• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Advisory Committees

  • Print
  • Share
  • E-mail

Open Public Hearing - Moderator, Aleta Sindelar, CVM Executive Secretary

MS. SINDELAR:  Take your seats so we can proceed.  All members are present.  Speakers Martine and John Baker?  Great.
 

We will proceed with the Open Public Hearing portion of the meeting.  Dr. Doyle, our Chair, will be reading the statement for public disclosure for all public hearing -- open public hearing and comment periods.  Dr. Doyle?

(Whereupon, Dr. Doyle read the statement for public disclosure into the record.)

So with that, I guess we are ready for the first comment.

Open Public Hearing

Moderator,  Aleta Sindelar

MS. SINDELAR:  Great.  I would like to invite our first registered speaker, Dr. Larry Glickman.  He is  Professor, Epidemiology of Public Health, University of North Carolina School of Medicine.

DR. GLICKMAN:  Is this okay?  Thank you.  I very much appreciate this opportunity to share with you my opinions on ProHeart 6.  My name is Larry Glickman and I am a veterinarian with a graduate degree in epidemiology and public health.  I currently hold faculty appointments in the Veterinary School at Purdue University and the Medical School at the University of North Carolina at Chapel Hill.  I have devoted the past 37 years to research aimed at improving the quality of lives for dogs and cats and have published greater than 300 scientific papers in the veterinary and human literature.

I requested this opportunity to address the VMAC about the safety and effectiveness of ProHeart 6 for heartworm prevention in dogs.  I disclose that I am not receiving financial compensation for my appearance today, nor am I currently affiliated with Pfizer Animal Health.

In January of 2005, at a previous VMAC meeting, I had an opportunity to present the results of an epidemiologic study I later published on the safety of ProHeart 6.  This controlled observational study reviewed the electronic health records for approximately 7,000,000 office visits for 2,000,000 individual dogs that had received primary health care at one of approximately 400 Banfield hospitals in the United States.  At the time, this study was the largest ever conducted on the health of pet dogs.

Both my colleagues at Purdue and I carefully analyzed the electronic records of all dogs visiting any Banfield veterinary hospital from January, 2002, to August, 2004, and identified those that either received ProHeart 6 or the most commonly dispensed oral heartworm preventive drug.

We also determined whether these dogs had received the vaccine at the same time.  We then followed each dog for a period of 30 days and documented whether they subsequently had a potential adverse reaction.

We found that the overall adverse reaction rate was remarkably similar for the dogs that received ProHeart -- 89.2 per 10,000 -- versus those that had received the most commonly used oral heartworm preventive -- 89.1 per 10,000.

Similar rates for ProHeart 6 and the most commonly used oral heartworm preventive were also observed for allergic reactions.  In fact, most of the allergic reactions that did occur could be explained by the dog having received the vaccine rather than by a dog having receiving a heartworm preventive drug.

Our conclusion at the time was that the safety profile of ProHeart 6 and the most commonly used oral monthly heartworm preventive was similar.

Based on these findings, we concluded there appears to be no scientific rationale for continued withdrawal of ProHeart 6 from the marketplace.  And by just -- by the way, just to address an issue that was raised, or a question that was raised, this morning, we found that the allergic reaction rate for dogs that received either oral or injectable ProHeart was about 15 per 10,000, while the reaction rate for these same products when concurrently administered with a vaccine was about 45 per 10,000, so about a threefold increase.

Following my presentation in 2005 to VMAC, members of the Committee were asked a question by the Chair:  Is ProHeart 6 safe for use in dogs?  One member of the VMAC responded:  “Yes, the Banfield data are very convincing,” while another said, “Banfield data are compelling.” A third member of VMAC concluded that Banfield data are not perfect, but very good, and that the real question should now be how this product, ProHeart 6, compares to the other heartworm preventives on the market.

Nothing has occurred since that time to change my mind on the safety of ProHeart 6.  This injectable preventive was reintroduced to the market under the RiskMAP, which was designed to insure safe, appropriate use to achieve maximum benefit of heartworm prevention while minimizing risks to dogs.

Unfortunately, the RiskMAP imposed severe restrictions on the administration of ProHeart 6 for the veterinarians and tended to restrict widespread use, so it discouraged widespread use.  This led to a reduction in use of ProHeart 6 by veterinarians which was associated with the rise in reports to FDA of lack of effectiveness for some of the oral heartworm preventive drugs.  For example, by December, 2005, FDA registered almost 6,000 reports of lack of effectiveness, a comment that this may be caused by owners not properly administering the drugs, or some dogs may not swallow the pills or could later vomit and lose the drug.

Of approximately 1300 reports that CVM analyzed in detail, lack of effectiveness was the term to be definitely related to failure of the products, and this probably explains why greater than 200,000 dogs each year in the United States are reported by veterinarians to be newly infected with heartworms and why greater than 50 percent of dog owners living in heartworm endemic areas failed to comply with recommendations for heartworm prevention.

In 2006, we published a second paper based on a review of approximately 11,000,000 electronic medical records of dogs visiting greater than 500 Banfield hospitals.  We reported that injectable ProHeart 6, when administered by veterinarians, was 86 percent effective in preventing heartworm infection whereas oral Ivermectin obtained by owners was only about 73 percent effective.

