Following is the transcript of the Roundtable Discussion on Compounding for the Equine Veterinary Profession sponsored by Luitpold Animal Health and held in New York on Aug. 30. In attendance were Gary White, DVM (Luitpold Pharmaceuticals, who acted as moderator); C. Wayne McIlwraith, BVSc, PhD, FRCVS, Dipl. ACVS, ECVS (representing the American Association of Equine Practitioners); Richard Mitchell, DVM (clinician and equine lameness expert); Joseph Bertone, DVM, MS, Dipl. ACVIM; and Robert Stenbom, DVM (Boehringer Ingelheim). Representatives from compounding companies and the FDA were invited, but didn’t attend.
White: I’m Gary White, I’m an Equine practitioner from Sallisaw, Oklahoma. I also own a contract research company and do consulting for pharmaceutical companies and I’ve been in practice for 26 years.
Bertone: I’m Dr. Joe Bertone, Professor of Equine Medicine Western University of Health Sciences, College of Veterinary Medicine. I am a member of the AVMA Council on Biologic and Therapeutic Agents representing Equine Practice. I spent five years as a veterinary medical officer at the FDA Center for Veterinary Medicine.
Stenbom: I’m Dr. Bob Stenbom, I’m the manager of Equine Professional Services for Boehringer Ingelheim Vetmedica. I was a practitioner for 14 years prior to coming to industry 11 years ago.
McIlwraith: I’m Wayne McIlwraith, Professor of Surgery and Director of Orthopedic Research at Colorado State University.
Mitchell: I’m Rick Mitchell, I’m a private practitioner in a group referral practice in Newtown, Connecticut. We are basically devoted to the sport horse. I’ve served on numerous association committees regarding the regulation of sport horse activities in the USAE, FEI, as well as advising numerous drug companies on product development.
White: Drug compounding in veterinary medicine has exploded since the mid-’90s. It seems to be a particular product problem in equine medicine, although it is a significant problem in other areas in veterinary medicine as well. I read recently an estimate that compounding accounted for $50-60 million in income a year. I for one, and I know there are others here who agree it’s probably a lot higher than that. It was also noted that 13% of equine prescription drugs in the average equine practice were compounded and in those practices that were exclusively performance horse practices, it was up to around 30%.
Compounding has always been part of veterinary medicine, it remains of value, and I think we need to recognize that. We also recognize that there have been a proliferation of compounding pharmacies that have engaged in unethical and possible illegal practices and we need to discuss what these practices are, why they are illegal or unethical. And we need to talk about solutions as well. We’re also going to discuss some off-label uses in equine medicine that are of concern to all of us.
The Place of Compounding in Equine Medicine
So we’ll start by talking about the value of compounded drugs in equine practice and I’d like to start with Dr. Mitchell since he is a practitioner; give us an idea of the importance that you place on compounded drugs in your practice.
Mitchell: Compounded products are quite important predominantly in our practice in the case of medications that have been heretofore approved and developed for use in the horse and in many cases have become unavailable from the normal manufacturing process. It’s left us in a bit of a lurch without a place to go to provide our clients and our patients with medications that we need. In those cases we will go to the compounders for medications. I think a beautiful example most recently has been trimethoprim sulfadiazine. We have been unable to obtain it from the normal manufacturer of Tribrissen, and we are acquiring that particular product for use as an antibacterial. And there are many other products that were once available that we’re now unable to acquire. It’s not so much a matter of cost for us as far as we’re concerned, it’s a matter of providing our clients and patients with the medications that they need.
I think it’s very important for us to have confidence in the compounder and to have some knowledge of their past record and the sort of quality of products that they’ve produced. We buy from very few compounders in our practice because we haven’t established a track record with the ones that we purchase from and their standards have met ours.
White: Joe, would you comment some on the point that Dr. Mitchell made about drugs that have been approved and are no longer legally available. You consider that a legitimate compounding activity, do you not?
Bertone: That is a legitimate and important compounding pharmacy activity. There are several reasons why drugs are removed from the marketplace. These include poor financial viability, manufacture line re-tooling, or loss of quality chemicals for manufacture. In these and other cases, compounding pharmacy is essential. I completely agree with Dr. Mitchell.
White: Yes. And he also made the point that financial considerations were not an issue. Dr. Stenbom, if you would comment on how legally compounding is supposed to be financed and how that is supposed to work so we could clarify that issue.
Stenbom: If my understanding of the transaction itself is correct, it was designed to follow what they call the “triad.” This triad consists of the prescribing doctor, the compounding pharmacist and the patient or owner--in the cases that are in veterinary medicine. In the face of a specific need for a specific animal, the doctor makes a prescription or requests or negotiates a solution with a compounding pharmacist who then makes the transaction directly with the client; that’s the way it developed on the human side, that’s the way it specifically remains there and that’s what we’ve drifted away from in veterinary medicine. The transactions are often made through the veterinarian and there is markup and some other activities that bear further discussion in this round table. The transaction itself has drifted away from what I believe was the original intent of the regulations and guidelines.
Bertone: Unfortunately, illegitimate compounding pharmacy has taken on aspects of drug distribution. That is illegal, and unethical compounding pharmacy with the help of veterinary medicine. Veterinarians are using compounded drugs distributed to them. By definition, these products are adulterated, mislabeled and misbranded. I would not want to be on the other side of that accusation. This is especially true when the drugs are pirated and counterfeit. In other words, drugs that are modeled after approved formulations for horses.
McIlwraith: I’d like to comment before we start saying across the board that people should not generally have compounded drugs available. Betamethasone is a good example. I do quite a lot of consulting surgery, as well. Our lab showed, for instance, that betamethasone, and it was Betavet Soluspan at the time, was very good for articular cartilage. It was an ideal steroid to use and we did that research on the basis of my observations in surgery that horses that had been injected with that had no secondary cartilage lesions, whereas we knew other medications such as Depomedrol, caused quite a lot of cartilage damage. When Betavet Soluspan became unavailable, we went to the human drug Celestone Soluspan; that then became unavailable, and I don’t think either of them was unavailable because they couldn’t make money at it; there were some manufacturing problems. And so, in this instance, we’re heavily reliant on compounding. The fact of the matter is that some of these medications are essential, and I’d be ecstatic if a company picked that one up and manufactured it. On the other hand, I get asked at least once a week on where they can get these products, and there’s a number of compounders producing it and I’m sure the quality is variable and we’ve had some instances of untoward reactions where the veterinarian gets very concerned about the legality of it.
White: Do you think that practicing veterinarians are taught this in veterinary school and do they understand it once they get into practice?
McIlwraith: We already are teaching our students in those types of instances that these are what their options are. We’re actually using compounded betamethasone in the hospital because our only two options with intra-articular corticosteroid therapy, which is still a really critical part of any sport horse practice is, as far as I’m concerned, are betamethasone or triamcinolone acetonide. We reserve our Depo-Medrol generally for distal tarsal joints; we don’t get concerned about the cartilage so much. These students are very well aware of the fact that there are other ways that they need to get the medication. They’re certainly, as far as I know, they’re not instructed on how to do it, but they certainly are instructed on the need to use some things.
White: I think we can all agree that it’s in the interest of both practicing veterinarians and academia to have a viable legal compounding industry. And I think that it’s encouraging that you’re teaching students at Colorado how to go about this and I think it’s important because I think a lot of practicing veterinarians do not understand this.
McIlwraith: I wouldn’t want to pretend that I’ve been just talking to these other guys yesterday. I wouldn’t like to say that they understand all the legalities of compounding and when to compound and when to not. I’m just saying they know that the certain medications that have to come from a source other than a legitimate pharmaceutical company. I think it’s something that we need to teach them the ethics and the legalities of it.
Approval Process for FDA-Regulated Drugs
White: I’d like for Dr. Bertone and Dr. Stenbom to summarize both from a manufacturing and an efficacy safety point what is required for an approved drug.
Bertone: One point to keep in mind is that we are talking about the drug as the formulation, not the active molecule alone. That is a very important point lost to our profession. Veterinary education has not imparted the understanding of the formulation as the drug and how formulation affects shelf life, pharmacokinetics, and efficacy. The drug is not only the active ingredient. Active ingredients behave differently in different formulations.
There is variation in the process, but I can give you a more common course. Firstly, a molecule is identified that potentially will have an impact on veterinary medicine. This is the discovery phase. Then an indication is identified. In other words, what will the drug do and for what species, etc. An economic analysis is performed and, if viable, the product’s regulatory development proceeds.
The critical components for non-food animals include safety in the intended species, efficacy, and chemistry and manufacturing. Is the formulation safe in the animal, does the formulation work, and then can the formulation be made consistently and does it have stability. Chemistry and manufacturing are critical. In fact that component is often the most difficult hurdle to complete.
Meeting the manufacturing criteria assures that what is on the label is actually in the bottle and that the formulation has some shelf life. The standards that need to be met are termed Good Manufacturing Practice Regulations, or GMP. This is a very difficult part of the approval process. Where veterinary education has failed is imparting to the profession the difficulty of having that assurance. In other words we, as a profession, are ignorant in terms of formulation chemistry. Attributes of this process include the assurance that the product has high quality, strength and potency is free of harmful contaminates. All those issues are evaluated and it is usually a fairly expensive part of the process. An injectable fill laboratory, as an example, may cost 8 to 14 million dollars to construct, meet FDA criteria, so that one is assured that the product is sterile, lacks endotoxins, etc. Boiling bottles in a double boiler, as some compounders have been known to do, is not adequate for FDA approval, nor should be acceptable by veterinarians.
