FDA’s announcement affects the following bulk drug substances:
To be excluded: (1) bromfenac sodium, (2) mitomycin-C, (3) nepafenac, and (4) hydroxychloroquine sulfate.
To be included: quinacrine hydrochloride (quinacrine).
Section 503B of the Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. section 353b) describes the conditions that must be satisfied for drug products compounded by an outsourcing facility to be exempt from section 505 (21 U.S.C. section 355) (concerning the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs)); section 502(f)(1) (21 U.S.C. section 352(f)(1)) (concerning the labeling of drugs with adequate directions for use); and section 582 (21 U.S.C. section 360eee-1) (concerning drug supply chain security requirements).
One of the conditions that must be met for a drug product compounded by an outsourcing facility to qualify for exemptions under section 503B of the FD&C Act is that the outsourcing facility may not compound a drug using a bulk drug substance unless: (1) the bulk drug substance appears on a list established by the Secretary of Health and Human Services identifying bulk drug substances for which there is a clinical need (the 503B bulks list) or (2) the drug compounded from such bulk drug substances appears on the drug shortage list in effect under section 506E of the FD&C Act (21 U.S.C. section 356e) at the time of compounding, distribution, and dispensing.
FDA will place a bulk drug substance on the 503B bulks list if it determines that there is a “clinical need” for outsourcing facilities to compound drug products using the bulk drug substance. FDA bases this determination on information submitted by the nominator, as well as other information it deems appropriate, including input from the Pharmacy Compounding Advisory Committee. If FDA determines that there is no clinical need to compound drug products using the bulk drug substance, it will not place that bulk drug substance on the bulks list.
FDA stated its position on determining clinical need in its March 2019 guidance titled FDA Guidance for Industry: Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act (84 Fed. Reg. 7390 (Mar. 4, 2019)). This guidance describes FDA policies for developing the 503B bulks list and the Agency’s interpretation of the phrase “bulk drug substances for which there is a clinical need” as it is used in section 503B of the FD&C Act. For substances that are a component of an FDA-approved drug, the Agency conducts its clinical need analysis by asking one or both of the following questions:
- Is there a basis to conclude, for each FDA-approved product that includes the nominated bulk drug substance, that: (a) an attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and (b) the drug product proposed to be compounded is intended to address that attribute?
- Is there a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product?
The Agency will proceed with its evaluation if the answer to both questions is “yes,” as this answer indicates that there may be a clinical need for outsourcing facilities to compound using the bulk drug substance at issue.
With respect to substances that are not components of an FDA-approved drug, FDA conducts a balancing test to determine clinical need based on four factors: (1) the physical and chemical characterization of the substance; (2) any safety issues raised by the use of the substance in compounding; (3) the available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists; and (4) current and historical use of the substance in compounded drug products, including information about the medical condition(s) that the substance has been used to treat and any references to the substance in peer-reviewed medical literature.
Although Congress passed the Drug Quality and Security Act in 2013, FDA developed the bulks list and regulated this space according to its Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug and Cosmetic Act (81 Fed. Reg. 37,500 (June 10, 2016)) (Interim Policy). Pursuant to the Interim Policy, bulk substances are nominated by industry stakeholders and provisionally placed by FDA into one of three categories of bulk drug substances: (1) eligible for inclusion and under evaluation; (2) presents significant safety concerns, and (3) nominated without sufficient support.
Notably, this is the second time FDA has sought to approve bulk drug substances to the bulks list from Category 1 of the Interim Policy (eligible for inclusion and under evaluation). Recall that FDA last sought to change the 503B bulks list in August 2020. At that time, FDA expressed its intent to exclude 19 bulk drug substances and aimed to approve four bulks drug substances from Category 1 of the Interim Policy. The comment period for the August 2020 proposal recently closed on February 8, 2021.
Interestingly, similar to the August 2020 proposal, all four drugs FDA seeks to exclude in this most recent announcement are components of FDA-approved products, while the one substance it seeks to approve is not. Although FDA evaluates bulk drug substances on a rolling basis, over the last several years, it has hastened its pace to exclude certain substances from the bulks list. Outsourcing facilities must continue to be attentive to the proposed changes to the bulks list.
We encourage industry stakeholders affected by this announcement to submit comments to the Federal Register, Docket No. FDA-2018-N-3240. FDA will accept comments until May 24, 2021, after which time it will consider no further comments.
Client Alert 2021-107
