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The price of certainty: when is a new therapy good enough?

“Our aim as scientists is objective truth; more truth, more interesting truth, more intelligible truth. We cannot reasonably aim at certainty.” Karl Popper (from In Search of a Better World, 1995). The enormous success of endovascular thrombectomy (EVT) for stroke treatment has engendered increasing interest from the medical scientific community as well as industry. New companies have been founded and substantial capital raised and used for the development of new technologies to further improve patient outcomes in ischemic stroke and in other conditions in the neurointerventional realm. These new technologies need to be developed and subsequently tested for their performance and safety in patient care. Prospective singlearm studies are a reasonable standard for the early phase of a device evaluation. For such studies, the comparator and its point estimate are typically based on a metaanalysis of historical data. Other study designs such as virtual comparator groups have been tested as well. Recently, more randomized controlled trials (RCTs) have been initiated relatively early following encouraging observations in multiple case series. The numerous RCTs that were started in the field of middle meningeal artery embolization are positive examples of this. This development indicates a trend towards better neurointerventional study quality that is also observed in RCTs whose purpose is the headtohead comparison of different devices. There are two common hypothesis scenarios for testing the primary efficacy endpoint (eg, clinical outcome after 3 months). First, testing for superiority regarding efficacy is chosen if the new therapy has the potential to be more costly or risky. Second, testing for noninferiority is conducted if the new therapy is comparable to the previous standard therapy but might offer advantages in other areas such as fewer side effects, improved ease of use, lower procedure duration or cost, and so on. In a noninferiority trial the aim is to evaluate whether a new therapy is not unacceptably worse than an older one. The question is defining what ‘not unacceptably worse’ means exactly. The challenging nature of this question is illustrated by the difficulties in interpreting the results of the mothershipnonintravenous thrombolysis (IVT)studies that have been published recently and that are currently being evaluated for the updating of existing guidelines. What chance of what potential degree of noninferiority of the new therapy (without IVT) is acceptable? Four RCTs that enrolled a total of 1633 individuals resulted in a risk difference of 1% (95% CI −4% to 5%) between EVT alone versus IVT plus EVT. Overall, this metaanalysis suggests that EVT alone is noninferior to IVT plus EVT for several, but not for the most stringent, noninferiority margins. When including the recently presented SWIFT DIRECT data (comprising an additional 408 individuals) this picture changes to −1.3% (95% CI −5.6% to 2.9%, P=0.54), which now shows a trend more towards IVT plus EVT (figure 1). What would be an acceptable degree of potential deterioration? The minimal clinically important difference (MCID) is the smallest change in a treatment outcome that a patient, a care provider, or both would consider worthwhile. 13 Determining the MCID is considered to be an essential step in designing noninferiority clinical trials. A recent survey among expert neurointerventionalists and noninterventional vascular neurologists judged that the MCID for the outcome of substantial reperfusion (Thrombolysis In Cerebral Infarction (TICI) 2b3) within three thrombectomy attempts in stroke patients with large vessel occlusion is approximately 3%–5%. When considering the socioeconomic dimension, a safe neuroprotective would be cost effective and clinically worthwhile if it improved the outcomes of 2%–3% of patients. For the clinical outcome of stroke therapy, in a survey among stroke experts the authors concluded that an MCID of 1.0%–1.5% is preferred as the proportion of patients benefiting in order to consider a novel stroke therapy as clinically worthwhile. Applying this specific MCID as a lower noninferiority margin for withholding IVT can be considered to be a very safe choice, and it needs to be pointed out that 32% of the experts indicated 2.0% or more as being their preferred MCID. Essentially it is very likely that different conclusions will be reached based on different MCIDs related to differing local conditions, specifically when considering healthcare economics.