also take the adverse event information, enter it into the database, and then it is available for my group to review.


So, what are the conditions of ProHeart use under the RiskMAP?  It restricts distribution to veterinarians that have completed the training and have agreed to the conditions.  I thought Janice made a great point that RiskMAPs are not designed to restrict, but they are designed to facilitate the availability of the products, and I thought that was an excellent point.

The age eligibility for dogs is 6 months to 7 years, and the 6 months is on the label, and that is just simply because ProHeart was not tested in younger dogs.  And the restriction to 7 years for the first dose was part of the RiskMAP to eliminate the confounding factors of geriatric dogs, as Steve pointed out.

Another requirement prior to administration:  Blood work should be taken, and heartworm tests, CBC blood chemistry and platelet count should be done. 

One of the main requirements was the exclusion of concurrent vaccination within 1 month of administering the product and also an agreement from the veterinarian that they would report all suspected adverse events. 

Again, as Steve mentioned, we report all adverse events to CVM regardless of their association or causality.  While we may internally make our own causality assessment on the cases we receive, we forward all of those cases on to CVM.  John Baker will be talking more about the adverse events we have received during this RiskMAP period.


Likewise, education for pet owners -- in my mind, there can never be enough of it.  It is only really restricted by the time and the money it takes to provide it.  But in this case, the Client Information Sheet is provided to all the pet owners.  It provides safety and efficacy information in a pet owner user friendly format and owners must read that as well as acknowledge that the veterinarian talked to them about the product, options for other heartworm treatments, and what to expect with this particular product. 

Owners also agreed that they would provide the veterinarian with any medical history of the animal that might be relevant.  They also agreed that they would alert their veterinarian if there were adverse events noted in their pet after administration.


So we have talked about adverse event reporting.  You had a presentation on what the normal process is.  We follow that guideline for all of our products and that is 21 CFR 514.80.  It is probably the only number I can know.  And with that, serious and unexpected reports are submitted as 15-day alerts. 

Periodic or non-serious events would be reported either every 6 months or a year, depending on the age of the product.  But with ProHeart, basically everything that we receive is submitted either as a 15-day or a monthly report.  And in addition, quarterly meetings are set up with CVM and we discuss every report that we have received.


This has been the RiskMAP participation through December -- number of veterinarians that have been trained and certified, over 6500, and the number of clinics represented, over 4,000, with approximately half of these, or 2,000,  purchasing ProHeart. 

The number of doses sold, roughly over 300,000.  Doses sold is calculated by the 20-mil vial.  We calculate that approximately 19 dogs would be treated by that vial, approximating the average dog to be 20 kilogram, but again, just an approximation. 

So you will see later as we create incidence rates, I just want to let you know ahead of time those are really, really rough estimates and used only to compare from time period to time period, not necessarily used to compare 1 product to another.        


The customer feedback on the RiskMAP has been variable, but unsolicited feedback from veterinarians and pet owners have identified some key barriers to adopting ProHeart 6 as part of their preventative health plan. 

The concomitant vaccination restriction increases the need for multiple pet owner visits and this can either be a logistical situation where you have to take extra time off from work or a financial burden for some pet owners.  The pre-treatment blood work requirement also makes treatment sometimes cost prohibitive for some owners. 

In addition, the client consent form sometimes is seen as an impediment to acceptance of the product by both the pet owners and the veterinarians.  Veterinary practices are not quite at the stage where a client consent form is required for every procedure.  Certainly, for surgical procedures, it is quite common; some practices, for vaccinations, require it.  But for others, it is still a new concept.  And so to make this something that has to be done before this product is administered makes it stand out as a potential barrier.


So, in summary, ProHeart 6, as you have heard before, it is the first animal health product to be marketed using a RiskMAP.  The goal of the program was to insure the safe and effective re-launch of this product, and I think it did that exceptionally well.  I consider it to be a real successful program for the last 18 months. 

What the RiskMAP did for me in particular, but for the product, it allowed for the very fine characterization of the safety profile of this product without the confounding factors of concomitant vaccination, increased age, underlying disease condition, some of which you may or may not be able to prove based on the presence or non-presence of a baseline blood work. 

The product demonstrated clinical effectiveness and expected adverse reactions.  John will be going into more detail, but generally we found the reactions to be quite specific to ProHeart, with mild allergic reactions, facial edema occurring immediately and resolving with treatment; otherwise, bouts of mild vomiting and diarrhea.  And we also were able to identify barriers to the previous levels of use of this product.


A little bit about -- you have heard that we did use the international market experience to -- it was part of why this product was re-launched, and ProHeart has been continuously marketed since its original launch in international markets.  ProHeart 6 is registered in Australia, Canada, the EU and Japan, while ProHeart 12, 12-month product, sustained release, is registered in Australia also, Philippines, Indonesia, Hong Kong, Thailand, Vietnam and South Africa where heartworm is endemic.  And in these markets there is no concomitant vaccination restrictions for ProHeart. 

The international experience, the adverse event types, and the frequencies were similar in all of these reporting countries and they all do report adverse events.  And, likewise, they were also very similar to those that we received in the U.S. during this 18-month RiskMAP period.

They are considered rare by the WHO classification of .9 adverse reactions per 10,000 doses distributed, and there have been over 9,000,000 doses distributed worldwide.  Again, most of these adverse events were allergy related; again, mild and transient, occurring immediately after administration and resolving within the first 24 hours with treatment.  But likewise, the efficacy profile -- there were only 2 possible lack of efficacy reports over the 9 years that ProHeart has been marketed internationally, and that is exceptional for a heartworm product.


This graph, it is in the RiskMAP.  It basically compares the adverse event report rate over time from 2000 to 2009, and you can see that it is coming in for the markets of Australia, Europe and Japan, had very low levels of generally around .9 per 10,000 doses distributed. 

What is also evident here is the precipitous drop in adverse events that occurs in the middle of 2002, and this was the result of the manufacturing changes that were made to ProHeart.


Again, it makes a nice graph.  It shows very low levels of reactivity, and more than that, consistency from year to year.  But just to let you know that in my shop, it is more important actually what the event was, how serious it was, and what was the resolution, because we read every single report received for the product.


So, in conclusion, under the conditions of the RiskMAP, ProHeart, it demonstrated very good effectiveness with expected and mild adverse reactions. 

We consider the RiskMAP to be very successful, and the results in the U.S. are comparable to that of the international experience with both ProHeart 6 and 12. 

We look forward to this VMAC process and appreciate people coming and participating.  We would like to develop a modified risk mitigation program that is acceptable to veterinarians, pet owners, and assures that the safe and effective use of this product for our pets, and that is ultimately what we care about.  Thank you.

DR. DUNHAM:  Well, thank you both, Dr. Sutherland, Dr. Hodge, for that very good presentation.  At this time, are there any questions from our panel?

          (No response)

DR. DUNHAM:  If not at this time, we will go ahead and take a break and then we will come back and continue the program.  So, 15-minute break.  Refreshments are outside.  And we look forward to seeing you right back.  Thank you.

          (Brief break)

DR. DUNHAM:  We will proceed now with the next round of presentations from the Center for Veterinary Medicine.  So, thank you all very much. 

It is my pleasure to welcome Dr. Martine Hartogensis to the podium.  Thank you.