Understanding Defense Strategies for 505(b)(2) Drugs


Recent litigation against generic manufacturers highlights that in litigation, not all drug applications are considered equal. Manufacturers of new drugs submitted for approval to the U.S. Food and Drug Administration under 505(b)(2) face different challenges than innovators or generic manufacturers. To develop the best defense strategy in light of these challenges, it is helpful to explore the framework of 505(b)(2) applications and the current state of the law.

A Hybrid Application

The 505(b)(2) new drug application (NDA) is one of three FDA drug approval pathways. This lesser-known pathway was created by the Hatch-Waxman Amendments of 1984, along with the avenue for generic drug approval. 505(b)(2) is a specific section of the Federal Food, Drug and Cosmetic Act created for new drugs to help avoid unnecessary duplication of studies already performed on a previously approved drug.

A 505(b)(2) is a hybrid application because it seeks approval to market a new formulation of a drug (like an innovator), but it can rely upon data, such as safety and efficacy information on the active ingredient, submitted for a preexisting FDA-approved drug (like a generic). A 505(b)(2) allows drug developers to leverage information used to support earlier approvals. It can also reduce the amount of data that an NDA applicant must submit to support the new drug application because the FDA is permitted to rely on data not developed by the applicant. The intent is a less expensive and quicker route to approval for new, differentiated products. Although the popularity of 505(b)(2) applications is growing, a recent study by the Tufts Center for the Study of Drug Development found that the abbreviated process has not led to shorter approval times.

The Duty to Warn

Design defect claims against prescription drugs are preempted because a drug manufacturer cannot both comply with federal regulations for drug approval and state requirements for product design.[1] For this reason, claims against drug manufacturers typically assert that a manufacturer has breached its duty to warn of foreseeable risks of harm. To determine whether a 505(b)(2) manufacturer’s warnings are adequate, it is necessary to understand the knowable risks of harm when the manufacturer submitted its application and what it learned over time that could have caused it to strengthen its warnings.

Two interesting aspects of a 505(b)(2) new drug application are that it relies on information already submitted to the FDA and the 505(b)(2) drug typically enters the market years after the innovator first obtained approval for the referenced drug. This means that the FDA should have a well-developed understanding of the drug from its interactions with the innovator and be in possession of clinical trial information and reports of post-market clinical experience. That is precisely the data not provided by the 505(b)(2) applicant on which the FDA is expected to rely in approving the 505(b)(2) application. That is also the kind of data that informs the creation and FDA approval of an adequate label.

Drug Labeling, the 505(b)(2) Manufacturer, and Failure-to-Warn Claims

Although the FDA must approve the label before a manufacture can market a drug, brand-name drug manufacturers — including 505(b)(2) manufacturers — bear the ultimate responsibility for creating the labels for their new drugs.[2] When approving a 505(b)(2) label, the FDA may consult the referenced drug’s label for guidance, but differences in the excipients, routes of administration or dosage formulation could result in a 505(b)(2) label that is different than the reference listed drug. There is no “sameness” requirement for a 505(b)(2) drug as there is for a generic one.

Failure-to-warn claims often are asserted as a failure to disclosure information to the FDA. Stated differently, if the FDA had reviewed an allegedly omitted piece of information, it would have required a stronger warning. But as discussed above, a 505(b)(2) drug typically comes on the market years after the innovator, which means that the FDA is already in possession of clinical data about the drug and its post market performance, which is information the FDA relies upon in approving a 505(b)(2) and its label. For this reason, failure to disclose a claim against a 505(b)(2) applicant should have little practical merit.

But more importantly, a claim that a 505(b)(2) applicant knew of adverse information pertaining to its drug that it failed to disclose to the FDA is the same as a fraud-on-the-FDA claim. Any claims predicated upon a 505(b)(2) manufacturer’s alleged failure to submit relevant data or information to the FDA or to comply with the FDA’s regulations should be preempted. Claims disguised as enforcement of the FDCA and its implementing regulations cannot be brought by private litigants because no private right of action to enforce the FDCA exists. Buckman Co. v. Plaintiffs’ Legal Comm.[3]

A failure-to-warn claim can also run up against a conflict between state tort law and federal regulations. If the claim is that state law required the drug manufacturer to have a stronger warning, but the FDA prohibited the manufacturer from modifying its warnings, then it is impossible for the manufacturer to comply with both state law and federal regulations. Where it is impossible to comply with both federal law and state law, federal law preempts a state-law based failure-to-warn claim. PLIVA, Inc. v. Mensing.[4] Therefore, in evaluating the viability of a state-law failure-to-warn claim, it is important to understand that federal regulations limit the ability of a 505(b)(2) manufacturer to change its label without first gaining FDA approval.

