Oncology compounds comprise about one third of the development projects in the pharmaceutical and biotech industry (see Figure 1). The features of oncology projects, while not unique to this therapeutic area, do create unique challenges and opportunities in clinical study management. These clinical programs often have a number, if not the majority, of studies done with an open label design. This allows the sponsor to make the most out of the near real-time information that comes with an EDC study. 

Oncology therapies are often toxic and the subjects involved in their trials are often chronically ill. Also, the ultimate utility and optimal combinations of these drugs may not be understood fully until after a number of postapproval studies are completed. These studies will often be conducted outside of the sponsor's control. EDC may be helpful in assisting the sponsor to become more aware of the conduct and outcome of Phase IV studies. 

Figure 1. A breakdown of the number of Phase IâIII trials conducted for various conditions. 

As I will discuss, these and other challenges make using EDC not only desirable but also indispensible in doing work in the oncology area. 

EDC in oncology has a number of functional challenges that must be addressed in order to fully utilize its potential. Among these challenges are study design issues, capturing measures of study efficacy, study safety monitoring, and the management of study logistics. Even simple dose escalation designs in oncology studies are compounded by complex stratifications such as prior therapy or specific indicators. These indicators may be as routine as baseline or treatment emerging platelet and white blood counts or as complicated as experimental tumor markers. Dose escalation within cohorts may also be dependent on a number of host or tumor response criteria. Pre-arranged study rules can optimally ensure subject safety as well as maximize the information learned from the study. These rules may result in data-driven dynamic study visit designs for multicycle visit schedules. 

Sophisticated EDC systems can accommodate these variations and can also allow for dynamic and "morphing" case report forms. It is also possible that patients can be enrolled in multiple complex treatment groups depending on the study conduct.  Adaptive study designs with creative statisticians and configurable EDC systems are required in order to do this properly. It is also extremely helpful to have an integral drug grouping assignment tool—whether delivered by a telephonic interactive voice response (IVR) technology or whether configured directly into the EDC study software. 

When imaging data are being collected, it is also optimal to integrate the logistics of the imaging data with the rest of the clinical trial data. 

The fact that many if not most oncology studies are open label allows sponsors to have much greater insight into the efficacy of their compounds than a double blind study. Ongoing determinations of efficacy are certainly useful and are the norm with real time data displays. Efficacy by subgroup (i.e., tumor biology, patient history, dose level, dose duration, drug combination, etc.) can be determined earlier than with paper and, as noted, can be important in adaptive designs. This feature has important practical issues, particularly with lightly capitalized single-product companies, as data are critical to raising additional funding. The faster the data are available, the more easily small companies can garner venture funding for their work. 

As a derivative of having real time data, real time calculations of tumor response such as RECIST scores (Response Evaluation Criteria in Solid Tumors) can also be displayed as soon as data are available following blinded reads. Sponsors are able to empower experts to review and analyze data in real time. Further, interaction and importing data from third-party image analysis experts can also be done in near real time for confirmation of the data. Finally, a very frustrating source of queries when performing oncology studies with paper data collection is overlooking a target lesion. Sometimes these data cannot be retrieved if the proper imaging modality was not performed at the appropriate time. The best EDC systems in oncology are specifically focused on this issue and make it impossible to forget the evaluation of an indicator lesion. When the EDC database is coupled with the image analysis database from the outset, it is logistically much easier to ensure the timeliness and completeness of the image data. 

Helping to ensure subject safety is probably the most compelling reason to use EDC in oncology studies. The studies are complicated and frequently long—and sometimes will feed into another study. As mentioned, the subjects are often chronically ill or will become so during the duration of the investigation. The study medications often have a very narrow therapeutic index and their tolerability in any individual subject may be determined by a number of factors besides simply the dose and duration of treatment. Finally, with the dual trends of recruiting large numbers of sites and having many of those sites outside the United States, using EDC technologies becomes critical if the sponsor has any hope of understanding treatment emerging events during the study. 

Besides a more "macro" approach to ensuring patient safety, EDC offers a number of other advantages that should be highlighted. Reporting adverse experiences in oncology studies may be carried out in a number of ways. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), or the older Common Toxicity Criteria (CTC), and potentially also continuing to code in the Medical Dictionary for Regulatory Activities (MedDRA), these dictionaries can be linked to the appropriate auto-encoder software. The most sophisticated electronic data management companies are capable of managing this and streamlining the coding process. 

