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spartansaver

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I agree I think alot of people think we need to get cases to zero before we open the economy again.  That wasn't the point of this lockdown.  It was to limit the deaths (but not prevent it entirely) by not overwhelming hospitals. 

 

In terms of mask, Dr Fauci originally stated masks weren't required but I believe he came around to suggesting it as an effective way of preventing transmission.  Originally I think the shortage of supplies for front line workers was the agenda behind the message of the masks effectiveness.  That may still be the case which is why they suggest most to wear scarfs, or some form of clothing around your mouth area instead of directly suggesting masks for the general public.

 

Flatening the curve was goal to not overwhelm our health system and as long as country can operate without causing health crisis, opening should proceed with tons of centralized testing. Without centralized testing , we may be flying blind when some region gets a spike.

 

I think that this is an extremely good point that has gotten lost over the past month or two. The goal is to avoid overwhelming the healthcare system, not to eliminate every potential death from the virus by remaining shut for a year. (Based on Canadian polling, it's pretty clear that Canadians in aggregate don't get it.)

 

On the "how to reopen" list, it shocks me that they aren't bothering to require masks, since it seems to be a cheap and easy solution to reduce transmission (and deaths and medical costs). I wonder if there was some reasoning behind that, or if they were just writing down stuff on autopilot, and not really thinking. If they decided not to include it for cultural reasons, that puts the US at a competitive disadvantage relative to other countries that are more open-minded about such things.

 

When you ‘mismanage’ the virus outbreak you have to resort to lock down. (And by mismanage i mean not being able to control the virus.) We all know that lock down exacts an enormous toll on the economy.

 

While in lock downs governments have a small window of time to pull together experts and implement a very detailed national strategic plan to combat the virus. This involves switching from playing defense to playing offense. The playbook is pretty straight forward: massive focussed and prioritized testing, quick results (within 24 hours), massive group of people to contact trace. How effective governments are with this stage will determine how quickly they can unlock the economy. And also, more importantly, how long the economy will remain unlocked.

 

If you have no detailed national plan for phase 2 (reopening of the economy) you are likely screwed. As you try an reopen the economy all that will happen is the virus will win again. It will start to silently spread. Clusters will form and governments will need to resort to lock down again.

 

We will find in the coming months which governments are up to the challenge.

 

This is NOT a debate about ‘health’ OR ‘economy’. This is a debate about leaders who are effective and leaders who are ineffective.

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https://www.statnews.com/2020/04/16/early-peek-at-data-on-gilead-coronavirus-drug-suggests-patients-are-responding-to-treatment/

The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir.

“The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.

The lack of a control arm in the study could make interpreting the results more challenging.

Looks promising. No control arm in the study is a caveat.

Market seems to absolutely love this. GILD up 15% in after hours, SPY up 3.5%. Wow.

isn't a control group re a life threatening disease (at least with respect to this severely ill cohort) an ethical issue?

You keep asking fascinating questions.  :)

I guess it has to do with how to collectively define rules to deal with uncertainty.

 

Let's say an institution has to decide who they choose in the future in order to invest an endowment. Cherzeca the great and cigarbutt the moron agree that the winner will be the one who has the greatest risk-adjusted return over ten years. After two years, cherzeca leads by 3% per year and declares victory. Is that OK?

 

New drugs need to go through investigational trials before adoption. Bringing trials to an end is controversial but there are rules. 1-The safety criteria: If investigators 'see' an unusual degree of significant and more or less unexpected side effects, under the first do no harm principle, the trial needs to be stopped and published. This happened not long ago with hydroxychloroquine (QT lengthening stuff and arrhythmias). 2-The futility criteria: If it becomes clear that results will be inconclusive, stop and publish. 3-The benefit criteria: This is a tough one. If results are clearly better, trial is stopped so that all can benefit.

 

The problem is defining "clearly better." Having a stock move up 15% after hours constitutes a significant incentive for positive results. The investigators need to pre-defined rules, rules have to reach statistical and clinical significance and need to meet peer recognition.

