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U.S. Department of Health and Human Services

Advisory Committees

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

Question #1, Part 1, Discussion

DR. DOYLE:  Well, shall we then move on to our questions?  This is the primary charge of this Committee, is to address these 2 questions, of which Question 1 has 2 parts.  And it is up here; we can read it together:  That is, we will just read the first question, first part.  And that is:

“The following statement is currently contained in the WARNINGS section of the product label:  ‘Do not administer ProHeart 6 within 1 month of vaccinations.’  Based on the data presented, should the statement be modified as a PRECAUTION, such as:  ‘Use with caution when administering ProHeart 6 within 1 month of vaccinations.  Adverse reactions, including anaphylaxis, have been reported following the concomitant use of ProHeart 6 and vaccinations.’”

So what I would like to do is open it up.  If there are any general comments or questions regarding this question, we will address that first, and then we will go around  individually and have each person comment on that question “yea,” “nay,” however they want to respond, and why.  Any general comments?  Mike -- Dr. Murtaugh?

DR. MURTAUGH:  The preamble is based on data generated:  “Should RiskMAP and/or the product labeling be modified?” whereas the question really relates only to the product labeling itself.  So how do you want to address the RiskMAP component of the question?  And a similar kind of question might come up again in the next part.

DR. DOYLE:  Yes?

DR. HARTOGENSIS:  Can I clarify that?  If the label is revised, then the RiskMAP would follow.  So, essentially, if the label statement was changed, then the RiskMAP would also include that information.

DR. DOYLE:  Okay, thank you, Dr. Hartogensis.  All right.  Yes, Dr. McKean?

DR. McKEAN:  Does that mean then that the data would be maintained in the RiskMAP regarding all vaccinations?  Or would that information be lost in the report?

DR. HARTOGENSIS:  No, that would be maintained in the RiskMAP.

DR. McKEAN:  Thank you.

DR. BAKER:  Can you clarify?  Are you talking the exact -- what the vaccination -- what vaccine was administered in addition to ProHeart 6 in what you are referring to, specific details regarding the vaccination?

DR. McKEAN:  I guess, based on the questions and comments that we have had so far, that it was general vaccinations, and I just wanted to be sure that it was going to remain to be captured when we made that change from a warning to a precaution.

DR. HARTOGENSIS:  Yes, the form that is filled out with the adverse event, the 1932 form, that is one of the questions, is “any concomitant medications, including vaccinations,” so all of that is generally captured.

DR. DOYLE:  Dr. Griffin?

DR. GRIFFIN:  Is that captured as a “yes/no” or is it captured in the detailed information?

DR. BAKER:  See, that is exactly what I -- that is where I was going with my comment, is that we would have to make sure that we worked with Pfizer to insure that we got the -- you know, enough details. 

It just didn’t say like, you know, “canine distemper,” but it said, you know, maybe just get a -- somehow get them to put the lot information, the name of the vaccine, in the Box 19, the narrative there.  We have to -- that is what we did with -- following the ProHeart 6 lot numbers, that we could track that. 

So we have to work out with Pfizer the details to be able to make sure we captured more than just “intranasal bordetella,” that we knew, you know, the actual vaccine trade name in the lot information, because then that might be useful information to have.  We can do that.

DR. HODGE:  Yes.

DR. BAKER:  Yes.

DR. GRIFFIN:  Would it be possible we also capture some other detailed information about the animals or about --

you know, breed continues, genetics continue to roll through my head?

DR. BAKER:  Oh, absolutely.  I think working with Pfizer to customize, you know, with that additional information.  They have a mechanism to capture whatever we discuss as any additional information we would like to see and maybe more follow-up information, especially in terms of

the -- you know, the liver function enzyme elevation is something that -- we can discuss that as well.

DR. HARTOGENSIS:  The 1932 form does have age, weight, breed, signal male/female and it does have all of that information in that.  But if there are specifics that we need to capture, we can work with the sponsor to target the  specific information that we need.

DR. GRIFFIN:  Does it also include previous exposure to compound?

DR. HARTOGENSIS:  To compound?

DR. GRIFFIN:  To whatever compound.  You mentioned this as a generic form for --- data.  So does it ask for previous exposure --

DR. HARTOGENSIS:  Exposure to Moxidectin?

DR. GRIFFIN:  -- to the drug in question?  For --- question?

DR. HODGE:  Yes, it does, and we would make every effort to actually almost to ad nauseam  collect information.  But we would already see areas of increased data collection for this product -- previous histories with the product, previous allergic history, vaccines, other.  We already do a very good job of collecting concomitant medications, but again, going as far as the vaccine name and manufacturer and lot number whenever possible.