Another huge advantage with EDC is the ability to better visualize the concurrent medications (ConMeds) the subjects have been given. While this is a frequent source of data queries in a paper-based process, this is not the case with the appropriate EDC environment, where the software will require full accounting for these medications. 

Sponsor notifications can also be set up to send alerts when specific events occur. By setting up alert notices ahead of time, sponsors can be assured they will be notified of conditions of interest whether favorable or unfavorable in real time. 

As mentioned, two trends that seem to have emerged in drug development are a greater need for larger studies and a greater emphasis on placing sites outside the United States and Western Europe. Also, as we acquire a greater understanding of tumor markers (how they might affect treatment response and how other individual patient characteristics may impact therapy), there will be a greater need to stratify studies to balance these characteristics. These factors make eligibility criteria more restrictive and will make studies more difficult to enroll. 

EDC technologies and real-time data display can both temporally and geographically unify the study environment, wherever the sites are located. Study operations data, such as site qualification administration, enrollment and randomization, image capture verification, grant payment data, and clinical trials supply data, flow rapidly and ensure that the study runs smoothly. Specific randomization algorithms and clinical dosing packets can be controlled with the EDC software. A unified randomization system (whether via telephonic IVR or computer-based) can be modified as the study needs demand. Further, since enrollment and subject randomization logs can be monitored in real time, adjustments may be made to eligibility criteria or study design to improve enrollment and ensure that the study is completed. 

EDC technologies also allow subjects and their full data sets to roll over seamlessly from shorter studies to longer studies if the clinical development plan requires this. In a similar manner, subjects can be transferred from one site to another if needed. Also, since many oncology studies are done in academic centers, site staff are both accustomed to using EDC technologies and actually expect them to be used. 

To run oncology studies optimally, a number of EDC technology features have to be part of the system. Certainly the system should have excellent responsiveness and speed needed to perform complex edit checks on the data collection forms. This generally implies that the edit checks can "fire" in real time. Flexibility and study rapid modification and validation may be necessary to handle adaptive study designs and the changes in the study that come as a result of emerging data, such as additional cohorts, changes in study size, additional visits or trial extensions. Fully integrated IVR or computer-based randomization linking directly with the study database will be needed to manage patient enrollment and treatment allocation, particularly if they are modified during the study. 

In terms of capabilities, the EDC system should be able to:  

Accommodate lab imports, both central and university labs, in a manner compliant with 21 CFR Part 11, which generally means that lab data should be collected in the system and not entered on noncontrolled electronic spreadsheets

Allow for the viewing of lab data in real time, along with all of the other data, including selected imaging derived data

Include patient logs as a feature and couple this with real-time data display that is accessible for all data at any time

Allow for bar coding input for large volumes of samples and be flexible so that a variety of users (under the sponsor's permission with password control) have access to the data.

As mentioned, two features that are must-haves with oncology studies are modules to track and compare indicator lesions and modules to track ConMeds and adverse events. These should be internal to the system, as they are critical in reducing the number of data queries in oncology studies. 

In addition to the EDC system, the reporting technologies are also extremely important in gaining the most from the oncology study. The reporting system should be customizable and easily configured to provide rapid interim data snapshots. Data summary displays and patient outcome reports can shorten the eventual reporting time and can speed clinical decisions. Finally, the system and the reporting structure should have an "event notifier" that provides a specific report to the sponsor or the sponsor's agents should an event occur (such as a serious adverse events, a complete response or some other event of particular interest) that is important. 

If the EDC vendor has a variety of other integrated data related services (e.g., IVR, data management, clinical safety, image analysis or statistics), it becomes much easier to maximize the full potential of EDC technology. Staff are completely familiar with navigating the complexity of oncology studies in the system on which they are working (which may be untrue for a CRO) and can more easily provide the sponsor with all the data the sponsor needs. Staff can also configure reports for both specialized data management and for integrated site management functions, such as grant payments. When the technology is fully utilized, it may also be possible for vendors to pass on their efficiencies to sponsors in the dual benefit of increased performance and cost reductions. 

EDC in oncology can provide a huge number of benefits over paper-based approaches. However, the EDC system and the services chosen are critical to realizing these benefits. 

