Best supportive care in clinical trials: Review of the inconsistency in control arm design

Randomized controlled trials (RCTs) for patients with advanced cancer often use a best supportive care (BSC) control arm, whereby patients randomized to this control arm receive supportive care exclusive of anti-neoplastic treatment (Macdonald, 1998; Cullen, 2001; Ahmed et al, 2004; Zafar et al, 2008; Cherny et al, 2009). However, supportive care interventions provided to patients in BSC control arms are often poorly described in protocols and manuscripts (Cullen, 2001; Cherny et al, 2009; Zafar et al, 2012). A prior systematic review found poor reporting of the components of the BSC arm and a lack of BSC standardization among trial participants (Cherny et al, 2009). As a result of this lack of rigor in defining and standardizing BSC, studies including BSC control arms may have problems with internal and external validity (Figure 1). These validity concerns may lead to biased outcomes or flawed conclusions. Figure 1 Poorly designed BSC can produce trial results that are internally and externally invalid. A panel of international experts developed consensus-based standards for delivering BSC in clinical trials (Zafar et al, 2012). The authors of this framework described four key domains that should be included in BSC delivery: (1) multidisciplinary care; (2) documentation of supportive care; (3) symptom assessment at least as often as the intervention arm; and (4) guideline-based symptom management (Zafar et al, 2012). Thus, this framework is intended to guide standardization of BSC in clinical trials similar to the way other frameworks improve consistency of RCTs and their reporting. For example, study interventions are described with great detail in the protocol; the CONSORT statement outlines a consistent approach for documentation and reporting of patient eligibility criteria, study settings, intervention components, and generalizability of the trial findings (Schulz et al, 2010). Although accepted standards for the delivery of BSC in RCTs exist, the literature has not described how well these standards reflect contemporary trial design. We conducted a review of the literature to determine whether the consensus-based framework for BSC delivery in RCTs reflects the design and documentation of recently published BSC RCTs.