Abstract
Background and objective
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 U.S. Food and Drug Administration (FDA),
which may corroborate the reliance on a single trial alone for approval decisions.
Study design
We did a metaepidemiologic 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, progression-free survival,
response rate, health related quality of life), and (4) multiple treatment comparisons
(e.g., multi-arm studies); and (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 one 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
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.
Keywords
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Article info
Publication history
Published online: May 31, 2019
Accepted:
May 28,
2019
Footnotes
Funding: This project was supported by the Swiss Cancer League (Grant No KLS-3587-02-2015). The Basel Institute for Clinical Epidemiology and Biostatistics is supported by Stiftung Institut für klinische Epidemiologie.
Conflict of interest: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf. Heiner C. Bucher has received grants, support for traveling, consultancy fees, and honorarium from Gilead, BMS, Viiv Healthcare, and Roche that were not related to this project in the 36 months before the submission of this manuscript. He serves as the president of the association contre le HIV et autres infections transmissibles. In this function, he has received support for the Swiss HIV Cohort Study from ViiV Healthcare, Gilead, BMS, MSD, and AbbVie. Benjamin Kasenda has received support for traveling and consultancy fees from Roche that were not related to this project in the 36 months before the resubmission of this manuscript. Aviv Ladanie is employed by Novartis Pharma AG, Basel, Switzerland. All other authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.
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