What They Said 2021 – An Overview of FDA Press Statements

Posted on January 12, 2022 by Mark Senak

Each year we look back to take stock of how the agency has been communicating in the course of the previous year and assess how that might compare to years gone by. In fact from year to year, there is a good deal of change that occurs. When Dr. Scott Gottlieb took the reins of FDA as Commissioner, the amount of communications material put out jumped enormously. And it did so again last year when the agency would have a lot to say about COVID-related activities.

This year, however, not only was the agency putting out less, the number of releases this past year represents a somewhat inflated number. In prior years, the agency statements under a heading called “FDA in Brief“. These are statements that differ in format and nature from a traditional press release. They are more general announcements than they are news. Press Releases announce approvals, for example, while FDA in Brief statements can be used to “remind industry” or to announce that the agency will be holding a meeting. Press releases are often (though not always) released in English and Spanish, while FDA in Brief statements are not. These statements were housed on the FDA website separately from press releases. This year, however, the agency not only listed the FDA in Brief statements under their own heading, they also begin listing them in with the press releases they agency sends out. Since they did not do this in years gone by, that means that the number represented in the press release category is inflated. This year there were 43 “FDA in Brief” statements included in with press releases. If you actually removed them from the count, then the actual number of traditional press releases from FDA this year is 241, meaning the agency issued about 57 percent of the releases they issued during 2020.

Why the plunge? Certainly there was a good deal going on related to COVID, and the agency also approved a solid number of new molecular entities during, falling just a few shy of last year’s record number. One possibility may be the presence (or not) of a full time commissioner. The arrival of Dr. Gottlieb certainly saw an impact in volume. During nearly all of 2021, FDA has been under the direction of an acting commissioner.

In any case, here is what FDA talked about this year.

  • COVID – 144 announcements were COVID-related in 2021, compared to 274 such announcements during 2020;
  • Approvals – there were 77 announcements related to approvals this year, 22 of which were COVID-related announcements. In 2020 there were 40 COVID-related approval announcements. There were 43 drug and gene therapy approval announcements in 2021 (7 of which involved EUA announcements), 24 device approval announcements (7 of which were COVID-related) and 8 announcements related to Vaccines;
  • Alerts – there were 9 Alerts issued by the agency this year, 4 of which were related to COVID – this compares to 16 Alerts issued in 2020, 7 of which were related to COVID;
  • Legal – there were fewer releases related to legal issues in 2021, with only 12 issued regarding warnings issued by the agency or consent decrees compared to 21 in 2020;
  • General Announcements – this category includes statements from the commissioner or from various division heads and here is where there the greatest numerical difference existed between 2020 and 2021. In 2020, there were 251 such pronouncements while in 2021 there were 156;
  • Translation – Sometimes FDA communications are issued in both English and Spanish, sometimes not. There is no discernible rhyme or reason to it. There is also no indication why all communications are not translated. The translation rate appears roughly the same for the past two years – in 2021, 57 of the 284 releases (20 percent) were translated into Spanish, compared to 88 of the 420 last year (21 percent).

As far as what 2022 will bring, given the events of the past two years, it is hard to say. If the pipeline continues to produce in spite of the pandemic, there will be new approval announcements. There will certainly be new COVID developments. And the existence of so many products authorized under emergency use authorization is certainly an issue that will have to be dealt with. When will the products be fully approved? And while the imprint of the communications style of a new commissioner is something that might be anticipated, we are getting a commissioner who we had once before in 2016-2017, a period where the quantity of communications was not robust. And new in 2022, FDA has occasionally begun issuing something called “FDA Roundups” but have provided to date no new “FDA in Brief” statements. Something to keep an eye on.

Photo by AbsolutVision on Unsplash

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FDA OPDP Look Back at 2021 – The Yawning Gap

Posted on January 10, 2022 by Mark Senak

Once again it was a quiet year with respect to the FDA’s Office of Prescription Drug Programs (OPDP). As noted in the past, there are two primary means for understanding the agency’s latest thinking with respect to promotional communications from pharmaceutical companies – the content and pattern of enforcement and the issuance of guidance documents to shed light on the parameters that exist. In that respect, 2021 was not a banner year.

The Numbers: Looking first at the quantity of enforcement, the numbers were low. This year there were 6 regulatory action letters issued by OPDP, the same as the previous year. The only other time in the past 24 years when enforcement was this low was in 2017. This year there two were Warning Letters and four were Untitled Letters.

The 6 letters issued involved 7 different communications vehicles for a total of 13 violations that were cited by the agency as reasons for the action.

