It Finally Happened – FDA’s OPDP Issues First Letter of 2023

For those who are regular followers of what FDA’s Office of Prescription Drug Promotion (OPDP) is up to, there was a surprise this week when the office posted the first regulatory action letter – in this case an Untitled Letter (a/k/a Notice of Violation (NOV) Letter) in over a year. The particulars of the letter are interesting, but first a quick review of recent enforcement from OPDP.

Enforcement Track Record – Looking all the way back to 1998, FDA issued a peak of 156 Untitled or Warning Letters in a single year (the prior year it had issued 139). That is the record high for a single year since that time and means that they were coming out a rate of over 12 a month on average. But the numbers began to dwindle and 2013 was the last time the office even issued 12 letters within a year (it did 23 that year). The numbers plummet in 2014 until the record low last year of only 4 letters. The last letter issued came just over a year ago in June, 2022.

Since then, crickets…..until this week.

The Newly Issued Letter – And now to the letter itself. True to form of late, this letter went to a company that is not a household name. It was the second letter for this company, the first having been issued in August, 2020 for a TV advertisement. The latest letter was issued for a website that promoted a treatment for hypercortisolemia in patients with Cushings Disease. The label for the medicine includes a boxed warning regarding potential issues related to complications for the liver (toxicity) and heart (QT prolongation).

OPDP took issue first with the description of efficacy which the agency said picked data points and reported efficacy of studies that, while accurate at that point in studies, did not reflect ultimate data points realized at the end of the final study. Further, the agency said, the product label reflected that a large number of patients discontinued treatment prematurely for multiple reasons and the omission of this information would impact the reader to assess efficacy.

On the risk side, the agency said the copy on the website that referred to monitoring and side effects failed to specifically outline the serious risks enumerated in the boxed warning, referring to them generally as serious side effects (rather than specifically calling out the boxed warning elements) and stating that testing will help a doctor avoid side effects. The agency felt that the lack of specificity combined with the implication that tests could help avoid adverse events minimized the risk realities given the seriousness of the potential adverse events and their frequency as outlined in the label. The agency acknowledged that full risk information was presented on the webpage, but felt that did not mitigate the overall characterization that minimized risk.

The ultimate lesson point in this action letter by OPDP is that when it comes to characterizing either efficacy or safety data, being as literal as possible in reflecting the label is important, particularly on the risk side when a product has a boxed warning.

A Note About Boxed Warnings – One might ask whether products with boxed warnings are more likely to face the possibility of an OPDP action letter. Going back and looking through 2020 at the products involved in letters, there have been a total of 17 letters (involving 19 different communications vehicles). Of those 17 letters issued, 8 had boxed warnings. Of those with 8 with boxed warnings, 5 of them were Warning Letters, as opposed to Untitled Letters. Of those without boxed warnings (9 in number), only 2 had Warning Letters. Not a huge pool from which to pull, but indicative nonetheless.

Back to Enforcement – At nearly the same time OPDP launched the “Bad Ad” program (2010) which is designed to deputize healthcare professionals and others to spotting and reporting potentially non-compliant communications, enforcement began to diminish. The agency holds trainings and gives continuing education credits. It forces the question why the agency would invest in such a program and then have fewer results to show for it? There are no apparent answers. It may be that the agency has focused resources on areas that present the highest risk and impact, and that this is not one of those areas.

Photo by Goh Rhy Yan at Unsplash

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FDA Announces New Study on Endorsements and DTC Television Ads

In today’s Federal Register, the agency has announced that the Office of Prescription Drug Promotion (OPDP) is adding a new study effort to its research portfolio. The category of that body of research that is currently underway includes a range of topics, including an assessment of terms and phrases commonly used in prescription drug promotion, studying the comprehension and understanding of multiple indications used in consumer television advertisements, and endorser status and explicitness of payment in Direct-to-Consumer promotion, among others.

