Brimming with such clearly expressed insights, Pavlos! I am especially struck by your observations on the cultural aspects of the problem, as revealed in words like talismanic, performative, aura, ritual, halo, and sacred.
This whole business invites comparison with the esotericism I identify at the core of Project Optimus in this PubPeer post. And of course, the whole docrine that [1]
The [dose-optimization] trial should be sized to allow for sufficient assessment of safety and antitumor activity for each dosage. The trial does not need to be powered to demonstrate statistical superiority of a dosage or statistical non-inferiority among the dosages using Type I error rates which would be used in registrational trials.
sounds like this hypothetical ‘internal monologue’ from your Significance article:
“We don’t have the money, resources or sample size to power a direct comparison, yet we want the aura of an RCT. So let’s randomise into two arms – say, an experimental therapy and a placebo arm – but we won’t do a formal comparison."
Compare again a quote from Anomal Pharm
"And so the purpose of randomization is not necessarily to establish that one dose of the drug is superior to another dose in a statistical way, or establish statistical non-inferiority between the two doses, but really to have trials that are sufficiently sized so that we can interpret these dose-efficacy and dose-toxicity relationships, and use that information to guide overall decision-making.”
So one dimension left mostly unexplored in your piece (although I do note you gesture toward “bureaucratic or regulatory insurance”) is the imprimatur some regulatory authorities may have granted RNCTs.