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

DR. APLEY:  So I am trying to think what I have as the basis for making this decision, and I come up with two things, one which is you had RiskMAP -- you had 40 reported anaphylactic reactions that were without vaccination, and you had 8 that were reported with vaccination without being able to put a real denominator to the rest of them, what (away from microphone ---.

Then I looked at the Banfield data that was published where you have ProHeart 6 with or without   vaccinations and then you have vaccinations with none. And recognizing Mary Bartholomew’s points on limitations, in that one -- in this one I can’t -- I don’t think I can use this to make a decision on that.  From the RiskMAP data, I don’t think there is something in there that tells me whether or not putting it with the vaccination makes the vaccination more likely to have an anaphylactic response from it.

The Banfield data, looking at that, they are like 15 percent, I think, somewhere in there was quoted, versus 45.  That is welcome input on limitations is what I am looking at here.  But I am looking for something to tell me that the original thing is not true and that it should be reduced, and if there is a piece of data there that is telling me that, I would be open for someone to tell me that we have data to say that “let us back off that.”

DR. HODGE:  I think we have the 9 years of international data where vaccines are used concomitantly, and that has been a fairly steady reaction rate over 9 years of use in that way.

I agree with you.  There is no question that, from the data that we have seen and that we know, vaccines cause more anaphylaxis than this product.  So obviously the combination of the two is going to lead to increased reporting of anaphylaxis. 

What we don’t know and what we don’t suspect is that the drug and a vaccine combination increases the risk versus one or the other.  In other words, I don’t believe they work synergistically to cause an anaphylactic reaction.

DR. McCHESNEY:  Can I say something, Mike? 

DR. DOYLE:  Dr. McChesney?

DR. McCHESNEY:  I think you are absolutely -- for Mike Apley, you are absolutely right.  Because of design of the RiskMAP, the 8 we are seeing were people who didn’t follow the RiskMAP --

DR. APLEY:  Right.

DR. McCHESNEY:  -- because they didn’t -- they treated -- the specific instructions within the RiskMAP, were:  “Do not use vaccination when -- do not give vaccination within a month when you use this product.”  And they didn’t follow those directions.  So, if in fact everyone had followed the directions, we wouldn’t have had any reports of anaphylaxis involving co-vaccine administration. 

So this was -- the way it is now, we will never answer the question because they are -- the veterinarian is basically told not to vaccinate and do ProHeart 6 at the same time. 

So I think you are absolutely right.  You can’t use this data to make a decision on that because it wasn’t -- the RiskMAP was not designed to answer that question.

DR. GRIFFIN:  But it is 8 out of 300-plus-thousand?


DR. GRIFFIN:  And 102 out of 300-plus-thousand?

DR. McCHESNEY:  Right, yes. 

DR. GRIFFIN:  I told you.

DR. McCHESNEY:  That is correct.  And, I mean, I think the point that was made, there -- we have no way of saying whether there were other cases in which the vaccine was -- a vaccine was given concomitantly with ProHeart 6 and there was no reaction.  There is no -- that wouldn’t have been a report.

So, you know, everybody that got it, they could have done that on every animal and you only have 8 getting it, or they could have done it on no animal.  You just have no way of knowing that.

DR. DOYLE:  Yes, Dr. McKean?

DR. McKEAN:  To help me with these two questions, it is a process question.  Assuming you go ahead and stay with the RiskMAP, how often would this process that we are going through today be repeated?  Once every few years?  When there is a change in data?  If we do nothing today, when will that process be reviewed?

DR. HARTOGENSIS:  Well, I think I can address that one. 

We are actually really following that guidance on RiskMAPs from 2005 that I referred to earlier.  And using that guidance, it recommends public -- intermittent public meetings and advisory meetings 12 months-plus -- every 12 months or plus during the RiskMAP.  But there is -- it is really flexible and it really depends on where the agency is on the product and what data they have received and whether they feel like an advisory meeting is appropriate.

DR. McCHESNEY:  And as a follow-up to that, we meet -- I mean, now with Pfizer, but before with Fort Dodge, and CVM meet quarterly to discuss each adverse event, so we have that handle.  And this VMAC actually was pushed out to 18 months really because of the acquisition of Fort Dodge by Pfizer and it took a while.  We had to be certain who was actually going to end up with ProHeart 6 and whether they were going to market, so, you know, Pfizer could have bought Fort Dodge but then could have sold ProHeart 6 to somebody else.

So this one actually got pushed back several months because of the acquisition.  We were hoping to have it within -- right at a year, but because of the acquisition, it was pushed back.  And so I think the answer is:  1, we work with the sponsor on a quarterly basis and we would likely have a process like this, you know, in the 12- to 18-month range on an ongoing basis.

DR. DOYLE:  Thank you, Dr. Hartogensis and Dr. McChesney.  Any other points or questions regarding this?