In relation to the the last, today’s study announcement is also focused on the role of endorsements – “Endorser Status and Actual Use in Direct-to-Consumer Television Ads”. The notice published by FDA states that the aim of this effort is to complement the endorser status noted above, which apparently has been completed. That study had looked at endorser types in print or internet use to see how disclosure of payment status might impact audience reactions. The new research effort will look at actual-use disclosures in the medium of television advertising. The agency notes that prior research had indicated that the most influential endorsements to lead to purchase intentions were by physicians or pharmacists, followed by consumer endorsements and in last place, celebrity endorsements.

The agency notes that when healthcare providers are used in an endorsement, there should be a disclosure of compensation and that industry principles also recommend that there be disclosure when an actor is being used to portray a healthcare provider, though industry standards do not mentions such disclosure when a consumer/patient is represented by an actor. With the new research, FDA intends to examine the influence of patient/physician endorsements as well as ads where there is a utilizer of the product or an actor to assess attitudes and perceptions of the audience with respect to risk/benefit and behavioral intentions.

Why is this noteworthy?

Two things come to mind. First, direction of OPDP research may sometimes shed light on a developing area of interest in relation to enforcement. In other words, the data that they reap in these studies might inform a principle or perspective with respect to the use of endorsers that could have an influence on what they are looking at with respect to taking enforcement action. That seems a bit of a stretch in this regard, particularly in light of the fact that visible enforcement by OPDP has been close to non-existent. No enforcement letters have been issued during this calendar year, and in fact, the last action letter sent by OPDP was 10 months ago in June, 2022. This seems mostly like an academic exercise rather than anything with substantive impact – still, those who are utilizing endorsements in promotional communications should pay attention to both of these related studies for insights.

Second, it also tells us that even though the tide in communications on both the part of patients and promoters has shifted dramatically to the digital realm – often viewed on mobile devices – FDA’s attention remains focused on yesteryear and DTC advertising on broadcast television.

Presumably the first endorsement related study will be published soon. Keep an eye peeled for insights.

Photo by Ajeet Mestry at Unsplash

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Thumbs Up, Thumbs Down – Minimizing Votes in AdComms

FDA Commissioner Califf has voiced a desire to limit voting in Advisory Committee Meetings

Recently there have been a spate of reports carried in trade media that Commissioner Califf would prefer to limit the voting mechanism customarily included as a key part of FDA Advisory Committee meetings. Traditionally, committee votes can be taken on a range of topics during the course of the meeting. These votes are usually interspersed with questions that the agency poses to the committee for the purpose of eliciting discussion about specific aspects in relation to the approval of a new drug application. Customarily this culminates in the ultimate question whether the committee believes that the benefit/risk ratio is such that approval is warranted. Now the Commissioner appears to be suggesting that the focus be put on discussion with less, if any, inclusion of what he refers to in one report as a “gladiator” vote of approval.

The notion to limit voting seems a bit contrary to the character of the current environment – one which would seem to beg for more transparency rather than less. In November 2020 FDA held a meeting of the Peripheral and Central Nervous System Drugs Advisory Committee to consider a new drug application for an investigational treatment – aducanumab – for Alzheimer’s. The standing voting members of the committee (7) were joined by 4 additional temporary voting members. FDA posed a total of 8 questions for the committee’s input into the agency’s decision, half of which were discussion questions and half of which were voting questions. It went something like this:

  • The first question posed to the committee in that meeting centered on one of the clinical studies that had been submitted in the application and asked whether it provided strong evidence of efficacy and the committee overwhelming voted that it did not (1 Yes, 8 No, 2 Uncertain).
  • The second voting question focused on a different study, asking the same point regarding efficacy and again the vote was overwhelmingly negative (0 Yes, 7 No, 4 Uncertain).
  • Asked whether there was strong evidence of a pharmacodynamic effect related to Alzheimer’s pathophysiology, the outcome was a little more balanced, but still not an endorsement (5 Yes, 0 No, 6 Uncertain).
  • Returning to the study voted on in the first voting question, the agency then asked whether it was reasonable to consider the study as evidence of efficacy in the treatment of Alzheimer’s and the vote was once again overwhelming (0 Yes, 10 No, 1 Uncertain).
  • Several months later, FDA approved the NDA under accelerated approval provisions, a possibility that was not something discussed at the meeting.

