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U.S. Department of Health and Human Services

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Risk Maps and Labeling by Dr. Martine Hartogensis, Deputy Director, Office of Surveillance and Compliance, CVM

DR. HARTOGENSIS:  Thank you very much, Dr. Dunham.  Good morning, and welcome.  I just wanted to say thanks to everyone for showing up today, particularly our panel.  I am really looking forward to this process and -- as I hope you are as well. 

So now that you have heard a little bit about FDA’s regulatory framework as well as the background on ProHeart 6, I would like to give you an overview of the Risk Minimization and Restricted Distribution Program itself and point out the very important label revisions that were implemented during the reintroduction of ProHeart 6.


I am going to start with a brief overview of how the sponsor reintroduced ProHeart 6 under the RiskMAP, followed by an explanation of the purpose and the key elements of the RiskMAP itself.  And finally, I will present the questions to the VMAC panel today that is subject to our meeting.


So as was mentioned before, ProHeart 6 was reintroduced to the U.S. market in June of 2008 under a Risk Minimization and Restricted Distribution Program, otherwise known as the RiskMAP. 

The RiskMAP was largely based on an FDA guidance for industry that published in March of 2005 that was published our Center for Drug Evaluation and Research as well as our Center for Biologics for People. 

These programs have been in place for human drugs and biologics since as early as 2002.  Some examples of drugs for people that have been marketed under RiskMAPs include Isotretinoin and --

MR.           :  Tysabri.

DR. HARTOGENSIS:  Tysabri.  Thank you, Janice.

Both of these drugs have very unique risks as well as very unique benefits that are associated with them. 

The reintroduction of ProHeart 6 also included a fairly extensive label revision to the product label as well as the Client Information Sheet.  And as was mentioned before, the label is really the cornerstone of all communications associated with a drug not only for the drug itself in the professional labeling but the labeling materials which are not only materials that you would traditionally think of that accompany the product but also promotional labeling, promotional materials, and advertising.  So, all of those materials are really essentially based on the approved label.  I will review all of those changes with you in just a few minutes.


So the purpose of the RiskMAP is to essentially enhance the risk/benefit ratio of the drug usage.  CVM received a large amount of feedback from both veterinary practitioners and dog owners after the product was recalled in 2004 that they were unable to adequately protect their dogs from heartworm disease using other products, particularly in areas of elevated heartworm disease prevalence.

The RiskMAP was designed to provide availability of the drug which was not otherwise available due to the safety concerns previous to 2004 that were identified while maintaining the risk/benefit balance. 

The focus of the plan is to provide enhanced communication, awareness and education to the dog owners and veterinarians so they can determine if the continued -- so they can determine if the product is appropriate for use in the pets.  Through continued monitoring, the RiskMAP is aimed at insuring safe and appropriate use before, during and after administration of the drug.


So as you heard from Janice’s previous presentation earlier, the 3 elements of the RiskMAP include enhanced communication and education, the reminder system, and the performance link system, all elements that were contained in the 2005 guidance that I mentioned earlier and all are elements in the ProHeart 6 RiskMAP.


So the first element really focuses on the enhanced communication and education.  This is probably the most important and crucial element of the program because the better informed and aware the veterinarian and the dog owner, the better the ultimate outcome for the patient

The 3 key arms to this element include the revised label with updated safety information and Conditions of Use as well as the safety information and Conditions of Use contained in the RiskMAP itself. 

Several outreach pieces designed towards explaining the drug’s return to market were included, such as the “Dear Doctor” letter, the press release, the CVM update, and finally the updated Client Information Sheet which is given to the dog owner prior to administration of ProHeart 6.  As a condition of the RiskMAP, the veterinarian is required to give the owner the Client Information Sheet, and I will show you where that is actually highlighted.


