It is easy to become overconfident that errors, biases, and other threats to trial validity are adequately controlled by practices such as randomization, investigator training, close monitoring, uses of reliability statistics, and so forth. Unfortunately, studies reveal that these practices do not always meet expectations. Such methods do not always prevent problems with dosing (2, 9, 25), biases (6, 7), ineptitude and deception (7, 26), protocol violations (6), or measurement errors (3–5, 25). Unfortunately, investigators cannot detect these troubling errors as they occur; rather, they must take preemptive actions (12, 25). Randomization, an effective support for blinding, will not necessarily also control biases (27). Even with extensive training, some clinicians do not develop adequate skills to participate in CTs (28, 29). Because investigators may not regularly evaluate the effectiveness of training or performance of staff that run CTs, imprecision, inaccuracy, bias, protocol violations, and other error sources can interfere with a study’s validity (4, 30). In two studies of antidepressants, only about half of all trained raters were able to detect drug effects on patients’ clinical status (3, 4). Even
