Coronavirus (COVID-19)

[mission27]

37 minutes ago, ramssuperbowl99 said:

We already have doctors effectively live-tweeting off label treatments. The problem is separating what works from the noise.

My question isn't random doctors giving anecdotal feedback on treatment X, my question is at what point do folks conducting a large scale study start to see meaningful evidence one way or another that might be valuable to treating people in this wave of cases

[ramssuperbowl99]

Just now, mission27 said:

My question isn't random doctors giving anecdotal feedback on treatment X, my question is at what point do folks conducting a large scale study start to see meaningful evidence one way or another that might be valuable to treating people in this wave of cases

That's going to require the peer review steps that take time, so I think you're going to end up with a timeline that takes months. It's tough to know how many. LIS earlier, this is pretty unprecedented, and people are taking unprecedented steps to try and expedite things.

[mission27]

Just now, ramssuperbowl99 said:

That's going to require the peer review steps that take time, so I think you're going to end up with a timeline that takes months. It's tough to know how many. LIS earlier, this is pretty unprecedented, and people are taking unprecedented steps to try and expedite things.

Of course, but if you're a doctor, wouldn't you want to see the research and react to the research before its gone through the full peer review process because you are likely prescribing stuff off label anyway and early results from a large scale study are more meaningful than prescribing whatever drugs someone on CNN or twitter said worked on a couple patients?  If you have 3 or 4 drugs you could prescribe to your sickest patients that information is probably better than nothing, right?  That's my question. 

I would think there would be value for the off label drugs in getting results out to the medical community real time to allow doctors to make the most informed decisions possible given we are very much in a throwing darts situation rn with no known effective treatments and the doctors are inevitably and rightly going to try stuff anyway.  Totally understand why there is usually a high degree of conservatism but like you say this is a completely unprecedented situation where many of the usual rules don't / can't apply. 

[ramssuperbowl99]

2 minutes ago, mission27 said:

Of course, but if you're a doctor, wouldn't you want to see the research and react to the research before its gone through the full peer review process because you are likely prescribing stuff off label anyway and early results from a large scale study are more meaningful than prescribing whatever drugs someone on CNN or twitter said worked on a couple patients?  If you have 3 or 4 drugs you could prescribe to your sickest patients that information is probably better than nothing, right?  That's my question. 

I would think there would be value for the off label drugs in getting results out to the medical community real time to allow doctors to make the most informed decisions possible given we are very much in a throwing darts situation rn with no known effective treatments and the doctors are inevitably and rightly going to try stuff anyway.  Totally understand why there is usually a high degree of conservatism but like you say this is a completely unprecedented situation where many of the usual rules don't / can't apply. 

I would guess that the CDC is trying to collect as much of that data as it possibly can, and if it starts to find trends, it's going to release guidance ASAP. There's been a push in recent years to conduct more virtual clinical trials using this type of data, but today I don't really know of any mechanism that gets you the Goldilocks zone of "probably statistically significant results" without all of the additional steps that science takes. Maybe it exists somewhere. 

(In clinical trials, this small scale proof of concept approach does exist. But clinical trials take months.)

[Shanedorf]

The clinicians and patients typically don't know who is getting the drug because of the placebo effect.
Just getting seen by an MD will lead people to say: "Yeah, I DO feel better"
That's why the gold standard is a double blind, placebo controlled trial to weed out all the noise.

For each trial, there is an independent review board and they are unblinded so they know who got drug - and they will look at the results of the study in an ongoing basis and they can stop the trial at any time because:
A) It works really well and there's little sense in continuing. 
B) Its not doing anything and we stop it for futility. Those are the easy ones.

The harder ones (and most drugs fall into this category) are we are seeing some positives and some negatives and we need to dive deep into the data to see what's real and what isn't. That's where the stats people get involved and tell us if what we're seeing is meaningful or not

They may also say that only the high dose group is responding, so let's stop the low dose arm and focus on the higher doses.
The pharmacokinetics ( what your body does to the drug) and the pharmacodynamics ( what the drug does to your body) are critical and that's where smart people like ramssuperbowl99 play a role in figuring the right dose for the right patients.