In fact, if you know a little bit about Good Manufacturing Practice Regulations, you can identify some of the unethical and/or unknowledgeable compounders. If you look at most products that are FDA approved as injectables, very few of them indicate on the label that they are sterile products. The assumption is that they have been produced by a sterile process that assures that the product will be sterile when completed. No guarantee of that specific bottle’s sterility can be made. It’s interesting that some of the less ethical compounders will place the word sterile on their bottles. They have no proof to support that statement whatsoever. Ethical and knowledgeable compounding pharmacists will not label their products as sterile, or make claims to the products sterility. That’s one little key feature to look for, that I recommend, when investigating and choosing a compounding pharmacist.
The approval process usually takes somewhere in the neighborhood of five to eight years. Then the drugs are monitored after the approval is awarded.
Stenbom: When I think about post approval and the relationship of an FDA-approved drug manufacturer to the FDA, I think of four particular areas in the post approval process that manufacturers are engaged in.
First, consistency. The FDA requires, not that they just can produce this consistently initially, but they have to be able to demonstrate that they can produce this consistently, batch after batch, lot after lot, over and over again, as long as they’re producing this product. They also have to certify their initial raw ingredients, and that’s part of that consistent manufacturing process.
Second, adverse event reporting is a very important part of these requirements following approval and for the life of the product. They have very strict guidelines on this, they have very extensive expectations and this is a very good thing from the standpoint of protecting the end consumer and the veterinarian in the middle.
Third, marketing and advertising oversight. The FDA also has much to say about how the company advertises the product. They just don’t let us go out and do our own thing from an advertising standpoint. Advertising must follow specific guidelines regarding claims and exactly how the product is being promoted.
And then fourth, they’re always on the watch to make sure that at any level within the organization, particularly when it comes to sales, technical services, that the extra label uses that develop for different products are handled in an appropriate fashion by those people in the company who are communicating publicly, be that in writing or verbally, they’re very concerned about making extra label claims on products.
There’s a huge divide between what happens in this regard between compounded drug products and FDA approved drug products.
There are post approval requirements from the FDA relative to the generic products as well. And it is identical as far as I know to that which is required for the original pioneer drug. Those things have to be attended to.
White: And that has to be submitted in an annual report to the agency.
Stenbom: Not only in an annual report, but as individual reports within a certain period of time following the initial complaint.
And I think it’s important to note that with generics, the company producing the FDA approved generics is required to also fulfill all those four major areas of post approval scrutiny and requirement that the original drug did and, once again, that’s something that is not being done on the compounded side.
McIlwraith: How does a reputable pharmaceutical company establish expiration date?
Bertone: Products are analyzed with accelerated stability studies that mimic environmental extremes. These studies will often cost $100,000 to $500,000, depending on the number of dosage forms, bottle sizes, etc.
White: Temperature and freezing are involved, and there’s an accelerated stability and then they have to do ordinary shelf life under the recommended storage conditions. If you want five-year expiration dates, you’ve got to have data for five years. Ordinarily they’ll get one to two years on accelerated stability and then you’ve got to show the data to extend it beyond two years.
Bertone: Shelf-life study conclusions assume the worse case scenario. However, after the expiration date, there is no assurance that the specific bottle you have in your hand meets clinical standards. Once an expiration date is passed, the product is legally defined as adulterated.
Generic Versus Compounded Drugs
White: Dr. Mitchell do you think it would be possible for a compounder to follow this sort of scenario; you’re talking about years and millions and…
Mitchell: I think it would be extremely difficult if not financially and organizationally impossible. But there’s one other thing I’d like to add a very important point: that a lot of veterinarians, very well educated people, don’t really realize the difference between generic medication and compounded medication, and they speak of them as if they are the same.
Most of the time when they’re distributing compounded medications to their clients, the clients perceive they’re getting a generic medication that has gone through the approval process, etc., etc., by some manufacturer at some point in time.
Bertone: That is a violation of the public trust, whether the veterinarian is educated in this area, or not.
McIlwraith: And the reason for that is that quite a few of the people selling those products are set calling them generics when they’re not.
Mitchell: Exactly, and it is a violation of public trust, but it’s also a misconception on the part of the practitioner. I think that hasn’t soaked in.
McIlwraith: I think they’re totally unaware. I’d like to add to that--Dr. Bertone talked about quality and Dr. Stenbom talked about post approval, but one thing that hasn’t been talked about much is the rigorous proof of effectiveness that it goes through in getting a drug approved and basically I think the public needs to realize that with an approved medication, or true generic preparation, that they do work and they’re safety has been proven.
FDA-Approved Raw Materials
White: And I think one other thing that might not have been clear, I think Joe might have touched on it a moment--the raw materials that go into making an approved product have to come from a manufacturer that is approved to manufacture that raw material by FDA. This is not so for compounding, would you like to comment, Dr. Bertone?
Bertone: In fact, a great deal of the chemicals used in compounding pharmacies are actually produced overseas and a great deal of these chemicals come from China, India and Pakistan. For the last five to 10 years, there has been an import alert on any chemical products brought into the country to be used in the production of compounded formulations for animals. However, most of these chemicals get through our seepy borders. No active ingredients that are found in FDA approved formulations are allowed into the US. So when you purchase omeprazole, as an example, from drug pirates, who pose as compounding pharmacists, the omeprazole at some point was smuggled into the United States.
One issue to consider is that generic drugs are FDA approved. Most of these drugs receive approval through pharmacokinetic studies to demonstrate bioequivalency. These products go through the same manufacturing and chemistry processes.
Compounded drugs are not generic drugs. There is no way they can meet the same quality standards as generic drugs. Ethical, legal and knowledgeable compounding pharmacists will always indicate that their products do not meet the FDA standards. If a veterinarian purports that a compounded drug is a generic drug he/she has violated the public trust.
White: One of the most common reasons for compounding, I think, is alternative dosage forms. For example, Dr. Bertone and I were looking at a flyer from a compounder this morning advertising an Omeprazole Suspension. I think there has been some indications that these are not stable. What are the pitfalls of alternative dosage forms and when is it legal and when is it not legal. One of you two guys can probably answer that as best. Is it legal to make Omeprazole Suspension for horses when a paste is available?
Bertone: Good Compounding Practice guidelines dictate that you can reformulate approved Gastrogard paste. However, drug counterfeiters and pirates don’t use the approved paste, they use bulk chemicals. Bulk chemicals are chemicals of varying quality in bottles, drums and plastic bags. In no case, is the pirate or counterfeiter using a bulk product with the same quality as the FDA approved drug.
There is a process whereby a chemical manufacturer develops what is termed a Drug Master File (DMF). That DMF assures that the bulk chemical is actually what the label says it is and that it is free of impurities. In other words, you know that what you have is actually what you have. Most compounding that goes on is done with bulk products and often times they come from manufacturers that cannot meet the criteria for developing a DMF for that product.
The production of counterfeit and pirated omeprazole is a clear demonstration of the producers poor knowledge of compounding pharmacy. It also is an indication that the pirate is unethical and has an illegal nature. Firstly, selling compounded omeprazole is illegal and unethical in and of itself. Good compounding pharmacists do not pirate or counterfeit drugs. Secondly, compounding 101 textbooks indicate that omeprazole degrades rapidly in a water based suspension. If a pirate uses an oil based suspension, to preserve the omeprazole molecule, they are infringing on the patent. Most pirate/counterfeiters use a water based suspension. If they use a water based suspension, they are selling you degraded omeprazole. So the act of selling you a counterfeit omeprazole is illegal and unethical, and may also indicate that the pirate is ignorant.
Another thing that some pirates have done is mix the questionable omeprazole bulk chemical with bismuth subsalisylate. This was the excuse given to by a university faculty member who presented it as “how they get away with it.” This faculty member thought that this was reasonable. Any marginally knowledgeable pharmacist can tell you that mixture of BSS, water and omeprazole will leave you with BSS, water and degraded omeprazole in a very short time. So either the pirate/counterfeiter knew that it was a useless formulation, and was still willing to sell it, i.e. unethical, or they were ignorant of compounding practice.
Another commonly illegally and unethically compounded product is, so called apple bute (apple flavored phenylbutazone). This should be made from the approved phenylbuazone tables. It is most often made from bulk chemical from China. The question to ask with a history of phenylbutazone treatment not being effective is “what was the phenybutazone source?” If the answer is “blank pharmacy,” then your answer should be, lets try real Phenylbutazone.
Altering formulations also alters shelf life, efficacy and safety of drug products.
Medical Risks of Compounded Medications
White: Let’s talk some about the risks again of using these products. And I see several risks. One, the product is sub-effective or not effective. Secondly toxicity and a third being adverse drug reactions. I’d like to have Dr. Mitchell comment on whether these have become an issue with compounded drugs. That is, lack of efficacy, toxicity or adverse drug reactions.
Mitchell: I would have to say that in our practice I believe there’s been some evidence of lack of efficacy. Generally speaking, we’ve been very careful about what medications we purchased and I think that we were able to fairly quickly identify those products that we weren’t getting an expected result from and just discontinued purchasing them. As far as toxic effects per se, I haven’t been personal witness to any toxic effects. I have had some adverse effects and I think the adverse effects issue is a potential time bomb for a lot of practitioners.
