Mark S. Senak's Blog, page 4

FDA Advisory Committee Review of 2021

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 vacanciesGastrointestinal Drugs Advisory Committee – 1 vacancyPharmaceutical Science and Clinical Pharmacology Advisory Committee – 4 vacanciesPharmaceutical Compounding Advisory Committee – 1 vacancy

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

The Definition of “Fully Vaccinated” Needs to Change

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.

The Once and Future FDA Commissioner

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.

Headache for the Next Commissioner – FDA’s Reputation Crisis

Recently it was reported that the President Biden appears ready to nominate former FDA Commissioner Robert Califf to boomerang back and head the agency for a second time. If so, he returns to very different circumstances than when he left FDA in January 2017 after an 11-month stay. While FDA is accustomed to controversy while making difficult decisions, lately, it is much more than that. A number of factors have been at play that together have begun to tear at the very reputational fabric of the agency, tarnishing the “gold standard” that has been maintained for so long.

In fact, on the one hand, FDA is doing pretty well. It has been maintaining operations throughout the COVID-19 pandemic. Like everyone else, the agency has had to convert operations to a virtual existence which is no small task when responsible for regulating one-fifth of the U.S. economy. For everything from inspections of manufacturing facilities to managing a large staff to conducting the regulatory review of new drug applications, including conducting advisory committee meetings virtually and transparently. In addition, the agency has maintained a solid pace. Last year in spite of the pandemic, there were 53 new molecular entities approved – nearly a record. And so far this year, there have been 41, which puts us on pace to nearly meet or exceed last year.

But on the other hand, a number of circumstances – all of which are inter-related, have come to play that have cast a shadow over the bright reputation of FDA and present some very specific challenges for the future.

Science is Under Attack – This is nothing new. In the middle ages the roundness of the Earth was rebuffed (and apparently still is). There were those who challenged the fact that our planet did indeed circle the sun and not the other way around. And anti-vaxxers have been a reality since vaccines came into being. And of course, the science behind climate change has been repeatedly attacked in the last few decades. But the COVID-19 pandemic has a potent chorus of science skeptics who, thanks to amplification provided by social media, have a louder voice than they otherwise would have. The bottom line is that for an agency where the very foundation is one of scientific rigor, an attack on science is an attack on the very bedrock of FDA.The Perceived Politicization of FDA – Against a backdrop of political polarization that is in hyperdrive, many have felt that the agency has become unusually politicized. During both the Trump and Biden Administrations statements about the use of COVID-related products were made ahead of the regulatory process that would consider their approval, making it seem for some that the outcome were pre-determined. In sum, even if not intended, the optics were not good. The fact that the process has not been politicized is separate from the perceptions that some may have. The COVID-19 Pandemic – From the origins of the virus to the degree to which it makes people ill, the pandemic has been a focus of controversy and extreme opinions. Suddenly everyone is an epidemiologist and virologist. Apart from the controversies, FDA entered some unprecedented waters utilizing the Emergency Use Authorization for prevention, treatment, vaccines and diagnostics – a regulatory mechanism with which most people were unfamiliar. The speed with which vaccines were developed and cleared, combined with a new vaccine platform added fuel for detractors and skeptics. FDA’s Accelerated Approval Program is Under Scrutiny – The Accelerated Approval pathway for expedited access for medicines where there is a high unmet medical need for serious health conditions has been a focus in recent months. Accelerated Approval allows for the early approval of drugs based on early indications and looking at outcomes that appear to offer promise, pending later confirmatory clinical trials by the drug manufacturers. This year FDA has been reviewing drugs approved under the program to assess approvals in light of the changing treatment landscape and the status of the confirmatory trials. This has led to a close-up critical examination of the pathway by critics and a defense by FDA officials. Controversial Approvals – And speaking of accelerated approvals – there are always going to be difficult calls on clearing the way for some treatments, particularly where patient populations are facing dire consequences and treatment choices are few or non-existent. But no approval has caused as much of an uproar among so many stakeholders as the approval this year of a new treatment for Alzheimer’s following an overwhelmingly negative vote against a recommendation for approval by an FDA Advisory Committee. Several members of the committee resigned in protest, following publications from both FDA and those in opposition to the approval. FDA approved the label and then reversed course to narrow the treatment for a subset of patients. Paragraphs could (and have) been written about it, but in the end, there was an investigation announced by both Health and Human Services and by Congress into the process for approval. Confidence in the agency and the approval process was left shaken.

