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DALLAS SMITH, CDC [00:05:22]
And so before I go into this outbreak, I just wanted to give a brief background about a recent, very similar fungal meningitis outbreak in Durango, Mexico, which really happened in November 2022, or really started November 2022.
And so during this outbreak, almost 1,500 patients were exposed to a similar type of procedure that was using epidural anesthesia. 80 patients were identified with meningitis, 39 of these patients died. So almost a 50% mortality rate. During the investigation that our Mexican colleagues carried out, they found that this outbreak was caused by for Fusarium solani.
That was isolated from several patients and also on PCR tests was had a lot of hits on it too. However, we also did find one case that was actually treated in the United States. Alternaria was cultured from one of these patients. And Mexico was able to investigate kind of the cause of this fungus outbreak. And although they don’t have a clear cause, they did determine that poor IPC practices probably played a role in this fungal meningitis outbreak.
And so I wanted to give that context because the outbreak that we’re experiencing now is pretty similar, and it has the capacity to have this high mortality rate, and just devastate families and communities.
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DALLAS SMITH, CDC [00:08:24]
CDC has come together with our colleagues in Mexico to initiate a public health emergency of international concern. And this was submitted to the World Health Organization on May 21st, 2023.
They, the World Health Organization is still considering this, but because patients in Mexico, the United States, Canada, and Colombia were on the exposed list, we wanted to make sure these countries were aware, and provide such situational awareness, through a public health emergency of international concern.
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DALLAS SMITH, CDC [00:10:04]
As of this morning, so May 26, we have 199 persons under investigation. We have 12 suspect cases and 10 probable cases in the United States. Two of these probable cases have passed away. And then we also have reclassified five cases, as not cases. These cases have not had the exposure of an epidural anesthesia. And so we got this list and we were able to remove five people from the list of patients.
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DALLAS SMITH, CDC [00:11:21]
There was 124 patients from Clinica K3 and 97 from Riverside Surigal Center. The majority of these patients exposed were female. However, we do have males that were exposed and just yesterday we did have our first probable male case. So a patient who was a male who had an abnormal LP, and symptoms consistent with meningitis.
The mean age of these patients was 35, with a range of 14 to 69. We have also been able to do in-depth interviews on 10 probable and suspected fungal meningitis cases combined. And so I wanted to provide an in depth overview of these patients. And so these cases come from three states – Arizona, Tennessee, and Texas.
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DALLAS SMITH, CDC [00:12:07]
As I mentioned before, two deaths have been reported. One of these deaths was caused by intercranial haemorrhage. And this patient was also an organ donor, and we– there’s been five recipients of these organs from this patient, all have been notified, and are under evaluation, and we were working with transplant centers and other partners to properly manage these patients who had these organs transplanted into their bodies.
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DALLAS SMITH, CDC [00:12:43]
And so from these in-depth interviews, we found that procedure dates range from January 24th to March 15th, which is a pretty wide range. Out of the exposed individuals, which are not on this chart, we have procedures going back to almost the beginning of January or mid-January. And so that kind of gives reason of why we wanted our exposure history to start at the beginning of January.
The demographic characteristics of these 10 in depth interviews, all of them were female. The mean age was 33 with a minimum of 26 to a max of 52. When we in, when we interviewed these 10 individuals, we found that 100% of these had liposuction procedures at these clinics in Mexico under epidural anaesthesia, 40% had breast augmentation and 30% had Brazilian butt lift.
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DALLAS SMITH, CDC [00:15:29]
Some additional testing that we’ve done with partners include two pan-fungal PCR tests at the University of Washington, which have been negative. We are also receiving brain tissue and spinal cord at the CDC for testing from a deceased patient.
And finally, one of our partners have been able to send CSF to a university in California, UCSF, for metogenomic testing, which can test for a variety of pathogens, including fungi, bacteria, and viruses.
And finally, our colleagues in Mexico has recently had four patients test positive for Fusarium solani from CSF by PCR. And so this – it’s kind of makes us think about this outbreak that happened in Durango, with a very high mortality rate. We are not sure if these two outbreaks are linked, but the fact that the same organism is most likely causing this fungal meningitis makes us worried about a high mortality rate. So that’s why it’s so important to get patients in early, even if they’re asymptomatic, and get them tested for potential fungal meningitis.
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DALLAS SMITH, CDC [00:17:06]
What we know is that medical tourism is common in U.S. citizens, especially cosmetic. And what we found through investigation and interviews is that there’s these agents that act as recruiters in the U.S. for patients, they link U.S. patients to these clinics to receive certain care, and certain procedures like cosmetic procedures. And so we’re working with them to figure out how we can raise awareness and identify more people who have been exposed, during this time period, to fungal meningitis.
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DALLAS SMITH, CDC [00:17:36]
Two of the main hypotheses that we have that could have caused this outbreak are the actual medicines used in epidural anesthesia. And we actually think the anaesthetic is unlikely, as it’s widely distributed, and there hasn’t been any other cases in parts of Mexico.
One of our other things that we’re looking at is morphine is added during this, during epidural anaesthesia, and there’s a shortage currently in Mexico, and there could be potential for a black markets that could have contaminated medicine.
The other hypothesis that we have is poor infection control practises. And oftentimes in Mexico at these clinics, anesthesiologists bring their own medications and prepare them on site. And so there could be possible contamination through that route as well.
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DALLAS SMITH, CDC [00:52:54]
So we do know that our colleagues in Mexico, during the Durango outbreak, did do sequencing as some of the isolates that they got Fusarium solani.
However, in order to do like really robust whole genome sequencing, and looking at the– if the two outbreaks are related, we need an isolate from this outbreak, which we currently don’t have.
I mean, you can do a little bit of sequencing of the little region you get from a positive PCR, but we probably need an isolate to really understand if these two outbreaks are related.
So yes, we, we are hoping to do that, but I think we need to grow at first either in the United States or Mexico.
QUESTION [00:24:08]
During a previous hot topic presentation, Dr. Marks indicated the FDA expected a 1% loss, I’m assuming they mean in donors, however, the final guidance stated that, indicates that the availability will not be impacted. What has changed?
PETER MARKS, FDA [00:24:32]
I think we– the number is half a percent to one percent loss of donors who might– these would be female donors who are having anal sex. The issue is that that may be more than compensated for by the requalification of donors now who would be men who have sex with men who are now qualified to donate, because they are only having sex with one other partner in the past three months, and don’t have multiple partners.
So I think when you, depending on exactly how you do the math, it comes out to be at least a wash, if not.
I will go into an area of controversy where I’m not sure our colleagues, that CDC would always agree with us, but I’ll at least mention this, that there are some that believe that by having a policy that is judged as more equitable and more fair, that we will ultimately increase the number of blood donations and blood donor drives, because college campuses that previously, I mean, I worked on a college campus that would not allow a blood donor drive to occur because of the previous policies.
So, hopefully now that we have a blood donor policy that is viewed as more equitable, some of those college campuses will allow blood drives. And so we may have an increase. How much that increase is? I don’t know, but I, again, I think the reason why we didn’t– why we’re not too concerned there is I think there’s probably going be a wash.
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PETER MARKS, FDA [00:30:35]
We would love it if you use all good due diligence to get things revised. On the other hand, it’s not like we’re gonna come out there and chase you, but we would like to see that.
It would be nice if an inspector came by, they just, a few months from now, they didn’t see the guidance like sitting dust with dust on it, and your computer system completely, no one doing anything about reprogramming your computer system. So I think making good faith efforts.
We understand the challenges here. Look, people are very resource constrained, we get it. But just as long as people are making good faith efforts that, okay, we have the plan in place to reprogram. We’re starting to reprogram. We’re starting to retrain. Even having the planning in place for that will be helpful. So, there’s not, unlike some guidance where there’s an implementation deadline, we don’t have that here.
But I would say this, to us as a collective group of people interested in collecting blood, that I think if this goes too slowly from too many locations, there might be people writing letters to Congress, like what happened in the indefinite to 12 month change. And that led to– it led to publicity that wasn’t as good as it could be. So I think we want to be making good faith efforts to move in the right direction.
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PETER MARKS, FDA [00:33:06]
Something that I would say that is remarkable to me, having been through this over the past decade plus, is the the fact that, as we’ve moved forward here, there’s been really good collab–
I think, compared to the original indefinite to one year change, this most recent change, the collaboration between blood collectors and the agency here to make sure that things went smoothly, and moved along, I think was quite remarkable. And I think that’s– it’s a really positive development.
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PETER MARKS, FDA [00:36:13]
I think the issue of of needing to defer people with PrEP, we simply don’t have a way of getting– and that was one of the other major comments that came in, why do we need to defer people on PrEP? And we simply do not have the science yet to ensure that our current technologies will detect HIV adequately in people on PrEP.
And there are some data from France to suggest that it might not be the case that they’re sensitive enough. So, I think that’s probably the answer to that.
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PETER MARKS, FDA [00:57:59]
This has to be done in an orderly fashion, in a safe fashion, that it takes time to implement. That computer systems take time to reprogram. And then it could take a few months to have this happen. That it’s possible that some blood donor centers may get there a little faster than others, especially hospital blood donor centers, where they can sometimes move much more quickly.
So I think we’ll be continuing to say that.
PAXLOVID that is labeled for use under the Emergency Use Authorization (EUA) remains subject to the terms and conditions of the EUA. Individuals being considered for PAXLOVID treatment must meet the eligibility requirements under the EUA at the time of prescription. For related and other important information on PAXLOVID, please refer to FDA’s FAQs at: https://www.fda.gov/media/155052/download
| Location | 24-May-23 | 17-May-23 | Difference |
|---|---|---|---|
| Total | 30422 | 30401 | 21 |
| Illinois | 1461 | 1452 | 9 |
| Maryland | 748 | 745 | 3 |
| New York | 4253 | 4250 | 3 |
| Alabama | 190 | 189 | 1 |
| Arizona | 592 | 591 | 1 |
| Florida | 2894 | 2893 | 1 |
| Louisiana | 314 | 313 | 1 |
| Texas | 3008 | 3007 | 1 |
| Utah | 197 | 196 | 1 |
| Virginia | 572 | 571 | 1 |
| … | … | … | … |
| Michigan | 399 | 400 | -1 |
| Epi date | Cases | 7 day average | Cumulative this month |
|---|---|---|---|
| 4/1/23 | 1 | 2.4285715 | 1 |
| 4/2/23 | 0 | 2.14285707 | 1 |
| 4/3/23 | 2 | 2 | 3 |
| 4/4/23 | 0 | 2 | 3 |
| 4/5/23 | 3 | 2.28571439 | 6 |
| 4/6/23 | 4 | 1.57142854 | 10 |
| 4/7/23 | 0 | 1.42857146 | 10 |
| 4/8/23 | 0 | 1.28571427 | 10 |
| 4/9/23 | 0 | 1.28571427 | 10 |
| 4/10/23 | 0 | 1 | 10 |
| 4/11/23 | 0 | 1 | 10 |
| 4/12/23 | 3 | 1 | 13 |
| 4/13/23 | 2 | 0.71428573 | 15 |
| 4/14/23 | 1 | 0.85714287 | 16 |
| 4/15/23 | 2 | 1.14285719 | 18 |
| 4/16/23 | 2 | 1.42857146 | 20 |
| 4/17/23 | 2 | 1.71428573 | 22 |
| 4/18/23 | 4 | 2.28571439 | 26 |
| 4/19/23 | 2 | 2.14285707 | 28 |
| 4/20/23 | 4 | 2.42857146 | 32 |
| 4/21/23 | 1 | 2.42857146 | 33 |
| 4/22/23 | 0 | 2.14285707 | 33 |
| 4/23/23 | 2 | 2.14285707 | 35 |
| 4/24/23 | 1 | 2 | 36 |
| 4/25/23 | 1 | 1.57142854 | 37 |
| 4/26/23 | 0 | 1.28571427 | 37 |
| 4/27/23 | 1 | 0.85714287 | 38 |
| 4/28/23 | 1 | 0.85714287 | 39 |
| 4/29/23 | 2 | 1.14285719 | 41 |
| 4/30/23 | 0 | 0.85714287 | 41 |
| 5/1/23 | 4 | 1.2857143 | 4 |
| 5/2/23 | 1 | 1.28571427 | 5 |
| 5/3/23 | 4 | 1.85714281 | 9 |
| 5/4/23 | 3 | 2.14285707 | 12 |
| 5/5/23 | 0 | 2 | 12 |
| 5/6/23 | 1 | 1.85714281 | 13 |
| 5/7/23 | 2 | 2.14285707 | 15 |
| 5/8/23 | 4 | 2.14285707 | 19 |
| 5/9/23 | 2 | 2.28571439 | 21 |
| 5/10/23 | 1 | 1.85714281 | 22 |
| 5/11/23 | 0 | 1.42857146 | 22 |
| 5/12/23 | 1 | 1.57142854 | 23 |
| 5/13/23 | 1 | 1.57142854 | 24 |
| 5/14/23 | 2 | 1.57142854 | 26 |
| 5/15/23 | 0 | 1 | 26 |
| 5/16/23 | 0 | 0.71428573 | 26 |
| 5/17/23 | 0 | 0.5714286 | 26 |
| 5/18/23 | 5 | 1.28571427 | 31 |
| 5/19/23 | 0 | 1.14285719 | 31 |
| 5/20/23 | 0 | 1 | 31 |
| 5/21/23 | 0 | 0.71428573 | 31 |
| 5/22/23 | 1 | 0.85714287 | 32 |
| 5/23/23 | 0 | 0.85714287 | 32 |
| 5/24/23 | 0 | 0.85714287 | 32 |
HILARY MARSTON, FDA [00:39:07]
FDA’s responsibility for drugs is to make sure that the drugs that are available are safe and effective, right? But that issue of quantity, of how much is out there, that’s not in our authorities.
That being said, shortages occur. And when they occur, we have to make sure that any actions that are taken to mitigate the shortage maintain those standards. Right? So that the public can be reassured that the drug that’s available is still safe and effective.
That means that the question of who is responsible for the amount is kind of a jump ball at this point. And there are a number of different agencies that play a role.
But the truth of the matter is, that overall, the entity that’s playing that role right now is the market. And unfortunately, this market is has some key economic issues that are resulting in drug shortages.
So what do I mean by that? So generic drugs, this is largely happening in generic drugs, you don’t see this largely in the innovator space, often in these really complex generic drugs, where you’re having to get sterile, complex molecules produced. So it’s not easy to do. And that means that it’s not easy for somebody to just start up right away and make some more of something goes into shortage.
We have some tools at our disposal in order to help when a shortage ensues.
But what’s happening in the market is that you have some generics companies that are ready to make, they are approved to make these drugs. You have some intermediaries that are purchasing from them, distributing, and the contracts that are in place, these generic companies are just competing against each other based on price, because it’s important that consumers go to their pharmacy, go to their hospital, and have some reassurance that drug A is going to be the same regardless of whom is producing it. So that that’s important. But that means that the generics companies are only able to compete on price.
And when they compete on price, unfortunately, they’re going into a race to the bottom. And they’ve gone so far in that race to the bottom that it becomes very difficult for these companies to invest in advanced manufacturing lines, or just upgrading their manufacturing lines, and certainly in having a buffer stock available. A lot of them are operating in this just in time setting.
So there– the issues that drive the market are ones that I think we all collectively need to think of creative solutions to address. The problem is, if it were easy to address them, it would have been done already. Right? So we’ve been having, in multiple settings, really robust exchanges about what needs to be done here. But it’s complex. And the solutions that is– there’s a lot of hot debate about what the right solution set is for it.
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HILARY MARSTON, FDA [00:42:18]
That being said, so what do we have at our disposal? So we have a lot of mitigation tools, and we have a very small but mighty team over in CDER that is working really hard on drug shortage mitigation, and what they’re able to do when they are notified of an impending shortage is that they reach out to the companies, they reach out to other companies, to see if those companies are able to and willing to make more.
We have no ability to tell companies to make more. We have no ability to dictate amounts, but we are able to encourage them. We are able to help them find alternate sources of raw materials. That’s something that we can assist in. We have some limited ability to help if there are international sources potentially.
But these are things at the edges, right? And in the interim, while we’re trying to work with these companies to improve supply, patients are waiting and looking for drugs. So this isn’t really a situation that we can watch continue. And it’s a reason why certainly a number of folks across government are trying to find additional solutions.
But we definitely welcome creativity in this area.
ROSEMARY SIFFORD, USDA [01:17:37]
We certainly have large volumes of exports of poultry and poultry products and certainly volumes of imports as well. So we’ve had lots of discussions and addressed a lot of the kinds of questions you’ve been hearing about during the panel sessions so far.
A couple of the big questions for us have been to think about how our trading partners would respond to any vaccination and what their expectations would be of us with regard to questions like surveillance, and spending a lot of time developing scenarios for surveillance plans and thinking about what that might look like so that we’d be able to talk to our partners about those plans in advance.
Another big question that has come up for us is the cost of vaccination, not only the cost of the vaccine, but all the associated costs, including administration and a surveillance plan. Earlier today, vaccine stewardship was mentioned and that is a part of the cost as well. The follow up that would be needed to ensure that we were continuing to follow a solid and sound vaccination protocol.
So those are the kinds of questions we’ve been dealing with. You know, within the WOAH code, the standards of surveillance are not well defined. And so we think that it is very appropriate for us to work beforehand with trading partners to understand the expectations and make sure we’re very clear to be able to lay out well developed plans for surveillance, in particular, to be able to reach agreement about appropriate levels of surveillance beforehand, before introducing a vaccine protocol so that we would be able to have those discussions and be confident in the answers up front.
Within our poultry industry, we have quite a bit of diversity of opinion about the use of vaccine. Certainly for us, turkey farms have been the most affected in terms of the scope of the number of farms affected, but our egg layer industry has been affected with the highest number of birds affected, and so certainly we hear differing opinions across all the sectors and the broiler industry, having been less affected, and certainly depending on a large export market, has a lot of concerns about moving too quickly to vaccination and wanting to make sure that we have a very strong plan in place ahead of time.
We also see quite a bit of interest from other stakeholders who are not a part of the industry, and talk about a lot of other factors and concerns to take into account, such as what the risk is to public health and how vaccination might improve or have other impacts on the possibility for spillover to humans. So that’s an important consideration.
And then I’ll close out by mentioning, too, that we have spent a lot of time talking about our regionalization and compartmentalization. We do think that there is a strong role for for those tools with the use of vaccination. And so the scenarios that we’ve been developing definitely incorporate the use of either regionalization or compartmentalization to think about how we might effectively use vaccination.
ASHISH JHA, WHITE HOUSE [00:19:29]
So we’re very much in the process of setting up this new office. You know, new offices, obviously inside the White House, raised all sorts of important issues.
You have to sort out, how does it interact with existing offices? How do you set it up and design it to be kind of optimally effective? So a lot of that work is happening.
And then the other part I would say on this is that making sure we have very strong leadership inside that office is also critical. And we just– we’re just working our way through that. And we’ve been doing it while we’ve been working on the unwinding of the PHE and as I have said publicly before, you know, at some point the COVID response team will cease to exist and we will have an Office of Pandemic Preparedness and Response, and it will play a pretty critical role in this broad set of issues, much in the way that that Congress had intended, certainly as Senators Burr and Murray articulated.
In terms of that kind of broader public health leadership, here’s what I would say, Steve. I mean, first of all, some of this transition is both very normal and completely predictable, right? In the third year of a lot of presidencies, you see people saying, I’ve been going 100 miles per hour for a while and I’m going to step down and take a break or do something else. That’s pretty normal.
So I think, and of course, I came in later. I didn’t come in at the beginning of the administration, but everybody who’s at all related to public health inside this administration, not just working in a normally difficult circumstances, but they’ve been working on a global pandemic for for two and a half years. So the kind of the unwinding of the PHE is also a natural moment.
So people kind of look at this and say, is this unusual? I’m like, no, you just sort of predictable that you would see something like this.
And in each of these, I always remind people senior leadership is very important, but a ton of the expertise is in the agencies, in among the scientists.
You know, I’ve spent a bunch of time, in the last, I’ve talked to you about this at other moments, I’ve been spending a lot of time at NIAID thinking about some of those scientific work happening there on next generation of vaccines and treatments, extraordinary work, yes, we don’t have an NIAID leader right now, we will, but the work continues.
Obviously, the critical agency inside HHS is ASPR. Dawn has provided– Dawn O’Connell has provided terrific leadership and that continues. And I think you’re going to see in the upcoming weeks more leadership announcements.
These are not issues that are going to fall off anybody’s radar. This remains a central set of issues, specifically the broader pandemic preparedness. And so under a normal sort of, in my mind, kind of pretty typical predictable transition period, you’re going to see new people coming in and really strong leadership.
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ASHISH JHA, WHITE HOUSE [00:23:56]
I will say, by the way, it is hard to predict when you’re going to get another Tony Fauci. I mean, Tony is such a singular figure in American public health history, arguably in just kind of in our country.
So the strategy is you pick the best people. Thankfully, we have a lot of very talented, capable scientific and public health leaders in our country that the administration can turn to. Who knows who will still be there 50 years later, 40 years later? That’s a– you only can hope we get another Tony Fauci. But I dare not imagine that’s going to happen.
