The compounding controversy: what veterinarians should know to protect themselves and their patients.

Abstract

While the controversy over compounding for animals is contemporary, the practice of compounding for animals is not. Pharmaceutical compounding is an ancient art and science. Compounding has been an integral part of the practice of veterinary medicine since the first cures were blended together to help an animal patient. Skilled healers have utilized compounds for both human and animal patients for thousands of years.With hundreds of species requiring treatment and dozens of new diseases emerging, the half-life of truth in veterinary medicine is particularly short. As a result of a complex and lengthy approval process, the veterinary pharmaceutical industry can never be expected to adequately supply labeled products to treat every disease encountered in every species. Consequently, in order to provide state-of-the-art veterinary therapy, the veterinarian must frequently alter commercially available dosage forms to meet needs for individual patients. This activity is defined as compounding by the major veterinary drug regulatory agencies in North America, the Canadian Bureau for Veterinary Drugs (BVD) and the United States (US) Food and Drug Administration Center for Veterinary Medicine (FDACVM). In some cases, as with potassium bromide and cisapride, there are no commercially available products for any species, and these life-saving therapies must be compounded from raw chemicals. Often, the safety of the caregiver also depends on the ability to get medications into the animal in the least invasive, most palatable manner possible. Compliance is paramount in achieving successful therapeutic outcomes, but many owners will not administer unpalatable or invasive therapies if they perceive that their pet will “hate” them as a result. Compounding based on individual patient need is an ageless solution for all of these problems.There is little argument that compounding is both necessary and beneficial in treating veterinary patients. A recent glimpse at the Veterinary Information Network1 (VIN) message boards revealed at least 300 different chat sessions between veterinarians regarding compounding or compounded products. The emergence of compounding-only veterinary pharmacies also indicates a high volume of compounding currently being provided for animals. A search of the Internet reveals hundreds of Internet pharmacies offering compounding services for animals. Compounding is, without a doubt, a well-established component of veterinary therapy. Unfortunately, some irrational and dangerous compounding has occurred; the majority has occurred due to naiveté, and a small fraction is a result of greed and a blatant disregard for the law. Because the FDA has received so many complaints about illegitimate or dangerous compounding, Dr. Steven Sundlof of the FDACVM recently stated that veterinary compounding and controlling Internet pharmacies were two of the top issues to be addressed by FDA in the coming year.2 Both the FDACVM and the Canadian Bureau of Veterinary Drugs recognize the need to compound curative treatments for veterinary patients and are committed to facilitating safe and effective use of compounds in animals. Interestingly, in the US, the reversal (in April 2002) of the Food and Drug Administration Modernization Act of 1997 caused compounding for humans to become technically illegal. Currently in the US, veterinarians are the only health care providers that can legally utilize compounded products in their nonfood-producing patients. In Canada, restrictions are less specific, but the use of compounded drugs is clearly considered to be extra-label, and use is allowed under extra-label regulations.In spite of well-established need, the regulatory environment for compounding for animals does not completely support the practice. The disconnection between regulatory agencies and compounding for animals arises from three major factors: 1) danger to human health (through direct exposure, through induction of bacterial resistance, or through contamination of the food chain); 2) harm to animal patients from irrational compounds, and 3) the proliferation of compounds that are imitations of commercially available, approved veterinary products. The veterinary pharmaceutical industry has little incentive to spend millions of dollars on the approval process if “me-too” compounds prevent a return on their investment. In 1993, FDACVM was concerned enough about these issues that it formed a Task Force on Compounding for Animals to examine the problems and make recommendations. That effort resulted in the current Compliance Policy Guide for Compounding for Animals (CPG 7125.40).3 Although compounding was technically illegal at the time, the CPG recognized the need for certain types of veterinary compounding and allowed FDA inspectors some latitude in enforcement. For example, a veterinarian would not be cited and fined for compounding a liquid suspension to be used in a small exotic patient, but he would be fined heavily, and perhaps prosecuted, for compounding a drug that resulted in a violative drug residue in a food-producing animal. To further facilitate enforcement of legitimate