Ann: Proposed issue of securities - CYP, page-9

But based on the above summary, I don't think the change happened after too many more patients than the first 6,

The reason initial trials are small is because they are expensive and time consuming so its practical reality of needed to get a result in a time frame and a budget that governs that.

But the reason they can't be too small is that the statistical inferences aren't valid if they are.

You say "I don't think the change happened after too many more than the first 6".

In the simple conceptual protocol you have standard of care versus treatment arms. But that won't work *statistically you can't validly infer" the treatment is better than standard of care IF your standard of care isn't STANDARD.

You have to have a common standard in your control group or you standard isn't a standard its two standards.

A patient that has a human caregiver attend them every day, talk to them every day, look at their wound every day whilst the dressing is changed (the reason for the caregiver to have gone there) is getting (I would strongly suggest BETTER treatment than a patient that only has their bandage treated every few days). The patient is going to feel more cared about in the first case even if nothing much is different in terms of the wound - but the caregiver in looking at the wound is also likely to respond to something they see that is wrong earlier in the case of the looking more frequently.

What I am saying is the standard likely isn't standard enough. Do you throw away the data from those first six patients where the old standard of care was in play - if you designed your trial to be optimal for having just enough patients to get a result in time and budget then chances are you can't because throwing away the data from the early six makes your sample too small.

But if you keep the data from the first six in then you've kept in a confounded standard.

I think I understand your point - changes had to be made - I think I can accept in human terms just as you can - that getting a good standard is likely to be very blood hard to do - but none of that actually changes hard realities - maths doesn't care how hard one is trying - the answer is the answer - the design is either valid or its invalid - if its invalid - if you muck up the standard of care such that it isn't standard - then however understandable the mistake - it still isn't standard.