Recap of FDLI #AdPromo2023

Disclosure: I sit on the Planning Committee for the FDLI Ad-Promo conference. This is an unpaid, volunteer position. The contents of this post were not discussed with or influenced by any member of the FDLI staff.

This post provides some of the highlights from FDLI's ad-promo conference. An on-demand version of the conference presentations is available at: https://www.fdli.org/2023/11/advertising-promotion-for-medical-products-conference-on-demand/

The Food and Drug Law Institute's (FDLI) Advertising & Promotion for Medical Products conference wrapped up last week. I attended the conference and also moderated a panel on data privacy and concerns about the use of health data for the targeting of advertising.

The first day kicked off with a fireside chat with Arun Rao from the Department of Justice (DOJ), Lauren Roth from the Food & Drug Administration (FDA), and Serena Viswanathan from the Federal Trade Commission (FTC), led by Christine Simmon of FDLI.

FDA and FTC both noted their recent guidance updates. For FDA, that means the new Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products Questions and Answers Guidance for Industry (SIUU) and the newly finalized Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer (DTC) Promotional Labeling and Advertisements. 

FTC has also been busy, providing updated guidance on endorsements, reviews and testimonials, and a distinct Health Products Compliance Guidance.

DOJ, FDA, and FTC also mentioned the extent to which they are still very much digging out from the backlog created by the pandemic. More than three years after COVID-19 first came to our shores, its effects are very much still being felt.

Rao also mentioned a new policy from DOJ to create a safe harbor for self-reported disclosures made in connection with a merger or acquisition. Under this new policy, companies that learn of wrongdoing at a company they have acquired can be protected from later liability if they report the wrongdoing to DOJ within six months of closing the merger or acquisition. This is as Rao described it a "very big juicy carrot" to encourage self-reporting of wrongdoing, and it also ramps up the need for effective due diligence during the M&A to ensure that all wrongdoing is uncovered and can be reported.

One final point mentioned by Roth is the importance to FDA of combatting misinformation about medical products. Commissioner Califf has repeatedly warned about the need to combat misinformation, and it is not a stretch to see FDA's SIUU guidance as one small step in that direction. By providing further guidance about exactly how sponsors can share truthful, not misleading information about unapproved uses, FDA is enabling efforts to get good information from the people who should be seen as the most reliable source of that information, the product's sponsors.

The next session of the day included an update from OPDP, APLB, CDRH, and CVM related to advertising and promotion.

Katie Gray from OPDP gave a detailed presentation on the Recorlev enforcement action from earlier this year and an overview of the SIUU guidance. Lisa Stockbridge from APLB provided a reminder on reminder advertising, indicating that this well-established category of communication continues to cause firms difficulties. Debra Wolf of CDRH emphasized that although there has not been a significant amount of publicly available enforcement actions from CDRH, the Agency continues to have many private communications with firms about their marketing efforts.

The next plenary session covered scientific exchange and pre-approval communications. Elisabethann Wright of Cooley provided particular insight into the EU's approach, which of course varies widely by country, and has been especially active on platforms such as LinkedIn. Of note is the extremely active role played by the industry's own associations in not merely promulgating guidance and establishing codes of conduct but in regularly enforcing violations of those codes against member companies.

After lunch, the first set of breakout sessions occurred including the panel I moderated on data privacy. I found the discussion very lively and enjoyed hearing from Elisa Jillson from the FTC, Lyra Correa from HHS's Office of Civil Rights, and Nancy Perkins from Arnold & Porter. I have previously opined that the 2020s will be most known for its focus on privacy, and while the cookie-less future we keep hearing about gets pushed back once again, there's growing awareness and concern about how much deeply personal information has been given up and on how companies are using (or misusing) that data.

Simultaneous sessions looked at the recently finalized guidance from the FDA on Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer (DTC) Promotional Labeling and Advertisements while another session looked more into the promotion of veterinary products. Because I was leading another session, I couldn't attend either, but I'm looking forward to using that link provided earlier to view the recordings. 