compounding for animals, the Animal Medicinal Drug Use Clarification Act (AMDUCA) was passed into US law in 1994.4 This landmark legislation allowed veterinarians to use drugs compounded from approved products in nonfood-producing animals as long as the veterinarian-client-patient relationship (VCPR) was present, and if harm or suffering might result without the use of a compounded therapy. The compounding CPG and AMDUCA also cautioned veterinarians to use professional judgment when determining whether to compound within the veterinary practice or to utilize the services of a compounding pharmacist. The compounding CPG notes that the compounding services of pharmacists should be utilized when the complexity of compounding exceeds the veterinarian’s knowledge, skill, facilities, or available equipment. The AMDUCA and the compounding CPG attempted to define boundaries that would ensure the usage of safe, quality-assured compounds in animal patients.While the laws regarding use of compounded products in animal patients have become clearer in the last decade, some major gaps still exist between reality and regulation. Compounding for food-producing animals is still illegal in the US. However, life-saving antidotes used to treat livestock herd poisonings are only available as raw chemicals that must be compounded prior to administration. Compounding from raw chemicals is still illegal in the US; but as with livestock antidotes, life-saving therapies such as potassium bromide and cisapride are only available as raw chemicals. (Imagine the consequences if veterinarians were not allowed to utilize potassium bromide for canine seizure disorders!) The AMDUCA and the compounding CPG both require that a VCPR be present and that compounds only be made pursuant to a prescription for an individual animal at the time of need. Apomorphine is no longer commercially available, and as an emergency emetic, it is hardly practical to expect the prescribing and dispensing process to work efficiently enough to allow administration at the time of need. The caution to utilize a compounding pharmacist for complex compounding is warranted, but does the average compounding pharmacist know enough about veterinary physiology, pharmacology, and toxicology to provide a compounded therapy that will have known safety and efficacy in the target species? Conversely, the average veterinarian has no knowledge of pharmaceutical chemistry and compounding techniques, and most lack the equipment and skills to provide a quality-assured product. Obviously, successful veterinary compounding will come only through partnership between the two professionals. Advice regarding the decision process employed by veterinarians to use a compound is beyond the scope of this article. However, when the veterinarian does, in his or her best medical judgment, decide that a compounded therapy is warranted, several measures can be taken to strengthen the likelihood of a successful therapeutic outcome and lessen the risk of regulatory action. The year 2002 was an exciting one for compounding legislation, and 2003 will probably provide many new dots in the regulatory time line. But until the controversy between practical and legal compounding is resolved, it is advised that veterinarians observe the following eight cautions when choosing to use a compounded therapy.The majority of veterinarians and veterinary technicians are not trained in pharmaceutical chemistry and compounding techniques. Drug integrity, stability, bioavailability, and efficacy are highly dependent upon a solid pharmacological knowledge base, skilled technique, and sophisticated equipment for preparation. Only properly trained persons should compound medications. Not even all pharmacists are adequately trained in complex compounding techniques. When choosing a compounding pharmacist, the veterinarian should attempt to discern appropriate credentials. If the pharmacist compounds complex dosage forms (e.g., sterile products, transdermal gels, medicated treats), can he produce evidence of specialized compounding training? If the pharmacist claims to be a veterinary pharmacist, what training or certification allows him to use this title? Does he appear to have knowledge regarding veterinary physiology, pharmacology, and toxicology? Fellowship in the International Academy of Compounding Pharmacists5 (IACP) is an excellent indicator of quality of practice and compounding ability. Fellowship in the IACP demands a rigorous credentialing and continuing education process with adherence to the highest standards for compounding pharmacy. Membership in the Professional Compounding Centers of America6 (PCCA) also provides the compounding pharmacist with a vast network of compounds, formulas, training, and equipment, as well as support by dozens of specially trained pharmaceutical compounding consultants. Fellowship in the American College of Apothecaries’ College of Veterinary Pharmacists7 (ACVP) also indicates a strong commitment to the practice of veterinary pharmacy. Fellowship in this organization requires adherence to 23 standards of professional and ethical integrity; ACVP appoints regional directors who conduct site visits to ensure adherence to these standards. Qualified veterinary