Not every EDC provider can provide all the features needed to maximize the clinical program. Vendor experience and the EDC system features designed for oncology studies are critical factors for success. The feature mix needed to optimize these studies is a lesson that is learned over years; and since not all EDC systems are alike, it is critical to ensure that the system to be used can be correctly characterized and has a proven ability to work within the oncology field. 

William Claypool, PhD, is president of Phoenix Data Systems, 901 East 8th Avenue, Suite 201, King of Prussia, PA 19406, email: 

Articles

Feature Article

Functional challenges aside, electronic data capture can improve cancer clinical trials.

EDC Possibilities in Oncology

Oncology clinical trials routinely rely on tumor assessments using medical imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) to demonstrate the efficacy of cancer therapies. While these technologies have greatly enhanced the development of oncology drugs, they also present trial sponsors and the scientific community with a number of challenges. One of the complexities surrounds the application of published accepted assessment criteria for imaging reviews in oncology trials. 

 (Photography: Ghislain & Marie David de Lossy, Getty Images) 

Among the most utilized assessment criteria in oncology clinical trials are Response Evaluation Criteria in Solid Tumors (RECIST),

  and the International Working Group Response Criteria for Non-Hodgkin's Lymphomas.

  While these guidelines have greatly improved the level of consistency and harmonization for the assessment of medical images, they don't often address the rigor needed for standardized assessments. Even the most widely utilized  accepted oncology assessment criteria require additional clarifications in order to provide a more objective and harmonized tumor response assessment that is tailored to the needs of the given oncology indication and clinical trial. 

The rate of change in both imaging technology and cancer therapies is a major factor behind the need to refine and clarify published assessment guidelines. Although current assessment criteria incorporate many of the existing imaging modalities, the constant improvements in imaging technology make it challenging for any published guideline to reflect the most recent developments, or to take into account the growing availability of certain technologies such as positron emission tomography (PET). 

Furthermore, the biopharmaceutical industry is continually developing novel treatments that target cancers in unique ways. For instance, there is an increasing trend within the industry to develop cytostatic compounds where tumor shrinkage as an outcome is unexpected or compounds that promote an immune response where tumor shrinkage may be delayed and preceded by interval tumor growth. These new approaches often require variations and flexibility in developing imaging assessment criteria to detect and measure disease responses in different and sensitive ways. 

Even when the guidelines are as up-to-date as possible for a particular indication or investigational setting, they are often not detailed enough to cover all the variables that arise when studying a specific oncology therapy. Current assessment criteria are not applicable for every indication in the same way. 

For example, RECIST is a common accepted criteria for solid tumors, and an ovarian cancer trial, melanoma trial, and prostate cancer trial may all use RECIST. However, there will be some differences in how RECIST is applied to each of these indications. The ovarian cancer study may utilize tumor markers to assess response, while the melanoma study may include measurements of skin lesions. Similarly, a prostate cancer trial may include patients with only nonmeasurable disease as part of the study population. In short, the published assessment criteria should not be considered as definitive but rather as a foundation upon which to build and refine. 

By further clarifying assessment criteria, the consistency, reliability, and usability of the imaging assessments may be enhanced. The optimal application of the assessment criteria ensures a more consistent and robust imaging review process that validates the treatment response and outcome of a trial. 

When evaluating the assessment criteria for implementation in a clinical trial, numerous factors must be taken into consideration, including: the applicability of the assessment criteria and specific imaging review challenges associated with a given cancer indication; recent studies that may have shed new light on a particular indication, mode of treatment or imaging technology; current accepted practices by regulatory authorities, such as the FDA and EMEA; and the specific imaging equipment used at the various trial sites. This will ensure that objective, comprehensive, and sensitive assessment criteria are in place for optimal reviewing consistency and reliable results. 

 Several of the medical and technological considerations related to oncology trials and medical imaging that should be addressed when clarifying the assessment criteria to support objective and harmonized reviews include but are not limited to the following recommendations (the examples provided are hypothetical for a Non-Hodgkin's Lymphoma trial): 

Developing clear definitions of measurable and nonmeasurable disease: For example, should nodules in solid organs qualify as measurable disease, and if so, under what circumstances?

Establishing and defining the number and categories of selectable measurable lesions: For example, should measurable nodal disease and measurable organ nodules be distinct categories?

Determining which modalities are to be used to identify and assess measurable lesions: For example, can physical exams be used to identify and assess measurable nodal disease?

