In an article published in Trials, Vickers and Scardino1 describe several novel clinical trial strategies that, on the surface, seem to hold some promise for relieving the burdensome aspects of randomized clinical trials (RCTs). The key principles of their paper are that the clinical experiences of patients should be virtually indistinguishable, whether or not they are randomized, and an attempt should be made to randomize every patient. Similarly, the clinical experience of doctors should not be notably altered by inclusion of their patients in the trial. The implication is that the marginal cost of putting an additional patient on trial is negligible. The authors propose minimizing eligibility criteria, relying heavily on obtaining outcomes data from routine clinical information, or from short web-based questionnaires. Vickers and Scardino1 note that developing a trial protocol through cancer co-operative groups such as Cancer and Leukemia Group B is a very slow process.2 Some delay might be attributable to the 'flat' funding that these groups have received for a number of years, which means that individuals at the protocol and data co-ordination centers are required to take on additional tasks. Clearly, there is room for improvement. The seemingly endless delays result in the death of many RCTs; treatment concepts become dated, and pharmaceuticals that held promise when a trial was conceived are no longer exciting by the time the trial is ready for activation. Pharmaceutical companies tend to avoid conducting trials in conjunction with academic institutions and co-operative groups because of delays and costs. An increasing number of RCTs are being performed outside the US, where they seem to be less hampered by cumbersome regulatory requirements and less costly.
We see a number of challenges to performing RCTs in the US. First, patient accrual to clinical trials is poor, representing less than 3% of individuals with cancer.3 Some of the suggestions made by Vickers and Scardino,1 such as integrating the clinical and research databases at an institution, and reducing the regulatory burden, would help to address this issue. Second, federal funding for clinical trials has been decreasing for a number of years, causing data co-ordination centers to be overwhelmed and mandating that only a subset of compelling scientific questions can be selected for RCTs. While superficially such selectivity seems prudent, some deserving avenues of investigation might be abandoned on the basis of cost and difficulty of randomization. Third, increasing bureaucracy presents a challenge. Two highly noble causes have demanded that clinical research be overseen: protection of human rights from abuse; and establishment of a formal structure within which efficacy and tolerability of drugs or devices can be interpreted. Since 1962, when the FDA reviewed the evidence for all pharmaceuticals being marketed, there have been innumerable layers of rules and regulations added, but little has been done to delete rules of little or no benefit.4 Such bureaucracy has led to skyrocketing costs of drug development, the emergence of clinical research organizations, and delays in trial design, conduct and activation. We are saddled with burdensome and duplicative reviews and documentation.
There must be change on a national and international basis. In the US, the concept of a national, centralized Institutional Review Board (IRB) has not been universally accepted. Navigating through the review process with local IRBs can be time-consuming, particularly as regulatory standards and, therefore, the paperwork required, change frequently. IRBs fear inspection, closure of their institutional research efforts, and loss of federal dollars.
A final challenge to the conduct of RCTs, although not explicitly addressed by Vickers and Scardino,1 and perhaps less tangible than the others, is the resistance to randomization shown by some members of the medical community. The urology journals are full of reports of patient cohorts who received prostatectomy or radiation therapy for local prostate cancer. The usefulness of these cohorts is limited because treatment assignment was not randomized; while the author gets a published paper to his or her name, the field is not moved forward. Important medical questions need to be answered, and randomized trials are the best way to do this. We need to consider the criteria by which investigators are evaluated for promotion at research institutions, and put weight on participation in RCTs, even if this does not result in publication. No matter how easy we make the management of clinical trials, we will still need physicians, and patients, willing to participate.
The good news is that many organizations are trying to use technology to increase the efficiency of conducting clinical trials. One example is the National Cancer Institute's (NCI) sponsorship of the Clinical Data Management System (CDMS).5 NCI is purchasing licensing rights for a commercial CDMS software product, as well as installation, support and maintenance services. It will be made available free of charge to all NCI-supported organizations conducting clinical trials in cancer. It will include on-site installation, training materials, telephone and e-mail support, and software upgrades. This system will provide full-function clinical data management capability to the entire NCI-supported clinical research community, allowing researchers to share information within a research organization, with other research organizations, and with the NCI. This enormous undertaking has taken many years of planning and bidding, and would not be possible without NCI funding. At the time of writing, the choice of system has not been formalized.
A number of companies are developing systems to integrate the patient chart and local data management within larger networks of participating institutions. One such company is Velos. Velos eResearch is a clinical research information system. Marketing material states that it "supports patient recruitment, patient scheduling, IRB and study monitoring, project planning, study design, protocol compliance, budget, invoicing, and milestone management; data safety monitoring, adverse event reporting, system integration and study execution".6 Such efforts to integrate data systems take time and require a large financial commitment. For example, the Michigan Institute of Clinical and Health Research recently reported that the annual total cost to run and support the Velos software locally is US$706,000.7 Small research facilities that see relatively few patients are unlikely to have the funds or personnel to take on this type of endeavor. Achieving international compatibility will require a Herculean effort.
Streamlining clinical trials using technology and simplified bureaucracy represents a balancing act. We must continue to safeguard the rights of the patient. Presenting a clinical trial to a patient in a clear manner and obtaining informed consent is a time-consuming process. The patient should not feel rushed and overwhelmed by a menu of trials. We also should be careful not to lose the personal connection with the patient. The relationship between the patient and study team is often the key to high-quality data and high compliance in a trial. Remote reporting of patient symptoms and other measures has definite merit (and is being explored in a number of settings8, 9), but relying too much on technology and not enough on personal contact could be detrimental. In their article, Vickers and Scardino1 also tend to minimize the costs of programming and supporting web-based applications. Different interventions, diseases and stages require different collection tools. There is no one-time cost.
The authors are to be congratulated on proposing some much-needed changes. We should study these suggestions, put egos aside, and try to reinvigorate the clinical trial programs in the US and beyond. By reducing the burden of clinical trial participation, many additional medical questions can be answered, and patients will have more chances to participate.