The afternoon plenary sessions resumed with a look at FTC's role in enforcement of healthcare advertising and closed out with a session on that perennial chestnut of social media usage.

Day two of the conference kicked off with an enlightening discussion of so-called CFL (Consistent with FDA-Labeling) claims. Torrey Cope of Sidley Austin provided an insightful look not just at FDA's enforcement post-guidance for claims that failed to meet the CFL standard, but also for taking the time to examine the nature and wording around the acceptance by FDA of so-called Real-World Evidence (RWE) in the context of product approvals. RWE is not the sole source of CFL claims, but Cope was able to provide some valuable lessons.

The afternoon's breakout sessions included one on artificial intelligence (which I attended), promotional challenges in rare disease treatments, and navigating accelerated approval promotion.

The closing session focused on other avenues for enforcement, including of course, the Better Business Bureau National Advertising Division's (NAD), as well as general counsel to general counsel complaint letters, filing complaints with the FDA, and perhaps even bringing a Lanham Act case.

The NAD's finding against Novartis earlier this year was of course a hot topic. But it is worth noting that in a more recent case, Viiv simply declined to participate in the NAD process. NAD referred the matter to FDA and FTC noting that decision, but as of the writing of this post, no further action by the government has been seen.

Alan Minsk of Arnall Golden Gregory noted the importance of determining your goal when looking at the appropriate path. If your goal is get a competitor in trouble then you really need to rely on the government or the courts, but if your goal is primarily to just get the company to stop the use of misleading promotion, then NAD or a direct complaint letter might be a far more cost-effective solution.

Overall, the conference was a huge success, though my opinion should be viewed as biased because I sit on the conference planning committee. FDA is definitely digging itself out from the pandemic backlog. I fully expect we'll see more from the Agency, as a very active 2023 has already demonstrated.

COVID-19 & Ad-Promo

The COVID-19 pandemic has brought to the fore some issues of ad-promo for FDA-regulated products. I'm posting here to highlight some developments and correct some of the discussion.

Snake Oil & Enforcement

One of the unfortunate things about any new health concern is that the snake oil sales start immediately. There are far too many scumbags who see an opportunity to profit in a crisis. The COVID-19 outbreak is no exception.

These people represent a real danger to the public. People who promote unproven treatments can convince the public that they don't need to take the outbreak seriously, can lead to reckless behavior, and in the extreme can contribute directly to increased deaths as their victims rely on the snake oil instead of trusting healthcare providers.

In this setting, FDA and FTC enforcement is essential. We need vigorous enforcement from the authorities to stop the spread of misinformation. I'm glad to see FTC and FDA have already taken some action in this regard. I hope we'll see more.

Off-Label Promotion & Outbreaks

Researchers, practitioners, and industry are frantically searching for any effective treatments. Currently, the science is unclear about whether any treatment works.

As I write this, there has been a lot of buzz around the possible effectiveness of an anti-malarial treatment, hydroxychloroquine sulfate. This is an already-approved drug being used for an unapproved indication, i.e., this is a classic off-label use of a product.

I have seen some misinformation in the media about off-label uses of products, so I thought it might be helpful to set out the background to all of this.

To bring a new drug to market, a company must submit a New Drug Application (NDA) to the FDA. Among other information, the NDA includes proposed labeling. The proposed labeling provides directions to healthcare providers explaining how to use the drug safely. That labeling sets out the proposed uses of the drug. The uses of the drug are known as the indications. Indications typically include a population, a condition, and the stage/severity of the condition (if applicable).

The FDA evaluates the NDA to determine whether the sponsor has demonstrated that the drug is safe and effective for the proposed indications. Assuming the sponsor meets the evidentiary burden, the FDA approves the proposed indications for the product.

After being approved by the FDA, sponsors may only promote their drugs for the specific indications approved by the Agency. Any other use of the product is "off-label" use.

