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.

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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.

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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 – 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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