Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section D – Preventing and Treating Cancer

Chapter 23 – Structures Supporting Cancer Clinical Trials

Jeffrey S. Abrams,Michaele Christian,
James H. Doroshow




Cancer clinical trials provide the evidence on which sound oncology practice is based.



Fewer than 5% of adult cancer patients participate in cancer clinical trials.



Providing greater access to clinical trials has been a major goal of the National Cancer Institute, cancer centers, and patient advocacy groups.



There are now many opportunities for physicians in private practice to participate in clinical trials sponsored by the National Cancer Institute and/or the biopharmaceutical industry.



Successful participation in clinical trials includes the following clinical components:



The attitude and commitment of the physician



Sufficient preparation and infrastructure



Trained staff, including at least some of the following:



Clinical research nurse



Clinical research associate






Affiliation with an institution or network that provides the protocol and scientific and administrative support, such as the following:



Cooperative group



Cancer Trials Support Unit



Cancer center network



Biopharmaceutical industry network



Research institution



Access to an authorized Institutional Review Board



Access to adequate laboratory facilities to process protocol-required specimens



Adherence to good clinical practices



Accurate and timely data reporting



Proper maintenance of primary source documentation



Adequate preparation for on-site audits



Adequate extramural financial support



Many organizations now provide access to clinical trials and/or provide the necessary training and certification; relevant Web sites are included in this chapter.


Modern oncology practice is founded on results from thousands of clinical trials conducted over the last four decades; thousands more clinical trials are ongoing at any given time and provide the evidence base for the rapidly changing therapeutic practices of this specialty. Motivations for the decision by an oncologist to participate actively in this extensive system of medical and scientific inquiry range from the ability to offer patients state-of-the-art treatments available through well-designed clinical trials, to the personal satisfaction and benefits that can be achieved from participation in this process. The commitment of time and resources necessary to participate effectively in such clinical research, and sometimes the unfamiliarity with clinical research requirements and procedures, prevent many oncologists from taking part. It has been estimated that only 3% to 5% of adult cancer patients in the United States are treated while taking part in clinical trials, with even lower rates of participation in many other countries. The lack of patient participation has been due, in part, to inadequate understanding of the clinical trials process. Fortunately, owing to intense publicity and educational programs by both patient advocacy groups and clinical trials organizations and widespread access to clinical trials information on the Internet, a growing number of patients now expect that available clinical trials will be included in the discussion of options for the treatment of their cancers. The purpose of this chapter is to describe some of the requirements, resources, and structures that are available to enable practicing oncologists to participate in clinical trials and to discuss the responsibilities that come with such participation. Numerous opportunities now exist for practicing physicians and their patients to participate in cancer clinical trials, including treatment, prevention, and cancer control trials, whether conducted by the National Cancer Institute (NCI), cancer treatment institutions, or the biopharmaceutical industry. Widespread access to the Internet has revolutionized communication and made it possible to provide regulatory information, educational and training materials, data forms, and documents online. A wide array of resources is now available to assist physicians and their staffs in placing their patients on clinical trials.


The NCI supports the development of over 100 agents (many in collaboration with pharmaceutical and biotechnology companies) and has an extensive clinical trials system that encompasses treatment, prevention, and cancer control studies. More than 800 trials are active at any given time, and several hundred new trials open each year. In the treatment area, the NCI has programs for early therapeutics development (primarily phase I and II trials), including many sites with grants and contracts to complete these early trials. The NCI also supports a large program of Clinical Trials Cooperative Groups that conduct later-phase trials, predominantly pilot studies and phase III trials. Phase III trials are conducted nationally, and participation in them is now possible even for oncology physicians who are not Cooperative Group members. Clinical Trials Cooperative Groups funded by the NCI ( Box 23-1 ) provide a standing mechanism for performing large-scale multicenter treatment and prevention trials. Over the years, this system has supported an experienced cadre of clinical researchers, biostatisticians, and research support staff who can respond to new clinical discoveries by organizing definitive phase III clinical trials. Because of their size and complexity, these trials require extensive infrastructure support to manage the necessary regulatory and data-reporting tasks. Although these Cooperative Group trials have provided a significant proportion of the evidence on which oncology practice is based, public advocacy for more rapid progress, increasing fiscal pressures on medical practice, and the accelerated pace of drug discovery caused the NCI to review and restructure aspects of its clinical trials program in 1998 and again in 2005. The major goals of these restructuring efforts were to increase access to NCI trials for patients and their physicians; to eliminate barriers to participation in clinical trials; to improve the coordination and cooperation among the functionally diverse elements of the NCI's clinical trials program, including relationships with industry and the U.S. Food and Drug Administration; to improve the prioritization process for developing clinical trials leading to increased scientific quality; to enhance the standardization of tools for clinical trial design and data capture; and to increase operational efficiency so that trials could be executed in a more timely manner.