After FDA approval, a 505(b)(2) manufacturer, like an innovator, may unilaterally change its label, but only based on “newly acquired information.” This is done using the changes being effected (CBE) provisions. Newly acquired information means data, analyses, or other information not previously submitted to the FDA, which may include data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data if the studies, events, or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA. Like an innovator, a 505(b)(2) manufacturer can unilaterally change its label based on newly acquired information, but what is considered newly acquired information for a 505(b)(2) manufacturer may be different than for an innovator.

For example, a failure-to-warn claim may be based on information that arises from the innovator’s post-market experience or follow-on clinical studies. For an innovator, such information can be “newly acquired,” coming after the FDA has approved its drug. But for a 505(b)(2) manufacturer arriving to the market late, the information will most likely be part of the body of scientific data available to the FDA. A court should dismiss as preempted under Buckman claims based on allegations that a 505(b)(2) manufacturer should have disclosed to the FDA information published before submission of its new drug application.

The only failure-to-warn claim that should be viable against a 505(b)(2) manufacturer is one that arises from information acquired by the manufacturer after the FDA approves the 505(b)(2) application. Even then, the newly acquired information must reveal risks of a different type or greater severity than previously disclosed to the FDA. Only with newly acquired information can the 505(b)(2) manufacturer change its label without first receiving FDA approval. Thus, even if a plaintiff argues that a manufacturer should have strengthened its warnings under state law, federal regulations may have prohibited it from doing so, thus preempting the state-law failure-to-warn claim.[5]

The above preemption defenses may be asserted as motions to dismiss at the pleading stage, depending on the nature of the allegations. Another important defense is available, but requires evidence developed during discovery.

Where it is alleged that a 505(b)(2) manufacturer should have unilaterally changed its label because it acquired new information, a court may preempt the claim if the manufacturer can present “clear and convincing evidence” that the FDA would have rejected a change to its label.[6] The nature of a manufacturer’s burden to establish a Wyeth preemption defense — “clear and convincing evidence” — means that it will rarely be available at the pleading stage and will require development of the evidence during discovery.[7]

In re: Taxotere (docetaxel) Product Liability Litigation; A Case Study

In 2016, women nationwide began filing lawsuits alleging that Sanofi-Aventis failed to warn users of the cancer drug Taxotere® (docetaxel) that they may be left with permanent hair loss. The plaintiffs allege that Sanofi-Aventis knew that this treatment was no more effective than alternative cancer treatments, yet carried a substantial risk of permanent alopecia. Sanofi-Aventis did not warn about permanent alopecia from use of Taxotere® until March 2016. Sanofi-Aventis based its label update on review of post-market activity prompted by an FDA inquiry. On Oct. 4, 2016, the Joint Panel on Multidistrict Litigation formed an MDL and sent the cases to the Eastern District of Louisiana (New Orleans).

Since Mensing, the plaintiffs have generally refrained from naming generic drug manufacturers as defendants, acknowledging that failure-to-warn claims are preempted. But in the in re Taxotere litigation, the plaintiffs named as defendants eight manufacturers that the FDA approved to market docetaxel under 505(b)(2). The plaintiffs call these 505(b)(2) defendants: manufacturers of “generic non-bioequivalent of docetaxel.”

In the in re: Taxotere litigation, the plaintiffs allege that the innovator, Sanofi-Aventis, received FDA approval for Taxotere® (docetaxel) in 1996. The plaintiffs also allege that the FDA approved the docetaxel applications from the 505(b)(2) defendants between 2011 and 2016; 15-20 years after Taxotere® hit the market. Following the FDA’s approval of Sanofi-Aventis’ NDA for Taxotere®, the only study about permanent alopecia that the plaintiffs mention in their complaints is a Sanofi-Aventis- sponsored study, GEICAM 9805. The plaintiffs alleged that the GEICAM 9805 trial revealed that docetaxel patients experienced persistent alopecia for up to 10 years and five months.[8]

Although not stated in the plaintiffs’ complaints, data from the GEICAM 9805 trial was reported in the Annals of Oncology in 2007 and in the New England Journal of Medicine in 2010; both predate FDA approval of the 505(b)(2) applications for docetaxel. It seems likely that if the plaintiffs were aware of the GEICAM 9805 trial, then it is equally likely that Sanofi-Aventis disclosed to the FDA the data from this study and the subsequent journal articles that relied on GEICAM 9805 data. As to the 505(b)(2) manufacturers, GEICAM 9805 is not “newly acquired information.”