consultants are also available to support fellows of ACVP. All three of these organizations have membership networks in both Canada and the US and provide excellent programming to educate pharmacists in areas of compounding for animal patients. Veterinarians should also schedule a tour of the compounding pharmacy to obtain visual assurance of quality and appropriate facilities. The compounding laboratory should be orderly and clean and should have a horizontal-flow laminar hood if ophthalmic and other sterile compounds are prepared. The pharmacist should be able to produce policies and procedures supporting quality assurance measures and should be able to provide evidence of stability for compounded products. Appropriate licenses and permits should be displayed, and there should be a legally appropriate ratio of pharmacists to technicians as required by state or provincial pharmacy boards. If the pharmacy has a veterinarian on staff, there should be an inquiry as to the purpose of employing the veterinarian. It is not legal for a staff veterinarian at a pharmacy to authorize prescriptions for a patient unless he has a valid VCPR with that animal.All pharmacies must be registered with the state or provincial board of pharmacy in the state or province to which they ship drugs. It is not the veterinarian’s responsibility to determine registration status, but veterinarians can be reasonably assured of proper registration if the pharmacy is located within their own state or province. One area of compounding that is considered highly actionable by the FDA is a “disproportionate quantity of compounds” being dispensed out of state. Distance undermines appropriate surveillance and monitoring that should occur within the VCPR, and climatic conditions during shipment can result in significant drug deterioration prior to administration. It is much easier to determine the storage conditions for medications picked up at a local brick and mortar pharmacy than for those that have been shipped across state lines. It is also difficult to verify the credentials and facility if the pharmacy is remote. It is particularly difficult to verify the legitimacy and quality of an Internet pharmacy offering veterinary services. The pharmacy may not truly be a licensed pharmacy at all and may be an illegal distributor of drugs. The National Association of Boards of Pharmacy’s (NABP) Verified Internet Pharmacy Practice Sites8 (VIPPS) stamp of approval for Internet pharmacies only applies to human pharmacy services. The American Veterinary Medical Association (AVMA) is currently working with the NABP to establish a veterinary VIPPS verification, but this has not yet been accomplished.Another area of high regulatory priority for FDA is the compounding of imitations of veterinary-approved products. In addition to the disincentive this causes for veterinary pharmaceutical companies, the safety, efficacy, and disposition of these imitation products cannot be guaranteed for the target species. Imitations of approved products can only be justified if there is demonstrated sensitivity to one of the excipients in the approved product or in emergency situations when the commercially available product cannot be obtained fast enough to initiate life-saving therapy.Compounds are to be made only pursuant to an individual prescription for an individual animal that is being treated within a valid VCPR. While some naïve pharmacists may be willing to compound bulk quantities of items to be redispensed at the veterinary clinic, this activity is most definitely considered illegal manufacturing and is highly actionable by the FDA. Both the compounding pharmacist and the dispensing veterinarian would be liable in this circumstance. A written order for an individual animal should be readily retrievable for all compounds dispensed. An exception to this would be for legitimate office use within the veterinary practice. For compounds such as apomorphine that are not likely to be dispensed to go home with clients, the veterinarian may write a prescription for small quantities for office use. Nonemergency medications (e.g., diethylstilbestrol and potassium bromide) for chronic therapies are not suitable candidates for office use.The compounding CPG clearly states that offering financial incentives in return for compounded products is an area of high regulatory priority. Several veterinary professional organizations strongly recommend against entering into financial incentive agreements. The AVMA Code of Ethics states that practitioners should not engage in offering or receiving any financial incentives in return for referral of product or service. Fellows of the ACVP must maintain an ethical standard that states they will not engage in offering or receiving financial incentives for products or services. The decision to use a compounded product is in itself legally complex. When a veterinarian puts himself in a position to receive a financial incentive in return for utilizing a compound, regulatory authorities can only further question his motives for not utilizing an approved product. Various Internet business models are emerging that allow veterinarians to receive monies in return for products remotely dispensed to clients. It is anticipated