Furthermore, ProHeart 6 offered significant residual protection for a period beyond the 6 months of label indication.  I think that was mentioned by someone this morning on the Committee. 

So I believe, based on all the available scientific data, that the incidence of heartworm infection in the U.S. is unacceptably high and that heartworm infection has been spreading to areas where it hasn’t been common before such as in the Northwest U.S. and Canada. 

High rates of heartworm infection in U.S. dogs can be attributed in great part to owners failing to comply with recommendations for monthly administration of oral heartworm preventive drugs.  The widespread use of injectable ProHeart will over time significantly decrease the incidence of heartworm infection in dogs, particularly if it is administered twice yearly in heartworm endemic areas.

ProHeart is extremely safe, based on large epidemiologic studies, and this database, the Banfield database, has been used to study many other health problems in dogs over the past 10 years.

I believe the low rate of adverse events in dogs associated with ProHeart 6 following implementation of the RiskMAP is consistent with previous large epidemiologic studies, and this gives me great confidence it is both a safe and reliable approach to heartworm prevention, especially since its effectiveness is less dependent on owner compliance than the oral heartworm preventives.  Thank you.

MS. SINDELAR:  Thank you very much, Dr. Glickman.  Our next speaker is AVMA’s representative, Dr. Charles Lemme.  He is a small animal practitioner and member of the AVMA Clinical Practitioners Advisory Committee.  He comes from Cedar Rapids, Iowa.  Welcome.  Thank you.

DR. LEMME:  Hi.  You covered the first part of my talk here already.  Good afternoon.  I am Dr. Chuck Lemme -- it is “Lemm-mee” -- and I am a veterinarian who practices small animal medicine in Cedar Rapids, Iowa. 

I am here representing the American Veterinary Medical Association, the world’s largest veterinary association, whose more than 80,000 members comprise approximately 83 percent of our nation’s veterinarians.  The mission of the AVMA is to advance the science and art of veterinary medicine.  Within the AVMA, I am a volunteer leader on the Clinical Practitioners Advisory Committee.  My comments today have been reviewed by fellow Committee members and also our colleagues on the AVMA’s Council on Biologics and Therapeutic Agents. 

Our comments are not offered today because we have interest in one product in particular; rather, I am here because we believe the adverse events reporting system and associated RiskMAP programs overall can have significant implications on veterinary drug access.  The AVMA paid for my travel to present these comments and I have no financial interest in Pfizer Animal Health.

First of all, I would like to thank you for the opportunity to provide comments regarding the RiskMAP process and the FDA’s adverse events reporting system.

The AVMA applauds the FDA for its continued efforts to insure the safety of drugs used by veterinarians to maintain animal health and relieve pain and suffering in our animal patients. 

We appreciate the FDA’s use of the current RiskMAP program, which was developed initially to provide availability of an injectable heartworm preventative while incorporating ways to increase the safety of administration.  While we find the intent laudable, the AVMA cautions against the unintended consequences that we believe, in some circumstances, could result from restricted availability of drugs approved by the FDA.

We come with three points today -- to share our perspectives on the RiskMAP process and to relay comments regarding the FDA’s adverse event reporting system and Veterinary Medicine Advisory Committee meetings.

First, the AVMA truly appreciates the FDA Center for Veterinary Medicine’s willingness to adopt a novel approach in providing for continued availability of FDA-approved products that have potential safety concerns.  Provision for a limited access program for these drugs can be a practical solution that allows for better evaluation of a drug’s safety post-marketing while still allowing for patient treatment and, by extension, protection of animal health.

Our concerns about RiskMAP programs are twofold. One, we believe the timing of RiskMAP program implementation is critical, and, two, we feel that the RiskMAP requirements must allow for adequate use of the drug.

In this particular case, ProHeart 6 was removed from the market because its safety could not be assured by FDA, based upon Veterinary Medicine Advisory Committee determination.  About 3 years elapsed until ProHeart 6 returned to the market.  During that time, veterinarians had to inform pet owners that the drug was no longer available due to safety concerns and pet owners had to utilize a different treatment program for their dogs.

When ProHeart 6 became available again in 2008, many veterinarians were reluctant to offer the drug to their clients because of embarrassment over previously recommending what was perceived as an unsafe drug.  In addition, some veterinarians and their clients still had concerns about whether it was truly safe to use.  It can be confusing for clients to try to understand how a drug that was previously deemed unsafe is now acceptable for use in their pets. 

We bring this to your attention because AVMA believes that in order to maintain confidence in FDA-approved drugs by both veterinarians and their clients, it is much more acceptable if a RiskMAP program is implemented while the drug is still commercially available, not after the drug has been taken off the market and then reintroduced.

It is also imperative that a RiskMAP program is not so restrictive that reasonable use of the drug is not allowed.  In the case of ProHeart 6, measures were put in place by FDA with the intent that it would help to insure safe, appropriate use while minimizing risk to the dogs in which it was used.  This plan included veterinarian education, laboratory testing, restrictions on age and concurrent vaccination, and informed consent documents signed by the pet owners. 

