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 – 6
  • Medical Imaging Drugs Advisory Committee – 1
  • Oncologic Drugs Advisory Committee – 2
  • Peripheral and Central Nervous System Drugs Advisory Committee – 4
  • Pharmaceutical 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.

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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:

  1. What happened? – A thorough explanation of events.
  2. Why did it happen? – What is the rationale for the series of events.
  3. What steps are you taking? – What is being done to grapple with the situation?
  4. 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.
  5. Who is responsible? – Who is in charge of this issue? Who was responsible in the sequence of events?
  6. What will be done to address the issue?
  7. What steps will be taken to avoid a repeat?
  8. 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!

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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.

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