The combined result has left FDA with a trust issue – not something one wants at any time, much less in the middle of a pandemic. The Robert Wood Johnson Foundation and the Harvard T.H.Chan School of Public Health conducted a poll “The Public’s Perspective on the United States Health System” earlier this year. FDA did not show up so well with a lower degree of trust than other sources like the CDC and the Surgeon General and a higher percentage of people stating that they did not have much trust. So if Dr. Califf returns, it is a very different set of circumstances by far than in 2017.

And as with any reputational crisis, there are no simple answers and a solution involves a process, not an event. (1) It begins with communication and lots of it. Dr. Califf’s successor Dr. Gottlieb was extremely engaged in communications and the number, range and types of communications increased dramatically while he was Commissioner. It may be time to take a page from that notebook. (2) There needs to be be not only a good volume of communications, but they need to be consistent. (3) The messaging – which needs to pass a smell test – on a wide range of topics needs to be pegged down and the leaders of the agency need to embrace and use that messaging. (4) In addition, there needs to be an effort to get the backing of third parties who are credible to the stakeholders. The RWJF/Harvard survey indicated people trust local sources more than national ones. A grassroots strategy may be advisable. (5) The agency needs to embark on an historical education effort and enunciate a vision rather than respond to each and every issue. (6) There are a lot of loose ends to clean up, particularly with the Accelerated Approval program and the agency has to ensure both transparency and consistency in dealing with them.

FDA has always been driven by science. But most of FDA’s stakeholders are not scientists and they need to have things explained very clearly, consistently with coordinated messaging that is repeated often and is well-planned. With care and effort, this crisis will resolve. Science has always been under attack, but the arc of progress in medicine thankfully always bends to the gravity of science and not the distractions that sometimes stand in the way.

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FDA Authorizes Third Dose – Some Implications

What does “fully vaccinated” mean today?

In the face of the widening spread of the SARS-Cov-2 variant, the rise in breakthrough cases, and data that suggests a slight waning effect over time of vaccines, FDA acted yesterday to protect some of the most vulnerable by amending the Emergency Use Authorization of the mRNA vaccines. People who have had organ transplants and people who are immunocompromised may now get a third dose.

There has also been some data suggesting a possible waning in individuals over 60 but there is no change for that group, so far. Israel, which has been a reliable bellwether for how the pandemic plays out, has authorized a third dose for those over 60, and it is likely only a matter of time before the U.S. follows suit. The sooner the better.

Extending protection to the most vulnerable is certainly a good thing. But there are always unintended things that crop up. We are concurrently in a phase where a growing number of institutions are requiring vaccination of employees and where businesses, theaters and restaurants will be asking for proof of full vaccination. As third doses become the norm, particularly only for specific populations, the definition of “full vaccination” shifts, depending on who you are. A transplant recipient today would be considered “fully vaccinated” after a third dose. In the near future, the same may be said for a person over a certain age. In other words, verification of status becomes a more complicated task.

The little vaccine cards do have two more blank entries that allow for entry of “other” – but at some point they will not be able to keep up. It begs the need (further) for reliable digital means of proof, such as the New York Excelsior Pass. For political reasons in some jurisdictions this is unthinkable, but for public health reasons it is going to eventually be an imperative. However, there will need to be a system whereby residents of any state can, if they want, avail themselves of such an instrument.

For those venues now seeking verification of status, the question arises whether or not they have to first determine a person’s characteristics – transplant status, immune status, age – before true verification can actually occur. For that matter, when considering persons vaccinated outside the United States, we may have to ask what type of vaccination they have received. Would an individual who received a Chinese or Russian vaccine be considered fully vaccinated. An if you are over 60 and from Israel, fully vaccinated now means someone with a third dose, but not if you are over 60 and from the U.S. In short – the term “fully vaccinated” does not refer to a monolith, but to an ever-increasingly multi-faceted set of people who have received some sort of vaccine and in varying degrees and number.