What works for me is different than what works for you and you want to give enough to treat, but not too much so the side effects become a problem
 

[ramssuperbowl99]

6 minutes ago, Shanedorf said:

The clinicians and patients typically don't know who is getting the drug because of the placebo effect.
Just getting seen by an MD will lead people to say: "Yeah, I DO feel better"
That's why the gold standard is a double blind, placebo controlled trial to weed out all the noise.

For each trial, there is an independent review board and they are unblinded so they know who got drug - and they will look at the results of the study in an ongoing basis and they can stop the trial at any time because:
A) It works really well and there's little sense in continuing. 
B) Its not doing anything and we stop it for futility. Those are the easy ones.

The harder ones (and most drugs fall into this category) are we are seeing some positives and some negatives and we need to dive deep into the data to see what's real and what isn't. That's where the stats people get involved and tell us if what we're seeing is meaningful or not

They may also say that only the high dose group is responding, so let's stop the low dose arm and focus on the higher doses.
The pharmacokinetics ( what your body does to the drug) and the pharmacodynamics ( what the drug does to your body) are critical and that's where smart people like ramssuperbowl99 play a role in figuring the right dose for the right patients.

What works for me is different than what works for you and you want to give enough to treat, but not too much so the side effects become a problem
 

We aren't ever going to get a controlled study here, but we'll get to the same answer using the current standard of care as the control. And given that >95% of people are going to get better on their own, I think option A is a pipe dream unless you end up with a study big enough that it's going to take a while to collect and process the data anyway.

In this case, I don't really think the PK/PD matters a whole lot unless we run into off target toxicity. No real sense in being coy here. Give people as much as they can tolerate for as long as they can tolerate it, don't kill anybody with it, and then hope it nukes the virus from orbit. 

[mission27]

8 minutes ago, ramssuperbowl99 said:

We aren't ever going to get a controlled study here, but we'll get to the same answer using the current standard of care as the control. And given that >95% of people are going to get better on their own, I think option A is a pipe dream unless you end up with a study big enough that it's going to take a while to collect and process the data anyway.

But doesn't the fact that there are so many trials going on simultaneously for the same drugs to treat the same condition, and the uniquely high degree of transparency and cooperation, get you to this point a lot more quickly because you can aggregate data from a bunch of different trials?  

I.e. any one study may not quickly show results that are statistically significant, but to your point, the WHO / CDC / Gates Foundation / whoever are getting all this information real time and should be able to see trends across a large number of studies of the handful of most promising drugs, more quickly than any individual study would reach a level of statistical relevance 

Also, while I agree >95% of people get better on their own (personally I think greater than 99.5% of people tbh) the CFR of patients in hospitals who would be likely to get these drugs is probably much higher than the general population and there are other ways to test efficacy than just a binary 'did they get better,' specifically how quickly did various symptoms go away and how quickly did they test negative?  That was really the basis of the admittedly small and anecdotal study in France of the drug we wont name that got everyone excited.  I would imagine if you have a highly effective drug you probably see some difference in recovery rates over N days that could be statistically meaningful in a study or across studies, even if the CFRs are high for both the 'control' group of people getting standard treatment and the group getting therapies being studied

[Shanedorf]

 

4 minutes ago, ramssuperbowl99 said:

In this case, I don't really think the PK/PD matters a whole lot unless we run into off target toxicity.

Agreed and it depends on which drug we're talking about. On the physician side, remember the oath: "first, do no harm"

Hydroxychloroquine is an example of off target issues, there are small COVID 19 studies and anecdotal reports and MDs can prescribe it off label.
But that drug was known to have cardiotoxicity issues and when they started using it off label, 30% of the patients showed QT prolongation which is a fancy way of saying it messes with your heartbeat.

