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U.S. Department of Health and Human Services

Advisory Committees

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Committee Deliberations - Question #1, Part 2 (Moderator, Dr. Michael Doyle)

 Question #1, Part 2, Discussion

DR. DOYLE:  “The current RiskMAP requires a collection of a CBC/chemistry panel, prior to product administration.  Should this requirement be modified in the RiskMAP and added to the label in a statement such as ‘Appropriate laboratory testing to establish hematological and serum biochemical baseline data is recommended prior to administration of ProHeart 6.’” 

So, do we have any general comments or questions that we want to start out with?  Or maybe I ought to step back a minute -- it is 3 o’clock.  We are scheduled for a break.  I know some of you have early flights.  Would you prefer that we just keep going and if you got the urge, you can just get up and go and come back?

(Nodding of heads “yes”)

All right, let us do that, then.  So let us go on to Question 2, then.  Any general comments or questions?  Yes, Dr. Poppenga?

DR. POPPENGA:  Just one question with regard to the CBS/chemistry opinion baseline.  I sort of had the impression from earlier discussion that that is more for FDA’s benefit in terms of the adverse drug event reporting.  Is this actually being used by practitioners to identify animals with pre-existing conditions and then not give the ProHeart 6?  Was that -- what was the reason for that CBC --

DR. BAKER:  Well, with the concern that was raised in the 2005 VMAC report with the liver lesions and the elevated liver enzymes, we wanted to rule out any pre-existing liver, you know, pathology or issues, you know, with some blood work to try to identify that there was elevation before the drug was given, have a baseline.  That was part of, you know, what we would get out of that. 

Then, you know -- and then with your comment, I think, about repeated, you know, injections, like Day 0, Day 6 Month, Day 12 Months, you know, you have that baseline, you know, and then at some point you will have -- you know, if something happened, they would do additional diagnostics and you would have some comparison prior to that.  But then there is a lot of time between then and whenever the next blood work was done.

DR. POPPENGA:  I mean, is there evidence that veterinarians are actually getting that data before they give the ProHeart 6 evaluation and then deciding not to give it because --

DR. BAKER:  Oh, the question is whether they got the results in a real-time basis.

DR. POPPENGA:  Well, are they actually using it to protect the pet?

DR. BAKER:  Well, if you draw the blood, you know, unless you have the instantaneous blood result, you will be given the --

DR. POPPENGA:  Absolutely, so --

DR. BAKER:  Right.

DR. POPPENGA:  -- the question is, I guess I feel like this -- to a certain extent, it is not being used to predict an individual that might have a reaction, then, you know, trying to avoid it, that this is an expense that the pet owner is having to bear with the large prospect that it is not ever going to be used because it doesn’t wind up in an ADE. 

I am kind of curious, then.  You don’t have any information with how this is being used in a preventive manner?

(No response)

DR. DOYLE:  Okay, thank you, Dr. Baker.  Dr. McKean?

DR. McKEAN:  In your labeling instructions, do you have any more detail than a CBC/chemistry panel in terms of what information you are asking the practitioner to accumulate?

DR. HARTOGENSIS:  Well, I think it was pointed out the red blood count and platelet counts are of particular concern as well as the liver, and if the practitioner can draw that conclusion based on what is listed in the adverse reactions section of the potential liver lesions, the immune-mediated thrombocytopenia and anemias, then yes.  But particularly I think you asked the question possibly before on, you know, what a practitioner particularly has to look out for and what patients should not be given the drug based on the blood results is not outlined specifically.

DR. McKEAN:  No, that is actually not my question.  My question specifically was:  Is there -- not asking the practitioner to draw the information from the adverse reaction potentials, is the -- in the labeling, is there a specific list of the data points that you would like to have collected?

DR. BAKER:  No, but not on the label.  There is not a specific definition of what tests, like whether it is an ALT versus an SAP or any CBC.  There is not any specific detail laid out in the label.

DR. McKEAN:  In the labeling?

DR. BAKER:  Correct.

DR. HARTOGENSIS:  Or the RiskMAP.  The RiskMAP is -- generally outlines the CBC/chemistry profile, like I said before.  But the current label does not refer to any blood work testing requirements other than the heartworm test.