So, first I am going to start and essentially go over what label revisions particularly that the sponsor made before the product was reintroduced.  For your convenience, the revised language is actually in blue so that you can tell what was already on the label and what was new.  The language that was omitted obviously is omitted, so if you are interested in further information about that, all of that information is located on our website.

So to begin, the warning section was revised to include a bolded warning against concomitant use of ProHeart 6 within 1 month of vaccinations.  The reasoning for this statement is that before the 2004 recall, approximately half of the reported adverse reactions included vaccine administration at the same time.

Other warning statements were added, including caution in dogs with pre-existing allergic disease such as food allergy, atopy, and flea allergy dermatitis.  Allergic reactions to ProHeart 6 can result in liver disease and death.

A statement was also added to both the label, RiskMAP and training materials for the veterinarian on how to treat these allergic reactions.  And this is really a key component of the RiskMAP, is that we wanted veterinarians to be aware of what to expect and know how to adequately treat those reactions and be prepared for them.


The label warning section also instructed the veterinarian to give the Client Information Sheet prior to administration and to advise their client to observe their dog for a potential toxicity.  The statement pertaining to which dogs should not be treated was revised to add dogs with a history of weight loss.  This was an important clinical finding that we found to reflect a review of the adverse drug events prior to the recall as well as some of the pre-approval studies that pointed out dogs with a history of clinical weight loss greater than 10 percent seem to be more prone to allergic and adverse reactions associated with ProHeart 6.  This is largely due to the lipophilic nature of the drug.


The adverse reaction section was also revised, based on re-review of a pre-approval field study.  This analysis revealed anaphylaxis, diarrhea with and without blood.  And again, dogs greater than 10 percent of weight loss were more likely to experience a severe adverse reaction, and these were newly added, as I pointed out in blue, to what was already existing on the label.


The pre-approval review also showed an effectiveness study with dogs containing 4- and 6-months old heartworm infections, experiencing signs such as vomiting, lethargy and bloody diarrhea.  These signs were more severe in dogs with younger infections in fact, including a dog that was recumbent and required supportive care.  This was all our re-review of the pre-approval studies when we went back prior to the re-introduction.


So, based on the adverse reactions that were reported when the drug was marketed in the U.S. prior to 2004, the label was also revised to break down the reaction by body system. 

Several adverse reactions were added as well.  Most of these signs were already on the label; however, the body system breakdown is designed to be much more user friendly.  General signs include anaphylaxis, anaphylactoid reactions, depression, anorexia, fever, weight loss.  Gastrointestinal signs such as vomiting with and without blood, diarrhea with and without blood, and hypersalivation, and neurological, convulsions, ataxia, trembling, hind limb paresis.


The adverse reaction section also includes dermatological signs of urticaria, head and facial edema, injection site pruritis and erythema multiforme which in layman terms are itching/swelling of the head and face, and erythema multiforme, which is an autoimmune-mediated dermatological condition.

However, both the hematologic signs such as immune-mediated hemolytic anemia, or immune-mediated anemia, elevated white count, and immune-mediated thrombocytopenia, or low blood platelets that have an immune component, and the liver signs such as elevated liver enzymes, hepatopathy, which is general liver disease, hypoproteinemia, low blood protein, and hyperbilirubinemia, which is elevated blood bilirubin, one of the enzymes related to the liver, were added to the label.

The respiratory signs reported following youth and heartworm positive dogs as well as the rare reports of deaths were consistent with the older label as well, so that was not any new information added.


We also, along with the sponsor, worked to update the Client Information Sheet, which was really a key component of the RiskMAP because it was a requirement that the client actually read the Client Information Sheet prior to their pet receiving ProHeart 6.  It was designed to be accessible to the dog owner and also was updated to include the revised label elements, as previously mentioned on the previous few slides.

The sheet advises the client which dogs should not be treated, including dogs -- the information about dogs with a history of weight loss, and breaks down the reported adverse reactions by body system consistent with the label.

