The question of marginality explored formally in my working paper On Marginal Therapy in Degenerative Disease (newly updated July 1) goes to the heart of your problem, Simon. If there is genuine reason to suppose that your candidate therapy could produce clinically detectable responses in individual patients, then randomization would be scientifically and therapeutically counterproductive. But if your 1-arm trial should fail to demonstrate any clinically evident response, the therapy looks increasingly marginal as n grows — a fact which must be conveyed as part of true informed consent. Provided that no more attractive candidate therapy has emerged in the meantime, your trial might reasonably add a placebo arm and randomize. Patients will be disappointed to learn during informed consent that you now believe the therapy is unlikely to produce any definite effect they will notice, but this may at least allay concerns about assignment to placebo.
Certain formal elements in the paper correlate nicely with Frank’s advice above:
- The question of “more discriminating … outcome variable” is addressed formally in the \theta_c parameter of the analysis
- Follow-up duration is addressed in footnote 3
- The entire analysis is Bayesian-sequential in character.