U.S. Food and Drug Administration issued the following announcement on April 3.
We’ve long recognized that compounded drugs can serve an important role for patients whose medical needs cannot be met by an FDA-approved drug product. But compounded drugs are not approved by the FDA and, therefore, have not been evaluated for safety or efficacy. We’ve seen firsthand the harm they can cause patients when they’re not appropriately compounded.
Over the past year, we’ve taken significant new steps to modernize and clarify our policies related to the quality of compounding in an effort to ensure continued access to compounded drugs for patients who need them, while also protecting patients from the risks of contaminated or otherwise harmful products. We’ve worked to refine our existing practices, shape new policies and increase the frequency of our communications with industry, Congress, states and patients concerning our programs. We anticipate that 2019 will be an equally productive year for the FDA’s compounding program, with better quality continuing to be our top priority as part of our ongoing effort to reduce the risks of these unapproved products. We have an obligation to advance our efforts to improve the quality of compounded products for consumers by ensuring we have a strong and modern regulatory framework in place.
Toward these goals, we’re pleased to share our 2019 compounding priorities. The FDA will continue to work with stakeholders to improve the quality of compounded drugs for patients who need these products.
Maintaining Quality Manufacturing and Compliance
In 2019, we’ll utilize appropriated funds provided in FDA’s 2019 budget to lay the groundwork for the “Center of Excellence on Compounding for Outsourcing Facilities,” including trainings on current good manufacturing practice requirements for outsourcing facilities. The goal will be to bolster the quality of compounded drugs produced by outsourcing facilities. We’ll provide more updates and opportunities for public participation in this effort.
Also, we’ll continue our effort to help compounders to identify insanitary conditions in compounding facilities so they can implement appropriate corrective actions. We’ve highlighted some of the poor conditions that our investigators have found at some facilities. To help prevent these practices, we’ll work to finalize our guidance to promote activities that help compounders ensure their drugs are not prepared, packed, or held under insanitary conditions.
While some compounders work hard to meet quality standards including avoiding insanitary conditions, we recognize that there are still compounders that are not in compliance. To address these risks, a key component of our 2019 work will be continuing to perform our risk-based inspection and pursue other enforcement efforts to identify compounders who produce drugs under substandard conditions or use inappropriate practices that could lead to serious harm. In 2018, the FDA sent warning letters to 23 facilities for adulterated product violations. These include insanitary conditions. We also worked with compounders on 50 recalls of products from the marketplace that raised safety concerns. Since 2018, FDA has entered into four consent decrees of permanent injunction to address the risk of patient harm from exposure to unsafe compounded drugs.
In 2019, we’ll build on these and similar efforts, advance other new policies to strengthen our regulatory oversight and continue to help improve the quality of compounded drugs.
Regulating Compounding from Bulk Drug Substances
Compounders sometimes produce a compounded drug starting from a finished, FDA-approved drug. Other times, they produce drugs using bulk drug substances, also known as active pharmaceutical ingredients. For example, when a patient has an allergy to an ingredient in an FDA-approved drug, a state-licensed pharmacist or physician, or an outsourcing facility, might compound a drug product using a bulk drug substance that does not contain the allergen.
While some bulk drug substances can be used for compounding, other substances may not be suitable to be used for compounding. This may be a result of potential safety concerns raised by these products, or due to availability of a similar FDA-approved drug product that can be used to meet a patient’s medical need.
We’re developing lists of bulk drug substances that compounders can use to compound from. These are the 503A bulks list and 503B bulks list. The names of these lists refer to sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act), and each list is used by different types of compounders. Section 503A applies to state-licensed pharmacies and physicians that have not registered with FDA as outsourcing facilities. They compound drugs only based on the receipt of a patient-specific prescription and may use bulk drug substances that are components of FDA-approved drugs, or drugs that have an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph. They may also use substances that FDA places on the 503A bulks list. Section 503B applies to outsourcing facilities, which are not subject to the patient-specific prescription requirement that applies to 503A compounders and may compound and distribute drugs for healthcare facilities to hold as office stock. To help protect patients—and the integrity of the drug approval process—section 503B of the FD&C Act limits the bulk drug substances that outsourcing facilities can use in compounding to substances that are used to compound drugs in shortage or that appear on a list developed by the FDA of bulk drug substances for which there is a clinical need.
Earlier this year, we issued a final rule establishing the criteria for evaluating substances nominated for inclusion on the 503A bulks list that state-licensed pharmacists and physicians can use to compound drugs and placing, for the first time, six bulk drug substances on the list.