ASHISH JHA, WHITE HOUSE [00:22:10]
We have a lot of vaccines right now purchased by the U.S. government. They will continue to be free. At some point in the fall, we anticipate there will be a new vaccine. I anticipate, because this is an FDA decision, FDA will make that decision in the upcoming months, when once the FDA make that decision, assuming they go with a new vaccine, assuming then the companies build those vaccines, when those arrive in the marketplace, the U.S. government will not have the resources to buy that.
Those will then go through the regular commercial market the way we do flu vaccines and other vaccines. And so if you have health insurance, it will be covered by free. And then we have this program for the uninsured.
Treatments are probably the trickiest. We have a good amount of Paxlovid. We have some Lagevrio.
What will happen with those is Pfizer has applied for full licensure. At some point, again, there will be a transition. We’re negotiating with Pfizer to make sure that people who are uninsured, underinsured, continue to have access to government supply, that we continue to have stockpiles.
So there’s a lot of complexity here. So simply thinking about this: vaccine, probably in the fall, treatment, probably sometime in the late summer or fall, we’ll start seeing that switch over, and between now and then, remains free, remains widely available, remains U.S. government stock.
CHRISTOPHER BRADEN, CDC [00:22:21]
I would like to point out is that it’s advantageous to have multiple studies to understand what vaccine effectiveness really is in the population. So these are three different studies that we’re publishing today. Each has a different data source. They have different methods and a different source of the data that they are looking at in their methodology.
So we need the different types of studies, looking at data in different ways, in order to come to probably a combined estimate that looks at across these studies to come to what may be the best estimate of vaccine effectiveness.
The other thing I would like to point out, and this is especially true for the two doses, is that each of the estimates is within the confidence intervals of each individual study.
So statistically, they’re not all that different.
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CHRISTOPHER BRADEN, CDC [00:23:27]
But I do get to the issue that, especially for the New England Journal of Medicine study, that the estimated estimate is lower than in the other studies.
A couple of things about the New England Journal of Medicine study, I think to point out, it is a strong study in that it has a lot of power in the number of cases and controls that were enrolled using a national database of anonymized medical records.
The other thing about the New England Journal of Medicine study is that all the eligible cases and controls were included in the analysis. The other case control studies depended upon the voluntary provision of information from cases and controls to be able to include the data in the analysis, and that volunteering, that aspect of volunteering, can introduce some bias to the estimates, either underestimating or overestimating the vaccine effectiveness.
The other thing that I would like to point out is that we still don’t know enough about the effect of this vaccine in the population of immunocompromised patients. And if you look at the New England Journal of Medicine article, when they did a secondary analysis, when they excluded immunocompromised persons, the vaccine effectiveness for two doses actually went from 66 to 76%, more in line with what we see with the other studies.
But we need to know more about the vaccine effectiveness in that group, and that’s an important group to study in our additional studies.
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ELI ROSENBERG, NY [00:25:42]
We often rely on triangulation from multiple data sources to arrive at truth. And that’s really the case for these three studies.
Here, our study today in MMWR really echoes the findings of the other two, particularly the other one in MMWR, finding up to 88% effectiveness for two doses. And then that study is using all reportable data in New York for both cases and immunizations outside of New York City.
So I think everything that we just said was really quite spot on. And these are all really quite statistically similar and compatible estimates.
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DEMETRE DASKALAKIS, WHITE HOUSE [00:26:41]
Different methodologies mean different views, and they do inform us in the same way, which is one dose is good and two dose is better.
And it’s also important to remember that this really focuses on prevention of infection, and even beyond the vaccine effectiveness measured with those outcomes, is the sort of other issue that we see reduction in some of the adverse outcomes of mpox, which makes this really important.
So as a weather forecast, this definitely tells us that that these vaccines work and that our strategy of vaccinating people and getting both doses really remains core to our efforts to prevent mpox.
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QUESTION [00:29:39]
Dr. Daskalakis, as you mentioned those ongoing studies. What are the chances you think that additional boosters might be greenlighted this summer, like for men who only got intradermal or ACAM 2000?
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DEMETRE DASKALAKIS, WHITE HOUSE [00:31:01]
What’s really important is that we have the studies that are ongoing to really ask some of the questions around durability of vaccine.
And so I think we’ve already, really immediately after seeing the Chicago cluster, convened folks within the U.S. government to discuss what the data is that we have and if there needs to be any change in vaccine strategy.
I just want to clarify one quick thing. There is no current change in vaccine strategy, and I want to just again emphasize that as you heard from Dr. Braden, there’s no difference between the subcutaneous and intradermal in terms of its vaccine effectiveness in the studies that will be released today.
So there’s specifically no indication for folks, if they’ve gotten two doses of vaccine at this time, to get any additional doses.
So I think the exciting news is that we are on it from the perspective of having the scientific discussions and are obviously, as sort of demonstrated in the track record of the response, really adjust our strategy based on what science is showing us. And so I think we’re really in that learning more about Chicago and making sure we maximize what we know about vaccines so we can make informed decisions.
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DEMETRE DASKALAKIS, WHITE HOUSE [00:45:49]
So the 21 cases, as you’ve heard, have been very mild to date. We’ve not heard of hospitalizations, which is great news.
We’re also hearing that that the mucosal symptoms, or the painful involvement that we tended to see in the outbreak before the rectal symptoms, that that’s been very limited in the folks in this cluster.
Additionally, even the number of lesions that they have also appears to be smaller, at least in the initial review of the individuals who had mpox after vaccination.
So I’ll say that again, the CDC continues to do the investigation. And so we’re going to learn more. And I’m sure Chicago will also share more as they learn more as well. But I think the the overarching message, at least anecdotally so far, is that we’re seeing very mild disease.
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CHRISTOPHER BRADEN, CDC [00:47:19]
We are looking into this in a number of ways. At CDC, we have three current ongoing studies. One where mpox has been endemic for a long time in the Democratic Republic of the Congo, where they’ve had a trial of using the vaccine now for some period of time.
But also in the current outbreak, we have studies ongoing in Washington, DC and Los Angeles. We hope to be looking at some of the early data on those studies soon to see if we can identify any clues or hints that the antibody levels, for instance, are declining, which may indicate that there’s some waning immunity.
But we don’t have that information yet, especially for the patients in the United States, they just haven’t been vaccinated for that long. So– but we’re going to be looking and interrogating that data as soon as we can to get some clues about what may be happening.
DAVID KASLOW, FDA [08:50:53]
Welcome all to this 181st convening of VRBPAC for an open session to discuss the available evidence and advise FDA on the safety and effectiveness of a RSV vaccine candidate, which was previously reviewed by VRBPAC on the 28th of February this year, but now for a proposed indication for use during pregnancy.
This is the third day that VRBPAC will have discussed specific RSV vaccines in as many months. And as noted when we met in February, these RSV vaccines are based on 21st century science and technology designed to overcome the shortcomings of previous efforts six decades ago.
These vaccines represent structural immunology and molecular engineering over empiric vaccinology against a respiratory virus that exacts its heaviest disease burden in the youngest and in older adults.
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DAVID KASLOW, FDA [08:51:48]
In the previous two day meeting of VRBPAC, we focused on RSV disease in older adults. This convening of VRBPAC focuses on respiratory syncytial virus disease in the early months of childhood, as will be reviewed by presentations during this morning’s sessions.
Following those presentations, VRBPAC will consider BLA 125768 submitted by Pfizer. While the vaccine is the same product as discussed previously, now the focus is on active immunization during pregnancy to provide passive immunity in infants, over several months after birth.
This VRBPAC is scheduled at an important point in the BLA review cycle. The FDA specifically seeks the committee’s advice on the available evidence submitted by the applicant in this Biologics License Application.
As noted in the FDA briefing document, we are asking the members today to discuss and vote on whether the results of the vaccine efficacy trial demonstrates evidence of vaccine effectiveness and to discuss and vote on whether or not the safety data support a favorable risk analysis, considering the discussion of the safety data, for example, premature deliveries and births.
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KATHERINE FLEMING-DUTRA, CDC [00:28:41]
RSV infection is the leading cause of hospitalization in U.S. infants. Most infants are infected in the first year of life and nearly all by age two years, and 2 to 3% of young infants will be hospitalized for RSV.
RSV is a common cause of lower respiratory tract infection in infants, which is what leads infants to be hospitalized.
Infants with RSV can have difficulty breathing and eating, and they sometimes need oxygen or other respiratory support and hydration.
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KATHERINE FLEMING-DUTRA, CDC [09:29:12]
Prematurity is a risk factor for hospitalization with RSV. Premature infants born at less than 30 weeks gestation have hospitalization rates three times higher than term infants. And additionally, children with chronic lung disease of prematurity and congenital heart disease are also at increased risk of severe RSV disease.
However, RSV can also cause hospitalization in healthy term infants. An estimated 79% of children hospitalized with RSV aged less than two years had no underlying medical conditions.
So in short, all young infants are at risk of severe disease with RSV.
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KATHERINE FLEMING-DUTRA, CDC [09:29:51]
Palivizumab, also known by the trade name Synagis, is the only RSV prevention product currently licensed in the United States. It’s a humanized monoclonal antibody targeting antigenic site two of the F or Fusion glycoprotein, and it requires monthly administration due to its short half life.
Currently, the American Academy of Pediatrics recommends use of palivizumab for prevention of RSV disease in infants at high risk of severe disease, including infants with the conditions listed here.
Approximately 5% of U.S. infants are eligible for immunoprophylaxis with palivizumab. However, data suggests that only 2% of U.S. infants receive one or more doses.
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KATHERINE FLEMING-DUTRA, CDC [09:30:44]
CDC estimates that, each year in the United States, among children aged less than five years, RSV is associated with 100 to 300 deaths, 58,000 to 80,000 hospitalizations, about 520,000 emergency department visits, and approximately 1.5 million outpatient visits.
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KATHERINE FLEMING-DUTRA, CDC [09:31:56]
This graph shows NVSN RSV associated hospitalization rates by age group from 2000 through 2004, in red, in 2016 through 2020, in yellow, and in 2021, in gray. RSV associated hospitalization rates are highest in young infants aged zero through five months and decrease with increasing age in childhood.
RSV associated hospitalization rates in infants age zero through five months are more than double than those among infants six through 11 months of age.
This pattern of seeing the highest rates in infants ages zero through five months is true across different time periods in which NVSN has conducted surveillance.
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KATHERINE FLEMING-DUTRA, CDC [09:41:09]
The following potential considerations will be important to help determine the optimal timing of RSV vaccine dosing during the year to best protect infants during the RSV season.
RSV vaccine dosing could be implemented for pregnant people as a seasonal campaign, or year round. Cost effectiveness may vary by timing of administration, due to RSV seasonality and maternal antibody decay, which leads to waning of protection.
So CDC will plan to examine cost effectiveness of seasonal RSV vaccine dosing compared to year round dosing. Year round dosing would simplify implementation though, and thus potentially increase vaccine uptake. And year round dosing could also help protect infants in the event of atypical RSV seasonality.
Next slide. Additionally, as we have discussed already, some U.S. jurisdictions have different or less predictable RSV seasonality and recommendations for RSV vaccine dosing in those jurisdictions would need to account for that. These jurisdictions include those with tropical climates, parts of Florida, Puerto Rico, U.S. Virgin Islands, Hawaii, Guam and the U.S. affiliated Pacific Islands and also Alaska, where RSV seasonality is less predictable and the duration of RSV activity is often longer than the national average.
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WILLIAM GRUBER, PFIZER [10:31:59]
The road to having an RSV vaccine that could provide protection against RSV in infants has been frustratingly long and difficult. It began with the discovery of the virus as a cause of infant bronchiolitis in 1957. Vaccine development efforts began in earnest, leading to an investigational, formal and inactivated RSV vaccine in the 1960s, which not only failed to protect, but resulted in enhanced RSV illness for some infected infants.
This stymied development until in the late 1970s, when Dr. Paul Glezen and collaborators demonstrated that RSV specific antibody following natural infection in women could be passed to their infants and provide protection during infancy.
As a medical student, I had an opportunity to help Dr. Glezen identify children with bronchiolitis from whom cord blood for antibody testing was available. Thus began my own career long quest for an effective RSV intervention.
Paul’s discovery was followed by purified F protein, live attenuated RSV vaccines and vectored vaccine approaches. In tandem, the first successful passive antibody interventions were approved, but only for very high risk infants. However, neutralizing antibody levels in recipients serve as an important benchmark for vaccine induced antibody likely to provide protection.
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WILLIAM GRUBER, PFIZER [10:33:57]
No RSV F vaccine has been licensed to date for maternal immunization to protect infants. We now know why.
Structural work by Jason McClellan and collaborators in the NIH lab of Dr. Barney Graham elucidated that RSV F on the virus exists in an unstable prefusion form. Only prefusion F can bind host cells for RSV to infect. It turns out that prior failed inactivated vaccine attempts were using the post fusion, or spent form, of RSV F shown on the right, a weak inducer of virus neutralizing antibody.
In contrast, the prefusion F trimer, shown on the left, which we call RSV pre F, is a very potent inducer of neutralizing antibody in animal models in humans. Jason and colleagues were able to stabilize RSV pre F. Pfizer then further stabilized the protein and developed a bivalent RSV pre F vaccine, including both A and B subgroups, to maximize protection.
This is the same vaccine which we described to you when seeking the older adult indication for prevention of RSV illness.
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WILLIAM GRUBER, PFIZER [10:38:46]
The dose level is 120 micrograms without an adjuvant. Each dose contains 60 micrograms of each prefusion protein, antigen A and B, in a 0.5 milliliter injection.
The presentation is lyophilized vial, with water for injection, in a prefilled syringe.
The vaccine is to be stored at 2 to 8 degrees Celsius.
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IONA MUNJAL, PFIZER [11:04:51]
In summary, RSV F was was safe and well tolerated. Local and systemic events were mostly mild to moderate and short in duration. The adverse event profile did not suggest any safety concerns for RSVpreF vaccination in pregnant individuals or in their infants.
There was a numerical imbalance in late preterm births in upper middle income countries, but not in upper income countries and low middle income countries. Most preterms occurred near term, and most were born more than one month after vaccination.
Mortality data were numerically favorable for the vaccine group for overall infant deaths, neonatal deaths and upper middle income country deaths.
Our extensive analysis of the safety data from the two maternal trials and three studies in non-pregnant participants support the overall favorable safety profile. Pharmacovigilance activities will continue to monitor outcomes in both populations.
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IONA MUNJAL, PFIZER [11:09:43]
The full results of the primary analysis have now been published in the New England Journal of Medicine, April 20th edition, and are presented here.
The primary efficacy objective for the MATISSE study was met for severe medically attended lower respiratory tract illness within 90 days after birth.
There were 33 cases in the placebo, and only six cases in the vaccine group, for a vaccine efficacy of 81.8%. Efficacy was met for all subsequent time intervals in this primary endpoint, including 81 total adjudicated cases overall, 19 in the RSV group, and 62 in the placebo, for 69.4% efficacy at 180 days.
The lower bound of the confidence interval was above 40 at all time points, which is well above the criterion to meet licensure is agreed upon with the FDA.
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WILLIAM GRUBER, PFIZER [11:20:06]
When we consider the global impact of RSVpreF vaccine, we see here that it has the potential to annually prevent a large proportion of hospitalizations due to RSV, spanning low to high income countries, shown from left to right.
Of the over 1,300,000 global hospitalizations shown on the right, universal RSVpreF maternal immunization could prevent over 950,000 hospitalizations annually. In the United States, based on the RSVpreF maternal immunization efficacy results, universally applied RSV maternal immunization has the potential to annually prevent up to 16,000 hospitalizations and over 300,000 sick visits in children less than six months of age.
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WILLIAM GRUBER, PFIZER [11:23:33]
So obviously if you heard from other presentations, breast milk may offer an advantage as far as protection is concerned. But I think one of the challenges that we faced, in the course of this trial, even though breastfeeding information was collected, is the level of antibody was so high and the protection is so high, it might be buried in that circumstance.
And so when looking at the populations that were either breastfed or non breastfed, we were not able to discern a difference. Now, once we go to post-approval effectiveness evaluations, it might be possible to tease that out, but we did not detect a difference in this trial between breastfed and non breastfed infants and we did not collect breast milk as part of this trial.
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YUGENIA HONG-NGUYEN, FDA [00:17:59]
FDA has recommended that the sponsor align the pharmacovigilance plan for a BLA 125769 proposed for older adults indication, with a pharmacovigilance plan for Abrysvo 125768, which is proposed here for the maternal immunization indication.
Presented here is the applicant’s pharmacovigilance review currently under review– pharmacovigilance plan currently under review.
As you may be aware, the applicant is seeking approval for the identical product we have discussed at a previous VRBPAC for an older adult indication. The applicant typically has one pharmacovigilance plan for a product.
So in this case, FDA has recommended that Pfizer harmonize pharmacovigilance plans between the two indications.
The applicant plans to perform a post-marketing safety study to evaluate pregnancy and neonatal outcomes in individuals exposed to Abrysvo in the general pregnant population, in addition to the immunocompromised population, pregnant population.
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YUGENIA HONG-NGUYEN, FDA [00:19:03]
The statistical criterion for study success, which was demonstrated of a vaccine efficacy greater than– demonstration of vaccine efficacy greater than 20% for at least one of the two primary endpoints was met.
Effectiveness of RSVpreF immunization during pregnancy was demonstrated to prevent severe RSV infant MA-LRTD within 180 days.
The data suggests that RSVpreF immunization during pregnancy is effective in preventing RSV MA-LRTD in infants. However, this endpoint was not met within 90 days after birth.
For vaccine efficacy against RSV MA-LRTD within up to one year after birth, statistical criterion for success was met with a confidence interval lower bound of greater than 0% at all time points. However, as I mentioned, these analyses represent cumulative RSV cases from day zero.
The number of new cases of RSV confirmed MA-LRTD after the 180 day time point were noted to be similar between treatment groups, with 35 new cases in the vaccine group and 39 in the placebo group. Interpretation of analyses beyond 360 days is limited by the low numbers of participants as of the data cutoff.
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YUGENIA HONG-NGUYEN, FDA [00:20:16]
Across all studies, the safety database included 3,797 maternal participants who received the final formulation of RSVpreF, with 47% from U.S. sites.
Severe local and systemic reactions following RSVpreF donation were uncommon. The reactogenicity of RSV was comparable between maternal participants enrolled in the U.S. and the overall population.
No meaningful differences were observed between treatment groups and the overall rates of unsolicited AEs within one month after vaccination. AEs and SAEs and infant participants reported at a similar frequency between groups.
An imbalance in the rates of prematurity, with more preterm birth occurring in the vaccine group compared with the placebo group, though not statistically significant, was observed. A similar finding was also noted in the phase two study. These findings may be of consideration for further safety evaluation through postmarketing studies.
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YUGENIA HONG-NGUYEN, FDA [00:24:25]
There is some efficacy, at least within the first 30 days, a little bit questionable at the later time points. Within the first 90 days, the confidence intervals were very wide, and a little bit difficult to interpret this.
And then when you were your other question, I think, or comment, was about kind of beyond six months.
As I mentioned, we have very limited data here in this study with very limited case counts beyond that time point. But I think because we’re talking about passive immunity here, I wouldn’t necessarily expect a very long duration of protection from this vaccine administered to maternal participants to protect their infants.
So I believe that our impression, as of our FDA review, as of now, is that there is efficacy demonstrated at least to six months.
But as I mentioned, and I could go back to the slides if you would like, but beyond the 180 time point, a little bit less pronounced.
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WILLIAM GRUBER, PFIZER [00:32:44]
The circumstance where enhanced disease was seen was in a very different different circumstance where you had naive young children exposed for the first time to an inactivated vaccine with the post fusion form and we know now, or have good evidence to believe, that that was due to an enhanced Th2 response and the presence of binding antibody that wasn’t neutralizing.
We don’t have that here. We clearly have high levels of neutralizing antibody that are passively transferred from women who had had prior exposure to natural infection, and we’re boosting that type of response. And as we’ve shown, that passes the placenta, reaches levels that are well above neutralizing levels, that would be associated with protection.
But in addition to that, if we can bring up slide number two, I think this helps inform in somewhat of an indirect way reassurance that we’re essentially not leading to enhanced disease farther on. So Dr. Munjal showed you a different version of this slide, but this just represents what was seen over time in terms of continued efficacy.
And as has been pointed out, the efficacy is really driven by what’s seen in the first 180 days. And you’ve heard that the split looking between 180 and 360 is 35, 39. So we can’t claim that there’s additional efficacy there. But there’s another reason why that’s important, because it’s suggesting we’re not kicking the can down the road, in that as antibody declines, those children who receive the vaccine are not worse off. There’s not an increased risk for them acquiring disease.
So I think that coupled with the overall efficacy where we’re preventing hospitalization, where we’re preventing severe LRTI and preventing LRTI, provides real confidence that there is no risk here of enhanced disease.
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WILLIAM GRUBER, PFIZER [00:36:15]
So we recognize the results that were obtained in the non-pregnant population for administration of Tdap. And it is correct that we didn’t meet noninferiority for the pertussis containing antigens, but did for the others.
I think there are two ways to look at that. And I think, as is noted in the FDA briefing document, we’re under discussion with the FDA about how this should be handled.