(No response)

Question #1, Part 1, Panel Decision


DR. DOYLE:  All right.  Well, shall we bore down then on the question regarding the change in the label from a -- basically a warning to a precaution?  Dr. Senior, do you want to kick this off and tell us what you think?

DR. SENIOR:  Well, it is really hard to interpret this data.  It is difficult to pin down exactly where we are and how this compares with other products. 

But I would say that there is at least some evidence that there could be an enhanced anaphylactic effect by giving vaccines at the same time, and for that reason I would say that, yes, I would go along with giving the vaccine at the same time.  

But if we do that, I would add another thing to the RiskMAP and say there has to be an observation period of the animal for 4 hours.  The vast majority of anaphylactic reactions will become apparent -- or some period of the time.  The vast majority of anaphylactic reactions will become apparent pretty soon after the administration of the medications, and after 4 hours, you are unlikely to see something that is really going to kill the animal. 

So I think this would put a really big safety cushion in there until such time as we can get hard data on how often this thing happens and how it does compare with other drugs.

I would say that if you could give me hard information here that this is no more risky than a vaccine -- and I am not hearing that, okay? -- then I would say:  Do away with the separation of vaccination and ProHeart 6 medication. 

But because we can’t have that -- I just have not gained that understanding -- I think the risk is there.  It seems to me that there is some evidence that the risk, the two are synergistic in that if you give a vaccine on the 1 hand, you will get X-number of reactions, and if you give ProHeart 6 on the other, you will get X-number of reactions, and if you give them both together, I am suspecting that you get more than 2 X-number of reactions.  And so I don’t know; I am just suspecting, from what we have just heard.

So my guess would be -- my thought would be that we can certainly give them together, but if we do so, there has to be an observation period factored in.

DR. DOYLE:  So you are agreeing that the label could be changed to the precautionary statement?


DR. DOYLE:  All right.  Dr. Poppenga?

DR. POPPENGA:  I guess the one thing that I sort of agree with is that there is a lack of data to make a really hard decision concerning this question.  But I guess I keep thinking to the international experience with this particular product and there are no restrictions in terms of giving it and vaccines at the same time. 

I think -- looking at the whole RiskMAP, I think there certainly is a barrier to the use of this product and I guess I would probably -- perhaps with it kept at an observation period, although I wouldn’t wonder if that is under the observation of the veterinarian or the owner, because if it is the veterinarian, I think that adds certainly some issues in terms of cost and convenience. 

I would say -- I would tend to say that the precaution seems justified.  We could move it from a warning to a precaution.

DR. DOYLE:  All right, thank you for that.  Dr. Murtaugh?

DR. MURTAUGH:  My thoughts fall under two categories. 

The first relates to the data.  It is my understanding one of our roles is to evaluate scientific data to help guide the decision-making process and that the issue here is the -- relates to our risk/benefit ratio.  And the American Heartworm Society states that all of the 16 approved heartworm preventatives are highly effective, at least in an analytical sense, when applied appropriately, do work. 

So the issue then is trying to understand relative risk/benefit ratios to see if this product does something that the other products will not do. The -- so some kind of comparative analysis then is -- seems to be required.

In terms of scientific data that addressed this point, I haven’t seen any controlled studies where you have case-controlled studies or blinded studies that are prospective, constitute kind of standard research models that are widely accepted and relevant here -- principles of randomness so that you can use statistical methods to analyze large datasets or even small datasets, statistical analysis of the data that is in hand, replication of the studies, all of these things which would, I think, lend weight to data and give it a more -- a higher level of objectivity might exist but I didn’t see them today.

The question of long-term safety of the product in my mind has not come up.  Something that is going to be applied repeatedly to dogs over their lifetime, does that constitute cumulative risks?

So in my feeling, we simply cannot use scientific data in making the decision today because it does not exist, and this is not -- this an endemic issue, I think, and throughout veterinary medicine; it is not unique to the case of ProHeart 6.

Having said that, I also have not heard anything today that suggests that there are unusual problems or risks with the safety of the product that has been on the market since it has been re-released.  The issues that have been brought up, again in my opinion, related to events prior to 2005 and I don’t see that -- but so and -- in the recent past and in the period in which the product has been sold under the RiskMAP, I haven’t heard that there any significant issues that have arisen during that time.

DR. DOYLE:  So, is it a yea or a nay in terms of   should it be a warning or a precautionary warning, or a change to a precaution?

DR. MURTAUGH:  I am comfortable changing it to a precaution.

DR. DOYLE:  All right, thank you for that.  Dr. McKean?

DR. McKEAN:  I think based on the international studies, based on the information that has already been discussed here about the lack of data that would point to the need for a warning, I really do encourage both Pfizer and CVM to get us better information in order to know better what is going on. 

