In Case You Missed It . . . . We Did! Prometheus Takes Action Against FDA Over Generic LOTRONEX Approval and REMS Waiver, and Then Promptly Drops Case

By Kurt R. Karst –      

We try our best to stay on top of the latest lawsuits against FDA, but every once in a while one gets past us without us quickly noticing.  That recently happened when Prometheus Laboratories Inc. (“Prometheus”) filed a Complaint and a Motion for Temporary Restraining Order and/or Preliminary Injunction in the U.S. District Court for the District of Columbia alleging that FDA violated the Administrative Procedure Act (“APA”), the FDC Act, and applicable regulations when the Agency largely denied a May 2013 Citizen Petition (Docket No. FDA-2013-P-0572) submitted by Prometheus concerning a single, shared Risk Evaluation and Mitigation Strategy (“REMS”) for irritable bowel syndrome drug Alosetron Hydrochloride Tablets (see our previous post here), and approved a generic version of the drug with its own REMS.  To our knowledge, it’s the first lawsuit against FDA challenging the Agency’s REMS authority. 

Approved under NDA 021107, Alosetron Hydrochloride Tablets is marketed by Prometheus as LOTRONEX only for women with severe diarrhea-predominant irritable bowel syndrome.  LOTRONEX is approved with a REMS with Elements To Assure Safe Use (“ETASU”) that restricts distribution of the drug.  Under the FDC Act, if a brand-name reference listed drug under an NDA is approved with an ETASU REMS, then a generic version of that drug that is the subject of an ANDA must also have an ETASU REMS.  (For a list of products subject to a REMS, see FDA’s database and our REMS Tracker.)  

Generally, NDA and ANDA sponsors share a single REMS system; however, the statute allows for a deviation from that single, shared system under certain circumstances.  Specifically, FDC Act § 505-1(i)(1)(B) states:

A drug that is the subject of an [ANDA] and the listed drug shall use a single, shared system under [FDC Act § 505-1(f)].  [FDA] may waive the requirement under the preceding sentence for a drug that is the subject of an [ANDA], and permit the applicant to use a different, comparable aspect of the elements to assure safe use, if [FDA] determines that—

(i) the burden of creating a single, shared system outweighs the benefit of a single, system, taking into consideration the impact on health care providers, patients, the applicant for the [ANDA], and the holder of the [RLD]; or

(ii) an aspect of the [ETASU] for the applicable listed drug is claimed by a patent that has not expired or is a method or process that, as a trade secret, is entitled to protection, and the applicant for the [ANDA] certifies that it has sought a license for use of an aspect of the [ETASU] for the applicable listed drug and that it was unable to obtain a license.

Prior to FDA’s consideration of a REMS for Alosetron Hydrochloride Tablets, the Agency granted a waiver from the singe, shared system requirement in only one instance – for Buprenorphine Transmucosal Products for Opioid Dependence.  That changed when FDA approved Roxane Laboratories, Inc.’s (“Roxane’s”) ANDA 200652 on May 4, 2015 for a generic version of LOTRONEX.  Roxane had previously requested a waiver from the single, shared REMS requirement, and FDA granted that waiver request when approving ANDA 200652, but with two conditions:

1.  Your waiver-granted REMS system shall be open to all current and future sponsors of ANDAs or NDAs for alosetron hydrochloride products.

2.  FDA is limiting the grant of the waiver to a term of three years.  If, at the end of the three-year period, Roxane seeks to continue marketing pursuant to the waiver, the Agency will evaluate whether an extension of the waiver is appropriate at that time.

A copy of the ETASU REMS FDA approved with respect to Roxane is available here. 

Prometheus alleged in the company’s lawsuit against FDA that the Agency’s decision to grant a waiver from the single, shared REMS system approved for LOTRONEX violated the law and puts patients as risk.  According to Prometheus:

The statute does not contemplate the attachment of any qualifications or conditions upon the waiver: either a generic drug qualifies for a waiver or it does not. 21 U.S.C. § 355-1(i)(1)(B).  In approving Roxane’s generic version of LOTRONEX®, however, FDA granted a waiver of the statutorily required single, shared REMS that was subject to Roxane meeting two conditions.  Because the statute does not contemplate attaching qualifications or conditions to the waiver, FDA’s conduct is unlawful, arbitrary and capricious and otherwise violates the [APA].  In addition, FDA’s grant of a waiver also was unlawful, arbitrary and capricious because it failed to meet the statutory requirements for a waiver. . . .

By creating two distinct REMS programs, FDA has increased and complicated the compliance obligations imposed on prescribers and pharmacists, which almost certainly will increase the occurrence of prescribing and dispensing errors and undermine the clarity and quality of the communications from prescribers and pharmacists that FDA has determined patients need to assure the safe use of alosetron hydrocholoride. . . .  By approving a separate REMS for the Roxane product, FDA has created a risk of confusion or error that can result in the wrong patient taking alosetron hydrochloride, in patients not taking the drug correctly, and in patients not appropriately responding to the symptoms that can signal a serious adverse event.

FDA and Intervenor-Defendant Roxane alleged in their opposition papers (here and here) that the lawsuit was merely a last-ditch effort by Prometheus to delay generic LOTRONEX competition.  Thus, for example, FDA alleges that:

after dragging its feet for more than three years rather than collaborate with Roxane, Prometheus asks this Court to take immediate and extraordinary action to require FDA to rescind or stay its approval of Roxane’s application, arguing that FDA has acted unlawfully by approving Roxane despite the absence of the single, shared system whose very development Prometheus itself blocked. . . .  Prometheus will face generic competition inevitably, and its pretextual appeals to safety as a means to delay that competition fall flat.  The fact that Prometheus does not like FDA’s decision does not render that decision invalid.  And no amount of gamesmanship by Prometheus can change the fact that the public interest is best served where, as here, the twin goals of increasing availability of lower-cost alternatives and ensuring the safety of marketed drugs are both advanced.

In a May 21, 2015 Minute Order, Judge James E. Boasberg denied Prometheus’ Motion for Temporary Restraining Order (the company’s Motion for a Preliminary Injunction was withdrawn), and set a schedule for Prometheus’ Motion for Summary Judgment, which was expected on June 17, 2015.  But that didn’t happen.   On June 11, 2015, Prometheus filed a Notice of Voluntary Dismissal Without Prejudice dismissing all claims in the action.  And so the case ended before it really began.