We had a particular instance, and I assume now is a good time to discuss it, where we had a large compounding pharmacy providing us with an injectable betamethasone product and the product had been used by our practice for well over a year. We had used over 1,500 vials of the product, packaged in a very similar proportion – exact proportion exactly to Celestone and the previous Betavet Soluspan and we had used, as I said, over 1,500 vials of this medication in a year’s time with not any apparent problems at all, and we felt that the clinical response we were getting to that product was equivocal to Celestone.
Suddenly one of our doctors, who has a very clean track record relative to his joint injections, had five seriously lame horses as a result of interarticular injection in the distal interphalangeal joint in all five cases. Ultimately, two of these horses had to be destroyed and they were not infected as best we could determine in any way by joint culture, subsequent arthroscopy. Dr. McIlwraith can actually speak to one of these horses, he actually did the arthroscopy on it. We thought for a brief period of time and perhaps still that our particular problem was going to be in a legal situation because the ultimate responsibility for the use of a compounded medication falls upon the practitioner. Fortunately, this particular company is very reputable, they carry insurance, they stand behind their products, and to this point have been extremely cooperative in handling the expenses and the problems that have arisen. In fact, in the cases of one horse that is not what he was before, but not actually not lame at the present time (who’s valued at a quarter of a million dollars) looks like probably that horse is going to get purchased by the insurance company. And it’s an awkward situation.
My partner was devastated by the experience. Needless to say, the other six doctors in my practice all stood and shook in their boots for about two months following this episode, waiting for the hammer to drop on one of us. And it didn’t happen and we were thankful for that, but this company, because of the nature of their practices, had lot numbers, called all the lot back, tested it, they allowed us to independently test it. So to me they performed as close to a reputable drug manufacturer as they possibly could, but I think they’re the exception to the rule. Many of the places and organizations aren’t big enough, they don’t have the finances for it, they don’t have the insurance, so it’s buyer beware. You’re really on your own, and in this particular case, we weren’t, because if we read the rules (and Joe can speak to these better than I can), the ultimate responsibility was my partner’s. And we folks only have one compounder at least that stands behind what they make.
White: Wayne, do you have any comments on that case or any other case in which you’ve seen sub-effectiveness, toxicity or adverse reactions to a compounded drug?
McIlwraith: Well, in that case it’s a good example just to add to what Rick said, is that it was really good that the company was understanding because the one that we arthroscoped did not look like an infected joint. You could dump it in the area of reactive arthritis, which is a really poorly understood condition in veterinary medicine and I’ve seen one instance with a FDA approved intra-articular product where we’ve got--it doesn’t fit the bill of sepsis, it also certainly doesn’t fit what we previously talked about with chemical synovitis, like these cases were very puzzling because it was a very delayed reaction, three weeks after injection. We did another one that we post-mortemed again, clean cartilage, obviously a severe reaction in the synovial membrane, in the soft tissue, but not in the cartilage, and I have seen it with legitimate use of Celestone when it was available as well. So it may be something to do with the product, but obviously when you get into legal cases, or if the veterinarian’s up against it in the legal aspect, you need some pretty understanding people to investigate it because we really did not know.
Part of the reason that I arthroscoped this joint was to make a decision whether it was okay or not. And you’re looking in there and using your conventional parameters of the cartilage being all right, and you don’t know what to tell these people. The owners got a lame horse, and the company wants to know, so it’s a big area. Rick’s instance and his practice’s instance is not the only one where I’ve seen it. But on the other hand, the other major instance I had of several cases was where they’ve been using this product for a long time. Well, put it this way, a lot of doses. It’s a big practice in California that injects a lot of joints and so it’s part of the vagaries and I think the most important take-home message is what Dr. Mitchell mentioned at the end that the company stood behind them.
Mitchell: Well, I think the people who will eventually read the transcript of this discussion need to understand that they’re the first--very ultimate source of the issue and the problem, and they may be the first to fall, so to speak, in many cases.
Bertone: I know you would both recognize the presentation of a septic joint. You both mentioned that you had not seen this type of joint reaction. My suspicion is that you were seeing a chemical reaction to unknown chemical contaminants never evaluated in terms of joint reaction.
Stenbom: Dr. Mitchell’s story about the betamethasone raises some of the safety and efficacy questions for me right there as I look at the way a lot of compounding pharmacy appear to be operating. Where we’re falling into a regulatory void here and kind of drifting from what I think the original intent of compounding was meant to be. As I said before, I think the legitimate intent of compounding is focused on individual horses or animals with individual specific needs. Much of the compounding operations were designed to fill those individual needs and we’ve multiplied those individual needs or the compounding industry is multiplying them and producing things in quantities that go beyond these individual needs.
So the situation Dr. Mitchell outlined where they identified this particular lot and were able to recall it from all the different places it went, makes it sound to me like they were manufacturing it in bulk quantities.
I think the intent of compounding is really supposed to be for specific horses, specific needs and maybe a little extra for doctor’s stock for something that you use frequently, but not beyond that. So it should have been very easy to identify where this problem product went (and Joe can tell me if I’m interpreting this right), there should have been only one location to pull that problem product in from.
White: Bob, you have experiences with lack of efficacy, toxicity or ADR with compounded drugs?
Stenbom: Well, we’ve certainly looked into this, when we were having larger problems than we are right now with illicit compounding of our Ventipulmin Syrup. We’ve had a number of practitioners come to us and ask us to check this out and it’s renegade product they or their clients had obtained through various compounding sources offering an inexpensive substitute for the FDA approved product. They were coming to us to analyze it for them to try and see if what they were getting was good. Of course we were very interested in doing this, not for the same reasons perhaps they were. Some of them were motivated to see what they were getting, with others it was concerns about efficacy or the quality of product their clients were accessing or requesting.. The analytical results were all over the board and none that we ever looked at met any of the specifications for the FDA approved product.
Bertone: I think there’s a great example. Before the compounding industry took off, we treated pituitary adenoma with Permax, approved pergolide, at a dose of one, to two milligrams per thousand pounds. Now four and five milligrams per horse of compounded pergolide is being prescribed and in some cases is not effective. Veterinarians should ask the source of the pergolide before they say that pergolide does not work, or that at that dose the cost is too high. In this situation, I often recommend that one try Permax at 1 to 2 mg/1,000 pounds. If that works, then find another compounding pharmacy.
Mitchell: I was going to speak to that same thing. I think Joe makes a perfect point. The other one is Omeprazole. We had done a study a few years ago and we’ve recently done a follow up where we looked at the incidents of gastric ulcers in sport horses and it’s amazing to me the number of horses that were on “generic” Omeprazole, as it was called, that had just rampant equine gastric ulcer syndrome. The people were frustrated because they were saying well, that Gastroguard stuff doesn’t work, to use Merial’s brand name, but they were using that product. And I think it’s a little example of what Joe was saying, that product is not properly packaged, presented or in any way protected against degradation and, in fact, probably would be degraded when it hits the stomach anyway with the form it’s in.
McIlwraith: Dr. Bertone mentioned the violation of public trust earlier. I regularly get told by clients when I’m doing surgery or discussing their joint problems that they’ve had the horse on generic Adequan or generic Legend, as the two most common examples at least in my situation. What are the legalities of that? What can you do about it? Because I certainly know who’s saying it.
White: We see the same thing in our practice. I noticed that a lot of people who were coming to us for treatment of joint problems were telling us their horses were on the generic Adequan, which is glucosamine injection. A clinical study has just come out this week, and it showed that the so-called generic that we actually tested that in our synovitis model was not effective.
Mitchell: We’ve had that particular product problem with horses to our hospital (for them to be maintained on it) while they were there for some other problem. And it sits on the shelf; it’s not given in my hospital.
Bertone: If a pirate, manufacturer, or veterinarian says that a product is generic Adequan or Legend, they are violating the public trust, because there is no generic product of either. Are we talking about devices misrepresented as generics, like Chondroprotec and MAP-5, or pirated products produced by so called compounding pharmacists.
White: Let’s limit it to those because we’ll cover the devices later.
Doctor’s Stock and Distributorship
McIlwraith: Okay, but having said that, Dr. Mitchell needs lots of betamethasone because as I mentioned before, it’s only one of the two decent options.
Stenbom: So that’s for doctor’s stock.
McIlwraith: So, are you suggesting that he should obtain it some other way? And if so, what is that other way?
Mitchell: Let’s be realistic. In my practice I would probably use 2,000 vials of betamethasone a year easily.
Stenbom: Let’s comment to doctor’s stock, because that is where we kind of start crossing the thresholds in this regulatory thing.
McIlwraith: What is doctor’s stock like--you haven’t answered my question. What does he do? Because the practice that I do, most of my surgery in, probably uses 5,000 doses a year. So you buy--what do you do? What do you tell them?
Bertone: Ordering large amounts of product and letting it sit on your shelf is wrong in so many ways. Clinically it’s inappropriate because you know nothing about shelf life with compounded products. Having drugs sit on your shelf is certainly an indication that you are not following prescription and labeling guidelines, and that your pharmacist is acting as a distributor.
White: Please explain that, we haven’t talked about the distributorship rule.
Bertone: An example of doctor’s stock would be an emergency drug like injectable dipyrone. You can’t make your order for dipyrone when you discover your horse has a 105 fever. Doctor’s stock usually applies to drugs for which the need is urgent. It would be difficult to make the case that betamethazone for articular injection is an emergency drug and therefore can be kept as doctor’s stock.