Anticipating changes in modality for tumor assessments during the trial and defining rules for assessment of those cases, if applicable: For example, can measurable nodes continue to be measured if there is a change from CT to MRI halfway through the study, and if so, under what conditions?

Creating clear response assessments for nonmeasurable disease: For example, should progressive disease of nonmeasurable nodal disease be based on a visual estimation of a percent size increase from nadir?

Defining minimum requirements for new lesions: For example, should new organ nodules be of a certain size to be considered new lesions?

These factors and others must be considered when developing an objective and comprehensive review process that provides credible, dependable, and uniform results that will withstand scrutiny by regulators or the scientific community (Table 1 provides further considerations for clarifying assessment criteria). Hence, a careful analysis of how a given criteria will apply to a particular oncology indication and clinical trial is a critical element to trial success. 

Table 1. Considerations when clarifying assessment criteria for oncology trials.

The benefits of imaging technologies in the development and clinical testing of oncology therapies are well established.  MRI, CT, and other imaging modalities can provide faster results in determining the efficacy of novel cancer treatments.  At the same time, the rapid development and growing complexity of imaging technologies, the increasing development of compounds with unique mechanisms of action, and the unique features of specific tumor cell types create significant challenges concerning image variability and accurate assessment of imaging data to determine disease response in patients. 

While published assessment guidelines have brought much needed standardization to the process of analyzing medical images in oncology studies, it is vitally important to go beyond these basic guidelines when establishing criteria for tumor assessments. Modifying the guidelines to fit the specifics of each trial and indication and defining the review process as precisely as possible can greatly reduce the variability and increase the reliability of the data from advanced imaging technologies. The result may be faster development and approval of new therapies for serious diseases—an outcome that benefits everyone. 

* MD, is medical director of oncology and 

, MS, MTPW, is senior medical writer at Perceptive Informatics, 200 West Street, Waltham, MA 02451, email: 

*To whom all correspondence should be addressed.References 

1. P. Therasse, S.G. Arbuck, E.A. Eisenhauer et al., "New Guidelines to Evaluate the Response to Treatment in Solid Tumors," 

WHO Handbook for Reporting Results of Cancer Treatment

, Offset Publication No. 48 (Geneva, 1979). 

3. B.D. Cheson, S.J. Horning, B. Coiffier et al., "IWC: Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas," 

Current guidelines for reviewing medical images need to be refined and clarified so that consistency becomes the norm.

Standardizing Tumor Assessment Criteria

The European Organization for Research and Treatment of Cancer (EORTC) has adopted a proactive pan-European strategy to develop, conduct, coordinate, and stimulate high-quality, science-driven translational and clinical cancer research, building on the rapidly evolving discoveries of clinicogenomic research.

  Implementation of the European Union Clinical Trials Directive 2001/20/EC, originally intended to protect the rights and well-being of human subjects and facilitate the regulatory procedures for the conduct of European clinical trials,

  continues to pose a major challenge for all those willing to initiate investigator-driven clinical trials. 

Additional hurdles to conducting clinically relevant cancer trials include the increasing costs of both translational and clinical research as well as the ever growing trend toward globalization of cancer research. New strategies are clearly required. As a leader in clinical cancer research over the past 45 years, the EORTC continues to devote its multidisciplinary expertise and research infrastructure platforms to further improve the standards of cancer care, advance the scientific understanding of the disease, and address pivotal strategic therapeutic questions. 

Dr. RÃ©my von Frenckell, director of methodology and operations; Dr. FranÃ§oise Meunier, director-general; and Dr. Denis Lacombe, scientific director (left to right). 

The EORTC is well positioned to forge new directions in clinical cancer research. EORTC clinical trials carried out within the EU, other European countries, and across the world accrued more than 20,000 patients in the period spanning 2003 to 2007. This total includes just over 5000 patients recruited alone in the year 2007. Annual follow-up continues on a further 30,000 patients from past EORTC trials and the EORTC clinical database, housed at the group's headquarters in Brussels, now contains treatment outcome data for over 160,000 cancer patients. Fifty-six clinical trials are currently ongoing at the EORTC and actively enrolling patients. 

In recent years, multiple novel agents have been discovered due to the remarkable developments in the understanding of the molecular basis of cancer. Further breakthroughs in the prevention, diagnosis, and treatment of cancer will be achieved primarily through translational research projects, efficient drug development, and the conduct of translational research-driven, large prospective randomized multicenter clinical trials. These require a global cooperative partnership approach coupled with new models of collaboration and funding to guarantee independent evaluation of new standards of care. Further significant improvements in the survival of cancer patients will depend on the ability of researchers to discover new drugs and novel treatment strategies tailored to the individual patient and to specific disease characteristics. 

