Impact of Cancer Research Bureaucracy onInnovation, Costs, and Patient CareDavid P. Steensma, Dana-Farber Cancer Institute-Harvard Medical School, Boston, MAHagop M. Kantarjian, The University of Texas MD Anderson Cancer Center, Houston, TX

The Thomas Edison National Historical Park in West Orange,NJ, is a monument to the prolific inventor’s aphorism that “genius isone percent inspiration, ninety-nice percent perspiration.”1 Batteredworkshop tables and crowded chemical benches bear silent witness tothe thousands of failed prototypes that preceded development of theincandescent light bulb, wax cylinder phonograph, and other techni-cal advances described in Edison’s record 1,093 US patents. Edisonoften went several days without sleeping and might have worked evenlonger hours than a 1960s medical house officer. He so detestedstopping work to wait for supplies from vendors that he kept bins andcupboards stocked with a broad range of exotic materials—anythinghis research teams might possibly need.

If Edison were an American cancer investigator working in theearly 21st century, delays in the supply chain would be the least of hisperspiration-inducing problems. His shirt might be soaked withsweat, but his productivity would likely be meager and his nameunknown at the patent office. Today, the inspirational idealism ofnewly minted medical faculty members with a driving ambition to“cure cancer”—oncology’s Edisons—is being smothered under amountain of red tape, their good intentions crushed by the logisticalreality of what it actually takes to open and execute a clinical study.

Trials of new drugs, especially in oncology, have become a longrow to hoe.2-4 For the last 25 years, well-meaning bureaucratic func-tionaries have introduced countless new regulations without fieldtesting or consultation with clinical investigators. The resulting prolif-erating complexity and unnecessary formalities involved in develop-ing and testing cancer therapies have stifled innovation, driven upcosts, and delayed development of new treatments—factors that mayultimately harm patients.5

Contemporary clinical trial processes are so arcane and Byzan-tine that a new industry has arisen to shepherd studies through thetangled regulatory underbrush: commercial contract research organi-zations (CROs).6 Burdensome auditing and documentation require-ments mean that it is usually easier for pharmaceutical sponsors andacademic medical centers to outsource data management tasks tofor-profit CROs, which themselves introduce new hurdles for investi-gators and have been called by some, “a proliferating cancer within thecancer trial process.” Repeated queries from CROs about minutiaecan seem financially self-serving to investigators, and it is unclear howoften such compulsive oversight translates into improved trial qualityor patient safety. As a result of the increasing regulatory requirementsand the need for CRO involvement, the cost of research per patient on

a phase IIIA oncology trial has ballooned from an average of $3,000 to$5,000 in the early 1990s to a range of $75,000 to $125,000 in 2013. Injust 3 years (from 2008 to 2011), per-patient clinical trial costs in-creased by 70%, without reassurance that we are obtaining propor-tionately more quality for those research dollars.7

A particularly troublesome aspect of trial conduct is the require-ment, rigidly enforced by CROs, for investigators to attribute patients’adverse events occurring during a trial to either study drug or under-lying disease, using subjective scales such as “unlikely to be related,”“probably related,” or “possibly related.”8 This quixotic task is flawedby interobserver variation in adverse event attribution and the multi-factorial nature of clinical developments. In view of this uncertaintyand ambiguity, it is perhaps not surprising that adverse events arereported as related to the study agent more than 50% of the time, evenwhen the study agent is actually a placebo.9

Because clinical trials have become so complex, drug sponsors canpointtothehighdegreeofdifficultyandtheunpredictablecostofbringinga new drug to market as justification for charging a high price once a drugisapproved—aprice that isoftenunrelated to theefficacyof thedrug.10,11

In his E. Donnall Thomas Memorial Lecture at the American Society ofHematology annual meeting in December 2012, Ley12 recalled a 1983azacitidine study he conducted for which the entire protocol had fewerthan 10 pages, an institutional review board (IRB) approved the protocolwithin 1 week of filing, and patients were enrolled and treated the follow-ing week.13 In contrast, the S1117 Intergroup study (ClinicalTrials.govidentifier: NCT01522976), which opened in 2012 comparing the samedrug, azacitidine, to two combination approaches for myelodysplasticsyndromes,requiredmorethan2yearsofpreactivationdevelopmentandhundreds of steps involving the US and Canadian national cancer insti-tutes, various cooperative groups, the National Cancer Institute’s CancerTherapy Evaluation Program (CTEP), and duplicative actions by bur-geoning ranks of local potentates at each of the 244 study locations (morestudy locations than the planned accrual of 240 patients). In our view, thisgrowth in complexity has not convincingly made the clinical trial processsafer for patients, but it has certainly frustrated investigators and patientsand delayed research into potentially beneficial therapies.3,4,14

In 2006, the oncology cooperative group clinical trials effort wassubjected to a formal process management analysis by Dilts andSandler,15-18 who assessed their own institution’s cancer center andVeteran’s Administration Medical Center, and subsequently analyzedthe Cancer and Leukemia Group B (CALGB, now part of the Alli-ance), the Eastern Cooperative Oncology Group, and CTEP. The

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results were troubling. In CALGB, for example, more than 370 preac-tivation steps were identified, and the complete process map, whenprinted, measured 243.5 � 41 inches in 8-point font. The results forthe Eastern Cooperative Oncology Group were similar.16,18 WithinCTEP, 296 distinct processes for phase III trial activation wereidentified, including at least 239 working steps, 52 major decisionpoints, 20 processing loops, and 11 stopping points, with a mediantime from formal concept submission to trial activation of approx-imately 20 months (602 days).19 Dilts and Sandler also identifiedseveral potential so-called infinite loops in each of the activationgauntlets (ie, processes in which one committee could not act untila second committee had made a decision, but the latter was unableor unwilling to act until the first committee had signed off on theprotocol). Most of the steps identified by Dilts and Sandler did notclearly add safety to the study and seemed to primarily serve todelay research and feed a self-sustaining enterprise.