The Substance: What triggered the enforcement actions? Back in 2009 you may recall that FDA issued 45 Untitled Letters aimed at 14 companies regarding the use of banner ads/sponsored links where clearly benefits of a branded product were available, but risk information only ascertainable by clicking on a link. This was a clear direction from the agency that risk information could not be incorporated by link. This year, three of the communications vehicles involved in enforcement actions were either banner ads or sponsored links where risk information was not included. One of them involved the more serious Warning Letter action, possibly because the product associated with that communication had a Boxed Warning in its label. The other communications vehicles involved DTC videos. Of the 9 violations that were cited in the 5 letters, 4 were for risk minimization or omission, 2 involved superiority claims, 1 unsubstantiated claim and 2 failure to submit Form 2253 to review.

Guidance Docs: As far as I can see, there have been no new relevant guidance documents, wither in draft or final form, that are focused on digital and/or social media and promotional communications. In the latest published guidance agenda from the Center for Drug Evaluation and Research, the advertising and promotion category had no slated guidance efforts listed.

Research. To a degree OPDP signals where it is headed in terms of enforcement and guidance by telling us what research it is conducting around promotional communications. Of the 13 projects currently underway by OPDP, 2 of them are focused on aspects of television DTC ads. There is one study comparing physician interpretation of information from scientific publications versus promotional materials. And curiously, one study is focused on assessing medical conference attendee observations about prescription drug promotion even though medical conferences have largely been virtual for the past two years. None of the studies underway are aimed at uncovering data that would be helpful in providing additional guidance related to the use of digital and social platforms by patients, prescribers and pharma companies.

Why This is a Fail. The way that patients and prescribers learn about medicine has changed significantly over the past 15 years. People do still watch commercial television, but in fewer and fewer numbers. Digital and social media are a primary resource for getting healthcare information and discussing treatment, especially now in the age of COVID. It is a continually evolving environment – there have even been an abundance of articles about how pharma companies should be using TikTok. In particular, for people who do not have access to computers, mobile access is the primary means of getting information. How websites are optimized for mobile is therefore important. FDA has traditionally taken the view that if it is wrong on television DTC, then it is wrong on TikTok. But these are all new platforms that have a lot of nuance to the use of the platforms, in addition to the fact that different populations may have different approaches to digital consumption as well as varied skills. There may be vast comprehension differences in digesting communications from digital sources than from traditional DTC television advertising. It is way past time for the agency to have applied effort to understand the role of that nuance and to make more detailed studies – and therefore guidance – on the best uses of digital media. And of course, there is the fact that FDA never really finished providing guidance related to social media inaugurated by the public meeting the agency held in Washington, D.C. in November 2009. At that meeting, the agency posed five questions as a framework for developing a guidance the following year. Guidance did not come for five years and then did not follow the framework, leaving the questions only partially addressed by two guidance documents – one on use of platforms with character space limitations and another on correcting misinformation posted by third parties. This leaves quite a bit of work not done as it relates to social and digital media, the source from which growing numbers of people get health care information.

FDA Changes Display of Warning/Untitled Letters. Finally, FDA has made it harder to get a view of the regulatory actions with respect to promotion. All letters, Warning and Untitled Letters used to be listed in chronological order. This year, for reasons that are incomprehensible, FDA moved the Warning Letters from the list of OPDP actions and lumped them into all of the other warning letters issued by the entire agency. Now to assess the activity of OPDP for the year, one must visit the list of Untitled Letters and then sort through the list of agency-wide warning letters.

One thing that did happen this year is that OPDP has new leadership. It takes a long time to steer any ships within an agency as large as FDA and to bring about true change. The gears grind slowly. But there is a yawning gap between communications realities on the one hand and the agency focus when it comes to promotional communications. One hopes that the agency will consider the shifts in communications that have taken place and the impact those shifts have on the decisions that patients and providers make with respect to treatment. Hopefully 2022 will bring greater attention to addressing the many deficits that exist in the current approach to enforcement by conducting more research that is appropriate to the communications environment.

Note: Following the original publication of this posting, in mid-January OPDP posted a letter dated December 19. The original of this blog posting has been updated to reflect that late addition to 2021 letters.