Box 23-1 

National cancer institute–FUNDED COOPERATIVE GROUPS



American College of Radiology Imaging Network (ACRIN): http://www.acrin.org



American College of Surgeons Oncology Group (ACOSOG): http://www.acosog.org



Cancer and Leukemia Group B (CALGB): http://www.calgb.org



Children's Oncology Group (COG): http://www.childrensoncologygroup.org



Eastern Cooperative Oncology Group (ECOG): http://www.ecog.org



European Organization for Research and Treatment of Cancer (EORTC): http://www.eortc.be/default.htm



Gynecologic Oncology Group (GOG): http://www.gog.org



National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG): http://www.ctg.queensu.ca



North Central Cancer Treatment Group (NCCTG): http://ncctg.mayo.edu



National Surgical Adjuvant Breast and Bowel Project (NSABP): http://www.nsabp.pitt.edu



Radiation Therapy Oncology Group (RTOG): http://www.rtog.org



Southwest Oncology Group (SWOG): http://www.swog.org

From the mid-1980s to the mid-1990s, accrual to Cooperative Group treatment trials reached a plateau at about 20,000 patients annually. Whereas the pediatric groups consistently enrolled about 70% of all cancer patients, the adult groups were able to accrue only fewer than 2% of all cases. Phase III trials in the adult groups took an average of 4.5 years to enroll patients and an additional 3 to 4 years of follow-up before a result was known. This approximately 8-year cycle before potential treatment advances could be confirmed was clearly too long. It therefore became imperative to enable more rapid accrual to clinical trials.

Surveys among physicians and the public found that the obstacles to accrual in adult oncology were multifactorial ( Table 23-1 ). [1] [2] [3] [4] [5] With these barriers in mind, the NCI undertook the extensive review of the clinical trials system noted previously, involving a wide range of stakeholders that included Cooperative Group and Cancer Center leaders, patient advocates, representatives from the FDA and the pharmaceutical industry, and government staff. The detailed reports of these reviews are available online from the 1998 review (http://ctep.cancer.gov/forms/ArmitageReport.pdf) and from the 2005 review (http://integratedtrials.nci.gov/ict/ctwg_report_June2005.pdf from 2005). Several pilot projects were developed from the 1998 restructuring effort that were aimed at modernizing the clinical trials regulatory and data collection systems, opening access to trials to more patients and investigators, and simplifying the role of local institutional review boards in multi-institutional clinical trials. New opportunities were created for community physicians to participate in a broad array of clinical trials, and new tools were created to enable this. Two major initiatives, the Cancer Trials Support Unit and the Central Institutional Review Board, are now integral parts of NCI's clinical trials system and are described next.[6]

