United States: FDA Proposed Rule Would Require Generics To Update Label Warnings Even Before Branded Pharmaceuticals Do

Last Updated: November 12 2013
Article by Michael Swit and Alan Klein

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.

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.

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.

This article is for general information and does not include full legal analysis of the matters presented. It should not be construed or relied upon as legal advice or legal opinion on any specific facts or circumstances. The description of the results of any specific case or transaction contained herein does not mean or suggest that similar results can or could be obtained in any other matter. Each legal matter should be considered to be unique and subject to varying results. The invitation to contact the authors or attorneys in our firm is not a solicitation to provide professional services and should not be construed as a statement as to any availability to perform legal services in any jurisdiction in which such attorney is not permitted to practice.

Duane Morris LLP, a full-service law firm with more than 700 attorneys in 24 offices in the United States and internationally, offers innovative solutions to the legal and business challenges presented by today's evolving global markets. Duane Morris LLP, a full-service law firm with more than 700 attorneys in 24 offices in the United States and internationally, offers innovative solutions to the legal and business challenges presented by today's evolving global markets. The Duane Morris Institute provides training workshops for HR professionals, in-house counsel, benefits administrators and senior managers.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Authors
Similar Articles
Relevancy Powered by MondaqAI
 
In association with
Related Topics
 
Similar Articles
Relevancy Powered by MondaqAI
Related Articles
 
Related Video
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
Mondaq on Twitter
 
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
 
Email Address
Company Name
Password
Confirm Password
Position
Mondaq Topics -- Select your Interests
 Accounting
 Anti-trust
 Commercial
 Compliance
 Consumer
 Criminal
 Employment
 Energy
 Environment
 Family
 Finance
 Government
 Healthcare
 Immigration
 Insolvency
 Insurance
 International
 IP
 Law Performance
 Law Practice
 Litigation
 Media & IT
 Privacy
 Real Estate
 Strategy
 Tax
 Technology
 Transport
 Wealth Mgt
Regions
Africa
Asia
Asia Pacific
Australasia
Canada
Caribbean
Europe
European Union
Latin America
Middle East
U.K.
United States
Worldwide Updates
Registration (you must scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.

Disclaimer

The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.

General

Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions