In a resounding victory for Pacira Pharmaceuticals Inc., FDA has agreed to formally withdraw its warning letter objecting to the promotion of Exparel (bupivacaine liposome injectable suspension) and to approve a labeling supplement specifying that the post-surgical pain treatment is not limited to any specific surgery or site.

FDA’s extraordinary concessions indicate the agency erred in its reading of Exparel labeling. The settlement also allows the agency to avoid another court ruling on its regulation of company communications about approved treatments.

For Pacira, the resolution allows it to resume promotion of the drug for broad use in post-surgical pain and may also lead to the closing of a Department of Justice investigation of Exparel marketing and promotion practices. Pacira announced the settlement on Dec. 15.

FDA said in a statement that the revised labeling is based on scientific evidence that was previously submitted as part of Pacira’s NDA. The agency emphasized that the terms of the agreement are particular to this case.

“It’s important to note that this resolution is specific to the parties involved in this matter,” the agency stated. “The FDA supports an open dialogue with companies regarding questions about the intended use and promotion of approved medical products.”

”FDA realized right away it had made an error,” Pacira CEO David Stack said.

FDA approved Exparel in October 2011 for administration into the surgical site to produce post-surgical analgesia. The company marketed it as a non-opioid treatment for post-surgical pain. In September 2014 the agency sent Pacira a warning letter objecting to promotional materials that suggested the drug is safe and effective for use in cholecystectomy and colectomy.

FDA contended that the approved labeling recommends dosing only for bunionectomy and hemorrhoidectomy surgical procedures. The agency also objected to Pacira’s claims that Exparel can control pain for up to 72 hours.

Pacira issued a correction but argued with the agency about its interpretation of the labeling. The company then sued FDA in September asserting that the agency was narrowly interpreting Exparel’s approved use and blocking “truthful and non-misleading” communication about its broad application ([A#14150909005]).

The parties began talking and the agency quickly changed its position.

“Based on our discussions, FDA realized right away it had made an error” and sought to “resolve the wrong and make it right,” Pacira CEO Dave Stack said in an interview.

A month after the suit was filed FDA took the extremely unusual step of withdrawing the warning letter from its website. The move signaled that the agency was moving to settle the case ([A#14151019007]).

Revised Labeling Clarifies Broad Post-Surgical Use

Under the settlement, FDA Center for Drug Evaluation and Research Director Janet Woodcock sent Stack a letter describing the agency’s rationale for rescinding the warning letter. She said that in reviewing the warning letter, the approved labeling and related materials, the agency “determined that different statements in various parts of the approved labeling created ambiguity with respect to the scope of the approved indication.”

“Based on the plain language of the Indications and Usage section of full prescribing information, as well as the clinical trials submitted in support of that approval, FDA determined that the indication approved in 2011, was not limited to bunionectomy and hemorrhoidectomy procedures.”

Woodcock said the agency also approved a labeling supplement submitted by Pacira to make it clear that Exparel is not limited to any specific surgery or site and to specify that infiltration into the transversus abdominis plane and infiltration to produce postsurgical analgesia at the site of oral surgery procedures, including tooth extraction, are covered by the approved indication.

The new labeling also specifies that the two surgical sites utilized in the pivotal trials were examples for the purpose of providing general guidance on administration of the drug.

In addition, the revised labeling includes a graphical representation of the mean pain intensity scores over time to show the significant treatment effect for Exparel compared to placebo over the first 72 hours in the pivotal hemorrhoidectomy study.

Stack said the company’s field force will now be able to talk to customers about the use of Exparel for all surgical procedures. As a result of FDA’s warning letter, the sales force had to send physician queries about uses of the drug other than for bunionectomy and hemorrhoidectomy to the company’s medical information department, which in turn emailed a response to the physician.

“It had a dampening impact on our ability to grow Exparel,” Stack said.

Sales of the drug have risen since its launch in April 2012. Net sales of Exparel in 2013 were $76.2 million. For the nine months ended Sept. 30, 2015, Exparel net sales totaled $172.7 million, a 33% increase from the same period in 2014.

Stack noted that the patient population for long-acting non-narcotics in the post-surgical setting is roughly 42 million. The company is looking to expand use of Exparel to other indications. It began an oral surgery trial in September and expects to complete enrollment in the first quarter of 2016.

In March the company received a complete response letter from FDA with regard to its supplemental NDA for the use of Exparel in nerve block to provide postsurgical analgesia. Stack said the company had submitted data for femoral nerve block and FDA indicated it wanted the company to conduct a study on a broader population. Pacira is conducting additional Phase III studies for upper extremity and lower extremity nerve blocks and expects to have data by the end of 2016.

Amarin, FDA May Soon Settle

While Pacira has resolved its differences with FDA and agreed to drop all legal actions against the agency, it is uncertain whether the resolution will impact the DOJ’s investigation. In April, Pacira received a subpoena from the US Attorney’s Office for the District of New Jersey requesting documents pertaining to Exparel marketing and promotional practices. Stack said the two are separate matters and that the company does not know the basis for DOJ’s action.

The settlement shows that companies have a chance of prevailing when they challenge FDA restrictions on communications about their products. It follows Amarin Pharmaceuticals Inc.’s favorable court ruling that it could tell physicians about the unapproved uses of its fish oil pill Vascepa (icosapent) ([A#14150807002]).

FDA is currently in settlement discussions with Amarin. In an Oct. 30 letter to the court, the parties requested further stay of the litigation until Dec. 17 to continue their talks.

The Pacira case is different from Amarin’s as it involves communication about approved uses of a drug. Stack said the company never reached the point of making a First Amendment argument but had focused on Fifth Amendment due process claims.

Pacira seemed to have a strong case that FDA was misinterpreting the Exparel label. Even Michel Carome, director of Public Citizen’s Health Research Group, which filed an amicus brief supporting FDA in the Amarin litigation, appeared sympathetic to Pacira's position. In an interview in September he said Exparel labeling seemed to apply to a variety of post-surgical procedures.

The Pharmaceutical Research and Manufacturers of America and the Medical Information Working Group, a coalition of pharmaceutical and device companies, had filed amicus briefs in support of Pacira ([A#14151026004]).

FDA Makes Broad Concessions In Settling Pacira Promotion Suit

More from United States

More from North America