This is not been a unique experience. There are other circumstances in which pertussis containing vaccines have been administered in conjunction with, for instance, meningococcal conjugate vaccines or influenza vaccines where the pertussis antigens did not meet non-inferiority. And yet, those vaccines continue to be recommended to be given together.
So that’s one possible outcome. And again, we’ll be discussing this with the FDA.
On the other hand, I want to be mindful of the fact that particularly in a U.S. population, particularly given the interval that was studied here, from 24 to 36 weeks, with women coming in with successive visits for prenatal care, there’s the opportunity to actually give the RSV vaccine at a separate time from Tdap, or for that matter, influenza vaccine.
So I think we shouldn’t see this as constraining, in my view, in terms of the ability to apply this vaccine to a pregnant population, because there there is the possibility that we could still administer it together or there’s enough spacing during the second and third trimester that we could space the vaccines.
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WILLIAM GRUBER, PFIZER [01:41:11]
So the question was asked about the nature of data that we have regarding common administration of influenza and RSV vaccine. We have done a study and just these results just recently became available and we provided them to the FDA. So they’re not in either briefing document.
This is in an older adult population in which Fluad was administered with 120 microgram dose of concomitant RSV and is represented here. You can see on the slide forest plots that speak to the nature of the geometric titer ratio, with one being an equal ratio, the requirement was that these were essentially above 0.67.
And I think you can see the lower bound being above 0.67, and I think you can see across the board, whether we’re talking about the influenza antigens or the RSV antigens, that non-inferiority was met in this population, again, a non-pregnant older adult population, but I think provides some reassurance about the potential to be able to administer the two vaccines together.
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WILLIAM GRUBER, PFIZER [01:48:07]
We don’t know about what other factors may have affected their results.
I would remind the committee, for those that are familiar with that data, that they actually saw an increased death rate in their study, which may have, of course, prompted, as you might imagine, the DMC to stop the study. We actually saw just the opposite of that. We’ve actually seen a lower number of deaths, albeit the total numbers are small, but certainly don’t fit with the experience that existed in the other sponsor study.
I will take a little bit of an exception to the notion that the vaccines are in some way identical. They’re not. True, they both essentially address the RSV protein, But the Pfizer vaccine has been stabilized in different ways than the GSK vaccine, manufacturing process is different, and the excipients are different.
I’m not saying that that necessarily explains one way or another, but I do want to dispute the idea that the vaccines are absolutely identical. The target is clearly the same.
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JOE TURNER, FDA [02:48:07]
This is a great discussion. And our colleagues at the ACIP provide, for clinicians in the United States, advice on vaccine administration. So it’s a topic for discussion as well, with, for that particular group.
AMANDA COHN, CDC [02:48:40]
I was trying to decide if I was going to jump in here or not, I will quickly jump in. I don’t remember all of the data, but we have had other times of where we did have coadministration data with pertussis vaccines, where 1 or 2 of the antigens was lower, specifically when coadministered with meningococcal vaccine, I think. And, in general for most healthy people, we do feel like that serologic data is not terribly helpful. You may need all of those antigens to be higher, in terms of maternal transfer of antibodies.
So I don’t think it’s– I don’t think you can take prior experience and apply it here. But I do think that we have managed some complicated coadministration issues in the past through the Advisory Committee on Immunization Practices.
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JOE TURNER, FDA [03:01:25]
It’s a great question. I guess it’s a concern with any clinical trial and any clinical development that we see and review at FDA, is it’s a self-selected population, generally healthier, and exclusion criteria apply. It’s a different population. And we always worry about that when we approve a drug or license a vaccine, we always worry in the post-market setting, once it’s applied to a general population.
So your question is a good one. And it’s just something that we pay close attention to during our review, we recognize it’s a healthier population, but also something that we want to pay close attention to post-marketing when a drug is approved or a vaccine is licensed.
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AMANDA COHN, CDC [03:04:10]
This is potentially the first vaccine I can think of in the U.S. where we are recommending a vaccine for a pregnant woman that is not recommended for the adult population in this age range. So it’s not recommended for persons who are not pregnant in this population.
And our post licensure monitoring plan sounds very familiar and similar, and not really very– I’m not very confident that we’re really going to be able to detect or sort through some of these many complicated questions that have been raised today.
For example, will we have more infant cases? Will we know maternal outcomes? Which I think we do care about the health of the mom who was getting this vaccine, not just the infant outcome.
And so I really like I guess I want to hear from Pfizer, like, has there been any discussion about more of an active type of approach, or using medical records, that are much more helpful than, for example, claims databases, which not only is it hard to link mother to baby, it’s also hard to link mother to vaccination status.
Moms get vaccinated very often outside the health care system. And so I’m just– co-administration, all of those different factors I think are going to be very, very hard to identify and then understand signals that come out of this type of large database, Medicaid study, that you guys do for, frankly, every single vaccine. And this doesn’t just doesn’t feel like a normal vaccine.
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SARAH MACDONALD, PFIZER [03:06:23]
The details for the analysis plan and the study endpoints are still in discussions and under development and we will be working closely with the FDA to finalize those plans. And the exact analysis.
As I mentioned, we are using very, very large health care claims data sources, which allows us to evaluate very rare outcomes and in large populations, including populations of patients that were excluded from the trial due to comorbidities and other reasons.
So we will have a very robust and large population size, which is a key advantage.
We also can conduct medical chart reviews for outcomes and so can further confirm the findings in that way for the final analysis.
So we feel confident that our approach is a robust approach. It will evaluate a number of key safety endpoints and we will be discussing the details of the specifics regarding the analysis and the outcomes with the FDA and ensure that we are evaluating the safety for these key endpoints in a robust manner.
We also have our pharmacovigilance system as well, which will be conducting near real time monitoring for safety endpoints. And as I mentioned, we can if a signal is identified through our pharmacovigilance system, we can then modify the safety study to further characterize the risks for those outcomes. So we feel confident that we do have a robust system in place to both identify signals and confirm and characterize those results in the safety study.
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AMANDA COHN, CDC [00:11:16]
I do want to say I think the study data are incredibly impressive. I think this is, having done this vaccine trial in pregnant women and in and of itself, is a huge accomplishment. And I think the company and FDA did an amazing job presenting the data at hand.
I do feel like we should be raising the bar higher than we have. And this is set out before we have an opportunity to review. So it’s not really related to the data that was shared today. But, we have multiple other vaccines that have enrolled, including COVID, many more thousands of people to look at for safety.
And we should have be doing that when it comes to pregnant women, especially given that there is not a risk of RSV in the pregnant women. That doesn’t mean that I don’t think this vaccine has incredible value. And I actually think to me, enrolling more people in these clinical trials and having really strong post licensure evaluations, because you still won’t detect real outcomes, will be what we need to reassure the public and to give pregnant women the data that they need to make the decision to get vaccinated.
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ARNOLD MONTO, VRBPAC [00:44:49]
I’m not sure about the idea of larger clinical trials as being necessary at this point. I think it has been a challenge to do anything during the past pandemic, and I think the sponsor should be complimented by moving ahead and doing this in spite of lack of seasonality, and other things which you would ordinarily be paying attention to in a study of this type.
I’m troubled, as everybody is, by the prematurity issue and I’m not sure that running it through another, maybe season, is going to give us an answer. And I think we’ve heard that observational studies, as we go forward, will fairly quickly give us an answer if there is a problem there.
We learned how to bite the bullet and get things out during the SARS-CoV-2 vaccine approvals.
I think things will straighten out as we learn more about return seasonality, because I can see that this vaccine is necessarily going to be given year round. If influenza vaccine is being given during a certain period, also if this vaccine is going to be given to an older population as well.
But we can’t wait for all that to take place because of something, which I’m surprised we haven’t heard more of, and that is the enormous impact of RSV in infants in the low income countries. And they won’t start using a vaccine until it’s approved for use in the United States. That’s the way things tend to go.
So I think for a number of reasons, I think I’m convinced that we have evidence and evidence that should give us some degree of comfort that we can bite the bullet and move ahead with robust observational studies to help us over.
PETER MARKS, FDA [00:16:12]
So one of the things we learned from doing previous guidance updates of shortening the deferral interval was how do– what are the snags we get into, one of the snags we get into is that blood donors, if anyone’s gone to donate blood, you notice that most places now use computers to do the donor questionnaire.
The problem with that is that when you change the donor questionnaire, they have to be reprogrammed. And we know from the past that that took a long time. So this time we tried to get a jump start on this.
One of the problems last time was we have a level to, a guidance, that basically goes into the standard donor questionnaire. And last time it took a while for us to get that done. This time we got out that guidance the same day as we advanced the policy.
And what we’re hoping now is that there will be a group of blood collectors that will be able to start collecting donations in June. There is some significance to June, so for the community. So I think that’s a nice thing. And there are actually local blood collectors here, you’ll see probably ads in the not too distant future, who are going to be trying to run donor drives.
Larger blood collection systems may take a little time because it’s true they have these large, in order to maintain a high level of safety, they have computer systems that need to be reprogrammed. And it costs a bunch of money and it takes some time to do. But I think this is a significant step forward. And it took a lot of effort from a lot of people.
SUSAN MAYNE, FDA [00:11:20]
We’ve also initiated work with the National Advisory Committee on Microbiological Criteria in Foods, which held a public meeting just yesterday to help us address some knowledge gaps about Cronobacter and its implications in food. Still, there is more we need to do and more authorities we need to do them.
First, it’s important that Cronobacter sakazakii infections become a nationally notifiable disease. Currently, only two states, Minnesota and Michigan, require reporting of Cronobacter infections to state public health departments. This lack of mandatory reporting nationwide significantly hampers our ability to fully understand the public health impact of Cronobacter. In June, the Council of State and Territorial epidemiologists will consider the issue of notifiability for Cronobacter. And we fully support them, adding Cronobacter to the list of notifiable diseases.
Between 4/18 and 5/15, 21 cases have been reported to CDPH (20 confirmed; 1 probable). Prior to 4/18, 5 cases were reported from the start of the year.
All cases were male.
Median age of cases was 33 (range 24-46).
17 cases (of 21) were vaccinated.
11 with 2 doses Jynneos, 1 with ACAM2000, 5 with 1 dose Jynneos; person receiving ACAM was vaccinated in London.
Of the 21 cases, 24% were living with HIV; all are virally suppressed.
No cases have been hospitalized.
2 cases received TPOXX.
6 cases had recently travelled.
CDPH is coordinating with CDC to investigate the outbreak. CDC is sending staff to Chicago this week.
CDPH continues to actively engage community and health care providers to share/receive information.
CDPH recommends individuals vulnerable to Mpox infection receive 2 doses of Jynneos.
DAWN O’CONNELL, ASPR [00:24:44]
I was a member of the Obama administration, in the role of deputy chief of staff, and did a lot of our response and preparedness work from the secretary’s office in conjunction with ASPR and others back then. And true then, and true now, the president will always want to have some sort of entity within the White House watching something of significance, no matter what it is. And in the response space, it can be at any number or level in which he would like to engage. And of course, the president should organize his White House however he chooses to.
In previous times and across even my experience back at HHS in this administration, we’ve worked with NSC on some things, we’ve worked with DPC on other things, we’ve worked with the COVID response team. So it will be no problem for us. In fact, we welcome the partnership to work with the new pandemic preparedness office. And we expect that the president will want to organize his White House in a particular way, and we will plug in and be good participants, leaders where we need to be, role players where we need to be. But we always expect to to work closely with the White House to make sure that we’re pulling the oar in the same direction.
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DAWN O’CONNELL, ASPR [00:26:54]
We’re highly invested in seeing successful global responses to any number of, and preparedness, to any number of potential threats. So that is an important interest of ours.
We are the focal point for the WHO. So when there is a disease or some sort of outbreak identified in the United States, it’s us, it’s ASPR, it’s our secretary’s operations center, that conveys that news and information to WHO. So that’s one of the places where we play directly with WHO.
And then we support others. CDC has in-country offices. So if there’s a, you know, an outbreak happening in a place where they have an office, we will be able to share our countermeasures or whatever we need to be able to end the outbreak where it started, to the extent that CDC is engaged, we would support CDC in that role. And we have an Office of Global Affairs that advises the secretary on those things. And of course, we would plug in where we need to as well.
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DAWN O’CONNELL, ASPR [00:31:07]
And for states that are interested in stockpiling on their own, there was a lot of interest, when we didn’t have what we thought we should in the Strategic National Stockpile, states began wondering if they needed to have the stockpiles themselves.
Some have moved a little bit away from that because it’s a hard job to rotate through, to understand what sort of inventory you need, to maintain the inventory over many years. But we continue to provide technical support to those states that want to do that.
I mean, it’s important to us that the states and localities have what they need and know where to find us. So this has been a focus and it’s something certainly in the stockpile that we know we can improve on and are continuing to do that, but like to keep the lines of communication open.
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DAWN O’CONNELL, ASPR [00:32:33]
At this point, the most important, I think, transition point for us is when it moves to the commercial market and when Pfizer begins distributing it within the regular health channels, whether it’s EUA or fully licensed, which we anticipate, you know I don’t want to get ahead of FDA, but I don’t have any reason to believe that’s going to be a problem. But again, not in those conversations. That’s for our regulators.
But wouldn’t anticipate that that would change the availability or the distribution of Paxlovid. From our perspective, we will get out of the business when we move it to the commercial market. And that’s the big thing that we’ve been planning towards. No timeline, no date certain yet, but we are watching very closely what are available, how much Paxlovid we’ve purchased, where it can be used, how much is needed.
We bought a little bit more anticipating a winter surge that never really materialized. And we don’t want the American people to pay twice. If we’ve purchased it for them with their taxpayer dollars, we want to make what we’ve purchased available to them for free, as we’ve been promising. But at some point, we know that we’re going to be out of this business, and we’ve been planning for what that’s going to look like when Pfizer takes over.
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DAWN O’CONNELL, ASPR [00:34:09]
We weren’t designed, nor has there been an expectation that we would continue to do that ad infinitum for future generations of vaccines and therapies. And we know that we’ve not been funded to do that or programmed to do that.
So we’ve been thinking about it, and I think the country expects things to move back to normal. This is one of those things that would move back to normal.
But accessibility and access have been really important to that to us in doing this, and running the program the way we have, making sure that anyone who needs it can get it. And we’re continuing to work, as we think about what commercialization will look like, what it will mean to move these to the commercial market.
This is an important part of the conversations that we’re having. Will they have enough manufactured available for nationwide accessibility? That’s, Alan, what you were saying. How are we sure that the manufacturers are ready to go and provide for the nationwide market? That’s one of the questions and things that we’re working through with them. The other thing is how can we be sure that those that have received these for free and might not be able to afford them otherwise, might not have the insurance coverage that they need in order to continue to get it at a discount or for free, how will they have access?
And the administration’s been committed to setting up a bridge program, making sure that some of the doses that we have procured, and will continue to have, that we make available through through federally qualified health centers and that folks can get them there. CDC is working to do this through the pharmacy network to make sure that the pharmacies continue to be a place where folks without insurance can access some of these. And then, of course, the manufacturers themselves have been looking at their provider programs to be able to to ensure accessibility.
The patients were primarily from South Texas but not all of them. The procedures were all cosmetic procedures and we wanted to note that this includes liposuction because some people may not consider that surgery. We don’t want to give the impression that the risk is only associated with cosmetic procedures. The important thing to note is that all of the procedures included an epidural.
ROBERT CALIFF, FDA [00:19:57]
As you well know, the role and mission of the FDA to protect public health was created, defined and delineated and mandated by Congress. The agency has made an extraordinary difference in the health and safety of American patients and consumers.
And today it’s under attack like never before. Indeed, our fundamental authority to regulate the safety and efficacy of products is being challenged. I’m not going to discuss any specific cases. I’m sure many of you follow them closely.
But what I want to ask you to do, as lawyers intimately familiar with and occasionally advocates, for the crucial role the FDA plays, is to stand strong for the work and principles of FDA, to not let them be distilled or destroyed through misinformation, disinformation or partisan legal challenges.
Many of you have worked at the FDA, often in key positions. Some of you have litigated on behalf of the agency. I participated in many discussions about the revolving door for biomedical scientists. But I’ve heard little discussion about the revolving door for lawyers. And while the considerations are not identical, there are significant similarities that deserve more attention and debate upon the correct position here.
I’m not asking you not to advocate, be advocates for your clients. My hope, however, is that in your current work, you go beyond simply abiding by the ethical rules governing lawyers who lead federal government practice for the private sector, and seek to strengthen the environment in which we all operate. Each of you have the ability to help shape the debate and discussion, to promote communication and collaboration, and to work productively to reinforce the importance of our institutions, to progress. No matter which side of the legal proceeding you’re on.
In taking this honorable path, you can help make sure that facts win out over misinformation and disinformation, that the principles we stand for are not eroded, and that our ability to protect patients and consumers is reaffirmed and preserved.
NIOSH is in the process of combining information from the urine antigen test results with responses from the questionnaire to look for possible exposure to Blastomyces inside and outside the mill. NIOSH will summarize the overall results of the medical survey (screening test and questionnaire) and will share summarized information—without employee identities—with management. The NIOSH environmental team collected environmental samples from a variety of locations in and around the mill and are awaiting results from those samples. It is important to recognize that there aren’t well-standardized methods for this type of assessment, so we are not sure if it will be informative. There are no plans to return to the mill at this time.
CARRIE REED, CDC [00:08:31]
We’ve been working for a while now with STLT partners to monitor people with known exposure to H5N1 viruses to quickly detect any cases that occur. Usually this is people that have been involved in poultry depopulation efforts. But given the severity of illness of the recent human cases, CDC has also been discussing with partners the feasibility of increasing surveillance efforts among severely ill persons in the ICU during the summer months, when seasonal influenza activity is otherwise low.
So this would would help us detect any rare human cases of H5N1. It would also help identify other potential cases of variant influenza viruses, which we often see associated with agricultural fairs and other agricultural events during the summer and late summer.
And so one of the challenges is that, while clinically available influenza tests will detect H5N1 and other novel influenza virus infections, most clinical testing doesn’t include subtyping. So while they would result as an influenza A positive, you wouldn’t necessarily know that a patient has an infection with something other than a usual H3N2 or H1N1 virus without further testing. And so to enhance detection over the summer, this would mean requesting that influenza A positive samples, from ICU patients that are not subtyped in the clinical labs, would need to be submitted to the state public health laboratories for subtyping.
So based on preliminary assessments and analyses in our branch, we think that an increase in influenza A testing like this over the summer would yield maybe about 150 specimens or less per week across the country. And so based on preliminary discussions with some partners, it seems that that number would be manageable for public health labs, again if we focused on patients in the ICU. And this could be done in different ways depending on what works best for the hospital.
Ideally, it would be sending influenza A positives from ICU patients for which subtyping was not performed, or the sample was subtyped but was negative for both H1 and H3 on testing. We recognize and we’ve heard from partners that identifying specimens from ICU patients in particular may be a challenge if clinical labs are unable to separate ICU samples from samples of other hospitalized patients. They could also submit influenza A positive specimens from hospitalized patients if needed.
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CINDY FRIEDMAN, CDC [00:16:43]
So when you go to the bathroom on a plane, it fills up a tank. There are about 3 to 4 tanks on a plane, depending on the size of the plane. And then when it comes in and they’re taking the baggage off on the tarmac, this truck comes over with it, attaches this device, and drains the waste. And you can see here we’re collecting a sample in that bottle off to the side.
So this is the workflow for the program. The international flight arrives at the airport, the sample is collected, we work with the ground handling crew at the airport and the airline, we have a staff member, I should say, off the bat, this is a public private partnership, so we’re– our partners are XpresCheck, which is on the ground at the airport, and one of their staff will be standing here handing the device to the the ground handler, collecting the waste.
And the other partner is on the laboratory side, which is Concentric by Gingko, which is Ginkgo Bioworks, is a biotech company in the Boston area, and we send the samples to their to their lab network for PCR testing. The positives are sequenced and this– and then the testing and sequencing results are shared, and the timeline for testing and sequencing– collection, testing and sequencing is about eight days.
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CINDY FRIEDMAN, CDC [00:18:18]
So this is a device, a custom device, that gets attached to the plane and to the hose. And it’s a standard fitting that every plane has. And then it has a sidearm that has a one liter bottle where the sample gets drained off and you can see the spigot, and so as the waste is coming off into the tube, in the second panel, we open the spigot, collect some, close the spigot, and then they switch tanks.
If there’s three tanks, we would open the spigot from the second tank, get a third of the bottle, and then likewise for the final tank.
This whole process takes like two minutes. It really– we’ve never had any spills. We’ve done hundreds of sample collections. There’s no delay for the ground handling operation. And we sort of work seamlessly with the ground handlers. And then the bottle is taken off, the device is taken off, the device, the bottle, is put in a package and it’s sent to the lab.
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CINDY FRIEDMAN, CDC [00:24:23]
On the aircraft wastewater side, the downside there is that not all travelers will use the laboratory. So it’s better to do this in long haul flights. There was a study by Jones and colleagues that showed that the chance of defecation on a long haul flight over six hours was around 36%.
There are, when we talk about viruses beyond SARS-CoV-2, there are other viruses that are more prevalent in urine. So it still doesn’t rule out aircraft wastewater as a modality for looking for other pathogens.
