FDA Publishes Notice to Remove Substances from its Bulks List I for Section 503B Outsourcing Facilities … and Let’s Watch What Happens Next

We posted last year about the dispute over FDA’s determination to include certain nominated substances on its Bulk Substances List 1 for Section 503B outsourcing facilities.  Recall that in 2017, after FDA approved Endo/Par’s Vasostrict® finished drug product, several entities nominated active pharmaceutical ingredient vasopressin for inclusion on FDA’s Section 503B Bulk Substances List 1.  After review of the nominations, FDA added vasopressin to Bulks List 1 in mid-2017.  Next, FDA’s nomination and listing process (already the subject of two Agency revisions and “redos” since 2014, blogged about here) ground to a halt.  The nominations process and the list itself was (and remains) the subject of contentious litigation involving FDA, Endo Pharmaceuticals and its subsidiary Par Sterile Products, and outsourcing facility Athenex Pharma Solutions.

After proposing to change the nomination process in March 2018 (here), which continued a stay in the litigation against FDA brought by Endo/Par, FDA received approximately 60 industry comments.  It published its final guidance for the section 503B nomination process on March 4, 2019 (here).  In response to those 60 comments “or on its own,” FDA stated it made certain changes in the final guidance document; however, those changes do not change the process in which FDA intends to engage to review a nominated substance.  Instead, FDA’s final guidance on the nomination process explains in more detail

how Congress’ limitation on bulk drug substances that can be used in compounding under section 530B helps preserve the integrity of the new drug approval process, and identifie[s] the process to request that FDA identify or remove a bulk drug substance from that list after the Agency has made a final determination with respect to that substance….

At the same time FDA published final guidance on the nomination process, FDA issued another final guidance document, this time removing two bulk substances from FDA’s interim Bulks List 1: vasopressin and nicardipine hydrochloride (here).

Addressing the more controversial subject of compounding using vasopressin, FDA stated among other reasons that nominations and comments it received did not identify an attribute of commercially available Vasostrict® that makes it “medically unsuitable for patients,” and that the compounded products “are intended to address” that attribute.  FDA also stated that the proposal for compounders to compound a “ready-to-use” formulation versus the commercially available Vasostrict® product for improved efficiency for prescribers or healthcare providers, or to address the possibility that the approved drug may be mishandled by a medical professional, is not a “clinical need to compound a drug product” using a bulk substance.

Not surprisingly, outsourcing facility Athenex Pharmacy Solutions LLC filed a lawsuit pursuant to the Administrative Procedures Act against FDA and others challenging FDA’s bulks determination (on the same day as FDA’s Federal Register notice announcing its vasopressin decision).  Although Athenex originally sought immediate injunctive relief from the D.C. District Court barring FDA from enforcing its vasopressin determination, FDA has agreed not to engage in an enforcement action against Athenex based solely on use of vasopressin until after the district court issues a decision on the merits concerning whether FDA’s actions removing vasopressin from its Bulks List 1 were appropriate.

In its Memorandum in Support of its Motion for Summary Judgment on the merits of the lawsuit, filed on March 18, 2019, Athenex notes that vasopressin has been used in medical care for almost a century to treat life threatening and emergency conditions.  Athenex argues that FDA made the decision to exclude the ingredient from its Bulks List because “a pharmaceutical company is using it to make a branded drug product … that FDA thinks that doctors should choose to use instead of Athenex’s compounded vasopressin drug product.”

Athenex argues that FDA has misinterpreted Congress’ “plain language” instruction concerning whether there is a “clinical need” for substances as “directing FDA to decide whether doctors should always choose an existing branded product over any compounded product made with that substance.”  Among other problems, FDA’s vasopressin determination wrongfully invades the practice of medicine.  In addition, because vasopressin is indeed a component of an approved drug product, FDA has “officially acknowledged” vasopressin is an active pharmaceutical ingredient that meets patients’ “clinical needs.”  Athenex also argues that the plain language of the statutory definition of “bulk drug substance” confirms the subject of the clinical need inquiry required under section 503B is for the active pharmaceutical ingredient and not the finished drug product.      

Athenex next argues that its vasopressin compounded formulation is different from Vasostrict® in clinically significant ways that FDA wrongfully and arbitrarily ignores.  First, unlike the commercially available drug, Athenex’s vasopressin formulation is provided in a ready-to-use formulation and thus avoids Vasostrict’s® 16-step administration process.  Furthermore, Vasostrict®, as stated on its own label, is contraindicated in patients with a known allergy to chlorobutanol and Athenex’s vasopressin is not.  Athenex argues that FDA arbitrarily disregarded these clinically significant differences when it determined to remove vasopressin from section 503B’s Bulks List 1.

We look forward to reviewing FDA’s opposition to Athenex’s Memorandum, and watching what happens next in this long-running “David versus Goliath” saga.