What to Do With the Participants/Patients in Phase III Clinical Cancer Trials That Have Been Stopped by the FDA.

JNCI J Natl Cancer Inst (2016) 108(12): djw252 doi: 10.1093/jnci/djw252 Editorial EDITORIAL What to Do With the Participants/Patients in Phase III Clinical Cancer Trials That Have Been Stopped by the FDA Frank L. Meyskens Jr. EDITORIAL Affiliations of author: Affiliations of author: Departments of Medicine, Biological Chemistry, Public Health, and Epidemiology and the Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA. Correspondence to: Frank L. Meyskens Jr, M.D., F.A.C.P. 101 City Dr,UCIMC,Bld 56 rm 252. email: Flmeyske@uci.edu. The two companion papers in this issue of the Journal are unique in that they address one way to salvage useful informa- tion when a drug is declared persona non grata by the US Food and Drug Administration (FDA), thereby obviating continuation of its use in a clinical trial (1,2). But first, before launching into the major thrust of this edito- rial, some historical background is needed for the broader audi- ence that is interested in the general topic of clinical trials. Starting in the early 90s, a widespread interest in specific cox-2 inhibitor observational studies and promising mechanistic data held the promise that high specificity would lead to enhanced efficacy and preclude some of the toxicities experienced in pa- tients receiving nonsteroidal anti-inflammatory drugs (NSAIDS) (3). A large number of randomized four-arm 2x2 chemopreven- tion trials were launched in the late 90s and early 2000s in pa- tients with precursors to colorectal cancer. In parallel, an interest in supplemental selenium for the pre- vention of prostate cancer, based on promising observational results and supportive mechanistic data, led to the launch of several phase III randomized selenium trials in patients at risk for prostate (4) and other cancers. At the time that concern was raised about the cardiovascular side effects of cox-2 inhibitors, the selenium trials were ongoing and too early to analyze. An excess of serious bleeding episodes was detected in the cox-2 inhibitor trials, and randomized trials involving this class of compounds were stopped by the FDA (5). This editorial does not address design or other issues related to the original trial , nor does it focus on important interpreta- tions when trials are stopped, such as the interpretation of clini- cal trials, particularly prevention investigations that are stopped early or challenges to data monitoring committees when regulatory authorities intervene (6,7). What to do with all these patients? In prior stopped or suspended trials, patients simply came off the trial and little to no useful information was gleaned. A sim- plified flow diagram of the follow-up trial is provided in Figure 1 to assist the reader in following the narrative. Complex flow di- agrams of patients are provided in the manuscripts. These investigations took a novel approach to this question, and my comments are focused on the information about out- comes and toxicities gained by morphing the stopped trial to a suspended one followed by a unique approach and a follow-up trial. After a brief hiatus, and with FDA, National Cancer Institute, and institutional review board concurrences, those patients who were in the cox-2 inhibitor (celecoxib in this trial) plus selenium arm or the selenium arm alone were offered sele- nium, and the majority of eligible patients were rerecruited to the follow-up described (1). Patients in the celecoxib arm only and those on the combination were offered follow-up by sur- veillance, and many received a colonoscopy (2). Now let’s examine here the overall conclusion of these two papers. First, the carefully stated conclusion that “selenium supple- mentation is not recommended for preventing colorectal adeno- mas in selenium replete individuals” (1): The design and analysis of this follow-up study in which selenium was restarted in participants who had been in the selenium only or the sele- nium plus celecoxib arm (now sans celecoxib) were impeccable. Although the overall results indicated that selenium did not af- fect overall recurrence of adenomas, a planned subgroup analy- sis of participants with advanced adenoma at baseline showed that adenoma recurrence was reduced in patients receiving sele- nium. Toxicity analysis demonstrated no difference in new-on- set type 2 diabetes (T2D), although subanalysis detected a Received: September 23, 2016; Accepted: September 27, 2016 © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 1 of 3