We plan to build on these actions by issuing another proposed rule to further amend the list of bulk drug substances that 503A compounders can use to compound drugs. This proposed rule, to be issued in 2019, would be based on FDA’s evaluation of additional bulk drug substances nominated for the 503A bulks list, identifying any additional bulk drug substances FDA proposes to add to the list, and also identifying bulk drug substances that the FDA has considered and is proposing not to include on the list of substances from which 503A compounders may use to compound drugs. The agency will continue to consider additional substances nominated by the public for inclusion on this list and will address them in future rules.
We’ve also made a final decision regarding whether to include certain bulk drug substances on the 503B bulks list. The FDA will continue to update this list as it evaluates nominated bulk drug substances. Our recently issued final guidancedescribes FDA policies for developing the list of bulk drug substances under section 503B.. This year, we’ll continue to develop the bulks list for outsourcing facilities to limit compounding from bulk drug substances to circumstances where there’s a clinical need for such products.
We’ll also continue to support research efforts on bulk drug substances with the National Academy of Science, Engineering, and Medicine (NASEM) and through the FDA's Centers of Excellence in Regulatory Science and Innovation with the University of Maryland and Johns Hopkins University. These efforts will help us advance the development of the bulks list. The two ongoing projects Clinical Use of Drugs Including Bulk Drug Substances Nominated for Use in Compounding by Outsourcing Facilities and Bulk Drug Substances Used to Compound Drugs for Patients with Autism Spectrum Disorder (ASD) will help inform the public, and our regulatory decision-making—specifically the agency’s decision about whether to include certain substances on the 503B bulks list. Our collaboration with NASEM will also continue to examine the clinical utility of treating patients with compounded bioidentical hormone therapy products and the available evidence of the safety and effectiveness of multi-ingredient compounded topical pain creams.
Finalizing our Memorandum of Understanding with the States
To secure our public health goals related to compounding, states play a critical role. We partner with them to address the potential risks associated with compounded drugs, while ensuring appropriate access. In 2019, we plan to finalize our memorandum of understanding (MOU) between the FDA and the states. Through the MOU, FDA will further collaborate with the states so that, working together, we can have the greatest public health impact while maximizing our resources. For example, if a compounder distributes drugs to multiple states, it can be difficult to gather information about possible adverse events associated with those drugs, connect them to the compounder and undertake coordinated action to address a potentially serious public health problem without some assistance from the states. These challenges were illustrated by the 2012 nationwide fungal meningitis outbreak. This tragic outbreak led to more than 750 cases of illness and the deaths of 64 individuals. The firm had used a compounded drug for injection that was supposed to be sterile but had become contaminated before distribution to patients and providers. Collaboration with the states has the potential to help prevent such serious and widespread outbreaks by helping to better identify adverse drug events and product quality issues across the country.
The MOU will address traditional compounders that distribute a certain percentage, known as inordinate amounts, of their compounded drugs across state lines. Last September, we issued a revised draft MOU for comment where states would agree to identify compounders that distribute more than 50 percent of their total prescription orders for compounded drugs interstate and report certain information to FDA about those compounders. Under the revised draft MOU, the states will also have greater flexibility on the mechanisms they can use to gather this information. We look forward to finalizing this agreement, taking into consideration stakeholder comments.
Compounding by Hospital and Health Systems
The agency recognizes that hospital and health system pharmacies are different than other pharmacies not owned by hospitals and from conventional manufacturers, and as such, have unique needs and challenges.
To that end, we plan to issue a revised draft guidance regarding hospital or health system compounding to provide further clarification on how the FDA intends to apply section 503A of the FD&C Act to drugs compounded at these facilities. Our revised policies will also provide guidance for hospital or health system pharmacies that might be considering registering as an outsourcing facility under section 503B.
Additional Compounding Priorities
Finally, we’ll continue to work closely with stakeholders on a number of other efforts that promote improving the quality of compounded drugs for patients who need them.
Among our efforts, we’ll hold a public meeting in May 2019 to discuss current good manufacturing practice (CGMP) for outsourcing facilities and gain public feedback to gauge the potential impact of proposed policies related to CGMP requirements on office stock access for health care providers. We’ll also hold additional listening sessions with stakeholders to better understand their views on key issues such as the substances included on the bulks lists and manufacturing requirements for outsourcing facilities as we develop policies that ensure appropriate access while protecting public health.
We look forward to continuing to advance a robust compounding policy framework in 2019 as part of our commitment to fulfilling our vital consumer protection role.
We recognize that there continues to be great interest in our work in this important program. We’re committed to providing detailed updates as we pursue additional actions on behalf of the American public.
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