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Guest cherzeca

@cigar

 

a lot of control groups are given placebos...meaning they are given something which purports to be a therapeutic but really isn't...hence the ethical issue for severely ill cohorts where you are in effect practicing deception...arguably good for science but not for the control group cohort

 

so I just think the lack of a control group in this GILD anti-viral example is a feature and not a bug

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And now we begin to see what the nationally coordinated plan is for the US for phase 2. After all this is a war (according to the President). The US is at the beginning of what is expected to be the worst recession since the Great Depression. This is a chance for Trump to show what he is made of and that he is up to the challenge.

 

As testing outcry mounts, Trump cedes to states in announcing guidelines for slow reopening

- https://www.washingtonpost.com/politics/as-testing-outcry-mounts-trump-cedes-to-states-in-announcing-guidelines-for-slow-reopening/2020/04/16/202ec300-7ffa-11ea-8013-1b6da0e4a2b7_story.html

 

Trump’s the-buck-stops-with-the-states posture is largely designed to shield himself from blame should there be new outbreaks after states reopen or for other problems, according to several current and former senior administration officials involved in the response who spoke on the condition of anonymity to discuss internal deliberations.

 

Governors have said one of the most important factors in making those determinations is testing data, but Trump’s plan does not contain a national testing strategy. Senior administration officials said that although the federal government will try to facilitate access to tests, states and localities will be responsible for developing and administering their own testing programs.

 

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Tim Duy’s Fed Watch: https://blogs.uoregon.edu/timduyfedwatch/2020/04/16/its-ugly-out-there/

- https://blogs.uoregon.edu/timduyfedwatch/2020/04/16/its-ugly-out-there/

 

... Still, on the theme of pragmatism, don’t dismiss the importance of that first pop of activity. It marks a turning point, a place to begin rebuilding the economy. The level won’t be where we want it to be and we will need to maintain pressure for ongoing policy support to foster the economy, but the economy will be moving in the right direction. Don’t become too enamored with either the pessimists or the optimists; the reality will fall somewhere in-between.

 

Bottom Line: Controlling Covid-19 requires drastically constricting economic activity; the proof that the plan is working is that the data collapses and we bend the infection curve. The former has definitely happened and it looks like the latter will as well – social distancing works. We still have a long way to go until we return to some semblance of normality, but expect people to begin working in that direction when the restrictions on activity ease. Most important now is to keep the pressure up on Congress to provide sustained support for the economy; that support should be open-ended, based on economic conditions not time or dollars.

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@cigar

a lot of control groups are given placebos...meaning they are given something which purports to be a therapeutic but really isn't...hence the ethical issue for severely ill cohorts where you are in effect practicing deception...arguably good for science but not for the control group cohort

so I just think the lack of a control group in this GILD anti-viral example is a feature and not a bug

When does speculation become investment?

When do you decide that conviction is sufficient to put 10% of your net worth in a specific investment?

---)You need to define a threshold.

I fully realize that comparing an investment decision to a life or death situation is different but you (we) need a framework.

 

It has been suggested (from various observational and rational reasons) that remdesivir could result in better outcomes than doing nothing for CV. We don't know the answer to this question. In order to answer that question, trials that involve randomized blind trials with control groups will be essential unless several trials done in different centers with different patients clearly show an advantage (pre-defined targets). When patients are recruited for the studies now, they have a choice to accept (and potentially get drugs that are potentially useful {or not and with negative side effects}) or not. Given the difficult situation, patients may get access to remdesivir through a company-sponsored expanded access program or through a compassionate program. The results do look promising and that should speed up the process.

The approach is obviously not perfect but has provided the shoulders on which future generations could see. How could you know if you don't know?

The pharma cemetery is full of ideas that looked good at some point.

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@cigar

 

a lot of control groups are given placebos...meaning they are given something which purports to be a therapeutic but really isn't...hence the ethical issue for severely ill cohorts where you are in effect practicing deception...arguably good for science but not for the control group cohort

 

so I just think the lack of a control group in this GILD anti-viral example is a feature and not a bug

 

Cherzeca, its an important question, but this already happens with other life threatening illnesses. I don't think its unethical to give a placebo if you *don't know* that the drug works. If it doesn't work then both people getting the drug and getting the placebo are going to have statistically similar outcomes. Thats the point of the trial: to see *if it works*. It would be unethical to charge for a drug which doesn't work, or has bad side-effects/interactions. Thats what doctors did for centuries, and it has only recently improved. Lets keep the improvement. Empirical evidence is very important, probably more than theory, as proved by the story of the doctor who advocated hand washing and ended up in a mental asylum since no one would believe him. https://www.npr.org/sections/health-shots/2015/01/12/375663920/the-doctor-who-championed-hand-washing-and-saved-women-s-lives

 

Other have considered the ethics, and the current scenario is the first place where they say a placebo trial is justified.