To meet the challenges of clinical cancer research in today's molecular era, the EORTC established the Network of Core Institutions (NOCI) to promote, support, and conduct high-quality translational research-rich trials across the EORTC disease-oriented groups. This strategy optimizes the transfer of basic molecular research discoveries to the development of targeted tailored cancer therapies in terms of time and quality by capitalizing on the broad research expertise and infrastructure of large institutions located in various European countries. Innovative translational research concepts are prioritized and evaluated in early Phase multitumor line trials. Further development is based on early trial outcome results, prospectively streamlined for validation in disease specific pivotal large Phase III confirmative EORTC trials. This represents a new project-focused research strategy that is time, resource, and financially efficient while at the same time provides a collaborative opportunity for both public and private sector research partnerships. 

NOCI trials involve innovative complex study designs, elaborate translational research, and allow for the large-scale collection of blood and tissue samples or biospecimens in a prospective manner. A centralized independent EORTC tumor biobank facility will provide for the storage and management of a representative selection of these biospecimens with electronic linkage to a treatment outcome database. The NOCI initiative represents an unmatched potential not only for the advancement of cancer research but also for investigators, patients, and governments faced with the financial challenges of providing all citizens with the best standards of care. The NOCI strategy also addresses and guarantees the future of independent academic clinicogenomic cancer research in Europe. 

The EORTC developed a classification system that defines three broad categories of trials and utilizes this categorization to determine the place of each new trial proposal within its overall scientific strategy. High priority trials include randomized Phase III studies designed to answer a question that directly contributes to defining new standards of care or those with a strong "targeted" translational research component that may permit a fundamental advancement in the understanding of a particular cancer. A second application of this approach allows for the prioritization of resource and/or funding allocation. 

This categorization facilitates the selection and prospective development of early phase multitumor clinicogenomic studies as well as "niche" specific and multimodality trials, thereby increasing the success of discovering and developing new standards of care. The EORTC will stimulate this scientific strategy by awarding several grants in 2008 for academic and clinicogenomic trial research proposals with the highest promise of defining new standards of cancer care. 

In addition, the EORTC is actively seeking new ways to collaborate with national cancer research groups within Europe to address specific strategic research questions involving multimodality cancer treatments, such as surgery and radiotherapy and to guarantee the study of the less common types of cancer. These goals are achievable through highly specialized large Phase III trials conducted in niche areas of disease-specific expertise and the pooling of patient accrual at a pan-European level. This approach also permits the best use of locally developed technical, scientific, and research expertise in nationally run clinical trials. 

This strategic approach to future EORTC clinical cancer research has a multilevel built-in mechanism to ensure and oversee the independence of EORTC research. This mechanism consists of several committees made up of experts that review and advise on all prospective EORTC clinical and translational research proposals and include the New Drug Advisory, Translational Research Advisory, Protocol Review, Scientific Audit, Quality Assurance, Independent Data Monitoring, Membership, and EORTC Headquarters Institutional Review Board Committees. 

The EORTC headquarters, based in Brussels, is a central facility staffed by more than 150 members representing 14 different nationalities and provides all necessary support and management of EORTC clinical trials to a unique network of investigators located in 300 hospitals throughout Europe. 

The EORTC has taken significant steps toward building upon successful past research initiatives; to setting standards for high-quality, scientifically sound, and clinically relevant cancer research; to working toward broader pan-European collaborations; and to establishing solid foundations for cancer research that will extend well into the 21st century. 

is a consulting medical communication manager for the EORTC and a radiation oncologist with 20 years experience in the field of clinical trials. She can be reached at: 

1. European Organisation for Research and Treatment of Cancer Current Research and Strategies Report 2008-2009, available at: 

2. Directive 2001/20/EC of the European Parliament and of the Council, available at: 

www.eortc.be/Services/Doc/clinical-EU-directive-04-April-01.pdf

Viewpoint

How one group is transforming clinical cancer research across all of Europe.