As mentioned previously, the label instructs the veterinarian to give the Client Information Sheet and tells them what to watch out for, all crucial information to the enhanced communication and education element of the RiskMAP.


Okay, so moving on to the reminder system element of the RiskMAP, veterinarians are required to take online training, as was mentioned in the previous presentation, prior to purchasing ProHeart 6.  The online training educates the veterinarian on space and appropriate use of the drug. 

As a condition of the enrollment in the program, the veterinarian must submit all adverse events suspected following administration. 

The veterinarian is also required to go over an informed consent form, which was also mentioned previously, and encourages discussion, acknowledgment that the owner has read the Client Information Sheet, and encourages the client to report any suspected adverse events.  This is really designed to encourage that conversation between the veterinarian and the client on determining whether the product is appropriate for their pet.  The sponsor is required to submit all adverse events to CVM monthly and meet with CVM quarterly to review the adverse events and the progress of RiskMAP, which we did successfully meet quarterly.


So the third element of the RiskMAP is the performance link system.  Veterinarians are required to register and confirm that they have taken the training, read the new label, and will commit to reporting any and all adverse events. 

The RiskMAP also restricts enrollment to dogs between 6 months and 7 years of age.  The upper limit, the 7-year age limit, is a new requirement that is not currently contained on the label.  This is aimed, again, at minimizing risk to patients.  Dogs also must have baseline hematologic parameters that were discussed previously, tested, including a complete blood count chemistry panel as well as a heartworm test if the dog is over 7 months of age.  This is consistent with the heartworm testing recommendations from the American Heartworm Society.

The distribution is further restricted in that veterinarians can only purchase ProHeart 6 from the sponsor itself rather than through various distributor chains as many, many drugs are commonly distributed and sold.


So as I mentioned earlier, the success of the RiskMAP is largely dependent upon the communication between the sponsor and CVM.  The sponsor and CVM met quarterly to discuss the progress of the RiskMAP, adverse events, and feedback from veterinarians and dog owners.  The process is iterative and dynamic, with a continued analysis of the risk and benefit balance.

Finally, again, using the 2005 guidance of RiskMAPs, there is opportunity for public input in CVM’s VMAC process, which is why we are here today.

So with that overview, I now want to pose to our VMAC panel -- and these questions will actually be repeated later this afternoon at 2:00 by Dr. John Baker -- but now that you have this moment, you can take a look at our questions now.

There are two questions which are largely based on the feedback that we have received on the program while maintaining the risk/benefit ratio. 

The first question is:  Based on the data generated by the ProHeart 6 RiskMAP, should the RiskMAP and/or the product labeling be modified in regards to the following two items?  And just keep in mind, this is just suggested language. 

We have many, many label experts within our Center to go over wordsmithing et cetera, but just to give you an idea of a potential wording change, the following statement is currently contained in the warning section of the product label:  “Do not administer ProHeart 6 within 1 month of vaccinations.” 

So based on the data presented today, 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 concomitant use of ProHeart 6 and vaccinations.”  Again, this is just a suggested wording change.

The current RiskMAP requires the 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 hematologic and serum biochemical baseline data is recommended prior to administration of ProHeart 6”?  

This statement change could allow the practitioner a little bit more flexibility when faced with a client that has a very tough decision or has economic barriers to collection of this blood work while still informing the veterinarian and client of the recommendation.


So the second question is a little bit more open and flexible and really turns it over to you, the panel:  Based on the information and data presented today, are there any additional modifications, additions or deletions to the ProHeart 6 RiskMAP and/or labeling that you suggest?

So with that, I leave you with those questions. 

I hope you have found this overview of the RiskMAP and label revisions to be very, very useful as we move forward with our analysis of the adverse drug event data next.

Thank you very much for your time and attention.  And I turn it over to our next speaker.  Do you have any questions based on that?

          (No response)


DR. DUNHAM:  Okay.  Thank you so much, Martine.  It is my pleasure now to have Dr. John Baker come up and give us an overview.