FDA Virtual Town Hall Series - Immediately in Effect Guidanc

Moderator: Irene Aihie April 22, 2020 12:15 pm ET 
Coordinator:  Welcome and thank you for standing by. At this time all parties are in a listen-only mode until the question and answer segment of today's conference at which time you may press star 1 on your touch-tone phone to ask a question.    

I would also like to inform all parties that today's conference is being recorded. If you do have any objections, please disconnect at this time.   

I would now like to go ahead and turn today's call over to Ms. Irene Aihie. Ma'am, you may begin.   

Irene Aihie: Thank you. Hello, I am Irene Aihie of CDRH's Office of Communication and Education. Welcome to the FDA's fifth in a series of virtual town hall meetings to help answer technical questions about the development and validation of tests for SARS-CoV-2 during the public health emergency. Today, Timothy Stenzel Director of the Office of In Vitro Diagnostics and Radiological Health in the Office of Product Evaluation and Quality and Sara Brenner, Associate Director for Medical Affairs, and Chief Medical Officer for In Vitro Diagnostics in the Center for Devices and Radiological Health will provide a brief update.
Following opening remarks, we will open the lines for your questions related to today's discussion. Now, I give you Timothy.   

Timothy Stenzel:  Thank you and thank you to all who have joined us on this call today. Thank you so much for what you are doing every day to help in this pandemic situation. We are working hard and we are working together to solve the issues on a day-to-day basis and we welcome your collaboration and your participation in this process.    

I'll make some brief introductory remarks -- mainly some updates. I'll turn it over to Sara for her to make some updates. And then we'll turn it over to question and answers. Look forward to that.    

So again just briefly I have stated previously on some calls that the Abbott ID Now has now been updated to remove VTM as a sample type. I think we're trying to get the instructions for use update onto our website soon. Again, VTM as a sample type should no longer be used with the Abbott ID Now. Rather, the direct swab approach is one that should be followed.    

Second, we've made a number of updates to our frequently asked question page. I would encourage you to review those on a regular basis and go if you haven't gone in the last week to go and take a good look at it. Some of the key updates that we made are that we have increased the number of the optional extraction chemistries, we've added the Kingfisher along with the RUO equivalent of the Kingfisher, the MagMAX. And those I believe are available through Thermofisher.

We continue to look at all available options. We are data-driven and databased in these decisions and we'll update our FAQ page as soon as we can when we have additional options. We know that it can give you the at least spot shortages on swabs, media, and on extraction reagents. So we continue to work hard to provide the maximum flexibility from a regulatory perspective so that labs and developers can have options.    

In regards to that, I did want to briefly remind everyone of some of the details of our March 16th updated guidance for labs who want to make certain modifications such as a change in swab media, extraction reagents, and PCR instruments. I simply do an (unintelligible) other bridging study that's appropriate under their own CLIA SOPs and compliant with CLIA. They can implement those changes without a EUA update. And we would love to see that on a voluntary basis so that we can perhaps make it more well-known. If you are adopting any swab, for a new manufacturer say, we would love to see that information but it's not required.   

For IVD manufacturers, they can also make updates to their EUA authorization. Once they have submitted that validation to the FDA, they are immediately allowed to market that update under EUA while the FDA reviews that data and can make an assessment. We will obviously make a quick assessment of whether there are any risks and if there are, we would immediately reach out to the manufacturer. But we assume that those are validated properly. And as soon as we can review that package obviously we'll make an amendment authorization. And that's what we did yesterday for the Abbott ID Now example.    

Let's see. One other major update is we did authorize the first home collection under this current emergency declaration. That was many of you may know it was a home collection kit for the LabCorp (LDT). That is a narrow authorization only for LabCorp. They did extensive testing showing that this was going to be safe and accurate. We also because of the particular swap type they use - it's a Q-tip style cotton swab - that we asked them to do a fairly extensive quality control testing of each lot of kits.
So while the cotton Q-tip style swab is now authorized for one entity, we would urge anyone who wants to consider a Q-tip style cotton swab that they carefully look at whether that affects their testing performance at all. Does it impact the sensitivity near (LOD)? Does it impact the sensitivity? And that is perhaps not an ideal swap type to use but obviously we felt under the conditions of authorization for LabCorp that we're appropriately protecting patients and ensuring accurate testing.    

So if any developers have any questions about that, we are happy to address that at CDRH-EUA-Teamplates@fda.hhs.gov. If you voluntarily want to show us any of your validation around these alternate cotton swab types, we would be happy to engage in a conversation with you. I would still remind all that home collection and/or home testing requires an FDA authorization before launching the EUA authorization. And this is to ensure that patients in the home, that safety is considered and that testing is accurate.    

We are in conversations with a number of such developers. We see that this is a great advantage for a number of reasons. One of them is that patients perhaps can be assessed at a distance, thereby reducing the risk to health care providers who otherwise would be performing potentially invasive sampling specimen collection procedures that would potentially put them at risk of acquiring SARS-CoV-2. So there are a number of reasons in addition to that but that is one of the prime drivers here is to do our best to protect our health care workers who are out there every day being heroes. So thanks for that.

Let's see. Anything else in those general updates? We are continuing to take a look at saliva as a sample type. We believe that a preservative may be necessary that preserve the integrity of the RNA. It may destroy RNases. Some of the preservatives that are capable of doing that are potentially toxic, so that is an important consideration in addition to the accuracy. And we would ask that developers who are considering saliva as a sample type, that they come in and to discuss those opportunities with the FDA. And that we together can assess the accuracy and the safety of such a sample type.    

Some of the data we have seen today has been variable and we have not been able to authorize based on existing data. And we are still trying to assess what the variables are around an adequate saliva sample that ensures accurate and safe testing.    

