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Will the FDA Change the Way it Regulates Off-Label Promotion? One Court Case that May Have Helped Pave the Way

April 13, 2017 | Ashley Godfrey, PhD, RAC, Clinical Research Scientist II | Regulatory Affairs

When it comes to off‑label promotion – promoting a prescription drug for a use that is not included in its approved labeling – the FDA has historically taken the position that doing so risks criminal misbranding of the product under the Food, Drug and Cosmetic Act (FD&CA). However, a number of recent court cases challenging this position on the basis that it violates the First Amendment rights of drug companies have paved the way for a potential change in the way FDA will be regulating off-label promotion. We are eagerly awaiting the release of a new FDA guidance on off-label communication. This guidance will be the subject of another blog post when it becomes available. But in the meantime, I thought I would briefly discuss the relevant history of one of the court cases, Amarin Pharmaceuticals, Inc. (Amarin) versus FDA, that helped put the potential policy changes in motion.

FDA’s Historical Position

To give a bit of background, here is a short look at what the FDA’s thinking has historically been on the topic of off-label promotion, and why off-label promotion has been associated with criminal misbranding in the eyes of the Agency.

Image courtesy of mapichai at

The FD&CA considers a drug misbranded if the labeling for the product is either:

  • false or misleading, or
  • lacks adequate directions for use.

Adequate directions for use are defined by the FDA as directions that can be followed by a lay person to “use a drug safely and for the purposes for which it was intended.”

Because labeling for prescription drugs cannot, by definition, bear adequate directions for use by a lay person, the drug must meet the FDA exemption for this requirement.

To meet this exemption, the FDA must approve the product’s labeling (and thus the adequate directions for use) via the NDA process. The FDA has long considered that off-label promotion creates a new “intended use” for the product, and since the existing labeling does not contain adequate directions on how to use the product for this new intended use (eg, dosing and administration instructions) the product is misbranded. The concept of “intended use” will be the subject of another forthcoming blog!

The FDA has historically taken enforcement actions against companies that engage in off-label promotion. However, this enforcement action has been challenged over time, as exemplified by the legal action brought by Amarin against the FDA. Momentum gained by this and other cases that followed swiftly on Amarin’s coattails could be enough to force a change in FDA’s position on off-label promotion.

Amarin versus FDA

The pivotal case between Amarin and the FDA surrounds VASCEPA®, Amarin’s approved drug indicated as an aid, along with diet, to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. The drug’s initial approval was based on a single Phase 3 clinical trial – the MARINE trial – conducted in patients with “very high” triglycerides (≥500 mg/dL).

Similar to their approach with the initial indication, Amarin designed a single Phase 3 trial to examine the effect of VASCEPA® on triglyceride levels among statin‑treated patients with persistently high triglycerides (the ANCHOR trial) and entered into a Special Protocol Assessment (SPA) with the FDA.

  • An SPA generally indicates FDA agreement that a study will support approval of the product’s marketing application:
    • If the study is conducted according to the protocol, and
    • the study achieves its agreed-upon objectives.

In connection with the ANCHOR SPA, Amarin also agreed to conduct the REDUCE‑IT trial to examine whether VASCEPA® would be effective in reducing cardiovascular events. As a condition, FDA required the REDUCE‑IT trial to be at least 50% enrolled before accepting Amarin’s sNDA for use of VASCEPA® in statin‑treated patients with persistently high triglycerides. Based on positive ANCHOR study results, combined with adequate enrollment of the REDUCE‑IT trial, Amarin submitted its sNDA for the additional indication in February of 2013.

The FDA convened an Advisory Committee to discuss the clinical validity of the agreed-upon ANCHOR endpoint of triglyceride lowering and whether it should be used as a surrogate endpoint for reduced adverse cardiovascular events (sufficient for its approval for use in patients with persistently high triglycerides). The Advisory Committee voted against approval of VASCEPA® for the second indication and FDA rescinded the ANCHOR SPA and issued a Complete Response Letter stating that:

  • Data were needed to show a reduction in cardiovascular events (i.e., data from the REDUCE‑IT trial), and
  • Any effort by Amarin to market VASCEPA® for the proposed supplemental use could be misbranding under the FD&CA.

And this led to the beginning of the legal battle between Amarin and the FDA. Amarin claimed that it had a First Amendment right to engage in truthful and non-misleading speech about the results of the ANCHOR trial.

Image courtesy of manostphoto at

A few key things to keep in mind:

  • Amarin had a completed clinical trial on the specific use it wanted to promote (with design and analysis prospectively agreed upon by the FDA).
  • The speech in question was only directed at healthcare providers and the off‑label use Amarin wanted to promote was very close to the approved indication.
  • Amarin was aware of and had agreed to disclose that they were specifically communicating only essential contextual information about the unapproved use that was truthful, scientific information that was non‑misleading.

The court agreed with Amarin’s arguments and issued a preliminary injunction against the FDA, preventing the Agency from taking action against the company. After 6 months of haggling, Amarin and FDA finally settled the case, allowing Amarin to engage in “truthful and non-misleading speech promoting the off-label use of Vascepa,” albeit under a limited set of circumstances.

Timeline of Events

The FDA’s Response

The results of court battles like the one with Amarin definitely left their mark on the FDA as indicated in CDER’s 2016 priorities from Director Janet Woodcock – a priority was to “re-evaluate our regulation of drug advertising and promotion in light of current jurisprudence around the 1st Amendment: ongoing, progress made, but more work needed.”

In a press release issued on 18 January 2017, the FDA recognized the high level of interest regarding their views on communications about medical products. The release of two draft guidances in January – one covering drug and device manufacturer communications with payors, and other covering medical product communications that are consistent with FDA-required labeling – are intended to clarify the FDA’s current thinking on these two specific types of communication. In addition, the FDA has re-opened the comment period after the November 2016 hearing on communications about unapproved uses of approved or cleared medical products (i.e., off-label promotion) – the date has now been extended until 19 April 2017. Along with this extension, the FDA added a memorandum to the docket titled Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products. This document provides background information as well as some of the FDA’s current thinking on the issues surrounding off-label promotion, including a discussion of first amendment considerations.

Stay tuned for future blogs on this very important topic!

Have any further questions?

IMPACT has experienced regulatory affairs professionals ready to assist you. If you would like to discuss your specific needs, please contact us or give IMPACT a call today at (919) 899-9248.

Category: Regulatory Affairs
Keywords: Off-label promotion, misbranding, Special Protocol Assessment

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