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

Aviv Ladanie; Benjamin Speich; Matthias Briel; Francesco Sclafani; Heiner C Bucher; Arnav Agarwal; John P A Ioannidis; Tiago V Pereira; Benjamin Kasenda; Lars G Hemkens

doi:10.1016/j.jclinepi.2019.05.033

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

J Clin Epidemiol. 2019 Oct:114:49-59. doi: 10.1016/j.jclinepi.2019.05.033. Epub 2019 May 31.

Authors

Affiliations

¹ Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland; Swiss Tropical and Public Health Institute (Swiss TPH), Basel, Switzerland.
² Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland; Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.
³ Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
⁴ Gastrointestinal Unit, Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
⁵ Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
⁶ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA USA; Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA, USA.
⁸ Health Technology Assessment Unit, Institute of Education and Health Sciences, Oswaldo Cruz German Hospital, São Paulo, Brazil.
⁹ Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland; Department of Medical Oncology, University Hospital and University of Basel, Basel, Switzerland; Department of Haematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany.
¹⁰ Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital and University of Basel, Basel, Switzerland. Electronic address: [email protected].

PMID: 31158450
DOI: 10.1016/j.jclinepi.2019.05.033

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: Cancer; Confirmatory evidence; Drug approval; FDAMA section 115a; Metaresearch; Single pivotal trial; U.S. food and drug administration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / therapeutic use
Clinical Trials as Topic* / statistics & numerical data
Drug Approval / methods*
Evidence-Based Medicine
Humans
Multicenter Studies as Topic / statistics & numerical data
Neoplasms / drug therapy*
Randomized Controlled Trials as Topic / statistics & numerical data
Reproducibility of Results
Time Factors
Treatment Outcome
United States
United States Food and Drug Administration*

Substances

Antineoplastic Agents