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The compounding conundrum

Dissecting the compounding guidelines that pit safety concerns against patient access

Dermatology World abstract illustration of mortal and pestle

The compounding conundrum

Dissecting the compounding guidelines that pit safety concerns against patient access

Dermatology World abstract illustration of mortal and pestle

By Victoria Houghton, assistant managing editor

In the fall of 2012, health officials and physicians received word that a mysterious number of cases of fungal meningitis and infections were being reported throughout the country. After some digging, the U.S. Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) zeroed in on the culprit. Steroid injections accidentally tainted with mold, traced back to the New England Compounding Center, had been distributed throughout the country resulting in a massive number of meningitis cases. When the outbreak was finally contained, 800 people had been sickened by the compounded drug and 76 people had died. 

As a result of this national public health tragedy, the safety of compounding facilities and compounded medications is being scrutinized by federal and state regulators and legislators. “I think the meningitis outbreak in New England was the presumptive trigger,” said Murad Alam, MD, member of the Academy’s Compounding workgroup. “I think there was certainly the perception that the problem was larger than one isolated bad outcome and actually a systemic failing in the level of regulation of these pharmacies.” As a result, Congress passed the 2013 Drug Quality and Security Act (DQSA) which tightened the FDA’s oversight of compounding facilities, giving the FDA the green light to take steps to restrict physician in-office compounding and office-use compounding. “The intent of the framers of that legislation was to have a relatively narrow interpretation such that compounding pharmacies that were producing higher-risk products — for intravenous use or intrathecal use — would be held to higher safety standards,” Dr. Alam said. “Instead, what happened was that the interpretation by the FDA and other regulatory agencies was much broader than anticipated by the framers.”

Consequently, in the name of safety, physician access to compounded medications and their ability to prepare drugs in their offices are under threat. Dermatology World takes a look at what’s happening with compounding regulations — and what the Academy is doing to ensure physician access to compounded medications.

Office-use compounded medications

During the inception of the DQSA, the Academy kept a close eye on its implementation and effects on medicine. “We regularly kept in touch with the Hill, the American Medical Association (AMA), and other specialties with a particular interest in compounding,” said Christine O’Connor, associate director of congressional policy for the American Academy of Dermatology Association (AADA). “Our message on Capitol Hill was that we support safe and effective compounding medications but warned against the unintended consequences. We were given promises that the DQSA would not restrict the practice of medicine. However, as the FDA began to implement the law, we started to see problems arise.”

As a result of the oversight it was granted under the DQSA, the FDA issued final guidance in December 2016 that slowed the pipeline between physicians and the entities where they procure compounded medications as office stock without having a patient-specific prescription: Section 503A traditional compounding pharmacies. According to the final guidance, Section 503A compounding pharmacies cannot dispense office-use compounded medications to physician practices without a patient-specific prescription. “Essentially, after being evaluated, patients are required to come back for treatment after a patient-specific prescription is filled with a section 503A compounding pharmacy,” said Natasha Pattanshetti, JD, AADA manager of regulatory policy.

Instead, in order to obtain office-use compounded medications to have on hand to be able to evaluate and treat patients with compounded medications in a single visit, physicians are often forced to turn to Section 503B outsourcing facilities. “The 503B facilities are subject to stricter FDA oversight, like adverse event reporting, current good manufacturing practices, and also routine inspections, which all cost more,” said Pattanshetti. “As a result, obtaining compounded medications through the 503B outsourcing facilities is cost prohibitive because they charge much more than 503A compounding pharmacies.”

According to Pattanshetti, the 503B outsourcing facilities also produce larger volumes of the drugs — likely more than an individual physician’s office needs to have on hand. Additionally, “the problem with outsourcing facilities is that obtaining compounded drugs from them is like a scavenger hunt. All you have is the FDA website listing the name of the outsourcing facility and current status of whether or not they have the drug you need,” said Pattanshetti. “You have to find out for yourself their contact information, what medications they offer, as well as pricing and volume information and product descriptions. They can ship interstate, which is good, but you still have to call around, and with an already busy practice, it’s just not workable for our membership.” 