New Strategies for Research

In oncology research, medical imaging is used to evaluate anatomical biomarkers such as change in tumor size. To document and quantitatively measure tumor change due to cytotoxic drug treatment, researchers measure and evaluate tumor size using computed tomography (CT) or magnetic resonance imaging (MRI) scans and Response Evaluation Criteria in Solid Tumors, known as RECIST criteria. 

 (Photography: Medioimages/PhotoDisc, Getty Images ) 

Emerging cancer therapies known as vascular-targeted compounds halt the flow of blood to and from the tumor, causing cell death within the tumor well before it actually begins to shrink. This cannot be measured by RECIST assessment. An emerging imaging procedure known as dynamic contrast-enhanced (DCE)-MRI is a more appropriate measurement of the effectiveness of vascular-targeted therapies because it can show metabolic changes such as the rate of blood flow to the tumor. 

This article will compare vascular-targeted and cytotoxic cancer treatments, introduce the DCE-MRI procedure, discuss the image acquisition process, and review some important considerations when planning oncology trials. 

Cytotoxic drugs used for the treatment of cancer (chemotherapy) interrupt the division of rapidly dividing cells, resulting in the shrinkage and ultimate destruction of cancer tumors. For clinical trials focusing on the effects of cytotoxins, tumor response is used as a biomarker and is measured at various stages using X-ray, CT, and MRI and evaluated by RECIST assessment. 

In contrast to cytotoxins that focus on the tumor itself, vascular-targeted treatments disrupt the tumor's blood supply. A tumor cannot survive without oxygen, which is delivered along with other critical nutrients by the blood. Disrupting the flow of blood to the tumor prevents the growth of new cells and inhibits tumor expansion. 

The formation of new blood vessels by the tumor, known as angiogenesis, can be inhibited by anti-angiogenic treatments. In contrast, vascular disrupting agents target existing blood vessels. Restricting the tumor's blood flow must take into account—and possibly target—both new and established vasculature. 

The potential of vascular-targeted cancer therapies is widely recognized by the medical and research communities. A variety of anti-angiogenics and vascular disrupting compounds are in development or undergoing clinical trials. Tumor size, the preferred biomarker for clinical trials involving conventional chemotherapy agents, is not appropriate for trials involving vascular-targeted treatments because shrinkage may not occur until well after blood flow has been halted. Instead, DCE-MRI is used to measure whether blood flow to the tumor has decreased, indicating the success of treatment. 

Primarily used in Phase I, the DCE-MRI provides physicians with two- or three-dimensional images taken as the patient is being administered an IV solution of paramagnetic contrast, the same gadolinium-based compound used in regular MRI studies. 

Specific image acquisition and contrast injection techniques make possible the measurement of blood flow to the tumor. Prior to dynamic imaging, an initial image is acquired to establish the tumor's location and provide baseline anatomical data. Dynamic image acquisition consists of continuous scans made at five- to 10-second intervals over a five to 15 minute time frame. 

Gadolinium administered concentrates at the tumor. As it circulates through the tumor vasculature, the contrast's paramagnetic properties permit blood flow to be visualized. Blood flow can be quantified using a special algorithm. Compared to tumor shrinkage, this biomarker allows the response of blood vessels to vascular-targeted cancer treatments to be detected and measured very rapidly using DCE-MRI techniques. 

DCE-MRI has many benefits in clinical trials. Besides indicating earlier anatomical response to the treatment, the technique does not involve ionizing radiation. In addition, it provides high-quality images and can be conducted using fairly common imaging center equipment, the 1.5 Tesla MRI scanner. 

Because the intricacies of DCE-MRI allow measurement variability to be introduced at numerous points, study protocol must be appropriately designed and strict quality control procedures must be followed. Due to the complexity of the imaging process, the choice of an imaging facility is critical to the success of the DCE-MRI study. 

Although many imaging centers use the 1.5 Tesla MRI scanner, the image acquisition process is much more complicated than conventional MRI techniques. Imaging technologists must be specifically trained in the imaging protocols to produce high-quality images, minimize variance, and ensure accuracy. The imaging technologist must pay special attention to precontrast scanning, contrast injection rate, and dosage and image timing and analysis. 

The DCE-MRI technique is most effective for studying areas of the body that are not impacted by involuntary patient movement, such as the central nervous system, pancreas, breast, brain, and bone marrow. Lung and liver tumors are more challenging because they are influenced by respiratory-related motion, leading to motion artifact. In such cases, patient movement should be incorporated into the clinical study design, including variables such as sample size, patient recruitment or exclusion criteria to filter out high-risk patients. 