We are feeling our way through this, necessarily responding to a quickly changing landscape. It requires patience, level-headedness, innovation and a view of the long game here. But as we adjust the sails to better navigate the pandemic, we must also take care to keep up on all fronts.

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AdComms – Is FDA Getting Less Advice?

As more drugs are being approved, is FDA getting less advice than in the past?

FDA maintains a vast network of outside advisors to provide input and counsel to the agency related to decisions on policy as well as product approvals. There are 31 advisory committees on matters ranging from food to medical devices to pediatric care. Within those focused on human drugs, there are 17 committees organized under therapeutic categories (Arthritis, Cardiovascular and Renal, Gastrointestinal, e.g.). Each committee is comprised of a number of experts, diverse for their expertise, geography and specialty – with some focused on statistics while others may be focused on areas of concentration within the category, such as the treatment of pediatric patients. There is an industry representative (non-voting) and a patient representative as well. Their terms are staggered – like the Senate – so that each year, some rotate off while others come on. FDA does not tap an advisory committee for every single approval or policy decision, but likely does when there are questions where they feel outside input is important.

Recently advisory committees (AdComms) have been in the news quite a bit due primarily to the controversy surrounding FDA’s decision to go against the advice of the Peripheral and Central Nervous System Drugs Advisory Committee in approving a treatment for Alzheimer’s where the committee vote was overwhelmingly against recommending approval. FDA does, from time to time, act contrary to a recommendation from an advisory committee – by my count a little over 10 percent of the time. This one, however, struck a nerve and after the decision, some members resigned from their role on the Advisory Committee.

And so we look at two things – how often is FDA consulting advisory committees and how many vacancies are there?

First, while the numbers are low enough that trends are not easy to discern, it does appear that FDA is consulting with advisory committees less and is doing so while more novel drugs are being approved. Below is a chart that looks at 3 numbers – the number of AdComms; the number of new molecular entities approved each year, and the number of drugs that had breakthrough therapy designation. Breakthrough Therapy is a pathway designed to expedite the consideration of a new drug for a serious condition where the drug may bring significant change to the treatment landscape. When Breakthrough Therapy (BT) designation is granted, then the drug gets Fast Track status and receives more intensive guidance – which can begin as early as Phase I clinical trials. The reason they are included here is that they could be a factor in the need for fewer advisory committee meetings – if these candidate compounds are demonstrating promise that gets them more intensive oversight it may negate the need for outside counsel. That said, BT would be a lagging indicator since it can be granted so early in the development process.

The blue represents the number of AdComms, Orange the number of new molecular entities and the gray the number of BT designations (Note that 2021 figures are through June 30):

What we can see here is that there is a significant body growing of BT designated compounds and a growing number, generally speaking, of new molecular entities being approved. At the same time, looking to 2018 when there were 29 meetings to consider new drugs, the number appears to be falling each year, with only 6 that occurred during the first half of 2021. Fewer meetings – more approvals.

If they did want to hold more, are they ready? That gets us to the issue of vacancies. Years ago, there would often be significant numbers of vacancies among the committees for considerable amounts of time. It is not an easy proposition to find willing and qualified participants who are not conflicted and to vet them all. It may be an easier management task now that meetings are virtual, but still it is a big organizational effort. Compared to yesteryear, it seems that vacancies are running pretty low. Of the 17 committees, only 6 appear to have vacancies:

Bone, Reproductive and Urologic Drugs Advisory Committee -1 Gastrointestinal Drugs Advisory Committee – 6Medical Imaging Drugs Advisory Committee – 1Oncologic Drugs Advisory Committee – 2Peripheral and Central Nervous System Drugs Advisory Committee – 4Pharmaceutical Science and Clinical Pharmacology Advisory Committee – 4

The most active of these committees with vacancies this year has been the Oncologic Drugs Advisory Committee. Also the vacancies on the Peripheral and Central Nervous System Drugs Advisory Committee largely reflect the protest of the FDA approval decision in Alzheimer’s.