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CINDY FRIEDMAN, CDC [00:27:26]
The expiration of the public health emergency will not impact our program for the next year. We will sustain the current footprint on both the nasal swab side and the wastewater side. And we’re going to be integrating multi-pathogen targets as well, both on the nasal side and the aircraft wastewater side. And we hope to expand to 2 to 3 new airports in the coming year.
CDPH continues to closely monitor mpox trends in California and has not detected an increase in cases in recent weeks. CDPH is working with local health departments, clinics and community-based organizations serving patient populations most impacted by mpox to prepare for Pride events and/or increases in cases, including supporting vaccination efforts.
I wanted to get back to you by the end of the day.
I haven’t gotten any other details, other than yes, CDPH will be working with CDC on sequencing.
If I get any additional details, I’ll get back to you asap.
We are closely monitoring but right now we are not seeing clusters. However, sporadic cases of mpox continue to be reported and we urge people to protect themselves by getting both doses of the vaccine.
NIRAV SHAH, CDC [00:12:08]
For example, on the early side, we will continue to have robust wastewater surveillance, which right now covers about 130 million people across the country. Roughly 40% of the population will also continue to have syndromic surveillance diagnosis data from EDs around the country.
We will also have a modified form of positivity rates, from a laboratory network called NREVSS that’s run out of NCIRD. It’s going online around May 25th. And then of course we will we will have the hospitalization data.
So we’ll still have a good view into what’s going on with COVID, even though it will be different. None of that, however, should be taken to say that our work around data and data modernization and data authority are done. We should still have the ability to access these types of data so we are ready to go for the next type of pandemic.
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HENRY WALKE, CDC [02:12:52]
So an example here is the Marburg 2023 response to the Equatorial Guinea and Tanzania outbreak, and that’s a center led response. It’s co-led by the Global Health Center and National Center for Emerging and Zoonotic Infectious Diseases. And, recently, we had a team actually in Equatorial Guinea of about 15 to 20 people over the last couple of months. And we’re pulling some of that staff back now. And actually we’re sort of at the end of that particular outbreak.
So Viral Special Pathogens was initially leading that at a program level, required a bit more assistance, multiple countries involved, Tanzania and Equatorial Guinea. And then we escalated that up to a center led response.
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HENRY WALKE, CDC [02:32:55]
One of the responsibilities, one of the functions within the Office of Readiness and Response, is really the inter-department coordination, inter-agency coordination, around preparedness and response. And what does that mean?
That we have a very tight coordination with ASPR, for example, within the department and with BARDA and with NIH related to response activities. So that hasn’t always been the case in the past. And so with COVID, and this really need to collaborate more, and with the COVID pandemic being an all U.S. government response, we have worked on our policies, our collaborations within the department, to set up these disaster leadership group to sync across all of our activities. And then of course, if we get into a large response, or we move into a FEMA led response.
Now, of course, depending on the administration, some of that is a bit more smooth than others. But that would be the idea that we then CDC has a response, we feed into the secretary’s operations center, actually at HHS, which then feeds into an overall FEMA coordinated response, for a very large event.
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HENRY WALKE, CDC [02:34:11]
For state and locals, this is an area that I believe, and I’ve pushed my team to that we’re going to work more on, is how our emergency operations center actually connects back to state emergency operations centers.
You know, there’s a number of states in this country and cities who have very strong emergency management operations and a very skilled workforce. And they are managing, within their own states, various disasters or responses. And we need to do more to sync with their emergency management workforce and operations at CDC. We should sync with their public health emergency operations more than we’re doing now.
So that’s an area that that we hope to make some some gains in the next couple of years, or in the next year or so.
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JILL TAYLOR, APHL [00:38:15]
I want to bring up the importance of genomic databases in especially in surveillance. There’s perturbing discussion in Science magazine at the moment about GISAID, the database was used a lot during the COVID pandemic. CDC set up SPHERES. There’s NCBI, there’s an European.
So at some point we got to have it in one place. It has to be transparent. It has to be sort of no strings attached. And I’m not– I mean, CDC absolutely has a role in that. I don’t know what the solution is, but I just want to raise the importance of that topic ultimately for surveillance.
HOWARD ZUCKER, CDC [00:39:00]
I think it’s a huge issue. And I think that this is one of those things where, relatively new field, it’s not so new genomics, but relatively new about using this as a way to detect diseases. And I think that there needs to be some basic platform. This is where it all goes. This is the information. It’s interchangeable. And until we get there, we’re going to have some challenges.
Yeah, this is an enormous issue. Enormous issue.
REP MICHAEL BURGESS [01:06:04]
During the run up to the last reauthorization of the preparedness bill, it seems like we had a lot of internal discussion, in fact, some even had in a classified setting, but placing the ASPR at the center of the the eye of the storm, if you will, when trouble hit, that seemed, if I recall correctly, that seemed to be the consensus that those of us who were on the committee back then, that that’s where we arrived.
It didn’t fare exactly as I would have anticipated then when when real trouble hits. Are we doing some sort of ongoing re-evaluation? Should you be the center? Should should the ASPR be the center? I believe it should. But are there ways to ensure that you stay at the center of that authority during the time of crisis?
DAWN O’CONNELL, ASPR [01:07:01]
Congressman, thank you so much for that question. Of course, I wasn’t here at the last PAHPA reauthorization or in this role and came into this role in June 2021 when the response was already in full swing and structures were already in place.
The department has been very clear that I am responsible for coordinating our department in making sure that I am the principal interlocutor with the secretary on issues around public health emergency and response. And I have played that role since I’ve been in this seat and I’ve had the pleasure of coordinating with my fellow panelists today on any number of very complex issues.
I also coordinate very closely with the White House and through the various responses I’ve led and other roles I’ve played within the department over previous administrations, I’ve interacted with either NSC, DPC, now a White House COVID team, and I am pleased to coordinate with, however, whichever president it is, chooses to organize the White House, I will be that conduit from the department to the White House on these issues and look forward to continuing to play that role.
But again, I’ve only been in this seat since June 2021 and have been able to do that since that point on.
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REP RICHARD HUDSON [01:39:26]
The president has yet to appoint a director, nor has there been any word on possible appointment or plans for an appointment. Can you speak to the status of this appointment process? Are you aware of any timeline for appointment to this position?
DAWN O’CONNELL, ASPR [01:39:39]
Thank you, Congressman. I cannot speak to the status. Of course, that is a discussion that the president is having at the White House.
REP RICHARD HUDSON [01:39:46]
How do you see your role as ASPR interfacing and coordinating with this director, both as leads in our nation’s pandemic preparedness and response efforts, as co-chairs of PHEMCE?
DAWN O’CONNELL, ASPR [01:39:56]
Well, I’ll look forward to the collaboration and the partnership with whomever the president picks to to run that office. It’s important to me that ASPR leads where ASPR can lead and that we’re role players and strong role players where we need to be. And when we’re a partner with someone at the White House, that’ll be just fine, and we’ll look forward to having a very collaborative relationship with the PHEMCE in this co-chair role.
REP RICHARD HUDSON [01:40:18]
Well, currently, in the case of disagreements among PHEMCE members or recommendations, the HHS secretary has the final decision making authority. Will this chain of command remain, even as it appears the intent of the new position would be to create a direct line of communication between the director and the president, on these issues? Do you– how do you see this playing out in a real time, real case scenario?
DAWN O’CONNELL, ASPR [01:40:38]
Well, as I understand it from the legislation currently, the PHEMCE reports to the secretary. And that will continue to be unless that’s changed in the new bill. That will continue to be the way that we do this.
REP RICHARD HUDSON [01:40:50]
Well, and I appreciate that. And I think one of the things that this committee’s got to kind of resolve and work through with this reauthorization is what’s that really going to look like? And I would appreciate your feedback through this process, including any concerns you might have about structural problems or any ideas you have of how we can make the chain of command more clear.
MIYA PATERNITI, FDA [09:15:56]
I would like to welcome you to this Pulmonary Allergy Drugs Advisory Committee meeting, where we will discuss the new drug application for epinephrine nasal spray, ARS-1, proposed for the emergency treatment of type one allergic reactions, including anaphylaxis in adults and children weighing 30 kilograms or more.
We would like to note that this differs from the indication included in the applicant’s briefing document and for the purposes of today’s advisory committee meeting, we will discuss the indication included on this slide as it aligns with the indication included in the NDA submission.
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MIYA PATERNITI, FDA [09:17:06]
Type one allergic reactions are also known as immediate reactions that involve IgE antibodies, resulting in release of histamine, and other inflammatory mediators.
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MIYA PATERNITI, FDA [09:17:16]
It is important to emphasize that this novel route of administration for epinephrine has no established regulatory pathway. And therefore, your advice to us today regarding this application will be impactful.
ARS-1 is a single use device which delivers two milligrams in 100 microliters via one nasal spray. The device used for one is the same as the device in other approved nasal sprays, including naloxone nasal spray.
The proposed directions for use instructs that if symptoms progress after ten minutes or an error is made in administering ARS-1, patients should administer a second dose with a new device.
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MIYA PATERNITI, FDA [09:20:58]
Although we have several approved epinephrine injection products, the approval process for epinephrine is unique, primarily based on its long regulatory history.
Epinephrine has been marketed in the U.S. since 1901, predating the original Federal Food and Drugs Act of 1906, which lay the foundation for the FDA. In 1938, the Federal Food, Drug and Cosmetic Act, or FD&C, required that new drugs demonstrate that they are safe for approval.
In 1962, Congress passed the Kefauver Harris Amendment to the FD&C Act, adding the new requirement that new drugs must be shown to be effective as well as safe to obtain approval. This amendment also required FDA conduct a retrospective evaluation of the effectiveness of drug products that had been approved by the agency as safe between 1938 and 1962.
The agency’s administrative implementation of the effectiveness evaluation was called the Drug Efficacy, Safety and Implementation, or DESI, process. Since epinephrine had been marketing since 1901, preceding the passage of the 1938 FD&C, it was not subject to DESI review. However, epinephrine was still required to comply with good manufacturing procedures and adequate labeling to ensure safe use.
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MIYA PATERNITI, FDA [09:22:25]
In 1987, EpiPen and EpiPen Jr, were the first epinephrine injections approved that remain on the market today. EpiPen was approved by FDA based on literature support for efficacy and safety. Clinical trial, and PK and PD data were not required.
More recent approvals of epinephrine injection products utilize the 505(b)2 regulatory pathway, which permits FDA to rely on previous findings of safety and effectiveness of an approved epinephrine injection product. In addition, chemistry, manufacturing and device data, along with human factors assessments, were required.
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MIYA PATERNITI, FDA [09:24:19]
Based on these uncertainties, the need for clinical efficacy trials was considered and clinical trial scenarios were discussed, but feasibility concerns were acknowledged. As you listen to the presentations today, we ask you to consider whether PK and PD is sufficient, or if clinical trials are needed.
Establishing a scientific bridge based on PK and PD introduced challenges due to the limited PK and PD data for approved epinephrine injection products, as PK and PD were not required for approval of epinephrine injection products. This resulted in several knowledge gaps, including which PK endpoints are critical to establish efficacy, and how to interpret PK and PD similarities as approved doses of epinephrine have not been validated by dedicated clinical efficacy trials.
In addition to the limited data, there’s also variability in PK profiles across epinephrine injection products. Due to this variability, the applicant and FDA agreed to a bracketed approach, in which the PK profile for ARS-1 would be bracketed between two different approved epinephrine injection products.
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MIYA PATERNITI, FDA [09:26:22]
FDA and the applicant agreed that nasal allergen challenge of subjects with allergic rhinitis may reasonably mimic the nasal findings that could occur in anaphylaxis. Therefore, the applicant agreed to evaluate epinephrine’s PK and PD profiles of ARS-1 under nasal allergen challenge conditions.
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MIYA PATERNITI, FDA [09:26:42]
Lastly, developing an epinephrine nasal spray for pediatric subjects was discussed due to the importance of epinephrine treatment in pediatrics due to nasal anatomic differences.
The FDA requested that the applicant conduct pediatric PK and PD studies to determine appropriate doses for children of different ages and body weights. The clinical pharmacology program to support was designed to address some of the development considerations for epinephrine nasal spray.
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MIYA PATERNITI, FDA [09:30:53]
As you consider the results for ARS-1, I would also like to remind the committee that although we have several approved epinephrine injection products, barriers to epinephrine use still exist.
We know that epinephrine is life saving and rapid administration can decrease the risk of death. Despite this, many patients, caregivers and health care providers, underuse or delay administration of epinephrine.
The reason for this is multifactorial and are listed here. Some patients, caregivers and health care providers may not recognize the signs of anaphylaxis. In addition, some patients may not have access to epinephrine due to supply chain issues or high cost.
Another reason for underuse or delayed use of epinephrine is that patients and caregivers may fail to carry epinephrine with them at all times because they did not fill the prescription. It’s burdensome to carry or they don’t anticipate that they will encounter the allergen.
Lastly, patients and caregivers may hesitate to use an injection device even when it’s available to them at the time of access. This can occur because patients or caregivers may not believe that the reaction is serious. They don’t understand how to use the device or they’re afraid of the injection.
The FDA recognizes that development of new routes of administration for epinephrine is important to address some of these barriers. But as noted here, the underuse of epinephrine is complex and multifactorial.
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RICHARD LOWENTHAL, ARS PHARMACEUTICALS [09:38:34]
As you know, epinephrine is highly effective for the treatment of anaphylaxis if administered in a timely fashion. The problem is that major barriers limit the rapid use of epinephrine in a community setting. Many patients fear needles and many are not comfortable with self injection. There is also the impracticality of carrying the current available devices and using them in public.
Our goal in developing Neffy was to address the community use issues with current epinephrine devices that limit the proper use of this lifesaving medication. Neffy is a needle free, easy to carry and easy to use approach to administer epinephrine rapidly for the emergency treatment of severe type one allergic reactions, including anaphylaxis.
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RICHARD LOWENTHAL, ARS PHARMACEUTICALS [09:40:37]
ARS has been working on packaging to allow patients and caregivers to carry their Neffy devices at all times to ensure epinephrine is available when needed. One of our concepts we hope to make available at launch is this slim Neffy carrying case that will hold two devices and directions for use, and have a QR code that directs users to a video on proper administration.
This easy to open zipper package like this will make Neffy quickly accessible, even to children when needed. The case will also have an alligator clip and could hold your keys or latch onto a backpack or inside of a purse so it’s readily available and can even include a tag if you lose it, that can be quickly found.
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RICHARD LOWENTHAL, ARS PHARMACEUTICALS [09:41:56]
We plan to file a supplemental NDA application for Neffy one milligram in these lower weight children shortly after approval of this current NDA. We are also conducting phase two placebo controlled trials with Neffy in refractory urticaria, where we observed rapid and near complete responses, as well as in patients with persistent asthma.
Given that efficacy studies in this indication are neither ethical nor feasible, and knowing that binding of androgenic receptors and pharmacodynamic responses would not differ in patients experiencing severe anaphylactic reactions, ARS and FDA agreed that clinical pharmacology studies could support the assessment of Neffy’s benefit risk.
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SARINA TANIMOTO, ARS PHARMACEUTICALS [10:03:12]
We have treated more than 600 type one allergy patients and healthy volunteers, with over 1000 doses, ranging from 0.5 to 4 milligrams. With both one and two milligram of Neffy, we have conducted single and twice dose administration, self-administration which replicates real world use, and various challenge studies.
Additionally, we have studied Neffy in more than 80 pediatric patients with type one allergy, aged 4 to 17 years old, weighing 15kg or greater.
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QUESTION [11:36:28]
What direct evidence, and I ask about direct evidence, do you have that this will actually be delivered in a greater proportion than, let’s say, EpiPen?
RICHARD LOWENTHAL, ARS PHARMA [11:36:41]
So so we’ve done a lot of research on this, a lot of patient research surveys and other information. There’s also a lot of literature. The allergists will know the literature on this that delayed administration carrying all these problems in the community.
And what we know from our research and surveys is that people will carry this device much more often. It’s much smaller, easier to carry. And as we mentioned earlier, we’re doing everything we can to facilitate carrying it. So, I can keep, can have this in my pocket all the time, with my keys or I can hook it in a bag and really help facilitate.
Because if it’s not– if it’s not with the patient, all these things we’re discussing about PK, PD, it doesn’t matter. If they don’t have it with them, it’s a moot point. They don’t deliver, they don’t have drug, they go to the hospital, and they delay administration because they have to get to the hospital to get a dose of epinephrine.
So that’s one. So we– from our patient surveys, basically we believe that the rate of carriage will increase significantly by about 35%. So right now, 55% with current dose or current products. And that matches the literature well from our studies.
And also we believe we will increase to roughly about 85% with Neffy.
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RICHARD LOWENTHAL, ARS PHARMA [11:38:13]
And then we also did a recent study. We’ve done multiple studies, so this is actually a study we did recently in 200 people that have actually dosed an EpiPen within the last 12 months. So they had very recent experience and a hundred were caregivers, a hundred were patients. And the survey explored different things.
But one of the things that explored was the time to dosing. And it appears like people were much more willing to dose the intranasal more quickly, and would dose really almost five minutes sooner, with the intranasal.
We have other studies that actually imply they would dose even 18 minutes sooner, but in people that didn’t have recent experience. So these are people that actually use EpiPen and are willing to use it very quickly and people that are less willing to use it.
The difference, or don’t haven’t used it in a long time, the difference seems to be much greater and up to 18 minutes delay. But in this study with people that actually use it, that have used it just recently, they they still see close to a five minute, you know, 4 to 5 minute advantage with the nasal spray.
So so we think there’ll be significant impact on the unmet medical need with this.
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JENNIFER LAN, FDA [00:50:46]
We acknowledge that a needle-less route of epinephrine may lead to earlier, more frequent epinephrine use.
There are multiple uncertainties relying on PK PD data to support the efficacy of ARS-1 that we need to consider.
First, there is no clinical efficacy trial to determine the efficacy of ARS-1. The benefit of ARS-1 relies on establishing a scientific bridge via bracketed PK, with supportive PD, to approve injection epinephrine products.
Second from PK PD epinephrine injection products are highly variable, making the scientific bridge challenging.
Third, whether PK PD in healthy subjects will be similar in anaphylaxis patients is unclear.
Finally, although much of the PK PD profile of ARS-1 is bracketed by profiles of approved epinephrine injection products, there are some differences that warrant consideration.
For example, there was a lower PK of ARS-1 within the first ten minutes of EPI-15 compared to epinephrine injection in normal nasal conditions. However, this trend is not seen in EPI-16 and EPI-17.
In the nasal allergen challenge study, epinephrine, PK and PD dropped to below the epinephrine injection comparator at around 15 minutes, and we do not have PK PD data for a repeat dose, raising questions regarding durability of effect.
For risk, for single and repeat dose studies did not raise safety concerns. However, it is uncertain if there would be adverse events, particularly local adverse events, for more frequent use.
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LEONARD BACHARIER, PADAC [04:14:48]
So I’d be interested in the committee’s view because we’re you know, we’ve we’ve seen a ton of data today and I think everybody is is struggling with the multiple, for lack of a better word, inconsistencies.
The PK doesn’t replicate the PD, one doesn’t reflect the other at one time point, one is better at one time point, one may look less less good. So I mean, we’re really struggling here with figuring out where are the most salient aspects of these data, what are really important, what are fine points that have theoretical value but may or may not impact patients. We heard many families and other groups remind us of the space that they live in and the value that such a product would bring to them.
And as I hear this and as we talk about this, I really struggle with the idea that doing one more study, with 45 patients, in under any set of circumstances will clarify any of it. You know, I think we spend our lives doing clinical trials of the disease of interest. And here we’re not studying the disease of interest. We’re studying multiple surrogates, be it PK or PD.
And we understand why we can’t study it in the setting of acute anaphylaxis for all the appropriate reasons that were laid out there.
So I guess my real question is what more can we reasonably legitimately expect? And if that turned out exactly the way we wanted it, would we have that much greater confidence than where we sit now?
I’m just not sure of that. I think there is just so much inherent variability with this type of drug and all the issues we’ve discussed that I just worry that a couple studies of 40, 50 patients are not going to give the most black and white of answers. And I think we have to make our best judgment based on the type of data that has been shared with us today.
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LEWIS NELSON, PADAC [00:03:48]
I just first want to say that I really want this product to work. I mean, we definitely benefit from a needle-less means of delivering epi. And I think the sponsor has done a nice job trying to find that balance. That said, I think we’re using weak surrogate data to assure ourselves that we could be confident in our ability to successfully treat one of the scariest clinical syndromes that we see in the public and in the ED and where I work.
And as Dr. Amirshahi mentioned before, it’s a devastating illness when you see and I know many people in the public session with commented on that.
And I think the bracketing approach makes sense. But we are comparing apples and oranges to some extent. And I think the FDA and sponsor understand this and tried to show equipoise between the various data sets, but I don’t really think we’ve done that sufficiently to make a clinical judgment that these that these devices will prove as successful as we see with the other forms of epinephrine that we use, particularly because we’ve really only used healthy patients or simulated ill patients, we really have not studied patients with disease that we’re interested in.
I do think that the most important part of the treatment trajectory that we deal with is particularly for the sick patients, as Dr. Armstrong said also, is the first ten minutes. And so the idea that this– or the data that show that this device works quickly in this patient population with swollen mucosa is very encouraging. But as I mentioned in my comments earlier and my question earlier, I don’t know that we can we can equate swollen mucosa with anaphylaxis. I mean, I could see where there’s some relationship, but it’s clearly two different diseases. One is a weak surrogate for the other.
