The Amarin Settlement Created a New Review Process

Frequently, people refer to the process of requesting advisory comments from the Office of Prescription Drug Promotion (OPDP)* on draft promotional materials as getting "preclearance" of those materials. But that's just not accurate.

Technically, FDA never provides "clearance" of materials to use, unlike, for example, the Pharmaceutical Advertising Advisory Board (PAAB) in Canada. Instead, FDA will review and comment on promotional materials, but even assuming that all of the comments are addressed, it is still possible (though unlikely) to receive an enforcement action from the FDA for engaging in violative promotion, and there is no requirement to modify promotional materials to address FDA's comments (though of course failing to do so is generally unwise).

It is true that under certain circumstances, FDA can require that promotional materials be submitted for advisory comments prior to use (e.g., because the product has received accelerated approval), and that this submission is independent of the submission under cover of Form 2253 prior to use, but even in those circumstances, the FDA does not "approve" or "clear" promotional materials. Instead, the FDA simply provides comments on promotional materials and does not typically see how a company addresses (or fails to address) those comments until the materials are submitted under cover of Form 2253 prior to use.

This was the situation until the Amarin settlement on March 8, 2016. For the most part, the final settlement simply codified the terms of the earlier injunction, so, most of my initial post on the topic still seems relevant. There was, though, one significant wrinkle.

In summary, the final settlement included the following provisions:
  1. Amarin may promote Vascepa for off-label use of patients with persistently high triglycerides and not have such promotion used as evidence of misbranding.
  2. The direction from the injunction regarding the promotional materials and required disclosures stands (based on the information known as of the date of that injunction**).
  3. Amarin is responsible for ensuring all of its future statements are truthful and non-misleading.
  4. Nothing in the injunction or the final order is to be "construed to limit Amarin's constitutional rights to free speech."
  5. There's a new procedure for Amarin to ensure that future communications about off-label uses are also truthful and non-misleading (more on this below). The court retains jurisdiction in the event of a future dispute about whether any given off-label communication is truthful and non-misleading.
  6. Additional dispute resolution procedure specified for issues other than new off-label communications.
  7. - 11. Assorted provisions about scope, waiving appeals, costs, etc.
It's provisions 5 and 6 that are most interesting for regulatory professionals engaged in reviewing promotional materials.

Traditionally, the advisory comments process is used in the launch phase of promotion to receive feedback from FDA prior to initial promotional materials being released and for television advertising.

And the way that process works is that materials undergo review at the individual company, and then, after being fully vetted, a new submission goes to the FDA with all of the accompanying references. FDA asserts that its goal is have the review completed in 45 days, but often (especially of late), the review takes 60 days or longer.

FDA comments in response and will often point out alleged deficiencies in the draft materials. Because of the lengthy delay involved in submitting materials for review, companies rarely submit revised versions. Instead, they do their best to adjust the materials and then proceed to finalize them, and (assuming they qualify as product promotion) submit the finalized version to the FDA to meet the 2253 filing requirement. 

The settlement establishes a new procedure. The first thing to note is that this procedure only applies to Amarin at the moment. So, whereas any company can submit any materials at any time via the traditional advisory comments, this new procedure is only available to Amarin.

In addition, Amarin can only do this for two communications per year, as opposed to the theoretically limitless number of requests a company may make for advisory comments. And note that although submissions for advisory comment are most often of a single commercial, other requests for advisory comments will typically include multiple communications, not just the two pieces to which Amarin is limited.

This procedure is explicitly identified as a "preclearance procedure," so Amarin won't simply receive comments from FDA akin to the traditional advisory comments that companies are used to receiving. Instead, FDA will provide clearance to use the materials.

FDA will have 60 days to review the communications and present any concerns or objections to Amarin, after which, Amarin will have 45 days to respond, followed by 30 days for FDA to report any remaining objections.

If the two parties cannot reach agreement after this 135-day process, either party can request that the court step in to resolve the dispute, so there is a formal appeal built in and it goes directly to the court.

The chart below summarizes the key differences between the new "preclearance procedure" and standard advisory comments.

One final note is that the settlement explicitly states that this only lasts until December 31, 2020. One hopes that prior to then, this issue will have been resolved without a further series of one-off agreements and lawsuits.

* Note that although I focus on OPDP within CDER in this post, essentially the same points are true of APLB in CBER.
** This is an important but seldom-noticed qualification. Should the scientific underpinnings of the situation change, all bets are off.