United States: FDA And Amarin Pharma Reach Milestone Settlement Allowing Off-Label Drug Promotion

Last Updated: March 31 2016
Article by Areta Kupchyk and Michele L. Adelman

A milestone Settlement Agreement was reached March 8, 2016 between the Food and Drug Administration and Amarin Pharma, Inc. that expressly allows Amarin to promote its drug product, Vascepa®, for unapproved – i.e., "off-label" – uses. Vascepa® is approved only for the treatment of severe hypertriglyceridemia, meaning patients with triglyceride levels at or above 500 mg/dL of blood. The settlement allows Amarin to promote Vascepa® to treat patients on statin therapy with persistently high triglycerides, a less severe condition describing patients with triglyceride levels ≥ 200 and ≤ 499 mg/dL of blood, so long as statements and disclosures are used to ensure such promotion is not false or misleading. This combination of statements and disclosures along with the use of a voluntary procedure for Amarin to pre-clear future promotional claims with the FDA marks a turning point for the regulation of drug advertising and promotional activity in the United States by easing FDA's long held and staunchly defended restrictions on drug marketing.

The Agreement resolves a lawsuit brought by Amarin against FDA for violation of its First Amendment right to Commercial Free Speech. Thus, the Agreement contains an acknowledgement by the FDA that under the decision in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), off-label promotion that is truthful and not misleading "may not form the basis of a prosecution for misbranding" against a pharmaceutical manufacturer.

Unique Aspects of the Amarin Case

The Amarin case, it should be noted, involved a unique set of facts that strongly supported statements the Court considered not misleading about Vascepa's unapproved uses. Amarin successfully completed a phase 3 clinical study demonstrating the effectiveness of Vascepa in lowering triglyceride levels in patients with persistently high triglycerides who were still on statin therapy. This study was conducted under a Special Protocol Agreement entered with the FDA, under which FDA agreed to approve Vascepa for this indication if Amarin satisfied certain requirements. These requirements included meeting pre-specified endpoints and enrolling at least 50 % of patients for an outcomes trial to examine whether Vascepa would also reduce cardiovascular event in patients with persistently high triglycerides. Amarin met the pre-specified endpoints for the SPA trial and met the enrollment criteria for the outcomes trial. Thus, Amarin believed it had satisfied FDA's SPA requirements for approval of Vascepa for the second indication. However, with the affirmation of an Advisory Committee, FDA concluded the endpoints previously agree upon did not establish the lower triglyceride levels in patients with persistently high triglycerides lead to fewer cardiovascular event. FDA thus rescinded its SPA, a rare occurrence, and refused to approve Amarin's supplemental application for the expanded indication; instead, FDA asked for more data.

In addition, the FDA warned Amarin that any promotion of Vascepa for the treatment of persistently high triglycerides would render Vascepa misbranded. Based on this "threat", Amarin brought its suit against FDA. It was with this background that the Court came to examine whether Amarin's proposed statements and disclosures to accompany promotion of Vascepa for this unapproved use would be false or misleading. After a detailed review, the Court agreed that most of Amarin's proposed statements would ensure that its promotion of Vascepa would not be false or misleading. In the Settlement Agreement, Amarin agreed to be bound by its proposed statements and disclosures as reviewed by the Court. Specifically, Amarin agreed to disseminate the results of the studies supporting the unapproved uses with the statement:

"Supportive but not conclusive research shows that consumption of EPA and DHA ** * omega-3 fatty acids may reduce the risk of coronary heart disease"

Amarin also agreed to distribute reprints of relevant peer-reviewed scientific publications. More importantly, Amarin agreed to make relevant "contemporaneous disclosures" to physicians, including:

  • FDA has not approved Vascepa to reduce the risk of coronary heart disease.
  • FDA has not approved Vascepa for the treatment of statin-treated patients with mixed dyslipidemia and high triglyceride levels.
  • The effect of Vascepa on the risk of cardiovascular mortality and morbidity has not been determined.
  • A cardiovascular outcomes study of Vascepa designed to evaluate the efficacy of Vascepa in reducing cardiovascular mortality and morbidity in a high risk patient population on statin therapy is currently underway.
  • Vascepa may not be eligible for reimbursement under government healthcare programs, such as Medicare or Medicaid, to reduce the risk of coronary heart disease or for treatment of statin-treated patients with mixed dyslipidemia and high (> 200 mg/dL and < 500 mg/dL) triglyceride levels. We encourage you to check that for yourself. Impact of the Amarin Settlement on Off-Label Prosecutions

FDA Accepts Caronia Case Outcome

The Amarin Settlement Agreement also signals the acceptance by federal authorities that Caronia establishes that off-label promotion through truthful and non-misleading verbal statements, standing alone, cannot form the basis of criminal charges for misbranding. In Caronia, the Second Circuit reversed the misdemeanor criminal conviction of a pharmaceutical sales representative, Alfred Caronia, for misbranding as a result of his verbal statements relating to off-label uses of the drug Xyrem®. That prosecution, consistent with some earlier government prosecutions, was premised upon the allegation that Caronia's promotional statements showed an intended use for Xyrem and the Xyrem label had inadequate directions for that use and therefore caused the drug to be "misbranded."

