FDA's One-click Study

At the beginning of November, FDA announced its intention to conduct a study looking at the so-called "one-click rule." As readers of this blog know, I've termed this, "The 'Rule' That Isn't."

The basic idea behind any version of the one-click rule is that companies can meet their fair balance requirement (21 CFR 202.1(e)(5)(ii)) by including a hyperlink to the risk information, rather than by providing the risk information itself in the original communication. As I've written about previously, this idea has had significant allure for marketers of prescription products but there has never been any indication from the FDA that it was open to it...until now.

I have been working with a few different clients preparing comments on the study proposal outlined by the FDA. Those will be posted to the docket and available for public view at a later date.

In this post, I wanted to take a step back and look at what this study means (and what it doesn't mean) for the immediate and future use of space-limited contexts by prescription product manufacturers and FDA guidance about this issue.

In 1998, FDA took its first enforcement action for Internet marketing. At the time, the FDA noted that "the link to the full prescribing information alone is insufficient to meet the requirements...that advertisements contain fair balance."

This began an 18-year history of the FDA making clear that it did not acknowledge a one-click "rule." This position was further solidified via FDA's 2014 guidance on space-limited contexts (the so-called "Twitter Guidance") that directly addressed the use of Twitter and search engine marketing formats that explicitly limit the number of characters. In that guidance, FDA asserted, "Regardless of character space constraints that may be present on certain Internet/social media platforms, if a firm chooses to make a product benefit claim, the firm should also incorporate risk information within the same character-space-limited communication." This is as explicit a rejection of any version of a one-click rule as FDA could possibly have made.

Just one sentence earlier in the guidance, FDA further asserted that, "If an accurate and balanced presentation of both risks and benefits of a specific product is not possible within the constraints of the platform, then the firm should reconsider using that platform for the intended promotional message (other than for permitted reminder promotion)."

Combined, these two statements established a framework that FDA was explicitly acknowledging could not be used by some manufacturers of prescription products for making claims about the benefits of their products. The consequences of this framework is that in certain contexts only products not subject to FDA's fair balance requirement would be able to provide benefit information about their products.

Of course, "benefit" information includes any suggestion of the product's indication. In practice, this means that prescription products manufacturers are frequently prevented from letting people know that their product(s) are possible treatment options for them; and that FDA's official position, as expressed in the 2014 guidance, is that this is fine.

Many people objected to this aspect of the draft guidance (see, for example, the comments from PhRMA), and that resulted in a brief movement to include a version of the one-click rule in the 21st Century Cures Act.

In that context, FDA's openness to studying these issues is a major step forward. Rather than simply assuming without any evidence that the public is harmed by companies following some version of a one-click rule, FDA is actually studying the issue.

This positive development is balanced, however, with the study design itself. In the proposed study, FDA is comparing a format that makes use of a one-click rule with a format that follows the recommendations from the 2014 guidance. One problem with this study design is that it is comparing a format that the FDA has acknowledged is not available to all product manufacturers because of the nature of their specific indications and risks. Indeed, I'm not aware of a single company that has attempted to use the format FDA demonstrated in that guidance for Google search or a Twitter ad.*

In addition, although FDA's willingness to study this topic is refreshing, the study announcement coming late in 2016 would seem to indicate that the status quo will remain for several years. It has been more than a year since FDA has released any new or updated guidance related to advertising and promotion (the last one was a minor revision in August of 2015), and the existing FDA guidance on space-constrained contexts has some glaring issues, independent of the position on one-click.

Taking a generous view of FDA's speed in fielding this research, it would be difficult to imagine that the final study results would be available before the end of 2017. FDA absolutely takes the work of its research team into account in developing guidance, including the ad-promo research. That probably means that the earliest we would see any update to the 2014 guidance would be 2018.

That's four years after FDA released the draft guidance and nine years after the 2009 hearings. FDA can't be expected to provide guidance that keeps up with the pace of technological change. Indeed, I think that's a virtue rather than a drawback to FDA's approach. It's better to have guidance that lags slightly behind innovation rather than wasting time developing guidance on topics that prove to be mere flashes in the pan. Consider the wasted effort if FDA had developed a guidance dedicated to Sidewiki after its 2009 hearings.

This, however, is a very different situation. FDA's enforcement activity related to its rejection of any version of the one-click rule has spanned nearly 20 years. Throughout that time, marketers of prescription products who want to inform the public about how they can help have been hindered in the ability to make that information available in the platforms that people are showing they prefer. And only now is FDA announcing its intention to see whether that position has any basis in actual experience. 