From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844122/

 

Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study;

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@cigar

 

a lot of control groups are given placebos...meaning they are given something which purports to be a therapeutic but really isn't...hence the ethical issue for severely ill cohorts where you are in effect practicing deception...arguably good for science but not for the control group cohort

 

so I just think the lack of a control group in this GILD anti-viral example is a feature and not a bug

 

Cherzeca, its an important question, but this already happens with other life threatening illnesses. I don't think its unethical to give a placebo if you *don't know* that the drug works. If it doesn't work then both people getting the drug and getting the placebo are going to have statistically similar outcomes. Thats the point of the trial: to see *if it works*. It would be unethical to charge for a drug which doesn't work, or has bad side-effects/interactions. Thats what doctors did for centuries, and it has only recently improved. Lets keep the improvement. Empirical evidence is very important, probably more than theory, as proved by the story of the doctor who advocated hand washing and ended up in a mental asylum since no one would believe him. https://www.npr.org/sections/health-shots/2015/01/12/375663920/the-doctor-who-championed-hand-washing-and-saved-women-s-lives

 

Other have considered the ethics, and the current scenario is the first place where they say a placebo trial is justified.

From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844122/

 

Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study;

 

This is why not having expertise is so not helpful. Control group is not necessarily placebos. People have figured out trial designs in difficult diseases (e.g. cancer) decades ago. In broad strokes, the control is frequently standard of care, which is not placebo in these cases but whatever is the standard of care in that field at that point in time. For covid, they will not stop current treatment (using whatever they are trying to currently use). They will keep all the underlying prescribed treatments exactly the same between treated vs control group *except* one variable, the new drug that is being tested being the only treatment factor that is different. Also has to be randomized (for subjects) and double blinded because, you know, doctors and drug companies also have biases. And surprise, there are cowboy doctors who do not know much about trial design (it is a specialty field which also needs expertise) but nevertheless make big claims with flawed trial design data (the french doctor who published paper on hydroxychloroquine).

 

P.S: Standard of care doesn't mean some drug, it can be devices (e.g. ventilator) or palliative care in the absence of no proven treatment options.

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@cigar

a lot of control groups are given placebos...meaning they are given something which purports to be a therapeutic but really isn't...hence the ethical issue for severely ill cohorts where you are in effect practicing deception...arguably good for science but not for the control group cohort

so I just think the lack of a control group in this GILD anti-viral example is a feature and not a bug

When does speculation become investment?

When do you decide that conviction is sufficient to put 10% of your net worth in a specific investment?

---)You need to define a threshold.

I fully realize that comparing an investment decision to a life or death situation is different but you (we) need a framework.

 

It has been suggested (from various observational and rational reasons) that remdesivir could result in better outcomes than doing nothing for CV. We don't know the answer to this question. In order to answer that question, trials that involve randomized blind trials with control groups will be essential unless several trials done in different centers with different patients clearly show an advantage (pre-defined targets). When patients are recruited for the studies now, they have a choice to accept (and potentially get drugs that are potentially useful {or not and with negative side effects}) or not. Given the difficult situation, patients may get access to remdesivir through a company-sponsored expanded access program or through a compassionate program. The results do look promising and that should speed up the process.

The approach is obviously not perfect but has provided the shoulders on which future generations could see. How could you know if you don't know?

The pharma cemetery is full of ideas that looked good at some point.

 

We need a controlled study - Remdesivir for Democrats, hcq for Trump supporters.

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@cigar

a lot of control groups are given placebos...meaning they are given something which purports to be a therapeutic but really isn't...hence the ethical issue for severely ill cohorts where you are in effect practicing deception...arguably good for science but not for the control group cohort

so I just think the lack of a control group in this GILD anti-viral example is a feature and not a bug

When does speculation become investment?