McIlwraith: Every lame horse, to a sports medicine doctor, is an emergency.
Bertone: That is true, but unfortunately it’s not the doctor or the owner that makes that decision; it’s the prescription and labeling guideline.
Mitchell: And my point with those would be that we would keep products on hand--and realistically we do keep [them] because the fact that [they are] compounded products, we don’t keep very much on the shelf because we are concerned about the very thing you say: shelf life. Because that hasn’t been in any way tested. We don’t really know. So we’re pretty careful about that aspect, but we are in a situation, as I’m sure many practitioners are, where they get a deal, they’re offered a deal to buy x-quantity, and they take it, and then it does sit on their shelf.
Bertone: Compounding pharmacy is similar to veterinary medicine in that quality practice requires knowledge and ethical behavior. In other words, do you know what you’re doing and are you ethical? We have very little ability to measure the quality and knowledge of compounding pharmacy, but we can assess ethical behavior. For compounding pharmacy, that means do they follow Good Compounding Practice guidelines and do they have your client animal’s well being in mind. Some questions to help you identify the ethical behavior of the compounder are: Can you make me Gastrogard, Adequan, or any other FDA-approved product, are your products just as good as FDA approved products, is your injectable sterile, do your products have shelf-lives longer than the prescription duration of treatment period? If the answer is “yes” to any of these questions, hang up the phone and look somewhere else. If they know what they are doing, then they are unethical. If they believe the answer they gave you is correct, then they are unknowledgeable.
White: I’m going to pitch out a quick opinion because Wayne and Rick have made the point that where can we get these drugs. I don’t think any of us, I know I don’t get too upset when a compounding pharmacy is supplying to a practicing veterinarian a product that’s not available anywhere else. I even don’t get that upset about larger quantities of such a drug done the way he’s doing it. Technically it may not be exactly according to the law, but I think it’s something that we in the equine practice have to do because of the lack of availability and we’re going to talk about that lack of availability later as well.
McIlwraith: But Bob made a big point of it, so that’s why I’m asking the question and I still haven’t got an answer apart from you said that, like me, you think it’s okay because it goes even further, which we didn’t mention. There’s eternal paranoia out there due to anecdotal repetition that Vetalog can founder a horse and that’s legally even worse to use. These guys are really stuck with betamethasone and I don’t care what the law says, but as far as what Joe was saying, it’s the law that makes the decision. You have got to be able to inject that joint on that day that it’s requested in a lot of instances. So you need to have it available as well. So I presume there’s some [middle] ground here.
Usually, we’re going to the companies. The profession is going to them rather than them hustling us in that instance. Like when Rick had his reactions or his practice had these reactions, I called someone else who I knew used a lot of compounded betamethasone and I said what company are you using because that’s what we wanted to know, if it was the same company. And they said well we’re using a different company and we’ve been really happy with them, we had some reactions with so-and-so and now we’ve had a good trot with these people. But it was the veterinarian going to the company, for sure.
Mitchell: Well, what I was getting at was that I was also going back to the issue of the practitioner that is in a different situation than myself perhaps, and is really shopping for the best prices on product and so forth. They can perhaps be lured into deals--and I’ve seen those--I’ve seen them right on the floor of the AAEP Convention, much to the disgruntlement of the Board who didn’t even really know what was going on unfortunately.
One of the things I want to know is how many bottles of medication I have seen from various companies, they are dated and they’re post dates, but there is no indication when the products were made.
White: There’s an expiration date.
Stenbom: How can they, if they know it’s illegal to do, how and why do they do it?
Bertone: They do it because they can get away with it and because that’s what veterinarians ask for. If you have a one size finished injectable product in a bottle, it will cost a pharmaceutical sponsor about $100,000 to $150,000 to identify an expiration date. The expiration date on a pharmacy compounded product is supposed to be the duration of the prescription. If you do a compounded script for a horse that is for a 30-day treatment, then the expiration date should be the last day of treatment. As an example, if the drug starts on Sept. 1, 2003, then the expiration date should be Sept. 30, 2003
Stenbom: Specific needs, specific horse again.
Bertone: One well-known drug pirate gave me a bottle of stuff at the AAEP in 1994. It had an expiration date of 1999 stamped on it. That expiration date is a complete scam. That clearly shows that that pirate is unethical or ignorant. I think this pirate was and still is unethical, knows full well what they do, is eager to violate the public trust, cares little about veterinary patients, and is willing to steal from your clients. Is that strong enough.
Stenbom: Back to the original betamethasone discussion. I don’t know if I was clear where I was going here, I am no way in critical of the need of this product or that you are accessing the best possible source you can. The example I made was one of where we start running into problems and threats with efficacy and safety, as we drift into this realm of bulk manufacturing by the compounders. And the threat that I was alluding to there because of the widespread need here, in the absence of an FDA-approved source – here is where the compounding pharmacies are almost being forced, whether that was their original intention or not, into producing these things in bulk. And that is where the big hazard is, that large quantities from the same lot are being distributed. If something goes wrong, it is perhaps more likely to occur with a compounded product than an FDA approved product because of the difference in regulatory oversight. The problem is likely to be amplified when the compounding pharmacies are producing this stuff in very large quantities. And so I bring it up as a hazard.
White: Let’s specifically address our legal risks in the use of compounded drugs. I wonder, and I think Dr. Mitchell’s very lucky to have had the compounder he chose, how many compounders do carry product liability insurance? According to the law, if I’m reading it correctly, when we choose a compounded drug, we are doing so at our own professional risk. Is that not everybody’s understanding of that?
Mitchell: Yes, certainly.
Stenbom: And that is poorly understood by the average practitioner, which is a big, big problem.
Compounding From Bulk Chemicals
White: Let’s talk about some illegal and unethical practices and I wanted you to explain the bulk and the wholesale, resale rules.
Bertone: There is no provision under the law for compounding drugs from bulk chemicals. Under the Code of Federal Regulations Section 500 and on, any time one uses a drug compounded from bulk product they are using a product that is considered adulterated, mislabeled and misbranded.
However, the FDA Compliance Policy Guideline (CPG) indicates that the FDA will use regulatory discretion to allow compounding from bulk chemicals when there is NO drug in an FDA approved formulation for the desired route of administration. This applies to non-food animals alone. What that says is that the FDA will take no action against this activity. There are many other stipulations. The fact that the FDA chooses not to prosecute does not change the fact that it is still illegal.
Markups Are Illegal
Bertone: The new CPG indicates that compounded drugs cannot be distributed to third parties that add a markup. So what that says to me is that if a compounding pharmacy is closed by the FDA, or pharmacy board, because they were selling to veterinarians that marked up the products, then the pharmacies may actually have legal recourse against the veterinarian who marked up the product. Veterinarians are marking up substantial percentages. They are selling the pirated products at the same price as the FDA approved products and in many cases making one and two thousand percent markup.
McIlwraith: So you are saying that if you get a compounded medication, you should never mark it up.
Bertone: You’re not supposed to mark it up.
McIlwraith: Okay, so but it would be okay to charge an administration fee.
White: Professional services fee.
Bertone: What you should charge is a prescription fee. A prescription fee is not 150% of the product’s cost. A prescription fee is the same $30 fee whether the price of the product is $10 dollars, or $1,000. Many veterinarians have found the sale of pirated products an incredible financial boon.
What many veterinarians don’t realize is that it is illegal to use pirated products and their use is by definition the provision of substandard care. No standard of practice finding can overcome the definition. The products are by definition mislabeled, misbranded and adulterated. I wouldn’t want that on the other side of that legal issue.
Mitchell: And I think that is again a very significant issue because I dare say there are very few practitioners that are aware of that regulation because they’re treated just as if they were an FDA approved product.
Bertone: Compounding pharmacies are not licensed distributors.
Mitchell: Exactly, but that’s not what the practitioner is in general doing.
Stenbom: It’s interesting, when I’ve gone out and spoken to groups of veterinarians about this subject and raised this issue of whether marking up the product is appropriate or not, under the umbrella of all these other things we’re discussing, they’re pretty bored really when you start talking about thou shalt not do this and thou shalt not do that. They sit up and take notice when you start talking about the fact that it’s in all likelihood illegal and/or unethical for them to be marking up these compounded products; that gets their attention.
Internet Pharmacies and Telemedicine
White: Moving on to other areas of common practices in small animal medicine, and I’m not sure in equine medicine I’d like to get all your input on it are the Internet pharmacies and compounding pharmacies who are selling directly to owners and trainers--your experiences.
Mitchell: My experiences would say that there are, that there are several Internet type pharmacies and some of these have distributorships at present on the competition grounds. I’m sure there’s one right here at the Hampton Classic and it’s very notable. They do a lot of advertising and they would claim that they always sell with a prescription, but I know many people that buy from them without a prescription, many, many drugs from them. And it is a real problem. And one of the issues is that legitimate products are being sold through the Internet pharmacies as well as compounded products. We’re not really sure how they’re getting those legitimate products, but they’re doing it.
Bertone: Some of the more egregious illegal drug manufacturers and, again, I don’t like to call them pharmacists, often sell directly to clients. In fact, my first experience with this issue was in 1995. A client handed me a bottle of injectable Diclazuril. Over the phone, in a conversation with receptionist at the pharmacy, the client’s horse was diagnosed as having equine protazoal myeloencephalitis (EPM). I guess this is a form of telemedicine. The client was sold the bottle at a cost of $500 with the instructions “your veterinarian will know how to give it.” That is the same outfit that gave me the five-year expiration date I discussed earlier. They are still doing a fantastic business.
