In the three years since contaminated injectable steroids compounded by a Massachusetts pharmacy caused a fungal meningitis outbreak, killing 64 people, drug compounding has drawn heavy attention.

State pharmacy boards scrambled to shore up their regulations. The U.S. Food and Drug Administration stepped up its scrutiny, issuing warning letters and/or unsatisfactory inspection reports to more than 170 compounding pharmacies, and logging some 30 medication recalls. Even Congress overcame its customary inertia to pass the Drug Quality and Security Act (DQSA), creating an avenue for the FDA to more closely monitor drugs compounded for human patients.

But the DQSA does not apply to veterinary medicine, a major user of drug compounding. As a result, veterinarians largely have had continued unchecked use of compounded drugs, observers say, often for reasons that some call questionable or inappropriate.

Compounding is a practice by which drugs are altered in dosage, form and/or flavor to accommodate the needs of a specific patient. It is distinct from pharmaceutical manufacturing, which operates under an extensive and expensive testing and approval process that in the United States is overseen by the FDA. The regulation of compounding historically has been in the hands of state boards of pharmacy.

The use of compounded preparations is allowed when manufactured drugs don’t serve — for example, if a medication isn’t available in the dosage needed for a parakeet, or a cat refuses to swallow a drug in pill form. Considering the variety of species in veterinarians’ care, compounding is considered indispensable to veterinary practice.

But some applications of compounding are not legitimate. Making cheaper mimics of manufactured drugs is illegal, as is preparing drugs for future sales to multiple patients unidentified at the time of compounding (a practice derisively dubbed “manupounding”).

Despite the industry black eye from the deaths and infections traced to the steroid from New England Compounding Center, veterinary compounding is as popular as ever, if not more so, said Dr. Fred Gingrich, a mixed-animal practitioner in Ohio.

“Compounding is a very common practice,” said Gingrich, a member of an American Veterinary Medical Association task force developing proposed legislation on veterinary compounding. “I would venture to say that compounding business has increased dramatically in the past five years, due to more and more drug shortages and the return of drugs that are many times the original price.”

The situation is on the verge of change, however. In May, the FDA issued a draft Guidance for Industry on Compounding Animal Drugs From Bulk Drug Substances, an aspect of veterinary compounding that has been particularly perplexing and on which the animal health community has been waiting for clarification for more than a decade.

The proposal is something virtually every practicing veterinarian will want to examine, said Dr. Ashley Morgan, assistant director of the AVMA governmental relations division. “Pretty much anyone who treats an animal patient is going to have some concern or thought or care about compounded preparations,” she said.

The FDA estimates that veterinarians write 6.3 million prescriptions for compounded drugs each year.

As drafted, the guidance has the potential to significantly alter the way veterinary compounding is practiced and the players and training involved. For example, veterinarians wishing to keep an office stock of compounded preparations would need to obtain them from “outsourcing facilities,” entities created by the DQSA for human medicine compounding, rather than from compounding pharmacies. (Compounding pharmacies could still fill prescriptions for individual patients.)

The draft guidance also gives explicit leave to compound medications from bulk substances — raw ingredients rather than finished drugs — activity that previously fell into a regulatory gray zone. The proposal raises the question whether veterinarians who wish to do so in their clinics would or should receive specific training in compounding.

“I see two cottage industries coming out of this,” predicted Gigi Davidson, director of clinical pharmacy services at the North Carolina State College of Veterinary Medicine, and an authority on compounding. “I see pharmacists contracting to go into veterinary practices and compound for them. … Or a training industry to teach veterinarians to compound, because that’s not taught in vet school.”

Whether it comes to that is uncertain in light of ongoing conflict over a more fundamental question: Does the FDA have the authority to oversee veterinary compounding at all? Compounding pharmacies contend that state boards of pharmacy are their regulators, not the FDA. Some are pressing to maintain the status quo, even if it means living with a hodgepodge of state rules and wildly divergent treatment of human compounding vs. veterinary compounding.

Davidson maintains that doing nothing to reconcile the differences is unworkable. “Can you imagine being an inspector (of compounding pharmacies) for a state board? It’s like the scarecrow in the ‘Wizard of Oz,’ pointing in two directions: ‘Oh, that’s for humans; oh, that’s for animals.’ I would not want to be that inspector,” she said.

“It’s a mess. Some bold, bright lines must be put into place on a federal level so that state boards of pharmacy and veterinary medicine can effectively regulate compounding practice by their constituents.”

Balancing risk, need

Trouble is, veterinary medicine differs in significant ways from human medicine, making universal rules tricky to establish. The DQSA, for example, prohibits physicians from dispensing compounded preparations from their offices. But veterinarians, unlike physicians, routinely dispense medication of all kinds from their clinics. Moreover, veterinarians serve a Noah’s ark of species, making it far more likely that they’ll have patients that need customized drugs.