When do you decide that conviction is sufficient to put 10% of your net worth in a specific investment?

---)You need to define a threshold.

I fully realize that comparing an investment decision to a life or death situation is different but you (we) need a framework.

 

It has been suggested (from various observational and rational reasons) that remdesivir could result in better outcomes than doing nothing for CV. We don't know the answer to this question. In order to answer that question, trials that involve randomized blind trials with control groups will be essential unless several trials done in different centers with different patients clearly show an advantage (pre-defined targets). When patients are recruited for the studies now, they have a choice to accept (and potentially get drugs that are potentially useful {or not and with negative side effects}) or not. Given the difficult situation, patients may get access to remdesivir through a company-sponsored expanded access program or through a compassionate program. The results do look promising and that should speed up the process.

The approach is obviously not perfect but has provided the shoulders on which future generations could see. How could you know if you don't know?

The pharma cemetery is full of ideas that looked good at some point.

We need a controlled study - Remdesivir for Democrats, hcq for Trump supporters.

Somebody has volunteered to head the ethics and advanced statistical analysis team:

"It could have a very positive effect, or a positive effect, maybe not very, but maybe positive, it’s very, very exciting."

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Not sure if this has already been posted:

https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

 

 

From NEJM posted about a week ago.

 

In this trial, Remdesevir was started a median # of 12 days after symptom onset. I think like 53% were already on a ventilator when the medication was started.

 

Not sure what # of days of symptoms the patients in the U Chicago Gilead had, but one of the inclusion criteria for the study was a positive viral PCR within <4 days (going on memory). Usually symptom onset is when people get tested.

 

So in other words, for the NEJM trial the median patient went almost a full two weeks of symptoms without starting the medication and I think that's a key difference. By that point if you're really sick, the virus has likely taken over lungs, you develop ARDS and the drug won't touch you. U Chicago data implies if you start patients early enough then it can make a big difference.

 

Still need controlled data but it's a good start.

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This is why not having expertise is so not helpful. Control group is not necessarily placebos. People have figured out trial designs in difficult diseases (e.g. cancer) decades ago. In broad strokes, the control is frequently standard of care, which is not placebo in these cases but whatever is the standard of care in that field at that point in time. For covid, they will not stop current treatment (using whatever they are trying to currently use). They will keep all the underlying prescribed treatments exactly the same between treated vs control group *except* one variable, the new drug that is being tested being the only treatment factor that is different. Also has to be randomized (for subjects) and double blinded because, you know, doctors and drug companies also have biases. And surprise, there are cowboy doctors who do not know much about trial design (it is a specialty field which also needs expertise) but nevertheless make big claims with flawed trial design data (the french doctor who published paper on hydroxychloroquine).

 

P.S: Standard of care doesn't mean some drug, it can be devices (e.g. ventilator) or palliative care in the absence of no proven treatment options.

 

Thanks for clarifying. Since you mention expertise on an internet forum, I assume you are a bio-statistician and run/consult for these kinds of trials?

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@cigar

a lot of control groups are given placebos...meaning they are given something which purports to be a therapeutic but really isn't...hence the ethical issue for severely ill cohorts where you are in effect practicing deception...arguably good for science but not for the control group cohort

so I just think the lack of a control group in this GILD anti-viral example is a feature and not a bug

When does speculation become investment?

When do you decide that conviction is sufficient to put 10% of your net worth in a specific investment?

---)You need to define a threshold.

I fully realize that comparing an investment decision to a life or death situation is different but you (we) need a framework.

 

It has been suggested (from various observational and rational reasons) that remdesivir could result in better outcomes than doing nothing for CV. We don't know the answer to this question. In order to answer that question, trials that involve randomized blind trials with control groups will be essential unless several trials done in different centers with different patients clearly show an advantage (pre-defined targets). When patients are recruited for the studies now, they have a choice to accept (and potentially get drugs that are potentially useful {or not and with negative side effects}) or not. Given the difficult situation, patients may get access to remdesivir through a company-sponsored expanded access program or through a compassionate program. The results do look promising and that should speed up the process.

