Speaking of Medicine – Mid-Year OPDP Enforcement Review

Posted on August 2, 2022 by Mark Senak

There are two means of gaining insight into the agency’s thinking about regulatory issues related to promotional communications by pharmaceutical companies; one is through the issuance of guidance documents, the other is through enforcement.

But when it comes to enforcement things have changed greatly over the years. In 1998, there were 156 letters issued in a single year. By 2002, the number had dropped to 28, reviving somewhat by the end of that decade when it reached 52 in 2010. And since 2014 the Office of Prescription Drug Promotion (OPDP) has broken double digits only 3 times, producing only 6 letters in both 2020 an 2021. So far this year, we are at 4, which is a pretty good clip these days.

While it is difficult to discern trends with such a small number, an examination of recent warning and untitled letters reveals some possible shifts in priorities and emphasis that may be worth noting. That is particularly true since we have a new FDA Commissioner, a new head of the Center for Drug Evaluation and Research (CDER), and a new head of OPDP.

The 4 letters issued this calendar year:

  • Involved 3 Untitled Letters and 1 Warning Letter – a profile not out of proportion given that about 33 percent of letters issued since 2004 have been Warning Letters. One of the letters came to attention of FDA reviewers through the Bad Ad Program.
  • These 4 letters related to 5 different communications vehicles, 4 of which involved digital forms of communications – 2 were videos, 1 was a web page and 1 was an Instagram posting, one of the rare letters involving a social media platform. If you would look back to 2008, when digital and social media were in ascendancy by pharmaceutical companies, and compared enforcement involving traditional means of communications to those on digital platforms, letters from OPDP more commonly involve traditional means of communications (brochures, DTC print ads, etc) over digital (web pages, social media). While these most recent letters represent a small sampling, the fact that digital is over-indexed here potentially signals a heightened scrutiny involving digital platforms.
  • It should also be noted that one of the videos involved an oral statement made by the CEO of a company which was posted to a third-party site. The characterization of investigative data resulted in a violation related to promotion of an unapproved compound. This perhaps emphasizes the role of media/message training prior to public-facing statement (at all stages of development).
  • The single letter involving a traditional communications platform was a printed information sheet directed to physicians.
  • Violations this year so far were 9 and included risk presentation deficits (3 letters) Superiority Claims and Unsubstantiated Claims (2 each) and Promotion of an Unapproved Drug (1).
  • Some of the triggers included
    • The use of studies in relation to a claim where the studies were unrelated and conducted in different patients for different lengths of time and were limited in design and analytic strategy;
    • Risk information that was presented in small bring, out of balance to the claims presentation as well as another risk presentation that offered risk in a fast-scrolling video that was out of sync with the benefits information;
    • A claim related to efficacy that did not more narrowly define the intended population as reflected in the label

When you view enforcement activity through a broader lens to get more examples to analyze, a few things stand out. Most notably, while promotion of an unapproved drug is a relatively rare violation, comprising only 2 percent of all the letters issued since 2004, it is 13 percent of all letters issued since 2016. Correspondingly, the instances of promotion of an unapproved use has diminished and was last named as a violation in 2019.

Finally, one characteristic of the regulatory action letters issued by FDA’s OPDP over the past several years is that they have principally involved smaller, lesser-known companies. It was very rare to see a company in the top 25 companies cited for violations. But this year and last year we saw Lilly receive two letters, Bausch receive one, and Amgen receive one. It may be an anomaly or it may signal a shift. For any trends to become apparent, there will need to be more enforcement actions. And for that, we must wait.

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New Approvals in 2022

Posted on July 5, 2022 by Mark Senak

We are at mid-year, a good time to check in and see how we are doing on a number of fronts – including where we are with new drug approvals. Over the years, Congress has acted to enhance the ability to bring more new treatments from test tube to medicine chest more quickly. Most notably in 2012 the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed into law, bring to bear among other things, breakthrough therapy designation. Since that time, there has been a healthy output of new treatments.

