Thumbs Up, Thumbs Down – Minimizing Votes in AdComms

Posted on March 21, 2023 by Mark Senak
FDA Commissioner Califf has voiced a desire to limit voting in Advisory Committee Meetings

Recently there have been a spate of reports carried in trade media that Commissioner Califf would prefer to limit the voting mechanism customarily included as a key part of FDA Advisory Committee meetings. Traditionally, committee votes can be taken on a range of topics during the course of the meeting. These votes are usually interspersed with questions that the agency poses to the committee for the purpose of eliciting discussion about specific aspects in relation to the approval of a new drug application. Customarily this culminates in the ultimate question whether the committee believes that the benefit/risk ratio is such that approval is warranted. Now the Commissioner appears to be suggesting that the focus be put on discussion with less, if any, inclusion of what he refers to in one report as a “gladiator” vote of approval.

The notion to limit voting seems a bit contrary to the character of the current environment – one which would seem to beg for more transparency rather than less. In November 2020 FDA held a meeting of the Peripheral and Central Nervous System Drugs Advisory Committee to consider a new drug application for an investigational treatment – aducanumab – for Alzheimer’s. The standing voting members of the committee (7) were joined by 4 additional temporary voting members. FDA posed a total of 8 questions for the committee’s input into the agency’s decision, half of which were discussion questions and half of which were voting questions. It went something like this:

  • The first question posed to the committee in that meeting centered on one of the clinical studies that had been submitted in the application and asked whether it provided strong evidence of efficacy and the committee overwhelming voted that it did not (1 Yes, 8 No, 2 Uncertain).
  • The second voting question focused on a different study, asking the same point regarding efficacy and again the vote was overwhelmingly negative (0 Yes, 7 No, 4 Uncertain).
  • Asked whether there was strong evidence of a pharmacodynamic effect related to Alzheimer’s pathophysiology, the outcome was a little more balanced, but still not an endorsement (5 Yes, 0 No, 6 Uncertain).
  • Returning to the study voted on in the first voting question, the agency then asked whether it was reasonable to consider the study as evidence of efficacy in the treatment of Alzheimer’s and the vote was once again overwhelming (0 Yes, 10 No, 1 Uncertain).
  • Several months later, FDA approved the NDA under accelerated approval provisions, a possibility that was not something discussed at the meeting.

The results were disastrous from nearly any way you look at it. FDA pointedly ignored the overwhelming sentiment of the panel, resulting in the unprecedented resignation of 3 of the advisory committee members. CMS issued a national coverage decision to limit coverage for the drug by implementing a policy that it would only cover monoclonal antibodies approved under accelerated approval for Alzheimer’s for those patients who had been in the clinical trials, pretty much guaranteeing that uptake would be limited. Confidence in the approval process was shaken and FDA’s reputation took a blow. The outcome fostered confusion among patients and physicians. And among the many negative side effects of the decision, there was a Congressional investigation highly critical of FDA’s lack of transparency in the process, among other things.

The Aduhelm case study is an example of why voting is in fact essential.

In referring to the voting tradition in the meetings as reported in trade media, the Commissioner stated words to the effect that the advisory committees exist to give the FDA advice and that approval decisions should be left up to full time civil servants. In the same article he’s quoted as saying that these meetings are like a democracy – where there is not always agreement – and therefore sometimes messy. But while the committees are there to provide FDA advice – and ultimately the decision does rest with FDA, AdComms also serve another very important purpose.

With votes, we get not only the qualitative insight yielded to us by the nature of the discussion, but a quantitative understanding as well. It makes the outcome concrete. We are left with a good perspective on whether the committee is wholeheartedly enthusiastic, fence-sitting, or in the case of aducanumab, very much against approval. We don’t have to read the tea leaves. Votes are a fundamental component of transparency to those of us on the outside and the considerations that go into an approval decision are known and understood by everyone. Part of understanding is provided by the discussion, but a part is also the mechanism of a vote. And to the Commissioner’s point regarding “messy democracy” – in point of fact, voting is a fundamental component of the democracy to which he refers.

Commissioner Califf’s thinking on this has been through various reported conversations and has not been embodied in a speech. The topic merits wider consideration though and a more thoughtful and contextual discussion. Hopefully that will happen.

Can we at least vote on it?

