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
12 Oct 2018, Other, Boston, United States

The New England Electricity Restructuring Roundtable has been meeting bimonthly since 1995 to discuss current topics related to important changes in the electric power industry in Massachusetts and throughout New England.

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