Off-label use is NOT inherently bad, wrong, or evil; and off-label use of a drug is also not prohibited. The other evening I heard a television news segment where the expert commentator spoke of using drugs in violation of FDA's rules. That's wrong.

FDA does not regulate the practice of medicine, and physicians are, for the most part, able to prescribe drugs as they believe is appropriate to treat the patients they see.

But the sponsors are not permitted to promote their drugs for any uses other than those approved by the FDA. Importantly, there is no explicit prohibition in law against the promotion of unapproved uses. You won't, for example, find off-label promotion listed as one of the items that causes a drug to be misbranded. Instead, there are multiple legal theories about this prohibition and what exactly makes such promotion illegal, including the failure to include adequate directions for use in the labeling.

FDA has made it clear that it sees the continued prohibition of off-label promotion as essential to protect the public, despite some adverse judgments by some courts.

If a company learns of a new off-label use for a drug and wants to promote the drug for that use, the sponsor must conduct additional clinical trials to demonstrate that the drug is also safe and effective for that new use. After completing the clinical trials, the sponsor submits an sNDA (supplemental New Drug Application) to the Agency.

Assuming the Agency approves the sNDA, the label is updated to include the new indication, clinical trial data, additional instructions for use, etc., and the company is then able to promote the new use of the drug.

So, FDA doesn't have to DO anything to make the possible off-label treatments available, despite several prominent people calling on FDA to take action. The drug being suggested for off-label use is already on the market and can be used for this off-label use.

Why doesn't FDA simply approve the new use?

Because FDA doesn't know if the drug works.

When FDA evaluates an NDA or sNDA it weighs the risks and benefits of the drug for each specific proposed use. As FDA has repeatedly made clear, each specific proposed use requires a separate risk-benefit determination.

It is possible (even likely) that a drug that has been proven to be safe and effective for one use might not be either safe or effective for another use.

Indeed, one frequent criticism of off-label use of drugs is that there simply isn't sufficient evidence of effectiveness for many off-label uses.

And that in turns leads directly to why FDA's prohibition on off-label promotion is so important to protect the public health. Using treatments without evidence and promoting such treatments can make things worse.

FDA has the tools to act rapidly to approve new uses of a drug, but it is unwise to short-circuit the approval process, and it's irresponsible to hype an off-label use without sufficient evidence to demonstrate its efficacy.

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 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.

Targeting a Competitor's Brand Name with Keywords

Although my article and presentation about search engine marketing included a lot of detail, there were some things that I didn't include.

One question that I frequently hear is about the propriety of targeting a competitive product name. In discussing this topic, I need to provide a disclaimer that I am not an attorney, and no advice from me should ever be construed as legal advice.

As for FDA compliance, I think it is perfectly OK to target a competitive brand with SEM ads depending on the type of ads and the way the targeting is conducted.

So, first a bit of background on keywords. From my recent article:

Keywords: Words entered into a search engine by a user. An advertiser identifies keywords that will trigger the appearance of their ad and places a bid for their preferred keywords. 

Negative Keywords: Words selected by an advertiser that will prevent their ad from appearing.

So, keywords and their negative keyword counterparts function analogously to a media plan in traditional media, but instead of buying publications that are read by 18-25 year-old women, an advertiser places an ad in front of people who are entering certain words into their search engine. As such, the same rules that apply to appropriate offline ad placement apply to what makes for an appropriate keyword.

That doesn't mean anything goes, but it does mean that we don't have to recreate the wheel to determine whether it's appropriate to use certain keywords. We simply apply the same principles from the offline world to the online practice.

So, with regard to disease awareness ads (these are ads that lead to disease awareness websites that do not themselves make any representation about a specific product), it is certainly OK to use the name of any product that is approved to treat the condition in question to serve up such ads.

Of course, if the product is being used off-label to treat the condition, then the advertiser might want to be cautious about the use of that keyword, but note that I would not automatically say that it is inappropriate even then.

