Abstract
This study uses the European Society of Medical Oncology Magnitude of Clinical Benefit Scale to evaluate the clinical benefit of anticancer drugs that gained approval by the US Food and Drug Administration based on single-arm rather than randomized clinical trials.
For regulatory approval, the US Food and Drug Administration (FDA) requires evidence of safety and efficacy of new drugs from adequate and well-controlled trials.1 Improved understanding of the molecular basis of cancer, has led to rapid development of new drugs. In combination with regulatory changes providing rapid review and approval of drugs for diseases with unmet need,2 this acceleration has led the FDA to use overall response rates (ORRs) assessed in single-arm trials as the basis for approval.
Fewer than half of randomized clinical trials (RCTs) supporting FDA approval meet substantial clinical benefit thresholds defined using validated scales such as the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).3 In this study, we applied version 1.1 of the ESMO-MCBS4 to single-arm trials that have supported FDA approval.
Methods
Data on trials supporting FDA approvals between January 1, 2006, and December 31, 2016, were collected as described previously.3 For single-arm studies, ORR was evaluated using the response evaluation criteria in solid tumors,5 published rules defining when measurable tumors regress, stabilize, or progress in response to treatment. Independent review committee was preferred over investigator assessment. For each trial, ESMO-MCBS grades were applied by 2 of us (C.M. and M.B.). Disagreement was resolved by consensus with a third author (A.T.). Substantial clinical benefit was defined as grade A or B for trials of curative intent and grade 5 or 4 for those of noncurative intent. Data were reported descriptively as proportions, medians, and ranges. Comparisons between groups were assessed using the Mann-Whitney and χ2 tests for continuous and categorical variables, respectively. Data analyses were conducted using SPSS version 21 (IBM Corp). Statistical significance was defined as a 2-sided P < .05. Per the Government of Canada, Panel on Research Ethics, this study was exempt from the requirement for ethical approval in view of its use exclusively of publicly available data.
Results
Of 134 individual studies supporting new anticancer drug approval, 4 reported subgroup analyses and were evaluated independently. Among these 138 data points, ESMO-MCBS could not be applied to 5 studies. Therefore, 133 data points were included in the analysis. The Table shows differences in study characteristics between approvals supported by RCTs and those supported by single-arm studies. Among all data points, 45 (33.8%) met the criteria for substantial clinical benefit using ESMO-MCBS. For single-arm trials, 2 (7.4%) met the threshold for substantial clinical benefit. These included trials evaluating osimertinib for T790M-mutated non–small cell lung cancer and crizotinib for ALK-rearranged non–small cell lung cancer, both scoring 4 on the ESMO-MCBS scale. Of the remaining single-arm trials, 8 (29.6%) scored 3, 8 (29.6%) scored 2, 5 (18.5%) scored 1 and 4 trials (14.8%) scored 0.
Table. Characteristics of Single-Arm Trials and RCTsa.
| Variable | No. (%) | P Valueb | |
|---|---|---|---|
| Single-Arm Trials (n = 27) | RCTs (n = 111) | ||
| Sample size, median (range) | 119 (12-370) | 540 (117-3752) | <.001 |
| Companion diagnostic test | 13 (48.1) | 24 (21.6) | .005 |
| Orphan drug designationc | 17 (63.0) | 48 (43.2) | .07 |
| Breakthrough therapyd | 10 (66.7) | 18 (28.6) | .006 |
| Priority review | 25 (92.6) | 81 (73.0) | .03 |
| Initial submission (vs supplemental) | 19 (70.4) | 42 (37.8) | .002 |
| Multiple trials supporting approval | 15 (55.6) | 24 (21.6) | <.001 |
| Supplementary trials | 5 (18.5) | 5 (4.5) | .009 |
| Accelerated approval | 17 (63.0) | 16 (14.4) | <.001 |
| First-line therapy | 4 (14.8) | 37 (33.3) | .06 |
| ESMO-MCBS, version1.1 substantial clinical benefite | 2 (7.4) | 43 (40.6) | .001 |
Abbreviations: ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; RCTs, randomized clinical trials.
This cohort included 134 trials, 4 of which reported data from multiple preplanned subgroup analyses each used to support approval. This resulted in a total of 138 data points.
Based on Mann-Whitney test for continuous variables and χ2 tests for categorical variables. All P values are 2-sided.
Orphan drug designation is applied to a drug used to treat diseases affecting fewer than 200 000 American citizens.
Breakthrough therapy designation came into effect in July 2012. This classification was only available for applications after 2011 (n = 64 [12 single-arm trials and 52 RCTs]).
Substantial clinical benefit defined as ESMO-MCBS, version 1.1 grade of A or B for trials of curative intent and 5 or 4 for those of noncurative intent.
Discussion
The observation of common and durable response to targeted therapy and immunotherapy has raised questions about whether traditional randomized trials are necessary to support drug approval.6 The ability to study a drug’s ORR, especially in clearly defined target populations, makes the single-arm study design appealing as a pathway to approval. The ability to identify target populations has been aided by increasing understanding of the molecular basis of cancer, which has allowed anatomically defined cancers to be subdivided into smaller, molecularly defined subtypes more likely to respond to targeted therapies. Our data confirm that ORR is a common end point in single-arm studies supporting accelerated approval of anticancer therapies. However, a small proportion of single-arm studies met the threshold for substantial clinical benefit defined by ESMO-MCBS, version 1.1. These results are unsurprising because, to meet substantial benefit thresholds using the ESMO-MCBS, a single-arm trial must show substantial efficacy as well as improvement in quality of life or have data from confirmatory postmarketing study. The low proportion of single-arm trials that meet the threshold for substantial benefit may reflect a lack of supporting data or unrealistic thresholds in the ESMO framework.
In conclusion, approximately one-third of trials supporting FDA drug approval meet the threshold for substantial clinical benefit as measured by ESMO-MCBS. Compared with RCTs, approvals supported by single-arm studies are less likely to show substantial benefit using ESMO-MCBS. It is likely that this reflects the high thresholds for substantial benefit used to calibrate the ESMO-MCBS for single-arm trials.
References
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