Inference Based on Small Randomized Oncology Clinical Trials: Is the Observed Treatment Effect True?

Cheng, Joyce

doi:10.23937/2469-5831/1510010

Cited by 1 publication

(2 citation statements)

References 9 publications

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“…Therefore, several of our operationalizations remain to some extent arbitrary. There is no established cutoff to distinguish between small and large trials [18], so we used a threshold of 200 patients, which was used previously to estimate the robustness of effect estimates depending on the size of oncology trials [19], and selected further thresholds in sensitivity analyses. For the "multiple endpoints involving different events" characteristic, we evaluated the primary endpoints used for regulatory decision-making, systematically perused OS, PFS and RR as the most frequently used and probably most important outcomes for approval of cancer drugs, together with quality of life which we also considered.…”

Section: Discussionmentioning

confidence: 99%

“…Since there is no established definition of what constitutes a large trial, we defined a trial with at least 200 enrolled patients (across all trial arms) to be large for our main analysis. We acknowledge that this threshold may be arbitrary, but this cutoff is commensurate with recent analyses distinguishing between small and large cancer trials [19]. Trials with more than one enrolling center were considered to have multicenter designs.…”

Section: Tables and Boxes Box 1: Example Of Explicit And Transparent Summarizing Statementmentioning

confidence: 99%

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Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies

Ladanie

Speich

Briel

et al. 2019

Journal of Clinical Epidemiology

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Introduction: Novel cancer therapies are often approved with evidence from a single pivotal trial alone. There are concerns about the credibility of this evidence. Higher validity may be indicated by five methodological and statistical characteristics of pivotal trial evidence that were described by the US Food and Drug Administration (FDA) which may corroborate the reliance on a single trial alone for approval decisions.Methods: We did a meta-epidemiologic evaluation of all single pivotal trials supporting FDA approval of novel drugs and therapeutic biologicals for cancers between 2000 and 2016. For each trial, we determined the presence of these five characteristics, which we operationalized as (1) large and multicenter trial (≥200 patients; more than one center); consistent treatment benefits across (2) multiple patient subgroups (in view of FDA reviewers), (3) multiple endpoints (including overall survival , progressionfree survival, response rate, health related quality of life) and ( 4) multiple treatment comparisons (e.g. multi-arm studies); (5) "statistically very persuasive" results (p-values <0.00125).Results: Thirty-five of 100 approvals were based on evidence from a single pivotal trial without any further supporting evidence on beneficial effects (20 randomized controlled trials and 15 single-arm trials). The number increased substantially from 1 approval before 2006 to 23 after 2011. Sixty-six percent (23/35) of the trials were large multicenter trials (median 301 patients and 63 centers). Consistent effects were demonstrated across subgroups in 66% (23/35), across endpoints in 43% (15/35), and across multiple comparisons in 3% (1/35). Very low p-values for the primary endpoint were seen in 34% (12/35). At least one of the corroborating characteristics was present in 94% (33/35) of all approvals, two or more were present in 54% (19/35) and none had all characteristics.Conclusions and relevance: Single pivotal trials typically have some of the corroborating characteristics, but often only one or two. These characteristics need to be better operationalized, defined and reported and whether single trials with such characteristics provide similar evidence about benefits and harms of novel treatments as multiple trials would do, needs to be shown.

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Section: Discussionmentioning

confidence: 99%

Section: Tables and Boxes Box 1: Example Of Explicit And Transparent Summarizing Statementmentioning

confidence: 99%

Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies

Ladanie

Speich

Briel

et al. 2019

Journal of Clinical Epidemiology

View full text Add to dashboard Cite

show abstract

Inference Based on Small Randomized Oncology Clinical Trials: Is the Observed Treatment Effect True?

Cited by 1 publication

References 9 publications

Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies

Single pivotal trials with few corroborating characteristics were used for FDA approval of cancer therapies

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