While we appreciate the intent, we caution that the use of the product must still be practical for the veterinarian and the pet owner.  Some of the reasons that may limit client willingness to consent to treatment can include:

Number one, economic concerns.  Requirements like laboratory testing can significantly increase the client’s cost to use to use a drug.

Number two, concerns about using the drug just due to the number of hurdles that must be cleared in order to use the drug.  I think a client might wonder, you know, if I have to do all these things just to use this drug, can it really be safe?

Number three are logistical challenges.  Things like having to bring a pet back to the clinic multiple times for required services can be a major problem for some clients, possibly more so with cats than dogs, but it can be a problem for dog owners also.

During the course of professional practice, veterinarians must treat a variety of animal species under numerous clinical settings.  We ask that the FDA strongly consider the realities of veterinary clinical medicine when developing the set of measures that must be fulfilled when administering a drug within a RiskMAP program.

Our second area of comment is regarding the FDA’s adverse event reporting system.  The AVMA is committed to the continuing availability of medicinal products for animals that are safe, potent and efficacious, and we encourage the continued development and strengthening of adverse event reporting systems.  This includes continued collaboration with constituent professional organizations, industry organizations, government entities and other stakeholders.

More specifically regarding the FDA’s adverse event reporting system, we are grateful to have had opportunities to work with the CVM as it has collaborated with other FDA centers to develop a new MedWatch electronic report system.  I was able to help beta-test the MedWatch system along with another veterinarian nominated by AVMA. 

We appreciate that the MedWatch system is a big step forward in providing for a comprehensive means for veterinarians, other healthcare professionals, and the public to report potential adverse events.  We are also pleased that changes to the CVM website have been made to facilitate reporting of adverse events and to allow quick access to information on drugs and drug safety.  We see the emphasis on adverse event reporting in the ProHeart 6 RiskMAP as a very positive aspect of the program.

Furthermore, and it has been mentioned earlier today, the AVMA has learned of a new FDA activity called the Sentinel program.  We see potential benefits in this initiative which may utilize existing datasets in corporate veterinary practices to assist in post-marketing surveillance and we look forward to learning more about this program as it is developed.

We do also recommend continuing to improve some aspects of the adverse event reporting system.  Specifically, the AVMA sees a need for ongoing efforts to improve the accuracy of the system with as much human bias removed as possible.  Utilization of new, advanced technologies to fully utilize the data obtained through MedWatch or Sentinel can improve adverse event reporting efficiencies and accuracy.

In addition, we believe there must be a strong, science-based, transparent and systematic post-market surveillance system, especially considering the wide scope of species and disease conditions that veterinarians treat. 

It is critical that the surveillance system provides for early and clear detection of associations between drugs and adverse events while maintaining adequate specificity to reduce spurious, false associations.  Sufficient data inputs, specifically adverse event reports, are imperative for a strong reporting system foundation.

In addition to those data needs, a strong system also requires that only statistically significant findings are utilized in the identification of adverse event causality.  Subjective assessments are not sufficient and may in fact be detrimental to analysis since bias may be introduced.

In the past, the AVMA has expressed concern to the CVM about the deliberation process during a VMAC meeting.  We believe that the individuals that make up this Committee have considerable expertise within their particular field and the sharing of that expertise during the deliberation process will result in the most thorough, accurate evaluations of the issues before them.  We look forward today to an open discussion among the Committee members of the facts and opinions presented during this VMAC meeting before any voting occurs.

So, to conclude, again the AVMA appreciates this opportunity to provide its comments for the VMAC Committee’s consideration.  A RiskMAP, or REMS process, when properly structured, is a valuable tool to help insure the availability of safe drugs for use in animals, and we applaud the CVM for their willingness to use this approach.

Thank you.

MS. SINDELAR:  Thank you, Dr. Lemme.  Our third, and last, registered open public hearing speaker is Connie Dominy.  She is a licensed professional counselor and comes to us from Macon, Georgia.

MS. DOMINY:  They told me I had to come up here because I have a slide show -- not that I want to be up here, okay?  Let us get that straight right from the beginning!

(Laughter)

MS. DOMINY:  This is not my normal thing to do.  I am Connie Dominy.  I am from Macon, Georgia -- oh, and I just clicked it already and don’t know what I am doing, so here we go -- but I will figure it out.  And first of all, I would like to say that I paid for my own way here. 

I was here in 2005.  I have 27 years in the healthcare industry.  I am very familiar with Pfizer pharmaceuticals and all the other pharmaceutical companies because before the last 2 years, you know, they used to come around and bring us nice lunches and pens and pads and all of this other stuff, so they were great.  But, in my opinion, Pfizer has been a cut above the rest in all that I have encountered, and I hope that opinion continues after today and with this drug.

So let me just say that I am definitely not opposed to scientific research, and things are going probably be falling off the stand here as I kind of figure out what to do.

        (Slide)

I have an Italian Greyhound who is named Flicka and she is currently in a study with California, Davis of California.  She had idiopathic sterile panniculitis that started in 2008, and this is what she looked like, and that is one of the least graphic pictures.  So, please understand anything that I can do to help research, that is what I am here to do.  She is still alive, by the way. 