On appeal, the defendant argued that he was convicted purely based upon his truthful and non-misleading statements about off-label uses of Xyrem, in violation of his right of free speech under the First Amendment. The government's opposition was that "Caronia was not prosecuted for his speech, but that Caronia's promotion of Xyrem for off-label use served merely as 'evidence of intent,' or evidence that the 'off-label uses were intended ones[] for which Xyrem's labeling failed to provide any directions.'" Id. at 160-61. The Second Circuit rejected this opposition because the government's consistent arguments at trial were that Caronia violated the law through his off-label promotion and marketing of Xyrem – not that this promotion merely served as evidence of intended use of the drug. Thus, "[t]he government never suggested, for example, that Caronia conspired to place false or deficient labeling on a drug. Rather, the record makes clear that the government prosecuted Caronia for his promotion and marketing efforts." Id. at 161 (citations omitted). The Second Circuit then went on to find that the government's restriction on Caronia's speech was not consistent with the First Amendment under the four-part test set forth in Central Hudson Gas & Electric Corp. v. Public Service Commission, 447 U.S. 557 (1980).

The Amarin Settlement Agreement takes the next step from Caronia: Not only are Amarin sales representatives free from prosecution for truthful and non-misleading off-label promotion of Vascepa®, the FDA has agreed to review such off-label communications up to twice a year upon Amarin's voluntary submission to confirm as much.

Pacira Pharmaceuticals Follows Amarin

Since the Amarin Court sent FDA and Amarin into its settlement negotiations, two cases have been brought and resolved in which the companies' off-label promotion has been permitted. First, Pacira Pharmaceuticals settled its lawsuit against FDA by reaching an agreement on a labeling change that effectively affirmed Pacira's promotion of its analgesic drug, Exparel®, for use in various surgeries rather than in only the two specific surgeries studied in the clinical trials supporting Exparel's approval. Pacira, like Amarin, had unique and compelling facts supporting Pacira's expanded promotion. Specifically, FDA had approved Exparel as a surgical analgesic without specifying the types of surgeries in the indications for use. Instead, the directions for use of the drug covered only the two types of surgeries. Upon being sued, with the Amarin case having just been decided, FDA agreed to revise the labeling to provide directions for use for various surgeries and thus permit promotion for such uses.

Medical Device Maker, Vascular Solution Inc, Follows Caronia

Most recently, a Texas jury found Vascular Solution Inc, a manufacturer of a medical device intended for ablation of superficial veins, not guilty on criminal charges of off-label promotion based on a conclusion that the promotion was true and not misleading.

So where will off-label prosecution go from here? While only time will tell, a good guess would be that criminal misbranding prosecutions will focus on blatantly false statements and non-speech evidence of intent to misbrand – such as internal marketing plans showing intended uses of a drug (that do not match the label directions), and incentive compensation plans that are designed for uses of a drug that do not match label directions. However, to avoid misleading promotion, statements about off-label uses should be carefully crafted with disclosures and qualifying statements. As the Amarin court noted, "[p]rior consultation with the FDA may prove a helpful prophylactic, and may avert misbranding charges where the FDA and the manufacturer would take different views of a statement in the end...."

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
Events from this Firm
25 Oct 2017, Webinar, Boston, United States

Foley Hoag will present a 60-minute webinar on Wednesday, October 25 at 12:30 pm EDT, offering guidance for in-house counsel regarding the basics of trademark and design protection in the European Union. Attendees will learn about the opportunities and pitfalls to be on the lookout for when looking to secure, protect, and enforce an IP portfolio overseas.

1 Nov 2017, Webinar, Boston, United States

Please join Foley Hoag on Wednesday, November 1, 2017 for a webinar that covers the details of drafting an appropriate arbitration clause for your company’s commercial contracts.

9 Nov 2017, Conference, Waltham, United States

Please join us on Thursday, November 9 at the Westin Waltham Hotel for our quarterly New England M&A Forum, which brings the latest in market trends and recent legal developments to the New England M&A professionals' community.

 
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.

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.