In addition, imaging equipment and software in multicenter trials requires standardization of equipment and uniform image acquisition across all sites. For this reason, single center trials are more feasible than multicenter trials. If a multi-center trial is needed, an imaging CRO should be selected based on its ability to manage data from multiple sites and modality vendors, and should be able to qualify hardware and software very early in the trial process. 

Likewise, a standardized reading process should use independent physician readers who have received specialized training in reading and analyzing DCE-MRI images, including inter- and intravariability training prior to reading any studies. A centralized reading process ensures that the same software and analysis techniques are used by all radiologists.  

DCE-MRI is an important emerging imaging technology in the research and development of emerging vascular-targeted cancer therapies, which prevent blood flow to and from the tumor. Because it provides visualization of the tumor's vasculature, allows blood flow to be quantified and measured rapidly, and shows earlier tumor response to treatment, DCE-MRI is a more effective biomarker than tumor shrinkage for studies of anti-angiogenic and vascular disrupting compounds. Although DCE-MRI studies use standard MRI scanning equipment, the image acquisition process is much more intricate than for conventional MRI scans. 

As vascular-targeted cancer therapies advance and more compounds are developed, the role of DCE-MRI technology in cancer trials will grow. Thorough study planning and protocol design, including careful training of imaging technologists and physician readers, is required to ensure high-quality images and accurate readings, as well as to minimize variance. 

 is the founder, chief executive officer, and medical director of ProScan Imaging, Inc., and ProScan MRI Education Foundation, and the chief medical officer at WorldCare Clinical. 

* is a senior radiology resident at the University of Illinois at Chicago and a research assistant at ProScan Imaging Midtown, 5400 Kennedy Avenue, Cincinnati, OH 45213, email: 

*To whom all correspondence should be addressed.

Dynamic contrast-enhanced MRI meets the needs of emerging cancer therapies that suffocate tumors.

Latest Imaging Technology a Good Fit for New Therapies

Measurement of workload is a complex, multifaceted area and an important but difficult subject. In reviews of measurement methods, radiotherapy workload is de scribed as being "poorly represented" by the use of simple parameters, as they do not contain any measure of treatment complexity.

(Photography: Jim Shive Illustration: Paul A. Belci) 

In the specialties of oncology and hematology, recruitment figures are the main focus of performance management, with little consideration given to study complexity, phase, and status of subject. Yet, these are key factors when considering workload and study complexity.

There is very little published on clinical research workload measurement, complexity, and capacity. The only comprehensive study, which was undertaken in Canada, expressed the need to be able to estimate specific costs and resources associated with clinical trials as the main reason for the study.

  The study measured trial activity throughout the study process and identified sponsor and study phase as important factors to consider when estimating cost and resource use, but it did not result in a complexity scoring tool. 

Within the UK, some work on trial complexity and parameters for scoring were presented at a recent conference.

  The components used included the areas of screening, randomization, treatment, pharmacovilgilance, samples and questionnaires, and tumor assessment and treatment. An interesting inclusion was that of patient group. 

In other studies, work activity over a certain number of days has been measured to try and determine research related costs.

  In other areas, instigation of monthly workload reporting has occurred, including the recording of number of queries and safety reports submitted in an attempt to quantify workload. An attempt to define the number of patients and trials that could be dealt with by nurses and data managers depending on complexity has been made; the conclusion being that it allowed more effective planning and flexibility to meet the changing demands of clinical research. 

Related work has also been undertaken by the European Organization for Research and Treatment of Cancer (EORTC) Clinical Research Coordinators Group. This is work in progress that is looking at the development of a workload measurement instrument by initially doing workload analysis to determine the staff requirements for a set of tasks by reviewing the processes, frequency, and time required. The group has echoed the sections developed within this tool (i.e., set up, recruitment, and follow up) by reviewing planning, implementation, data collection, and closure (see Table 1). Further collaborate work is planned with this group. 

The Complexity Scoring Tool Broken Down by Section and Category 

Therefore, although there is very little literature and work in progress, attempts have been and are being made in this important area. 

If a complexity scoring tool enables units to demonstrate the complexity and components of the work they undertake, then it can also act as a valuable communication tool both within and outside the organization. The tool the author used in a pilot study was developed over a year with a research team and in collaboration with research colleagues. 