“Veterinary medicine is unique,” said Dr. Lori Thompson, a veterinary dermatologist and chair of the AVMA Task Force on Veterinary Compounding Legislation. “We treat a multitude of species ranging from cats and dogs, farm animals, herd situations, zoo animals, aquaculture, rescue situations, shelter animals, laboratory animals … the list goes on and on. Compounding will always be a necessity for veterinarians, given the limited number of FDA-approved drugs for the many species and conditions we treat.”

Dr. Colleen Currigan, another member of the AVMA compounding task force, owns a clinic in Chicago that caters strictly to cats. Currigan said her practice uses compounded medications daily.

“Cats can be challenging for many owners to medicate (and frankly, sometimes for veterinarians and team members as well!),” she said in an interview by email. “Having a medication available in a form that increases and assures client compliance in administering it, while maintaining the human-animal bond, is important, and this drives much of the compounding in feline practice. This may mean having the medication compounded into a palatable liquid form, small palatable chew, or a transdermal gel …”

Thompson said the challenge in veterinary compounding is giving doctors the flexibility to care for a gamut of animal patients without making it too easy for them to choose compounded drugs without considering safety, quality and efficacy, simply because they’re less expensive.

Economics is not a sanctioned reason to choose compounded medications, but veterinarians say affordability of medication is an issue.

“The reality for many veterinarians is that cost is a factor in some owner decisions regarding treatment, and it is likely one (factor among many) that has led to the increased use of compounding by veterinarians,” Currigan said.

Gingrich agreed. “I’d ... postulate that the reasons for (the popularity of) compounding are not medical. They’re economical,” he said. “The drugs are cheaper — way cheaper. They don’t have to go through the FDA-approval process.”

Research suggests the less-restrictive environment under which compounded drugs are prepared may compromise their quality. A paper published in the journal Drugs in R&D in March 2013, “Potential Risks of Pharmacy Compounding,” summarizes the findings of multiple studies in which compounded preparations were found to be contaminated with fungus or bacteria; or with potency significantly greater or less than the labeled dosage.

Have patients been harmed? It’s unclear. The authors write, “According to the Government Accounting Office, the extent of health problems related to the quality and safety of compounded drugs is unknown, as there is no requirement to report adverse effects of compounded drugs to FDA.”

(That’s no longer the case. Under the DQSA, outsourcing facilities must submit adverse event reports to the FDA regularly, and the agency must receive information from state boards of pharmacy about disciplinary actions taken against compounding pharmacies and recalls of compounded drugs. The new draft guidance for animal compounding also has reporting components.)

Gingrich takes care of food animals — for which very few compounded preparations are allowed — as well as companion animals. Even with his small animal patients, he said he uses compounded drugs rarely, owing to his sense that it’s too risky. “You have no idea what you’re putting into them when you buy from a compounded pharmacy,” he asserted.

He believes many of his colleagues are unaware of the risks. If they knew, he said, “They would be hesitant to use compounding so cavalierly.”

Marcy Bliss, president of Wedgewood Pharmacy, one of the largest veterinary compounders in the country, takes umbrage at the idea that some veterinarians may overuse compounded preparations out of ignorance.

“I give our customers, veterinarians, a lot more credit for their education,” Bliss said “I believe they’re already using restraint and ordering and prescribing compounded medication only when it’s called for. I believe …. they have the clinical experience with these medications, and they know the risk; they’ve used them forever. …”

Referring to the FDA, she added, “No outsider needs to question their medical judgment.”

Regulatory history long, complicated

The struggle to reconcile the diverging needs of veterinarians and physicians for compounded medications has endured for decades. It plays out in a welter of laws and regulatory and court documents. The underlying legislation is the Food, Drug and Cosmetic Act (FDCA), of which the DQSA is an amendment. Provisions specific to veterinary medicine are found in an older FDCA amendment, the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA).

Under AMDUCA, veterinary compounders are to use only finished, approved drugs as their starting material, not the active pharmaceutical ingredients — bulk drug substances, in FDA parlance — that manufacturers use. But while compounding with  finished drugs works in some applications, it’s impractical for every instance, compounding pharmacists and veterinarians alike say. Some tablets don’t lend themselves to being transformed into a solution, for example, because inactive ingredients in the tablet form clumps and strings.

The FDA long has acknowledged that compounders need to use bulk substances under certain circumstances. It promised in 2004 to issue guidance to clarify the circumstances under which it would exercise “regulatory discretion” — in other words, to look the other way.

It wasn’t until this May, 11 years later, that the agency finally posted its current thinking on the subject.

Before that, the agency was embroiled in court over its authority to regulate veterinary compounding. A recent case stemmed from an attempt in 2010 by the FDA to close Franck’s Pharmacy of Florida, a drug compounder for human and veterinary patients.