You know, one can seek medical care pretty quickly, whether it’s the EMS or through an emergency department or whatever. And patients can always re-dose. And I know there’s some questions about how functional that will be, you know, in a swollen mucosa, which I assume we are thinking about somebody with anaphylaxis. So the rapid fall in epi concentrations don’t concern me that much, although I obviously would rather not see that.
And to answer the clinical question, the clinical data question, I strongly believe that we need some clinical data to support this product. I do think that it’s it’s feasible to perform a study. It’s hard. But, you know, we study stroke, we study MIs, we study cardiac arrest. You know, we do all kinds of pre-hospital studies that involve very sick patients. And we, from what we heard in the public session, there are millions potentially of patients who could be enrolled in the study. And we could identify those patients, proactively, get them enrolled in a trial where they might have a rescue medication or a failsafe mechanism in case this drug failed to reverse the the anaphylaxis with the initial dose.
But I really would hate to learn, without some better clinical data, that we recommend approval of a product on the basis of surrogate data that’s inconsistent and somewhat confusing and, ultimately because of that, patients are harmed. So I do think we need to have more data, clinical data. I just don’t think surrogate data is going to be adequate to allow this indication to to support this indication.
DEMETRE DASKALAKIS, WHITE HOUSE [00:13:56]
I think that we’re in close communication with CDC from the White House about looking to see if there are other jurisdictions experiencing similar upticks in mpox. So think we’re going to hear more, and thankfully we have what is it, 575 folks from around the country who may also be able to give us a sense of if they’re seeing things on the ground right now.
I think really this is about, again, being humble. I think that what’s been really important is that and think, as Patrick said, we’ve been really signaling the risk of a resurgence using modeling and data.
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DEMETRE DASKALAKIS, WHITE HOUSE [00:17:30]
I think that there’s a lot of science questions that we don’t know and I think we don’t know how durable the vaccine protection is. We also don’t know how long it lasts. And we also don’t have full data on vaccine effectiveness in general.
I can say that down the pike, we are going to be seeing releases of more of VE data. And the the view into that data is that it’s about as we expect, based on what has already been published, and that is important to remember, represents a range of, if you look at the VE data that’s published on the CDC website, about 69% vaccine effectiveness for a two dose vaccine.
But the range is– the confidence intervals go from 41% all the way to 81%. So think we have to have a lot of humility.
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CHRIS BRADEN, CDC [00:23:35]
So think it might be helpful to go over some of the reasons why we can see cases in vaccinated persons.
One is that the vaccine may be less effective than we have determined in studies so far. We’ve talked a little bit about that. We do have three VE studies coming out next week which will add to the literature and add to the evidence basis for the effectiveness of vaccine.
Number two is another one that we’re talking about, is immunity may wane over time. And we are trying to study that actively as we go on. It does take some time to determine if and by how much immunity wanes. But we don’t know that it has waned at this point, and we don’t anticipate right now a change in recommendations. We’re looking for the data to be able to make recommendations in that regard.
The virus may change to overcome immunity. And I’ve seen in the chat some questions about sequencing, and certainly we would like to sequence as many viruses as possible, so that we can determine whether or not there are any changes that would induce immune evasion.
Specific vaccine doses or lots may be compromised. So when we have a cluster of people who had been vaccinated but now are infected, we want to look at that to see if there are common lots among them and so forth to determine whether that might be an issue.
Also, especially with relatively few cases, we may observe random clustering of vaccinated persons among cases. So this is the issue of chance observation. We we see this often in epidemiology. So we need to be careful, especially around small numbers of cases, about whether or not this is what we’re observing, and continue to monitor.
And then vaccinated people may be among those in continuous care, and more likely to be diagnosed, and then be part of our surveillance of cases. And so it may be a surveillance artifact in that way. There are probably other reasons, but all of those may apply. And so we’re going to be trying to go through those different reasons in our investigations.
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CHRIS BRADEN, CDC [00:28:26]
So we’re currently working on a method to request Tpoxx that will also include the assessment of patients, or the willingness of patients, to participate in the STOMP trial. So we really think that this, for those who are eligible and willing to participate in this trial, is very important so that we can get some real data on the effectiveness of tecovirimat with this particular illness.
That being said, if there aren’t eligible or are not willing to participate in the STOMP trial, then there will be a way to request the vaccine from the stockpile through the CDC expanded access IND protocol.
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CHRIS BRADEN, CDC [00:29:39]
Each jurisdiction and state is a little bit different. And the methods that they use to report to CDC, some are faster, some are a little bit slower. Some states do batch cases to some degree.
That being said, what we’ve seen nationally, and what is on our website is a very slow decrease in the number of cases that we’ve seen over the last couple of months. There was actually a time on our website where the average daily number of cases was zero over a seven day period.
But we know that that wasn’t actually the case, because then subsequently cases were reported during that period of time. So we’re working with jurisdictions to try and increase the speed and completeness of reported cases.
It’s a few cases still that are being reported each day, but we are very concerned that we are going to see more of what Chicago has experienced. And we also see some wastewater detections in a number of different jurisdictions that may be a harbinger of things to come. So we are very concerned, like I said, about the assessment of risk for the near future. And we want to be able to prevent outbreaks, if we at all can.
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CHRIS BRADEN, CDC [00:45:12]
We were on a trajectory to where we weren’t seeing clusters and only very few cases, and so we had decreased the frequency of reporting. But obviously, in the face of the increase in cases or clusters, we will need to be more forthcoming and frequent with with our surveillance.
State laws and regulations specify which diseases and conditions must be reported and support the collection of individually identifiable information necessary to conduct a case investigation. Making a disease or condition nationally notifiable does not change the immediate public health action taken in response to an outbreak, case, or cluster of public health importance. However, it codifies the use of established processes for submitting and aggregating data at the national level. Diseases and conditions are added to the nationally notifiable conditions list by CSTE through a collaborative process that involves public health agencies and CDC.
In December 2022, CSTE convened a working group of experts on Cronobacter infection from CDC, public health agencies, and laboratory partners to collaborate regarding Cronobacter disease surveillance strategies, including the collection of epidemiologic and laboratory information. Through these working group discussions, CDC and jurisdictions drafted a position statement that would establish a standardized surveillance case definition for Cronobacter infections in infants. The group will also examine whether to recommend adding the condition to the list of nationally notifiable conditions. All draft position statements will be presented to Council members for consensus approval at the CSTE Annual Conference in June 2023.
Matthew Cone
The TAG-CO-VAC will meet in Geneva on 11-12 May to consider the genetic and antigenic evolution of SARS-CoV-2 variants, the performance of vaccine products against circulating SARS-CoV-2 variants and the implications for COVID-19 vaccine antigen composition. Based on this assessment, recommendations to either maintain current vaccine composition or to consider updates will be issued.
A statement with recommendations on COVID-19 vaccine composition will be published during the following week (week of 15 May).
No recommendations on vaccine composition have been or will be made before the meeting concludes.
Best,
Media Relations
Daniel Epstein
What you are seeing in the CDC’s case counts are older cases that have just been reported after DSHS worked with a jurisdiction to reconcile some of their cases. At least 17 of the newly reported cases are from 2022 and 3 are from January and February of this year.
The CDC also had an issue with processing our cases in their system recently so we believe that there may also be a few duplicate cases that were counted in the most recent data.
Lara M. Anton
| Location | 26-Apr | 10-May | Difference |
|---|---|---|---|
| Texas | 2972 | 3003 | 31 |
| Illinois | 1437 | 1452 | 15 |
| California | 5755 | 5759 | 4 |
| Louisiana | 309 | 313 | 4 |
| New York | 4246 | 4249 | 3 |
| Alabama | 188 | 189 | 1 |
| Florida | 2890 | 2891 | 1 |
| Oregon | 279 | 280 | 1 |
| Michigan | 401 | 400 | -1 |
| North Carolina | 737 | 712 | -25 |
ERIN MURRY, FDA [09:51:01]
We did review the extensive protocol document in detail. However, with respect to the applicant’s unusual way of counting selectors, that was not flagged, was not in keeping with FDA guidance, and we did not agree to it.
We have gone back to the actual protocol, and the applicant’s brief mention of this approach is confusingly worded and open to interpretation. However, we did want to make it clear the FDA did review the protocol in detail.
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CHRISTINE NGUYEN, FDA [10:33:53]
The progestin only pill is less forgiving, for the reasons that were discussed: it’s once daily, and at the same time, allowing for a three hour window. And it’s obviously the side effects, so to say, when adherence is not stringent, is an unintended pregnancy. So missing a pill would with COC versus a progestin only pill may differ as far as the risk for unintended pregnancy.
Another consideration I’d like to raise that we haven’t really discussed is, unlike condoms, when you don’t use them, you’re clearly at risk for pregnancy, and you can choose to use emergency contraception in a timely manner if one is taking a pill every day, but not taking it at the same time every day, that risk of pregnancy may not be self-evident, and there is a missed opportunity to take emergency contraception in a timely manner.
So for adolescents, I think that’s particularly important to consider.
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ERIN MURRY, FDA [10:37:31]
As an overall matter, we would ask the committee to consider the labeling as it has already been tested. The labeling as it already stands and it has already been tested.
If the committee feels that changes are necessary to the labeling in order to ensure safe and effective use in the U.S. nonprescription environment, we would expect that the committee would then be stating that the application as presented as inadequate, and that the sponsor would need to go back and change the labeling, retest, and resubmit an application. That’s what we we would expect.
So please consider the application and the labeling as it already stands and has already been tested.
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JEENA JACOB, FDA [10:42:50]
25% were lost to follow up. We do not know why those participants did not complete the study.
In terms of the 21% that withdrew from the study, 60% provided the reason that they withdrew due to the subject, deciding they wanted to discontinue use of the product. There were a significant number of the participants who were in that category who did discontinue due to adverse events, and then another 24% provided the reason of discontinuation due to adverse events.
All of the adverse events that were reported in the subgroup that decided to withdraw due to decision to discontinue, as well as withdraw to an adverse event, were accounted for in the overall discontinuation of the study, and that made up of 7% of the user population that discontinued the study drug due to an adverse event.
In terms of the remaining participants that withdrew from the study, five cited the reason of COVID reasons due to COVID 19. We don’t have any more information regarding that.
11 withdrew consent. 2 withdrew due to their their own personal physician basically making the decision with, in conjunction with the participant, that the participant needed to withdraw from the study.
8 provided the reason of withdrawn because they were they were pregnant and 4 had a protocol violation as the cited reason.
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PAMELA HORN, FDA [10:44:42]
I just want to call your attention, Dr. Barron, to the last row where there were only 46% of participants who had a known end of study home pregnancy test result. I think that that was concerning to us in terms of there being a lot of missing information about what we knew about pregnancy outcomes from this study. And, combining that with the concerns that we had with the self-report data, I think it does raise a lot of concern for us about what we know about the outcomes from this study.
In terms of actual use study dispositions in general, there are definitely examples of actual use studies where there’s much higher completion rates and much less dropout than what we saw in this study. But, the actual use studies span a wide range of different conditions and indications. And so, it’s kind of hard to make much comparison in that way.
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PAMELA HORN, FDA [10:57:40]
I once again want to emphasize that we recognize the many challenges that women of reproductive potential face in accessing contraception in the U.S. currently, and the importance of making decisions that it will enhance women’s health.
The public hearing yesterday was filled with courageous, compelling stories testifying to these challenges. We support women’s autonomy and empowerment in making their own decisions with the best information available.
When an applicant applies to change a drug available prescription to non-prescription, the applicant is required to provide data to demonstrate that the benefits of the drug will continue to outweigh the risks. And we owe it to women of reproductive potential in the U.S. to ensure that the data the applicant provided is sufficient to support the likelihood of safe and effective use without interaction with the health care provider, and that the data demonstrate that labeling has been optimized to support this use. And that is our charge to the committee this morning as well.
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KATHRYN CURTIS, CDC [00:09:33]
We were presented a lot of data, and I echo Dr. Shaw’s comment yesterday that it’s a little difficult to take all of the disparate sponsor and FDA analyses into account. But I think looking overall at the general population, looking over both actual use and the comprehension data, and looking at sort of the key endpoints on taking the pill every day, taking it the same time every day, and especially factoring in the mitigating behavior, I think we can say for the overall the general population that, at least the pill taking behavior and comprehension, are good.
I did want to make a comment about the delayed pill study presented by the sponsor. To me, those data are reassuring. I agree with FDA that there’s certainly not enough data to expand that three hour window. But I do think measuring cervical mucus and ovulation are standard measures of proxies for pregnancy risk when pregnancy isn’t feasible to measure. And so those data were reassuring to me.
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ABBEY BERENSON, ORUDAC [00:11:17]
We have to think about if people take the pill the same time every day when they do see a provider. And I think all of us that have had experience taking care of adolescents and adult females realize that it is very difficult for people to long term take even birth control pills, when they see a provider, the same time every day.
So I just think that we should think about the big picture and not just the over-the-counter use. So given what’s been presented, I feel it is as safely taken without a prescription as it is with the prescription.
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MARIA COYLE, NDAC [00:21:42]
There does seem to be support across the panel, of those who have spoken, that use of the norgestrel tablet in a safe and effective manner seems very reasonable in the OTC setting, particularly for the general population of females, given that there are challenges even to prescription adherence, and not maybe a general sense that that health care provider interactions substantially may affect that, or may be available in such a way, as to make it a necessary component of safe and effective use.
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MARIA COYLE, NDAC [11:38:59]
In speaking to the effectiveness of the norgestrel tablet in the OTC setting, the panel expresses, I think, great confidence in the effectiveness not only in the general population of females, but also in adolescent populations and those with limited literacy for a variety of factors that we’ve discussed.
I think in terms of risk, risk from the medication itself seems to be– the panel seems very comfortable with the limited number of risks from the medication itself. So physical risks from taking a norgestrel product on a daily basis, maybe particularly in adolescent populations that are overall quite healthy, and less prone to the kinds of conditions that would be a contraindication, such as breast cancer.
And in fact, the benefit may far outweigh the risk from, if that were the the sum total of the equation, I think risk from unintended pregnancy because of not understanding or not adhering to a daily regimen taken very close in time each day, maybe the greater risk that we’re discussing, and I have heard a little bit of mixed opinion, many people expressing that it is better than what is currently available, and that it would not necessarily be information or directions that would be beyond the capability of all of these populations that we’ve talked about thus far, maybe with the possible exception of very young adolescents.
And in that case, maybe some some further information or data would have been helpful to understand that that that aspect of of risk for for very young adolescents.
So to to wrap up, oh one other point that wanted to make, because I’ve heard it in all of our conversation or several of the comments made by panelists thus far, was that even looking at the more conservative analysis provided by the FDA of the data from the ACCESS study, think there’s still quite a bit of confidence in this product in the OTC space.
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PAMELA SHAW, ORUDAC [11:43:08]
I think there was some discussion and concern yesterday about specifically the emergency use contraception and whether or not people would be taking that and when taking this over-the-counter progestin only pill.
And I personally did not have raised concern regarding that specific concomitant product, and that it would be unlikely if people are already on, I think, oral contraceptive, that they would be also seeking that out and that just the overall safety profile of the medication.
So for me, that did not raise additional concern.
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JESSE CATLIN, ORUDAC [11:52:11]
So I would ask us to consider that we probably could request a study that goes the other way. But would it yield– we’d be having a different conversation now of whether it represents actual use.
So I think, now we’re having a conversation that maybe the study couldn’t wasn’t necessarily restrictive enough, which led to some messy data and some problems.
But I think if we have things like a chat feature, if we did other stuff like that, does it actually represent how the consumer is going to use the product when they’re when they’re left to their own devices?
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KAREN MURRY, FDA [01:01:38]
I just want to first of all, thank the panel for all of their extremely useful input. And I just want to emphasize from the FDA that we really realize how important it is that U.S. women have increased access to effective contraception. And I don’t want I don’t want any of our discussion or our pointing out of the deficiencies of the development program to take away from that message.
We realize that it is extremely important and we thank the panel for their many comments that had to do with their experience, apart from their interpretation of what the study showed. We do want to point out, though, that when a development program is proposed for a nonprescription drug, we can’t just approve it based on the experience in the prescription setting, without the applicant doing adequate studies to look at what’s likely to happen in the non-prescription setting.
And it would have been a much easier time for the agency if the applicant had submitted a development program and an actual use study that was very easy to interpret and did not have so many challenges. But that was not what happened for us.
And so the FDA has been put in a very difficult position of trying to determine whether it is likely that women will use this product safely and effectively in the non-prescription setting. But I wanted to again emphasize that FDA does realize how very important women’s health is and how important it is to try to increase access to effective contraception for us women.
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KATHRYN CURTIS, CDC [YouTube 4;17;38]
I voted yes. And I voted yes because the evidence demonstrates that the benefits clearly exceed the risks. The benefits of moving Opill over the counter include increased access to contraception, especially those who face multiple barriers that we heard about yesterday, reduction in unintended pregnancy and associated risks, and improved reproductive autonomy and improved equitable access to contraception, which you also heard about so passionately yesterday.
So for all of these reasons, I think Opill has a potential to have a huge positive public health impact.
With respect to risks, for safety, safety was established 50 years ago when the original approval was made and the accumulating body of evidence since then has shown that these pills are safe with very few contraindications and long term safety concerns. With effectiveness, effectiveness was also established 50 years ago, and while the methods for assessing effectiveness and the population characteristics have changed over the years, all of the estimates that we heard about over the last two days fall somewhere between two in four per hundred, which is much lower than any of the other over the counter products, and lower than the generally accepted typical use failure rate of seven for oral contraceptives received in the prescription setting.
So the large body of evidence and the safety and effectiveness is very reassuring. The data presented over the last two days from the applicant on comprehension of the label and actual use were also generally reassuring, even with the problems with the data.
And even for those groups of younger adolescents and those with lower literacy, those were the two groups that did sometimes have some of the lower scores, even for these groups the risk of harm is low and the potential for benefit is high. And so that’s why I believe that the evidence demonstrates that the benefits exceed the risks.
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PAMELA HORN, FDA [YouTube 4;46;06]
I just want to thank the panel so much for all of your careful consideration of the data and for taking the time to explain your votes carefully to us. We paid very careful attention and we appreciate the time you spent reviewing this application and giving us the expert advice that we wanted from the meeting. So, thank you all.
ALLISON ARWADY, CHICAGO [00:37:36]
I’m going to go ahead and turn just to a few updates and, actually if we can pull the slides up, we’re going to start with mpox, monkeypox.
We are seeing the beginnings of an increase in mpox cases here in Chicago. Just since mid-April, we’ve had 12 new probable mpox cases reported in Chicago. The dashboard will update as those cases are confirmed.
But if you look at the dashboard here, it was really last summer that we were seeing 126, 143, 110 cases a week, lots and lots of cases. And then it came down to a point where you can see that in February and March and April, most weeks we didn’t see a single mpox case, maybe one or two in a higher week. But just these last couple of weeks we saw two, then five, now another five or six coming in. So we’re at 12 already.
And in that context, I just want to– we’ve been putting this on social media and there’s a lot more information online at Chicago dot gov slash mpox.
But just a reminder, this one is also not over. It’s important that people protect themselves. It’s serious. It’s preventable. You can easily get your vaccine for mpox. And people who are– who may be exposed to mpox should receive two vaccine doses. You’re not fully vaccinated unless you’ve gotten two doses of that vaccine.
PAMELA HORN, FDA [09:43:27]
We will now proceed with introductory remarks from Dr. Pamela Horn.
Good morning and welcome to the Joint Meeting of the Nonprescription and Obstetrics, Reproductive and Neurologic Drugs Advisory Committee. My name is Pamela Horn. I’m the director of Division of Nonprescription Drugs to in the Office of New Drugs.
Thank you for joining us for this important discussion of an application to switch norgestrel tablet from the prescription to nonprescription setting today. I would especially like to thank the advisory committee members who have taken the time out of their very busy schedules to help us consider this application, as well as the many members of professional groups and the public who will be testifying and have written comments to the docket.
FDA appreciates the importance of promoting reproductive health in the U.S. We acknowledge the complexities of this, particularly as it pertains to family planning, which includes emergency contraception, for which there are currently two approved drugs, one of which is available without a prescription, and various contraceptive methods, including birth control pills.
Today, we will not discuss all these topics. Rather, we will focus the discussion on one type of birth control pill, norgestrel tablet, which has one hormone, and not the combined birth control pill, which has two hormones, and considerations for whether norgestrel tablet would be safe and effective without a prescription.
As a person who has devoted my career thus far to public health and a person who cares deeply about women’s health, I’m driven to make recommendations and decisions that will improve women’s health. I would love to have unambiguous data to support these recommendations and decisions, but my years of experience in regulatory science have taught me that this is rarely the case, and today is no exception.
We have an application to discuss with many complicated issues and uncertainties, including data with questionable reliability. FDA and this review team are committed to making the best decision that we can with the information available to us.
We are acutely aware of the importance of this application and we have worked extremely hard to bring you the most comprehensive and thoughtful evaluation of it that we can.
