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FDA draft guidance on drug compounding may limit access to affordable medications
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The FDA has introduced draft guidance that, if finalized, would expand the agency’s oversight of drug compounding and restrict the production of compounded drugs in FDA-registered outsourcing facilities.
Although the guidance — which is open for public comment until the end of May — aims to protect patients from potentially harmful drugs, there is concern that the proposed regulations may decrease patients’ access to affordable treatment alternatives to FDA-approved products.
Moreover, because the more stringent regulations apply only to drug compounding facilities that are registered under the FDA, some argue the guidance could discourage facilities to work with the agency, thereby resulting in more drugs that are developed under lower compounding standards.
The FDA defines drug compounding as a practice in which a licensed pharmacist, physician or individual under the supervision of a licensed pharmacist modifies the ingredients of a drug to create a treatment for an individual patient whose needs cannot be fulfilled by an FDA-approved product. Drug compounders can either develop their products using an FDA-approved drug or a “bulk drug substance” that is identical to an active pharmaceutical ingredient (API). Bulk drug substances are often used when the FDA-approved product contains ingredients that are “inappropriate” for the patient, according to the FDA, However, the agency warns that using bulk drug substances in compounded drugs may be not be as safe for patients.
“As our draft guidance explains, compounding from bulk drug substances generally presents greater risk to patients than compounding from FDA-approved drugs,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “There are fewer assurances of safety and quality associated with a bulk drug substance than with an FDA-approved drug. Compounding from bulk drug substances also involves more numerous and complex steps than compounding from approved drugs. This process can introduce increased risk for compounding errors or contamination.”
These guidance documents stem from a fatal fungal meningitis outbreak in 2012 that was linked to a contaminated drug produced by the New England Compounding Center (NECC). According to court documents, employees at the compounding facility did not properly sterilize the compounded drugs and failed to act after environmental monitoring repeatedly detected mold and bacteria within the facility. The documents further stated that the NECC shielded operations from regulatory FDA oversight. The outbreak, which caused more than 750 illnesses and 64 deaths, prompted Congress to pass the Drug Quality and Security Act (DQSA), which, among other priorities, aims to preserve access to compounded drugs while limiting exposure to drugs that are not regulated by the FDA.
Since the passage the DQSA, drugs are compounded under two pathways. Under the first pathway, in section 503(A), state-licensed pharmacies — or traditional compounding facilities — compound drugs for patient-specific prescriptions in accordance with U.S. Pharmacopoeia standards. Under the second pathway, in section 503(B), drugs are compounded by a new category of compounders known as “outsourcing facilities.” Drugs compounded by outsourcing facilities are produced in compliance with current good manufacturing practice (cGMP) standards in an FDA-registered facility. Unlike traditional compounding facilities, the FDA allows outsourcing facilities to compound drugs without patient-specific prescriptions, and health care providers can then hold on to these drugs in case a patient needs them.
The FDA encourages compounding pharmacies to register as outsourcing facilities, which Gottlieb said “are subject to higher quality standards.” However, of more than 2,000 compounding pharmacies in the United States, 71 are currently registered as outsourcing facilities, according to Imprimis Pharmaceuticals, an outsourcing facility.
In its new draft guidance, the FDA proposes regulations for outsourcing facilities that limit the use of bulk drug substances to formulations for which the FDA decides there is a “clinical need.” The FDA stated that bulk drug substances should be used only if the agency — not the physician — determines that an FDA-approved product is “medically unsuitable” for the patient.
“For example, if an approved drug contains peanut oil, the FDA would consider whether there was information indicating that patients with a peanut allergy need a drug product compounded without the allergen,” Gottlieb said in the statement. “The FDA would further consider whether there was information suggesting that the drug product needs to be compounded using a bulk drug substance, rather than the approved drug, because the type and number of manipulations necessary to remove the peanut oil from the approved product would adversely impact the overall quality of the drug.”
In a written response to the FDA’s draft guidance, Imprimis emphasized that “making the FDA the arbiter of ‘clinical need’ effectively removes a physician from making clinical decisions for the optimal treatment of a patient.”
The FDA said it will develop a list of bulk drug substances, known as the 503B Bulks List, that outsourcing facilities will be permitted to use for patients who require them. A bulk drug substance that is not on the list can be nominated for inclusion by the public.
“The time frame in which FDA makes a final determination about whether to include a particular bulk drug substance on the 503B Bulks List and publish its decision in the Federal Register will vary depending on several factors, such as the number of uses that the drug product containing the nominated bulk drug substance is considered for,” an FDA representative told Infectious Disease News.
By limiting bulk drug substances, the FDA said it will reduce patients’ exposure to drugs that have not been proven to be safe and effective while preserving incentives for companies to invest in research and testing that is required for FDA approval.
“It was clear at the time of the fungal meningitis outbreak that there is a safety issue with compounding pharmacies,” Infectious Disease News Editorial Board member William Schaffner, MD, professor of preventive medicine at Vanderbilt University, said in an interview. “We continue to be concerned that there is a residual safety problem. This guidance seems to be another step to make the process more rigorous.”
Despite statements from Gottlieb over the last year that addressing rising drug prices was a priority for the agency, the FDA stated that it will not consider “supply issues, such as backorders,” and high drug costs as a “clinical need,” which raises concern for some. Imprimis CEO Mark Baum said the guidance would not allow the company to make its more affordable treatment alternative to Daraprim (pyrimethamine; Vyera Pharmaceuticals) for toxoplasmosis, a parasitic infection that can cause severe illness in patients living with HIV. Former pharmaceutical executive Martin Shkreli boosted the cost of Daraprim by 5,000% more than 2 years ago. The cost of the drug still exceeds $800 per pill in many pharmacies. Shortly after the price increase, Imprimis began compounding a pill that combines 25 mg of pyrimethamine and 5 mg of leucovorin, which the company sold for approximately $1 each. The active ingredient used by Imprimis is the same API as Daraprim. If this new guidance passes, however, Imprimis would be required to compound its product using the FDA-approved Daraprim, which would significantly increase the cost.
“For Imprimis, being effectively made to buy Daraprim instead of the exact same inexpensive bulk chemical (pyrimethamine) Vyera buys will take us out of the market,” Baum told Infectious Disease News. “Despite what [President Donald J. Trump] said about controlling drug costs, this is the first time I ever heard the FDA say, ‘we do not care about prices,’ which blows my mind because data show that one out of five prescriptions are not filled because people cannot afford their medication.”
Importantly, Baum said that restricting the use of bulk drug substances will cause most outsourcing facilities to deregister, reducing the availability of drugs compounded under cGMP standards.
“The need for these important compounded drugs isn’t going away, despite these guidance documents,” he said. “The question is whether the FDA wants them made to cGMP or a lower standard — such as the one that NECC was held to. I want more drugs made to cGMP. This guidance will cause more compounded drugs to be made to non-cGMP standards. That is the chief problem. And in my view — and consistent with what the FDA said only a few months ago — this isn’t in the best interest of patients.” – by Stephanie Viguers
Reference:
FDA. Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act. 2018. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM602276.pdf. Accessed April 12, 2018.
Disclosure: Baum is CEO of Imprimis. Schaffner reports serving on Data Safety Monitoring Boards for Merck and Pfizer, and is an occasional consult to Dynavax, GlaxoSmithKline, Novavax, Sanofi-Pasteur and Seqirus.