FDA’s OPDP Issues Two New Untitled Letters

While enforcement has been at a low ebb for quite some time with FDA’s Office of Prescription Drug Promotion (OPDP), this week took a different turn with the posting of two new untitled letters sent October 31. That brings the total number of letters issued by OPDP to five this year – one Warning Letter that came out in August respecting a sales aid used in promoting a treatment for COPD, and 4 untitled letters – one in June, one in August, and now two in October.

The first letter posted this week was issued on October 31 and was in sole relation to a direct-to-consumer brochure that contained promotional claims for an on demand contraceptive. In it, language was used to assign a specific percentage in relation to the product’s efficacy. FDA said that the use of this specific statistic was misleading in that it did not use a validated methodology and did not agree with the means used to describe efficacy in the PI for the product.

Likewise, the second letter posted this week, also issued on October 31, involved two different communications vehicles – a DTC broadcast advertisement and a banner ad that contained promotional language regarding an adjunct therapy for major depressive disorder – but focused on the same issue as the previous letter in relation to the promotional issue that concerned OPDP. Here again, OPDP compared the statistic used to describe efficacy with that of the PI for the product and found a difference between the two, resulting in the issuance of the untitled letter.

Looking for trends in recent enforcement, one does not see any pattern in terms of the types of communications vehicles – 2023 involved a Website, a sales aid, two banner ads, a brochure, and a DTC broadcast advertisement. And while contraceptives were involved in two of the 2023 enforcement actions, it seemed more like a coincidence than an area of concentration on the part of the agency. And they were pretty evenly divided between digital and traditional communications vehicles. There was no concentration among products with boxed warnings.

But there has been one trend worth noting. In fact, looking back to enforcement beyond this year through March of 2022, one can see that the last 7 letters issued by OPDP to pharmaceutical companies about promotional communications all involved a tie between a particular efficacy claim and the data from which it was derived, or where an efficacy claim appeared unsupported by data. So there is perhaps a message worth paying attention to here. The trend would indicate extra caution may be prudent when pharmaceutical and biotech companies are assigning specific performance percentages to their promotional claims when being derived from sources other than the PI for the product.

This leaves us with a total of five letters this year, more than last year, and less than the year before. In a period of such low enforcement it is difficult to discern a trend. But we still have several weeks left to the year, and in 2016, OPDP issued several letters in December to boost the total for that year into double digits. We’ll have to wait and see for 2023.

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FDA Launching New Advisory Committee on Digital Health

FDA announced this week the formation of a new advisory committee – the Digital Health Advisory Committee – for the purpose of providing the agency with advice on matters related to digital health technologies (DHT). FDA does not form new advisory committees all that often, making it a notable development in more than one respect.

FDA stated in the agency’s press release that the committee’s subject matter jurisdiction will include helping the agency explore and assess issues regarding artificial intelligence/machine learning (AI/ML), augmented reality, virtual reality, digital therapeutics, wearables, remote patient monitoring and software. That is a broad spectrum of subject matter. The AI/ML portion alone is growing rapidly in breadth as is its uptake.

Simultaneous to the announcement, the agency began recruiting for its membership for the nine members the agency is seeking to comprise the membership of this committee. By design there are currently none voting members – which includes the Chairperson – comprising the committee. FDA is looking for a consumer organization to fill a voting slot and nominations and self-nominations will be considered by the agency to fill both consumer and individual seats. According to the Federal Register notice, individuals should be “full-time employees of firms that manufacture medical device products, or consulting firms that represent manufacturers or have similar appropriate ties to industry.”

The agency provided examples of areas where the Commissioner may seek advice which included real world data and evidence, patient generated health data, personalized medicine and use of DHTs in clinical trials to name a few. Right now it is a stand-alone committee subject matter area, not housed under Human Drugs Advisory Committees or Medical Devices. Given the speed and span with which AI/ML is developing, it is easy to think that there will be a basis for future expansion and just as Medical Devices is sub-divided into panels by subject matter jurisdiction, one could imagine the future of the new committee taking on a similar structure given the prolific nature of DHT.

Troy Tazbaz, director of FDA’s Digital Health Center of Excellence stated in the FDA press release – “Many of these technologies are novel and tend to rapidly change; it’s our duty to seek as much knowledge on them as possible as we determine and implement appropriate regulation to encourage innovation while protecting the public health.” This is one to keep an eye on for sure – not only to see what subject matter comes before the committee, but how rapidly it grows.

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What Happens When You Talk About Adherence in Promotional Communications?

FDA has announced that the Office of Prescription Drug Promotion (OPDP) is planning a study to evaluate the influence that statements made in a promotional communication about patient adherence to a medication may have on the resulting preference for a medicine.

OPDP regularly conducts research on a wide-ranging scale to help define the agency’s perspective on how various conditions might impact a target audience of a promotional communication. In particular, the agency states in the Federal Register notice that it has previously conducted research around market claims that discuss characteristics not directly related to approved label. They give the example of past research on the use of the phrase “#1 Prescribed”, for example, assessing the impact it might have for preference. Here, you can find an overview of OPDP’s past research, on-going research and research pending peer review and publication.

For this particular research, OPDP is seeking to gain insight into how an appeal to the possibility of greater adherence or whether or not there is a statement that other patients or prescribers prefer a specific medicine might impact the outlook of the target audience. In addition, they will look at whether the inclusion of a disclosure accompanying such a claim – for example “there is no conclusive research on whether DRUG A results in better adherence” – will serve to impact the perception. OPDP notes in the Federal Register Notice that while disclosures often can help shape an outlook, they have not been studied in this particular context.

The specific questions FDA is seeking to answer in this proposed research effort is whether the presence of absence of a stated or implied adherence claim impact consumer outlook with respect to their intent or perception of risk and benefit. In addition they will explore whether the presence of both adherence and preference type of claims have an impact, as well as exploring the effect of the presence of a disclosure statement as noted above. The agency is including both patients and primary care physicians, looking for 253 and 294 participants respectively. Each participant will view various versions of a mock consumer web page promoting a fictitious medication and respond to a questionnaire.

There is a long tail to this type of research. It will have to be finalized, recruited, assessed and written up as well as undergo peer review. But in informing the agency’s perspective on a particular topic, the research undertaken by OPDP may be a window into future directions, considerations and even potential priorities for the agency in terms of enforcement. Those in promotional communications may wish to take note now.

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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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