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FDA Advisory Committee Review of 2021

Posted on January 5, 2022 by Mark Senak

FDA has scheduled the first advisory committee meetings of 2022. One meeting of the Oncologic Drugs Advisory Committee is set for February 10 to discuss a new application for the proposed treatment of Non-Small Cell Lung Cancer (NSCLC. And a meeting of the Anesthetic and Analgesic Drug Products Advisory Committee is meeting jointly with the Drug Safety and Risk Management Advisory Committee on February 15 to consider an NDA in the pain category . But before heading into 2022, it is perhaps time to take stock of AdComms and what they did or did not do during 2021. Fewer Meetings. First and foremost is that as noted earlier this year (See August 5, 2021 FDA Adcomms – Is FDA Getting Less Advice?), there were fewer 2021 meetings held to consider new drug applications than in years gone by. And it isn’t even close. In all there were 20 advisory committee meetings scheduled by FDA this year, but only half of those involved deliberations regarding an application for a new medicine. In fact, the number of AdComms to consider new products was the lowest it has been in a decade, less than one-third what it was ten years prior.

FDA Adcomms have been declining in number even as the agency approves more drugs

Of note, this tally does not include meetings of the Vaccines and Related Biologic Products Advisory Committee held to consider a recommendation for COVID-19 vaccines, but includes only drugs and biologics.

  • Of the ten 2021 meetings, one of them was to consider a supplemental application in oncology – a new indication for Keytruda;
  • One of the 2021 meetings was consider approval under Emergency Use Authorization (EUA) for use of molnupiravir to treat mild to moderate COVID-19 at risk for progression;
  • While there have been many new oncology drugs to come before FDA this year, only two had advisory committee meetings – the sBLA for Keytruda and a BLA for retifanlimab for anal carcionoma;
  • The number of meetings represents a fairly sharp decline in the number of times FDA has gone to advisory committees for input, though the number of novel drug approvals at the agency this year hit a robust 50 for the year. In fact, the decrease in the number of AdComms does not appear to have a correlation to the number of new molecular entities being approved by the agency.

One might be inclined to think that the decline in AdComms is due to the pandemic due to the the complications inherent in staging a meeting under these circumstances. But in fact, FDA has been holding virtual meetings for a long time now. Rather, it is possible that the agency is seeking the input of advisory committees because it is more engaged in reviewing new applications that have priority review status, which is a more interactive effort between the agency and the sponsor.

FDA Outcomes.

  • Of the ten AdComm meetings considering new product approvals, companies got a recommendation for approval in half of them, two of them in diabetes. FDA has acted on seven of these recommendations;
  • Neither of the two oncology filings got a recommendation for approval.
  • Most of the votes taken by the committees were quite lopsided, with only a few of them being close splits, one of which was the vote on molnupiravir for the treatment of COVID-19 (13-10 vote recommending approval).
  • So far this year (and unlike last year) there have been no instances where FDA has gone against the advice of a committee. Last year, FDA acted against the recommendations of the committees four times – twice to approve in the face of a recommendation against approval and twice to decline approval where there was a recommendation for approval.

Taking Care of AdComm Vacancies. And speaking of divergent outcomes – one of the most notable occurrences in 2020 was the number of resignations that occurred in the wake of FDA’s decision to approve Aduhelm for Alzheimer’s Disease after an overwhelming committee vote recommending the agency decline to approve. While a count last month showed many vacancies, now FDA is listing very few. Here is where FDA currently has vacancies:

  • Bone, Reproductive and Urologic Drugs Advisory Committee – 4 vacancies
  • Gastrointestinal Drugs Advisory Committee – 1 vacancy
  • Pharmaceutical Science and Clinical Pharmacology Advisory Committee – 4 vacancies
  • Pharmaceutical Compounding Advisory Committee – 1 vacancy

In coming days, we will be doing more look-back’s at FDA activities during 2021.

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The Definition of “Fully Vaccinated” Needs to Change

Posted on December 15, 2021 by Mark Senak

The COVID-19 pandemic is a rapidly changing landscape. We are long gone from the days of being threatened by a rampant Alpha virus to having several successive variants. It now appears that the very fast-spreading Omicron may become dominant over yesterday’s Delta variant. We now have multiple vaccines – mRNA and traditional in the U.S. and an even greater array outside the U.S. We have the emergence of monoclonal antibodies and protease inhibitors being utilized or being considered as treatments for various stages of disease. We even have a pile of misinformation.

Today CDC provided important insight into the ability of the new variant to make headway with a highly vulnerable population when it released data on infections in the nursing home environment.

What is evident in looking at the profile provided by the CDC is that the most at risk or infection in the wake of the rise of Omicron is naturally among the unvaccinated. However there is also an alarming rise among people who have completed their primary vaccination. While there were people who were infected with the booster, the profile and trend is low.

This begs the question that has been circulating for a while now with a new urgency. Many policies – from return-to-work to allowing admission to various facilities have been premised on people showing evidence of being “fully vaccinated” meaning having completed two rounds of vaccination with an mRNA vaccine or had one dose of the Johnson & Johnson vaccine.