DR. McKEAN:  Is that testing profile laid out in the Web education?  Is there any place where I could go and know that I am meeting this minimum standard?

DR. BAKER:  The Web-based materials had a, you know, a comment about taking -- you know, drawing blood work prior to the product administration.  It is one of the slides, in the webinar, WebEx training they do.  It is -- there is a slide that says that in addition to saying it in the RiskMAP document itself.  But it is not in the label.

DR. DOYLE:  Okay.  Dr. Griffin?

DR. GRIFFIN:  And the reason for doing that was to document animals that were not well, is that not right?


DR. GRIFFIN:  It was to get your hands around objective definition of not healthy beyond the physical examination the practitioner would normally provide?


DR. GRIFFIN:  Thank you.

DR. DOYLE:  Okay, thank you, Dr. Hartogensis.  Okay, Dr. Apley?

DR. APLEY:  Thank you.  So the entire association of this drug with potential liver problems are based on ALT, right?

DR. BAKER:  Correct.

DR. APLEY:  So I did go on PubMed, as threatened, and I had luck finding one article on ALT and AST with liver in the German study with humans.  They thought it was fairly well -- I wasn’t able to pull up the actual article, so we are in danger of looking at abstracts instead of evaluating the article.  They reported about 25 percent of humans have an elevated ALT, just stock out of the box. 

I found one that I was unable to pick up the actual article off of our --- side; it wasn’t available online to us -- out of Veterinary Clinical Pathology in ’97, and it is entitled “Absence of Liver Specificity for Canine Alanine Aminotransferase.”   This is a 1997 -- I have  not reviewed the article, I have not looked at it. 

But as we look at these tests as a baseline, I think if the agency recommends tests, they should also be willing to say exactly how they would interpret those tests in relation to this drug.  I can just say if I have a student come up to me and recommend running a test and they don’t know how they are going to interpret it and they don’t know how the results are going to affect their clinical direction, it is not pleasant.


I would hold the FDA/CVM to the same standards.

DR. DOYLE:  Okay, thank you for that, Dr. Apley.  Any other thoughts or comments from a general perspective related to this question?  Yes, Dr. Murtaugh?

DR. MURTAUGH:  Sure.  The current RiskMAP requires collection of CBC/chemistry panel prior to product to product administration.  It wasn’t clear from the data this morning that that is adhered to in a rigorous manner -- barely at all.

Then the suggestion is to add to the label statement such that -- implying not only will the sample be collected, but establishing the baseline prior to administration of ProHeart 6 is not going to be adhered to at all. 

So if you want to be transparent, it seems to me that not only will you not add that label, but you will take off the requirement for collection of the blood sample itself.  If that is going to be maintained, there needs to be some kind of follow-up to determine what the compliance with that requirement is.

DR. DOYLE:  Any thoughts from our panel?

(No response)

DR. DOYLE:  The CVM panel?  No?  Okay.  Dr. Senior?

DR. SENIOR:  Well, I just want to be specific with that question.  With your analysis of the data, looking at those, when you did have an adverse reaction, adverse event report, how many of those had liver enzymes and CBC and platelet information with them and how many did not?  But what proportion actually did what they were told to do?

DR. HODGE:  Well, I think out of the adverse events, I think there were 33-some percent that had pre-treatment blood work taken.  And one of our arguments -- obviously a baseline a blood work is recommended for any treatments so that you know, A, what you are dealing with, and, B, how to interpret the data afterwards.

But in this case, it is, other than being predictive of who is a good candidate for administration, it is not -- the pre-existing blood work is not a good predictor of a possible adverse event because we are getting primarily allergic and digestive disorders.  So in that regard, the blood work is not predictive.

Is it helpful to have as a baseline in case of an adverse event of another type?  Yes.  But does that warrant a requirement for blood work?  And probably not.  And not based on you can’t really extrapolate between the number of people that took pre-treatment blood work in the adverse event population to the population at large.

DR. DOYLE:  Thank you, Dr. Hodge.  Any other questions?  Comments?

(No response)

Question #1, Part 2, Panel Decision

DR. DOYLE:  All right.  Well, let us then individually respond to this question and maybe we could start with you first this time, Dr. Altier.

