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U.S. Department of Health and Human Services

Advisory Committees

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Data Analysis by Dr. John Baker, Veterinary Medical Officer, Division of Surveillance, CVM

DR. BAKER:  Thanks, Bernadette.  I have worked at CVM for the past 18 years in various positions, and I am currently the team leader of the Pharmacovigilance and Medical Review Team.  I have also been active in small animal clinical practice for the past 25 years. 

Good morning, and before we discuss results of the RiskMAP, we should briefly review some historical background information that provides insight as to how we have arrived at this point.

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Specifically, in 2004, at the request of CVM, Fort Dodge Animal Health instituted a voluntary recall of ProHeart 6 because of drug safety concerns.  Following the recall, at the 2005 VMAC meeting, the following safety signals were reviewed:  Death, anaphylaxis/anaphylactoid reactions, seizures, liver lesions, elevations in ALT liver enzyme, low platelets, and immune-mediated hemolytic anemia.

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Furthermore, at the 2005 VMAC panel, the panel discussed that the additional data was needed to characterize whether ProHeart 6 was safe for use in dogs.  From this recommendation, the RiskMAP approach was adopted which provided some key items such as drug availability.  Veterinarians and pet owners can make a risk/benefit assessment in regards to heartworm disease prevention in individual animals and determine whether to use ProHeart 6.

Because of the large number of animals, the statistical power to protect uncommon events was provided by the RiskMAP.  And also, by removing the concomitant vaccination with ProHeart 6 administration, the confounding interaction of vaccine administration specifically regards to anaphylaxis and other allergic events such as autoimmune hemolytic anemia and immune-mediated thrombocytopenia was eliminated.

We also utilized enhanced adverse drug event reporting where reports were submitted monthly, which allowed us to more closely monitor drug safety.

Finally, it provided data gathered from a large clinical practice-based case series.  And why this is important is discussed in the next slide.

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A discussion of the case series concept starts with the recognition that the adverse drug event database provides a source of observational data for a large, diverse population which is used to develop the case series. 

The case series is a summary of descriptive clinical information that characterizes the drug’s safety profile and risk factors.  This information includes the clinical  laboratory manifestations and course of the event; demographic characteristics such as age, breed and gender; the exposure duration; time from the initiation of product exposure to the event; dosage information; use of concomitant medications, and the presence of co-morbid conditions, particularly those known to cause the adverse event, such as underlying hepatic or renal impairment.

I have also provided the following link to the guidance for industry titled “Good Pharmacovigilance Practices and Pharmaco-epidemiologic Assessment.”  That is the link right there.  This provides a very detailed discussion of this concept, that link.

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This slide illustrates a case series summary for ProHeart 6.  The information has been taken from the product label and describes various risk factors of concern such as:

“Do not administer ProHeart 6 within 1 month of vaccination.”

“ProHeart 6 should be administered with caution in dogs with pre-existing allergic disease, including food allergy, atopy, and flea allergy dermatitis.”

“Do not administer ProHeart 6 to dogs who are sick, debilitated, underweight, who have a history of weight loss.”

“Caution should be used when administering ProHeart 6 to heartworm positive dogs.”

And finally, in field studies, it would seem that dogs with clinically significant weight loss, greater than 10 percent, were more likely to experience a severe adverse reaction.

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With this background information, let us proceed to a discussion of the RiskMAP data. 

This slide provides a snapshot of the data.  The summary includes an 18-month time period where approximately 321,000 doses were distributed.  There were 102 dogs with adverse drug events reported, 30 reported cases of lack of effectiveness.  The age range of dogs was from 5 to 101 pounds -- that would be from 6 months to 9 years of age, sorry.  The weight range was from 5 to 101 pounds.  We saw a distribution of breeds that reflected breed popularity in the general population, and males and females were equally represented in the ADE reports.

An important observation is that there was poor pre-administration blood work compliance where we noted that 90 of 132 of the reports lacked the baseline blood work data. 

On the next slide, we will discuss our analysis efforts.

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To summarize our adverse drug event findings, we can use a reporting rate calculation that is defined as the total number of spontaneously reported adverse drug events over the doses distributed.  With this in mind, we should take a moment to remind everyone that this is not an incidence rate and that ADEs are typically substantially underreported, which is the numerator, and except in this case where we suspect that we have raised everyone’s level of awareness through the RiskMAP communication effort, so we may have a better reporting of the events.  And one final comment regarding this calculation is that accurate data on the number of exposed patients, which is the denominator of the incidence rate calculation, is often lacking.

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The following chart displays the application of this calculation to both the 2005 VMAC and the RiskMAP data.  The 2005 information is in the first column and the RiskMAP 18-month data is in the second column. 