        (Slide)

I am not unfamiliar with the loss from heartworms.  Previously, heartworms in cats has not been that important, but in 2007, I lost a cat named BB to heartworms.  This is a documented case, and the necropsy was done at the University of Georgia.  He also had several visits to the University of Georgia, as did other animals of mine.  So I am definitely not -- but I don’t you all giving ProHeart 6 shot to cats, yet --

okay?
 

        (Slide)

When we were here before in 2005, I was just -- you know, I was just new to this.  I had already experienced some incidents. 

As far as what had happened between the time that my dog got a ProHeart 6 shot and the time I got here is that the ADE coordinator was removed, and as far as I am concerned, at that particular point, the FDA, as well as the CVM, lost a lot of credibility, and they haven’t gained it back yet.

I am one that wants full transparency of all of the information that was presented, and I believe I have heard several of you ask questions about information prior to the removal of this product voluntarily, of course, from the market.  I for one, as a citizen, as a consumer, would like to see full disclosure as well.  I don’t know where that data is or if it still even exists.

        (Slide)

This is Champion Izat Reddy When You Are.  Please look at that face.  Isn’t he adorable?  How can you look at that face and say, “Hey, we will -- we still want to have this product out there that we are still not sure is really safe for our animals?”

He is a survivor.  I put a little bit about it in here in your presentations which are in your packet.  From the time that he received this injection on 9-27-03, he weighed 14 pounds and 2 ounces, and he began to have problems on 9-28.  They continued for a while, and I won’t bore you with all the details.

        (Slide)

But what I will say is that it bothers me greatly that this product is supposed to peak between 7 and 14 days.  I have heard variations -- 7 and 14, 7 and 10, 7 and 11, but the product information at that time said 7 and 14 days.  So my question is:  How in the world can the Fort Dodge, at that time, rep say that -- or vet say that, you know, it just didn’t happen. 

Over the next 7 months, I continued to have problems.  His symptoms were hemorrhagic throwing up and diarrhea.  That was on the sheet. 

I was told by the Fort Dodge vet myself, and my vet was also told, and I did bring a copy of the records if you would like that, my vet medical records, but I did everything in my power to find out what in the world caused this. 

He got no other vaccinations that day, none.  He had been sitting in my house since 6-14 of ’03 when he became a champion, and as you can see, this started in the 9th month.  He was not exposed to anything, but they kept coming up with all these reasons that it could not be ProHeart 6.  And as far as I am concerned, and as far as what I have seen, I have not had any reports from the Center for Veterinary Medicine nor from Fort Dodge to say, “Yes/no.”  All I talked to was some woman out there, and her name is included in your packet and I won’t call her name at this point, that it obviously couldn’t be the product.

So, you know, I guess I am basically very upset with the attitude that consumers are treated like we are stupid, we are idiots, we don’t know our animals.  And I am telling you:  I know my animals, and so do all of the pet lovers in this country.  We know our animals.  So don’t try to tell us we don’t know just because you want to deny that “Oh, it couldn’t possibly be.”  And that is one of the things I have looked at all over the reports and everything.  If you can find something wrong with an animal, then it is obvious the product did not cause that!  How can you say that?  How can you say that because they had a cyst that ProHeart 6 didn’t assist in that cyst busting?  But then you are going to say, “Well, the cause is the cyst; it is not the medication.” 

I think there are far-reaching examples and there are far-reaching effects in terms of more stuff that has to be done, and I hope to goodness that Pfizer steps up to the plate.  I am not really sure that that is going to happen.  I hope they cleaned house at Fort Dodge, too.  If you are going to lay down with dogs, you are going to come up with fleas, Pfizer, so I hope you all did your research before you took over the company, but it doesn’t really sound like that to me today.  It sounds like you are going from 18 months ago forward. 

Then I understand one of you went over there and sat with Fort Dodge, but, you know, they have a bunch of -- what is it? -- 483s that they have had cited against them, and I am sure they cleaned up their act before you ever went over there, but how did the FDA allow that to continue for all of those years with things that would possibly affect the sterilization of the area that you are manufacturing your drug in? How do you know that that didn’t have anything to do with it? 

So maybe since the FDA didn’t have the gonads to stand up and close them down years ago when they really should have been, maybe Pfizer will step up and close down that part.  I hope so.  I got off on a tangent there -- sorry about that. 

        (Slide)

But when you go back and we hear it was reformulated in 2002 and it was reformulated -- that just shows some -- okay.  It was reformulated in 2002 and in 2003, and in 2004, the low residual solvents had already been removed. 

But I think if you go back and demand transparency from this agency that you will see that nothing really changed in the adverse event reporting.  So how can that be?  They are talking like it is new information.  It is not new information; we are dealing with old information.  But we want to go from 18 months.  I am saying:  Go all the way back, folks.  Go all the way back.  Look at all of it from 2001.

Okay.  There was supposed to be another VMAC meeting before it returned to the market, but there never was. 

