The ordinary miracle of cancer clinical trials.

Isn’t it remarkable that so many clinical trials come to fruition? When one considers all the events, or lack of events, that can induce a newly conceived treatment study to abort during its multiyear preactivation gestation, and all the obstacles that a toddling activated study can stumble over and be unable to get up again—not to mention the endless, mindless bureaucratic tedium that every study team must endure to avoid being labeled as deviant protocol guardians by external auditors—it is a genuine marvel that so many bright ideas reach maturity, making their way into the world of journals and conferences and influencing clinical practice. Each successfully activated and fully accrued cancer clinical trial is not just a biomedical research ordinary miracle (with apologies to singer Sarah McLachlan), it is also a testament to the desperate needs of patients, the dedicated stubbornness of resourceful oncologists, and the enormous financial rewards possible for corporations who bring blockbusters like rituximab or trastuzumab to market—as well as the ability of like-minded human beings to cooperate and accomplish great things, even within a cumbersome and confusing system. Although the brutal development gauntlet that clinical trials undergo could be considered a necessary selection process akin to “nature red in tooth and claw,” ensuring survival of only the fittest studies, it may be just as likely that protocols that successfully endure this merciless winnowing are among those attracting the least attention from predators—the least objectionable, least controversial, and least innovative study designs, destined to yield the least exciting results. The tortuous, twisting trail between an investigator’s therapeutic brainstorm and the nervous excitement of a podium presentation at the annual meeting of the American Society of Clinical Oncology is arduous enough for straightforward, single-institution studies that involve only one study sponsor. When the proposed study is instead large and complex—and especially when it can only realistically be conducted through one or several of the National Cancer Institute (NCI) –funded cooperative groups—the glorious, long-awaited day of trial activation can begin to seem like a meeting of Procrastinators Anonymous: perpetually postponed. For the last several years, David Dilts (who holds a PhD in management science) and Alan Sandler (an oncologist), codirectors of Vanderbilt University’s Center for Management Research in Healthcare (Nashville, TN), have been working to develop a more detailed understanding of the processes currently required to conduct a clinical trial for patients with cancer. Dilts et al first looked at the VanderbiltIngram Cancer Center and its affiliates to understand singleinstitution activation processes more clearly, and then began their study of NCI-funded cooperative groups by assessing the Cancer and Leukemia Group B (CALGB). Disturbingly, but not surprisingly, they found that the trials that opened in CALGB between 2002 and 2005 required a median of 784 days (range, 295 to 1248 days) from initial conception to activation. The CALGB preactivation sequence was noted to involve 370 distinct processes—317 work steps, 42 decision points, and 29 processing loops—of which 63% were beyond the direct control of the principal investigator (PI) and the cooperative group. A follow-up study of the Eastern Cooperative Oncology Group (ECOG) confirmed that CALGB is not unique; in fact, slightly greater complexity is involved in opening a study in ECOG: 481 processes, which include 420 working steps, 61 major decision points, 26 processing loops, and 13 stopping points. In ECOG, preactivation processes consume 54% of the entire time required to conduct a phase III trial. Screening and enrolling patients, administering protocol therapy, and answering data queries are, apparently, the easy parts. At a recent semi-annual meeting of ECOG, the cooperative group’s leaders arranged for the protocol development process diagram outlined by Dilts and Sandler’s team to be printed on large sheets and posted along the wall of a hotel ballroom. Stretching more than 20 feet long, and nearly 4 feet high despite a minuscule font—perhaps aspiring to be the type of environmental installation art that Christo and Jeanne-Claude create—this diagram served as both conversation piece and sobering reminder of the continuing challenges that cooperative groups face. We now know that even when everything proceeds as smoothly as possible—when an experienced investigator has tried to anticipate every imaginable hitch, when it is obvious to all informed observers that the study is asking an important question, when contract lawyers and scientific review committees are feeling particularly genial—still, at least 10 months and nearly 500 individual processes are required to turn a concept into a legitimate clinical experiment. This might satisfy some unimaginative functionaries, but for those of us who care for patients directly, as for our many administrative colleagues who have not forgotten why clinical trials are done—and, most importantly, for suffering patients themselves— these time scales are unacceptable. I am a member of the ECOG Leukemia Committee, and I attended the meeting where the convoluted process diagram was on display. When I walked past the diagram and realized just what it was, it stopped me cold; reflection on the implications caused a surprisingly emotional reaction. Somewhere along the line, our collective research enterprise seems to have lost a critical sense of urgency, confusing the conduct of oncology clinical trials with less-essential processes, such as the update of an automobile design, when last year’s model was just fine for moving passengers from point A to point B in safety and comfort. But there is no comparison: people with cancer are dying of their diseases by the thousands every day (approximately 1,500 daily in JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 11 APRIL 1