Moving on, serology -- so to date we have authorized four serology tests. None of them yet are point of care even though some of them are designed to be performed in the near-patient point of care setting. And this is because data has not yet been submitted for anything that we could authorize yet that shows accurate testing in the lay user hands. That is usually the point of care patient setting.    

These lay user studies are important as outside of trained laboratory professionals performing testing, we want to ensure that accurate test results are obtained.   

I want to give an update on our interagency testing that's going on. It's a voluntary testing program. We have received the number of kits from a number of different manufacturers. Testing has begun. We will make results known as soon as we find a way to do that. I would just say that some of this information is proprietary.
We are looking at ways to make that information known. We will in all likelihood offer those manufacturers who pass a certain bar of performance in this interagency testing a somewhat streamlined approach to EUA authorization. And that is one clear way that we can make the testing performance measured by this interagency team available to the public.    

This interagency collaboration involves careful and great collaboration with entities such as the CDC, NCI, NIH, and (BARDA) and the FDA. So we thank our interagency partners for coming together in this awesome way to be able to assess the performance capabilities -- at least at certain levels -- on these voluntary manufacturers to come in.    

We are also connected to other international efforts to assess performance across not just serology tests but other tests as well.    

I would say that if we come into information that indicates that certain tests are not performing as expected and potentially are putting accurate results at risk or safety at risk, we will investigate all of those. And those include complaints. And we will address them accordingly to protect patients.    

I would also say that we are nearly completed with a serology template that can be made public on our website. And look for those on our website to be made available as soon as we clear those with all appropriate parties internally.    

Next, I would like to address a scientific issue related to serology testing. This may be known by most parties but I think it's important to review. When we talk about test performance at the FDA, we are not talking about the step by step procedure that a laboratory person or a point of care person would do in order to obtain a result. When we talk about performance, we talk about what is the sensitivity of the assay, what is the specificity of the assay. And at times, depending on what the comparative is, we call sensitivity percent positive agreement and sometimes they call a specificity negative percent agreement.
Those are just an initial look at what performance is. It's also important -- and I believe especially for serology tests -- to understand what the prevalence of disease is as far as the impact on the actual clinical testing performance and what the clinical testing results mean. We look at things such as positive predictive value and negative predictive value to tell us in certain populations what is the impact of testing and in fact what is the impact of actual sensitivity and specificity.    When we measure sensitivity and specificity, we do require calculations of the 95% confidence interval. And we do look closely at the lower bound of the 95% confidence interval because for any given sample size involved in testing, the smaller the sample size the greater potentially the spread of the 95% confidence interval.    So for example, you may actually measure a fairly high specificity but if the sample size is low, the lower bound of the 95% confidence interval can be quite low. That is why we always favor larger studies over smaller studies. Some of the high volume, high-throughput serology central lab tests that we've seen the data on -- one of which we've already authorized -- tests more than a thousand patients for specificity determination. Obviously when you test that many patients, your 95% confidence interval is going to be even more narrow.  

However, even though it's narrower, the lower end of the 95th percentile confidence interval is important for looking at the full range of possible results. And I would say that you know, some of the specificities are quite high, you know, in the mid-99 percentile-- so 99.5, 99.6 -- in the lower bound is around 99%.    

If you look at positive predictive value in a population that has a prevalence of 1% we don't yet know what the actual prevalence of COVID-19 is across all of our communities in the United States and as an overall measure. Those efforts are underway and those efforts are very important for us to understand how to apply a given test sensitivity and specificity to your specific situation.    But I just wanted to give a couple of performance numbers so that you understand the impact of prevalence and specificity on actual positive predictive values. Positive predictive value is a measure of how many times out of a hundred is a positive result, a true positive. So if you take a test that is 99% specific -- and I'm using the lower end of the 95% confidence interval here -- and you measure it in a population that has a 1% prevalence of disease, your positive predictive value is 49%. That means only 49 times out of 100 is that positive result a true positive. The rest of the time it is a false-positive result. You might falsely assume a patient developed an immune response to SARS-CoV-2.    

If you reduce the specificity of 95% -- that same prevalence of 1% -- the positive predictive value falls to 15.4%. Only 15 times out of 100 is that positive result a true positive.    

One thing that we're examining is if you combine two serology tests back-toback and you require a positive for both serology tests, how does that impact the positive predictive value. If you take two highly specific tests and that same lower and bound of the confidence interval is 99% and you have the same 1% population, the positive predictive value rises to 98.9% -- a pretty decent number.
Even if you start out with the lower serology test that has a specificity of 95% but follow it up with a more specific test such as 99% specific in a 1% prevalent population, your positive predictive value rises to 94.5%. So just under 95% -- also a fairly decent number.    

So I thought it was important to go over their performance characteristics of tests and how they're applied to populations and what a positive result can really mean and perhaps the importance of doing a confirmation serology test if the information from a serology test is important to you.    

I want to just move on quickly to one other thing and that is they continue to hear complaints about inappropriate marketing or perhaps fraud. We do have a fraud email. We appreciate all submissions to that email.    

And also I would also remind you that we have an active MedWatch going. You can go to the MedWatch FDA site and report any problems you see. We do review those complaints and those data and make appropriate decisions based on it.    

With that Sara, I want to turn it over to you briefly before we go into questions and answers. Thank you.   

Sara Brenner:  Great. Thank you, Tim. I'll give a brief update on the topic of laboratory data harmonization. In this context, it's sometimes an overlooked but really essential aspect of understanding how many infections we have in the country at any given time. The detection of the emergence, prevalence, and spread of infectious diseases is essential to inform efforts to protect and preserve public health from the local, state, and national levels.
So currently surveillance efforts are hindered due to inabilities to pool and compare data derived from laboratory diagnost