The results were disastrous from nearly any way you look at it. FDA pointedly ignored the overwhelming sentiment of the panel, resulting in the unprecedented resignation of 3 of the advisory committee members. CMS issued a national coverage decision to limit coverage for the drug by implementing a policy that it would only cover monoclonal antibodies approved under accelerated approval for Alzheimer’s for those patients who had been in the clinical trials, pretty much guaranteeing that uptake would be limited. Confidence in the approval process was shaken and FDA’s reputation took a blow. The outcome fostered confusion among patients and physicians. And among the many negative side effects of the decision, there was a Congressional investigation highly critical of FDA’s lack of transparency in the process, among other things.

The Aduhelm case study is an example of why voting is in fact essential.

In referring to the voting tradition in the meetings as reported in trade media, the Commissioner stated words to the effect that the advisory committees exist to give the FDA advice and that approval decisions should be left up to full time civil servants. In the same article he’s quoted as saying that these meetings are like a democracy – where there is not always agreement – and therefore sometimes messy. But while the committees are there to provide FDA advice – and ultimately the decision does rest with FDA, AdComms also serve another very important purpose.

With votes, we get not only the qualitative insight yielded to us by the nature of the discussion, but a quantitative understanding as well. It makes the outcome concrete. We are left with a good perspective on whether the committee is wholeheartedly enthusiastic, fence-sitting, or in the case of aducanumab, very much against approval. We don’t have to read the tea leaves. Votes are a fundamental component of transparency to those of us on the outside and the considerations that go into an approval decision are known and understood by everyone. Part of understanding is provided by the discussion, but a part is also the mechanism of a vote. And to the Commissioner’s point regarding “messy democracy” – in point of fact, voting is a fundamental component of the democracy to which he refers.

Commissioner Califf’s thinking on this has been through various reported conversations and has not been embodied in a speech. The topic merits wider consideration though and a more thoughtful and contextual discussion. Hopefully that will happen.

Can we at least vote on it?

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Big Decisions – Reviewing FDA Advisory Committee Outcomes Since 2020

In January we took a look at FDA Advisory Committees (AdComms) – FDA AdComms – When the Going Gets Tough – noting, among other things that there had not only been fewer meetings but also that it appeared that the outcomes were increasingly negative.

Just to recap, for the entire year of 2022 there were only 14 meetings held to consider whether new medicines should be recommended for approval, a slight increase over the 10 the year before, but considerably lower fewer than 2018 and 2019 when there were 29 and 22 meetings held, respectively. And as can be seen by the increase in red bars (negative outcomes) and the decrease in positive outcomes (green bars), the outcomes have skewed increasingly negative, with 2022 being a particularly negative year. Note these numbers cover meetings about drug applications only, not including vaccines or cellular therapies.

By contrast, already in 2023 there have been eight AdComm meetings scheduled by FDA for the purpose of considering a new medical treatment, three of which have occurred and all resulting in votes in favor of the sponsor, so perhaps 2023 is heading to less negative territory. During the balance of this month and into next, there are five more meetings scheduled, so we shall have to see.

That tells the collective story, but how do each of the committees fare?

The committee with the most AdComm meetings was also one of the committees with the highest number of negative outcomes – the Oncologic Drugs Advisory Committee. The committee met a dozen times during 2022 and only voted in favor of recommending approval four times. Two committees – the Endocrinologic and Metabolic Drugs Advisory Committee and the Antimicrobial Drugs Advisory Committee were among those that met the fewest times – once and three times, respectively, but both had purely positive outcomes. In fact, bottom line, there were nine different committees that had meetings to consider new drug approvals last year, only four of them voted positively 50% or more of the time, with five of them voting negatively more often.

There are a lot of variables that factor in. Drugs for cancer face a whole different set of criteria for assessing safety and efficacy than do other therapeutic categories. That said, beginning in 2020 meetings began skewing to more negative outcomes and 2022 was the first year where the number of negative outcomes outweighed the number of positive outcomes. As noted earlier, this coincides with the transition to virtual meetings over in-person ones.