Unfortunately, given the recalcitrant nature of bureaucracies,20

no major changes have occurred in these processes as a result of theanalyses by Dilts and Sandler. If anything, cooperative group bureau-cracy is more onerous in 2013 than it was in 2006. Officialdom tends toproliferate unless external pressure is brought to bear—the US Navy,for instance, currently has more admirals than it has ships (by com-parison, the ratio was 30 ships to 1 admiral in 194521), and the BritishColonial Office reached its employee numbers zenith in the 1960swhen there were no more major British colonies left to administer.22

IRBs have a central duty to protect human subjects. This is oneimportant difference between clinical trials and the inventive activitiesof Edison and his team, who were not experimenting on people andthus could be more tolerant of failure in the trial-and-error paradigm.But IRBs are increasingly entangled in trivia, requiring changes inprotocols and consent forms on the basis of local templates that haveno meaningful effect on study conduct or safety. One investigationdemonstrated that 76% of IRB-required changes were about formrather than substance.23 In one instance in our personal experience, aninformed consent form for a myelofibrosis trial was rejected because asection of the form, copied from a sponsor-provided template, used afont that was not the institutional standard (but still readable). Makingthis font change took only moments using Microsoft Word, but therevised consent form required resubmission and a response out-lining the remediation plan. By the time the IRB approved a revisedconsent form and the investigators received formal minute items,opening of the trial had been delayed by several weeks. In anotherinstance, consent form approval was delayed by a disagreementbetween the investigator, IRB, and study sponsor about whether“itching” should be accompanied by the word “pruritus” in paren-theses, as well as whether itching represented a “moderately likely”or “unlikely” risk, given that the frequency of itching in earliertrials of the study drug was right at the 5% threshold used by theIRB to distinguish these categories. Patients with advanced cancerswaiting for such trials to open might miss important opportunitiesto receive symptom-ameliorating or life-prolonging therapies.

Much IRB scrutiny focuses on informed consent documents. Dopatients actually want, or are they better informed, by the extra infor-mation provided in the more than 30-page study consent forms nowcommon in the United States? A recent study assessed how closelyparticipants in an online genetic study conducted in the United Statesactually read consent documents.24 The investigators estimated thatan average reader would require almost 10 minutes to read the entire

document, yet the median time to consent was just 53 seconds. Parentsconsenting to the study on behalf of their minor children did so evenmore rapidly, with a median consent time of 13 seconds. Only 2.5% ofparticipants identified an embedded hyperlink in the consent formthat could only be found by reading the whole consent material.

The authors’ experience is that many patients base their decisionto participate in a study on their trust in the treating physician andinstitution and do not read the details in the consent forms, even whenencouraged to do so.25 Consent forms frequently include risks that areas numerous as they are improbable or are expressed in language thatis difficult for patients to understand26 so that patients often just askwhere to sign on the dotted line. Although institutions and investiga-tors may perceive consent forms as an important means of providingliability protection in case of an adverse event, successful lawsuitsrelated to poor clinical trial outcomes for patients who had beenprovided detailed consent documents call that assumption into ques-tion; informed consent does not equal indemnification.

Our comments are not meant to focus on any particular IRB,given that the examples we have described are undoubtedly represen-tative of the culture of scrutiny adopted by many IRBs throughout theworld. We acknowledge that oversight is essential to prevent errors orabuse. We suggest that such oversight be more nuanced and decisionsmore rapid, enabling investigators to focus more effectively on theelements of the clinical trials process that truly matter to patient safetyand scientific rigor.

How can we improve on this needless, wasteful cancer researchbureaucracy and bring back brisker clinical trial innovation withoutcompromising patient safety? Both local institutions and nationalorganizations such as the National Cancer Institute and CTEP musturgently review and dramatically streamline their clinical trial pro-cesses. Not every step required for approval adds value to a clinicaltrial; the work of Dilts and Sandler and others who have conductedformal process analyses suggests that only a small proportion of suchsteps do. Steps to trial activation that are in place just because “that’sthe way we’ve always done it,” or because it seemed politically expedi-ent to have a review by an individual or committee with clout, must beeliminated. Human safeguards absolutely need to be in place, but fewof the current obstacles to trial activation serve to protect patients, andthe ultimate affront to human safety is when research studies are leftundone because of bureaucracy, safeguarding only the status quo ofexisting, inadequate therapies.

Given the extent of the clinical trial bureaucracy, it sometimesseems a wonder that successful trials occur at all.3 Imagine if, everytime Edison or one of his competitors such as George Westinghousehad an idea, they had to wait 9 months and let an application toexperiment proceed through numerous committees, each with arbi-trary ideas about how the experiments should be run, to get approvalto try the idea. We would have no recorded music and no electric fans,and instead of seeing films, we would sit at home and read by gaslight.But as dramatic as these technological advances are, they are primarilylifestyle changes. For patients with cancer, the stakes are far greater:bureaucratic impediments to new drug development have the poten-tial to impact their quality of life and survival, factors that strike at theheart of why many of us have chosen to be physicians and oncologists.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe author(s) indicated no potential conflicts of interest.

Comments and Controversies

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AUTHOR CONTRIBUTIONSManuscript writing: All authorsFinal approval of manuscript: All authors

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DOI: 10.1200/JCO.2013.54.2548; published online ahead of print atwww.jco.org on January 6, 2014

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