The approach is obviously not perfect but has provided the shoulders on which future generations could see. How could you know if you don't know?

The pharma cemetery is full of ideas that looked good at some point.

 

+1

 

As usual you said it better than I did CB.

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This is why not having expertise is so not helpful. Control group is not necessarily placebos. People have figured out trial designs in difficult diseases (e.g. cancer) decades ago. In broad strokes, the control is frequently standard of care, which is not placebo in these cases but whatever is the standard of care in that field at that point in time. For covid, they will not stop current treatment (using whatever they are trying to currently use). They will keep all the underlying prescribed treatments exactly the same between treated vs control group *except* one variable, the new drug that is being tested being the only treatment factor that is different. Also has to be randomized (for subjects) and double blinded because, you know, doctors and drug companies also have biases. And surprise, there are cowboy doctors who do not know much about trial design (it is a specialty field which also needs expertise) but nevertheless make big claims with flawed trial design data (the french doctor who published paper on hydroxychloroquine).

 

P.S: Standard of care doesn't mean some drug, it can be devices (e.g. ventilator) or palliative care in the absence of no proven treatment options.

 

Thanks for clarifying. Since you mention expertise on an internet forum, I assume you are a bio-statistician and run/consult for these kinds of trials?

 

First, my apologies, I was not trying to be confrontational, in-fact was trying supportive of what you were trying to explain and add to it. But it came out very different. Full disclosure, we consult on clinical trials and other aspects of pharma/biotech business but not in the capacity of card carrying clinical design statistician. But sitting in some of the meetings where they discuss the trial design really helps me understand the complexity, limited information and very aggressive deadlines people in this field have to work with. Hence my deference to them. They surely get it wrong sometimes but their batting average will put anyone else to shame if they tried to do it a few times without the expertise.

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This is why not having expertise is so not helpful. Control group is not necessarily placebos. People have figured out trial designs in difficult diseases (e.g. cancer) decades ago. In broad strokes, the control is frequently standard of care, which is not placebo in these cases but whatever is the standard of care in that field at that point in time. For covid, they will not stop current treatment (using whatever they are trying to currently use). They will keep all the underlying prescribed treatments exactly the same between treated vs control group *except* one variable, the new drug that is being tested being the only treatment factor that is different. Also has to be randomized (for subjects) and double blinded because, you know, doctors and drug companies also have biases. And surprise, there are cowboy doctors who do not know much about trial design (it is a specialty field which also needs expertise) but nevertheless make big claims with flawed trial design data (the french doctor who published paper on hydroxychloroquine).

 

P.S: Standard of care doesn't mean some drug, it can be devices (e.g. ventilator) or palliative care in the absence of no proven treatment options.

 

Thanks for clarifying. Since you mention expertise on an internet forum, I assume you are a bio-statistician and run/consult for these kinds of trials?

 

First, my apologies, I was not trying to be confrontational, in-fact was trying supportive of what you were trying to explain and add to it. But it came out very different. Full disclosure, we consult on clinical trials and other aspects of pharma/biotech business but not in the capacity of card carrying clinical design statistician. But sitting in some of the meetings where they discuss the trial design really helps me understand the complexity, limited information and very aggressive deadlines people in this field have to work with. Hence my deference to them. They surely get it wrong sometimes but their batting average will put anyone else to shame if they tried to do it a few times without the expertise.

 

Thanks. Yes those people are good, and they charge big bucks.

Glad to have someone here with the relevant experience to talk about trials. I think it will be a recurring topic.

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I agree I think alot of people think we need to get cases to zero before we open the economy again.  That wasn't the point of this lockdown.  It was to limit the deaths (but not prevent it entirely) by not overwhelming hospitals. 

 

In terms of mask, Dr Fauci originally stated masks weren't required but I believe he came around to suggesting it as an effective way of preventing transmission.  Originally I think the shortage of supplies for front line workers was the agenda behind the message of the masks effectiveness.  That may still be the case which is why they suggest most to wear scarfs, or some form of clothing around your mouth area instead of directly suggesting masks for the general public.

