Facing Continuation of the Endo/Par Vasopressin Lawsuit, FDA Publishes Notice Concerning List of Drug Substances for Which there is [NOT?] a Clinical Need under Section 503B

For regular readers of compounding news on our FDA Lawb Bog, the “bulks” saga for outsourcing facilities continues with a whirlwind of activity.

A bit of background: FDA published a new bulk substances list for Section 503B outsourcing facilities on July 23, 2018, where vasopressin somewhat surprisingly remained on FDA’s Bulks List 1.  Proposing to compound using vasopressin, outsourcing facility Athenex, Inc., successfully intervened in the Endo/Par federal district court lawsuit against FDA over the Section 503B Bulks List, and its inclusion of vasopressin in particular (see our previous posts here and here).  Athenex also filed a motion for a declaratory judgment against Endo/Par in New York federal district court.  On August 25, 2018, the U.S. District Court for the District of Columbia lifted the stay in the Endo/Par federal lawsuit at the request of the parties.  Yesterday, Endo/Par filed a Motion for Preliminary Injunction in its D.C. lawsuit.

Throughout its blistering Memorandum in Support of its Motion for Preliminary Injunction filed in that case, Counsel for Plaintiffs dubs FDA’s Section 503B interim Policy on Bulk Substances a “Bulk Compounding Decree,” which it claims is “flatly violative of the law.” It further states that FDA is permitting compounders to “sidestep” the drug approval process –an interesting legal theory given FDCA Sections 503A and 503B explicitly exempt compounders from FDA’s drug approval process (i.e., FDCA Section 505).

FDA published today its Notice of Intent to remove vasopressin from Section 503B Bulks List 1.  In addition to seeking to remove vasopressin from the list, FDA’s Notice also addresses its intent to not include two other substances on Section 503B’s Bulks List 1.  These substances are bumetanide and nicardipine hydrochloride.  FDA had previously placed bumetanide, vasopressin, and nicardipine hydrocholoride on Bulks List 1 after those substances were originally nominated under FDA’s published 2014 nomination process (see our previous post here).  Notwithstanding FDA’s original Bulks List I decision for all three substances, reflecting FDA’s determination the substances met FDA’s prior published interim criteria for inclusion on the list, FDA seems to have changed its mind.  (Note Bumetanide was nominated back in June 2017 by QuVa Pharma, the same entity that nominated vasopressin).  FDA’s motivation (at least in part) for seeking an exclusion of vasopressin from Bulks List 1 likely is the renewed interest in and continuation of the Endo/Par lawsuit.  However, we are left guessing why FDA seeks the early cut for the other two substances.  FDA also acknowledges in footnote 11 of its Notice that the Drug Quality and Security Act (DQSA) requires notice and comment rulemaking when seeking to include a drug substance on the Bulks List, yet not when it intends to remove the substance after the nomination and evaluation process.  FDA states it will take input from both public comments and its Pharmacy Compounding Advisory Committee (PCAC).  It will also continue to review the clinical need determinations for these and other nominated substances, and intends to evaluate nominated bulk substances on a rolling basis.

We continue to wonder why (and possibly how…) FDA can publish its proposal to eliminate three substances from its Bulks List 1 for Section 503B facilities when FDA has not yet issued final guidance on the nomination process itself (recall FDA’s latest draft guidance on the process, published in March 2018, here).  FDA also relies on its proposed draft nomination process (and not its prior process to which the three bulks substance nominations at issue adhered) to show why these three substances should not be used in compounding (i.e., whether the approved drug product sufficiently meets patients’ clinical needs, whether there is a showing of clinical need by the compounded formulation that is unmet by the approved product etc.).  FDA’s prior nomination process did not include such a rigorous clinical need review compared to what FDA now seems to now expect.

FDA is accepting comments on the three substances for the next 60 days after publication of today’s Notice intending to exclude the substances. Will FDA now receive comments addressing the clinical need component for compounded versions of vasopressin, bumetanide, and nicardipine hydrochloride?  And, other than vasopressin, why did FDA choose to remove these two other bulk substances?  Does the Agency intend to review every single substance on Section 503B’s Bulks List 1 to determine whether their first “clinical need” determination was correct, or that the nominator otherwise made an adequate showing?  Will FDA conduct such a review using its “old” nomination process, from 2014, which facilities relied on at that time (and expended significant resources), or its new process, which is the subject of the March 2018 draft re-nomination guidance (and likely prompted by the Endo/Par lawsuit)?  In addition,  we wonder where this leaves FDA’s Section 503A interim bulk substances policy, in which FDA had adopted a similar approach to nominations (but for the fact that Section 503A explicitly permits pharmacies to compound using components of approved drugs).  It also seems that, notwithstanding the Endo/Par lawsuit, hospital system pharmacies would be able to continue compounding using vasopressin and other components of approved drugs, and provide the compounded formulations to its hospital patients under other current FDA guidance.   Inquiring minds …. so much to resolve.

One more Note: FDA’s Division of Drug Information’s announcement on the release of the Notice also mentions that its action on the Bulks List is part of a series of steps that FDA intends to take:

between now and the end of 2018 to further implement the DQSA. It specifically mentions that it will be issuing this year a revised draft Memorandum of Understanding with states that will describe a more flexible approach to addressing certain distributions of compounded products by 503A compounders; a revised draft guidance on insanitary conditions at compounding facilities that will, among other things, address concerns that were raised by providers around the potential implications of the agency’s prior draft guidance; and a revised guidance on current good manufacturing practice (CGMP) requirements for outsourcing facilities that, we believe, will take a more tailored approached to make it more feasible for more 503A pharmacies to become 503B outsourcing facilities.

As always, stay tuned.