Definition of randomized evidence available for inclusion in systematic reviews

We pre-specified the year 2009 as a starting point for our analyses in order to allow for a sufficient amount of evidence (in terms of both randomized trials and available systematic reviews) regarding the comparison between competing second-line treatments for advanced NSCLC to initiate a comparison between the available randomized evidence and that covered by systematic reviews. From 2009 to 2015, we identified the cumulative list of trials eligible for inclusion in systematic reviews; we checked that each trial identified would have been eligible for inclusion in at least one systematic review (i.e., corresponded to the selection criteria in terms of patients, interventions, and comparators). For each trial, we identified the earliest report of results and considered the corresponding publication date as when the trial became eligible for inclusion in systematic reviews. Considering the inevitable time lag between completion and publication, most recently published trials could not be selected by any systematic review, so we considered a 6-month lag period as recommended by the Cochrane Collaboration (i.e., we listed all trial results published up to July 1 each year, and up to August 31, 2014 for 2015) [16]. We also compiled the cumulative list of treatments and treatment comparisons assessed in eligible trials; finally, we calculated the cumulative number of patients included in trials as a measure of the available amount of randomized evidence.

Definition of randomized evidence covered by systematic reviews

We considered all systematic reviews published up to December 31 each year from 2009 to 2015 (up to March 2 for 2015). The reference date for a systematic review was the publication date of the full-text article or online publication date, if any. We compiled the cumulative list of all relevant trials selected by these systematic reviews and the cumulative list of treatments and treatment comparisons and cumulative number of included patients in the trials selected by the systematic reviews.

Assessment of randomized evidence not covered by systematic reviews

We evaluated the overall number and proportion of treatments, treatment comparisons, trials, and patients not covered by systematic reviews from 2009 to 2015.

We constructed cumulative networks of randomized evidence. Each node was a treatment and each edge was a treatment comparison (i.e., an edge connected two nodes when at least one randomized trial compared the two corresponding treatments). In multi-arm trials, doses of the same drug were lumped under a common node. The node size was proportional to the total number of patients randomly allocated to the corresponding treatment across all randomized trials available for inclusion; we represented the proportions of randomized patients not actually covered by systematic reviews by pie charts overlaid on nodes in the network. The edge width was proportional to the total number of randomized trials between the corresponding treatments available for inclusion; we represented the proportions of trials not selected by systematic reviews by a percentage bar chart overlaid on edges in the network. The evidence for a treatment comparison was considered partially covered when systematic reviews did not cover all the evidence available for this treatment comparison.

In sensitivity analyses, we discarded trials potentially ineligible for inclusion in any systematic review: trials of drugs that did not successfully pass phase II; trials that did not report treatment effects on overall survival or progression-free survival; and trials with results reported in conference abstracts only. In a last sensitivity analysis, the lag period to define randomized evidence available for inclusion in systematic reviews was defined by the last date of search for the last published systematic review.

Analyses involved use of R version 3.2.1 (R Development Core Team, Vienna, Austria).

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