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Alerts and Updates

FDA Proposed Rule Would Require Generics to Update Label Warnings Even Before Branded Pharmaceuticals Do

November 12, 2013

FDA Proposed Rule Would Require Generics to Update Label Warnings Even Before Branded Pharmaceuticals Do

November 12, 2013

Read below

The proposed rule, if finalized as written, will trigger a paradigm shift in how warnings are handled by generic drug firms.

On Wednesday, November 13, 2013, the U.S. Food and Drug Administration (FDA) will publish a proposed rule in the Federal Register that will mandate that generic drug firms update their labels for drugs under approved Abbreviated New Drug Applications (ANDAs) to add warnings, precautions, adverse reactions, contraindications and certain other information [hereafter collectively referred to as "warning(s)"] even if the corresponding branded company has not implemented the same labeling change. The entire pre-publication version of the proposed rule can be viewed here.

At present, FDA's regulations do not allow an ANDA holder to update its labeling to add new safety information until the brand company that holds the New Drug Application (NDA) that serves as the "reference listed drug" (RLD) for the generic changes its labeling. The current approach, which implements the statutory requirement arising under the Hatch-Waxman Act that a generic's labeling be the same as the RLD, has been a key issue in several recent U.S. Supreme Court cases addressing the duty to warn for both brand and generic drugs (see the Products Liability Implications of the Proposed Rule section below). While criticized by some, the current approach provides consistency among the labeling of therapeutically interchangeable drug products.

How the Proposed Rule Would Work

Whenever an ANDA holder has "newly acquired information" that constitutes "sufficient evidence of a causal association" between an unlabeled warning and the approved product, the generic would have to submit a Changes Being Effected-0 (CBE-0) supplement to its ANDA and immediately implement the changed labeling. To ensure that the new warning is communicated promptly, FDA will allow an ANDA holder to distribute a "Dear Health Care Provider" letter and also will require that the changed labeling be submitted in "structured product labeling" (SPL) format, which allows FDA to promptly place the changed labeling on websites such as DailyMed (run by the National Institutes of Health).

At the same time as the ANDA holder submits the CBE-0 supplement to provide for a new warning, it also must notify the RLD holder in writing of the proposed labeling change. The notice to the RLD holder also must include a copy of the information supporting the labeling change. FDA anticipates that the RLD holder will use the information to either propose a matching change in its labeling or to comment on the change proposed by the ANDA holder. The proposed CBE-0 change in labeling also would be promptly placed on a dedicated FDA website for public review and for access by other generic firms.

The proposed rule also would change how quickly a generic firm needs to change its labeling in the wake of a change approved for the RLD. Currently, FDA tells ANDA holders to revise labeling to conform to the RLD "at the very earliest time possible." Under the proposed rule, ANDA holders would have 30 days after FDA approval of a change to the RLD labeling to submit a CBE-0 supplement covering that change.

What About Sameness in Labeling?

While FDA is allowing generic labeling to differ, at least temporarily, from the branded product, it has devised an approach that it believes addresses the "sameness" issue—i.e., the Hatch-Waxman Act's mandate that generic and brand labeling be the same. Specifically, under the proposed rule, the official approval of the change initiated by the generic drug would be deferred until the corresponding brand has submitted and secured approval of the labeling change originally initiated by the generic.

In essence, the official "approved" labeling would never be different. In the agency's eyes, this "approach ensures that the approved labeling for a generic drug continues to be the same as the approved labeling of its RLD."1

Will This Proposal Cause Confusion Due to Differing Labels Being in the Market?

FDA, in its discussions in the preamble to the proposed rule, acknowledges that there may "concerns about temporary differences in safety-related labeling … especially if multiple ANDA holders submit CBE-0 supplements with labeling changes that differ from each other and from the RLD."2 FDA believes that the dedicated web page devoted to CBE-0 labeling supplements will address this concern.

FDA Regulatory Implications for Industry

Generic firms always have had a duty to track and report adverse event information on their marketed products. If the proposed rule is finalized, generic firms will need to ensure that they have the systems in place to not only continue to handle the reporting duties for adverse events, but also to perform the types of analyses that the proposed rule would require to assess "newly acquired information" and to evaluate whether that information constitutes the appropriate level of evidence that would trigger a need to update a label to add a warning or other safety information under FDA's drug labeling regulations.

Complicating these analyses is the fact that the regulatory standards for when certain labeling changes are needed vary depending on the type of labeling change. For example, the standard for adding a warning or precaution is that it be done "as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established."3 In contrast, an addition to the adverse reactions section of the labeling must be for a reaction for which "there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event."4

Products Liability Implications of the Proposed Rule

The proposed rule changes are expressly intended to abrogate much of the impact of important federal preemption decisions flowing from the U.S. Supreme Court's rulings in Pliva v. Mensing in 2011 and Mutual Pharmaceutical v. Bartlett earlier this year. In those cases, and in dozens of others both before and afterwards, state and federal courts dismissed generic drug companies from products liability cases because generic drug labeling and design, under the Hatch-Waxman Act and FDA's regulatory scheme, were required to be the same as the brand drug at all times. As generic drug companies were unable to change either the design or labeling of their pharmaceuticals without running afoul of federal law, courts found that state law-based failure-to-warn and design defect claims, and similar claims derivative of them, were barred, or preempted, by the U.S. Constitution's Supremacy Clause.

FDA's proposed rule, if implemented, would require a generic drug company to initiate label changes whenever new information comes to its attention creating a causal basis for an increased risk of harm from the use of its product. As FDA recognizes in its Notice, the interpretation of post-marketing safety data is both "complex" and "often a matter of judgment." Without additional guidance and measurable benchmarks or criteria established of when such label changes are required, the implementation of the proposed new rules may lead to confusion and uncertainty, with a risk of companies over-reporting or underreporting newly received or observed safety information to FDA.

This likelihood suggests itself by the proposed requirement that information about all pending CBE-0 applications be promptly reported on FDA's website to inform prescribing physicians and enable other companies making or distributing the drug an opportunity to weigh in on the necessity of the requested label change. As FDA states in its notice: "(t)his approach to considering information from other application holders is intended to mitigate concerns that a single ANDA holder may not possess sufficient data to perform an adequate assessment of the potential new safety concern raised by the newly acquired information."5

The new rules also may subject generics to additional products liability suits premised on a failure to timely warn prescribing physicians of newly received reports of adverse events, or an increase in the frequency of adverse events previously reported as a part of the company's pharmacovigilance activities, or new science reported in the professional literature, generated internally or through post-market clinical trials by the generic drug company or other manufacturers, or a generic's reanalysis of post-marketing surveillance data.

Comments on the Proposal

The proposed rule, if finalized as written, will trigger a paradigm shift in how warnings are handled by generic drug firms. Interested persons may comment on the proposed rule during the 60 days following its official publication in the Federal Register, or until January 12, 2014. Information on how to submit comments is contained in the proposal.

For Further Information

If you have any questions about this Alert or would like more information, please contact Michael A. Swit or Alan Klein, any member of the Generic Pharmaceuticals Practice Group, any member of the Products Liability and Toxic Torts Practice Group or the attorney in the firm with whom you are regularly in contact.


  1. See, Proposed Rule, pre-publication version, at 34.
  2. Id., at 18.
  3. 21 CFR 201.57(c)(6).
  4. 21 CFR 201.57(c)(7).
  5. Id., at 25.

Disclaimer: This Alert has been prepared and published for informational purposes only and is not offered, nor should be construed, as legal advice. For more information, please see the firm's full disclaimer.