But recently in the larger environment, there have been several factors that may have inhibited the flow of the medicine pipeline. The most obvious impact is that of COVID-19 to recruiting and maintaining clinical trials. And then there is the fact that a number of clinical trials were being conducted either in Russian or in Ukraine prior to the outbreak of the war. On top of that, COVID-19, while representing a good deal of medical progress, also represents a tremendous diversion of resources in time, money and effort that might have been otherwise utilized. Finally, COVID also impacted FDA’s ability to manage the regulatory process itself. Advisory committee meetings have been far fewer and observationally speaking, FDA seems to be extending PDUFA dates quite regularly.

So how are we doing? There are a few things to look at.

  1. New Molecular Entity Approvals – The most obvious is to see how we are doing on new molecular approvals – those approvals representing entirely new treatments. Looking at past years and where we were at the mid-year point and where we ended up each year, can give us some insight into this year. The news is not so hot. By the end of June this year, FDA had approved only 16 novel drugs. By this time last year, there were 27. Below is a chart that compares year by year the rate of novel approvals as of the end of April and by the end of year.

This is not to say that the balance of the year might not make up for the slow first half. by mid-year 2019, there were only 13 approvals of new entities but the year netted out with a respectable 48. It all depends on what’s in the pipelineSo let’s look at PDUFA dates.

2. PDUFA Dates– PDUFA dates are proprietary and FDA does not publish a list of upcoming dates. Still, one can compile a list by capturing public announcements of new drug or biologic applications with FDA, many of which mention the specific PDUFA date and many that allow a guess based on counting from the date of a press release. Subtracting out applications for supplemental applications, there do not appear to be an overwhelming number of upcoming dates, which might undermine any recovery in the second half of the year to a more robust number of approvals of new molecular entities.

3. AdComms – Finally, as noted in a prior posting, the number of advisory committee meetings that FDA has been holding has diminished considerably overall. That means that the agency is utilizing outside counsel less frequently, perhaps due in some part to the advent of breakthrough therapy designations which means that the agency is having a higher level of interaction with drug sponsors that may negate the need for an AdComm. But one could also surmise that AdComms are reserved for circumstances where FDA wants outside counsel because an investigative compound is exploring new territory. In any case, the only recent advisory committee was one of the Cellular, Tissue, and Gene Therapy Advisory Committee which by its nature, is likely to be in regard to a new molecular entity.

In short, the outlook for output this year does not appear at this juncture to be promising. But there are many moving parts and when and if they do move, it can change the picture considerably. Certainly there have been years past where at mid-year, there was not a robust output, but which ended up much improved over the final half of the year.

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Enforcement Update: OPDP Issues Untitled Letter

Posted on April 13, 2022 by Mark Senak

We are four months into the year, and this week OPDP has issued its fourth regulatory action letter of 2022. Two of the previous were Warning Letters, considered the more serious of the two categories, and two, including the latest, were Untitled Letters.

As noted in past updates, FDA’s OPDP enforcement letters have dropped off considerably over the years. In fact, over the past two years, the office issued only a total of 6 letters which means 2022 is going at a heightened clip. Of course, if OPDP only issues two more actions for this year, it would be on par with the recent track record – and sometimes several weeks can go by before OPDP issues a letter.

I like to take an approach to examine both the historical context and the substance of each individual letter.

The Letter. The recipient of the letter was Bausch Health Companies and it was in regard to two different communications vehicles – one a “DTC video” that appeared on Lifetime TV’s The Balancing Act – and the other the efficacy webpage of the healthcare professional website. The medicine that was the subject of these communications was DUOBRII (halobetasol propionate and tazarotene) a topical lotion indicated for the treatment of plaque psoriasis in adults. The risk profile of this medicine includes contraindication in pregnancy as well as risk of sunburn among other stated risks.

