Pacira has announced that it settled its lawsuit against FDA over the labeling and promotion of its postsurgical analgesic drug, EXPAREL®.  FDA approved EXPAREL (bupivacaine liposome injectable suspension), in October 2011 for “administration into the surgical site to produce postsurgical analgesia” based on two clinical trials involving pain after bunionectomies and hemorrhoidectomies. Although the drug’s indication statement contained no limiting language, the Clinical Studies section warned that “EXPAREL has not been demonstrated to be safe and effective in other procedures” and dosing instructions were provided only for bunionectomy and hemorrhoidectomy.  Following approval, Pacira allegedly promoted EXPAREL for use after other surgical procedures such as cholecystectomy and colectomy.

Importantly, EXPAREL promotional materials contained several disclosures, including that EXPAREL was only approved based on trials with bunionectomy and hemorrhoidectomy procedures; and that information on any other procedures was based on the experience of specific doctors.  In keeping with its longstanding position on promoting for populations not studied in the pivotal trials, FDA issued a Warning Letter to Pacira in September 2014, objecting to these materials as an unlawful broadening of the approved indication.  FDA claimed that the company’s disclosures did not “mitigate the overwhelming impression that EXPAREL is safe and effective for use in cholecystectomy and colectomy.”  After Pacira implemented a corrective active plan and agreed to limit similar promotion, FDA issued a close out letter.

But on September 8, 2015 — nearly a year later — Pacira filed suit in the Southern District of New York (the same district where the Amarin preliminary injunction was issued) against FDA making two main arguments: 1) that the promotions were not off-label because the approved indication statement was broad enough to encompass procedures other than those examined in the pivotal studies, and 2) in the alternative, that the First Amendment protects commercial speech about off-label promotions that is truthful and not-misleading.  Pacira Pharmaceuticals, Inc. v. FDA, 15-cf-07055 (SDNY Sept. 8, 2015).  In large part, the company’s pleadings focused on the regulatory history of EXPAREL including an early Agency proposal during labeling negotiations to limit the indication and a final decision to reverse its position.  Pacira also advanced a medical argument that the procedures and endpoints studied in the pivotal trials were specifically chosen to permit broader extrapolation to similar procedures.  On October 13, 2015, FDA withdrew the Warning Letter from the Agency’s website without comment.

As part of the December 14th settlement, FDA confirmed that EXPAREL is “approved for ‘administration into the surgical site to produce postsurgical analgesia’ for use in a variety of surgeries not limited to those studied in its pivotal trials.”  Settlement Agreement Ex. A at 3.  FDA also agreed to approve a labeling supplement that Pacira submitted in November 2015 to avoid any future confusion about the scope of the approval.  The revised labeling eliminates the language “EXPAREL has not been demonstrated to be safe and effective in other procedures” from the Clinical Studies section.  Finally, FDA issued a statement to Pacira “clarifying the reasons for the withdrawal of the Warning Letter.”  Settlement Agreement Ex. A at 2.  In it, FDA explained that it determined that the Indications and Usage statement was ambiguous as to “surgical site[s]” and therefore not limited to bunionectomy and hemorrhoidectomy procedures.

The legal significance of this settlement is noteworthy. The Warning Letter followed closely on the heels of two DOJ settlements in which the government took the position that the scope of drug labeling must be interpreted narrowly.  For example, in the GSK Advair settlement, DOJ took the position that a broad indication statement had to be interpreted in the context of language in the Dosing & Administration section of the drug’s labeling.  The EXPAREL settlement could limit DOJ’s ability to make such allegations going forward.  Additionally, this is the first time, to our knowledge, that CDER has withdrawn a Warning Letter.

Going forward, we expect FDA to be more careful in approving broadly worded indication statements, which could affect the agency’s class labeling policies.  At the same time, we do not think that the settlement necessarily opens the door for sub-population or disease subtype claims for products with broad indication statements.  It does, however, provide an opportunity for companies in these situations to advance a clear medical argument to support broader extrapolation (e.g., taking into account the drug, its mechanism of action, the characteristics of the population/ disease subtypes), especially where they have a favorable regulatory history on point.

Click here for the Pacira Complaint

Click here for the proposed Settlement Agreement

Click here for FDA’s letter regarding its withdrawal of the Pacira Warning Letter