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Table 1 Clinical trials for which ethics commissions, physicians and patients demand cross-over designs, i.e. the option of switching to the therapy of the other study arm

From: Patient relevant endpoints in oncology: current issues in the context of early benefit assessment in Germany

A considerable efficacy advantage compared to the standard therapy can be expected for the substance to be tested

A considerable efficacy advantage is demonstrated in an interim analysis e.g. with regard to a benefit in survival of patients without their disease getting worse (i.e., progression-free survival, PFS).

The decision to switch typically is being made at the individual patient level.

 

  ◦ As soon as a benefit in terms of the efficacy of the tested substance compared to the comparator becomes apparent, patients wish to be treated with the new therapy.

 

  ◦ For ethical reasons, this must therefore be made possible, even if and especially if the survival time analysis is influenced by it.

 

  ◦ No trial participant can be asked to be treated with an inferior therapy until the end of his or her life, only to make the superiority of the better therapy more clearly apparent in terms of overall survival (OS).

Even if a trial does not provide for a cross-over, e.g. because the superiority of the new therapy is still uncertain, trial participants can terminate their trial participation at any time in order to be treated with the new medication (e.g. if it is already approved for another indication) or with similar pharmaceuticals.

 

  ◦ Even this unplanned cross-over influences the survival time analysis (in a conservative direction).