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Background: Little is known about the total patient burden associated with clinical development and where burdens fall most heavily during a drug development program. Our goal was to quantify the total patient burden/benefit in developing a new drug., Methods: We measured risk using drug-related adverse events that were grade 3 or higher, benefit by objective response rate, and trial outcomes by whether studies met their primary endpoint with acceptable safety. The differences in risk (death rate) and benefit (overall response rate) between industry and nonindustry trials were analyzed with an inverse-variance weighted fixed effects meta-analysis implemented as a weighted regression analysis. All statistical tests were two-sided., Results: We identified 103 primary publications of sunitinib monotherapy, representing 9092 patients and 3991 patient-years of involvement over 10 years and 32 different malignancies. In total, 1052 patients receiving sunitinib monotherapy experienced objective tumor response (15.7% of intent-to-treat population, 95% confidence interval [CI] = 15.3% to 16.0%), 98 died from drug-related toxicities (1.08%, 95% CI = 1.02% to 1.14%), and at least 1245 experienced grade 3-4 drug-related toxicities (13.7%, 95% CI = 13.3% to 14.1%). Risk/benefit worsened as the development program matured, with several instances of replicated negative studies and almost no positive trials after the first responding malignancies were discovered., Conclusions: Even for a successful drug, the risk/benefit balance of trials was similar to phase I cancer trials in general. Sunitinib monotherapy development showed worsening risk/benefit, and the testing of new indications responded slowly to evidence that sunitinib monotherapy would not extend to new malignancies. Research decision-making should draw on evidence from whole research programs rather than a narrow band of studies in the same indication., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To quantify the proportion of trials for unsuccessfully licensed drugs that are not published., Design: A systematic assessment of the availability of published research reports for publicly registered trials testing drugs stalling in clinical development ("stalled drugs") and drugs receiving regulatory licensure in the same time period ("licensed drugs")., Data Sources: Searches of clinicaltrials.gov, Google Scholar, PubMed, Embase, and electronic query of contacts in registries to identify trials and assess publication status., Eligibility Criteria: The cohort of licensed drugs consisted of all disease modifying drugs in cancer, cardiovascular disease, or neurological disorders that received Food and Drug Administration licensure during 2005 to 2009 inclusive. The cohort of stalled drugs included unlicensed drugs in the same disease areas that had at least one completed phase III trial before 2009 and no evidence of any clinical trial activity after 31 December 2009. Inclusion criteria for registered trials advanced into publication searching were an intervention tested in a disease modifying, phase II, III, or IV trial registered on clinicaltrials.gov, with enrolment of at least one patient, that reported primary outcome collection end date between 1 January 2006 and 31 December 2008., Results: The unadjusted publication proportion for registered trials of licensed drugs was 75% (72/96) versus 37% (30/81) for stalled drugs. The adjusted hazard ratio for publication was 2.7 (95% confidence interval 1.7 to 4.3) in favour of licensed drug trials. Higher publication rates for licensed drug trials were observed regardless of disease type, sponsorship, trial phase, and geography. The rate of non-publication of stalled drug trials was significantly higher for studies that did not complete enrolment compared with licensed drug trials. A total of 20,135 patients participated in trials of stalled drugs that were never published., Conclusions: Much of the information collected in unsuccessful drug trials is inaccessible to the broader research and practice communities. These findings provide an evidence base and rationale for policy reforms aimed at promoting transparency, ethics, and accountability in clinical research., (© Hakala et al 2015.)