Betelgeuse, Betelgeuse, Betelgeuse! The ANDA “RLD Theory of Liability” Rears Its Ugly Head

By Kurt R. Karst –      

Like the character Michael Keaton plays in the 1988 film “Beetlejuice,” in which spirit (a “bio-exorcist”) comes back from the afterlife (after having his name said three times) to wreak havoc and to try and scare away the new inhabitants of a home, the so-called Reference Listed Drug (“RLD”) theory of liability is being used by plaintiffs’ attorneys in an attempt to exorcize the U.S. Supreme Court’s June 23, 2011, 5-4 landmark decision in PLIVA Inc. v. Mensing from generic drug product liability litigation.  In Mensing, the Supreme Court ruled that generic drug manufacturers are not permitted to change their labeling except to mirror the label of the brand, RLD manufacturer whose drug product is approved under an NDA.  The RLD theory posits that FDA’s regulations impose new or additional responsibilities on an ANDA sponsor whose drug product is unilaterally designated by FDA as an RLD once the brand-name RLD NDA drug product is discontinued and withdrawn from the market, and that the Court’s Mensing decision is inapplicable under such circumstances. 

By way of background, FDA’s practice has been to designate a single RLD – the market leader at a given point in time as determined by the Agency on the basis of unconfirmed commercial data and other information – when the brand-name drug product and former RLD is no longer marketed and is moved to the Discontinued Drug Product List section of the Orange Book.  Specifically, FDA has stated that the Agency “will designate [RLDs].  Generally, the [RLD] will be the NDA drug product for a single source drug product.  For . . . multiple source drug products without an NDA, the [RLD] generally will be the market leader as determined by FDA on the basis of commercial data.”  FDA, Final Rule, ANDA Regulations, 57 Fed. Reg. 17,950, 17,958 (Apr. 28, 1992).  That RLD designation does not change, “even if the drug is later replaced as the market leader.”  Id.  FDA has stated time and time again that when an NDA designated as the RLD is discontinued for reasons other than safety or effectiveness, approved ANDAs that refer to the NDAs “are unaffected by the discontinued marketing of the products subject to those NDAs,” and that “[i]f FDA determines that labeling for these drug products should be revised to meet current standards, the agency will advise ANDA applicants to submit such labeling.” 

We’ve seen the RLD theory raised before.  First, Nevada State Court Judge Jerry Wiese II alluded to it in his recent decision in three propofol hepatitis infection cases (see our previous post here).  Second, Public Citizen alluded to it in its recent Citizen petition (Docket No. FDA-2011-P-0675), in which the organization states its understanding “that under current regulations, a generic manufacturer is designated by the FDA to maintain the label of a drug when the name-brand manufacturer of that drug withdraws from the market,” and says that “[t]his procedure manifests the FDA’s confidence in the ability of generic manufacturers to perform ongoing pharmacovigilance duties – which makes sense, given their substantial scientific and financial resources, as well as the effort they must already invest to comply with post-approval safety regulations” (see our previous post here).  Now, the RLD theory has taken center stage in the Court of Common Pleas of Philadelphia County in In re: Reglan/Metoclopramide Litigation. 

Morton Grove Pharmaceuticals, Inc. (“MGP”), a U.S. affiliate of Wockhardt USA LLC (“Wockhardt”), recently filed a brief with the Court of Common Pleas of Philadelphia County in the metoclopramide litigation refuting Plaintiff’s RLD theory of liability.  MGP also recently submitted comments to FDA requesting that the Agency deny the Public Citizen petition and “affirmatively state that the holder of an approved ANDA does not bear any additional responsibility for the content of product labeling if and when FDA unilaterally designates that ANDA drug product as the RLD.”  MGP/Wockhardt clearly has a significant interest in the issue, given that FDA unilaterally designated Wockhardt’s ANDA No. 074703 for Metoclopramide HCl Oral Solution as the RLD in 2006.  The “+” sign in the Orange Book indicating RLD status has transformed into crosshairs, making MGP/Wockhardt (or any other ANDA RLD) a target for Plaintiffs’ attorneys.  

MGP states in its comment to FDA on the Public Citizen petition that “[a]ny argument that FDA’s unilateral RLD designation imports responsibility to an ANDA sponsor for the content of the label has no legal, or regulatory, mooring.  This premise directly and irresponsibly contradicts the current regulatory framework, well-established responsibilities of generic drug manufacturers, and the Supreme Court’s decision in Mensing.”  MGP goes on to state that “FDA’s unilateral designation of an ANDA drug product as the RLD does not in any way alter the well-established regulatory framework established for brand and generic drug manufacturers with regard to labeling.  It does not transform an ANDA into an NDA or somehow create new responsibilities for the ANDA holder.”  Among other things, MGP cites various FDA guidance documents and Federal Register notices to support its position, including FDA’s April 2011 “Draft Guidance for Industry – Safety Labeling Changes – Implementation of Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act,” in which FDA outlines its notification procedures for required safety labeling changes once FDA has determined that new safety information is available and should be included in labeling.  “In identifying the categories of manufacturers to whom notice will be given,” says MGP, “FDA clearly delineates between the holder of an NDA, on the one hand, and an ANDA without a marketed NDA RLD, on the other hand.”  The bottom line for MGP is that:

to avoid future instances in which an ANDA sponsor is unfairly targeted – e.g., in product liability litigation – merely because FDA has identified its drug product as the RLD, FDA should include in its response to Public Citizen’s petition (and in the preface to the Orange Book) further confirmation that a RLD designation of an ANDA when the brand-name reference drug is withdrawn does not confer any additional or special responsibilities or obligations on an ANDA RLD sponsor.

Several of the points MGP makes in its comments to FDA are reiterated in the MGP/Wockhardt brief recently filed with the Court of Common Pleas of Philadelphia County in In re: Reglan/Metoclopramide Litigation.  According to MGP/Wockhardt:

Plaintiffs here are improperly, and without the support of any legal authority, attempting to impose “brand” or “NDA” status, and the responsibilities that come with such status, on ANDA holder Morton Grove where no such responsibilities exist.  An ANDA holder cannot step into the shoes of an NDA holder.  Plaintiffs have not cited to a single statutory or regulatory authority that imposes any additional responsibilities upon a generic manufacturer who is subsequently and unilaterally designated an RLD by FDA. . . .

FDA unilaterally designated Morton Grove as the RLD so that subsequent ANDA applicants have a drug to reference for purposes of application submission and approval. See 314.94(a)(7).  However, this unilateral designation does not alter the well-established regulatory framework for brand and generic drug manufacturers with regard to labeling by transforming Morton Grove, and ANDA holder, to an NDA holder.  Such a position directly contradicts the current regulatory framework, well-established responsibilities of generic drug manufacturers and the [Supreme Court's] decision in Mensing.

The Plaintiffs in the case recently fired back with their response to the MGP/Wockhardt brief, stating that “[t]he Mensing Court did not address and, therefore, did not preempt any claims arising against a generic manufacturer that has become the RDL holder, the issue central to the RLD holder preliminary objection here” (emphasis in original).  According to them, “[t]his distinction is critical because neither the Court nor FDA even considers an RLD a generic drug for regulatory purposes.”  This is quite a shocking statement, as it seems to indicate the Plaintiffs’ position that a drug product approved under an ANDA is somehow magically transformed into an NDA when the brand-name RLD NDA drug product is discontinued.  But it fits hand-in-glove with the Plaintiffs’ endgame: that “a court should apply the impossibility preemption analysis utilized in [Wyeth v. Levine] for name-brand drugs and require that the manufacturer show by clear evidence that FDA would have rejected the label change thus made.”