Just as the U.S. Food & Drug Administration (“FDA”) promised in its 2019 compounding priorities statement, FDA published a notice and proposed rule in the Federal Register in the past week related to bulk drug substances that can be compounded subject to the conditions of Section 503A and Section 503B of the Federal Food, Drug, & Cosmetic Act (“FDCA”):

(1) On September 5, 2019, FDA published a proposed rule regarding its intent to amend its regulations to add five bulk drug substances that can be used in compounding under Section 503A (the “503A Bulks List”) and proposed excluding another 26 bulk drug substances from the 503A Bulks List. Specifically, FDA proposes to amend the 503A Bulks List to include glutaraldehyde, glycolic acid, L-citrulline, pyruvic acid, and trichloroacetic acid (TCA), and proposes not to include 7-keto dehydroepiandrosterone (DHEA), acetyl-L-carnitine (ALC), alanyl-L-glutamine, Aloe vera 200:1 freeze dried, artemisinin, astragalus extract 10:1, boswellia serrata extract (BWSE), cesium chloride, chondroitin sulfate, chrysin, curcumin, D-ribose, deoxy-D-glucose, diindolylmethane, domperidone, epigallocatechin gallate (EGCG), germanium sesquioxide, glycyrrhizin, kojic acid, nettle, nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide disodium reduced (NADH), rubidium chloride, sodium dichloroacetate, vanadyl sulfate, and vasoactive intestinal peptide (VIP).

(2) On September 3, 2019, FDA published notice of its intent to exclude nine more bulk drug substances from its 503B clinical need list (the “503B Bulks List”). These substances are: dipyridamole, ephedrine sulfate, famotidine, hydralazine hydrochloride, methacholine chloride, sodium bicarbonate, sodium tetradecyl sulfate, trypan blue, and vecuronium bromide.

If the bulk drug substances above are ultimately not included in the 503A Bulks List, compounding pharmacies will not be able to compound with the substance unless the substance appears on an applicable United States Pharmacopeia or National Formulary monograph or if the substance is part of a commercially available drug product. Additionally, if the bulk drug substance does not appear on the 503B Bulks List (which is based on FDA’s interpretation of whether there is a “clinical need” for the substance), FDA-registered outsourcing facilities will not be able to compound with that substance unless it appears on the FDA drug shortage list. The Agency’s revisions to these Bulks Lists could significantly impact the compounding practices of these facilities nationwide and their ability to get patients access to the unique and critical compounded medications they need.

FDA’s Role And Progress In Developing The Bulks Lists

FDA has been consistently evaluating bulk drug substances that were nominated for inclusion on the abovementioned Bulks Lists. During this interim period while the Bulks Lists are being formally developed, FDA operates according to its 2017 interim policies, which set out conditions under which the Agency does not intend to take action against compounding facilities that compound drug products from bulk drug substances that cannot otherwise be used in compounding under Sections 503A and 503B.

FDA issued a proposed regulation in 2016, in which it proposed to place six of the nominated bulk drug substances on the 503A Bulks List and proposed to exclude four substances, and the FDA identified the criteria it will continue to use to evaluate bulk drug substances for inclusion on the 503A Bulks List. The six substances proposed for inclusion were: Brilliant Blue G, also known as Coomassie Brilliant Blue G-250; cantharidin (for topical use only); diphenylcyclopropenone (for topical use only); N-acetyl-D-glucosamine (for topical use only); squaric acid dibutyl ester (for topical use only); and thymol iodide (for topical use only). The four substances the FDA proposed not to include were: Oxitriptan, piracetam, silver protein mild, and tranilast. After considering public comments to this proposed regulation, the Agency will issue a final regulation as to these substances.

At this time, FDA has not placed any bulk drug substances on the 503B Bulks List but it has decided not to include two substances: Nicardipine Hydrochloride and Vasopressin.

Could More Litigation Be In FDA’s Future?

Depending on where these bulk drug substances are ultimately placed (that is, whether they are approved for inclusion on the Bulks Lists or formally excluded from the same), there may be litigation—as there already has been.

Most recently, earlier this year in March 2019, FDA determined that there was no clinical need to compound bulk drug substance Vasopressin, and thus Vasopressin would not be placed on the 503B Bulks List. In response, New York-based outsourcing facility Athenex, Inc. (“Athenex”), who submitted the original nomination to FDA for Vasopressin to be included on the 503B Bulks List, sued the Agency based on allegations that the Agency’s interpretation of key provisions of Section 503B ran afoul of Congress’ desire that FDA not interfere with the practice of medicine.

The drug manufacturer of the only commercially available vasopressin product on the market intervened in the Athenex suit as defendants on behalf of FDA, supporting the notion that FDA’s determination on Vasopressin was well within the bounds of FDA’s discretion. In August 2019, the U.S. District Court for the District of Columbia ruled in FDA’s favor, finding that: (1) the Agency’s method of determining whether there is a “clinical need” for a bulk drug substance gives effect to the intent of Congress; and (2) the exclusion of Vasopressin from the 503B Bulks List was not arbitrary and capricious. Athenex has indicated it plans to appeal the ruling but has ceased compounding with Vasopressin for now.

In light of the above, we encourage stakeholders to remain apprised of FDA’s ongoing evaluation and placement of bulk drug substances on the Bulks Lists. Stakeholders interested in submitting comments to FDA’s proposed rule on the 503A Bulks List have until December 4, 2019, to comment, and those interested in submitting comments to FDA’s notice on the 503B Bulks List have until November 4, 2019, to comment. FDA’s recent proposed rule and notice in the Federal Register are further indications that the Agency is actively engaged in the implementation of the Drug Quality and Security Act, the federal law that regulates human health compounding practices.

Should you have any questions regarding the notice or any of the issues raised in this alert, please do not hesitate to reach out to Rachael Pontikes or Kelly Kearney for further discussion.