McIlwraith: I’m not disagreeing, but tell me how if you get USA Today on a Friday, there’ll be at least three advertisements for “1-800 call and get your Viagra for the weekend.” Seriously!
Stenbom: But the thing is, that’s equally inappropriate and illegal, right?
Bertone: In human medicine, doctors are required to write you a prescription that you can take to any pharmacy, including one on the internet. In veterinary medicine, only the state of California requires veterinarians to write scripts when requested by the client. Clearly, there is no medical value in not providing prescriptions to clients and I would hope that all states adopt the California policy.
McIlwraith: So you do not have to have, because obviously the MD writing it is sitting in some office somewhere in the country, does not know you…
Bertone: You go to your MD and you say you would like to try Viagra, you get the MD to write you a script, and you submit it to the Internet pharmacy.
Mitchell: And you’re saying that these Internet pharmacies do require scripts and that you can’t buy without them.
Bertone: I think most follow the rules.
McIlwraith: That’s why I was bringing it up because some of them say no prescription required. The thing is that in doing that without a prescription, the client-doctor relationship…
White: Let’s remember what a prescription is, it’s for a specific animal and it contains dosage, number of refills, and all this information, and it’s good for that one individual animal or farm, I would suppose.
Bertone: There are legal experts that would argue that a valid client patient relationship can be developed over the telephone with some medications. Clearly, this is not the case in veterinary medicine.
McIlwraith: I get at least 10 emails a week on “problems with my horse’s lameness.” Sometimes you throw them away, but sometimes you end up consulting on a problem outside the veterinarian. Sometimes you get the veterinarian’s advice, but we do that a lot and it’s already being discussed to see as to consulting across state lines. When you don’t hold a license in that state, you don’t know what the legalities are, but it is something that I think veterinarians in the field have a very poor understanding of, as do I. So I sort of thought you implied that telemedicine was a bad word.
Bertone: No. Here was a receptionist who over the phone says your horse tripped in the show ring, it must have EPM.
Enforcing Compounding Laws and Regulations
White: We’re going to talk about who enforces compounding regulations, who should and maybe why it’s not being done and there are essentially I think three regulatory components, FDA, State Pharmacy Boards, State Veterinary Licensing Boards and between these three the job isn’t getting done so we’ll start with Joe and go around the table on who should regulate and what should they do and when should they do it.
Bertone: To be honest with you, veterinarians need to regulate this as a matter of our responsibility to the public and animal well-being. FDA hardly takes issue when compounded drugs are used in food animals and contaminate the food chain. In a recent closure, it took three years of Bayer Animal Health submitting clear evidence that a pirate was providing counterfeit enrofloxacin to feedlots across the Midwest before any action was taken. Rumor has it that the pirate had enough bulk powder called enrofloxacin, made in China, to make $4 million worth of product. They were distributing this to 30 or more feedlots. Therefore, your food and your children’s food was contaminated with this stuff made in China for three years. Not only is that a major food safety issue, but clearly a homeland security issue as well. I really don’t believe that we can expect to see any significant regulation from FDA.
Stenbom: Well, I think in some respects, in the FDA’s defense and looking at this graphically, no matter how frustrating it might be, the FDA, like any other government agency, has limited resources. And I think they prioritize those resources. Obviously they’re number one priority is human health. Their secondary priority would be food animals because of the potential impact on human health. The companion animal issue, just from a practical standpoint of the allocation of resources, I think has to take a back seat and unless specific funding goes there and a specific need is identified, you’re not going to see this. We do have a situation where most of the regulation appears to be directed toward those who wish to be regulated. I liken the regulation of the pharmaceutical companies (the companies that manufacture FDA-approved drugs to FDA standards) to the situation where veterinarians go to the state licensing boards to be regulated. The state licensing boards are perceived by the public as protecting them from quack practitioners and unqualified practitioners, when, in fact, many state licensing boards have a difficult time doing that. I think the same holds true , of course, with the FDA and the compounding products. The FDA is most effective at regulating those who wish to be regulated--those pharmaceutical manufacturers that wish to manufacture FDA-approved products.
McIlwraith: Well a couple of comments. I think I agree totally to what Bob’s saying. My perception is, and I think we mainly talked about the situation as it currently is, regulated by veterinarians. Obviously the big question that gets big is how do we do that? But everything seems to be a reaction. In other words, Bob mentioned the fact that if the state licensing board gets a complaint, they have to investigate it. My personal view is all state licensing’s ridiculous anyway, and that we should be national. And the other thing I see in instances like Bob’s company was involved in when they were getting hurt by compounders or interfered with, or whatever word you want to use, what do they do? They went to the FDA, and the FDA became involved. And that’s probably the only way you’re going to do it. So everything’s a reaction. How do you have a proactive plan? As Joe said, veterinarians are going to have to do it and the main way we can do it is with education. Like this roundtable’s a good example of it and then you get the word out because a lot of people are doing a lot of things totally unknowingly and if the other agencies aren’t going to enforce it, we need to.
Another important issue is the nutraceuticals market and the question is all I’ve asked a hundred times is why doesn’t FDA care about this? And then I’m told well, they do, but they never got a handle on it. And it challenges everything about us. It challenges the ability of the veterinarian to make a diagnosis because he or she is the last person to get consulted. Horses come to Dr. Mitchell and me all the time, but they’ve already gone through several hundred dollars worth of nutraceuticals for want of a better word. And so we should care about, apart from the legalities and apart from the fact that a lot of us are doing things that we don’t even know are wrong, the veterinary-client relationship is getting seriously infringed by some of these other rampant non-licensed use of nutraceuticals I know we get into the medication versus nutraceutical, you know what I’m talking about. So I think that veterinarians should be involved more and can be.
White: What I really say Amen to the education, I think that’s one of the real keys is I think you’ve hit the nail on the head. People, if they don’t know what they’re doing is ineffective or wrong or improper, we can’t expect them to follow rules they don’t know or understand.
Mitchell: I believe it’s a huge moral ethical dilemma, I really do. And I think that it’s great to think that we can have veterinarians ultimately regulate this, but they’re faced with a huge moral ethical dilemma. It’s going to be a very hard thing to convince the young struggling practitioner, who’s possibly having trouble paying his electric bill, in this day and time to not seek what seems to be, at first glance, a good deal, particularly in view of the fact that many of them are ignorant of the current compounding laws, and the difference between compounded and generic drugs and FDA approved medications. They see these as a way to make a viable living, keep their clients happy, everyone’s looking for a bargain, and the only way to get there with them is the educational process.
A perfect example, the symposium that we’re going to have at AAEP this year is an excellent way, and it’s really needed because it’s a misunderstood subject. I really think we need the FDA, and I think the FDA needs to look at itself really hard because it’s difficult for me to understand why legitimate medications can get approved in half the time in other countries. I know we have a high margin of safety and it ensures quality etc., etc., but I do think that there’s product that gets inordinately slowed down, and that’s why in many cases practitioners turn to compounded products. So, I think that FDA needs to look inward a little bit.
White: I think you make a really excellent point and I have to say that I think the way current FDA approval regulations for non-food animal drugs are structured has contributed greatly to this problem we’re sitting here talking about today. Because there are a number, and having been in the pharmaceutical industry, I know this, there are a number of extremely useful equine drugs that would sell one to five million dollars a year. No one is going to invest the time and money to go through the current approval process for that amount of return. It’s just not sensible. Could we structure something like the orphan drug people laws in humans, which says that if less than x number of cases of a certain disease exist a year, then it makes it--greatly reduces the cost and time of an approval.
McIlwraith: Well, I just want to come back to a couple things that Rick’s brought up because when I agreed with Joe on veterinarians regulating themselves, that was purely out of giving up on FDA. I agree with you, they should be doing it ideally, but they haven’t done it. No offense to anything else said here, but all this stuff about half life and source and bulk and everything else, the bottom line is a lot of stuff being sold out there, outside the veterinarian that has no proof of effectiveness and that is still my big beef. It’s almost like we need a sort of intermediate role, like I’d be happy from a practitioner point of view, if we at least had requirements to prove effectiveness to start with. My only reason was for us to do it as a profession because nothing’s happened with FDA.
Bertone: I think educating students is an issue. This problem is not in the university world. In fact some universities support the practice by their ignorance. Universities don’t educate students in pharmaceutics. In fact, many university faculty don’t even know the problem exists. We have to educate university faculty, students, and veterinarians. Unfortunately, I think education may occur sooner in the public domain, in the courtroom, in liability actions, by our clients who will accuse us of selling the public junk and violating the public trust.
I have seen practices build by telling clients that this stuff in this bottle is not generic Adequan, it is trash. I only sell Adequan because your horse is worth it. If you want to buy this (compounded) stuff, you go to another practice. If the client stays with you, you want them as clients. If the client goes somewhere else, that is to your benefit.
Mitchell: Totally agreed and that’s the way we run our practice.
Bertone: You can build a better practice by promoting yourself as the quality practitioner than by giving a client the cheap way out.
The other surface is the FDA drug approval process. Many small products are simply not financially viable. Anything the FDA can do to reduce the encumbrances would welcome. However, the Animal Drug Availability Act, whose intent was to increase drug availability has been scuttled by the FDA. So I would expect no help from them.