 503A vs. 503B

  • 503B outsourcing facilities are subject to stricter regulations than 503A compounding pharmacies — such as mandatory adverse event reporting, current good manufacturing practices, and routine inspections. These additional regulations are costly and therefore the medications are more expensive.

  • 503B facilities produce larger volumes of drugs than 503A facilities — often more than an individual physician’s office needs on hand.

IN-OFFICE COMPOUNDING

While the FDA’s interpretation of the DQSA has resulted in reduced physician access to office-use compounded medications, it has also hit close to home, as the FDA has issued a draft guidance that threatens dermatologists’ ability to prepare drugs in the clinical setting, such as buffered lidocaine and reconstituted botulinum toxin. “The DQSA says that no drug can be compounded in insanitary conditions. This FDA draft guidance implementing the statutory language applies to ‘compounding entities’ and physician offices are considered compounding entities, despite the fact that drugs prepared in dermatology offices are low risk and in low volumes,” said Pattanshetti. Essentially, per this definition, physicians would be subject to the same equipment and process requirements as large compounding facilities when conducting in-office preparations. “Physicians would need to follow all of these strict requirements to prepare anything that is not made pursuant to a manufacturers’ labeling — from diluting a drug with saline to mixing sodium bicarbonate with lidocaine and epinephrine. Under the draft guidance, there currently is not an exception for physician in-office preparations but that is something we are advocating in support of,” Pattanshetti said.

“One of the insurmountable obstacles in these guidelines is that you would need to have laminar flowhoods and a special room for in-office preparations,” Dr. Alam said. “For a small dermatology practice, this would essentially be impossible in terms of the facility, space, equipment, and time required.” Indeed, while some simple dermatologic procedures are currently performed in 20 or 30 minutes, preparing compounded medications for such a procedure, like a biopsy that requires anesthesia, could now take much longer than the entire rest of the procedure, says Dr. Alam. Additionally, under the prescription requirement final guidance, physicians would only be allowed to have a 30-day supply of in-office compounded medications, which could affect buffered lidocaine and reconstituted botulinum toxins. “Logistically, in terms of space, equipment, time, and effort, these guidelines are excessive, unreasonable, and unnecessary, and for practical purposes what they mean is that in-office mixing just can’t be done.”

Again, while these guidelines pose logistical headaches for physicians, the effects are greater on the patient, says Dr. Alam. “There are many procedures that provide a lot of patient benefit that wouldn’t be able to be done. For instance, many dermatologists mix lidocaine with bicarbonate for minor cutaneous procedures, thereby reducing patient pain by perhaps 50%. This helps a lot of patients who have anxiety about needles. If you start the procedure by hurting the patient, it makes it hard for them to proceed with the rest of the procedure and they may not come back for the follow up or for treatment of a subsequent skin cancer.”

Additionally, physicians would not be able to dilute pharmaceutical products with water. “Steroids for injections typically come in two strengths: 10 mg/ml and 40 mg/ml. If you needed a different strength to treat a scar or cyst or keloid, which literally happens on a daily basis in most dermatologists’ offices, you wouldn’t be able to do that. The patients who have that cyst or keloid that’s painful and bothersome and mitigates their range of motion and makes it hard for them to sleep are potentially just out of luck,” Dr. Alam said. “A number of minor, safe, very well-tolerated and successful procedures that alleviate patient discomfort and improve patient quality of life could soon simply not be available to patients.”

Fortunately, for physicians and patients, the FDA’s guidances are just that: guidances. “FDA regulates the drugs themselves and physicians are regulated by state regulatory boards,” said Pattanshetti. However, the FDA is working in collaboration with both the United States Pharmacopeia (USP) – an independent, non-government body that makes recommendations pertaining to the potency and purity of drugs. “USP does not have federal or state government oversight. They set standards and then the federal and state policy makers can adopt the standards,” Pattanshetti said. 