It would seem that Omicron has rendered that definition outmoded. Because so many decisions, both institutional and personal, rely on that definition, it is clear that it needs to be changed to incorporate the role of additional vaccination.

The change is not only important for the immediate environment, but it stands to reason that as future variants emerge, there is going to be a need to consider additional interventions, either by boosting existing vaccine status with more shots, or with the development of multi-variants. What is fully vaccinated today may not be fully vaccinated tomorrow. It is clear that COVID is something we are going to have to learn how to live with and work around. Given the fluidity of the environment, part of that effort includes re-examination and recalibration of the way we talk about the pandemic, particularly with definitions on which so much policy is decided.

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The Once and Future FDA Commissioner

Posted on November 18, 2021 by Mark Senak

In what has been a glacially paced nomination process, the Biden Administration announced on November 12 that it would, in fact, be nominating Dr. Robert Califf to return to his role as FDA Commissioner. Acting Comissioner Janet Woodcock indicated in a tweet that she would be remaining in the role of Acting Commissioner during the confirmation process.

Since he has been confirmed before it would seem likely that he will be confirmed again. Though, of course, it is a very different political climate and a different Senate than it was the first time. Media coverage regarding the nomination has been largely focused on concerns expressed by some about Dr. Califf’s past work with pharmaceutical companies in clinical research. More specifically some are concerned that this association might be problematic vis a vis addressing the opioid epidemic in this country. Ultimately this past was not an issue the first time in 2016 when he was confirmed by a vote of 89 to 4.

One of those four votes against confirmation has already announced opposition this time around. The reasoning is again based on Dr. Califf’s association with the pharmaceutical industry – an objection that seems less sure-footed this time around. In the first place, he has already been FDA Commissioner and there was nothing during his tenure that would suggest his industry associations had a negative influence on FDA policy during that time, whether on the topic of opioid policy or any other issue. Secondly, one actually wants someone who knows research and understands the industry to be the head of FDA. It would therefore seem to be even less of an issue today.

What is perhaps more substantive this time around is that FDA is in such a different spot than it was in 2016 when Dr. Califf was first at the helm of the agency. Focus should be less on the perennial concerns about past associations with industry (which is always a question during FDA Commissioner confirmations) and more on addressing the issues that have torn at FDA’s reputation since Dr. Califf’s first tour of duty with the agency.

For example, any nominee should face questions about the future role of the accelerated approval program. For all of 2021 trade media have carried headlines about the fact that this regulatory pathway is under attack and FDA officials have stepped up to defend the program. Two recent white papers – one by Friends of Cancer Research and one by the Institute for Clinical and Economic Review (ICER) have outlined suggestions for reform to the accelerated approval program designed to make it more transparent and consistent. What will a new commissioner do to shore up this critical pathway?

Another related issue is the loss of credibility from the recent self-inflicted harm by the agency in its approach to approving a new treatment for Alzheimer’s, resulting in an unprecedented level of criticism directed at the agency with a consequence that three members of the FDA advisory committee resigned in protest, creating a crisis for the entire advisory committee process. (It is perhaps noteworthy that some committees at present are experiencing large numbers of vacancies – Gastrointestinal 6 vacancies; Oncology 2 vacancies; Peripheral and CNS 4 vacancies; Pharmaceutical Science 5 vacancies.) How will a new commissioner restore confidence in the advisory committee system for both the public and research community?

And this week a bill was introduced in the U.S. House of Representatives by Representatives Diana DeGette (D-CO) and Fred Upton (R-MI) that, if passed, would be the follow-up to the 21st Century Cures Act that was signed into law in 2016 designed to speed up regulatory consideration of new treatments. Among other changes the proposed law would bring, the new and improved version offers the possibility of altering the accelerated approval pathway even further by allowing use of a wider range of evidence for efficacy, including real world evidence. Dr. Califf is an expert in clinical study. His opinion on this is much more substantive than his past associations with industry. How does a new commissioner assess the role of real world evidence in the approval of new medicines?

These are the kinds of substantive issues at question that should serve as a basis for examination of any new incoming FDA Commissioner.

This job is not an easy one. If confirmed, Dr. Califf deserves our best wishes. There are patient communities in true need, there is a large industry with good and bad players, there are multiple competing interests – there are those who believe in the agency and those who never will. There is an endless supply of critics and skeptics. It takes courage, fortitude that support the pursuit of clear goals that are clearly communicated to a myriad of stakeholders. Good luck to any nominee who is confirmed and to any person who must assume the role of Acting Commissioner while the process plays out.

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