For example, if a sponsor is currently investigating a product for an indication where there is not any FDA-approved treatments, and in the absence of any approved treatment, use of Product X has become the only resort for treating Condition Y, then a disease awareness campaign seeking to increase public knowledge about Condition Y might include Product X among its keywords, though probably only in conjunction with other keywords or negative keywords to try to target those people who are searching for information about treatments for Condition Y, rather than the audience of people who are searching for information about the approved indication for Product X.

Regarding redirecting ads, black box ad formats, and reminder ads, it would certainly be appropriate to target a competitor's product if both products have an identical indication or an identical population for at least one indication.

To see why, consider the following thought experiment. Imagine a breakthrough drug that creates an entirely new category of treatment. There is a long history of such medicines. Now, imagine a medical journal dedicating a special issue to the 10th anniversary of the approval of the first medicine in that category.

Would there be anything wrong with placing an ad for one of the newer medicines in that category in such an issue? For me, that answer is clearly no. So long as the newer medicine that is being advertised in that issue has the same indication (or a significantly overlapping indication) as the medicine that is the subject of the issue, then it would be OK to place the ad. The ad itself would have to be compliant, regardless of where it was placed, and that would mean that if the ad mentioned the competitive product that was the subject of the issue, then the claims would be comparative and in need of appropriate substantiation, but there's nothing inherently comparative in the placement itself.

The most common objection to such targeting is that such targeting can only be done if there is a head-to-head trial comparing the two drugs. I believe, however, that this conflates the content of the ad with the ad's placement. An ad whose content is not otherwise comparative in nature does not become comparative by virtue of placing it against a competitor.

In the case of a reminder ad or a black box ad, the compliant usage of such an ad format guarantees that there's nothing comparative in its content.

But what about the content of redirecting ads? Well, that's another blog post, and I'll address it tomorrow.

What constraints would I apply to targeting reminder ads or black box ad formats at a competitive product?

I find Venn diagrams the easiest way to explain the different scenarios:

Scenario 1: Product A & B have identical indications

In Scenario 1, Product A & B have identical indications. As I mentioned above, I think it's perfectly acceptable for either product to include its competitor among its keywords and deliver a branded advertising message via a reminder ad or black box ad to the users.

Scenario 2: Product B population is subset of Product A

In Scenario 2, everyone who is indicated for Product B is also within the indicated population for Product A. This can happen, for example, when Product A has an indication covering adolescent, adult, and geriatric populations for a condition, but Product B only has an adult indication. My view is that Product A can use Product B as a keyword to deliver branded messaging because by hypothesis everyone indicated for Product B is also indicated for Product A. I do not, however, think the reverse is true. Product B should take precautions such as using "geriatric" and/or "elderly" as negative keywords if Product B wants to include Product A as a keyword.

Scenario 3: Product A & B have overlapping, non-identical indications

In Scenario 3, both Product A & Product B might be able to use their competitor as a keyword, but the questions I would want to consider would be things such as how much overlap is there between the two indications, is it possible to distinguish people searching for Product A who ARE indicated for Product B from people searching for Product A who are NOT indicated for Product B. In some cases, such as when products have multiple indications, these questions might be very easily answered. In other cases, it might not be nearly as easy to target the appropriate population.

In all of these cases, my concern is not with the content of the ads themselves. Instead, my concern is that intentionally targeting a population that is not indicated for using my product on label could be evidence of an intent to market the product off-label. So, before engaging in such competitor targeting, I would want to be certain that I could justify my targeting practices as indeed being limited to the currently approved population.

New Reprint Guidance

I have been reading the new guidance from the FDA on distributing reprints while preparing a Regulatory Alert, which should be released on Monday or Tuesday. One thing that really stood out to me is the change in the background section.
The background section from the 2009 final guidance had a three-paragraph section lasting less than one page. By contrast the new guidance has a background section that spans five pages and 15 paragraphs, with almost as much contained in footnotes detailing the legislative history as in the guidance itself.
This document definitely reads to my eyes far more as if it were written with the intention of being defended in a court of law than the 2009 version.
I'd love to hear from anyone who had a similar impression.