Practising evidence-based medicine in an era of high placebo response: number needed to treat reconsidered

Abstract

The number needed to treat (NNT) statistic was developed to facilitate the practice of evidence-based medicine. Placebo was assumed to be therapeutically inert when the NNT was originally conceived, but more recent data for conditions such as major depressive disorder (MDD) suggest that the placebo control condition can have considerable therapeutic effects. Complications arise because the NNT calculated from randomised controlled trials (RCTs) reflects a comparison between medication plus clinical management and placebo plus clinical management, whereas, in the clinical setting, physicians choose between prescribing open medication, observing a patient over time with a supportive approach, and doing nothing. Thus, NNTs derived from clinical trials are not directly relevant to clinical decision-making, because they are based on control conditions that do not exist in standard practice. Additional difficulties may arise when using NNTs to compare alternative treatments for MDD, such as medication and psychotherapy, since these comparisons require the control conditions upon which the respective NNTs are based to be similar.Whereas pill placebo conditions include intensive clinical management and elicit expectations of improvement, attention control conditions for psychotherapy research are less well developed. Often the effects of psychotherapy are gauged against a wait-list control condition, which has substantially fewer therapeutic components than a pill placebo control condition. To improve the clinical utility of NNTs for the treatment of MDD, we advocate effectiveness studies that include treatment conditions resembling actual clinical practice, rather than using placebo-controlled RCTs for this purpose. Until such studies are performed, the effect of bias in comparing NNTs across treatments can be controlled by ensuring that the RCT control conditions upon which the NNTs are based are comparable.

John D. Loeser Award Lecture: Size does matter, but it isn't everything: the challenge of modest treatment effects in chronic pain clinical trials

“…In addition, because the clinical trials we examined were limited to studies of efficacious medications for chronic pain, analyses of clinical trials of devices (eg, spinal cord stimulators) or of other nonpharmacologic treatments (eg, cognitive-behavior therapy and physical therapy) might also produce different results. For example, it has been observed that treatment effect estimates from RCTs of psychosocial treatments for depression are generally greater than those from trials of antidepressant medications; this observation may be explained by attenuation of the antidepressant treatment effect in trials in which a medication is compared with placebo and both groups are receiving intensive clinical management, which can be “substantially more therapeutic for patients with depression than doing nothing.” 90 …”

“…In addition, analyses of RCTs of depression 72 and Parkinson disease 45 have suggested that effect sizes might be smaller for patients who are enrolled later in the trial than for those enrolled earlier, perhaps due to the enrollment of patients who do not fulfill eligibility criteria because of pressure on sites to complete enrollment requirements. Also, with longer trials—for example, durations of 12 weeks or more rather than 5 to 8 weeks—there may be greater placebo vs active group improvement resulting from, as discussed in the next section, a greater number of study visits 90 and an increased opportunity for patients to develop supportive relationships with study staff. 87 , 91 …”

Evidence-Based Psychotherapy: Advantages and Challenges

“…In addition, often times the randomized controlled trials compare an active intervention with a waitlist control or attention control condition that does not exist in the community. Until efficacy and effectiveness studies include treatment conditions that resemble practice in the real world, it is challenging to draw conclusions from the existing data that can meaningfully affect clinical practice [36]. Similarly, there are limited data regarding the mechanisms of change in an intervention that produce effective outcomes [37].…”

The fallacy of the placebo-controlled clinical trials: Are positive outcomes the result of ‘indirect’ treatment effects?

“…However, association is not causation (Bollen & Diamantopoulos, 2017;Bollen & Pearl, 2013). When clinical trials use inert placebo, the treatment will perform relatively better than when compared to an active placebo (Howick, 2017;Howick et al, 2013;Roose, Rutherford, Wall & Thase, 2016).…”