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
 
In association with
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
Check to state you have read and
agree to our Terms and Conditions

Terms & Conditions and Privacy Statement

Mondaq.com (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

Use of www.mondaq.com

You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). 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 & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about Mondaq.com’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.

Disclaimer

Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd 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 or performance of information available from this server.

The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.

Registration

Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.

Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

If you do not want us to provide your name and email address you may opt out by clicking here .

If you do not wish to receive any future announcements of products and services offered by Mondaq by clicking here .

Information Collection and Use

We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to unsubscribe@mondaq.com with “no disclosure” in the subject heading

Mondaq News Alerts

In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.

Cookies

A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

Log Files

We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.

Links

This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

Surveys & Contests

From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.

Mail-A-Friend

If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.

Emails

From time to time Mondaq may send you emails promoting Mondaq services including new services. You may opt out of receiving such emails by clicking below.

*** If you do not wish to receive any future announcements of services offered by Mondaq you may opt out by clicking here .

Security

This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to webmaster@mondaq.com.

Correcting/Updating Personal Information

If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to EditorialAdvisor@mondaq.com.

Notification of Changes

If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

How to contact Mondaq

You can contact us with comments or queries at enquiries@mondaq.com.

If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at problems@mondaq.com and we will use commercially reasonable efforts to determine and correct the problem promptly.