Here we look at Australia and European markets, and for all of you who might be interested, I don’t think they included the Australian data in there, but I have a disk of the Australian data that you asked to see that hasn’t been presented, so I am sure that that can be entered into. I also have the Freedom of Information summary that I would like to enter into this meeting today that I couldn’t even pull up on the website until yesterday.  I had to get it by hook, crook and every other method I could find.  But I am a tenacious woman, so I found it.  Okay, in 2005 they said that they needed more information, right? 

        (Slide)

Well, they didn’t get a whole lot except from the European markets and from Australia.  We know what their reporting mechanisms are.  And, people, I am standing here to tell you:  I didn’t know about adverse event reporting until I had a dog that reacted, and I couldn’t find anything else that made any sense.  I even had him tested for von Willebrand’s.  He is a little stud dog, okay?  I didn’t want anything there that I was going to breed into another animal.  So I, you know, had him tested for everything, trying to rule out anything, on my own.  I asked Fort Dodge for nothing.  As a matter of fact, I got really ticked off at the vet that I talked to out there and said a few choice words to her because she obviously didn’t know what was in her own product label at that time.

So, one of the concerns that has been expressed here today are the elevated liver enzymes, all of the anaphylactic. All those reactions are still there.  They are a little bit more elevated, but yet they have a smaller sample size.  To me, with a smaller sample size -- I am not a statistician and I am not one trying to do all this, but a smaller sample size, I don’t think you would be seeing an elevation, would you?  If you are seeing an elevation, then is there a problem?  What happens after the drug peaks in 7 to 10 days?

This passive reporting system -- forget it.  Vets are not going to report, you know?  Why would they do that?  They are not going to. 

You have got in this RiskMAP thing -- I think it is a great idea; please understand that.  It is a wonderful idea.  But you have got the fox in charge of the hen house.  You are reporting to Pfizer, and if they are anything like Fort Dodge, they covered up, and that is a fact.  Is my time up?

MS. SINDELAR:  Yes, ma’am.

MS. DOMINY:  Well, it is not 10 minutes yet.

MS. SINDELAR:  Yes.  We are on the clock.

MS. DOMINY:  All right.  We are on the clock.

MS. SINDELAR:  Yes.

MS. DOMINY:  Basically, can I just tell you what I want?
 

MS. SINDELAR:  Can you do it ---

MS. DOMINY:  I can do it.  Please do it?  Thank you, ma’am.  Because I want you to really investigate the old guard that is sitting right up here that was involved in cover-ups, involved in not giving you all information, involved in a lot of stuff that were illegal and criminal while yet they were taking the person who was in charge of collecting all of our data and trying to get her removed and criminally charged, but your Commissioner, all the way down -- and you need to go in and not believe a word they tell you, you need to ask for proof.

So, what I would like to see is for us to start all over with all of the information to begin with.  That information is there unless they have destroyed it.  So -- I have to get down now?

MS. SINDELAR:  Yes, ma’am.

MS. DOMINY:  Okay.  I will get down.  Boy, that was a quick 10 minutes!

MS. SINDELAR:  --- real quick!

MS. DOMINY:  It was a quick 10 minutes, wasn’t it?  Okay.

MS. SINDELAR:  Connie, thank you for coming.

MS. DOMINY:  Thank you.  Oh -- wait.  Here you go.

        (Slide)

This one, deceased.  This one, still alive.  He is still a champion, and I still love him.  And he doesn’t have any babies yet, so don’t ask for any.  Thank you all.

MS. SINDELAR:  Thank you.

MS. DOMINY:  Thank you for tolerating me.

MS. SINDELAR:  Thank you.  That concludes our open public speakers.  And what we do is open the mike to the floor. 

We suggest that each person who seeks to present comments or information to please state any conflict of interest information, any relationship to -- financial relationship with the sponsor, or even competing sponsors, as well as narrow your comments to 5 minutes.  This way, it allows the maximum number of speakers within the hour of open public hearing.  Thank you very much.  The floor is now open.

MS. BROAD:  Good afternoon, ladies and gentlemen.  My name is Jean Broad.  I am from Thornton, Colorado.  I was here in January of 2005 at the last CVM meeting.  I have no financial interest in the companies represented here today.

I am here to speak for the victims of ProHeart 6, those who have been made ill and/or were killed by ProHeart 6.  I am also here to speak for the unsuspecting consumers and for the dogs that will be affected by ProHeart 6 from this day forward because, you know what?  A label change is not going to change the pain and suffering this drug can, and most certainly will, cause.

4 days after ProHeart 6‘s supplemental approval in 2002, I had 3 dogs that were deemed completely healthy before receiving 1 shot of ProHeart 6.  If their adverse events reports have not been destroyed, you can go back and refresh yourself on one’s IMHA and the other’s liver disease.  My third dog, Casey, is a long-time survivor of ProHeart 6, but since the shot, and for the rest of his life, he will be on medication to regulate his immune system.

I am forever scarred by placing my trust in veterinarians, the uninformed decision I made by allowing my dogs to receive this drug, the horrible death my 2 dogs suffered, and the daily worry of how and when my dog Casey will die. 

