Vasopressin Ruling May Greenlight More FDA Limits On Bulk Drug Compounding
Executive Summary
By siding with the FDA against bulk compounding of vasopressin, is court encouraging more limits to Section 503B outsourcing facilities?
A recent court ruling applauded by the US Food and Drug Administration paves the way for further restrictions on compounding of drugs that are commercially available, assert Nathan Brown and Howard Sklamberg, partners at the law firm Akin Gump.
The US District Court for the District of Columbia on 1 August upheld the FDA’s rationale for excluding vasopressin from the list of bulk drug ingredients that outsourcing pharmacies can used to compound drugs.
Brown, a former FDA official and Senate health committee staff member, and Sklamberg, a former FDA deputy commissioner, said in a 5 August industry alert that the decision gives the agency a “green light” to move forward in reviewing and excluding more substances from compounding under Section 503B of the Food, Drug and Cosmetic Act.
The advisory was issued in response to the court decision affirming the FDA’s policy on compounding with bulk drug substances, and rejecting Athenex’s motion to strike down the agency’s exclusion of vasopressin from the bulk drugs list.
The attorneys asserted that the decision is significant in that it will “reinvigorate” the FDA’s evaluation of bulk drug substances nominated to the 503B bulks list, applying the framework established in the draft guidance in March 2018 that established the criteria for meeting unmet medical need. In March 2018, the FDA issued draft guidance explaining how it would determine whether a bulk drug substance would qualify for the clinical need list. (Also see "FDA Proposes Criteria For Allowing Bulk Compounding To Address Unmet Clinical Need" - Pink Sheet, 27 Mar, 2018.)
The decision is also significant, they say, because it signals that the FDA will no long exercise enforcement discretion regarding use of vasopressin in bulk drug substance form by outsourcing facilities. They urged hospitals and health care providers to closely review their supply arrangements to evaluate any drug preparations that include vasopressin or nicardipine hydrochloride, both excluded for the 503B bulks list, to ensure they are sourced from FDA-approved drugs rather than bulk ingredients.
Acting FDA commissioner Ned Sharpless and Center for Drug Evaluation and Research director Janet Woodcock said 6 August that they were "pleased" with the court’s decision, which they called in a statement a "victory for public health in the first such case since the Drug Quality and Security Act (DQSA) was enacted.”
DQSA requires that the FDA create a list of bulk drug substances for which there is a clinical need unmet by approved drug products, but did not define what is meant by unmet clinical need.
The FDA Uses Two-Part Analysis
The FDA’s March 2018 guidance established a two-part analysis to determine whether there is a clinical need: There has to be a basis for concluding that the nominated substance has an attribute that an FDA product does not have to treat certain patients. Also, there has to be a basis to conclude that the product proposed to be compounded is produced from a bulk drug substance rather than an FDA-approved product. If the FDA answers no to either question, the agency will not place the nominated substance on the bulk dug substance list.
Following up on this policy, the FDA in August 2018 announced its intention to exclude vasopressin. (Also see "FDA Proposes Banning Outsourcers From Bulk Compounding Of Three Drugs " - Pink Sheet, 4 Sep, 2018.) The agency asserted that in following the two-step process outlined in the draft guidance, vasopressin did not make it past the first step.
In March 2019, the agency took the step of formally banning vasopressin and nicardipine hydrochloride from the list of bulk drug substances that outsourcing facilities can use to compound drugs. The agency said there was not an unmet clinical need for these drugs under Section 503B of the FD&C Act. (Also see "FDA Begins Restricting Bulk Compounding With First DQSA Determinations" - Pink Sheet, 6 Mar, 2019.)
Athenex Says The FDA Wrongly Banned Vasopressin
Athenex Inc. subsequently took legal action against the agency after the FDA’s March announcement. The company contended that the FDA wrongly excluded vasopressin from the list of bulk drug substances that can be used in compounding and asserted that there was a clinical need for its ready-to-use, preservative-free compounded formulation of vasopressin. (Also see "Athenex Sues FDA To Get Vasopressin On List Of Drugs That Can Be Compounded" - Pink Sheet, 20 Mar, 2019.)
The FDA said that a drug was already on the market that addressed this need: Par Pharmaceutical Inc., now a subsidiary of Endo International PLC, submitted a new drug application for Vasostrict in 2012 and the FDA approved the intravenous drug in 2014 as a treatment for septic shock and post-cardiotomy shock. It is currently the only IV vasopressin approved by the FDA.
Court Rejects Athenex’s Interpretation
A central part of the court decision hinged on whose interpretation of “unmet medical need” the court agreed with: Athenex’s or the FDA’s. The court ultimately sided with the FDA; the decision said that agency had correctly interpreted Congress’s intent in the statute while Athenex misinterpreted the framer’s intent.
Athenex said in the complaint that since vasopressin is the active ingredient of an FDA-approved drug, its therapeutic value had already been confirmed by the agency.
The court rejected this argument on the grounds that the company misinterpreted Congress’s intent. The decision said that “Congress plainly thought that there are some bulk drug substances for which there is a 'clinical need' and others for which there is not. Otherwise, why else would Congress direct FDA to answer the question? Congress therefore meant for the 'clinical need' inquiry to perform a sorting function. FDA’s understanding of 'clinical need' carries out this purpose; Plaintiffs’ does not. This becomes clear when a bulk drug substance is thought of as an active pharmaceutical ingredient.”
The decision further noted that “plaintiffs’ construction of Section 503B ... would make the agency’s expertise largely irrelevant to the listing process…. Congress clearly wanted FDA to play a substantive role in the listing process.”
It further said that “FDA’s method of determining ‘clinical need’ better comports with the DQSA’s primary objective of protecting public safety. … no good purpose is served by requiring FDA to certify hundreds, if not thousands, of bulk drug substances already contained in approved drugs.”
Akin Gump’s advisory said that Athenex’s interpretation of clinical need would “open the flood gates to outsourcing facilities compounding with every bulk substance contained within FDA approved drugs, a point accentuated by Endo Par, whose attorneys had printed out the entire Orange Book of approved drug products with therapeutic equivalence evaluations and brought it to oral argument.”
Endo Applauds Decision
Endo International, which fought having the bulk drug substance placed on the list, “applauded” the decision. “At Endo, delivering high quality products and ensuring patient safety are our top priorities and we are pleased with the district court’s decision confirming the FDA’s determination that there is no clinical need to bulk compound vasopressin,” said Matthew Maletta, executive vice president and chief legal officer of Endo.
Athenex has already announced plans to appeal the ruling and also announced that it will cease producing and marketing its compounded vasopressin product until it is permitted to recommence production by the court and the FDA.
Jeffrey Yordon, chief operating officer of Athenex said that “while we are disappointed by the court’s decision, it does not come unexpected. We believe our vasopressin product helps to meet an important clinical need."