Adverse Event Cases involving Drugs used to Treat Corona Virus Infections.

Background: The FDA Adverse Event Reporting System

The FDA monitors the safety of marketed medications using a database known as FAERS (FDA Adverse Event Reporting System). FAERS is huge. There are thousands of adverse event (AE) reports submitted daily, and you can kind of search the database using the FDA's public dashboard, but to perform any kind of 'sophisticated' searching, you need the raw data. 

Enter the raw data

In addition to the dashboard, the FDA also releases its newly-received AE case reports every 3 months in the form of enormous ASCII (text) files. You can find them here.

Well, the FDA just dropped its most recent text files (covering the first 3 months of 2020) on Friday, which means that those files contain the first glimpse of AE cases involving drugs that may have been used to treat the SARS‑CoV‑2 virus (colloquially known as the "corona virus").

How many AE cases were reported during the use of drugs intended to treat corona virus infections?

There are many ways of trying to mine the newly released data.

For example, we can ask "How many AE cases involved hydroxychloroquine (or chloroquine), which have been speculatively touted as viable treatments for the viral infection?" More on that later.

But in addition to telling us what drugs a patient was taking when an adverse event occurred, the FAERS case reports can also list what condition/malady a drug was used to treat. With this in mind, I searched FAERS for any cases where any drug was indicated for the treatment of "corona virus infection."

There are 61 such cases in FAERS that report a drug being used to treat "corona virus infection."

We can look at these cases by the year in which the FDA received them.

You can see the results below. Nine cases (total) were reported from the years 2015 to 2019. These nine cases almost certainly involve the treatment of some other corona virus (not SARS-CoV-2). I suppose it's possible that the cases received in 2019 involved SARS-CoV-2, but I think this is unlikely because the case reports were received from April to October of 2019, which seems a bit early for the pandemic, and they were all filed from the US.

Any of those AE Cases involving hydroxychloroquine?

Maybe a little surprisingly, only 6 of the 61 cases involve chloroquine or hydroxychloroquine (or the branded version of hydroxychloroquine known as Plaquenil). But there are a few things to keep in mind regarding "only" 6 cases (at least one of which resulted in patient death).

• First, FAERS is a voluntary database. That is, you can file a report into the system if you want to, but you're not obligated to do so, which means that the true number of cases is almost certainly much higher than what you see in FAERS.
• Second, 5 of those 6 cases came at the very end of March (March 27, 30 and 31), so we should expect to see the metaphorical avalanche of submissions when the FDA does its second-quarter data-dump three months from now.
• Third, if you simply search FAERS for adverse event cases involving hydroxychloroquine (without restricting it to cases indicated for the treatment of corona virus), you find over 6500 cases filed in the first 3 months of 2020 alone. And over 40 % of those cases indicate that hydroxychloroquine was used for an "unknown" purpose. It seems reasonable to speculate that in many of those "unknown" cases hydroxychloroquine was used to treat SARS-CoV-2.

What other drugs were we throwing at the corona virus?

We can then ask, "If we look at the other case reports, what drugs (other than hydroxychloroquine) were being used to treat 'corona virus infection'?"

The answer to this question involves four broad classes of drugs:

• Antivirals (including: ALUVIA, ARBIDOL, AVONEX, FOSCARNET, INTERFERON ALFA-2A RECOMBINANT, KALETRA, LOPINAVIR/RITONAVIR, OSELTAMIVIR, PEGASYS, PEGYLATED INTERFERON NOS, RIBAVARIN, TAMIFLU, TRUVADA)
• Antibacterials (AMOXLCILLIN/CLAVULANATE, AVELOX, AZITHROMYCIN, CEFTRIAXONE, FOSFOMYCIN, IMIPENEM, LEVOFLOXACIN, UNASYN [SULTAMICILLIN], VANCOMYCIN)
• Anti-inflammatories/other drugs used to ameliorate symptoms (CICLESONIDE, FLOLAN, METHYLPREDNISOLONE, MUCINEX DM, ORAL REHYDRATION SALTS, ROACTEMRA, THYMALFASIN)
• Other (Human Immunoglobulin (NC), QING RE QU SHI KE LI). 

Given the diverse assortment of antivirals shown above, it looks like clinicians were throwing whatever they had at their disposal at the virus with the hope that something would be effective.

Also, I have no idea what Qing Re Qu Shi Ke Li is.

What was the Age Distribution for Patients Filing Reports?

I was expecting to see cases heavily skewed toward older populations, but the distribution is more uniform than I would have expected (see pic below). Also note that 12 case reports did not specify a patient age.