Taking the video first, there were a couple of things. First was the most common violation cited in OPDP letters – the presentation of risk information. The agency stated that material facts about the risks were not properly conveyed with particular regard to advising women about the risks during pregnancy and noted that the package insert advises a pregnancy test within 2 weeks prior to therapy initiation and advises on the use of contraception during treatment. The video portrayed a women of child bearing age – with two children – making the statement that she used the product during a flare up, implying it can be used any time. FDA did acknowledge the presence of information regarding fetal risk is present in the video, but indicated that the lack of specific reference to the need for testing and use of birth control were material. In addition, the patient in the video is depicted out of doors with exposed shoulders and arms, but did not mention the photosensitivity and risk of sunburn in the video. Finally on the issue of balance, FDA noted that the additional risks were addressed in small text at the bottom of the screen while benefits were being conveyed verbally by a narrator.

The other issue for the video was making an unsubstantiated claim regarding efficacy and an implication of superiority. The video stated that the medicine was the “first and only” topical combining two active ingredients, while FDA asserted that there was at least one other such combination. In addition, the patient depicted said that she had tried other creams that did not work for her. FDA said clinical superiority had not been established and that the statement implied that the medicine would be effective in patients who failed to respond to other treatments. While it may be accurate for this patient in particular, the agency said it could not be broadly applied to all patients.

When it came to the webpage, FDA took issue with language that made the claim of “superior efficacy” to mono therapies based on evidence that was characterized by the agency as a post hoc analysis of a single phase 2 trial not designed to support this type of conclusion.

The Context. It is important to look at context to see if there are any emerging patterns related to enforcement with respect to treatment categories, companies or communications vehicles. There are a couple of things of note. First OPDP enforcement over the past few years has not only diminished, but the actions have generally involved smaller, lesser well-known companies. However of the 11 letters (both Warning and Untitled) sent since 2021 began, Some larger, established companies have been included – such as Amgen and Lilly (which received 2 letters). Also of note, the treatment of pain, in particular migraine, was the subject of 3 of these 11 letters. But perhaps most noteworthy is the fact that the most common communications vehicle that was the target of enforcement were DTC videos which were the subject of 5 of the 11 letters.

Finally, it is noteworthy perhaps that OPDP acquired new leadership last year. That may mean an emerging difference in the way the office engages in enforcement.

Until next time.

Image by Goh Rhy Yan at Unsplash

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New Landscape for the Old Pandemic

Posted on March 30, 2022 by Mark Senak

Tectonic pandemic plates are shifting respecting the COVID-19 pandemic. For weeks now we have been watching caseloads in the United States broadly fall. It feels as if we are indeed shifting gears. There are other moving parts that are in motion as well. It is a fundamental re-shifting of the landscape. And there are consequences.

First, government funding supporting access to vaccination and treatment for COVID has run out and so far, is not replenished. The government established program to fund access for the uninsured has stopped accepting reimbursement claims for treatment and will stop shortly for vaccines (on April 5). For the insured and affluent, not much of a problem. For those without, it can become a major roadblock. And if you need therapeutics, the same problem, but with harsher consequences, especially once the federally purchased stockpiles of therapeutics and vaccines are gone.

Second, next week an FDA Advisory Committee had scheduled a meeting for April 6 (the day after the government program will stop accepting claims for vaccines) to consider whether or not to authorize use of two of the COVID-19 vaccines as a “second booster” or actually a fourth shot, either for people over 50 years or for everyone. Then on March 29, FDA issued an authorization for use prior to the meeting of the advisory committee, quickly followed by a supporting update for providers to permit access from CDC. A fourth shot will likely be authorized by CDC, though access may be different than in the past, especially after the government stockpile recedes.