McIlwraith: With regard to that culture, something that I had done, sometimes successfully, but commonly not, is to talk to that small company. They haven’t got the money to go through the current FDA process, but I say you know, if we look at it in a controlled study, we can still give papers on it. It’s better than nothing. What I’m trying to do is find out for myself whether it indeed works or not. At least they’re a step up on the others. We try and do it that way by at least having something that we’ve shown to be in a study to be effective.
Bertone: To add to the mix, I also consider unethical, those companies that promote drugs that have no efficacy. No one has ever been able to show any bioavailability of oral abuterol syrup and yet this is sold as a replacement for Ventipulmin.
White: If we don’t make some attempt to regulate this ourselves, there are a number of attorneys who will get wind of this that are hungry and they’re going to say we’re sitting on a gold mine! Look what these dumb guys are doing! And we’re going to get regulated in the courts with liability suits.
McIlwraith: And the important thing is that we’re dumb because a lot of the time these vets are listening to these people. MAP-5 is a great example. These guys are going out, the distributors, and telling the veterinarians it’ll do everything Legend does and it’s safe. And these guys get it and give it because it’s cheaper. Back to the scenario Rick talked about, it’s cheaper than putting in Hylartin or Legend, and so yeah, that’s where it all gets back to education.
A panel on ethics at the upcoming AAEP is going to address this. It is progress. The other side of the attorney thing is how dare you go judge me because I’m going to sue you for defamation, and it stops people from doing the right thing.
Bertone: When you say this, you mean this panel?
McIlwraith: No, there’s a panel at AAEP on ethics and one of the big issues is compounding nutraceuticals.
Mitchell: The title of the keynote speech is The Compounding Conundrum.
McIlwraith: And there is also going to be a keynote speaker, Dr. Bill Brown, who’s an expert in these areas in ethics.
Bertone: And who’s on the panel?
McIlwraith: The moderator is Jim Morehead, and panelists include Andy Anderson, Tom Brokken, Bill Brown, Nancy Goodman, Charlotte Lacroix, Midge Leitch, Rick Mitchell, Scott Palmer, and Bill Moyer.
Off-Lable Uses of Drugs, and Illegal Uses of Medical Devices
White: This is a good time to bring up the subject of off-label use of medical devices and supposed nutritional supplements as drugs. We have talked about Map-5 and Chondroprotec, which Map-5 is a preservative for semen, it’s an HA product, Chondroprotec is labeled PSGAG, which is the drug that is in Adequan. It is not PSGAG, it’s chondroitin sulfate and it’s labeled as a topical wound dressing. Both are openly promoted as generics of Legend and Adequan respectively. For many years we’ve seen nutraceuticals principally glucosamine and chondroitin, which are being sold as “oral substitutes” for Adequan or Legend. I’d like to go around the table and talk about, is this ethical to substitute these and tell our clients that they’re getting a “generic Adequan.”
Bertone: It actually is not extralabel drug use. There is no provision in the law to use these products as drugs because they are approved as devices, not drugs.
McIlwraith: That was my question. Tom Lenz pointed that out in a memo to the AAEP members and I’m quoting here: “However, drugs that mimic FDA approved drugs cannot legally be compounded.” Does that mean they cannot legally be given as well?
Bertone: We are discussing Map-5 and Chondroprotec. They’re not drugs because they’re approved as devices.
Bertone: They are approved as devices, not drugs. The Animal Medical Drug Use Clarification Act provides for the extralabel use of drugs. It does not provide for the extralabel use of devices as drugs. Map-5 and Chondroprotec are registered as devices.
McIlwraith: Didn’t you say it was just not illegal because they’re devices?
Bertone: Extralabel drug use only pertains to drugs. For instance, under the Animal Medical Drug Use Clarification Act, Naxcel, which is approved for respiratory disease in adult horses, can be used for peritonitis in foals. That is extralabel drug use.
McIlwraith: I understand that. I’m getting confused with the use of the word “legal,” and the only reason I’m not as confused over “devices,” as Dr. Mitchell said, is because I got informed by Gary and Bob yesterday that a device does not affect any other cells in the body.
The fact is, it’s a joke to characterize HA or something like that as a device, because obviously they are taken up by cells. They certainly act on receptors on the cells. So this is really an important point. I thought I heard you say because it’s a device it’s not off-label use.
Mitchell: He says it’s not off-label, he’s not implying that that makes it okay.
Bertone: I’m saying that you are not protected under the law when you use a device as a drug.
McIlwraith: Yes, but the take home message is that if a veterinarian gives MAP-5 and tells the client this is generic Legend and that it’s the same as Legend, that’s illegal.
Bertone: That is illegal. You have no protection under the law for doing that whatsoever.
McIlwraith: But some of these things have not even gone through approval as a device, and how can you say…
Bertone: Well here we’re talking about Map-5 and Chondroprotec.
McIlwraith: They are both listed as devices. So how did Chondroprotec get licensed as a device?
White: It’s a human topical wound dressing. Map-5 is a cryopreservative for semen and they’re both approved as devices, and there’s no approval requirements…
McIlwraith: That’s a wound dressing that they call the Chondroprotec.
White: A topical wound dressing, yet it comes in a sterile vial with a rubber stopper. Beside that, there is absolutely no evidence that they are effective or safe. In fact, we have evidence, just published evidence to the contrary, that they are not effective.
McIlwraith: Where is that published?
White: The Journal of Equine Veterinary Science, July 2003 issue. Chondroprotec is labeled as a polysulfated glucosaminoglycan, (PSGAG). But PSGAG is actually an approved new animal drug, marketed as Adequan. The molecule in Chondroprotec is actually chondroitin sulfate, and is approved by the FDA as a device. It is not the same molecule as the one in Adequan, and this latest clinical study shows that Chondroprotec is not nearly as effective as Adequan. What’s more, Chondroprotec should not be called a PSGAG, because Neogen (its manufacturer) got it approved as a device.
McIlwraith: Well, that is something that education could do a lot for. Because, going back to the scenario of the vet that’s having trouble with his electricity bill, or her, if they also know that it’s illegal, I think that helps them make some other decisions as well.
Mitchell: Well, I totally agree and I think, certainly for me, it’s very clear. There is an approved product to use. If I have a problem with that product, I have a large pharmaceutical manufacturer behind me to say that--to investigate it, to make sure that it indeed there could have been a problem with the product or whatever. I’m providing the highest known quality product for my client and it’s a no-brainer to me. And if they don’t wish to have those products, then as Dr. Bertone alluded to earlier, they can go down the street and get it from somebody else, but they won’t get it from me. And that’s really the way I feel about it. And I actually feel the same way about a lot of the nutraceuticals, too. There’s a few of those, actually there’s only one that I think has really shown any kind of data at all that they might have some efficacy; the others, I don’t recommend them, I can’t. There’s no substantiation for them whatsoever.
Bertone: One thing that needs to be understood as well with things like Map-5 and Chondroprotec, is that neither one of them fall under drug Good Manufacturing Practices for drugs, so they are little more than pirated compounded products
Bertone: Basically there you have no guarantee whatsoever that those products are any better than a product that would be compounded in a pharmacy.
McIlwraith: And the interesting thing there is that’s where I think that we could, well I’m using the royal “we,” but the veterinarian profession could do something about it. It’s one thing if I was smart enough to figure out that cheap HA exists as a cryopreservative and was HA and I found out what’s it’s made of and the weight was, and I decide to put into joints. But it’s a totally different thing to have their sales force going out and promoting it as an intra-articular treatment, which is obviously illegal. So can’t we turn around and get a cease and desist letter there?
White: That has been tried.
Bertone: Well, as I mentioned to Gary, I think the approach should be to go to Devices (at the FDA) and not to Center for Veterinary Medicine.
McIlwraith: So if you say you tried, can you talk about that?
White: FDA has essentially told us yes, this is illegal, we know that it’s illegal, it’s not a priority, we don’t have the money to enforce it. That’s basically what we’ve been told, is that not basically true?
White: They don’t consider it an immediate hazard to the health of the animal served and treated. Maybe we could attack it from that direction, but they essentially said yeah, we know it’s illegal, but we really don’t have time.
McIlwraith: So it’s like getting a traffic light and someone needs to die first. If they kill a horse with it, then…
White: Then it’s a threat.
Future Drug Development
White: Do you think that the proliferation of compounded drugs and the illegally used or unsupported nutraceuticals and medical devices will have an effect on the future development of drugs for equine medicine?
Stenbom: Well, that’s a tremendous concern of mine and I think I can speak for the pharmaceutical industry as a whole. You know it used to be when you were making decisions about whether to move forward in the development and approval process with a pharmaceutical, whether to invest the money, what you were really looking at was what your probability of success for approval was, how long it would take for you to get there and how much of an exclusivity of patent you would have left over at the end of that process to recover your costs. Today, I think we’re faced with not so much that issue, but the issue of how long will it be after you get approval, these other things aside, before somebody starts “renegade manufacturing” the product. I have heard through the industry grapevine, that there have been some very interesting products not pursued in recent years just because of that issue. And I think more than anything else, this is perhaps what’s got the FDA a little more interested now than they perhaps have been in the past. There may not be anything for CVM to approve as time goes on. And I think this is a big problem. And I think if we look at most of our lifetimes here in veterinary medicine, and we’re all pretty contemporary sitting at this table, when we first came into the profession, most of the animal health companies were subsets of a larger human pharmaceutical parent. And a lot of the new drugs obviously came from that parent. We were almost stepchildren of those parents and we got a lot of things that we didn’t have to really develop ourselves, at least not initially--the initial discovery. Today that is not the case. Many of the larger pharmaceutical companies have divested themselves of their animal health interests, we’re kind of going in on our own and we have to make our own way in discovery. And it’s become an expensive, difficult and lengthy process and I think the threat of renegade manufacture subverting the drug approval process is going to further aggravate this issue.
