In Praise of the Negative Trial
We all love when our studies produce a major new finding that changes standard of care and directly improves the lives of our patients. But, we've also been claiming for decades that even negative trials matter. Mostly though, we knew this through experience. Now, we have good, positive, published data, about negative studies. SWOG statistician Joe Unger, from the Fred Hutch, just issued findings in JAMA Oncology that supported this long-held view and which garnered national attention - also triggering an enthusiastic editorial.
According to this notable SWOG assessment, cancer clinical trials with negative results don't make an immediate splash in the scientific literature, but they do have a long-term impact on cancer research. First reports of the results of positive phase III cancer trials were twice as likely to be cited in scientific journals, Dr. Unger and the team observed. But when all articles associated with the trials were considered, the scientific impact of negative trials and positive trials was essentially the same.
The team - which included Drs. Dawn Hershman of Columbia University, Scott Ramsey, Bill Barlow, and Mike LeBlanc from Fred Hutch and myself, here at the Group Chair's Office at Oregon Health & Science University - analyzed every randomized, phase III SWOG trial completed over the 30-year period stretching from 1984 to 2014. That's 94 studies, enrolling 46,424 patients. Of those trials, 26 were positive. Primary manuscripts first announcing these encouraging results were, as might be expected, published in journals with higher impact factors and as stated were also cited twice as often as negative trials. But citations for primary plussecondary articles were similar, suggesting that the total scientific impact of negative trials was substantial. Unger stated that negative trials had "sizable scientific impact" through "generating important scientific observations and new hypotheses and by showing what new treatments should not be used." The authors also indicated it is "essential to publish negative trial results given the costliness of trials; the high probability that the clinical experiment is unlikely to be repeated (or, conversely, to reduce the risk that a similar trial is repeated due to lack of knowledge of a negative trial's results); and importantly, in fulfillment of the obligation to the trial participants who volunteered to participate" (emphasis mine).
Even if I weren't an author, I would agree! Negative trials will always be with us, unless, and probably even if, we are absolutely convinced a new treatment to be tested is better than the old. SWOG publishes nearly 100% of all completed trials (positive or other), and we and the other Network Groups have been trying hard to eliminate the bias against publishing negative studies. The accompanying editorial stated negative trials are often called failures or deemed poor uses of publicly-funded dollars. Unger's paper gives us more ammunition in our arguments for making sure they see the light of day.
I can't say it better than the editorial, so I will close with Drs. Huntington's and Gross's words: "The important work by Unger … supports the notion that cooperative group trials are a sound public investment, and a new wave of publicly funded clinical trials are needed to help define the next phase of high value cancer care." Two very positive statements!
Note: Spring break is here, and The Front Line and the SWOG TM Link of the Week are taking a hiatus next week. We'll be back in your inboxes April 1.