The U.S. Food and Drug Administration (FDA) is required by statute to maintain a list of drug products that cannot be manufactured by pharmaceutical compounding because they are demonstrably difficult to compound. In a notification released on Wednesday, December 4, FDA announced that it is accepting nominations for drug products to include on the list. In order to be considered for the inaugural list, nominations must be received by March 4, 2014.
Background: List Prevents Some Drugs from Qualifying for Compounding Exemptions Ordinarily, manufacturers of new drugs are required to submit their drug products for premarket approval, and are required to comply with labeling requirements and current good manufacturing practice (cGMP). However, two provisions in the Federal Food, Drug & Cosmetic Act (FDCA) permit the compounding of new drugs without premarket approval. Under FDCA 503A, passed in 1997 as part of the Food and Drug Administration Modernization Act (FDAMA), pharmacies are permitted to compound a drug for an identified individual patient without premarket approval or compliance with certain labeling or cGMP requirements. Last month, Congress passed the Drug Quality and Security Act (DQSA), which adds a second provision exempting drugs compounded in outsourcing facilities from premarket approval and certain labeling requirements. The coverage of both provisions does not extend to drugs that FDA identifies as drug products that “present demonstrable difficulties for compounding.” FDA has issued this notice to begin the process of identifying drug products for inclusion on the list of products that cannot be safely compounded.
The December 4 notice represents FDA’s second attempt to publish a list of difficult-to-compound drugs. FDA originally began developing such a list in the year 2000 as required under FDCA 503A and convened a Pharmacy Compounding Advisory Committee to make recommendations for the list. The Committee recommended criteria for determining whether a drug product should be included on the list; in addition, the Committee recommended that the list ban from compounding: metered dose inhalers, dry powdered inhalers, transdermal drug systems, and sterile drug products not compounded in accordance with guidance from the US Pharmacopeia for sterile drug products for home use. However, the Supreme Court struck down a provision of FDCA 503A governing advertising or promotion of compounding before FDA could act on the Committee’s recommendations, and FDA thereafter took the provision that all of 503A had been struck down because the offending provision was not severable from the rest of the Act. As a result, FDA had not attempted to promulgate a list of difficult-to-compound drug products until the integrity of FDCA 503A was affirmed in November 2013 by adding a severability clause through DQSA. With the mandate to promulgate such a list restored in FDCA 503A and repeated in 503B, FDA is preparing to identify candidates for inclusion in the difficult-to-compound list.
Evaluation Criteria FDA has stated that they may include drug products or product categories in the difficult-to-compound list because of the “potential effect of compounding on the potency, purity, and quality of a drug product, which could affect the safety and effectiveness of the drug product,” or because of “adverse events that could result when the drug product or drug product category is not made according to appropriate conditions.” The Agency has specifically identified seven factors that it may use to determine whether compounding affects safety and effectiveness:
- Drug Delivery System – does the drug require a sophisticated delivery system to administer consistently?
- Drug Formulation and Consistency – Does the drug product require a sophisticated formulation? If so, is there concern about batch variability, and are variations in formulation particularly likely to affect safety and efficacy?
- Bioavailability – Is it particularly difficult to maintain uniform bioavailability?
- Complexity of Compounding – are there multiple, complicated, or interrelated steps, increasing the potential for error?
- Facilities and equipment – would compounding require the use of sophisticated facilities or equipment to ensure safe and consistent production?
- Training – would compounding require specialized training?
- Testing and Quality Assurance – are quality assurance tests particularly sophisticated or difficult? Is there a significant potential for harm if quality assurance is incorrectly performed?
In addition, the Pharmacy Compounding Advisory Committee will evaluate each nominated drug product or product category and advise FDA on whether to include the drug on the difficult-to-compound list. The Pharmacy Compounding Advisory Committee must include representatives from the National Association of Boards of Pharmacy, the United States Pharmacopeia, pharmacists with current experience and expertise in compounding, physicians with background and knowledge in compounding, and patient and public health advocacy organizations.
How to Submit Nominations FDA will receive nominations of drug products to include on the list until March 4, 2014. Nominations should include the name of the drug product or drug product category and reasons why the drug product should not be included, referencing the factors listed above and taking into account risks and benefits to patients. Nominations may be submitted to http://www.regulations.gov or to the Division of Dockets Management at FDA. Submissions should reference Docket No. FDA-2013-N-1523. FDA has stated that nominations “that are supported by the most complete and relevant information will likely be evaluated first.” We expect strong interest by numerous companies in this process, in an effort to proactively protect key drug products from unsafe or excessive compounding.
After March 4, 2014, individuals may petition FDA to make additional list amendments. FDA will also consider later nominations for updates to the list, which FDA has described as an “ongoing process.” FDA is required to update the list at least once every four years, and may update the list more frequently at its discretion.