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Big Decisions – Reviewing FDA Advisory Committee Outcomes Since 2020

Posted on March 6, 2023 by Mark Senak

In January we took a look at FDA Advisory Committees (AdComms) – FDA AdComms – When the Going Gets Tough – noting, among other things that there had not only been fewer meetings but also that it appeared that the outcomes were increasingly negative.

Just to recap, for the entire year of 2022 there were only 14 meetings held to consider whether new medicines should be recommended for approval, a slight increase over the 10 the year before, but considerably lower fewer than 2018 and 2019 when there were 29 and 22 meetings held, respectively. And as can be seen by the increase in red bars (negative outcomes) and the decrease in positive outcomes (green bars), the outcomes have skewed increasingly negative, with 2022 being a particularly negative year. Note these numbers cover meetings about drug applications only, not including vaccines or cellular therapies.

By contrast, already in 2023 there have been eight AdComm meetings scheduled by FDA for the purpose of considering a new medical treatment, three of which have occurred and all resulting in votes in favor of the sponsor, so perhaps 2023 is heading to less negative territory. During the balance of this month and into next, there are five more meetings scheduled, so we shall have to see.

That tells the collective story, but how do each of the committees fare?

The committee with the most AdComm meetings was also one of the committees with the highest number of negative outcomes – the Oncologic Drugs Advisory Committee. The committee met a dozen times during 2022 and only voted in favor of recommending approval four times. Two committees – the Endocrinologic and Metabolic Drugs Advisory Committee and the Antimicrobial Drugs Advisory Committee were among those that met the fewest times – once and three times, respectively, but both had purely positive outcomes. In fact, bottom line, there were nine different committees that had meetings to consider new drug approvals last year, only four of them voted positively 50% or more of the time, with five of them voting negatively more often.

There are a lot of variables that factor in. Drugs for cancer face a whole different set of criteria for assessing safety and efficacy than do other therapeutic categories. That said, beginning in 2020 meetings began skewing to more negative outcomes and 2022 was the first year where the number of negative outcomes outweighed the number of positive outcomes. As noted earlier, this coincides with the transition to virtual meetings over in-person ones.

But the nature of AdComms may be in flux calling into some question the role and influence of voting. Recently, Commissioner Califf was quoted in a few articles this month reporting on a moderated discussion in which he participated at the Biopharma Congress meeting held in Washington, D.C. in mid-February. The coverage in part focused on his thinking that advisory committees need to be less aimed at actual votes rather than on having a full discussion of the issues. Apparently these comments did not come in the form of a speech which would be listed on the FDA’s website which might provide some context – because on their own, they are rather confusing. More thinking about this in an upcoming posting, but it signals perhaps that the nature of AdComms may begin to skew less to circumstances where there are voting questions posed to the committee and that there may emerge a more consistent use of “discussion” points instead. If so, that will certainly complicate future big picture analyses, forcing the discussion to be more qualitatively than quantitatively focused.

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Emerging from Emergency – Two COVID-Related Developments This Week

Posted on February 1, 2023 by Mark Senak

Two announcements occurred this week, both of note and connected only by the fact that they are emblematic of the slow metamorphosis from a COVID emergency world to a post-COVID emergency one.

Emergency Ends – First, the Biden Administration announced that it would be allowing the Public Health Emergency (PHE) declaration to lapse this coming May. In a separate (and pointless) development, the U.S. House of Representatives voted to end the declaration – theater-legislation given that the initiative would never be passed into law and the policy decision was already made. The PHE, initiated during the prior Administration and extended repeatedly by the current Administration, put into place a number of policy initiatives in relation to the COVID-19 response, most significantly initiatives that enhanced the ability freer access for people to get vaccines, medicines and testing. With the end of the PHE declaration, access for individuals will shift away from government support and rely on a person’s insured status (either public or private) and any state policies in effect.

  • Impact on EUAs? One aspect largely missed in the media reporting on the PHE conclusion is in regard to whether or not the action has an impact on the Emergency Use Authorization (EUA) status conferred by FDA on a number of vaccines, diagnostic tests, and medicines during the COVID emergency. However, the PHE that will end on May 11 is distinct from the separate from the mechanism that allows FDA to issue EUAs for medical products. Therefore the status of those medical products that have EUAs will not be affected by the ending of the PHE, declared under the auspices of the Public Health Service Act. The emergency declaration that confers the ability of FDA to issue EUAs is a separate regulatory mechanism and is part of the Federal Food and Drug Cosmetic Act. FDA has stated in an updated FAQ on the topic that any change that would impact EUAs would first be published in the Federal Register with ample time provided for transition of products from EUA status.