DR. ALTIER:  Certainly.  I am in favor of the change.  I think that since there is no standard set for this blood work that would prevent an animal from receiving the drug, I don’t see it is valuable in that way.  It is perhaps a useful data-gathering tool as was the last question we addressed, but I think that it should not be a requirement but simply a recommendation.

DR. DOYLE:  Thank you for that.  Dr. Apley?

DR. APLEY:  I would be in favor of moving from a mandatory -- I would be much more receptive to a different wording where appropriate laboratory testing prior to drug administration may be useful to establishing --- and serum biochemical baseline data.  I think it is bringing it to their attention that if something happens, you have a baseline to go from.  I think it is pointing to the fact that they would find themselves, if something goes wrong, in the much better place of having a change, which has its own caveats, versus just wondering how far up they are to the norm, so --

DR. DOYLE:  Thank you for that. Dr. Griffin?

DR. GRIFFIN:  I guess I disagree with your comments about it is useful when you do have an adverse event because in fact they are allergic. As you mentioned, GI and CBC/chemistry panels seldom have anything at all to do to help us define what those are.

DR. HODGE:  Oh, and I absolutely agree with that.  I was just stating it early on in the RiskMAP.  That was its purpose, that in case there was an event involving of low platelets, which there weren’t any, but that would be its main purpose.

DR. GRIFFIN:  So, I mean, I am not sure I know how to word it, but I don’t like either choice.  I honestly think that the -- it is a waste of money and that a good physical exam has more to do with it. 

I wholeheartedly agree with Dr. Apley in that if you can’t explain to me what you want from a test and how it applies to the problem at hand, then I don’t know what is in it other than the dog has to give blood and somebody has to pay for it. 

So to word that in such a fashion that a dog be carefully examined to be healthy and that appropriate laboratory testing, if clinically deemed appropriate, be collected prior to -- that seems more appropriate, somehow.  And I am not -- I haven’t gotten the wording quite right on that one, but I really don’t like either choice, so --

DR. DOYLE:  So, Dr. Griffin, I sense you don’t like it.  Does that mean “no” or “yes?”  I don’t want to put words in your mouth.

DR. GRIFFIN:  But if I say no, then that means that we are going to keep the CBC and chemistry panel, which is -- yes, change something.


DR. DOYLE:  Yes, change something, all right.  Okay, Dr. Mathew?

DR. MATHEW:  As the blood work does not seem to be predictive or is not being used for that and it appears it may be somewhat beneficial for data collection only after the fact, it doesn’t seem appropriate to leave it as is.  It seems to be a barrier for some dogs to be treated.

I guess I would recommend something to the effect of the wording close to what Dr. Apley mentioned, but to use the term “strongly recommend” this.

DR. DOYLE:  So you are saying yes, you would have us recommend that change?

DR. MATHEW:  Right.

DR. DOYLE:  Thank you.  Dr. McKean?

DR. McKEAN:  I believe that we should not leave the CBC/chemistry panel in place.  I am still troubled by is recommended “prior to administration” without further clarification of what you are going to do with the data when you get it.  And whether that is the drug sponsor’s responsibility or the CBMs in the labeling, there should be some information to that effect.  And I am not going to sit here now because I can’t do it and tell you exactly what those words are, but that is my sentiment.

DR. DOYLE:  So I -- if I understand you correctly then, you suggest there should be a change, but the wording needs to be changed?

DR. McKEAN:  I would change the language to something appropriate, testing to evaluate the animal be completed prior to the administration of the product, yes.

DR. DOYLE:  Yes, there should be a change.  Thank you.  Dr. Murtaugh?

DR. MURTAUGH:  I think that a change in the labeling is appropriate.  It is my opinion that the wording as it is relates more to liability issues than it does helping guide the client in making a decision on use of the vaccine. 

DR. DOYLE:  So you are for it? 

(Nodding of head)

DR. DOYLE:  Dr. Poppenga? 

DR. POPPENGA:  Well, the one thing that came to my mind would be alternative wording there where obtaining the serum biochemical baseline data is recommended.  I would wonder about liability if the veterinarian didn’t follow that.  It is not something I could address.  But if they decided not to follow that, then would they be more liable in case something did happen? 

I would agree with Dr. Griffin; I don’t like either one.  I don’t think -- if there is no predictive value to it, I think it just adds unnecessarily to the barrier to the use of the product and expense to the client.