McIlwraith: We’re already there. I agree with Bob because I know it’s not just hearsay, I do know of medications that are really promising that companies don’t want to spend the money on to get them approved. I think there’s a number of aspects to it and just quickly be summarizing, and some of this repeats what Bob says, there’s no incentive to prove efficacy with all the oral nutraceuticals. I know; I’ve actually heard it stated by some of them, they’re just here for as long as they can go. They don’t want to do a controlled study because it may be shown to be less effective or not effective and therefore their market’s dried up, at the moment they’re doing well. They’re selling product, people are buying product. There’s a terrific market out there and these people are doing it. And yes, I tell clients that it’s far better to spend their money on Adequan than an oral nutraceuticals, but there’s a lot of people doing it. And so we just got a total discouragement of proof of efficacy, that’s one frustration. As a clinician, that’s obviously a frustration because I don’t know, and I get asked every day, it would be no exaggeration to say at least one person per day asks me about do they work and we don’t know. I want to have a proven product. As a researcher I can only speak to the medications that have been legitimately assessed and we’ve either done it or it’s in the literature from another lab. It’s just a big black hole, but the bottom line is we want to have approved medications, we want to have better medications, and we’re already there as far as discouragement for the companies to put the money in.
Mitchell: I’m very concerned for a lot of the same reasons that Bob and Wayne both stated. I feel today that we as practicing veterinarians are going to have a dwindling source of legitimately produced drugs. The market is small and the cost of proving the efficacy and safety in medications is high and I think the compounding situation is doing a great deal to threaten further research and development of products. This is one of the reasons why we need to be very careful in our selection and use of them.
Bertone: I think it’s already happened. I think we’re already well beyond that point as everyone else has alluded. The reality is that the greatest boon to quality medicine in this century was the Food, Drug and Cosmetic Act.
This drug piracy problem is clearly the devolution of veterinary medicine. It overrules all the achievement of the FDCA and removes public protection through the veterinary professions ignorance and avarice. We are heading back to 1800’s. If we want to move forward, we need to support legal, scientific and ethical behavior. If the profession intends to move backwards, then we should support nutraceuticals, drug piracy and other unethical, unscientific, and illegal actions that violate the public trust.
White: I think we all agree on that.
The Role of AAEP and Professional Associations
White: What is the role of the AAEP in these particular issues and has the AAEP in the past been effective in getting this message out?
McIlwraith: I’m a past president of AAEP and Dr. Mitchell has been on the Board of Directors. The short answer to your question, or the last part of your question is no. I think in the past the AAEP has not, and that’s not a self-criticism because I think it’s just that things come up as they come up and get prioritized. It’s an issue that is being discussed before an ethics panel coming up in the November meeting in New Orleans. It’s been a pet peeve of mine for a number of years. This panel is actually the results of a process that started a few years ago with an ad hoc committee on ethics that I appointed and was then turned into a standing committee because of concern about all those issues.
There are two other parts to this. The first one is AAEP’s education systems. Neither Rick nor I are now on the Board, but I don’t think anything’s changed, you’ve got the article by Dr. Lenz, which was in the newsletter in the last year, which is a good example of trying to educate the members, so I penned a statement on why you should use FDA approved medications for the same purposes--for education. Because education is key. It’s going to be at least 90% of the solution I think. So AAEP’s doing that.
Now there’s another area that AAEP, and it was sort of alluded to by you before, and that is the fact that we have compounders exhibiting at our trade show. First of all, we’re relatively young and naive when it comes to trade show, because it’s so big people don’t recognize that it is relatively young. It was not allowed for the first 30 years of the annual meeting. A lot of people would be surprised at that now when you see what’s it become. And the bottom line is it was only when we went to a new system and new Executive Director that we had exhibits and, of course, now it’s become--and it is a major--we couldn’t do without our exhibitors; we couldn’t have the meeting, the AAEP membership fees would be huge. But, we have had members come to us concerned, and I think Rick was on the Board when I was President Elect, and at that time someone had, we had received some question as to why do we have those exhibitors in there. And the bottom line is that if you talk00and maybe it was a mistake to talk to our attorneys, but it’s all another can of worms if you try and exclude someone from a trade show. But we do have that right and we have done it. And there was00they remain nameless00but there was one company that we would not allow exhibit based on what they were exhibiting to be inappropriate. And there’s a lot of overlap between legitimate compounding as we sort of talked about with the betamethasone issue and less than legitimate. So my personal opinion is yes, we have some real concerns, but there’s a lot of other--it’s not just an AAEP issue, it’s a veterinarian issue. There’re AAEP members as individuals involved in some of these practices. I think the AAEP is very aware and I’ll ask Rick to comment as well on the difficulties there. And it’s been thrashed out at the Board level.
Mitchell: Yeah, I think I agree with what Wayne has said and I think that the primary focus in AAEP is education. That’s the primary focus of the organization. And the trade show is education and it’s wrong to exclude those compounding pharmacies that are truly legitimate that are providing a service and to, I think, to avail the veterinarian of the opportunity to interact with them. So I think that there’s a real reason for those companies to be represented in our trade show. What happens is that they get a little out of hand, some of them, and they start advertising and making claims for products that are just blatantly not correct and illegal. I believe that the AAEP could respond to practices like that are discovered when they are discovered, and the offenders asked not to return. But it’s all a developmental process, I think, and in this case a process for the organization as well as veterinarians involved. The demographics in our organization are changing so dramatically as far as the nature of who the equine practitioner is, how they practice, what sex they are; it’s really changing profoundly and what people expect from drug companies and pharmaceutical companies is changing. We need to stay on top of that and I do believe AAEP is really making an aggressive effort in their strategic plan right now to put education on a high priority and we need to continue.
McIlwraith: With education the veterinarians can challenge these people. It’s not like they’re just there--no one refereed. You’ve got your educated members, they can go down there and challenge them to a lot of these things because a lot of the time you’ll talk to that person who’s not a veterinarian, he works for the company, they’ve just been fed a line to go out and sell and they don’t understand the other things. And most of them are really decent people; they want to hear the other--they want to know as much as they can. And so they’re educated, they’ve got degrees, they can understand the other side of the point. So I think you get a lot of good exchange. And I think that--but it all gets back to education because we have a great spectrum, you can never generalize with a veterinary profession as with any profession in naiveté, because--if they have been exposed to it as we talked about it before--they haven’t got it in school, they’ve gone out into single person practice and they haven’t got it in practice and yeah, it’s--I think things are going to change in that regard.
Bertone: All bulk compounding is illegal. Clearly, some of the large CE meeting’s lawyers have not really looked at the law. If you wanted to remove the illegal compounding pharmacies, you could. Clearly the responsibility of these meetings is to educate. At the AAEP last year, the vast majority of pharmacies present were promoting sales of pirated drugs. That was just a walk through. No real deep and detailed investigation. Under the table handouts listing the availability of clenbuterol, enrofloxacin, Legend, etc., were common. They would actually use the word “Legend.” The claim was they can make it. That is a lie.
Too many veterinarians assume that since it can be sold at the AAEP, the AAEP endorses the action.
I’ll be frank, I have recommended that the pharmaceutical firms, in unison, boycott all the meetings that do not support good clinical medicine. I find drug piracy a tremendous threat to the practice of veterinary medicine and our position in the public eye.
McIlwraith: I hope I didn’t insinuate that it has any value to me.
Bertone: No, I know that.
Mitchell: If, and correct me, Wayne, if I’m wrong, I’ve not heard of Bayer, Luitpold, Boehringer Ingelheim, and whomever, coming to the Board of the AAEP and saying look, this is going on. This is blatantly illegal and telling us that this is an issue. We can’t exclude them unless we have substantiation for that, I don’t believe. And we have that substantiation, as you say, I agree with you, what you’re saying obviously is offensive to the other companies and to the veterinarians themselves and it is perceived as being endorsed. And if that’s the case, then we need to be aware of it, but if we’re not aware of it, you know, it’s…
McIlwraith: I need to answer that question first. As far as I know we have had one company come to us to talk about that specific area. Bob was there, and it was at a meeting in 2002 Tahoe.
Mitchell: That was on Clenbuterol, right?
McIlwraith: Yes, and they asked for some advice. They didn’t come in a threatening role, they came for advice--we’ve got a problem, we had a good talk and they went away and solved their problem. I don’t want to imply that we solved their problem for them, but they solved the problem. One thing AAEP can’t do is let one exhibitor chuck out another exhibitor or influence you to chuck out another exhibitor or your integrity goes out the window. We’ve discussed all this, don’t worry, we’ve been there because it has been proposed at the Board level that we should just throw them all out.
Mitchell: But they haven’t been challenged by a group of the major industry players.
McIlwraith: And the thing is that I have been only slightly less impassioned about is why we have an ethical initiative. I often hear we’re just a membership organization; we’re here to serve our members; we can’t go out and make waves because we can’t afford a legal suit. Some of that is true, but we still need to do the right thing. Even though it may not be apparent today, we’ve come a hell of a long way on this issue as far as doing something about it.