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HELENE GUILLARD, HRA PHARMA [09:48:30]
This is an important day for science, public health, and importantly, individual women, their partners, families and communities. With this in mind, I also want to thank the many thousands of people who participated in our clinical program.
On May the 9th, 1960, a pill for oral contraception was approved in the U.S. for the very first time and exactly 63 years to the day, we are in this meeting to discuss making an oral contraceptive pill available over the counter for the first time in history.
Today, you will give careful consideration to this important clinical application. And no doubt the results of your deliberations will have far reaching impact. Even women who want children at some point in their life spend most of their reproductive years trying to avoid pregnancy.
However, women in the U.S. face unnecessary burdens in accessing effective contraception. And unfortunately, the nonprescription options are limited to the least effective methods, such as condoms or withdrawal.
Opill is a more effective option than all current nonprescription methods. Today, we’ll show you data demonstrating that using the proposed labeling, women of all reproductive ages can use safely and effectively without health care provider supervision.
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IRENE LAURORA, PERRIGO [11:00:56]
In our first post-hoc sensitivity analysis, we excluded all data from the 261 over-reporters. This assumes the data provided by the reporters was non-informative of their use of Opill at any time during the study. Neither the root cause analysis nor our own quality assurance activities have identified any problems with diary reporting for those participants that did not over report. This includes a robust population of 622 participants.
Interestingly, we did find a precedent for this. Another actual use study for Oxytrol, a treatment for overactive bladder that was approved for Rx to OTC switch, observed overreporting. However, all participants who reported using 25% more patch applications in their diary than were purchased were excluded from their sensitivity analysis. Ours is a more conservative approach, as we considered even a single excess dose as overreporting.
Let’s look at the results of this analysis, excluding over-reporters. Here are the results for the various primary adherence related endpoints. The pre-specified analysis is highlighted in yellow and the sensitivity analysis presented below. The sensitivity analysis results across each endpoint are very similar to the results of the pre-specified analysis. Each point, estimate and the confidence interval show that participants followed the label directions.
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IRENE LAURORA, PERRIGO [11:18:57]
Let me remind you that the need for effective and accessible contraception in adolescents is particularly urgent. Adolescents face the most significant barriers to obtaining the more effective contraceptive products, and 72% of their pregnancies are unintended.
Additionally, we had sufficient representation of those with limited health literacy across the development program, including 13% in the ACCESS self-selection population and 14% in the user population. And this is consistent with the proportion of limited health literacy population in the two most recent actual use studies for products approved for OTC switch by the FDA.
We sized the study such that the subgroups of limited health literacy participants would be of an absolute size sufficient to draw conclusions about performance among those in that group. And importantly, these participants performed consistently as those in the entire population across all primary endpoints assessed.
Overall, the totality of the evidence from ACCESS study is fully informative of potential use in the OTC setting and demonstrates that women adequately adhere to taking Opill in the OTC setting, demonstrating that involvement of a health care provider is not necessary to ensure good adherence. This supports that women, including adolescents and those with low health literacy, would achieve the intended benefit in an OTC setting.
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STEPHANIE SOBER, PERRIGO [11:21:30]
There is a perception that POPs may not be as effective as combined oral contraceptives. This is based on data from the 1970s and early 1980s showing two things. First, that ovulation is less suppressed in POP users than COC users. And second, according to small pharmacokinetic studies, that low serum levels of progestin remain after 24 hours from intake.
The pharmacokinetic data was then extrapolated to create the concept of the three hour window. In other words, that missing a pill by more than three hours could result in pregnancy, though this is not based on any clinical efficacy data.
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STEPHANIE SOBER, PERRIGO [11:24:30]
When used correctly, 67% of women did not ovulate and another 10% ovulated with an abnormal luteal phase likely not compatible with pregnancy. Thus, only 23% of subjects ovulated with a normal luteal phase. This demonstrates that ovulation inhibition and follicle growth disturbance provide an important contribution to Opill’s mechanism of action. In fact, they likely provide a larger contribution than previously thought.
Second, when used correctly, fertile cervical mucus was absent throughout the entire cycle of use. So although approximately one third of users did ovulate during correct use, the contraceptive effect is nonetheless maintained by the hostile cervical mucus.
Third when pill intake was delayed by six hours or missed altogether, neither the percentage of women in whom ovulation was suppressed nor the frequency of fertile cervical mucus were significantly different from that during correct use. This suggests Opill can be expected to effectively protect against pregnancy even if a woman takes her daily pill late or misses it entirely.
These data reassure us that the window for maintaining efficacy if a pill is delayed or missed is likely wider than previously thought. We acknowledge that there are no data available to assess the impact of missing more than one pill on pregnancy risk. It is also not known how many pills would need to be missed before contraceptive efficacy is significantly reduced. Even with these reassuring data, HRA has maintained the three hour window language in the proposed OTC label. And as you heard earlier, the ACCESS study demonstrated excellent pill taking behavior. 97% of women either took Opill daily as instructed or took appropriate mitigating action if pills were missed.
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STEPHANIE SOBER, PERRIGO [11:31:27]
Overall, the data showed no signal of concern for use in the OTC setting, and reassuringly data from the final pivotal label comprehension study do show that consumers understand these key messages. To summarize, our consumer studies show that women of all reproductive ages can safely use Opill in the OTC setting. Across two pivotal studies, women were able to appropriately self select whether Opill was right for them and follow the label instructions to guide use.
Data from the ACCESS study demonstrated that the drug facts label is sufficient to guide women to correctly take a pill every day. There was high adherence to taking the pill every day at the same time, and few pregnancies occurred.
Given the inherent safety profile of norgestrel, situations in which users need to consult a health care provider, take a pregnancy test and or stop use in response to certain new symptoms are all uncommon and no different than what patients face in the prescription setting.
Overall, the proposed drug facts label contains all the information needed to select and use Opill safely and effectively without incremental clinical risk, making Opill appropriate for OTC use.
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DEBORAH ARMSTRONG, CMTE [11:49:32]
The first is, is Opill available over the counter in any other countries?
UNKNOWN, PERRIGO [11:49:38]
No, Opill is not currently available in other countries, but some other progestin only contraceptives are.
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HELENE GUILLARD, HRA PHARMA [12:09:08]
So women indeed are able to access oral conception without a prescription in a number of countries worldwide, around 100 countries. And since 2021, another progestin only pill containing another progestin, which is called desogestrel, is also available without a prescription through pharmacies in the United Kingdom. There is no safety signal whatsoever about the use of POP without a prescription in any of those countries.
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DEBORAH ARMSTRONG, CMTE [11:50:24]
Is there any potential issues for women who might elect to switch from a prescription combination oral contraceptive to a POP if it became available over the counter?
UNKNOWN, PERRIGO [11:50:39]
We do not see any potential issues with that. In fact, switching from a combined oral contraceptive to Opill will be very easy. You can start Opill on the very next day after you complete your– stop taking your COC.
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RUSSELL BRADFORD, PEGASUS RESEARCH [11:54:14]
In an actual use trial, these are participants responding to advertisements who are interested in the product. And so what we what we find in these studies is, typically, a proportion of low health literacy in the amount that we saw here.
You mentioned also wondering about how we assessed for low health literacy. We use the REALM, or REALM-TEEN, which is a test where participants are asked to read and pronounce 66 health related words. And their literacy assessment is based on how many of those words they pronounce correctly.
This is a test that’s widely used in Rx to OTC programs, but like every one of these rapid tests, it has– it certainly is limited and only evaluates one component of of literacy, in indeed reading and pronouncing words.
But I think the to to sort of wrap that all up, what I’d like to point out is that the proportion of low health literacy is less important, in my view, than the total number. That is the total number, the absolute size of those low literacy groups, were appropriate in order to allow us to to draw conclusions about how they perform.
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PAMELA HORN, FDA [01:04:51]
Unlike a prescription drug approval, when a drug is approved for a switch to nonprescription use, there is no mechanism for approving it with a REMS to ensure that the benefits outweigh the risks, and there is no third ‘behind the counter’ class of drugs in the U.S. like there is in other countries, including examples that were noted this morning.
Drugs in the U.S. are either non-prescription or prescription. There is also no option for approving an application with post-marketing requirements for the applicant to conduct additional studies with the goal of addressing remaining uncertainties about the safety of a drug, or to inform the need for possible label changes.
Finally, if one were to decide that substantive changes would be needed to the proposed labeling to support approval, they would need to be tested in consumer behavior studies prior to approval.
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ANANDI KOTAK, FDA [01:09:56]
Of the birth control pills, there are two main types. One contains two hormones, progestin plus estrogen, and the other type contains one hormone, progestin only.
Our discussion today focuses on one type of progestin only pill, norgestrel tablet, specifically for the indicated use of pregnancy prevention in the nonprescription setting.
In the prescription setting, progestin only pills are prescribed in a highly selective population, namely lactating females or in females who have contraindications to estrogen. And this population is generally highly motivated to use the product correctly.
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ANANDI KOTAK, FDA [01:18:47]
The applicant conducted study 151042002 to evaluate the impact of a delayed or missed pill on cervical mucus and ovarian activity. Of note, the study was conducted voluntarily without FDA feedback.
The applicant states that there were no differences observed in cervical mucus scores or ovarian activity scores after a six hour delay, or missed tablet. However, cervical mucus and ovarian activity scores are not primary measures for contraceptive efficacy, but may be supportive evidence of contraceptive effect, when considered together with the Pearl Index from phase three trials.
In addition, the study lacks generalizability, as a sample size of 50 would not adequately capture the wide variations in serum progestin levels previously mentioned, and females with BMI greater than 32 were excluded from enrollment.
In conclusion, study 002 cannot demonstrate that delayed intake of normal tablet does not alter the risk of unintended pregnancy. Changes in the characteristics of the population since the 1970s may also impact the effectiveness of neurological tablet today.
The prevalence of obesity in the United States has more than tripled since 1960. This is especially concerning given that recent approvals of hormonal contraceptives have shown that efficacy may be decreased as much as 40% in females with increasing BMI.
However, the impact of obesity on the efficacy of norgestrel tablet has not been directly studied. Available sources of data to inform effectiveness of new tablet and the non-prescription setting include the original clinical trial data, published literature and the actual use study conducted by the applicant in support of this application.
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ANANDI KOTAK, FDA [01:25:38]
In summary, the expected contraceptive efficacy of norgestrel tablet as a non-prescription product for prevention of pregnancy is unknown, for the reasons listed here. Real-World estimates of the failure rate for oral contraceptives, another way to think of the Pearl Index outside of the research environment, range from 4 to 9%, depending on the source of the data.
However, these estimates are primarily based on COCs. And recall that the Pearl Index for COCs in the 1970s was less than one. Because POPs account for 10% of oral contraceptives prescriptions in the U.S. and because the Pearl Index for POPs may be more than double that of COCs, as previously discussed, it stands to reason that the failure rate for real world effectiveness of POPs such as norgestrel may be quite a bit higher than 9%, meaning norgestrel may not be nearly as effective as we might think out in the real world.
..
ANANDI KOTAK, FDA [01:33:09]
Drug interactions with norgestrel are another important consideration for the nonprescription setting due to the potential for reduced contraceptive efficacy of norgestrel with concomitant use of an interacting drug. Many drugs and herbal products induce hepatic enzymes such as CYP3A4, increasing the metabolism of CYP3A4 substrates such as norgestrel. This in turn may decrease contraceptive efficacy of norgestrel.
Conversely, norgestrel may also decrease the efficacy of other drugs, such as the emergency contraceptive containing ulipristal acetate.
As seen here several drugs known to decrease the contraceptive efficacy of norgestrel are used to treat conditions that commonly occur in the population likely to use this product, including medications to treat seizure disorder, anxiety or muscle spasms, HIV or depression. When concomitant use of an interacting drug cannot be avoided, the prescribing information for a norgestrel tablet recommends the use of additional non-hormonal contraception, such as condoms, when initiating and throughout concomitant use of the interacting drug, as well as for 28 days after discontinuation of the interacting drug.
However, if the use of an interacting drug is expected to be chronic, use of an alternative method of contraception should be considered.
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ANANDI KOTAK, FDA [01:35:03]
Because nonprescription use of norgestrel would occur without the assistance of a learned intermediary, opportunities to address additional concerns such as use in adolescents, potential impact of projections on bone mineral density, and current use of contraception would be missed.
Adolescents are a population of special interest because comprehension of key messages may differ by age group, sexual practices may differ compared to adults, and the opportunities may be missed for interactions with and counseling by a health care provider.
However, we reiterate that prescription norgestrel tablet is approved for use in all females of reproductive potential regardless of age.
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ANANDI KOTAK, FDA [01:36:05]
The concern arises from chronic unopposed progestin use, which induces a hypo estrogenic state and may result in decreased bone mineral density in users of any age. The magnitude of this hypo estrogenic effect likely depends on progestin’s structure, dose and route of administration.
The potential for greatest impact lies in long term progestin use in individuals who have not yet attained peak bone mass, namely adolescents. Recovery of bone mineral density after discontinuation may also depend on the duration of exposure and the potency of the specific progestin.
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BARBARA COHEN, FDA [01:57:33]
Dr. Kotak also discussed a concern about drug interactions. Specifically, ask a doctor or pharmacist if you have used an emergency contraceptive in the past five days.
This was a secondary end point, but an important one, because drug interactions can negatively impact the effectiveness of either or both products have taken together.
If you look at the lower bound, this was at 78% comprehension.
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BARBARA COHEN, FDA [01:55:16]
And here are the statements on the DFL about safe use, but with comprehension scores that did not come close to meeting the 90% threshold.
Do not use if you have or ever had breast cancer. This achieved a lower bound of only 80%. Here, an examination of the verbatim showed that there was confusion with the other DFL statement about asking a doctor before use with any cancer.
And a further concern, in analyzing these results by age, we note that among adults who are, of course, the population at most risk for breast cancer, comprehension of this statement was only 75% lower bound.
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BARBARA COHEN, FDA [02:02:31]
The results show that the threshold was achieved. But again, this was in an almost total normal literacy population. The applicant reported correct deselection was 94%. But I want to point out this still does involve six participants who incorrectly stated it was okay to use.
These results also includes a seventh who said it was okay, who the applicant then subsequently agreed it was okay, but FDA did not agree on the seventh participant, and we also classified four additional participants as incorrect selectors, because they stated that they would need to ask a doctor, rather than automatically articulating that it was an absolute contraindication.
Part of the reason we’re being very conservative about this coding is because it’s because if someone needs– if someone says they would ask a doctor, it’s unclear whether they would do so before starting use of a product, particularly if this doctor is not easily accessible to them.
The FDA reported correctly deselection endpoint was 91%, which still exceeded the threshold. We conducted some further sensitivity analyses and the correct selection still approximated the threshold at 88%.
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JEENA JACOB, FDA [02:22:22]
Although the applicant did not note this in the study report at the time of the supplementary NDA submission, upon review of the submitted data, FDA queried the applicant whether there were participants reported more tablets taken than the total number of tablets dispensed.
The applicant confirmed that there were participants with reported tablets taken that was greater than the number of tablets dispensed. The applicant later reported that there were 261 participants, which comprised 30% of the user population, who reported taking more tablets than dispensed and referred to this phenomena as improbable dosing.
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JEENA JACOB, FDA [02:27:57]
The magnitude of improbable dosing in access is a limitation in the assessment of adherence endpoints, and raises concerns regarding whether the data in the actual use study can be relied upon, as other participants who were not part of the improbable dosing group may have incorrectly used or incorrectly reported use who were not identified with improper use.
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PAMELA SHAW, ORUDAC
I look at the presentations from the sponsor in the FDA, you are analyzing a different primary endpoint, in the sense that the primary endpoint for purchase for selection from the FDA is based on that question one, on slide 99, and should not include any purchase information. And as FDA mentioned, there’s very clear guidance in the 2013 guidance for nonprescription drugs, that purchase information should not be used in the selection evaluation, but that the sponsor is using purchase information to calculate a primary endpoint.
So what I see is that there are two different primary endpoints in question here. One presented by the sponsor and one presented by the FDA. And so I guess what I’m trying to understand is how this happens? To what extent was this discussed at the start of ACCESS, or before it was conducted, versus sort of after it’s conducted in all those women who dedicated their time, and this sort of data is now a question.
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BARBARA COHEN, FDA [03:06:12]
The study was a complex one, so I appreciate the opportunity to clarify it a bit more.
I’ll just start by saying that this– I mean, I personally, I’ve been at FDA since 2011. I have not ever seen a self-selection study analyzed in this way. And although we didn’t discuss it in regulatory development, because we didn’t know there was anything to discuss, per se. And when we received the application, there was not really a clear mention of this made either, that they had disagreed with the guidance, that we’re analyzing it in this way.
So, I’m just saying– the applicant is free to disagree with us, but we just didn’t know beforehand. So there was a limited opportunity for discussion about it. The discussion happened, and in the application itself, there was no mention of the magnitude of how many people this affected. So that was the other key element of this.
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JEENA JACOB, FDA [03:18:45]
One of our concerns is about the magnitude of improbable dosing in the user population. In terms of the participants that had improbable dosing, about 50% reported in excess of 29 tablets or greater, and about 10% of the population of the improbable dosing population reported in excess of 113 tablets or greater.
There were also two participants reported an excess of 500 tablets, one of which reported close to 700 tablets.
So our concern is really not only how prevalent improbable dosing was in the user population, but the magnitude.
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PAMELA HORN, FDA [03:29:23]
I think that our concern about being able to rely on the data in the study overall comes from the fact that we don’t have an understanding of why people over reported in 30% of the study population. If we felt confident we understood what happened there, I think that would perhaps change the picture for us. But we don’t have an understanding of that.
And the only– there’s potentially only a difference of whether someone over reported just less than the number that they were dispensed, or just more than they were dispensed, between the improbable dosing group and the rest of the study participants, which is– I mean, I think we could say that that’s sort of an artificial line to draw when we’re talking about trying to understand actual adherence.
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THERESA MICHELLE, FDA [03:31:55]
I think that’s a really profound kind of question to ask and one that we’ve asked ourselves quite a lot with this. And I just wanted to note that this finding of improbable dosing in this study is really quite extraordinary. This is not something we see in a typical actual use study.
And the results have to be incredibly extreme to show up in this kind of a study, because we’re really looking at a very blunt instrument for determining this finding. In order for us to pick up on the fact that consumers were reporting doses that they didn’t take, they had to way over report to the point where they were reporting dosing beyond the number of tablets that they received.
So if we got that result in 30%, that’s almost a third of the subjects in the trial, you really have to wonder about what happened with the other two thirds if they also over reported, but just not to the extent where we could pick up on it.
So that’s the question that we’re asking the advisory committee to ask themselves, which is what we’ve spent quite a lot of time asking ourselves, as we consider this.
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ERIN MURRY, FDA [03:26:20]
It’s important to note that nonprescription means something different in the U.S. than it means in most of the rest of the world, including the vast majority of the quoted over 100 countries in which women can get a routine oral contraceptive without a physician’s prescription.
In the U.S. we only have two types of drugs: prescription and non-prescription. Here, prescription means no health care professional is involved. In other countries, there’s often a third category of “pharmacists dispensed” and in that case, while the consumer might not have a physician’s prescription for the product, they still have to talk to a pharmacist, who may or may not dispense the product after talking to and often counseling the consumer.
Pharmacists are definitely highly trained health care professionals, and in the U.S. we don’t have that legal third category of drug. Here there will be no such interaction and if this product is approved, people might get it in a pharmacy, but they also might get it in a gas station or a big box store, with no health care professionals around.
Therefore, FDA can’t really rely on the experience in those other countries to truly inform what would happen in the situation of wide open and restricted access access in the U.S.
And I don’t want the advisory committee to be misled into thinking that over 100 countries have nonprescription status equivalent to what would occur in the U.S. In fact, very few countries do.
MURRAY KESSLER, PERRIGO [00:10:59]
As I mentioned earlier, the FDA advisory committee meeting begins today to discuss the potential switch of Opill. This is an important day for all women and people in the U.S. and it epitomizes our commitment to the women’s health space.
The FDA’s approval of Opill OTC would increase access to safe and effective birth control, while allowing women to take control of their contraceptive needs on their terms. While the FDA will be scrutinizing this application, there are over 35 independent organizations voicing support of Opill. In the year 2023, women should have ready access to oral contraception.
As a reminder, the FDA advisory panel vote is non-binding. We expect the agency to render a decision on approval later this year.
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QUESTION [00:43:45]
One more on this week’s ad comm on Opill. Curious, just any thoughts you could give around that on how they’re going to think about this? And then also, if it is approved, your thoughts around just the market opportunity in the U.S.? Is this going to basically add to the market or will it take some of that share? And then any color you could give on the timeline to launch and impact to the things?
MURRAY KESSLER, PERRIGO [00:44:16]
Well, now I think I read in in your note, but it is not– and I think everybody knows that in investor day, it’s not in our current modeling, it’s not in our– any of the guidance we’ve given over the next few years because it’s– you’re talking birth control and this is a big change having– so it’s only upside. And I think we’ve been giving a year one estimate of roughly 100 million in revenues.
And then by the time the FDA got into a position, I think that next 2 or 3 months for them to make a decision once they review all the data and what the advisory panel has to say about it, and you’re talking very end of the very end of the year, beginning of next year, I don’t think we have a set that date yet. It depends how the FDA, when they come to their decisions, and any implications of those.