that when tested in the courts, these models will be found in violation of US trade law, as were human home health care pharmacies offering such schemes in the 1980s. It is best to avoid these schemes entirely and identify revenue generators related to veterinary expert care and service that cannot be outsourced to Internet models.Safety, efficacy, and pharmacokinetic disposition have not been determined for most compounded products, and they probably won’t be. Compounding is incidental in nature, and every compound is ideally prepared for an individual patient with individual needs. For this reason, just as with any extra-label use, veterinarians should determine prior to dispensing what parameters will indicate whether the compound is efficacious, subtherapeutic, or toxic. For example, practitioners requiring transdermal administration of methimazole for a hyperthyroid cat should determine an appropriate time for recheck to assess whether serum T4 has decreased and to perform complete blood chemistries to monitor for adverse effects, such as neutropenia. The veterinarian should also have a plan of action in the event of toxicity or a lack of therapeutic response. The veterinarian should discuss all of these parameters and observable clinical signs of improvement or toxicity with both the pharmacist and the client to ensure that all parties are involved in surveillance of the patient.The decision to utilize a compounded product is always in the best interest of the patient. To ensure that the client fully appreciates the value of a compounded product in achieving compliance in his or her pet, veterinarians should fully discuss these decisions with their client to emphasize the benefits of a chosen regimen. Unfortunately, in spite of well-planned, rational compounded drug regimens, adverse events are always possible. As compounded drugs have never been through exhaustive safety, efficacy, and toxicity testing in multiple numbers of patients, the likelihood of an unpredictable adverse event from a compound is higher when compared to approved products. Clients should be made aware of any potential risks.Due to the incidental nature of compounding, it is unreasonable to expect scientific evidence to support safety and efficacy of all compounds prior to use. Slight differences in excipients, compounding technique, or intraindividual variation may completely change the disposition of a well-tested drug from patient to patient. Evidence for safe use of these drugs must come from clinical experience and from documenting successes and failures with individual patients. Over time, trends will develop that determine which compounds can generally be used safely and which are associated with a significant level of risk. Some retrospective reports have recently been shared that support the efficacy of transdermal methimazole in reducing T4 in hyperthyroid cats.9–11 Reports that contain objective assessments such as diagnostic and posttreatment laboratory values are much more valuable than those reporting only a subjective improvement in clinical signs. For example, reports of the efficacy of transdermal insulin are not convincing if they lack reference to diagnostic and posttreatment blood glucose values. Adverse effects associated with compounds should at the very least be reported back to the compounding pharmacist, and on a more global level they can be reported through the US Pharmacopeia Convention’s (USP) Veterinary Practitioners Product Reporting Program at www.usp.org. Cases reported in the USP database have provided insight into species or breed-specific adverse events that were missed in preapproval trials (e.g., retinal toxicity of certain quinolones and hepatocellular necrosis from oral diazepam in cats, keratoconjunctivitis sicca and hepatopathies from certain nonsteroidal anti-inflammatory drugs in dogs). Surveillance, documentation, and communication are the most effective weapons against dangerous or irrational compounding.The privilege to legally compound for animal patients should be diligently protected by veterinarians and pharmacists. While compounding for nonfood-producing animals utilizing approved products is currently legal, the FDA has recently made many overtures that indicate a commitment to completely eradicate compounding from raw chemicals. Should this raw chemical ruling be unilaterally enforced, the owners of tens of thousands of dogs currently maintained on potassium bromide for seizures will present to veterinary clinics all over North America desperately seeking alternatives. The veterinary patient care quadrangle (e.g., veterinarian-client-patient-pharmacist) is ultimately catalyzed by the choices of the veterinarian. Compounding for animal patients can only occur pursuant to a valid prescription from a veterinarian within a valid VCPR. It therefore behooves the veterinarian to practice due diligence in not only making the decision to compound, but also in recommending or choosing the services of a qualified compounding pharmacist. With careful navigation within the boundaries of the eight criteria listed above, the veterinarian can safely sail the waters of veterinary compounding and ensure that the ability to compound for animals will remain for posterity.