Mitchell: Another of the problems is educating the membership, because I can promise you if we had a trade show that didn’t have the compounding pharmacies, the membership, currently as it stands, would be outraged. And I’m not saying that’s right, I’m just saying that’s the present state of affairs and they need to understand why they shouldn’t be outraged, perhaps, but they would be.
McIlwraith: I’d also be outraged because, going back to the start of our discussion, we’ve got to have betamethasone. Joe’s contention is, well, you need to make some sacrifices because of these other things. But if we didn’t have betamethasone, it would be serious. The “NAHMS Study” says around 60% of equine problems that we treat are lameness and the majority of those are joint disease. Corticosteroids have not been supplanted.
Bertone: The compounding pharmacies need to sign a statement that says they guarantee that they follow the Compounding Policy Guideline, and if they fail to meet the requirements as deemed by the CE meeting police, then they will pack and go and never return.
McIlwraith: I’m okay with that…
White: One of my own experiences, one of your predecessors as an AAEP President, Joe and I went through the exhibit area, this was several years ago, and made a list of who was doing things that are legal and what they were doing illegal specifically and I typed it up and sent it to him.
McIlwraith: Well, what did he do with it?
White: Nothing, that I know of. Even if we don’t kick them out, even if we merely say look, you’ve got to stop promoting this or you’re gone. Even a warning…
McIlwraith: Rick made the comment you go and look at the first paragraph, wherever the program chair has his introduction. I read Dr. Bramlage’s introduction on the plane, and he reiterates that our number one purpose is education of our members. In every strategic plan or every survey we’ve done it comes back as that’s the number one thing--the members want to be educated. We need a distillation of what we’ve talked about today. If we turned around and said these products, such as MAP-5 and Chondroprotec are illegal as they are being used; that in the newsletter would be huge. You could eliminate a lot of the problems because none of these people have a gun to their head when they buy them. And we turn around and we can do it through education rather than confrontation. That sounds like a politician, but…
White: That’s education, too.
McIlwraith: But I think you can do it with education. I think if we just tell our members, they’re smart enough that with the appropriate education, they can make the selection themselves and obviate the problem. And I have no disagreement with, if you’ve got someone selling clenbuterol, they should be right out of there, I agree. And I don’t think that’s asking too much.
Bertone: That would not be unwise, either, is to have a list of drugs that you were not allowed to promote.
McIlwraith: No, I think we just need to have a list.
Stenbom: It needs to put together by somebody other than those of us from the pharmaceutical companies. Somebody’s got to be the legal and regulatory arbitrator on this. I think that’s one of the problems. Rick, I can assure you that at last year’s AAEP, there were a number of major pharmaceutical manufacturers upset about compounding pharmacies promoting renegade and inappropriate formulations in the exhibit hall. I know our management was very upset during the AAEP meeting last year and brought the AAEP’s administration into the discussion at that time as well as following the meeting. Whether that was brought to the Board or not as an issue, I don’t know, or if it’s just being thought about. I can guarantee you there has been considerable communication on this issue and that it will come up again in the future.
McIlwraith: Last year’s Board meeting was my last Board meeting and yours, too.
Stenbom: Some of the major exhibitors were to the point where they were discussing not exhibiting if compounding operations engaged in illicit drug manufacture were allowed to exhibit at the AAEP.
McIlwraith: When you’re talking about majors, you’re talking about major pharmaceutical companies, right?
Stenbom: …yes, and we’re all sitting there saying what are we doing this for? I mean, there are all kinds of illicit formulations being promoted openly or being dealt under the table so to speak. My boss looks at our company as an educational partner and a major exhibitor. She was getting militant about it!
Mitchell: He did come to the Executive Director with it.
Stenbom: Yes. And to the point where we even got a--there was considerable interchange after that point. But the problem I see is AAEP can’t police it, unless you are completely educated in all the legal aspects. I wouldn’t, if I were in your shoes, take the company’s word for it necessarily, even though we may be absolutely right, you really need a lawyer and a regulatory person going around consulting you as to--where you could put yourself in a liability position. I understand why it’s difficult for the AAEP to police this thing.
Now, back to my comment about the AAEP and the educational effort and what they’ve done with this. I think it’s important to realize that where we’ve seen the AAEP really do a lot of things lately, I think a lot of people say well, why is it taking so long? Well, I think it’s been a very quick response. Remember, we’ve already stated today that this compounding industry is a very new industry and if we haven’t stated it, I’ll state it right now. It’s proliferated greatly, it’s grown at a fantastic rate over the past few years, and I think the AAEP has just really in the last couple years become aware of the downside of this and I think their response, both in working with individual companies like my own, as well as recognizing the need for an educational effort has been very good. I think it needs to be continued and I think it can be expanded. However, I don’t think they can rely on the FDA to regulate this issue, or the State Pharmacy Boards or State Veterinary Licensing Boards. That’s not going to happen. I think we have an opportunity from the educational standpoint as a team to educate the practitioner. The AAEP is just part of that team effort, because we’re all pulling in the same direction here, to better the profession or maintain the integrity of the profession, but the AAEP shouldn’t have the sole responsibility of education on this issue. They’re extremely important, however, the AVMA also has to be involved and I think they’re becoming more aware. I believe those of us in industry have a role, and a number of us are working on the educational effort by sponsoring speakers and educational initiatives. Luitpold is doing a phenomenal thing in the way of education with this round table--groundbreaking as far as I’m concerned. The media has become more aware of this. Fortunately in a non-threatening way, in an educational way. Publications like The Horse have tried to address this issue for the horse owner and the veterinarian. And again, I say if we don’t educate there, we’re going to get media and legal play that’s almost regulatory. The last educational piece of the team is one we often overlook in this discussion. And that is what I call the legitimate compounding pharmacies. Those with a mission to do things right. They’re trying to do things in appropriate fashion and I can tell you from having them in my audiences when I’ve spoken on this subject, that they are as with us on this subject on illicit compounding and renegade drug manufacturing and drug piracy as the other constituents are. They do not like the illicit compounding pharmacies and they are very much in favor of this educational effort as well.
Bertone: I’m going to speak to them in Nashville in September.
Stenbom: We have to emphasize, compounding is an essential part of veterinary practice. I can hardly imagine an equine practitioner who doesn’t compound every day, even though they don’t realize they’re compounding and that goes to the fact that they’re not familiar with the regulations. But every time a veterinarian makes his tranquilizers, sedative, anesthetic combination, they’re compounding! And that’s appropriate compounding. And that’s really I think what compounding was always meant to be; taking FDA approved drug substances and either combining them for a specific need or altering one of them in some way to fit a specific need. This has all been – this is where the illicit part has taken off. And this is where the regulatory void has allowed the illicit compounders to kind of twist and turn things around for their own devices. But that’s really the intent and that goes back to an unanswered question of the names. And Wayne, when we were talking about the off-label drug use, brought up the couple of sentences in Tom Lentz’ guardian article about manufacturing from bulk substances. Basically, as I see it, all this compounding was really meant - originally meant to involve taking an FDA approved substance and changing it to fit a specific need for a specific situation. This bulk thing is coming through the back door and is basically inappropriate. And one of the best ways you can tell if you’ve got something that’s legitimate or not legitimate is if it costs less than the FDA approved product it’s probably renegade. Technically with a lot of these things they’re supposed to be starting with FDA approved product and modifying from there. And that’s what’s being referred to there rather than the off-label issue. But that’s really the heart and soul of a lot of this and all the rest of it. You know, changing the administration, which was originally thought of to be for an adult medication that they need in a pediatric form, being it human or veterinarian. It’s small animal medicine, something labeled for the dog, but they want to use it in an iguana, that type of situation. The illicit compounders have gone at it backwards and manufactured from bulk substances finished products that are in a different dosage form or a different concentration than the FDA approved product and have passed that off as legal. And that’s not at the heart and soul of what I understand as legitimate compounding.
Bertone: The law is not adequate. For example, some people would argue that flunixin meglumide at 125 mg per cc is OK. Or the mixture of Omeprazole with BSS gets you around the law. Clearly that is skirting the law and the intent, and appropriate clinical practice and compounding pharmacy.
McIlwraith: Just to finish it off on Bob, AAEP can do a lot for you. As members of AAEP, you have a right to ask the AAEP governing body to have an ad hoc committee or set up guidelines. We have position statements on some things and not on others. We generally, for a number of reasons, want to minimize the number of position statements we make. However, I think it’s quite appropriate for AAEP to draw up a list for the membership of things that are illegal or inappropriate or whatever. I predict that will happen. I’m going a lot further than what Tom Lenz has done and what I did and being more specific because I’ve learned a lot today and I know that there’s plenty of people out there who don’t know either. So that’s really important, because our members get battered from all sides. You’ve got the so and so Grand Prix and so and so stakes races. In people’s eyes, that makes them a legitimate drug. I know it’s a big stretch from a horse race or a Grand Prix, but it makes them legitimate. And we just need to get the real word out there and I think you can convert a lot of people pretty easily.
White: Thanks to all of you for your participation. I think this has been a wonderful experience.
About the Author
Kimberly S. Brown was the Publisher/Editor of The Horse: Your Guide To Equine Health Care from June 2008 to March 2010, and she served in various positions at Blood-Horse Publications since 1980.
POLL: Horses Living With Livestock