But, like philosophically though, this is a product that has been on the market since the 1960s. There is reams and reams and reams of safety data on this. And when taken in a whole, we believe the FDA should approve this application, period. There’s lots of pushback in there, which is their job, and that’s what they’re supposed to do. And we have many experts, they’ll be testifying, and we’ll see how it comes out. Ultimately, we believe this will get approved and hopefully it gets approved this time through, but again, it’s not in our numbers this year. Next year, it’s all upside.
NIRAV SHAH, CDC [00:12:02]
Although next week marks the end of the public health emergency, it is not the end of COVID 19. COVID 19 remains a risk, and CDC remains committed to preventing severe illness and death associated with COVID 19, particularly for those who are at higher risk. This includes older Americans, people who are immune compromised, and those who are living with disabilities.
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NIRAV SHAH, CDC [00:12:30]
We have the right data for this phase of COVID 19. Though our data going forward will be different. They will continue to provide timely insights for CDC, for local health officials, as well as for the public to understand COVID 19 dynamics at the community level.
There are two important points about these metrics. First, we will continue to keep our eye on the COVID 19 ball, and we will do so through a multitude of metrics. Indeed, our epidemiological understanding of COVID 19 after the end of the public health emergency will be deeper than what we have for other viruses like RSV and influenza.
Second, the specifics of some metrics are changing, but the key insights remain intact. For example, our COVID 19 community levels rely in part on aggregate case rates and those case rates may not be reported to CDC by jurisdictions after the end of the public health emergency.
However, the replacement, based solely on hospital admission data, will be a strong indicator of COVID 19 status at the local level. CDC scientists have back tested this, and as noted in the forthcoming MMWR, since February of 2022, there has been a 99% concordance between the CCL – the community levels which are being retired – and the new hospital admission driven metrics.
In short, we will still be able to tell that it’s snowing even though we’re no longer counting every snowflake.
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NIRAV SHAH, CDC [00:14:18]
The changes that we’re discussing today are happening because the end of the public health emergency means that CDC will have less authority to collect certain types of public health data. That means less data will be available to us.
That said, we will have good sightlines into COVID 19, and that’s because at this stage there is not one single metric of the moment. Instead, we will continue to use a multitude of metrics to understand how COVID 19 is unfolding, and those exist on a continuum.
Some metrics rise earlier and are more sensitive, some rise later and are more specific. But the broad panoply of metrics that we will use will continue. That includes wastewater testing, emergency department diagnoses, laboratory testing for positivity rates, as well as hospital admission data. All told, these will continue to give us a full view in as timely manner as possible.
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BRENDAN JACKSON, CDC [00:16:31]
Hospitalizations will continue to be reported from all hospitals nationwide, though on a different cadence moving from daily to weekly. This reporting will continue to provide a detailed, stable look at trends down to the county level. Hospital admissions will serve as our primary surveillance metric for COVID 19.
Now, will hospitalizations provide the best national level view of COVID trends?
There are also metrics that provide earlier signals of change in COVID activity. First, CDC reports emergency department visits for COVID 19 on our COVID data tracker website down to the state level. This is a key early indicator of evolving trends.
Second, wastewater testing performed at hundreds of sites nationwide and covering nearly 140 million people is also a good early indicator in areas where it’s available.
Third, later this month, we’ll shift our source for test positivity data to a long standing system called the National Respiratory and Enteric Virus Surveillance System, which is based on voluntary reporting from over 450 laboratories nationwide.
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BRENDAN JACKSON, CDC [00:18:15]
Now let’s talk about case data.
As the pandemic has progressed, case data have become less reliable because of increases in home testing. As you all know, the results of which are often not reported. An increase in mild and asymptomatic infections have further decreased testing rates. Also, once the PHE expires, some jurisdictions may lose the authority to collect COVID 19 case data at all.
These factors, coupled with a shift in focus towards tracking severe COVID 19 rather than counting infections, is leading us to remove case data as a primary metric on COVID data tracker beginning May 11th.
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BRENDAN JACKSON, CDC [00:18:47]
Finally, let’s talk about two implications of these changes. One, as Dr. Shah mentioned, COVID 19 community levels or CCLs, which are used to guide individual and community actions, will be discontinued since they rely on those case data in part.
That said, this change, again is not as big a deal as it might sound, since they’ll be replaced by these hospital admission levels, which were again the main driver of the community levels. Again, with that 99% concordance since they were established between the two.
CDC will continue to use these levels to provide prevention recommendations that people, especially those at higher risk of severe COVID 19, can use to determine how best to protect themselves.
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BRENDAN JACKSON, CDC [00:19:23]
Now, the second key implication of the data changes is that COVID 19 transmission levels, which are different from the COVID community levels, these transmission levels can no longer be calculated and will also be discontinued since they’re baseline based on case and county level test positivity data.
These levels have mainly been used in health care settings to inform source control or masking, as well as to inform admission testing in nursing homes.
Because of this change, CDC is updating its infection prevention and control recommendations to make sure that health care facilities have appropriate information to inform their infection control processes. I want to reiterate that we’re still monitoring COVID 19 intensively, even as we work to integrate into the broader fight against respiratory diseases.
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NIRAV SHAH, CDC [00:25:31]
Going forward, we will continue to receive a significant amount of data around COVID hospitalizations as compared to what we were getting before.
For example, one of the categories of things that’s going away with respect to COVID hospitalizations are around suspect cases. At this juncture in the pandemic, with testing so widely available, there really isn’t a suspect case anymore.
That core data around COVID will continue to come in to CDC in a manner that it does not come in for RSV and influenza. That’s that’s one concrete example. I can tick through a couple more if you’d like, but that’s one example of how we will have better insight into the dynamics of COVID as compared to RSV and influenza.
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NIRAV SHAH, CDC [00:31:08]
To answer your question of how we will know when a situation is getting more significant in any particular jurisdiction. And I sort of think about this on a continuum of data points, but and those are the ones that we will continue to be putting on our website.
So, for example, if in a particular jurisdiction we saw an increase in wastewater in a particular area, that’s an early sentinel indicator of potential increases in things like cases. Now I’m going to dive into this for a quick second. Dr. Jackson can go deeper, but what we are not going to be receiving is aggregate case data. However, because many jurisdictions will still be reporting in, because as we noted earlier, it’s still notifiable, we will still have line level data available on our website at data.cdc.gov. So that’ll be another indicator that we could use to the extent that states are reporting it.
Then we’ll have the the constellation of laboratories from the NREVSS system that Dr. Jackson noted. This is over 400 or about 450 laboratories across the country that give us insight from a surveillance perspective of the volume of testing as well as increases in positivity.
Next, we’ve got the emergency department visit. This isn’t just people who are visiting. This is people who are going to the emergency department and getting diagnosed with COVID in the ED.
And then finally, we will have an indicator around hospitalizations, who’s getting hospitalized, whether they’re ending up in the ICU. We also couple that with the improvements in the death system, the death reporting system, which is far more timely now than it was before.
All of those factors, when taken in total, give us an insight into what’s happening at a local or jurisdictional level.
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BRENDAN JACKSON, CDC [00:38:14]
We’ve got a new metric that goes there, that is the percent of all deaths that have been reported for that week that are caused by COVID. And what this does is this gets, sort of addresses the problem of where, you know, deaths can sort of come in and get reported at slightly different times. And that addresses for that.
When you look backwards from there, you’ll still get the total number of deaths as they fill in. But definitely we’re still going to have those data. It’s just going to look a little bit different in terms of how those are displayed. And you’ll still yet be able to see the number of deaths that have been reported for the last week.
Just understanding those are still going to be incomplete for a couple of weeks while those data fill in.
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BRENDAN JACKSON, CDC [00:40:27]
The COVID Community Level, which are again, targeted at the public and individuals, those are basically going to remain largely intact, just switching to the COVID hospital admission levels. I’ll point out that right now, 99 point plus percent of the population is in a low Community Level, and that would be basically the same for these new hospital admission levels.
We understand that there’s going to be a mix of uptake in this and the uptake may be low in some areas, but we feel it’s important to put out there that when things get to a high level and when hospitalizations, if they do, we don’t know if they will in large part, but get to get to those high, was Community Levels, now the hospital admission levels, there will be a recommendation at least for people to wear masks.
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BRENDAN JACKSON, CDC [00:41:17]
At a minimum, the recommendation is for health care facilities to recommend facility wide masking when it’s recommended in the community. So following those same levels that we just discussed for the public.
There will be additional recommendations for when facilities may wish to also implement either sort of unit wide or facility wide masking recommendations based on the type of patients that they’re caring for. Are they a higher risk patient group versus a lower risk patient group? And also sort of the broader picture of what’s happening in their facility, whether they’re having a facility based outbreak?
And also this is sort of tying back to like pre-existing pre pandemic infection control guidance that has already been in place, which is if you’re seeing lots of respiratory disease in the community, whether it’s COVID or something else like flu or RSV, that might be a time to also put in place sort of masking recommendations for the facility.
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BRENDAN JACKSON, CDC [00:42:05]
In terms of the timing, I will defer to others on the exact timing of that. I don’t believe it’ll go ahead tomorrow, but it’ll be coming quite soon, within the next week.
TEDROS ADHANOM GHEBREYESUS, WHO
This virus is here to stay. It’s still killing. And it’s still changing. The risk remains of new variants emerging that cause new surges in cases and deaths.
The worst thing any country could do now is to use this news as a reason to let down its guard, to dismantle the systems it has built, or to send the message to its people that COVID 19 is nothing to worry about.
What this news means is that it’s time for countries to transition from emergency mode to managing COVID 19 alongside other infectious disease.
I emphasized that this is not a snap decision. It’s a decision that has been considered carefully for some time, planned for and met on the basis of a careful analysis of the data.
If need be, I will not hesitate to convene another emergency committee should COVID 19 once again put our world in peril.
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DIDIER HOUSSIN, EC
It is true that the virus continues to circulate in every country and that the pandemic is not over. It is true that there are many uncertainties, particularly regarding the evolution of the virus. It is true also that there are big gaps in surveillance reporting and health care, particularly in the most vulnerable countries.
However, the situation has markedly improved, with less mortality and an increased immunity against the virus, immunity which is vaccine induced or naturally induced, and better access to diagnostics, vaccines and treatment.
…
DIDIER HOUSSIN, EC
The second reason is because it is time to change the tool. The tool, which is PHEIC, is a tool offered by the IHR has played its role, which consists in placing forward an imperative – the emergency – to generate mobilization and reaction.
However, this tool should not be overused because it is not adapted to events which become subacute or chronic, which is the case presently with the COVID 19 epidemic.
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DIDIER HOUSSIN, EC
It is better now to look in the IHR toolbox for a better, more adapted instrument. This instrument and its use was suggested yesterday to the director general of WHO. It is to go for standing recommendations rather than just temporary recommendations.
Such standing recommendations will allow to better integrate risk assessment and risk management concerning COVID 19 in the broader framework of pandemic preparedness and response. It will also allow to reinforce the link between surveillance prevention and treatment of COVID 19 and the strong system established since many years about influenza viruses in animals and humans.
SD Biosensor Inc., the manufacturer of the Pilot COVID-19 At-Home Test, informed Roche that this issue was identified during routine quality assurance testing. Potentially harmful bacteria were found in the liquid buffer solution (liquid inside pouch 2 of the kits) of specific lots of Pilot COVID-19 At-Home Tests sold in the U.S. With a direct focus on patient safety, Roche, as the exclusive distributor of these test kits in the U.S. market, immediately informed all distributors and retailers who received the affected lots and asked them to quarantine those lots at the distributor level while the investigation is ongoing. Roche and SD Biosensor have worked closely with the FDA to ensure any further action required is taken as quickly as possible.
As a result of our investigation to analyze the cause of this contamination, it was confirmed that one of the raw materials of specific lots of liquid buffer solution was contaminated.
To date, no such illness has been reported and to date no impact on performance has been confirmed.
We will no longer use the raw materials of the company that caused this issue. SD Biosensor, Inc. will improve and strengthen the QC process to minimize microbial contamination in the manufacturing process when for both stocking raw materials in warehouse and releasing final products to customers. We will reduce the chance to occur the same situations for liquid buffer solution because we will do full inspection from warehousing to shipping.
We hope this statement has provided the clarity you were seeking. If you have any further questions, please do not hesitate to contact us.
Thank you for your understanding and continued support.
Kind Regards,
Evie Baik
PR Manager, SD Biosensor
PETER MARKS, FDA [00:14:12]
So as we go through this strain selection process, we will try to pick the best strain to include. That’s what will happen on June 15th based on all of the available data, whether we will have continue to have a bivalent or monovalent vaccine will be something for discussion.
But if one were to look at the data right now, one would be thinking that we may be having a monovalent XBB-type vaccine, but we’ll see where things evolve – and the next slide – so we will continue to follow these things closely.
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QUESTION [00:41:42]
Is the individual who is not over 65 but has other comorbidities or indications for risk, they aren’t immunocompromised either, but maybe they have COPD, they have a history of something that’s going to make them much more likely to be at increased morbidity and mortality. Do we have recommendations for them? If not, are we anticipating any in the future?
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PETER MARKS, FDA [00:42:25]
There’s no right answer to that question. The data– the problem is that the data suggests that it’s a very enough group– that there probably– there’s not enough waning of immunity, at least in the data that we looked at, to justify recommending another dose, at this point.
It’s true, these are individuals who may have– there’s there’s not waning immunity. If they get COVID, they might have a a a more severe outcome. And that’s, I think, the question that’s being asked here.
We did not feel that at this point we would recommend the additional dose in that population. We did feel like there was enough data in individuals 65 and up, particularly in 75 and up, for the second dose.
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PETER MARKS, FDA [00:48:01]
I can’t tell you when, but I can tell you that obviously there is there’s work for all of the EUA products, with the exception of any product that’s been withdrawn for some reason, if it’s still being used under EUA, we are trying to work those products over towards either biologics license applications for vaccines, or new drug applications for things like Paxlovid.
And that’s a matter of working with the manufacturers to get them to submit their full applications and then to get those through the review process. But I can tell you that we’re anxious to do that as well, because for some technical reasons, it will be much easier for us to when they are approved products, rather than emergency use authorized products.
So coming hopefully in the not too distant future.
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PETER MARKS, FDA [00:55:31]
Imprinting is something that we know happens. We have it happens with influenza vaccines. And we don’t get really– we don’t we don’t say, ‘oh, no, don’t go and get your seasonal influenza vaccine because of imprinting.’ It’s something that we accept.
It probably leads to some decrease in effectiveness, in some way, but not so much that it’s– it’s more something that is on a population level. On an individual level, there’s no reason not to continue to get your flu vaccine, because at the end of the day it’s highly beneficial.
And I think what we see with the COVID vaccines is that, despite people who have gotten multiple COVID 19 vaccines now of different generations, they do seem to continue to derive benefit. And so I don’t see us, at least from from what we can see, although there may be some amount of immune imprinting, and studies have shown there might be some, I don’t think that’s a reason to run from continued immunization here, because it’s the best that we have right now and the effect seems to be modest.
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TIM UYEKI, CDC [01:04:09]
There have been outbreaks, you probably have heard about an outbreak that occurred in last September and October in framed mink in Spain that attracted a lot of attention. There was probably mink to mink transmission.
But you have to understand that these are very, very congregate, highly dense cages, facilities. And if virus is infecting some of these mink, transmission from mink to mink is not surprising. And it’s likely that the source of that was the mink were fed poultry meat, and also they were open to the air, to the environment. And so there might have been wild bird exposures as well.
At any rate, there’s clearly been a wide range of mammalian species, both terrestrial and mammal species, and with H5N1. But there’s not really any evidence that there’s sustained transmission of this virus among mammals.
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TIM UYEKI, CDC [01:19:10]
I’ll just say that, some of you may or may not be aware, but the most recent case in Chile, that was the one that was negative in an upper respiratory tract specimen, but the diagnosis was made by sampling a BAL– testing a BAL specimen.
There were a few mutations that were identified in that virus, in the PB2 gene by sequencing, that was– that are associated with mammalian adaptation in animal models, including maybe enhanced replication and increased pathogenicity in inoculated mice.
I will just say that there’s no evidence of these mammalian adaptation mutations in wild birds or poultry, and so it’s likely that this represents some evolution of the virus in the infected patient. But there were no indications that this virus has developed the ability to infect the human upper respiratory tract, so it doesn’t bind to receptors in the upper human upper respiratory tract, which is our biggest concern.
If that were to happen, that would really increase the risk of transmission from birds to people and, frankly, from people to people. So we haven’t seen that yet. But what it emphasizes is the importance of really sequencing every virus that’s identified not just from people, but from birds, wild birds, from poultry, from mammals, and then infected people.
ROCHELLE WALENSKY, CDC [00:18:24]
Before I begin, I would like to take a moment to acknowledge that our CDC family suffered a tremendous loss yesterday with the death of Amy St. Pierre, who was killed in the shooting in midtown Atlanta.
Amy was a valued member of our team at the Division of Reproductive Health, where she worked every day to save lives of mothers and infants.
Our hearts are with her, her family, friends and our colleagues as they remember her and grieve this tragic loss.
In addition to the work that people like Amy do every day to fight disease and support communities, I’m here to talk about how CDC works 24/7 to protect America. And I want to thank you for this important opportunity.
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ROBERT CALIFF, FDA [00:05:07]
For example, under the CARES Act, FDA received new authority to require medical device manufacturers to submit shortage notifications during a public health emergency. FDA used this information to help mitigate approximately 350 shortages. Unfortunately, these notifications will no longer be required following the end of the current COVID 19 public health emergency.
However, we know medical device shortages occur in many situations that are unrelated to PHEs, including natural or human made disasters, recalls, geopolitical conflicts, production shutdowns and cybersecurity incidents. We also know that these shortages most often impact our most vulnerable and underserved populations, like children, rural populations and our veterans and VA hospitals.
Additionally, most drug shortages were historically due to manufacturing issues that disrupted supply, for which manufacturers of drugs and active pharmaceutical ingredients or APIs are required to notify the FDA. The agency has relied on these notifications to help prevent supply disruptions by working closely with manufacturers, expediting review and exercising temporary regulatory flexibility.
However, we’ve recently seen unprecedented demand for drugs that would benefit from similar notification. The ability to require drug manufacturers and distributors to report surges in demand to FDA could help the agency to prevent or mitigate shortages, including for some critical over-the-counter drugs like we saw in the fall.
Additionally, improvements should include reporting API sources and the extent of manufacturer reliance on certain suppliers in the drug supply chain and ensuring FDA has an opportunity to inspect certain over-the-counter drug facilities before such products are distributed.
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ROBERT CALIFF, FDA [00:35:09]
Since you mentioned the FDA specifically, let me just say FDA officials are employees are prohibited from owning any stocks in any of the relevant entities that they regulate.
And for us, that’s almost, you know, it’s 20% of the economy. So even like airlines, because they serve food and food is a big part of our equation. So I take great pride and really appreciate what you said.
What could be done to help the most is, say a few nice things about federal employees. They work hard and we can verify they work extremely hard, particularly during the pandemic. They were doing all the regular work, plus the pandemic work, at the same time.
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ROBERT CALIFF, FDA [00:55:10]
As infant formula has gotten better, I’ve gone now to almost full time drug shortages, because we have hundreds of shortages. Over 200 in the last year we preempted by working with the manufacturers, but it’s– that number is going up.
We’re keeping the actual shortages at the same level, but our employees can only plug a certain number of holes in the system, which has got real problems, particularly the generic drug pipeline. So we’ve got a lot of work to do.
We’ve asked, as I said in my opening statement for help, so we have better data so that we can get out in front of this more. There’s a lot more to it than that, and I look forward to working with you on it.
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ROBERT CALIFF, FDA [01:07:24]
We’ve had a good discussion here today about platforms and how important they’re going to be in the future, where you can mix and match and insert a new element and come up with a new therapy in a very short period of time compared to what it used to be. That’s a reality with messenger RNA, but there are many others.
So we are asking for a team of people that are dedicated to this who can be looking to the future. It’s included in some of the things already in play, but we want to do more of it so that we have these platforms ready to go. And then you can depend on the platform. You don’t have to redo all the regulatory work that you would do if you were developing a drug from scratch.
Let me also quickly mention relative to several other questions. I’m 71. I got my bivalent vaccine a few days ago, which is why I look a little tired.
SEN JOHN HICKENLOOPER [01:08:10]
I’m just kidding. (laughs)
ROBERT CALIFF, FDA [01:08:12]
I threatened to wear a sawed off t shirt as a demonstration project. I still have the Band-Aid, but my staff told me that was not allowed in a Senate hearing.
LAWRENCE TABAK, NIH [00:19:54]
There will be a chilling effect on the entire biomedical research enterprise. It’ll decrease interest in research careers. And as you well know, in times of fiscal stress, disproportionately young investigators are the ones who suffer the most. It really bodes poorly for the future of biomedical science.
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LAWRENCE TABAK, NIH [00:21:35]
So as you know, the NSABB recently provided its report to HHS, and this is informing ongoing discussions across the USG. I can’t presume what those discussions will yield, but I can speak to what NIH is doing in the meantime.
First, we are considering how best to elevate the transparency and oversight of the decision process that we use in NIH that feeds into the HHS oversight function.