Franck’s made headlines in April 2009, when a compounding error there killed 21 polo ponies. An FDA spokeswoman said it was Franck’s use of bulk ingredients, not the polo pony incident, however, that led the agency to seek to shut it down.

The FDA was rebuffed by a U.S. District Court judge in the Middle District of Florida, who, in a 2011 ruling for Franck’s, stated that the FDA had inadequately established jurisdiction over animal compounding.

The federal government appealed the decision but Franck’s went out of business the following year, so the case closed before the question was resolved. (Beyond the FDA, Franck’s was hit with nearly 150 civil suits between 2010 and 2014; about 80 remain open.)

When the New England Compounding Center fungal meningitis disaster spurred Congress in 2013 to reform the practice of compounding, there were early attempts to include provisions for veterinary medicine. However, the players — pharmaceutical companies, compounders and veterinarians — couldn’t agree on the details. A particular sticking point was whether to create a list of bulk ingredients that could be used in compounding, and if so, what the list should include, according to Morgan of the AVMA.

Anxious to move forward on the legislation, sponsors ended up removing references to veterinary compounding, Morgan said.

In its draft guidance for veterinary compounding, the FDA has borrowed two key aspects from the DQSA.

One is reliance on outsourcing facilities for compounded sterile drugs (such as eye drops and injectable medications). This new type of entity is held to higher manufacturing standards than compounding pharmacies, and must register with and regularly report adverse drug reactions to the FDA.

Veterinarians wishing to keep compounded preparations for office use and dispensing would be routed to outsourcing facilities for their supplies because “office dispensing is where the mass casualties can occur,” said Davidson, the compounding expert and North Carolina State veterinary pharmacist.

She explained, “If you make a mistake in a medication (obtained from a compounding pharmacy) for one cat, you kill only the one cat.” Mistakes in preparations kept for office use, by comparison, have the potential to affect many more patients. “That’s why the FDA wanted to corral the office-use compounding into a higher quality and more regulated practice,” Davidson said.

Another aspect in the FDA draft guidance borrowed from the DQSA is the creation of a list of bulk substances that would be allowed for use in compounding by the outsourcing facilities. (The list would apply only to outsourcing facilities; veterinarians engaging in compounding would not be limited to the list.)

The DQSA indirectly affects veterinary compounding in another way, too. Because it prohibits physicians from dispensing compounded preparations from their offices, some states, in aligning their regulations with federal law, have adopted the same prohibition for all medical practitioners, veterinarians included.

Affected veterinary communities have pushed back, with mixed outcomes. Examples:

• In Florida, a Board of Pharmacy rule adopted in June 2014 required practitioners to sign an agreement with compounding pharmacies not to dispense compounded medications they obtained from the pharmacies. The Florida Veterinary Medical Association, in concert with compounding pharmacies, advocated for legislation that makes an exception for veterinarians, with no restrictions. The law passed unanimously, was signed by the governor and took effect July 1.
  
  
• In Virginia, the state veterinary medical association also successfully lobbied for legislation to preserve practitioners’ right to dispense compounded preparations from their clinics. But unlike in Florida, the association agreed to limit the practice such that veterinarians may dispense no more than a three-day supply. Additional supplies must come to the client directly from the pharmacy.
  
  
• In New Hampshire, practitioners are now prohibited from dispensing compounded medications from their clinics, although “small amounts” for emergency purposes may be kept at the office, according to Dr. Jane Barlow Roy, president of the New Hampshire Veterinary Medical Association. The emergency provision “is a gray zone,” she added. “It’s a bit confusing when you sit down and try to weed through the updated rules.”
  
  Asked how veterinarians are handling the restriction, Barlow Roy said they are doing their best to cope, such as by changing the medications they prescribe.

The AVMA provides a state-by-state rundown of the widely varying regulations and laws.

Many players believe the best hope to resolve the disparities and ambiguities in state and federal rules is through federal legislation aimed specifically at veterinary compounding. Morgan said the AVMA task force will continue to meet this fall and into the spring to develop a workable proposal.

In the meantime, the FDA has its proposal for veterinary compounding with bulk substances on the table. The provisions, when final, won’t be mandatory. The document states upfront, “It does not .. operate to bind the FDA or the public.” All the same, players including Morgan and Davidson say that following the guidance is the wiser course.

“It represents the thinking of the FDA, and therefore, that’s how their staff will enforce (the law),” Morgan said. “Getting called out by the FDA (for violations) and having warning letters posted online is not a small matter for pharmacies. I don’t know what the (state) boards of veterinary medicine would do if a veterinarian were found by the FDA to be doing something inappropriate since (the guidance) is not legally binding, but what veterinarian wants to be in that position?”