United States: Changes Being Effected To Drug Labeling Regime: FDA Releases Proposed Pathway For Generic Safety Updates

Last Updated: December 13 2013
Article by Jonathan Berman, Jennifer J. Chheda and Colleen Heisey

On November 13, the U.S. Food and Drug Administration ("FDA") published a proposed rule concerning "procedures for application holders of an approved drug or biological product to change the product labeling to reflect certain types of newly acquired information prior to FDA's review of the change" that would, specifically, allow abbreviated new drug application ("ANDA") holders to update product labeling for their "generic" drug products in advance of its reference listed drug ("RLD"; i.e., the approved drug product to which the generic version was compared to show bioequivalence).1 FDA's proposal would permit—for the first time—a generic drug product label to differ from the RLD product label, ostensibly for a limited and temporary time period.

Background

The proposed rule changes a long-standing industry standard that a generic product's label match that of the RLD, with the RLD holder primarily driving label changes. FDA has generally taken the position that a generic drug must maintain the same labeling as the RLD through the generic product's lifecycle. A generic drug is required to have and maintain the same labeling as the RLD, except for changes required because of a difference approved under a suitability petition or because the generic and RLD are produced or distributed by different manufacturers. The few permissible differences contemplated by this latter category are described by regulation.

FDA's proposed amendments are, in part, a response to recent Supreme Court decisions, Wyeth v. Levine, 555 U.S. 555 (2009), Pliva, Inc. v. Mensing, 131 S.Ct. 2567 (2011), and Mutual Pharmaceutical Co., Inc. v. Barlett, 570 U.S. – (2013), pertaining to generic drug companies' insulation from state law tort claims due to the federal labeling requirements, and an August 2011 Citizen Petition (Docket No. FDA-2011-P-0675), requesting that FDA amend regulations to establish a requirement for generic drug companies to update product labels to ensure drug labeling provides warnings based on new information. FDA responded to the Citizen Petition at the same time it issued the pre-publication regarding the proposed rule, granting the petition in part and stating in its response that the proposed amendments set forth in the Federal Register would address some of the requested revisions to the regulations. (For a discussion regarding the Supreme Court cases and the possible implications regarding state law tort claims, please see Jones Day Commentary entitled "FDA Proposed Drug Safety Warning Rule that May Eliminate Preemptions Defenses in Some Failure-to-Warn Cases," available at www.jonesday.com/fda-proposes-drug-safety-warning-rule-that-may-eliminate-preemption-defenses-in-some-failure-to-warn-cases-11-15-2013/.)

Proposed Regulatory Pathway and Procedures

If the proposed rule were to be implemented without changes, an ANDA holder would be authorized to submit a "changes being effected" ("CBE-0") supplement to update a generic drug label to reflect certain newly acquired information regardless of whether the updated label differs from the RLD label. New drug application ("NDA") holders have had a basis for updating their labels under a CBE-0 supplement for decades, although FDA has revised and clarified the policy and rules over time. Stating the Agency is creating parity among application holders, the proposed rule would explicitly extend the mechanism beyond NDA holders to permit ANDA holders to submit CBE-0 supplements to add or strengthen a contraindication, warning, precaution, or adverse reaction for which there is satisfactory causal association; to add or strengthen a statement about drug abuse, dependence, psychological effect, or overdosage; to add or strengthen an instruction about dosage and administration that is intended to increase the product's safe use; to delete false, misleading, or unsupported indications for use or effectiveness claims; or any labeling change normally requiring a supplement and FDA approval that FDA specifically requests.

The proposed amendments would require a CBE-0 supplement to contain the following information: (i) the application number(s) of the drug product(s) for which the CBE-0 supplement is being submitted: (ii) a description of the proposed labeling change; (iii) the basis for the proposed labeling change; (iv) a copy of the proposed product labeling; and (v) for an ANDA holder, confirmation that notice of the proposed labeling change in the CBE-0 supplement, including a copy of the information supporting the change, has been sent to the NDA holder for the RLD at the same time that the ANDA supplement is submitted to FDA, unless the approval of the NDA has been withdrawn.

Providing the ANDA holder CBE-0 authority would require a new procedure for coalescing product labels, particularly where multiple generics are available for one RLD or where the RLD has been discontinued. FDA has crafted one example of how the procedure may work. See Figure 1 below from the Federal Register.

FDA proposes that the ANDA recipient of newly acquired safety information (following submission of adverse event information, as appropriate) would simultaneously: (i) submit a CBE-0 supplement in the form described, (ii) distribute revised labeling at the time of submission, and (iii) notify the NDA holder of the RLD, if any.

To make the proposed labeling change information available to prescribers and patients as quickly as possible, FDA proposes to post the CBE-0 information to an FDA website, immediately and without review of the supplement information. The submitter would be responsible for verifying that the correct CBE-0 supplement information appears on the webpage and for contacting FDA within five business days of the posting if the information is incorrect. The webpage posting of the supplement would continue during FDA's review of the proposed labeling change and determination of whether the change meets the criteria for a CBE-0. The supplement would be available on the webpage until FDA has completed its review and issued an action letter.

FDA explains that a copy of the information supporting the labeling change described in the CBE-0 supplement should be sent to the NDA holder because the NDA holder, in most cases, has substantial knowledge about the post-marketing experience of the drug product and "FDA's analysis of whether the labeling changed proposed by an ANDA holder in a CBE-0 supplement should be approved (and required for inclusion in the labeling of all versions of the drug) would benefit from the views of the NDA holder for the listed drug that was the basis for the ANDA submission."2 The NDA holder would independently review the information contained in the notification from the generic company and may submit a labeling supplement or correspondence to its NDA regarding the change proposed by the CBE-0. If the NDA holder for the RLD does not submit a supplement seeking approval for a label change that is related or conforming to that in the CBE-0 supplement, FDA may request that the NDA holder submit such a supplement. Indeed, FDA states in the description of the proposed rule that "[i]t is expected that a valid safety concern regarding a generic drug product also would generally warrant a change to the labeling through a CBE-0 supplement by the NDA holder for the RLD ... [I]f the NDA holder declined to submit a supplement to make the change that FDA has concluded is appropriate, FDA would consider whether the NDA holder's failure to update its labeling would warrant the initiation of proceedings to withdraw approval of the NDA."3 

If the proposed change meets the criteria for a CBE-0 supplement and FDA approves the change, both the ANDA submitter's and RLD label revision would be approved at the same time. These changes to the RLD label would require other ANDA holders to update their labels with conforming language via a CBE-0 within 30 days of posting of the RLD labeling change to the FDA website. However, if the Agency were to issue a complete response not approving the CBE-0, the application holder(s) must revert to the previous product labeling and cease distribution of the product with the revised label.

FDA Requesting Comment

FDA is requesting comments on the proposed rule, including specifically the proposed approach for informing prescribers and patients of proposed labeling changes for a particular generic product via a new or existing webpage and whether five business days is sufficient for an applicant to verify the accuracy and completeness of posted information. FDA is proposing the rule become effective 30 days after the date of final publication. Thus, FDA intends the proposed rule, if finalized, to apply to any submission received by FDA on or after the effective date. However, FDA has invited comments on how the final rule should be implemented. FDA has established a 90-day docket for the collection of comments; interested individuals may submit electronic or written comments through January 13, 2014. 

Footnotes

1 78 Fed. Reg. 67985 (Nov. 13, 2013).

2 78 Fed. Reg. at 67991.

3 78 Fed. Reg. at 67992-3.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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
Jonathan Berman
Jennifer J. Chheda
Colleen Heisey
 
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.