 

Flatening the curve was goal to not overwhelm our health system and as long as country can operate without causing health crisis, opening should proceed with tons of centralized testing. Without centralized testing , we may be flying blind when some region gets a spike.

 

I think that this is an extremely good point that has gotten lost over the past month or two. The goal is to avoid overwhelming the healthcare system, not to eliminate every potential death from the virus by remaining shut for a year. (Based on Canadian polling, it's pretty clear that Canadians in aggregate don't get it.)

 

On the "how to reopen" list, it shocks me that they aren't bothering to require masks, since it seems to be a cheap and easy solution to reduce transmission (and deaths and medical costs). I wonder if there was some reasoning behind that, or if they were just writing down stuff on autopilot, and not really thinking. If they decided not to include it for cultural reasons, that puts the US at a competitive disadvantage relative to other countries that are more open-minded about such things.

 

When you ‘mismanage’ the virus outbreak you have to resort to lock down. (And by mismanage i mean not being able to control the virus.) We all know that lock down exacts an enormous toll on the economy.

 

While in lock downs governments have a small window of time to pull together experts and implement a very detailed national strategic plan to combat the virus. This involves switching from playing defense to playing offense. The playbook is pretty straight forward: massive focussed and prioritized testing, quick results (within 24 hours), massive group of people to contact trace. How effective governments are with this stage will determine how quickly they can unlock the economy. And also, more importantly, how long the economy will remain unlocked.

 

If you have no detailed national plan for phase 2 (reopening of the economy) you are likely screwed. As you try an reopen the economy all that will happen is the virus will win again. It will start to silently spread. Clusters will form and governments will need to resort to lock down again.

 

We will find in the coming months which governments are up to the challenge.

 

This is NOT a debate about ‘health’ OR ‘economy’. This is a debate about leaders who are effective and leaders who are ineffective.

I fear the healthcare workforce is going to be the biggest loser in this mismanagement. Still trying to figure out what this will mean to healthcare workers long term. Many who are high risk (or their family members are) may choose to walk away after a few rounds of mismanagement...

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Peggy Noonan in a WSJ post

 

https://www.wsj.com/articles/needed-a-little-give-and-a-lot-of-integrity-11587079973?mod=hp_opin_pos_3

 

Here’s the part about integrity. Our federal government has to stop making empty and misleading claims about testing.

Leave to history how much the Centers for Disease Control and Prevention and the Food and Drug Administration were allowed to screw up. Since then, White House announcements on testing have been all showbiz. Tests are always coming in 10 days, they’re in the pipeline and being shipped next week, we’re scaling up. Wednesday Mike Pence crowed at the daily White House briefing: “We have conducted and completed 3,324,000 tests across the nation.” That’s barely 1% of the population three months into a crisis. That’s not an achievement, it’s a scandal.

 

President Trump said, “We have the best tests in the world.” If so, poor world.

 

There’s a complete disconnect between the numbers with which Washington mesmerizes itself and facts on the ground. Operatives give credulous cable hosts excited reports of new tests: You spit in a vial and results are immediate—it’s like a gender reveal, they shoot cannons with colors! We’re developing a home test that’s a pinprick. Elizabeth Holmes comes to your house; Theranos is on the case!

 

Ha ha, kidding, not true I think.

 

Testing is a national responsibility because a pandemic is a national problem. From the beginning it needed to be priority No. 1. It was never priority No. 1. If it had been, we’d have tests.

 

The federal government’s lack of integrity has been destructive. No opening of America will be sustained until it’s got right.

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Guest cherzeca

thanks for the control group info.  clearly if a patient can select between the GILD anti-viral and plaq/z-pack, then I wouldn't see any ethical issue.

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thanks for the control group info.  clearly if a patient can select between the GILD anti-viral and plaq/z-pack, then I wouldn't see any ethical issue.

 

I'm assuming this is a typo. But obviously if a patient can select between two experimental drugs, it isn't a blind or random study!

 

Plaq/z-pack isn't standard of care, so it wouldn't be the control.

 

The patient enrols in trial knowing they get 50/50 chance at Remdisivir. This is informed consent. Any clinical trial needs to be approved by multiple ethics boards, so don't waste too much time thinking about the ethics.

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