Unfortunately, USP is currently revising its chapter 797 on sterile preparations of compounded drugs and will most likely affect the practice of medicine in the office setting for in-office-preparations. A second round of draft revisions is expected within the next year but the AADA is hopeful that USP will incorporate more physician input. “State pharmacy boards often use these USP rules as the basis for their own state guidelines,” said Dr. Alam, “which essentially makes them the law of land on a state-by-state basis. That’s a concern.” According to Lisa Albany, JD, AADA director of state policy, some state boards of pharmacy have proposed to adopt chapter 797. However, “we have asked the state pharmacy boards to refrain from adopting 797 until the language is finalized.” 

While these guidelines are currently in a holding pattern, the Academy has taken steps to battle these recommendations at all levels. “We have met with the FDA to educate them on the access issues and the safety of in-office compounding,” said Pattanshetti. “There are no documented examples of safety issues in dermatology in-office compounding.” Additionally, the Academy is advocating for a 24-hour exception where if the drug is prepared and administered within 24 hours, physicians would not be subjected to these in-office equipment and process requirements. “We have studies that show that buffered lidocaine and botulinum toxins will not grow bacteria for up to four weeks. We are asking for at least 24 hours because policymakers want a one-size-fits-all-specialties approach and do not want in-office preparations stored in a clinical setting for longer than that,” said Pattanshetti.

From the state side, “We are working with states and other specialties to oppose language that would negatively impact patient access to compounded medications,” said Albany. “We are submitting joint comment letters with impacted specialties and the medical societies.” Additionally, the Academy is working to educate USP on the safety of in-office preparations. “The Academy, along with the AMA, other specialties, and our dermatology sister societies are working together to engage with USP. We are offering studies that we have on the safety of compounding in dermatology offices,” said Pattanshetti. “We want to convey information to them about some of the unintended consequences of these rules,” adds Dr. Alam. “Once they have that information, it might help them inject a little more nuance in the rules, and so allow safety to be maintained without unreasonable restrictions on processes known to be safe that have significant patient benefit.”

SECTION 503A BULK DRUG SUBSTANCES LIST

In addition to regulating access to traditional compounding facilities and recommending strict guidelines for in-office compounding, the FDA — with input from the FDA Pharmacy Compounding Advisory Committee (PCAC) — has been working on a list of drugs that can be compounded by physicians and pharmacists. Down the road, if an ingredient is considered for addition to the list but is not approved to the list, physicians will not be allowed to compound the drug. While the Section 503A Bulk Drug Substances list is still in its infancy and has not been finalized, there are dermatology-related drugs that are currently going through the process of being added to the list.

The process, according to Seemal R. Desai, MD, member of the PCAC, involves a number of steps. Dr. Desai was nominated to the PCAC by the AADA and the American Society for Dermatologic Surgery Association, and is the only dermatologist on the committee. “Companies, compounding associations, and the pharmaceutical industry can nominate ingredients and products for inclusion onto the bulk substance list. The FDA researches every nomination and will present to the PCAC their opinion of the drug based on stability, access ease, toxicology studies, and other related studies around it. Ultimately, in the FDA’s presentation they will give their recommendation that either yes, it should be included, or no, it should not be included.” Following the FDA’s presentation, physicians, pharmacists, lawmakers, and patients can testify on whether or not to include the ingredient on the list during the Open Public Hearing. “Then the PCAC members vote and we have to give our rationale for those votes. The FDA usually takes the PCAC’s recommendations to include something and it will then go through a final rulemaking process.”

