Drug Approvals and FDA AdComms in 2023

Having passed the mid-year point, it is always an interesting exercise to take stock of where we stand with respect to the approval of new medicines. Overall, when considering the volume of activity, things would seem to be looking up – at least in terms of the volume of activity. First let’s look at the approval of new molecular entities, and then at the number of Advisory Committee meetings being held, and compare them to the first half of 2022.

New Molecular Entity (NME) Approvals – These approvals are an important indicator of innovation coming from test tube to patients. Last year was not looking particularly good at mid-year, with only 16 NME approvals by June 30 and only 37 for the entire year – the least number since 2016. This year, however, with 26 NME approvals at mid-year. there has been a significant uptick – more in fact than any other previous mid-year check-in with the exception of 2021. It looks like we are off to a good start, and if annualized would mean that we would possibly see 52 NME approvals for the year, which is on par with the years 2019 – 2021 (2022, as you can see in the chart below was a bit anemic). But in fact, as can be seen in previous years such as 2019, 2018 and 2015, the mid-year tally (in red) is not always predictive of what we may see by year’s end (in blue). The second half could move either faster or slower. There are still many decisions and publicly available PDUFA dates with many novel treatments among them, including investigative treatments for sickle cell disease and ALS.

AdComms and Approval Votes Are Up – In addition to NME approvals, there have been an increased number of FDA Advisory committees held to discuss new treatments. That could indicate (1) more new medicines up for considerations and/or (2) more situations where FDA feels it needs the advice of consultants in the course of deliberations.

By my count, during the first half of 2022 there were only 4 advisory committee meetings held to discuss new drug applications (NDAs), compared to 17 held during the first half of 2023 – which is kind of a whopping 300 percent increase. In fact, by mid-2023, there were 17 AdComms held, outpacing the number held during all of 2022 when there were 14 for the year (19 had been scheduled, but 5 of them did not take place).

But there is another important contrast between last year and this and that is in regard to outcomes – of the 4 meetings held in the first half of 2022, the vote was negative in 100 percent of them. In fact, in 2022, there were only 4 approval recommendations out of the 14 meetings held that year. In other words, 71 percent of the 2022 outcomes were negative. By contrast, in 2023, of the 17 meetings held to discuss NDAs during the first half of the year, the vote was positive in nearly all of them – 16 recommendations for approval – or 94 percent approval recommendations – also a rather eye popping reversal in trend.

Individual AdComm Frequency – The AdComm that met more than any other was the Antimicrobial Microbial Drugs Advisory Committee with a total of four meetings, followed by the Oncologic Drugs Advisory Committee with 3, and the Peripheral and Central Nervous System Drugs Advisory Committee with 2 meetings. All the other meetings held during the first half of 2023 – Cellular Tissue and Gene Therapy, Endocrinologic Drugs Advisory Committee, Gastrointestinal Drugs Advisory Committee Obstetrics, Reproductive and Urologic Drugs Advisory Committee, the Psychopharmacologic Drugs Advisory Committee and the Pulmonary-Allergy Drugs Advisory Committee all had a single meeting. The committee that had the sole negative recommendation was from the Gastrointestinal Drugs Advisory Committee which did not recommend approval for an NDA involving a treatment for pre-cirrhotic liver fibrosis due to NASH.

Other Approvals – Of course, there are many drugs approved that are not NMEs and which do not have Advisory Committee meetings. One last indicator is to review the number of press releases about drug approvals this year compared to last. During the first half of 2022, FDA issued only six press releases about drug approvals compared to 13 during the first half of this year.

There are other approvals not included here that occurred as well. But looking to these indicators – NME approvals, AdComm recommendations and FDA press releases, 2023 is carving its own unique profile. If 2023 continues at this pace, it looks to be shaping up as a banner year for both the volume of FDA advisory committee meetings well as for the proportion and number of approval recommendations.

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FDA’s OPDP Issues Third Letter of 2023

For the second time this month and the third time this year, FDA’s OPDP has posted notice that it has taken an enforcement action. Last week, a Warning Letter was posted regarding a sales aid. This week it action came in the form of an Untitled Letter (NOV) sent to a company regarding a paid social media posting. Enforcement this year was non-existent until June when the agency posted its first letter in a year. This week’s action makes a total of three letters sent this year, all within a three-month period.

The Untitled Letter posted this week involved an oral birth control pill which has a specific of contraindications contained in the label as well as a list of warnings and precautions and of the most common adverse events. The communications vehicle in question was a social media sponsored posting.

OPDP took issue with three specific aspects of the promotional communication. First, while presenting the indication in the posting, there was no risk information included in the communication. Second, a claim was made in the communication that OPDP said was not supported by the clinical studies section of the package insert. And third, the communication was not submitted under form FDA-2253 for review.

It would seem that the omission of any risk information combined with the review issue would have been enough to trigger action by OPDP. But as discussed last week, previous to this letter there were four letters in a row that held efficacy claims up against studies that might support the claims and found them wanting. This is now the fifth letter in a row that took issue with an efficacy claim with OPDP scrutiny of the underlying data that may or may not exist to support the claim. Pharma communicators take note.