Face-to-Face Meetings – On a separate note, it was reported this week that FDA will be engineering an eventual return to in-person meetings with industry. FDA has provided an update on the website regarding Face-to-Face (FTF) meetings with staff transitioning in 2023 to return, at least part of the time, to the FDA campus.

  • Impact on AdComms? While it is almost impossible to think of that absolutely HUGE campus empty all this time, the return naturally raises the important question as to how this change will impact industry, with specific attention to FDA Advisory Committee meetings. In a prior post, it was noted (without making a causative connection) that since meetings went virtual, they have also gone more negative, with a higher rate of “no votes” than in prior years. In the communication regarding the transition, FDA has stated that they will be re-fitting conference rooms with some fancy new equipment – face/conversation tracking cameras and boom forming microphones for example – and the agency will have in-person participation likely limited to those with speaking roles, while others will be relegated to a virtual presence. Hence, a hybrid meeting. Because the number of rooms will be limited, but growing over time, these types of meetings will seemingly start out few and expand as re-fitted facilities come on line. The agency is targeting smaller industry meetings for this effort. Sadly, no mention yet of FTF AdComms.

It would appear that we are emerging, in some respects, glacially from the COVID era. As noted in the previous posting, FDA is talking less about the pandemic than before. And while it is good to have this in the rear view mirror, it is worth noting that daily mortality is still high, people are still hospitalized at a high rate, and many people are still getting sick with it for the first time. We are moving on, but the pandemic is still very much with us.

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What They Said – Looking Back at FDA Press Releases During 2022

Posted on January 26, 2023 by Mark Senak

Each year Eye on FDA provides a look-back to see what the agency was talking about and what has changed over time. This year is a telling one and FDA may be changing the nature of the way they are communicating with the public. Moreover, this year is marked by the fact that the agency appeared to have less to say than in most recent years – perhaps taking a breather after the frenzy of the COVID-19 pandemic years.

  • Overall Fewer Press Releases – During 2022 the agency issued fewer press releases than in most previous years – 237 down from 285 the previous year and the fewest releases since 2017. There may be several factors at play. Not only was there less activity in relation to the COVID emergency, but we have had a change in leadership at FDA, which can have a big impact on how the agency communications. For example, when Dr. Gottlieb became FDA Commissioner he embraced the issuance of “Statements from the Commissioner” as a vehicle for talking about a vast array of topics, causing a huge spike in the number of releases from the agency. Prior to that time, such statements were very rare. With Dr. Califf at the helm, those statements have been used with far less frequency, issuing only a few this year. And in addition, there were far fewer new drug approvals in 2022, particularly new molecular entities, which means that there was less to talk about in that regard.
  • The Air is Gone from the COVID Balloon – Needless to say, as the COVID-19 pandemic picked up pace, so did the agency’s involvement in approving new vaccines, new treatments and in addressing the thirst for reliable public health information. But the volume of COVID- related news has fallen off dramatically as has the agency’s activities. In 2020 there were 277 press releases related to COVID, with 144 in 2021, falling precipitously to only 27 in 2022. The chart below demonstrates the diminishing role on a month-by-month basis of COVID related releases (represented by the red area).
  • FDA Began a New Method for Dispersing News – In prior years, the agency used to post news items that were not quite worthy of press release status in a vehicle called “FDA in Brief” that were posted in a place on the FDA website apart from traditional press releases. Beginning in 2022, however, FDA began to issue “FDA Roundups” which were included as part of the lineup of press releases, and “FDA in Brief” postings came to a halt. The new FDA Roundups contain a hodgepodge of news items rolled up into a single communication, topics which are not likely on their own worthy of a press release and which include mentions of COVID-related developments. They are generally issued usually twice a week, every third or fourth day, but not always. Unlike many of the agency releases, they are not translated into Spanish. This mechanism signals a whole new way for the agency to communicate its activities.
  • What They Talked About – Finally, when they were talking, what were they talking about. As already noted, there were fewer approvals and less COVID-related material. There was a higher number of releases that were available in Spanish as well as English – and since there were fewer releases, that means that a higher proportion of releases were also in Spanish over years past.