I am sure the majority of you are here to sing the praises of ProHeart 6.  You will say it is great for repeat business in your veterinary practice, you never experienced any problems with it, and so on and so on.  But the truth is, and what you won’t dare tell the consumer, is: ProHeart 6 can harm dogs.  Not only can it harm dogs, it can kill them.  We know this from when it was on the market full-time and we see this while it has been on the market in a restricted fashion for the last 18 to 20 months.

I have a list of side-effects from the FDA database before ProHeart 6 was withdrawn from the market that is 17 pages long.  I was told that the list grew to over 20 pages.  Of course, no one is able to see how many dogs were affected by ProHeart 6 and just how exactly, since the database was revised, so consumers and veterinarians won’t ever have a true picture of why this drug, I feel, is so harmful.

It is unfortunate we couldn’t hear from Dr. Victoria Hampshire, the ADE reviewer assigned to ProHeart 6, so we could learn the facts she uncovered.  What happened to the vital data she compiled?  Why didn’t the FDA, especially in the form of Dr. Lester Crawford, allow Dr. Hampshire to fulfill her job duties and present her findings in January, 2005? 

It seems like somebody or somebodies didn’t like what she was going to say, and as a consumer, I feel like I was cheated by not hearing what Dr. Hampshire had to say.  I feel sound judgment was ruled by fear and greed, and, unfortunately, consumers and their dogs are going to continue to pay dearly for this lack of sound judgment.

You say ProHeart 6 is good for compliance reasons since consumers are too forgetful to give their dogs a monthly pill or 2?  But the bottom line is, if consumers don’t have the money to pay for pills or choose in the first place, they certainly won’t be able to pay for a vet visit and an injection and they certainly won’t be able to pay for a vet visit and an injection, and they certainly won’t be able to pay for treatment for adverse reactions that their dog may suffer.

I want to know:  What is so safe about ProHeart 6 now?  So what the vets had to undergo web-based training!

From reviewing the material presented for this meeting, specifically the ADEs that were submitted, it is clear to me that during the 18 months under the risk management plan, some vets apparently didn’t pay very good attention to what they were supposed to learn because dogs were administered ProHeart 6 in conjunction with vaccines et cetera.  The dogs were affected, and subsequently died.

Did anyone happen to notice that some of these dogs got the ProHeart 6 shot back in 2004 or ’05?  And here they were given the shot once, or twice again, under the risk management plan, and they died.  This is exactly what we found from the written complaints we received from consumers when ProHeart 6 was still new in the market.  Many people said their dog had received the shot once, twice, 3 or 4 times, and, bam, their dog died.  I firmly believe if I allowed my dog Casey to receive ProHeart 6 again, he would be dead in a week.

The comments from the adverse reaction -- excuse me; adverse events reports in your meeting materials look to be coming from Fort Dodge. It still appears Fort Dodge has been blaming anything and anybody else for what happened to the dogs under the influence of ProHeart 6.  I don’t see how there has been any improvement in the number of adverse events between the 300,000 doses sold under the risk management plan and the 18,000,000 doses sold prior to ProHeart 6 coming off the market.  In fact, I know --

MS. SINDELAR:  Jean, can I invite you to summarize?

MS. BROAD:  I am sorry?

MS. SINDELAR:  Can I invite you to summarize your comments --

MS. BROAD:  Yes, okay.

MS. SINDELAR:  -- your remaining comments?

MS. BROAD:  Okay.  Give me one minute here.

Where I stand, and what I have learned, ProHeart 6 is the same poison but different manufacturer, different day.  It is unnecessary, uncalled for, and unwanted.  There are several oral heartworm preventatives on the market with a proven track record.  At least, if there is a reaction to those oral methods, the dog’s body is rid of the chemicals within a matter of days.

One more comment.  As long as drugs like ProHeart 6 are approved by the FDA and are allowed to hurt animals in the name of profit, distrust with veterinarians, drug companies and the FDA will continue to grow among the public.  Vets will lose business and the animals will be the ones who will pay with their lives.  Thank you for your time and consideration.

MS. SINDELAR:  Thank you very much.  The mike is open to a next speaker.

DR. DUNN:  Good afternoon.  My name is Dr. Charles Dunn.  I am a veterinarian who practices in Pennsylvania, New Jersey and Delaware.  I have been in private practice for about 14 years and the last 4 years I have worked with Banfield, the pet hospital. 

We as an organization have 750 hospitals, approximately, in the United States.  And what we are asking the Committee today to consider is that we continue to monitor what is going on with this product.  I think that is very important.  But we are also asking that the restrictions that go about vaccinations and the blood work can be limiting to our clients and can really reduce owner compliance. 

This is a product that must be monitored.  This is a product that does have some side-effects in some pets.  But it also does a lot of good in many pets.  And what we are asking is, if we are going to keep this on the market and keep this available, that we do have some lessening of the restrictions associated with vaccines and associated with mandatory blood work.  Thank you very much.

MS. SINDELAR:  Thank you, Dr. Dunn.  Next speaker?