FDA has had its reputation tested not only by that decision but by the events of the past few years that called into question a possible politicization of the process and all of the misinformation around COVID-19 and vaccinations. One pathway to preserving reputation is with the support of outside experts and with the advisory committee system, FDA has a built in means to add outside voices and credibility to the agency’s actions. But for that, it needs to be utilized.

Crisis Communications and FDA

In the face of a crisis situation, it is a given that the clarity and thoroughness of the communications response is key to resolving the issue and mitigating any reputational damage.

Perhaps no other decision by the Food and Drug Administration has garnered as much controversy, as the recent one to authorize the accelerated approval a new treatment for Alzheimer’s. Media reporting has been wide and deep on the issue. One of the most insightful was a recent article published in The New York Times that goes into extensive review of the decision and the fallout from it. The scope of the story and the revelations underlying indicate that FDA is experiencing a crisis. The agency’s response so far does not.

Just to recap the outcome of the decision – three members of the FDA Advisory committee that reviewed the application and provided an overwhelming recommendation against approval resigned in protest making it clear that they did not feel the agency valued the role of the committee’s deliberations; at least two congressional committees are investigating the approval; there may be an investigation by the Inspector General; FDA may be conducting its own internal investigation. This is an abbreviated list.

Fundamental to any crisis response is the development and delivery of a narrative that offers explanation for the events. It must be believable and clear. I, the audience, should be able to repeat it. In other words, there must be clear and digestible information that provides an explanation that is both comprehensive and credible. Lacking that sort of narrative, the story gets stitched together by the responses of others. The picture gets built from multiple sources, particularly if there are gaps in the narrative or questions which are still outstanding. Moreover, the narrative must be consistent. When the story changes, credibility erodes.

At least judging from the reporting, the FDA narrative has not always been consistent. For example, The New York Times piece points out the fact that the agency had indicated that the surrogate endpoint upon which was relied upon for the accelerated approval – the reduction of protein plaques in the brain – would not be used as a basis for approval. Then it was. That is an example of the type of thing that must be addressed in a comprehensive narrative.

Once that is devised, then the agency has the job of delivering it. That, too, requires a plan. At this point, anything said by the agency in just about any forum is going to be scrutinized and people are going to take issue with it. However, it gives one the advantage of shaping the discussion to a degree. To be reactive only allows the discussion to be shaped by others.

When providing crisis counsel, there are some key things that I always think need to be accomplished in the communications around the situation. I believe them so critical that if communications fails to address them, it raises the likelihood that the issue will continue to fester. They are:

What happened? – A thorough explanation of events. Why did it happen? – What is the rationale for the series of events. What steps are you taking? – What is being done to grapple with the situation?How are stakeholders being affected? – Demonstrate a grasp regarding the points of view of both supporters and detractors and the impact of the issue on them.Who is responsible? – Who is in charge of this issue? Who was responsible in the sequence of events?What will be done to address the issue?What steps will be taken to avoid a repeat?Are you sorry?

The agency is in a tough spot. In any crisis, people have more sympathy for acts done to you (acts of nature, for example) than things you did to create the issue that is of concern. Nevertheless, these 8 things are essential to answer.

I have no inside knowledge what kind of communications planning is going on within the agency. Sound communications planning may already be underway. One hopes so. There is more than the reputation of the agency at stake, though that in and of itself is extremely important for obvious reasons during this time.

But there are additional considerations. The accelerated approval program which was conceived as a means of getting patients access to promising drugs earlier in the review process and was a direct result of both the needs presented by an out of control AIDS epidemic. It works by giving a treatment a green light based on a surrogate endpoint with the proviso that confirmatory clinical trials bear out the approval, but opening up access for patients. With its beginnings in virology, the accelerated approval program has been used extensively in oncology. The controversy surrounding this approval gives the program a black eye.

Moreover, with many withholding their decision to vaccinate for COVID-19 pending an FDA decision on the vaccines for approval beyond emergency use authorization, credibility is really important now more than ever. For these reasons, if no other, FDA should be doing all it can not only to address the controversy but to be taking a proactive approach to addressing the crisis at hand. That begins with a solid narrative.