For compromised patients, this is a significant concern -  especially if they are on a vent already. They aren't getting enough O2 and now their heart isn't beating right and that impacts the blood flow and you are potentially making the situation worse instead of better. This is such a brutal situation
Can we dose that drug at a level that slows the virus without messing with your heart ? TBD

The MDs license and livelihood is on the line, so they have to weigh risk/reward in each case all while under immense and unrelenting stress.
My heart goes out to them

Just try it, what's the worst thing that could happen ?
The worst thing would be dying from a heart problem when you may have recovered from the lung problem . Rock/hard place

The risk/reward equation for Ivermectin "appears"  better...and there are others moving forward as well.
There is hope and the number of people working on it 24/7 is absolutely amazing, its the Manhattan Project for our generation

[ramssuperbowl99]

5 minutes ago, mission27 said:

But doesn't the fact that there are so many trials going on simultaneously for the same drugs to treat the same condition, and the uniquely high degree of transparency and cooperation, get you to this point a lot more quickly because you can aggregate data from a bunch of different trials?  

I.e. any one study may not quickly show results that are statistically significant, but to your point, the WHO / CDC / Gates Foundation / whoever are getting all this information real time and should be able to see trends across a large number of studies of the handful of most promising drugs, more quickly than any individual study would reach a level of statistical relevance 

Again, I'm just guessing, but that type of data aggregation is something I'd imagine would come from the WHO/CDC in consultation with the FDA/OECD/MHRA etc. etc.

7 minutes ago, mission27 said:

Also, while I agree >95% of people get better on their own (personally I think greater than 99.5% of people tbh) the CFR of patients in hospitals who would be likely to get these drugs is probably much higher than the general population and there are other ways to test efficacy than just a binary 'did they get better,' specifically how quickly did various symptoms go away and how quickly did they test negative?  That was really the basis of the admittedly small and anecdotal study in France of the drug we wont name that got everyone excited.  I would imagine if you have a highly effective drug you probably see some difference in recovery rates over N days that could be statistically meaningful in a study or across studies, even if the CFRs are high for both the 'control' group of people getting standard treatment and the group getting therapies being studied

So what you're talking about is called a biomarker - basically a secondary parameter that we can use in place of "did you die or not". The problem with biomarkers is that you have to find them and you have to prove they are predictive, so you have another few doors to knock down before that's an option.

Some of the biomarkers might be obvious. The % O2 the patient needs would be an example, I don't have proof that'd be a good biomarker, but it's a pretty short putt. The problem is that physiological biomarkers like lung capacity, blood pressure, or as @Shanedorf noted QT prolongation are noisy as hell and the additional variability means you need more subjects, which means it takes longer.

[mission27]

3 minutes ago, ramssuperbowl99 said:

Again, I'm just guessing, but that type of data aggregation is something I'd imagine would come from the WHO/CDC in consultation with the FDA/OECD/MHRA etc. etc.

To the extent those guys have too much on their plate the MoL would be happy to step in, right @TLO?

I'm confident our spreadsheets are just as good if not better than whatever models the WHO can cook up, tbhwy

[TVScout]

2 hours ago, ramssuperbowl99 said:

biomarker

Viral load from daily or hourly testing?

[ramssuperbowl99]

1 minute ago, TVScout said:

Viral load from daily or hourly testing?

Maybe, but if this crap is sticking deep in the lung tissue sampling is going to be a huge pain in the ***. You'd have to assume the bloodstream would be a solid proxy.

[TVScout]

1 hour ago, ramssuperbowl99 said:

deep in the lung tissue

It is also in the nose and throat.

[ramssuperbowl99]

Just now, TVScout said:

It is also in the nose and throat.

I understand, but what we are seeing in the deep tissue in the lungs may or may not be strongly correlated with viral concentrations elsewhere. If that correlation is weak, it won't work well as a biomarker.

[dtait93]

Did somebody say biomarker? https://id2020.org/

What is ID2020?

"With the opportunity for immunization to serve as a platform for digital identity, the program harnesses existing birth registration and vaccination operations to provide newborns with a portable and persistent biometrically-linked digital identity. The program will also explore and assess several leading infant biometric technologies to offer a persistent digital identity from birth, unlocking a potential global public good." https://www.pymnts.com/news/biometrics/2019/id2020-alliance-unveils-digital-id-program/

Not hard to see how this would extend past newborns with the demand for a vaccine for immunization (as stated above) for the pandemic we face now. When this is implemented it will be known and tracked who has the vaccine and who does not.

Some of the major ID2020 Alliance partners include - Accenture, Gavi the Vaccine Alliance, The Rockerfeller Foundation, Microsoft, and IDEO.org. This is no small thing.