To date, the AADA has testified on cantharidin, trichloroacetic acid (TCA), and glycolic acid. The FDA PCAC voted in favor of adding glycolic acid and TCA to the list in 2016. “Cantharidin is expected to be added to the list,” Pattanshetti said. “But with cantharidin, we still have issues with the office-use prohibition and as a result, you cannot obtain it without a patient-specific prescription from 503A compounding pharmacies.” 

A drug that the PCAC voted against including on the list, which remains up for discussion, is quinacrine — which is sometimes compounded with hydroxychloroquine for lupus patients — as its use has been linked to safety concerns, deemed by experts as outdated. Victoria Werth, MD, works with patients with autoimmune skin diseases, and for her patients with lupus, access to quinacrine is imperative. “I have hundreds of patients on the drug and it really works. This compounding approach — which we’ve used since 1993 — none of us have really had any problems with it,” Dr. Werth said. “Back in the Vietnam era, quinacrine was given in much higher doses, and there were a few reports of aplastic anemia but they were rare.” Additionally, “it’s still a concern for the FDA that someone could use quinacrine for the sterilization of women, which has been done in India. It’s just not a realistic problem here.”

To justify its use, Dr. Werth has testified before the PCAC on the safety of compounded quinacrine, using preliminary research she has conducted at the University of Pennsylvania. “I testified at the original PCAC about a year and a half ago and then went back with new data that we had organized from the patients who I see at Penn. We also went through records to see how much physicians were dispensing, because one of the concerns at least from the PCAC and the FDA is that once it’s approved and on the list, then anyone can prescribe it.” According to Dr. Werth’s data, at the University of Pennsylvania, dermatologists, rheumatologists, and several internal medicine physicians were the primary prescribers, so concerns over mass use or misuse wasn’t an issue. “We also wanted to document the safety profile. We went through hundreds of patients who have been on antimalarial drugs and were able to determine what the side effect profiles were for the three different antimalarials that we use and in combinations. It showed that there were no cases of aplastic anemia with quinacrine and quinacrine didn’t seem to have ocular toxicity. By and large it was quite safe.”

(To compound or not to compound? Read more about the dos and don’ts of in-office compounding in staging.aad.org/dw/monthly/2017/august/dos-and-donts-of-in-office-compounding.)

Dr. Werth went back to the FDA a second time to educate the FDA on the safety and efficacy of quinacrine, this time with a lupus organization and a patient. She returned a third time with the AADA to discuss the importance of continued access to quinacrine and review efficacy and new safety data. “I think the FDA is now aware of the importance of the drug. The head of the area that we’re talking to is a rheumatologist and she’s quite aware at this point. We’ve also published data about the efficacy of quinacrine as well. She’s aware of all of that, but it’s a slow process.” 

The AADA has formed a coalition with the American College of Rheumatology, lupus patient-advocacy organizations, and compounding pharmacy groups to advocate for quinacrine’s inclusion on the list. As for other dermatology-related drugs, the Academy will continue to monitor movement with the bulk drug substance list. “When the meetings are announced we see what drugs are up for a vote and then decide if we’ll comment, either in person or in writing,” Pattanshetti said. “Then we monitor its way through the regulatory process and, if necessary, attend and speak at the open hearings during PCAC meetings. We’ll work with the industry nominator as well.”

For Dr. Alam, the office-use regulations, in-office guidelines, and bulk substance list represent a regulatory process that is trying to solve a problem that never existed. “While we support the need to assure patient safety, which we think is of paramount importance, and we respect the FDA’s efforts in that regard, we’d rather they focused on solving the compounding problems that pose a risk to patients rather than the mixing processes that don’t.” Dr. Alam is hopeful that the compounding conundrum that exists between safety and access will be resolved, but it won’t happen overnight. “Like all regulatory changes, it’s going to take a while. Regulators don’t like to move quickly in general, because if something goes wrong, they’re held accountable. That’s not necessarily bad for our patients. A grey area is still much better than having a black and white resolution that immediately eliminates the services we can provide. This grey area might persist for a very long period of time, and if it does, that might be the best that we can get.”