* If anyone is aware of such an ad, please share it in the comments or via the contact form in the right rail.

Google's Latest Ad Format Update

Google recently announced a change to its standard ad unit. This marks the third significant change affecting marketers of prescription products in the past year who are using Google.

At this point, I'm definitely seeing the need to revisit my article on using Google to market prescription products and even the presentation from last fall's FDLI Advertising and Promotion conference is now out of date. Over the next few months, I will be providing more on that.

In the meantime, here's the skinny on the update.

Google is fully embracing a mobile-first world view and is expanding the character count limitations for text ads.

The chart below (lifted from Google's public blog post) shows the breakdown between the current and the new formats.


For the ad copy, an additional 35 characters will be available for the headline, and an additional 10 characters will be available for the description. As pointed out by Convergence Point Media, in practice, this might expand the total characters available in a description even more than 10 characters because the description will no longer be treated as two separate 35-characters fields. That might mean that marketers are able to avoid the waste that sometimes is entailed in the current two-line description.

The primary benefit for marketers of prescription products is that it will be easier to meet their requirements for promoting drugs without a black box via a reminder ad and for black box drugs to fit all of the required elements for a reminder-like ad. This is most particularly relevant to fixed dose combination products. When the product being promoted has four or five active ingredients, it can very quickly be difficult to fix everything into the current character count limitations. Yet, failure to use the full established name remains on FDA's radar both in guidance and enforcement as a key regulatory requirement.

In addition to this expansion of the character counts, the display URL will be treated differently. Currently, marketers are able to manually enter a distinct display URL for their ads. In the new ad format, the display URL will be "automatically extracted" from the destination URL, with some (but only minimal) ability to customize the display URL seen by users.

This change has far greater implications for prescription product marketers, as it is precisely the ability to have a difference between the destination and the display URL that enables marketers to make use of redirecting ads.

If the ads automatically extract the base URL from the destination URL, then the mismatch between display and destination URL that is essential to redirecting ads will no longer be possible. This would significantly limit prescription product marketers' options. 

The biggest concern is for smaller, less well known brands. For those brands a reminder ad is not viable because very few people are already aware of their brand name; hence a reminder ad that doesn't describe the product's use has no value. But if the redirecting ads are eliminated, then such lesser known brands would have no way of attracting people who are looking for treatments. By assumption, these brands are not as well known which also means that their organic listings are not likely to be very high, so this would have a deeply chilling effect on the information available to people using Google. In essence, Google paid search would no longer be a viable means for building brands, but only for maintaining brands built on other platforms.

At the moment, Google has not provided any information about when this update will move beyond its initial testing to be available for everyone, or when it will be mandatory that ads adopt this new format. For now, this is simply something that marketers and regulatory professionals will need to stay abreast of.

It is also important to note that Google isn't synonymous with search, though it is the largest platform by a significant margin. Yahoo! and Bing remain very large players in this arena, and there's no reason to assume that Yahoo! and Bing will automatically adopt Google's changes. As a practical matter, this will probably mean having multiple sets of paid search campaigns going through the review and approval process.

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.

The Value of Virtual Communities

At last week's Drug Information Association's (DIA) Marketing Pharmaceuticals* conference, Kim Belsky of OneSource Regulatory spoke about the DIA Ad-promo group. Kim and Tracy Rockney, who founded OneSource, are co-chairs for the group.

This is a virtual community open to DIA members, and there are monthly sessions with set topics. Today's call is slated for noon, and the announced topic is the 2015 enforcement activity from OPDP. I suspect, however, that the agenda might be hijacked by the settlement between Amarin and FDA that was announced last night.

I'm still reading up on the settlement and expect to add to my previous discussion of the issues raised in this legal challenge.

I wanted though to note how nice it is to be able to hop on a call while this topic is fresh and hear what others are saying. There's a vibrant community of ad-promo regulatory professionals, but we tend to be dispersed around the country, and any given company will rarely have more than 10 of us. So, being able to jump on a call and hear the perspective of others is fantastic.

If you aren't already a member of the DIA ad-promo group, I hope you'll join. Just hop over to the DIA communities page and select the link for the Regulatory Affairs A&P group.


* BTW, I hope to post a recap of the conference in the next few days. You can see my live Tweets on Twitter using the hashtag #MarketingPharma16

Google SEM Changes Update

In June, Google announced changes to the ways search engine marketing (SEM) would work for marketers of prescription drugs. The background on the changes and the full original update is available here.