But I am persuaded at this point that the use of a precaution as opposed to a warning would be appropriate.  And that in part has to do with the answer that I got that this will be an ongoing process that will allow -- if that is not the correct -- if better data comes to us that we have the potential to make changes based on that quality of data.  But the quality of data today, I am convinced in my own mind that this -- there may be some increase in risk with vaccine, but it is not an overwhelming risk, and so I would say, use the precaution statement as is drawn up.

DR. DOYLE:  Okay, thank you for that.   Dr. Mathew?

DR. MATHEW:  I would agree with a change to a precaution.  I have strong faith in the veterinary community and practitioners, and what I have seen hearing from them including the ADMA committee, is that they would like more latitude.  They would like to be able to use the medication in the way they best see fit.  Practice, as someone mentioned, the science and art of medicine.  So I vote “yes.”

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

DR. GRIFFIN:  The lack of scientific information (away from microphone) ---

DR. DOYLE:  Dr. Griffin, use your microphone.  All right -- thank you.

DR. GRIFFIN:  The lack of scientific information for data is disturbing, and it seems to be very disconnected, what has been presented.  If I were Pfizer, I would ask for that label to be left alone to protect myself.

I understand that it is likely to be in the interest of convenience, but I trust Dr. Glickman’s data.  And seeing nothing to refute that, I would vote to leave the label as it is.

DR. DOYLE:  Okay, thank you.  We are not voting.  We are just asking for your opinion at this point, so you would say leave it as it is.

DR. GRIFFIN:  Leave it as it is.

DR. DOYLE:  All right, thank you.

DR. APLEY:  I need to preface my comment with 1 quick question for Dr. Glickman.  You are 15, 15 and 45 figures that you quoted, ProHeart or vaccinations alone, roughly 15 ProHeart 6 alone, roughly 15, and then 45 combined for anaphylaxis, did that include -- was that just through 2005 or did that include these last couple years?  When was that time period?

DR. GLICKMAN:  So those numbers are rates per 10,000.  They are not percent, for sure.

DR. APLEY:  Okay.  But those --

DR. GLICKMAN:  And those were numbers based on pre-2005.

DR. APLEY:  Okay, thank you.  That is what I need.  Thank you very much. 

So my first point is, I don’t have any data with the new formulation other than the RiskMAP.  A prospective study is about impossible with the slow incidence rate, I think?  It would be really rough to come up with enough end numbers, I mean, to actually make a decision?  1 month was the time period, as I understand it, to try to separate vaccine  and ProHeart 6 effects for the RiskMAP.  There is no scientific basis to say that separating them that far would minimize risk.

So I am in favor of turning it to the precautionary statement rather than a warning because I think the one month is completely unfounded and I think it is fiction to put it on there as a warning because it was pulled out as the way to try to separate data, has no clinical support.

I would suggest adding a phrase that says “This relationship is not well documented.”  It is not documented at all.  It is supposed, and as I sit here, I am thinking of our ranking of evidence by which we do things, and it starts with prospective randomized, case-controlled studies, and then it falls down through case cohort -- cohort or case-controlled  studies, and then goes into case observations and stuff and eventually you get down to consensus statements, down here -- and I am breaking out in hives right now; you may have a VMAC ADE to report!  But I am uncomfortable with trying to put any definitive statement behind that.

So I would support going to a -- the precautionary statement, but would suggest in addition to that that the relationship is not well characterized.  And as I struggle with this, I would say one more time, and I will let the horse get up and stop beating it, that I would encourage in the future VMAC with a RiskMAP approach that ahead of time you prepare some data, masked data, from other drugs in the class if you can do so without violating confidences, or across to give us an idea of where we are floating amongst the other drugs that you monger.

DR. DOYLE:  Okay.  Thank you, Dr. Apley.  Dr. Altier?

DR. ALTIER:  I am in favor of a change to a precaution.  I agree with what Dr. Apley just said, that this was instituted primarily, or exclusively, as a means to separate data, not that there is any correlation between vaccine adverse effects or the drug’s adverse effects. 

So what we do lose in this, however, is likely people will begin to use this drug at the same time as these vaccine and we could get confounding data again.  We have all talked about how we would like to have more data.  That data could be confounded because of that.  However, that doesn’t preclude us from gathering more data as time goes on.  So I am in favor of the change.

DR. DOYLE:  Very good.  Thank you. 

Dr. Wolf had to leave early and I am going to read to you his comment regarding this question.  He says, “Yes, pending suggested practices to clarify use with cautions.”

So the way I read this there is a consensus that it would be all right to change to the precautionary wording.  My experience with risk assessments from the microbiological world is that there is never enough data.  I don’t know one risk assessment that has had enough data, and we just, as risk managers, have to use the data that we have and the best judgments that we can make, based on the risk/benefit.  And I guess we have done that, so let us move on to the next question.