The tool was designed to score studies according to complexity across five categories. Each study was initially allocated a predicted category according to its requirements to allow comparison. Once developed, the complexity tool was piloted by volunteers throughout the UK, who were asked to review face validity, reliability, and repeatability by undertaking three different exercises. 

The tool was developed in response to problems and requirements related to clinical research management at a cancer center within a Clinical Trials Unit in the UK that organizes predominantly multicentered research studies coordinated elsewhere—the majority of which are Phase I to III. The pilot tool was reviewed by research teams based mainly in NHS Trusts within England and Wales; all but one of the participants worked within the specialities of oncology and hematology. 

In terms of participants, from the 36 pilot packs sent out to people who had expressed an interest in piloting the tool, 18 (50%) completed the face validity exercise, 14 (39%) completed pilot tools for the reliability exercise, and eight (22%) completed pilot tools for the repeatability exercise. 

It was concluded that the idea and the tool were worth further development based on the findings of this project and with consideration of the following recommendations:  

A future project should be a large, multicentered, prospective study reviewing current workload (with ongoing follow up included) that's designed by a collaborative group, with centers that have complete buy in and that are stakeholders in the tool's development.

Future work should include further exploration of the pilot findings and a plan for semistructured interviews with participants at different stages to ensure that the problems, concerns, and interpretations are discussed.

Expert advice is fundamental to the weighting and scoring.

Future work needs to link to and complement other work being undertaken.

Staff using the tool need a minimum level of knowledge, clear definitions, and comprehensive guidance. A training package should be built into future studies to ensure all centers are completing it in a uniform way.

Needs to be flexible enough to account for changes in requirements (updated and reviewed yearly).

Needs to be computer based and able to link with the organization's existing IT; it also needs to include a Quality Control system that leaves an audit trail of changes.

The categorization of the projects should be expanded to include categories for the different sections as well as an overall category. It is important that sections are meaningful as well as have an overall project category.

The project was the first important step on the developmental journey through this complex, fascinating, and vital topic in the bid to manage, understand, and predict clinical re search  requirements well in the future. Good management of clinical research within the research environment is vital. 

Since undertaking this work, the author has collaborated with colleagues working on a related project. A larger prospective collaborative project is now planned, working with the EORTC and the National Cancer Research Network. The aim of the project is to validate and link together the EORTC Workload Measurement and complexity instruments in order to provide a comprehensive "toolkit" of workload management and complexity tools for research staff to use at various stages depending on their differing requirements. The project is currently in the data analysis stage and will be reported shortly.  

 RGN, MSc, is research network manager at the Peninsula Stroke Research Network–Royal Devon and Exeter Foundation NHS Trust, (formerly Wales Cancer Trials Network), William Wright House, Royal Devon and Exeter Hospital (Wonford), Barrack Road, Exeter, EX25DW, UK, email: 

1. P. Craighead, C. Herring, C. Hillier et al., "The use of the Australian Basic Treatment Equivalent (BTE) Workload Measure for Linear Accelerators in Canada," 

2. N.G. Burnett, D.S. Routis, Murrell et al., "A tool to Measure Radiotherapy Complexity From the Basic Treatment Equivalent (BTE) Concept," 

3. K. Roche, N. Paul, B. Smuck et al., "Factors Affecting the Workload of Cancer Clinical Trials: Results of a Multicenter Study of the National Institute of Cancer Clinical Trials Group,"

4. N.A. Roche, R.M. Given-Wilson, V.A. Thomas, N.P.M. Sacks, "Assessment of a Scoring System for Breast Imaging," 

5. L.A. Batt, L.K. Branston, T.S. Maughan, Assessing Cancer Trial Complexity and its Impact on Workload, Poster Presentation, NCRN Conference, 2004. 

6. E. Oddone, M. Weinberger, A. Hurder, W. Henderson, D. Simel, "Measuring Activities in Clinical Trials Using Random Work Sampling: Implications for Cost-Effectiveness Analysis and Measurement of Intervention," 

7. S. Owenby, "Reorganisational Plan Helps Staff Manage Workloads," 

Developing a process and management tool for scoring complexity in cancer clinical trials.

Supplements-05-02-2008

EDC Possibilities in Oncology

Standardizing Tumor Assessment Criteria

New Strategies for Research

Latest Imaging Technology a Good Fit for New Therapies

Real-World Workload Needs