MS. DOMINY:  No, I am not coming back to finish mine, but Laurryn Simpson was here in 2005 and she was supposed to be here today and she could not be.  She has some medical issues that prohibited her from being here.  So I am here to read her statement.  She said:

“Thank you for allowing me to speak.  I speak on behalf of the hundreds and hundreds of people I have personally heard from since 2003.

“As much as I condemn the FDA/CVM for not doing more when problems first arose with this product, not expecting more from the manufacturer regarding more testing such as the innovative product, I do commend them for the recall of 2004 and for the RiskMAP imposed, even if it was without another VMAC meeting. 

“I was going to talk about policies and procedures, but you all know how many things are supposed -- how things are supposed to be done.  Instead, I would rather give you reminders.

“In the booklet for the VMAC meeting 2005, it was stated:

“’Executive Summary of Fort Dodge:  Many of the adverse events could be attributed to concomitant vaccine administration.

“’ProHeart 6 Introduction:  The true incidence of allergic events to ProHeart 6 is confused -- is confounded because many dogs received concurrent vaccinations.’

And she goes on, and I will just read not exactly where everything is, but: 

“37 percent of the reports including concurrent vaccine administration, which likely contributed to the reporting rate.”  These are all in quotes.

“Concurrent vaccines use were reported in 42 percent of the non-allergenic reports.

“As it is true with each of the systems, causality assessments are confounded by concurrent vaccines used in 47 percent of the AERs.

“49 percent of the cases classified as cardiac events included concurrent vaccinations.

“Taking a quote from Dr. Marguerite Brown at the last meeting, 63 percent, 58 percent, 53 percent, and 51 percent, consecutively, did not have any other reasons to react.

“Why are we here today?  RiskMAP, should it be changed?  Should ProHeart 6 be given with other vaccines?  With their own statistics, the only answer would be no.

"Canada’s Veterinary Drug Directorate in April of 2006 issued an advisory statement to be added to the label and package insert because of its potential for serious adverse drug reactions and the absence of identifiable risk factors associated with these reactions.  ProHeart 6 is only indicated for dogs in which alternative preventatives cannot be effectively administered.

“It would be interesting to note that Pfizer has 1 of those preventatives on the market through their Animal Health.  In your booklet today, there is a letter from a vet from one of the Carolinas who attended a veterinary continuing education seminar in August/September 2008 at which the luncheon -- lunch presentation was on ProHeart 6.  The person was very disappointed to hear the company rep respond to questions with the answer of ‘This is not about safety; it is about building a pristine database for the FDA.’

“On the ProHeart 6 briefing package from background and objectives of the VMAC manufacture states, these studies include additional toxicology and pharmacological evaluations.  Yet according to the supplemental approval under target animal safety, CVM did not require target animal safety studies for the supplemental approval.  It also continued to say which suggested the potential allergenic nature of some of the residual solvents that were utilized in the manufacturing of ProHeart 6. 

“As a result, Fort Dodge changed the manufacturing specifications for ProHeart 6 and marketed the modified packet in international markets.  However, in the last VMAC booklet it stated:  ‘On January 14th, 2004, the sponsor stated that the anaphylactic reactions may be due in part to minimum residual solvents and that the elimination of these solvents might reduce those reactions.’  However, CVM continued to receive ADEs for the anaphylactic/anaphylactoid reactions with zero residual solvent lots. 

“So was it corrected January, 2004, or since the last VMAC meeting in 2005?  I don’t believe it was.

"This may have been a problem all the way long, considering during a pre-approved inspection on 4-25-01, the firm was informed they do not monitor for mold and yeast in the environment per industry standards.  Then at an inspection of 12-03, when a 483 was filed and warning letters sent out specifically when the firm discovered the heat exchanger use in small volume --- manufacturing rooms for 643 and 644 was contaminating the WFI cooled through it with bacteria.  Their investigation did not extend to reviewing what impact use the contaminated heat exchanger may have had on previously manufactured products.

“In addition, the firm continued to manufacture --- products using the heat exchanger after becoming aware of its contaminated state.  The heat exchanger is used to reduce the temperature for the water for injection that is then used to wet the pre-filter and sterilizing filter prior to product filtration from the bulk tank and the sterile surgical tank.  The firm’s investigation did not evaluate the impact other heat exchangers may have had on products manufacturing throughout the facility in their control.”

MS. SINDELAR:  Connie, can we summarize?

MS. DOMINY:  Okay.

MS. SINDELAR:  Thank you.

MS. DOMINY:  Let me see what she summed it up, basically. 

Basically, she talked a little bit about the initial studies, and I do have a copy of that for the new product that was released.  And she says, “I have a little pug, but you won’t find any adverse reports on her.  After losing one pug after a rabies injection to pug encephalitis, I wasn’t sure if it was the rabies this one received in 2002 or the ProHeart 6 injection.  Now I can’t help but wonder if this RiskMAP when it was in effect at that time, maybe she wouldn’t have started having seizures to this day. 

“Many people are counting on all of you to do the right thing for our dogs.  Thank you.  Laurryn Simpson.”

MS. SINDELAR:  Thanks, Connie.