Were there any serious outcomes associated with these adverse event case reports?

The short answer is "Yes." The FDA classifies all outcomes shown in the pic below as serious (including "Other"). Note that the number of cases does not add up to 61 because a patient can suffer more than one type of serious outcome.

What is the sex distribution of patients in these case reports?

It is skewed toward males by about 2:1 (see pic). This is in keeping with data indicating that men are more susceptible to SARS-CoV-2. I should also emphasize here that if we look at the FAERS database as a whole (looking at case reports for all drugs), the case reports are skewed toward women (data not shown), which makes the result shown below perhaps a little more striking. 

Who is filing these case reports?

Finally, we can also look at which countries were filing those 61 reports. The results here are simultaneously expected and yet somewhat surprising. Specifically, China reported the largest number of cases (23) with the US coming in at a distant second (12). 

On the one hand, these numbers are expected because China was at the leading edge of the pandemic and these 61 cases are an early snapshot of what was happening. On the other hand, the numbers are a little surprising because FAERS is a US database and it is typically dominated by reports filed in the US. <speculation>The fact that China has the largest number of submissions into a database in which they they normally contribute a tiny minority leads me to speculate that there are/were a whopping number of unreported drug-related adverse events involving SARS-CoV-2 treatment in China.</speculation>

FDA fixes another error with its MAUDE database

I feel like a broken record, but I am going to talk about another error in the MAUDE database.

For those playing along at home, the FDA tracks medical device malfunctions and adverse events using a database known as MAUDE. They are nice enough to make the entire database available for download. You can download the data files here. Last week, I noticed that one of the data files was missing reports from January 2018.

• I emailed them informing them of the error.
• They emailed me back explaining that everything was fine.
• I emailed them back, explaining that it wasn't.
• They emailed me back (see pic below) and fixed the issue.

I don't know how/why these errors keep cropping up, but it's the 3rd error I've found in MAUDE over the past year.

FDA Updates their MAUDE Production Database LIVE and on-the-fly

The FDA uses a data-base/search engine known as MAUDE to monitor the safety and malfunctions of FDA approved medical devices.

A few days ago, I downloaded the FDA's MAUDE "raw" data-set (located here). I do this a few times per month, and today I noticed that at least part of the data-set is corrupt. I won't go into the gory details, but some of the 2018 data seems to have been mistakenly vaporized from the current data-set.

While, I was trying to figure out what was corrupted, I ran a test search using the FDA's MAUDE search-engine (located here).

I searched for the word veritas and I got ZERO results.

Now, I KNOW there are reports in MAUDE involving the veritas collagen matrix because I've run the search before, so when I got ZERO results, I knew that not only were the "raw" data-files corrupt, but something was also corrupt with the FDA's live search-engine.

As I was writing my email to the FDA, I started to tell them that their error was NOT ONLY with the "raw" data-set, but their search-engine was corrupted, too!

Then I decided that I should take a screenshot of my search results just in case they thought I was crazy.

So, I re-ran the veritas search.

But this time, when I ran it, I got 62 RESULTS! See pic below. I started to think, "Maybe I am going crazy. Maybe I punched in the wrong search term, or maybe I selected an incorrect parameter."

But then, I ran the search again (2 minutes later), and I got 64 RESULTS!

Approximately 1 hour later, and we are up to 145 results.

So...just in case this is confusing....

• The FDA is correcting errors on its production database.
• In the middle of the day.
• On a Friday.
• And they're doing all of this while the search-engine is LIVE.
• I can tell because I'm watching it happen in real time.

To the database and software-dev people out there, that is some cowboy stuff.

FDA Repairs its MAUDE Database

I have posted several times this year about an error in the FDA MAUDE database (see here, here and here for previous posts).

To summarize, the FDA's MAUDE database captures reports of malfunctions and injuries associated with medical devices. The MAUDE database is supposed to capture patient outcome information like:

• Did the patient die during/as a result of the device malfunction?
• Was the patient hospitalized due to the malfunction?
• Was the patient disabled?
• etc.

About 2 years ago, the FDA's MAUDE database stopped reporting patient outcomes and replaced these outcomes with a cryptic code of "8.".

As you might imagine, this is a pretty serious omission. It seems kind of important to know what happened to the patients when a device malfunctions.

I contacted the FDA earlier this year and informed them of the error.

Today, I received an email indicating that the database has been fixed and the outcomes are back!

FDA was also kind enough to explain what "8." meant:

End of Story.