We are also developing approaches to partner more effectively with our applicant organizations by developing new materials, which will clarify both institutional and NIH responsibilities, in the process.
We’re also performing a comprehensive review to our resisting recombinant DNA and synthetic molecules policies to ensure that we capture biosafety considerations related to emerging technologies like CRISPR.
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RICHARD HODES, NIA [00:27:24]
In terms of Alzheimer’s disease research. We’re clearly had a very exciting juncture, as many of you will have seen in the news, at which, to be perfectly clear, the outcome of congressional support and NIH funded research has led from translation of basic practice into clinical trials, which are now showing effects for the first time.
The necessary funds to continue research in this area are important, as we recognize that from the brains of people with Alzheimer’s, it’s really a very diverse disease. Now, no one treatment is likely to be sufficient for all and promising reflection of what we’ve been able to accomplish, for example, there are now some 59 early stage phase one and phase two clinical trials, only eight of which are targeted to amyloid. The other 51 towards other diverse targets such as inflammation, protein folding, and ultimately is going to the ability to personalize which of these is most effective for individuals.
So your question about budget and momentum reflects on the fact that if there were limited resources, we would of course do our best to ration them appropriately, but would mean a slowing of this whole very successful pipeline from basic discovery through clinical trials and research.
I’d also add that as we are seeing a time when clinical trial results are going to be translated into common practice in the communities, we are going to have to look very carefully at what happens when a treatment reaches the community. Which individuals profit most? Who is most at risk for side effects? And this is going to be monitoring these outcomes in a way that we haven’t done before.
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SEN PATTY MURRAY [00:33:36]
I am really appalled by recent reporting that an NIH funded scientist who faced institutional disciplinary action because he was found to have sexually harassed colleagues was simply able to transfer his award from one university to another research institute where he then harassed a trainee in his new lab.
And even worse, NIH awarded him a new $2.5 million grant that happened despite the fact that Congress directed NIH to make it mandatory for institutions to inform NIH when scientists or key staff are removed or otherwise disciplined due to harassment, bullying, retaliation or hostile working conditions, despite NIH posting publicly that you require notification from all of your award recipients, despite NIH knowledge of the investigation’s finding.
And I just have to say it is completely unacceptable. So I need to ask you today, what is NIH doing to fully implement the requirement under last year’s law that such actions must be reported to the agency? And how are you using that requirement to enforce workplace protections against harassment?
LAWRENCE TABAK, NIH [00:34:56]
Chair Murray, I want to assure you that we take this issue very, very seriously.
We’ve handled over 650 allegations of harassment, discrimination and hostile work environments. We have dedicated staff addressing these allegations, and about 30% of those allegations have been substantiated.
In dozens of cases, principal investigators were removed from grants. The issue that you point out this morning, the so-called pass the harasser problem, we of course are well aware of that and the specific case, unfortunately, the original institution was not completely forthcoming about the extent of the investigator’s behavior, and it was only after the individual’s grant was was allowed to transfer to the second institution that we became aware of the greater severity of what the issues were.
We are now working with the second institution to understand what the most recent allegations are. And I can assure you that if these allegations are sustained, we will take immediate action as required.
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RICHARD HODES, NIA [00:41:32]
And in terms of what this could mean to the public, we are preparing, for when final FDA approvals and CMS coverage occurs, to do what we can to to monitor, ensure that we understand in populations that are diverse, rural, urban, racial, ethnic, which are likely to differ in just which treatment at what time is best, that we have the infrastructure and the trials in place to optimize their impact on society.
This is the next stage. Having first found successful interventions, to learn from these first leads and to optimize them. So I agree with you, the impact on the broad population can be huge, and it’s our research commitment to make sure that we are prepared to assess this.
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NORA VOLKOW, NIDA [01:27:35]
I know it’s a very important problem that has grown actually very, very fast, I would say, in the past 3 or 4 years.
So the first thing that we needed to understand is why more and more of the drugs, particularly fentanyl and heroin, were sold mixed with xylazine. And what it appears to be happening is that xylazine basically expands the duration of the effects of fentanyl or heroin. So it allows the dealers to actually basically create a product that has a characteristic that may be more reinforcing and therefore greater value.
It’s become very challenging because whereas Naloxone serves to reverse an overdose from fentanyl, the response is when you combine these two drugs are not the same. So current research is ongoing to try to determine, both in animals and– in animal models and in humans what should be the optimal target to try to prevent deaths associated with a combination of fentanyl and xylazine.
They act by very different mechanisms. Fentanyl inhibit respiration and breathing so you don’t have oxygen in your blood. But xylazine also by a different mechanism that doesn’t engage at the same receptors is decreasing oxygenation. So you have, when you combine these two, two mechanisms that are deal are exacerbating the outcome, which is why in some instances that use when you use a naloxone, Narcan, to reverse the overdoses, you don’t get adequate responses.
And research is ongoing to develop therapeutics that can actually help in those overdoses.
To clarify, the FDA did not approve a New Animal Drug Application (NADA) for the genome-edited pigs you referenced. The FDA’s Center for Veterinary Medicine recently received an Investigational Food-Use Authorization (IFUA) request from a developer at Washington State University – this is a request to put a specific number of investigational animals in the food supply. After thoroughly reviewing the data and information included in the request, the FDA determined that the food from five pigs containing an intentional genomic alteration (IGA) is safe and is authorized for food use. This decision does not authorize commercialization of this line of genome-edited pigs; it covers only the specific pigs involved in ongoing researchthat will enter the food supply. IFUAs are helpful to developers because they allow animals (or their products) fit for food to enter the food supply instead of being wasted. This is the first time FDA has granted an IFUA for human food use of genome-edited livestock.
An IFUA permits edible tissues from animal species treated with investigational products like new animal drugs, food additives, and investigational genomic alterations in animals to be used for food. The FDA issues letters authorizing the food use of a specific set of animals after evaluating data to identify any potential food safety hazards and ways to avoid them to ensure the safety of the edible products (e.g., meat, milk, eggs, honey) entering the human food chain. IFUA letters are not posted publicly because they typically contain confidential information.
ROBERT CALIFF, FDA [00:10:17]
This is an interesting day for Alzheimer’s because a Lilly press release came out, and Dan, you know that I’m obligated and duty bound to say we have to wait and see what the data shows, not just a press release, but if you assume that the data and the press release, which is highly likely going to look like the data is going to look like the press release, we’ll have now a mountain of data about reduction in the rate of decline of cognitive function.
But then there’s a question of who should be treated. Is it everybody? Is it a particular subgroup based on amyloid or some other characteristic? We’re now at the phase of technology where I feel like we shouldn’t be using marketing to make those decisions. We ought to be generating evidence in the post-market phase. And that’s not primarily in FDA’s lane, but I think around the world, whether it’s CMS in the United States or tech assessment in Europe, there’s going to be a push to get much more evidence.
And we used to say, well, it’s impossible because it would be too expensive. But we got 320 million Americans with electronic health records. I think it’s pretty hard to say it’s not possible to do it.
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ROBERT CALIFF, FDA [00:50:55]
Well, to be completely transparent, we have the pandemic preparedness hearing with the Senate tomorrow. So that’s what I’m mostly thinking about. You guys are second in my thoughts right at this moment.
But in terms of your interest, I think that the this new class of Alzheimer’s drugs, again, I want to be perfectly clear, as you know, sometimes the press releases and the data, when you see the actual data turn out to be different. I don’t think that’s going to be the case here, but we’ll see.
So with that caveat, that is going to raise a huge number of questions, which I think are closely related to what you’re talking about. I mean, if I had a family history of early Alzheimer’s, and was not yet affected, I would be asking the question, you know, should I be starting this? And of course we don’t know because the trials have not asked that question.
So they’re going to be addressing, I think, some of the things that you’re raising.
And as you well know, think the obesity drugs are going to be the other area which has, the first big obesity without diabetes outcome trial is going to report out soon. And it’s going to raise a lot of the same kind of questions.
And as far as I know, the mechanisms there are very complicated. So we could say, we sort of know the systems that are involved. We don’t really know how the mechanisms play out, but it seems to be a general effect on a lot of things that are impacting chronic disease. So, it’s a fertile time to be talking about this, and I’m glad you’re doing it.
PATTIE SIMONE, CDC [01:32:14]
So first, I just want to say welcome back. We are so glad to have all of you here in person. As you may recall, the last time we were together was in 2019. This is a picture of the opening session. There were a few people there, and then we were all ready to go for 2020 when we canceled the conference pretty late in the process. As you know, we were dealing with COVID and all of the presenters were going to be deploying so that conference was canceled.
In 2021, it was the 70th anniversary of EIS and we had a virtual conference. We were really planning on having a conference in person again, but COVID threw us another curveball. We pivoted and did abbreviated conference that was fully virtual, including having remarks by Dr. Walensky, Dr. Schuchat, who I see sitting right back there, and the Langmuir presentation was by Dr. Bill Foege.
Then we did something even a little different last year. We flew in the presenters to make their presentations live in front of the cameras, but the rest of the whole conference was virtual. So this is sort of the studio setup that we had during the opening session, and we had about 900 people joining online last year.
And we are really excited to be back with all of you together in person and we’re excited to be able to offer streaming option for our sessions. You know, we all learned a lot about how to do things virtually and how to get a lot of work done virtually. And we learned that there’s some really good benefits from offering virtual options, which is that many more people can have access and participate. But we also know that there’s no substitute for in-person networking and reconnecting.
We weren’t really sure how many of you were going to show up for this conference, but we’ve really received so many positive comments about the opportunity to be together and people expressing their gratitude for this opportunity to be together. So we had over 3,000 people register, including 756 who– an additional 756 who registered on site. We had about 1,800 people pick up their badges, but we don’t really check badges. So it could be many more people here. And we think there were.
And then for the streaming sessions, we had an average of 200 to 400 people participating virtually for those sessions. So good attendance.
ROBERT CALIFF, FDA [00:23:32]
And it is fair to say that while trust has been eroding in all of our scientific enterprises, all of our institutions, it’s still the case, I think if you look carefully at the data, there’s still a lot of trust. People focus on the part of the surveys that say, do you have great trust in CDC or FDA? That’s down, definitely. But if you include sort of general trust, it’s much more on the positive side than the negative side.
But having said that, we need to be really diligent here and up our game, given the environment that we’re in, and I still think the most important aphorism with regard to this is that in order to gain trust, you have to act trustworthy. And so that means first and foremost, above all else, we need to be promulgating reliable and truthful information and also informing people about the degree of uncertainty that exists in the information that we have, which is one of the most difficult things to do.
Because think, you know, in my amateurish study of human cognition, you know, the human brain is configured to like to see things as one side or the other, not something in between. But if we fail in informing people that there is uncertainty and in fact, the whole endeavor of science is to progressively reduce uncertainty, and change the answer when you get new information, then we made a mistake.
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ROCHELLE WALENSKY, CDC [00:26:02]
So this movement of eroding vaccine confidence has taken traction over this last year, in the context of, or several years, in the context of mis-, dis-, and mal-information, as Rob outlined.
There’s a lot that we at CDC and think all of us across USG need to be doing. First, we need systems and tools in order to do the combating. As we are thinking now about the rollout of information and our confidence around this information, as Rob duly noted, much of what we’re doing is saying where are the pieces of mis- and disinformation that we need to prebunk. Not debunk in the moment, but provide the information that we think people are going to need to debunk what may be coming.
We also need coordination across all of the U.S. government and I would say across all of science that we are sending a consistent, informed message, also consistent with the information that we have, but also with the uncertainty around that information, as Rob very much highlighted.
And then we need actually the American public to engage in these conversations as well, because people don’t necessarily recognize that they’re propagating some of the mis- and disinformation. They’re unintentionally doing so, but they’re propagating it.
And then maybe something that will probably get back to is the context of trust. Who is it that this community might trust? And while we all are working, I know across CDC for all of us to promote trust, as Rob said, by acting trustworthy, we also have to recognize that people may have trust in other places, in their local fire department, in their local community based organization. And so we have a responsibility to provide the information that we have to those, as we’ve frequently said, trusted messengers so that they can be the ones to help deliver that information for us.
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LEE FLEISHER, CMS [00:34:10]
So I was here first as a career. You two came in with this administration. And I came in, and they had closed all the nursing homes to all visitors because it was the best decision at the time, with CMS and CDC working together and saying, what can we do in the height of the winter, spring of 2020.
Would we do it the same way again? To the same extent? So how do we sort of say we had to learn on the fly? Because people keep saying, you know, why did you do this? We did this for very good reasons at the time because of that uncertainty, we were trying to keep people alive.
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ROCHELLE WALENSKY, CDC [00:34:58]
I’m a decision scientist by training, and chapter two of the gold standard textbook in decision science is titled managing uncertainty. And the fact that one has to make a decision in the absence of perfect information. And what you do is you make that decision and then you update that information and then you update your decision.
However, it is the case that sometimes you have to make a decision without all the information that you would want. And I have frequently said in my academic life, and in my CDC life, that the absence of a decision is a decision into itself. And that we really we– someone had to go out on the line and say, close those nursing homes or not. And someone had to say, what are the data that we have to inform this and we will then update those data.
I do think that our memories, for probably purposes of healing, do not allow us as a public, to go back to the real fear we were feeling in February and March of 2020. The footage we were seeing, the morgues, as you noted, that were sitting outside of hospitals, our colleagues who were getting sick and in ICUs after delivering patient care, our uncertainty about what was going to happen to our elders and our family members, and the real fear that we were feeling at the time.
And so I’m not necessarily saying, given what we know now, we would have made all the same decisions. We can make better informed decisions. We have better priors now. But I think at the time, it is hard to go back to really understand what the massive amount of uncertainty we had about where we were heading, and what would happen if we didn’t take some of those dramatic actions.
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ROBERT CALIFF, FDA [00:37:42]
And so I’ve called all the experts I can find on this topic, and I think everyone agrees the best counter to misinformation is direct human interaction with someone they trust. Now, the odds that you’re going to change someone’s mind who you don’t know sitting on the airplane is low. But I still think it’s worth the effort, because it is a direct human interaction.
And here, we talked about professional responsibility, I think for the individual clinicians out there, one point I really wanted to make today is there have been several recent surveys that are abundantly clear and not surprising to us, who do people trust the most about health care? It is their individual doctor, a nurse, nurse practitioner, physician’s assistant, pharmacist, and nurse. The people that they interact with in the health care system.
And one thing I took home at Alphabet was, unless you actively are asking people about what’s influencing the decisions they’re making, they are not likely to tell you, because they don’t want to upset you. But I can tell you that people, as they’re leaving your clinic after a visit, are searching the Internet to try to understand what it was you were trying to get across to them in the 15 minutes or less that you had. And so think each of us, the most important thing to FDA I think, right now, is a network of truth tellers who are routine, every day, frontline clinicians taking care of patients, whether it be a doctor or a pharmacist. This is, I think, the most important element for us.
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ROCHELLE WALENSKY, CDC [00:43:49]
First, let me just say the importance of any action that would happen in the context of our whole vaccination program in this country. And maybe I will just highlight that, given the eroded confidence in vaccines at this moment, we are doing a real disservice to our children, who by some estimates, we have a quarter of a million kindergartners who are starting not fully vaccinated, year after year, and that that number is increasing over time, not protected from the standard things that our children get protected from. And so this moment is really critically important.
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ROCHELLE WALENSKY, CDC [00:40:11]
One other piece I think that’s really important to sort of lay in there is there’s intentional mis-, dis-, mal-information, but there’s also sort of the layer of confusion that is happening in the complexity of displaying science in a two minute soundbite on the evening news.
And there are pieces in the weeds, in so many academic meetings, there’s a pro con debate on a really interesting scientific dialogue that is happening. We do those all the time in infectious disease meetings, I imagine you do those in other meetings as well, two sides of the coin where we don’t yet have enough information in order to make a decision.
That kind of debate we we absorb and take into effect in our scientific dialogue. But that kind of debate is now happening in front of the American public, who now have to digest two very informed experts, who differ on an opinion about something where we don’t have enough scientific information.
And that does lead to confusion in the American public.
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ROBERT CALIFF, FDA [00:29:30]
I think when we’re relaying information to groups of people, what I say is common in both is there’s some things that we’re almost completely certain of. If large scale randomized trials have done, been done, showing that a vaccine reduces your risk of being dead, that’s probably, very high likelihood, very little uncertainty, in general.
There are some things we know are not true, like there are not radioactive devices and vaccines or little microchips, as people have said. So we need to be clear about those in both cases.
But then that middle ground, which is much larger than the certainty ground, I think when we talk to groups of people, we need to be hyper vigilant about expressing the uncertainty publicly, and also the quest for resolving that uncertainty through both further information and research.
With individual patients and families, I think that’s a whole different issue. Some people really want to hear about the uncertainty. Some people let you know very quickly they don’t want to hear about it. And that’s a matter of knowing your patient and knowing your family and being responsive to that.
But as public officials, I think we’ve got to really do a better job of expressing that uncertainty in that middle ground.
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ROBERT CALIFF, FDA [00:32:36]
In the chronic disease spectrum, you often you study things over years. And the standard at the FDA, for example, is bring us the data. We have that old saying, in God we trust, all others must bring data.
But when you’re in the middle of a pandemic and you have trucks parked outside of morgues because there’s not enough room. You have to make decisions in the face of great uncertainty. And, getting across that difference, I think, is important.
People would love it if you had all the data and could make an evidence based decision, but you got to go with what you have. It’s a lot like the ICU, Lee, where I know you spent a lot of tough nights with a lot of uncertainty. But if you wait until the next morning, the patient may be dead, and you need to make your best option.
ANGELA HWANG, PFIZER [01:12:26]
After April, we are we continue to have Paxlovid available, but it will be accessed through an out of pocket payment mechanism. So if you’re a private patient, you can get it. If you’re a public patient, you can get it. You just need to be able to pay out of pocket for it. And we intend to continue to work with the public and with the Chinese government to ensure its access.
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ANGELA HWANG, PFIZER [01:23:36]
We’re preparing for launch now, but as we’ve said, we’ve shared before, the date of launch and exactly how that’s going to happen is still very much subject to our discussions with the U.S. government. So we’re going to align with guidance from them in terms of how that’s going to happen.
Of course, in the meantime, we are preparing for the commercialization of Paxlovid and payer discussions around the world is critical. So those have begun.
Obviously, it’s too early for me to share the price of Paxlovid, but suffice to say that the price ranges that we have brought to our payers, together with the value arguments that we have been able to develop through robust real world evidence from the number of hospitalizations, the number of deaths that we’ve been able to avert through the treatment with Paxlovid, is very much supportive of the pricing ranges that we’re talking about.
So think very soon we’ll be able to share more.
ERIC PEVZNER, CDC [00:07:42]
I know we have a lot we want to say to each other, because it’s great to be back together. Thank you. We haven’t had an in-person EIS conference since 2019, for good reason, and we’re very happy to have all of you back together.
You know, a lot has changed because of the pandemic. But even throughout the pandemic, there were some constants. And one of them is the officers throughout EIS throughout the pandemic, continuing the great legacy of EIS of service and scientific excellence. And that didn’t change.
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ROCHELLE WALENSKY, CDC [00:13:00]
Thank you, Eric, and good morning, everyone, in person. So exciting to be here. First in person since 2019, I– a lot’s happened since then. I am so thrilled, so happy, to shake so many hands of EIS officers and laboratory leadership service, LLS, fellows, both both past and current. And let me take a moment, please, to acknowledge the contributions of our state, local tribe, and territorial, STLT staff, and those who serve as EIS supervisors, many of you are here today. Thank you for your support of EIS and LLS and our programming, which is so very critical for our success.
Please know how grateful I am to all of you for all you have done to build a healthier nation, and truly a healthier world. I’m certain you’ve taken on duties far beyond what you might have expected when you signed up for EIS and LLS. And I am grateful, and I know all of CDC, and truly all of the country is grateful.
There is no doubt that over the last three years, we have seen the ultimate test in public health for epidemiologists as well as for laboratory scientists, the pandemic and so many other public health events during the same time, placed immense demands on EIS and LLS– EIS officers and LLS fellows. And yet, truly, every time they have been asked and sometimes even before they were asked, they’ve stepped up and they have delivered solutions.
HHS launched an investigation in potential EMTALA violations by the hospitals and then issued the formal notice of deficiencies outlining steps needed to comply with the minimum EMTALA requirements. CMS requires corrections to be made in a timely fashion to participate in Medicare. These corrections need to be verified onsite by surveyors.
As of today, both hospitals have taken steps towards coming into compliance. CMS is continuing to work closely with them to ensure that they do so. For your reporting, I would not characterize the case as closed. Coming into compliance is a process but once they are in compliance as verified by CMS, then we would consider the case closed.
As mentioned, these hospitals are taking steps to come into compliance, but for your viewsers’ interest, hospitals must achieve compliance to continue participation in Medicare. Failure to comply with the requirements can be grounds for termination for participation in Medicare.
CMS would also refer them to the OIG. HHS-OIG may also exclude physicians from participation in Medicare and state health care programs and can impose civil monetary penalties (CMPs) against them. HHS-OIG may also impose CMPs against hospitals that violate EMTALA.
CMS cannot share details of an ongoing investigation. No additional enforcement measures have been announced.