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What They Said – FDA Press Releases Mid-2021

It has been a regular feature of the blog to give a read on what FDA has been talking about, at least through the form of press releases. It is not always an easy task because the nature of FDA’s practice in this respect has evolved over time. But here is what we see looking at the first 6 months 2021, and comparing it to mid-years past.

You may recall from the last posting on this topic at the beginning of the year, during 2020, FDA had a lot to say – a real lot, and that isn’t surprising given the agency’s role in facilitating treatments, diagnostics and vaccines to respond to COVID. Last year the agency issued over 400 releases on a range of topics (65 percent of releases were related to COVID-190. And while we are still in the midst of the pandemic, it is somewhat surprising to see that the overall number of releases during 2021 has fallen off a bit – to 153 so far this year (54 percent have been COVID-related), which if this pace kept up, would annualize to only about 300. Of the 153, only 33 of them were translated into Spanish.

It is even more surprising considering that the agency started listing releases under “FDA in Brief” in with its listing of Press Release materials, which serves to inflate the total number of press releases. Consider “FDA in Brief” releases as a sort of press release-lite. They have their own section in the FDA Newsroom and usually involve topics that are not quite press release-worthy by my observation. They generally have a more limited audience and a different format than FDA press releases. And while some, but not all, of FDA’s press releases are also issued in Spanish, FDA in Brief releases do not seem to ever be available in Spanish. It would appear in May of this year, the agency began adding “FDA in Brief” releases into the list of regular press releases, while still listing them separately under their own heading, adding about 20 entries. So what that means, if you backed those out is that the agency actually only put out about 133 press releases by mid-year, compared to last year when FDA put out 218 press releases.

Also by mid-year last year, FDA announced 55 approvals, including several Emergency Use Authorization (EUA) announcements for drugs and devices compared to just 44 approvals, EUA’s, or label expansions so far this year (though the number of new molecular entities is running at a very high pace during the first half of this year). This year 10 of these approval announcements have been in relation to COVID-related medicines or devices, while last year it was 17.

Further, last year FDA introduced regular Coronavirus Updates as part of the press release regimen. Last year during the first half of the year there were 134 such updates. This year there were only 67 Coronavirus Updates in the first half.

With regard to other subject matter, there were 6 alerts issued by the agency during the first half of the year and 9 releases regarding legal actions including seizures, consent decrees and warnings.

There is no telling for the reason or reasons there has been a drop-off. Certainly last year may have been an anomaly given the circumstances. But this year there were also fewer releases by mid-year than in 2019 when there were 155, though on par with the mid-year level in 2018 when there were 126. Any number of factors could be affecting the agency’s output, including the fact that the agency is still working with an Acting Commissioner. As we saw with the “Gottlieb effect”, Commissioners can make a difference in the agency’s approach to communications. We’ll check in again at year end.

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Author’s Note: Unfortunately the first automated mailing to subscribers last week did not work out so well and subscribers received a blank email when they should have received a blog posting about an Untitled Letter issued by FDA’s OPDP. Apologies for the misfire, but hopefully we are working more smoothly now. Thanks!

OPDP Sends Untitled Letter

Upfront Author’s Note: This is the first posting in a while as I have been working to migrate the subscription service to a new provider. As such, some subscribers were lost in the process. Anyone who signed up for a subscription prior to 2019, would need to sign up again. Apologies for the inconvenience and thanks for your patience.

Years ago, a single regulatory action letter issued by FDA’s Office of Prescription Drug Promotion (OPDP) would not have merited a blog posting in and of itself. That is because OPDP used to issue scores of letters each year. In the last several years, however, FDA’s enforcement arm has issued only a few letters each year. Yesterday they posted a new one and as such, it merits some discussion.

Let’s talk first about though enforcement patterns. There have been a total of 4 letters issued this year by OPDP, two of which were Untitled Letters and two of which have been Warning Letters. It might also be noted that this year the four letters involved five different communications vehicles, two of which were Banner Ads (the subject matter of the most recent letter).

Long time readers will know that enforcement by OPDP dropped off significantly beginning several years ago. There has been lots of speculation as to why and many theories. But in 2018 there was some definitive output from Dr. Janet Woodcock, then head of the Center for Drug Evaluation and Research (CDER) which houses OPDP. In one article she was quoted as saying that First Amendment issues curtailed enforcement activity. In the same article, however, she was quoted as saying that the agency would rather let companies sort it out among themselves rather than involve the agency in comparative claims.