Last year the agency only issued a total of four letters. Enforcement trends are impossible to predict but certainly it has picked up and there could be more to come. After all, back in 2016, the agency issued six letters in the month of December alone. Stay tuned.

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FDA’s OPDP Issues Second Regulatory Action Letter of 2023

In what has been a long period of relative low activity, FDA’s OPDP has taken the opportunity to remind us that low enforcement does not mean no enforcement when it comes to promotional speech by pharmaceutical companies.

This past June FDA posted an Untitled Letter, the first regulatory action letter in a year, reported on here regarding a website communication. This month FDA posted another letter, this one a Warning Letter involving a Sales Aid. This second letter of 2023 makes a total of six letters for the combined years of 2022-2023, two of which were Warning Letters and four of which were Untitled.

With so little activity, trends are often difficult to discern, but one does appear to emerge.

In examining four of the last six regulatory action letters issued by OPDP, one discerns that there is possibly an emergent sensitivity the agency has in looking at communications that make claims about a product, even when citing published papers as evidence.

The last four letters from OPDP:

Each of these letters have a common thread – in each of the last four letters issued by OPDP the agency was taking issue with the support that existed for efficacy claims being made in the communication about the medicine. In each situation, OPDP closely analyzed the studies for their applicability to the claim being made, assessing whether or not they were adequate to the task from the perspective of the agency.

With four in a row, that would seem to signal that promotional communications that deal with efficacy claims may be speech that is of special interest to the agency right now, and that enforcement actions are sending that signal. Future letters will indicate if this persists as a point of interest.

By the way, for those who want to follow or examine the letters, FDA now separates the reporting of Untitled Letters from Warning Letters. To view the former, you can go to this page and see the Untitled Letters issued each year. If you want to see Warning Letters, you must go the Warning Letters page and perform a search specific to the issuing office – Office of Prescription Drug Promotion.

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What They Said – Reviewing the First 6-Months of FDA Communications

Every six months, we do a look-back to see what has changed in the way that FDA is communicating. One might not think there is much difference over time, but there is. For example, the air has pretty much gone out of the COVID balloon. And there is more to tell.

How many? First of all, consider volume. The number of press releases issued by FDA during the first six months of the year declined to 101 from the 125 issued by June 30 of last year, the lowest number at mid-year since 2017. In 2018, FDA issued a much larger number of releases – trend that continued through 2022, all years with much larger numbers than were seen in 2017.

The increase can be attributable to two factors. First, the upward tick in releases beginning in 2017 that climbed steeply in 2018 and following slightly the following year matches the tenure of Dr. Gottlieb as FDA Commissioner. During his time at the post, the Commissioner’s office turned the relatively rare practice of issuing statements from the commissioner to a very common one. The second spike occurred in 2020, coinciding with the COVID-19 pandemic. In 2022, the agency issued 27 releases that involved the subject of COVID, 18 of which were during the first half of the year. In 2023, there were just 4.

One factor in the decrease is of course the near-absence of COVID-related news from the agency. But one cannot talk about volume without talking about the different way that FDA is putting out news – specifically the “FDA Roundup“. Prior to 2022, FDA posted news that did not quite meet the press release threshold through a mechanism called “FDA in Brief” which were halted in 2022 and seemingly replaced by the “FDA Roundup” which is housed on the press release page, but which contains a hodgepodge of news items covering actions by the agency during the past few days such as workshops being held or articles that have been published. While the FDA in Brief documents covered only one topic, the FDA Roundup can cover several and includes an update on COVID-related activities, meaning that while the overall volume of releases is down, the overall volume of information may, in fact, be up.

What did they talk about? Looking to press releases by category, there was

So far this year, the agency has had releases in the following categories with a comparison the first six months of last year. There were fewer releases this year, mostly due to a drop in the General Announcement category the bulk of which are the Daily Roundups. There was an increase in the number of approval related announcements (though it should be noted that in the case of Tobacco, the releases were largely in regard to the denial of approval). In 2023 so far, there have also been an increase in Legal (Warnings, e.g.) and Rule (guidance docs, proposed rules). Also of note, while there were 6 alerts in the first half of 2022, there have been none in 2023.

Did they speak Spanish? There are two large Spanish-language television networks operating in the United States, as well as weekly, semi-weekly and daily publications. Over the years of these look-backs, one thing that has stuck out about the press releases is that some of them are translated into Spanish, while many are not. Yet there seemed no obvious way to discern which would be bilingual and which would not. In the first half of 2023, there were 35 releases that were in both Spanish and English – about one-third of the releases overall. In the first half of 2022, there were 44 bilingual releases – also about one-third. But in 2020, there were only 34 bilingual releases out of the total of 154, or about one-fifth. (The Roundups are not bilingual.) It would appear that there may be an indication that FDA is upping the effort here to reach this important audience, though there is still a way to go. And the increase in profile of Spanish releases would also be higher when there are fewer press releases if the number of bilingual communications remained the same.

Overall, there have been shifts in the way the agency is communicating. We’ll be back at year end to see how we netted out.

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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.

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