All docetaxel-related information concerning permanent alopecia in the plaintiffs’ complaints predate the 505(b)(2) approvals and cannot form the basis of a failure-to-warn claim. Alleging that a 505(b)(2) manufacturer failed to disclose certain information or data to the FDA at the time the manufacturer submitted its 505(b)(2) application amounts to a fraud-on-the-FDA and is preempted.

Because the plaintiffs did not allege that the 505(b)(2) manufacturers acquired new information, any claim that the manufacturers should have strengthened their warnings should be preempted under Mensing; it would be impossible for the 505(b)(2) manufacturer to both comply with state law (requiring them to unilaterally strengthen their warnings) and federal law (prohibiting unilateral label changes without new information).

At this early stage, a potential claim could be based on Sanofi-Aventis’ March 2016 label update. Although not plead, the plaintiffs could argue that this label change was “newly acquired information” to the 505(b)(2) manufacturers, which should have prompted them to change their labels using the CBE provisions. This kind of “failure to timely update” claim may be technically viable, like post-Mensing failure-to-warn claims against generic manufacturers, but of little value.


The defenses available to 505(b)(2) new drug manufacturers that are not available to the innovator of the same drug are fact-based. It is important to closely review the allegations setting out the type and dates information that a plaintiff believes should have led to a stronger warning. That information will set the boundaries for and limit the 505(b)(2) manufacturer’s exposure to product liability litigation.

One good pharmacovigilance practice for a 505(b)(2) manufacturer is to continually review the reference listed drug label for changes and independently evaluate whether any change made by the innovator is also appropriate for the 505(b)(2) manufacturer. Regarding the in re: Taxotere litigation, the 505(b)(2) manufacturers should have reviewed the label change made by Sanofi-Aventis in March 2016 to determine if the same warning about permanent alopecia was also appropriate for their drug. Making the label change, if appropriate, would narrow their exposure window.

[1] Mut. Pharma Co. v. Barlett, 133 S. Ct. 2466 (2013). See also, Amos v. Biogen Idec Inc., 28 F. Supp. 3d 164 (W.D.N.Y. June 25, 2014); Booker v. Johnson & Johnson, 54 F. Supp. 3d 868 (N.D. Ohio 2014); Yates v. Ortho-McNeil Pharm. Inc., 76 F. Supp. 680 (N.D. Ohio 2015); Brazil v. Janssen Research & Dev. LLC, 196 F. Supp. 3d 1351 (N.D. Ga. 2016).

[2] Wyeth v. Levine, 555 U.S. 555 (2009).

[3] 531 U.S. 341 (2001); see also Marsh v. Genentech Inc., 693 F.3d 546 (6th Cir. 2012); Rheinfrank v. Abbott Lab. Inc., 119 F. Supp. 3d 749 (S.D. Ohio 2015) aff’d No. 16-3347, ___ F. Appx. ___, (6th Cir. Feb. 21, 2017); In re Byetta Cases, 2015 WL 7184655 (Ca. Super. Nov. 13, 2015); Utts v. Bristol-Myers Squibb Co., ___ F. Supp. 3d ___, 2016 WL 74294498 (S.D.N.Y. Dec. 23, 2016).

[4] 564 U.S. 604 (2011).

[5] In re Lipitor (Atorvastatin Calcium) Marketing, Sales Practices & Prods. Liab. Litig., 185 F. Supp. 3d 761, (D.S.C. 2016); Utts v. Bristol-Myers Squibb Co., ___ F. Supp. 3d ___, 2016 WL 7429449 (S.D.N.Y. Dec. 23, 2016).

[6] Wyeth v. Levine, 555 U.S. 555 (2009); see also Dobbs v. Wyeth Pharm., 797 F. Supp. 2d 1264 (W.D. Okla. 2011);

[7] In re: Fosamax (Alendronate Sodium) Prods. Liab. Litig., 14-1900, et al., (3d Cir., March 22, 2017). In this recent case, the Third Circuit held that the term “clear evidence” from Wyeth refers to a standard of proof that is to be read as “clear and convincing evidence.” To the extent the Third Circuit is correct in its holding, Wyeth-styled preemption will most likely never be available at the pleading stage.

[8] The plaintiffs also alleged that a Denver-based oncologist observed that six percent of his patients suffered from permanent alopecia from docetaxel treatments, but do not allege that this oncologist published his clinical experience in a journal article or state a mechanism by which the 505(b)(2) manufacturers would have learned of this oncologist’s clinical results.

“Understanding Defense Strategies for 505(b)(2) Drugs,” by Terry M. Henry and Ann E. Querns was published in Law360 on March 24, 2017. To view the article online, please click here.