Yet that is exactly what seems to have happened with the newest action from FDA. The letter from OPDP to Amgen took issue with statements made in a banner ad which compared delivery systems for Neulasta which the agency said created an impression of a higher risk associated with one over another. While a study was referenced in the sponsored communication, the agency did not find that the relied upon research was adequate to support a claim of greater safety for one delivery system over another due to the limitations of the cited study. The only violation cited in this Untitled Letter was in relation to this claim. So contrary to the earlier indication from FDA, the agency is getting involved in a comparative claim, perhaps because this claim was in regard to an implication of safety over one of efficacy.

In any case, Dr. Woodcock has since moved on (up) the ladder as Acting FDA Commissioner and OPDP has a new acting lead. FDA’s OPDP certainly has held its powder in the recent past when it comes to enforcement and we will have to wait and see if this newest letter is an indication that there is change coming.

Finally, for those who watch this space, FDA took a simple listing of the regulatory action letters issued by OPDP and made it extremely complicated. One used to be able to look at Warning and Untitled letters in one combined list, but no more. You now can view Untitled Letters by year here. To see the Warning letters issued by OPDP during that same year, you must navigate to a different page and perform a sort on “Office of Prescription Drugs” to narrow the list to only those letters issued by that office. But if you don’t want to do all that, don’t worry, I will do it for you and have created a tab (located in the black bar at the top of the posting and underneath the lead logo banner) on the blog site that lists the letters with links to the letters issued so far the year. This list will continue from here on out.

Photo by Goh Rhy Yan on Unsplash

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Virtual Reality – FDA and AdComms

Vaccination has been robust. Cities are opening up. Plans are underway for back-to-school. Travel is robust. Offices are cautiously re-opening. There are multiple hallmarks that, whatever the consequences, we are going back to normal. The age of COVID-19 will likely continue, but with the emergence of a significant proportion of the population with vaccines pumped into them, we headed back on almost every level. Not FDA.

Today the FDA announced an upcoming meeting of the Cardiovascular and Renal Drugs Advisory Committee set for July 15 and once again, it is slated to be virtual. As the rest of the country prepares for Return to Travel, Return to Work, Return to School, this raises the question of “when” FDA is going to get off the virtual dime and migrate back to in-person meetings? One has to think that is is highly likely that nearly all people who attend an FDA Advisory Committee meeting as members are going to be vaccinated individuals. And that while travel might be required, CDC has stated that vaccinated persons “who are fully vaccinated with an FDA-authorized vaccine of a vaccine authorized for emergency use by the World Health Organization can travel safely within the United States.”

At a time when almost everyone is returning – at least partially – to pre-COVID patterns – what signal does it send when the agency responsible for approving the vaccines many of us just took is not? One branch of Health and Human Services (HHS) – the CDC has said – albeit in uncertain fashion and with an indelicate process – that masking is no longer necessary for the vaccinated while another HHS agency stays virtual.

As anyone who has had to sit through the misery of a virtual FDA Advisory Committee meeting can attest, and as recently noted on this blog, there is a significant amount of wasted time and inefficiency with an e-meeting over the old fashioned in-person variety, not to mention pain for those of us having to endure it. Moreover, while virtual platforms (when they work) have been a lifesaving substitute – from telemedicine to online cocktail parties – they lack the important nuances of human interaction as well as that je ne sais quoi that adds quality to the experience.

Also noteworthy, application has been made for full approval by one manufacturer for the COVID-19 vaccine and another will soon follow suit. Presumably there will be an advisory committee meeting associated with those applications – one that might be soon given that the application is a Priority Review. One has to consider that an advisory committee meeting for that deliberation would certainly raise some eyebrows if not held in person. It would be ironic to say the least.

FDA appears to be swimming outside the current. Perhaps there are policy and logistical questions to consider. Thinning out the seating pattern might be one – requiring people to produce evidence of vaccinated status might be another. But the world is moving on. Hey there FDA, think about the optics if nothing else. Let’s get together again.

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