Recently, Google has provided additional detail about the new vanity URL policy, some new options, and hard dates for implementation.

First a quick backgrounder (see the earlier post for a more extensive background).

Background

Google eliminated the black box ad format that was created in 2009, and it announced that changes would be coming to its policy on the use of redirecting URLs (aka vanity URLs) by marketers of prescription products. SEM ads that make use of redirecting URLs are one specific instance of a more general category of ad I call redirecting ads.

Redirecting ads are not limited to search engines, but they're featured very prominently in search engine marketing. The basic idea behind a redirecting ad is that the ad itself does not promote a prescription product, instead it directs viewers to another location (website, toll free number, etc.) where a prescription product is being promoted. Marketers of prescription products make use of them extensively in space-limited contexts, such as SEM, because it can be difficult to fit all of the required elements from a full product promotion into such contexts.

For SEM ads, marketers often have to use these ads because their only other option is using a reminder ad, and a reminder ad is by definition worthless if the person seeing the ad doesn't already know the name of the product.

So, the key features of a redirecting SEM ad are:

  1. Does not mention or imply a specific prescription product
  2. Provides a link to a prescription product website
  3. Displays a URL that does not match the destination page URL
It's that third element (the mismatch between the display and the destination URL) that has caused Google some agita. Google has long had a policy that prevents advertisers from having a significant mismatch between the display and destination URL. Google has previously been making an exception to that policy for marketers of prescription products precisely because there didn't seem to be any other option for them when a reminder ad would not work.

June Announcement

In June, Google announced that it would be changing its exception to that policy. At the time, Google said that instead of permitting marketers to invent their own display URL, Google would limit marketers to just three options.

  1. Use CompanyName as the display URL
  2. Use CompanyName.com as the display URL
  3. Use "Prescription treatment website" or "Prescription device website" as the display URL

Latest Update

Now, Google has changed those options. First, Option 1 is no longer available. The only possible display URL using a company's name is for the display URL to be CompanyName.com. Moreover, to use that option, the URL itself must be live and the advertiser must own the URL. It is important to note that although the DISPLAY URL will be CompanyName.com, the DESTINATION URL  (i.e., the page people land on when they click on the ad) is completely under the control of the advertiser and does not have to be the company's main website.


In addition, the display URLs available under Option 3 have expanded significantly. Whereas the June announcement mentioned only two possibilities ("Prescription treatment website" or "Prescription device website"), there are now six display URLs available in both English and Spanish. Those display URLs are:
  1. Prescription treatment website
  2. Prescription device website
  3. Medical device website
  4. Preventative treatment website
  5. Prescription contraception website
  6. Prescription vaccine website
In Spanish:
  1. Sitio de tratamientos con receta
  2. Sitio de dispositivos con receta
  3. Sitio de dispositivos médicos
  4. Sitio de tratamientos preventivos
  5. Sitio de anticonceptivos con receta
  6. Sitio de vacunas con receta

Again, just as was previously announced, manufacturers of prescription products will be able to choose any of these display URLs, but whereas "CompanyName" in CompanyName.com is a template that will be filled in with the actual company's name, the options above must appear exactly as presented.

Timing

In addition to this change in the number of options, and the Google text options, Google has also announced the timing for these changes to take effect. There are three timing deadlines to keep in mind. The first is now.

Marketers who choose to make use of the option to use CompanyName.com as the display URL can immediately begin doing so. There is no need to wait, but there's also no requirement to do that immediately.

The next milestone is February 1, 2016. Beginning on that date, all of the 12 display URLs (six in English and six in Spanish) will be available as possibilities for redirecting ads to use.

Finally, the deadline for transitioning to these new options is March 1, 2016. On that date, no ads that are running using customized vanity URLs will be able to run. All ads must switch over to either of the two options:
  1. CompanyName.com
  2. One of Google's 12 display URLs
    1. Prescription treatment website
    2. Prescription device website
    3. Medical device website
    4. Preventative treatment website
    5. Prescription contraception website
    6. Prescription vaccine website
    7. Sitio de tratamientos con receta
    8. Sitio de dispositivos con receta
    9. Sitio de dispositivos médicos
    10. Sitio de tratamientos preventivos
    11. Sitio de anticonceptivos con receta
    12. Sitio de vacunas con receta

Implications

Search engines are vital to people using the Internet looking for health information. Consequently, marketers cannot afford to ignore SEM ads, and since these changes have been announced, there is plenty of time to update SEM campaigns to conform to these new Google-specific guidelines, and it is worth emphasizing that as I write this blog post, there is no word as to whether Yahoo!, Bing, or other search engines will also be adopting similar policies.

