Summer 2013 

Tony R. Reid, MD, PhD, is the director of the early phase clinical research program at UCSD Moores Cancer Center, University of California at San Diego, and chair of the AACI Clinical Research Initiative's steering committee.

Commentary Overview

* Delivering the right drug to the right patient requires the right clinical trial to provide critical evidence of safety and efficacy.

* The emergence of personalized cancer therapy has dramatically increased the complexity of conducting a definitive clinical trial.

* Clinical trial success can be compromised by many variables including prolonged approval times, slow accrual, insufficient data collection and management, excessive bureaucracy, cumbersome procedures and poor coordination.

* Through its Clinical Research Initiative, AACI has taken the lead in developing effective solutions to the challenges facing clinical trial management.
About AACI Commentary

As part of AACI's efforts to promote the work of its member centers to both general audiences and the cancer research community, AACI has launched AACI Commentary, a quarterly editorial series. Written by cancer center leaders, each edition will focus on a major issue of common interest to the nation's cancer centers.

The Right Drug for the Right Patient:
Optimizing Clinical Trials Management


In a 2010 report evaluating the U.S. cancer clinical trials system, the Institute of Medicine (IOM) concluded that nearly half of all trials are not completed due to excessive bureaucracy, cumbersome procedures and poor coordination, and that the clinical trial infrastructure was approaching a state of crisis. While universities and pharmaceutical companies are identifying the molecular foundations of cancer and developing drugs specifically targeted to these oncogenic pathways, the ability to consistently deliver the right drug to the right patient remains elusive. As the IOM report indicates, there is emerging recognition that delivering the right drug to the right patient requires conducting the right clinical trial to provide critical evidence of safety and efficacy.

Success in defining the causes of cancer has broadened our understanding of its complexities and sharpened our focus on therapeutic targets, opening the door to personalized cancer therapy. However, such therapy, based as it is on molecularly defined genetic and epigenetic expression patterns, has dramatically increased the complexity of conducting a definitive clinical trial. For example, while there are about 46,000 new cases of pancreatic cancer per year, only about three percent of patients enroll in trials. Consequently, only about 1,300 patients are available to help develop the knowledge needed to identify the best treatment options for pancreatic cancer. With molecular characterization, this group of willing patients will be subdivided into even smaller groups. For example, if less than 10 percent of these patients have the right genetic phenotype to qualify for a specific targeted therapy, then only about 100 patients nationwide would qualify for the study. With such limited availability of appropriate patients, bringing the right trial to the right patients requires a new, efficient and integrated approach to clinical research that crosses geographic, financial and institutional boundaries.

Clinical trial success can be compromised by many variables. For example, a large fraction of clinical trials are terminated due to prolonged approval times and slow accrual. Recent studies have described the complex processes for initiating and maintaining clinical trials and the increasing clinical trial management burden being placed on investigators and clinical research teams. The proper execution of clinical trials requires considerable institutional commitment and resources. Notably, activation processes, including Institutional Review Board review and approval by other institutional committees, are costly and essentially independent of enrollment. Therefore, low accruing trials are of particular concern because of high cost and minimal benefit. An analysis of 831 clinical trials found that up to one-third of institutional trials enroll few if any patients and, consequently, have little scientific or clinical merit but consume considerable resources. Another analysis of 764 trials supported by the National Cancer Institute's Cancer Therapy Evaluation Program between 2000 and 2007 found that 82 percent of studies were not completed within the expected period of enrollment, and 37 percent failed to achieve minimum accrual goals by the time of study closure, regardless of how long the study remained open.

The ongoing maintenance costs of low accruing trials add to the overall cost with little additional benefit. As a practical matter, a large fraction of institutional costs are incurred before enrollment can begin, and predicting trial enrollment is complicated and inexact. As a result, closing low accruing trials cannot recover lost resources. Therefore, it is critical to address one of the root causes of low accrual--the prolonged approval process.

Recognizing the rising cost of slow accruing trials, former Food and Drug Administration Director Mark McClellan has recommended a number of measures to "bend the curve" to improve medical care quality and accelerate the development of novel cancer therapies while limiting overall cost. These proposals seek to reward operational efficiency and effectiveness over volume and strike a more rational balance between regulation and market forces. One effort to accelerate the drug approval process is the iSpy-2 trial supported by the Foundation for the National Institutes of Health. The objective of iSpy-2 is to pilot an adaptive clinical trial methodology that would allow for the rapid evaluation of new therapeutics, promoting the most promising therapies for accelerated development. However, reliable testing of multiple drugs within the same protocol must be done with equipotent dosing schedules. Otherwise, active drugs may fail due to suboptimal administration rather than lack of efficacy. In addition, graduation of drugs could be constrained by delinquent data, leaving the trial well behind its accrual and graduation goals. Complex trial designs impose additional challenges for enrollment, trial amendments and data management, while barriers to successful completion of the trial include understaffed research teams, off-mission mandates, high staff turnover and the high cost of replacing and training new staff members. Nevertheless, if executed effectively, the iSpy approach could accelerate the efficient development of new therapies and the progress of this trial will provide valuable information to guide future efforts.

To address the data bottleneck, the federal government has mandated implementation of electronic health record (EHR) systems, with penalties for failure to achieve meaningful use starting in 2015. In conjunction with the adoption of EHR, the processes involved in the management of clinical trials has evolved significantly in recent years, primarily due to the migration of clinical research data from paper-based systems to electronic data capture (EDC) systems.

Despite the availability of EHR and EDC systems, data quality remains well below potential standards, especially in the areas of patient safety and clinical efficacy. One of the primary shortcomings is limited institutional capacity for managing data integration between newly adopted EHR and EDC systems and legacy institutional systems. In addition, manually moving data between these systems diverts the time and expertise of highly trained physicians and research teams away from patient care. Moreover, many clinicians do not have the expertise for managing these complex operational issues.

The mandated implementation of EHR systems provides a portal for improving acquisition and analysis of clinical research data. However, the proliferation of different EHR and EDC systems poses logistical and integration challenges, while improvements and updates to different database systems require ongoing maintenance to effectively and accurately share data. In the absence of effective data sharing between systems, manual data entry becomes necessary, leading to duplication of effort. Of even greater concern are the substantial hidden costs in providing quality assurance for the various databases, including correcting entry errors and other deficiencies.

It is imperative that we relieve physicians and research staffs of the operational burdens associated with clinical trials and allow them to focus on developing the knowledge and evidence needed to efficiently deliver effective cancer therapies. To help achieve that, AACI, through its Clinical Research Initiative (CRI), has taken the lead in developing effective solutions to the challenges facing clinical trial management.

Now in its fifth year, AACI's CRI provides a forum for clinical research leaders to share information and to advocate for improving the national clinical trials enterprise. The initiative's activities are led by a steering committee of oncology clinical trials medical and administrative directors who are experts in clinical trials operations, and its success is driven by Special Interest Groups (SIGs) that create and implement new tools to share across the AACI cancer center network. To date, the following seven SIGs have been established: Academic, Industry and Government Relationships; Business and Administration Integration; Managing Networks and Subsites; NCI Clinical Trials Reporting Program; Regulatory and Pre-Activation Processes; Training, Quality Assurance and Monitoring; and Trial Metrics.

References for this article and further reading on clinical trial management are available here.

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