Really, the take home message from this table is that this comparison rate shows that we continue to see the strongest signals in regard to anaphylaxis and ALT elevation.  There is our anaphylaxis and there is our ALT elevation.

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This is simply a histogram that displays the reporting rates in the previous slide as a bar graph.  The RiskMAP data is represented by the purple bars and the 2005 VMAC data is represented by the blue bars.  So visually, for those who like visually to look at it, so there is the anaphylaxis and elevated ALT calculation shown there. 

Again, this comparison shows that we continue to see the strongest signals in anaphylaxis and ALT elevation.

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Now I would like to drill down into the cases that served as the basis for the calculations for the various adverse drug events of interest.  We will start with the anaphylaxis/anaphylactoid reactions, of which there were 40 cases reported.  The most common clinical signs were facial swelling, hives and itching.  However, we did have 2 cases of anaphylactic shock, which is the most severe manifestation of anaphylaxis.

The onset of all signs for all 40 cases was typically less than a day, and commonly less than 1 hour, and there was a complete recovery of all cases with appropriate supportive care.

An important comparison to point out is that CVM reviewed 20 reports of death by anaphylactic shock in 2004; conversely, none of the anaphylaxis reactions reported during the RiskMAP resulted in death.  Management of anaphylactic shock was emphasized in the training materials for veterinarians that were a part of the RiskMAP.

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Another safety signal of interest is the ALT liver enzyme elevations. 

We should point out that the enhanced reporting component of the RiskMAP is a possible source of the increased reporting rate, and that of the 7 cases, 5 had mild enzyme elevations.  Also, the cases were often confounded by other factors such as concomitant diseases and concomitant administration of other drugs. 

With this data, we cannot identify any apparent association with ProHeart 6 administration.

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In regards to seizures, there were 4 cases that we have outlined here that are considered as possibly drug related.  I have listed them here.  However, we acknowledge that we cannot rule out other causes of seizure, such as epilepsy.

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In consideration of the concern with ProHeart 6 administration and death, we have provided a likely cause of the 8 cases of death that were reported.  We have 4 cases of neoplasia listed there.  1 case of parvovirus infection, 2 cases of cardiomyopathy were reported, and 1 case of liver failure in an animal with pre-existing liver disease and possible phenobarbital toxicity. 

Again, in summary, the clinical histories of these animals provide alternative diseases as likely etiologies.  Also, for your information, we have included the full adverse drug event reports for these cases in the briefing package.

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For completeness, we mentioned 2 cases of low platelets, neither of which is considered related to ProHeart 6 administration.  1 is considered a normal platelet consumption response to post-surgical infection and a bloody diarrhea event.  The other appears as a spurious result from possible laboratory error.  There are the 2 cases.

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In regards to autoimmune hemolytic anemia, there were no cases reported.

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We would also like to take a moment to discuss the label warning regarding concomitant vaccination and the experience that we noted in the RiskMAP. 

We received adverse event reports of 8 cases that also received vaccines in addition to ProHeart 6.  3 cases had mild anaphylaxis signs, 1 case involved a seizure, 2 cases had neurologic signs, 1 case was a lack of effectiveness report, and in 1 case, there was no assessment possible since information was lacking.  We have concluded that this is insufficient information to assess a possible interaction with ProHeart 6 administration and vaccination.

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In closing, we would like to discuss the following points. 

First of all, no new safety signals were detected during the RiskMAP.  In addition, in regards to known safety signals, there was signal strengthening in regards to the anaphylaxis/anaphylactoid reactions.  However, the ALT elevation required additional evaluation in consideration of the suspected poor compliance with baseline blood testing that I pointed out earlier in the presentation. 

So there are our two issues of signal strengthening.

Also, in our recommendations, it is our recommendation that the RiskMAP be continued.  And it should be remembered that it is an iterative process where the adjustments can be made based on the data that is generated during the course of the RiskMAP.  What I mean by that is, as the RiskMAP proceeds, we gain additional information that may provide feedback for us to adjust the different requirements of the RiskMAP based on the data that we receive, so it is an iterative process where we respond to the information that we receive and analyze.

With this in mind, as stated in our two questions presented by Dr. Hartogensis, we recommend additional emphasis be placed on baseline blood testing by adding this recommendation to the product label, the expectation being that this would raise the importance of this aspect of the RiskMAP, thereby creating more compliance. 

Also, as noted in the questions, we would like the panel to consider the proposed change of the label warning regarding concomitant vaccination to a precaution.  This may allow more flexibility for the use of the drug by practitioners while maintaining the oversight inherent in the RiskMAP.  We will closely -- we will continue to closely monitor for adverse events while maintaining drug availability to those patients in need.

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Thanks for your attention and interest.

DR. DUNHAM:  Thank you very much, John.  At this time, do we have any questions of the panel or the presentations you have heard this morning?  Yes?