Third, the BA.2 sub variant 0f Omicron is poised to cause an increase in U.S. caseloads as it has in other parts of the world, thought it is not certain when. According to the Centers for Disease Control (CDC) it is now the dominant strain. After weeks of falling caseloads, some areas like New York City and New York State have seen the rates per 100,000 start to rise again and the 14-day change in cases has risen 92 and 78 percent, respectively as of yesterday, and have been increasing for the past several days. With the fourth booster in hand, those most vulnerable might opt to take it now (while there is stockpile) only to see it wane if the BA.2 wave in the U.S. does not happen until later in the year.

Fourth, the rise in availability of home testing is likely masking (pun intended) the actual numbers. Whole families may be find they are feeling unwell, testing and finding they are sick, but never getting sick enough to get medical attention. So they are completely under the radar when it comes to the numbers that we are counting and upon which we are basing policy decisions, like mask requirements.

Fifth, the masks are dropping. Attending a theatre performance this weekend I was double bagged – a KN95 underneath and a second (more fashionable) cloth mask over it. But I was in the minority by far. The lowering of mask requirements and inclinations may spur the emergence of the sub variant, or future variants.

Sixth, speaking of new variants, in places around the globe where there large numbers of people are being infected there is a potential fro the development of new variants.

In short, we are being dealt a new hand. A more spreadable virus is among us just as our vigilance is waning. More vaccine doses are authorized, but access is narrowed. Cases are increasing while mortality – a lagging indicator – has dropped. And perhaps most important, we are not assuring widespread access to vaccines and treatments to the most vulnerable, we are not accurately counting, and we are not taking precautions. From a policy perspective, perhaps we needed a new hand, but one thing remains – in the face of on-going infection, access to vaccines and therapeutics remains essential. While we are looking at a new landscape, we are also facing certain obstacles.

Photo by Casey Horner on Unsplash

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Are We Moving On From Covid?

Posted on February 22, 2022 by Mark Senak

Mask mandates are dropping like flies. Restrictions are being lowered. In my observation, it feels that they are going to the wayside not only because of dropping caseloads, but also because people are just more than ready to move on. There may be some complacence – a feeling that the ubiquitous Omicron has fostered a feeling of inevitability about exposure and eventual infection. But mostly, we are just tired – there is a strong sense of COVID fatigue, not just among people, but it seems even institutions.

Even perhaps FDA. In a recent blog posting, I looked back at the profile of FDA press releases over the period 2013-2021 (See What They Said 2021 – An Overview of FDA Press Statements). In it we saw that FDA had a good deal to say in 2020 putting out over 400 press statements, but that output fell considerably in 2021.

Not only was the agency saying less, it was saying less about COVID. Communications regarding aspects of agency work vis a vis the pandemic fell in 2021 compared to the year before, despite the number of developments in vaccines and therapeutics during the year. Looking at it on a month by month basis, you get a real impression of how much oxygen COVID-19 took of FDA’s communications.

COVID-related releases are indicated in orange while non-COVID are in blue. Looking to the right axis of the graph above, one can see that during 2020, COVID was over 50 percent of the discussion nearly all of the time. In April 2020, COVID-related statements comprised three quarters of FDA’s public facing releases, and it never went below 50 percent during the rest of the year. By contrast during 2021 there were some spikes, but the overall profile of COVID talk fell below the 50 percent mark during several months. And the first month 2022 (not a big month for press statements from the agency in general) saw a steep decline. The overall trend is definitely downward.

Why is this important? It may not be, but it also may be a signal from a communications perspective that it may be easier to get back to some of the topics – and some of the science – that we have maybe pushed aside for the past two years. Maybe there is opportunity to talk about the cancer moonshot, or the goal of ending HIV/AIDS or other pressing issues from which we were distracted#C.

Perhaps the pandemic is becoming normalized, perhaps we are just tired, or could there be less actually happening? Maybe it is a combination of all three. It is likely too early to tell. Certainly there are many mysteries remaining with respect to what it means to have COVID, to prevent it and to treat it and many more with respect to what it has done to us as individuals and collectively. But it would be nice to get back to other topics. We will have to see.

Photo by Isaac Quesada on Unsplash

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