While the number of press releases did diminish this year, given the added information going out in the regular roundups, the actual volume of information may increase. As we look forward to 2023, it may be important to note that since the month started 24 days ago, FDA has issued only 3 press releases in January, with the bulk of information being sent out via the Roundups.

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When the Going Gets Tough – FDA AdComms in 2022

Posted on January 17, 2023 by Mark Senak

Through its Human Drugs Advisory Committee process FDA has a vast array of outside experts to consult on matters related to product approval as well as questions about policy or safety issues concerning approved products. The mechanism provides an open and transparent process whereby people can see and hear the deliberations and have input during open public comment as well as through a docket established for that purpose.

But for those who have spent years watching – one thing has become clear. FDA Advisory Committees (AdComms) ain’t what they used to be.

First of all, they are all still virtual. At the beginning of the pandemic, FDA moved to staging virtual meetings. For anyone who had to suffer the onerous security ritual at FDA’s campus where the meetings were generally held that may be good news. In-person FDA AdComms were not really fun. The parking lot was light years from the entrance, the security screening was slow and laborious and once you were in, your eating options were quite limited. The switch to virtual meetings has meant that you can now watch and participate from the comfort of your own home – where presumably you can get whatever you want to eat. Ultimately, the virtual meetings certainly get the job done in terms of the exchange of information – even if you do have to put up with a lot of people needing to be reminded to unmute. But certainly the meetings have lost the personal touch lost in all virtual re-setting. You could see who showed up and who talked to who. I can recall a sitting U.S. Senator walking into a meeting to confer once. And there were many open public comment periods that were quite moving as a result of patient presentations in a way that they might not be in a virtual setting. The networking that used to occur – the informal interchanges – those are not happening. So that is one – albeit small – way in which AdComms have changed. But there are others.

Second, and perhaps more important, there have been fewer of them. In 2012 there were 35 meetings held by FDA for the purpose of considering new drug approval which is almost 3 meetings a month. By contrast in 2021 there were only 10 (see blue bars below in the chart tracking meetings from 2017 – 2022).

Yet in the midst of that range, the number of new molecular entities approved by FDA actually increased. Looking at the second chart below, one can see that the number of AdComms since 2018 peaked in the same year FDA approved a record number of new molecular entities (NMEs). But if you look at more recent history, you will see that during years of robust approvals for NMEs in 2020 and 2021, the number of AdComms went down considerably. That means that as FDA was approving more drugs of first impression it was consulting with outside experts through the transparent process of Advisory Committee meetings with less frequency.

As has been speculated here in the past, the drop-off may be a result – at least in part – of the rise of new pathways for drug approval such as Breakthrough Therapy Designation which promise enhanced access to FDA decision-makers, thereby perhaps diminishing the need for outside consultation.

During 2022, the number of AdComms held to consider new products rose a bit over the previous year to 19 scheduled meetings. However, with 4 of them cancelled, there were only 15 applications considered this year through the AdComm process. Pre-pandemic numbers were consistently higher. But conversely, in 2022 the number of NMEs plummeted.

Third, AdComms aren’t as approving as they used to be. In terms of votes for recommendations of approval for new drugs, the track record was a little brutal this year. Of the 15 applications for new drug approvals in 2022 that went to AdComm consideration, the committees gave a thumbs up to only 4 (the green bars) – and in one of those FDA’s decision went against the approval recommendation of the committee and the sponsor received a Complete Response Letter. Moreover, of the 4 approval recommendations, none of them were unanimous votes in favor of the application. On the flip side – there were 11 votes on applications that failed to get a recommendation for approval (the red bars) and one of them was unanimous. In addition to the more negative tone as expressed by fewer approval recommendations, during 2022 there was an increase in meetings that were either cancelled or postponed.

So in sum, over the past few years, AdComms have been consulted less frequently while more NMEs were being approved. And when they were consulted, the outcome has been increasingly negative. Does the COVID-19 pandemic figure in here? It certainly seems that there is a difference between pre-and post- COVID patterns. Perhaps the virtual means for these meetings has an impact beyond the obvious in the deliberation. Or perhaps it is a coincidence. For those having an AdComm in 2023, we will watch and see what happens.

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