Update # 2 on "8." MAUDE Database

I've previously written (here and here) about an error in the FDA medical device adverse events database known as MAUDE. The error prevents the database from reporting patient outcomes (death, hospitalization, etc.).

I received correspondence from someone at the FDA last week indicating that they may have found a fix (see screenshot of email).

However, so far, they have not implemented the fix. You can see this in two ways:

First, if you download the patient outcome file from the FDA website and open it up, you see a series of "8"s where the outcome data should be (see pic).

Second, you can query the MAUDE database using the OpenFDA platform and count the distribution of patient outcomes in the year:

As of this moment, if you click on this link, you will see the distribution of patient outcomes in the MAUDE database from the beginning of 2016 until yesterday. You can see from the pic below that there are no outcomes, only variations on "8."

Update on "8." and MAUDE Patient Outcomes

I have previously posted about the FDA's adverse events database for medical devices (known as MAUDE). In past years, the MAUDE database had captured patient outcome information (whether the patient died, was hospitalized, suffered some form of disability, etc.).

The database no longer reports patient outcomes (it stopped doing so in late 2015). Instead, the database field that should contain outcome data contains the cryptic entry of "8." (the number 8 with a period). I recently contacted the FDA, asking why MAUDE no longer provided patient outcome data. I received the following responses (thus far). I've edited out identifying information (and superfluous text).

This is from an email dated 28 July 2017. It's moderately encouraging. In particular, it's encouraging to know that the patient outcome information  is _still_ captured, and it will probably be added back to the database once they determine what the error is.

I will post updates as they develop.

 Dear Dr. Danese,

Thank you for contacting the Division of Industry and Consumer Education (DICE) at FDA's Center for Devices and Radiological Health (CDRH) xxxxxxx@fda.hhs.gov e-mail account. As far as I am aware, patient outcome information is still collected on so adverse event reporting forms. So, at this time I am not clear on why this information is not included in the data sets for 2015 and beyond. I am in the process of researching the issue and contacting the medical device reporting staff. I apologize for the delay but hope to have an answer for you next week. .... Sincerely, xxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxx Division of Industry and Consumer Education Office of Communication and Education Center for Devices and Radiological Health U.S. Food and Drug Administration

I then received a follow-up email on 4 August (Friday)

Dear Dr. Danese, 

Thank you for your patience while I looked into your inquiry. I have spoken with a member of the Information Analysis Branch and it seems some of the patient outcome information may have been inadvertently excluded from the downloadable zip files. xxxxxx has kindly agreed to look into this issue to figure out what happened and how the problem may be corrected. Please feel free to contact xxxx directly. xxxxx name is xxxxxxxxxxxxxx and xxxxx email address is xxxxxxxx@fda.hhs.gov. I hope you have a pleasant weekend. Sincerely, 

xxxxxxxxxxxxxxxxxxxxxxxxxxx 

xxxxxxxxxxxxxxxxxxxxxxxxxx

Division of Industry and Consumer Education Office of Communication and Education Center for Devices and Radiological Health U.S. Food and Drug Administration

And then this email from the Information Analysis Branch (dated 7 August)

Paul, I was notified of the issue by xxxxxx on Friday, and we are currently investigating. We will get back to you when we know more. Thank you. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx Information Analysis Branch Division of Post Market Surveillance Office of Surveillance and Biometrics Center for Devices and Radiological HealthUS Food & Drug Administration 

Clustering of Drugs by Side Effect Profile

Others (here, here, here + others) have clustered medications based on side effect profiles. Everyone has done it a little differently.

In this post, I perform a similar type of clustering using slightly different methods (details forthcoming). I'm not providing m̶u̶c̶h̶ any of the methodological details in this post, but I just wanted to show a pretty plot with nice clusters.

Drugs were clustered using t-SNE (here and here), which is a method that is remarkably good at taking high-dimensional data (in this case, thousands of different side effects) and clustering it into 2-dimensions while maintaining much of the "nearest neighbor" information that was present at high dimensions.

You can see the 2-D "cluster plot" (after t-SNE transformation) below.

• Hover over the data points to see drug names.
• I colored the data points by running k-means on the 2-D data (very quick and dirty and probably not the best approach).
• Still, you can see pretty good functional clustering. For example: 
• the dark green points on the left edge of the plot are almost all related to cholesterol and lipid pharmacotherapy. If you zoom in, you will also find daptomycin (an anti-bacterial), but it clusters there b/c it is associated with reports of myopathy and rhabdomyolysis (adverse events that are somewhat characteristic of the "statins").
• red and blue points on the left edge are primarily involved w/ Type 2 diabetes.