Thread by @ProfDFrancis

John Mandrola has a kind face.

And this letter below shows that he has earned the right to it.

I would never have thought to open with such kind words.

Nevertheless he makes clear what is needed.

Oh wait.

Oh dear.

"Objection, your honour!"

Hmmmm.... what does the Twitterverse think?

If you spend millions of dollars on a trial, of in i.v. drug which is made up in a solution, and in the control arm, if you do NOT have the plain solution with no drug, what does that mean?

And the problem is two-fold.

First, if the clinical staff are malignantly, intentionally biased TO MAKE IT LOOK like the drug works, when making a 50:50 decision whether to step down care (e.g. reduce O2 flow rates etc),

and it is a CONTROL-arm patient, what might they do?

And this would make the control arm patients tend to look a little sicker at the evaluation-time-point (e.g. on higher flow oxygen, not yet extubated, etc).

The trial would be statistically significantly positive.

And it would be a true positive, not a false positive.

Because the statistical significance is not a test of whether the drug works, but of whether the rated outcomes are better in the drug arm than not (regardless of whether this is due to the drug or due to the biased therapy).

This is Paul Ridker, famous statinologist and all-round outspoken person.

I had the honour to meet him at a CVCT congress, when I had spoken about ORBITA and it was being criticised by panelists.
"Blinding is not needed, just randomise," blah blah.

And he said this (this is a genuine quote, not an EHJ quote)

"Randomization balances confounders BEFORE trial entry.
Blinding balances confounders AFTER trial entry."

Paul Ridker,
CVCT Congress,
Washington DC, 2018.

That shut everyone up.

More efficient than running round punching people in the face, which was my original plan.

However, the problem is bigger than that of imaginary people with share options in the remdesivir company who might stick an extra face mask on the odd patient or two.

Problem 1.

If the trial is positive, skeptics will have an avenue of criticism. And the company will have no defence.

It would have no explanation for not adding in a placebo saline bag, even at this late stage.

As they say in TV infomercials for kitchen implements,

"But wait, there's more!"

Two patients are on your ward, with a haemoglobin of 9 (or 90, depending on your units).

One is a previously healthy young man who had a car crash, and was successfully operated, and is walking round the ward crying about his wife.

His wife was the passenger. She too was injured, and has had a torrid time. She is still being ventilated and is on inotropes and things.

Who gets the 2 units of blood that you have available?

Why did you make that choice?

WTF ...

How did you know who needed it more?

A. Random

B. You knew what challenges they would face, from the full clinical context

And it can also be affected by treatment.

Suppose Mr & Mrs Patient had the same injuries, but Mr Patient DID have his surgery, and was now ambulating, while Mrs Patient could NOT (due to some allergy to anaesthesia, or refusal to have surgery)

Who gets the blood transfusion?

OK now two people have Covid.

A got Remde [We can use half its name because NEJM published half a trial], the miracle drug

B got a slap in the face, in the control arm

If you believe the drug is excellent, which patient is in more NEED of O2 etc?

So:

Problem 2

Even an HONEST, non-cheating clinician, who doesn't give a damn about the Remde company, and hates their guts, if she believes the drug is good, might take extra pity on the control patient and give them an extra day of something, that makes them score worse.

But is it too late to add it now?

Well, well, well.

Now those have you who have been following that naughty boy Chris Rajkumar (@rajkumar_chris), will know the correct answer to this.

As you know, Chris wrote a disappointingly disrespectful and cheeky article in Circ CQO: ahajournals.org/doi/full/10.11…

A side effect of which is that we all know a couple of things now.

1. You can change Clinical Trials . gov, any time you like.

It is all documented automatically so you don't need to worry, anyone can follow the audit trail.

2. You can choose to delay your update the Clinical Trials . gov up to one year afterwards, and that is all legit.

(Don't believe me? Check out the complaint letter where they argued that it was fine.)

Moreover, this change is an undeniable benefit to the trial. A trial with a placebo arm instead of an open control arm has all the SCIENTIFIC benefits of the open-control version, and many more.

Nothing has to change other than the addition of an ampoule, syringe, bag, or whatever, of Normal Saline, in the control arm.

And the paperwork/consent can be updated quickly.

This is not a TABLET trial, where someone is going to have to make placebo for tens or hundreds of thousands of dollars, to resemble the active tablet.

This is an i.v. drug.

Oh what about the IRB approval? Won't that take ages?

No! You go up to the IRB and say.

"You know you approved this trial, without asking for placebo arm? Yeah?"

"Yeah, what about it"

"Why did you forget to ask for a placebo arm?"

"..."

"So I'm gonna do a deal with you. You quickly approve adding the placebo arm, and we will forget all about finding out why you failed to ask for it before."

"You mean you want us to do a cover-up????!"

"Yes"

"OK"

Oh but won't people complain about the protocol change, when we come to publish?

Yes. Stupid people who don't know what to complain about.

But I won't complain. And I am happy to announce that those people are stupid. And so will all intelligent people on Twitter.

Adding a placebo control is:

Is scientifically good

Is harmless to patients

Needs little added work now

Costs almost nothing and ...

Will help you sell more of the damn stuff!

I commend it to you, Remdesivir investors worldwide, in the strongest terms.