General discussion 517 13 willingness to keep participating in a clinical trial, and eventually even cause selective trial dropout [768]. To a limited extent, we have likely also observed these consequences of blinding during the execution of the EfFECTS trial: several patients sought additional counselling with their physician to express their insecurities and/or incomprehension with regard to the concealed [18F]FDG-PET/ CT result and allocation. The EfFECTS of blinding in combination with diagnostic misestimation are discussed in more detail in the paragraph on diagnostic misconception and misestimation below. Similarly, insufficient blinding may also influence a patients’ HRQoL or even willingness to continue trial participation, for example when a patient would feel that their allocation (i.e., most likely when allocated to the control arm) leads to insufficient personal gain from trial participation. HRQoL EfFECTS of (the unblinded) active surveillance are discussed in the paragraph on challenges of active surveillance below. Blinding of physicians In a diagnostic RCT, it is considered unethical to blind the treating physicians to the results of the diagnostic intervention, if they are responsible for any subsequent clinical decision-making. This can be avoided if treatment options are well defined by the trial protocol. On the other hand, blinding may have unintended consequences on the validity of trial results by removing the physician’s role in the clinical decision making, which may be subjective to a certain extent but also an adequate reflection of daily clinical practice [35]. In addition, blinding of physicians in diagnostic RCTs may have another challenge. In the EfFECTS trial, it has occurred a few times that a treating physician would re-evaluate a trial participants’ eligibility for diagnostic thyroid surgery or active surveillance after the trial had provided a blinded treatment advice. This re-evaluation would be based on the patient’s baseline characteristics and on (more than once wrongly argued based on the treatment advice) assumptions about the (blinded) [18F]FDG-PET/CT results and patient allocation. For example, a trial participant would receive an active surveillance advice based on an [18F]FDG negative nodule, but immediately afterwards, his/ her physician would openly question whether the patient shouldn’t undergo diagnostic surgery because it concerned a Bethesda IV index nodule with some suspicious ultrasound characteristics. By reviewing the trial design and concurrent odds and risks with the respective physicians, these issues were resolved and did not result in undesired protocol violations (i.e., physician-initiated noncompliance to advised treatment). Yet, this example illustrates the importance of the information provision and continuous dialogue between physicians and researchers in diagnostic RCTs in order to deal with any persistent ambiguities regarding the complexity of the trial design or any possible issues regarding the diagnostic confidence in the investigated diagnostic. In the EfFECTS trial, overall diagnostic confidence of the physicians and patients was high, a prerequisite to successfully execute any RCT (Chapter 4) [501].
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