In order for the agency to place a bulk drug substance on the Bulks List, FDA must first determine 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 no clinical need to compound drug products using the bulk drug substance exists, FDA will not place that bulk drug substance on the Bulks List. FDA does not consider supply issues, such as backorders, in the clinical need analysis, nor does it consider cost as compared to the commercially manufactured product.

This announcement reiterates FDA’s position on determining clinical need set forth in its March 2019 Final Guidance for Industry, Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B. Specifically, FDA reviews each substance on a rolling, case-by-case basis and distinguishes between substances that are a component of an FDA-approved drug and substances that are not. 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:

1. 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?
2. 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?”
   If the answer to both of these question is “yes,” then according to FDA there may be a clinical need for outsourcing facilities to compound using the bulk drug substance at issue and the agency will continue its evaluation.

With respect to substances that are not components of an FDA-approved drug, FDA conducts a balancing test 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 in peer-reviewed medical literature.

Although Congress passed the Drug Quality and Security Act in 2013, to date FDA has not placed a single bulk drug substance on the 503B Bulks List. Instead, while FDA develops the list, the agency regulates this space according to its Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug & Cosmetic Act (“Interim Policy”). Under 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.

While FDA has for the first time moved to approve four bulk drug substances from Category 1 of the Interim Policy to the Bulks List, FDA has previously taken the affirmative step to exclude two Category 1 bulk drug substances from the Bulks List: nicardipine hydrochloride and vasopressin, the latter of which resulted from contentious litigation involving FDA, an outsourcing facility, and a commercial manufacturer. In September 2019, FDA announced a further nine bulk drug substances it intends to exclude from inclusion, but it has yet to finalize that decision.

For those keeping score at home, to date FDA has formally excluded two bulk drug substances, proposed the exclusion of an additional 28, and sought to include only four on the Bulks List. Perhaps not coincidentally, all 19 bulk drug substances that FDA has proposed to exclude in the July 31 announcement are components of FDA-approved drug products, while the four substances it seeks to approve are not. Whether this trend will continue remains to be seen, but what is certain is that FDA has quickened the pace of its activity in this space, and outsourcing facilities must be increasingly vigilant about the proposed composition of the Bulks List.

We encourage industry stakeholders effected by this announcement to submit comments to the Federal Register, Docket No. FDA-2018-N-3240. FDA will accept comments until September 29 after which it will consider no further comments.