MS. BROAD:  I just have one more, and I promise it is not long.  This was sent to me by a victim of ProHeart 6.  And it is kind of low, so hopefully you guys can hear me.  Anyway: 

“Dear Committee Members:

"I, like many, have lived the ProHeart 6 nightmare.  This Committee deemed the drug unsafe back in January of 2005.  ProHeart 6 has not been reformulated in any way, nor has any additional product research been done, so what makes it safe to use now?  As with any drug, we look to its benefits and weigh their side-effects before any administration.

“I believe as scientists and veterinarians, you need to ask the question:  Would I administer this to my animal?

“It makes for an interesting question since the clinic where my dog was injected, not a single doctor chose to use the product on their animal, nor at the teaching facility that fought to keep him alive, not a single clinician administered ProHeart 6 to their pet.  When asked why, the response echoed was that they chose a well-tolerated oral preventative with an excellent track record.

"Unlike many dogs that were taken so suddenly, I was able to see the long-term effect of ProHeart 6.  From time of injection in 2003, my animal continued to defy and rewrite medical pages.  He lived post-injection but had many trouble times in his life. 

“In a quest to find answers for him and a diagnosis for us, we sought help.  We listened to all the endless potential diagnoses and allowed for testing.  Never once was a diagnosis reached.  The university even sent blood to multiple other facilities seeking answers, but came up empty.

“This was a dog that was either in ICU or out walking 4 miles a day.  There was no in between.  How do you put an animal down that can walk 4 miles, swim 10 hours, and have endless energy?  The answer?  You don’t.  You spend the $65,000 it took to keep him alive and with no regrets and love on him every day. 

“To Pfizer, I understand the business impact that losing the patent to Lipitor at this year’s closing will have.  But, please, spare our animals their lives and look to other means to replace this financial loss.

“To the Committee members, you have an obligation to the animals on which you an oath to protect.  I ask that you leave here today making a sound and permanent medical decision.  Please make ProHeart 6 a part of past medical history so those that have suffered its devastation did not die in vain.  Thank you.”

And it signed “Victim of ProHeart 6.”

MS. SINDELAR:  Is that all the identification, Jean, on it? 

MS. BROAD:  No, I don’t have a name.

MS. SINDELAR:  You don’t have a name?

MS. BROAD:  (Away from microphone) ---

MS. SINDELAR:  Okay, thank you.  Thank you.  Are there any other comments?  Our esteemed statistician, Mary Bartholomew.

DR. BARTHOLOMEW:  Yes.  Mary Bartholomew, FDA/CVM.  And I would like to just make a comment or 2 related to the Banfield study that was reported at the VMAC meeting in 2005.  And we heard characterization that the VMAC members said that it was very compelling.  And I think that one thing is that there was not an awful lot of time to consider all the factors about the VMAC study, and I would like to bring out some of the other pointers that came out through longer-term review.

That is:  It is indeed a very large database for the purpose of conducting the business on tracking medical procedures at Banfield, and as such, it is not really designed as a database and to do research and particularly to answer the ProHeart 6 research question.

So one of the VMAC members acknowledged this, some limitations, and I would just like to talk about what some of those limitations are.

First of all, there was not a good record of patient histories on patients transferred from other clinics to ProHeart -- to the Banfield clinic.  There was also loss to follow-up of patients that did not return, and we had anecdotal reports of people who had received ProHeart 6 injections and then had difficulties and did not return either because it was after hours or just because they wanted to seek a second veterinary opinion after that time.

There was lack of information in that, the follow-up on a lot of the cases, also because there were 3-day phone calls after administration of treatment and there was not a procedure in place for getting the information from those call-backs back into the medical record.  And you have also all been privy to some of those call-backs and you know that a lot of times you don’t get any information from those in the first place.

There was also -- the original record evaluation that was reported to the VMAC was limited to 30 days following treatment, and as you know, some of the adverse events that we were considering may have been reported 45 or 90 days or so following treatment.

We considered that there were probably a number of biases that -- in the data.  For one, there was -- there were patients who received no treatment whatsoever and the death rate per 10,000 visits was something on the order of 200 or so for those patients, whereas for the ones that received heartworm medication, it was more like 15 per 10,0000 encounters.  We consider that that is a function of differences in the conditions of the animals that were in these subsets. 

Even among the heartworm preventives -- there was heartworm preventive 1, 2 and ProHeart 6 -- there are different indications for why you choose each 1 of those, and these are differences in the subsets that may have contributed to some of the differences that might have been seen in response rates.

There were, as I said, non-ignorable missing observations, and there were also differences in definitions of terms for how Banfield recorded some of the events versus how we were looking at them, and so there was not very good comparability from one dataset to the other.

So all in all, we decided that the Banfield data, although large, was not really addressing the safety issue that we were looking at, and I think that was one of the motivations then to go after the information through the way of the RiskMAP.  Thank you.

MS. SINDELAR:  Thanks, Mary.  Any other comments from the floor?

(No response)

MS. SINDELAR:  So at this time what we will do is just pass the baton to Dr. Doyle to begin the Committee discussions.  And let me remind the Committee members that you are permitted at this time to pose any questions to the former speakers at the table and hopefully to address any additional issues you may want to address with the floor speakers, the non-open hearing speakers as well.  Thank you.