There is still confusion apparently, even after the federal authorities’ attempts to make their interpretations of the 2013 Drug, Quality and Security Act all the clearer. In that law, passed after a fatal, fungal meningitis outbreak in 2012 started in a Massachusetts compounding facility,1 the FDA was given responsibility for drug compounding safety and supply chain security. It divvied up compounding facilities into two groups: 503B and 503A.2 But, per normal, lawmakers left it up to the FDA to figure out how to implement the law in the form of guidances.
Those in the 503B designation can make and ship drugs in quantities, but under strict FDA regulation. The 503As, under less federal supervision, can make compounds once they get a patient’s prescription. This reverses long-standing traditions: Physicians have developed relationships with these smaller compounders and have come to rely on them for immediate delivery of medications, like vancomycin. And stockpiling compounded medications has become taboo.
In January, the FDA released guidance documents as part of its 2018 Compounding Policy Priorities plan. These documents explain the FDA’s intended policies on sections 503A and 503B, including that compounders cannot produce copies of commercially available drugs. Drugs are safer, says the FDA, when all steps leading to the drugs’ production and distribution are overseen by the agency.
“Because they are subject to a lower regulatory standard,” says the January guidance, “compounded drugs should only be distributed to health care facilities or dispensed to patients to fulfill the needs of patients whose medical needs cannot be met by an FDA-approved drug.”3
Exceptions, not the rule
The FDA’s guidance documents are “an attempt by the agency to strike a balance on the issue of compounding facilities ‘copying’ commercially-available drugs,” says Jim Rehovsky, RPh, vice president of the ophthalmology division of Avella Specialty Pharmacy. However, the FDA also recognizes there will be instances in which a physician believes a compounded medication may be more beneficial to a specific patient and, if the physician can demonstrate clinical need, could still have that medication prepared. Essentially, Mr. Rehovsky says, “the agency wants to ensure compounding is an exception, not the rule, when there are commercially-available versions of such drugs on the market.”
Because 503A and 503B serve different compounding providers and patients – large groups of unknown patients vs. specific patients with prescriptions – 503A has a slightly different exemption for making a copy. First, the commonalities: Both types of compounders can make a drug if it is discontinued and no longer marketed, or in shortage. Neither can make a drug if it has the same, similar or easily substituted strength within 10% of the commercial product ingredients, route of administration, dosage form and strength and excipients. The FDA also touches on additional topics, like recommending that compounding pharmacies maintain records documenting statements of significant difference for at least three years, and noting if a drug is compounded when a commercial drug is unavailable and/or in shortage.
The records will help ensure “that compounded medications are only dispensed and distributed to patients whose needs can’t be met by FDA-approved drugs,” said Mr. Rehovsky. “It will help put a stop to issues associated with compounding of steroid suspensions such as triamcinolone PF, and other sterile commercial products such as Hyaluronidase that are readily available.” Now for a difference. Quoting from the guidance, here is 503A: “As provided by section 503A(b)(2), a prescriber determines that there is a change, made for an identified individual patient, which produces, for that patient, a significant difference from the commercially available drug product.” Says Mr. Rehovsky: A compounded drug product is not essentially a copy of a commercially available drug if a prescriber has determined that a change produces a significant difference for the patient, whether removing a dye or preservative and/or a difference in strength.
On the Hill
In late January, a House subcommittee heard how these guidances would impact medicine, including ophthalmology. George Williams, MD, AAO president-elect and practicing retina specialist from Michigan, told the Energy and Commerce Committee-Subcommittee on Health that a primary concern was continued access to nonbiologic, compounded drugs for office use. “[This access] enables ophthalmologists to have these treatments readily available should patients arrive at the office in need of emergent care due to conditions such as severe infection,” he says. “A delay in treatment, even by a few hours, can result in permanent vision loss.”
Dr. Williams added that this final guidance on office use threatens access to compounded drugs by requiring a patient-specific prescription before a traditional compounding pharmacy can distribute a compounded drug. “As implementation efforts move forward, we would urge a greater emphasis on ensuring policy that promotes patient safety does not do so at the expense of patient access to these vital treatment options.”
Scott Gottlieb, MD, FDA commissioner, told the committee that the FDA is working on guidance to help those with 503A designation to become outsourcing compounders.4 This way, patients’ needs would be met while outsourcing facilities would be required to hold to “good manufacturing practice requirements, FDA inspections according to a risk-based schedule, specific adverse event reporting requirements and other conditions that provide greater assurance of the quality of their compounded drug products,” according to an FDA spokesman. (On March 23, the FDA issued a draft guidance for a nine-month public comment period that would affect 503B compounding facilities. The discussion: how to interpret “bulk drug substances for which there is a clinical need,” as written in the 2013 law.)
At the compounders
Compounders are left wondering what this means for their production line. The FDA “has taken the position that you can’t copy an FDA-approved drug” unless the FDA-approved drug is on the agency’s drug shortage list, says Mark Baum, founder and CEO of Imprimis Pharmaceuticals in San Diego. So, “our biggest concern is continued access to compounded formulations made in FDA-registered outsourcing facilities” because the agency, he continues, has signaled that it may narrow the list of what can be compounded. Charles Leiter, PharmD, quit his position as CEO at Leiter Compounding Pharmacy over the FDA’s stance. “Right now the physicians don’t know where to get the meds,” he says. “The longer it takes these meds to get to the patient, the worse it is for the patient.”
In the clinic
There are interesting questions over what defines a copy, said Russell Swan, MD, an ophthalmologist with Vance Thompson Vision in Bozeman, Mont. “If you have three individual medications that are FDA-approved but no one has created a combination one, does the combining of those create a new drug, or is it the same drug?”The guidance could affect combination drops used after cataract surgeries or LASIK, which are produced by multiple companies.
Dennis Saadeh, PharmD, FACA, vice president, Product Strategy, Imprimis, says many of the custom-compounded therapies are just that — custom. They are not commercially available in the concentrations necessary to treat serious, emergent infections. “Often, the infections need to be treated empirically, meaning without the benefit of cultures and sensitivities to certain antibiotics, in an effort to cover a broad range of microbes.” Such antibiotics include vancomycin and tobramycin in concentrations above 0.3% drop. There are no commercial drops to treat some forms of keratitis including fungal and parasitic infections. Even for some forms of ocular cancer, there are no commercial options. OM
- CDC. Multistate outbreak of fungal meningitis and other infections. cdc.gov/hai/outbreaks/meningitis.html. Accessed March 26, 2018.
- Gabay, M. The Drug Quality and Security Act. Hosp Pharmv.49(7); 2014 Jul. 615-676.
- FDA. Compounded drug products that are essentially copies of approved drug products under section 503b of the Federal Food, Drug, and Cosmetic Act. January 2018. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM510153.pdf. Accessed March 26, 2018
- Rosenthal M. House subcommittee meeting points to compounding turf war. Pharmacy practice news. Feb. 6, 2018.