DR. DOYLE:  So, yes?

DR. POPPENGA:  So I guess I am more in favor of emphasizing to the veterinarian that, you know, within reasonable means, they try to determine if the animal is healthy, and if they decided they wanted to do a CBC and a serum chemistry as part of that, then they could.

DR. DOYLE:  So you would suggest there not be a change, then, or --

DR. POPPENGA:  I would suggest there be a change, but we have Option 3 or 4.

DR. DOYLE:  Okay.  Thank you for that.  Dr. Senior?

DR. SENIOR:  Yes.  The test probably costs about $100.00, and the way it is currently administered, the procedure wouldn’t help an individual pet because it is all after the fact.  It doesn’t call for any pre-testing and then interpretation, so it is $100.00 spent by the owner for really no benefit for their pet in terms of “should we or shouldn’t we administer the medication?” as it currently stands.

The interesting thing is the two patients where you may have picked up something that are in the fatalities, that is, the two patients with cardiomyopathy, and it could well be also in the patient that had a pancreatic or gall bladder-type perm mass, that the -- that you may have picked up an ALT elevation, but these values are not shown in the test results that we have here.  They are not included in the patient histories and the like. 

So ALT is a very labile enzyme and it is cytosolic, so any small change in the permeability of the liver cell membrane will cause it to be released into the blood and it can be fairly minor things can sometimes cause an elevation, so even chronic congestive heart disease, which these animals may have been -- the cardiomyopathy patients may have been going into, you could have picked up a mild elevation.  It is quite possible.  Whether that would trigger enough on a veterinarian because they are so used to seeing, you know, mild elevations in this enzyme, whether that would put the red light out and they put the brakes on an administration of a drug, I don’t know. 

But as it currently stands, that statement doesn’t help the patient at all, okay?  So I don’t think it is helpful from that respect.

Does it help the surveillance system?  There doesn’t seem to be any evidence from what we found on this that it helps that, either. 

So clearly if you were going to use a pre-testing technique as it was just described, you would do a proper physical examination, you would gain some further information about the animal from a CBC and chemistry panel.  If you thought you had a patient that might be at risk, older patients, whatever, then that would be a great idea. 

Obviously, it has to be changed, and I think it is appropriate to put the onus on the veterinarian to -- I don’t like saying “baseline data” because it suggests the data is for something else.  I would like to have it worded as more to get a compete patient evaluation prior to administration of ProHeart 6, but “baseline” sounds like you are collecting it for some database. 

Evaluating the patient properly suggests that you are actually looking after the animal and you are taking a few precautions to make sure that the safety situation with the drug administration is as good as possible.

DR. DOYLE:  That is a pretty long statement.  How would you write the words?  We are going to get into that next.  Well, think about that.

DR. SENIOR:  Oh, I think we could easily reword it.

DR. DOYLE:  Say again?

DR. SENIOR:  I think we could easily reword it.

DR. DOYLE:  Yes -- but are you saying “yes,” that this statement is appropriate but needs tweaking, or totally revised -- I mean, totally eliminated and --

DR. SENIOR:  The statement as it currently stands doesn’t help the patient and doesn’t help the Food and Drug Administration because you only find out the results after the fact.  So clearly it has to be changed.

DR. DOYLE:  Okay.


DR. DOYLE:  But you think a statement should be there?

DR. SENIOR:  There has got to be some statement.

DR. DOYLE:  Got you.  All right.

DR. APLEY:  Chairman Doyle?

DR. DOYLE:  Yes, sir?

DR. APLEY:  Could I just point out that in the label there is a statement in there already:  “Do not administer ProHeart 6 to dogs who are sick, debilitated, underweight or who have a history of weight loss.”  It is clear in there that you should not administer this to an animal that is sick.  Where we are stepping over into now, in my opinion, is telling the practicing veterinarian their patient side, how to perform their task --- (away from microphone).

DR. DOYLE:  Okay, thank you for that comment.  Dr. Wolf, in regard to this question, has responded “yes,” modification is fine. 

So my sense is there is a consensus that this statement is appropriate but needs a lot of tweaking, and I think that is a segue to bring us into the next question in terms of, you know, what should be on the label.  You are still all right to keep going?

(No response)

Don’t need a break?

(No response)