Additionally, marketers and their regulatory counterparts will have to review these ads to determine whether they need to be adjusted beyond the change in URL to avoid the implication of a specific prescription product; and we will have to wait to see how users adapt to seeing multiple ads using the same words as their display URL for unique ads.

21st Century Cures Act Tracker

I found this handy legislative tracker, so I'm adding it to the blog, so you can bookmark this post to stay updated on this legislation. Currently, it's in the Senate and has been assigned to a committee.

The Amarin Injunction

On August 7, 2015, a federal district judge issued a preliminary injunction prohibiting the FDA from taking action to prevent Amarin Pharma from disseminating off-label information about Vascepa for the treatment of patients receiving statins who also had persistently high levels of triglycerides. This action has been widely hailed as a significant blow to FDA's authority to regulate off-label promotion and also as a major victory for defenders of the first amendment rights of pharmaceutical companies, and while I've seen and read many blogs and news stories dissecting the ruling for attorneys (I recommend this and this from FDAlawBlog), I haven't seen anyone discuss how this affects FDA regulatory professionals. That's what this blog entry is intended to address.

For this post, I feel the need to reiterate that I'm not an attorney, and nothing you read on this blog should be construed as legal counsel.

Background

Amarin's Vascepa is currently approved by FDA as a drug indicated along with diet to lower triglyceride levels. Amarin sought expanded approval for patients who were taking statins and continued to have higher cholesterol levels. To gain this approval, Amarin entered into a Special Protocol Assessment (SPA) with FDA, where FDA sets out and agrees to a specific study design, endpoints, etc. Generally, if companies abide by the SPA and the study meets its primary endpoints, approval is a foregone conclusion.

In this case, Amarin followed the SPA and met the primary endpoints, but the FDA decided that research conducted in the interim had cast doubt on whether the endpoints were meaningful, so FDA convened an advisory board, which voted against approval, and then FDA issued a complete response letter to Amarin denying the approval. FDA stated in its complete response letter that Amarin should NOT promote Vascepa for the expanded indication.

Amarin filed suit against FDA stating that FDA was attempting to preemptively prevent Amarin from disseminating truthful, non-misleading information about its products.

In response to this suit, FDA sent a letter to Amarin (and the court) stating that FDA did not object to any of the information that Amarin intended to disseminate, so long as Amarin made certain disclosures about that information.

That takes us to the preliminary injunction.

Key takeaways from the Amarin ruling:
1. Dissemination of off-label reprints is uncontested.
Though previous FDA guidance on this topic would seem to have firmly enabled this practice, there nonetheless have been holdouts and suspicion about its provenance. This ruling further enhances the confidence companies can have in the permissibility of disseminating these reprints.

2. Disclosures are crucial.
One key component of the injunction that was ignored by many is that Amarin wanted to omit information about FDA having declined to grant approval for the use being studied. The judge disagreed with Amarin, and though he didn't entirely accept FDA's proposed wording of the disclosure, he did agree that Amarin needed to provide the information that not only was the use not currently approved, the FDA declined to approve that indication.

3. There's more to come.
The judge issued this ruling on August 7 granting Amarin the preliminary injunction it sought. The preliminary injunction was a sign that the judge thought Amarin was likely to succeed based on the merits of the case, but it was not itself a final decision; and it appears unlikely that such a decision will be reached because on August 28, Amarin and the FDA requested that the judge hold off on ruling on the underlying case because the two parties were working out a settlement. The nature of that settlement might provide greater clarity, if it is publicly released.

4. The status quo is unchanged.
As much as the ruling itself was heralded in many circles as a significant blow to FDA's authority to prohibit off-label promotion, at the end of the day nothing has changed. FDA had already stated that it would not have objected to Amarin's dissemination of the information if certain disclosures were provided. So, the injunction ruling prevents FDA from taking an action that FDA had already said it didn't intend to take.

This wasn't so much a landmark ruling against FDA as it was tweaking around the edges of how to follow FDA's off-label reprint guidance, but the specifics of the case are highly relevant. Unless your company happens to be in the 2nd circuit and to have entered into a Special Protocol Assessment with FDA and to have had the specific indication rejected by FDA, it will be very difficult to apply the principles of this ruling to your situation (such as how to modify your disclosures outside of FDA's guidance on the matter). And in the meantime, companies should feel quite comfortable disseminating off-label reprints in accordance with FDA's previously issued guidance while avoiding off-label promotion itself.