But the nature of AdComms may be in flux calling into some question the role and influence of voting. Recently, Commissioner Califf was quoted in a few articles this month reporting on a moderated discussion in which he participated at the Biopharma Congress meeting held in Washington, D.C. in mid-February. The coverage in part focused on his thinking that advisory committees need to be less aimed at actual votes rather than on having a full discussion of the issues. Apparently these comments did not come in the form of a speech which would be listed on the FDA’s website which might provide some context – because on their own, they are rather confusing. More thinking about this in an upcoming posting, but it signals perhaps that the nature of AdComms may begin to skew less to circumstances where there are voting questions posed to the committee and that there may emerge a more consistent use of “discussion” points instead. If so, that will certainly complicate future big picture analyses, forcing the discussion to be more qualitatively than quantitatively focused.

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Emerging from Emergency – Two COVID-Related Developments This Week

Two announcements occurred this week, both of note and connected only by the fact that they are emblematic of the slow metamorphosis from a COVID emergency world to a post-COVID emergency one.

Emergency Ends – First, the Biden Administration announced that it would be allowing the Public Health Emergency (PHE) declaration to lapse this coming May. In a separate (and pointless) development, the U.S. House of Representatives voted to end the declaration – theater-legislation given that the initiative would never be passed into law and the policy decision was already made. The PHE, initiated during the prior Administration and extended repeatedly by the current Administration, put into place a number of policy initiatives in relation to the COVID-19 response, most significantly initiatives that enhanced the ability freer access for people to get vaccines, medicines and testing. With the end of the PHE declaration, access for individuals will shift away from government support and rely on a person’s insured status (either public or private) and any state policies in effect.

  • Impact on EUAs? One aspect largely missed in the media reporting on the PHE conclusion is in regard to whether or not the action has an impact on the Emergency Use Authorization (EUA) status conferred by FDA on a number of vaccines, diagnostic tests, and medicines during the COVID emergency. However, the PHE that will end on May 11 is distinct from the separate from the mechanism that allows FDA to issue EUAs for medical products. Therefore the status of those medical products that have EUAs will not be affected by the ending of the PHE, declared under the auspices of the Public Health Service Act. The emergency declaration that confers the ability of FDA to issue EUAs is a separate regulatory mechanism and is part of the Federal Food and Drug Cosmetic Act. FDA has stated in an updated FAQ on the topic that any change that would impact EUAs would first be published in the Federal Register with ample time provided for transition of products from EUA status.

Face-to-Face Meetings – On a separate note, it was reported this week that FDA will be engineering an eventual return to in-person meetings with industry. FDA has provided an update on the website regarding Face-to-Face (FTF) meetings with staff transitioning in 2023 to return, at least part of the time, to the FDA campus.

  • Impact on AdComms? While it is almost impossible to think of that absolutely HUGE campus empty all this time, the return naturally raises the important question as to how this change will impact industry, with specific attention to FDA Advisory Committee meetings. In a prior post, it was noted (without making a causative connection) that since meetings went virtual, they have also gone more negative, with a higher rate of “no votes” than in prior years. In the communication regarding the transition, FDA has stated that they will be re-fitting conference rooms with some fancy new equipment – face/conversation tracking cameras and boom forming microphones for example – and the agency will have in-person participation likely limited to those with speaking roles, while others will be relegated to a virtual presence. Hence, a hybrid meeting. Because the number of rooms will be limited, but growing over time, these types of meetings will seemingly start out few and expand as re-fitted facilities come on line. The agency is targeting smaller industry meetings for this effort. Sadly, no mention yet of FTF AdComms.

It would appear that we are emerging, in some respects, glacially from the COVID era. As noted in the previous posting, FDA is talking less about the pandemic than before. And while it is good to have this in the rear view mirror, it is worth noting that daily mortality is still high, people are still hospitalized at a high rate, and many people are still getting sick with it for the first time. We are moving on, but the pandemic is still very much with us.

Photo by CDC on Unsplash

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