Table 23-1   -- Barriers to Clinical Trial Participation

Physician Related

Patient Related



Inadequate funding for data management personnel



Burdensome regulatory requirements



Institutional Review Board



Informed consent



Conflict of interest



Inadequate reimbursement



Lack of time



Resistance by third-party payers



Doctor never discussed or offered



Unaware of trials as option



Concerns about insurance coverage



Fear of receiving placebo



Cancer Trials Support Unit

The Cancer Trials Support Unit (CTSU) is designed to facilitate one-stop online access to a broad menu of predominantly phase III trials by a national network of NCI investigators. The network investigators include not only members of Cooperative Groups, but also physicians in practice with no group affiliation. They can access the CTSU menu of treatment trials from the public Web site (www.ctsu.org). The menu consists primarily of Cooperative Group phase III trials, although selected internationally led phase III trials, Cooperative Group phase II trials, and some trials led by U.S. cancer centers are also available. The scientific leadership for each study remains within the organization that developed the trial, but patient enrollment can come from any network physician across the country. By providing more physicians and their patients the opportunity to choose from a broader menu of trials, the CTSU promotes faster accrual to individual trials, allows increased access and broader treatment options to more patients nationwide, and renders trials involving uncommon cancers more feasible. Although the clinical trials menu is the most visible aspect of the CTSU, another major function of the CTSU is its centralized regulatory database. For all Cooperative Group members and nonmember physicians in the network, the CTSU maintains important demographic information about their sites or practices, including Cooperative Group(s) and academic/practice affiliation(s), Office for Human Research Protection assurance numbers for their sites, Institutional Review Board (IRB) approvals for specific protocols, and conflict of interest forms for investigators. This enables physicians, nurses, and clinical research associates to register once annually instead of having to register for each group or trial in which they participate. Initiated in 2002, the Regulatory Support System requires that investigators complete a 1572 investigational drug form once yearly, along with a supplemental information form and a conflict of interest form.[7] Nurses and clinical research associates who participate in group trials also register once annually online (registration is available at https://iapps-ctep.nci.nih.gov/ctepar/main.htmlfiReset). Information from this registration database is accessible to all Cooperative Groups, as the CTSU Web-based system is shared and maintained in a coordinated manner with all the Cooperative Group operations offices. Centralizing regulatory data has reduced the workload for investigators in the field, consolidated duplicative work, and allowed Cooperative Group staff to partially offload this activity to the CTSU and focus instead on protocol development and analysis.

Cancer Trial Support Unit Trial Services

The CTSU maintains a public Web site that provides patients with information about all the clinical trials on the menu.

The widespread availability of Internet access in physicians’ offices has made it possible for the CTSU to make the necessary documents, forms, and tools readily available. For physicians and their staffs, a password-protected members site contains the information that is needed to enroll a patient in one of the trials on the menu. Online access is provided to the protocol, case report forms, adverse event reporting forms, NCI pharmacy forms, site registration documents, patient enrollment documents, and education and training materials. Informed consent documents with Spanish translations are also available. In addition, detailed IRB application packets can be downloaded so that the process of obtaining local IRB approval is much less time consuming.

Regardless of which organization is leading a protocol on the CTSU menu, the CTSU manages site registration, protocol eligibility checks, and treatment randomization, obviating the need to interact with multiple different Cooperative Groups to treat patients on a variety of different protocols. Local site registrars can verify online that their site has successfully completed all the registration requirements for a specific protocol. In addition to the documents that are needed to conduct the study, the CTSU provides abstracted Time and Events Calendars and Protocol Schemas to assist medical staff with protocol adherence, a PowerPoint slide presentation to help physicians promote the trial, and patient education materials that provide information about both clinical trials in general and the specific trial under consideration. Physicians can also obtain quarterly accrual reports by study and by site and can order copies of investigator brochures when trials involve experimental drugs.

Data collection has been standardized on CTSU trials across all different Cooperative Groups and across diseases, to the extent possible, to facilitate ease of reporting, data sharing, and exchange. This has been possible because of the development of Common Data Elements (CDEs) through a project that NCI began several years ago in collaboration with the Cooperative Groups. For each disease, there now exists a set of commonly defined terms and values that are used to report information in a uniform manner. CDEs have now been developed for all the diseases that are treated in phase III studies by the adult groups and are currently being developed for pediatric and phase I and II trials. Currently, data collection is done by using paper case report forms. However, following an extensive evaluation, an electronic remote data capture system that will help to standardize the entire NCI Cooperative Group clinical trials system is on the verge of adoption. This effort, performed in conjunction with the larger NCI-wide bioinformatics initiative (caBIG, the cancer bioinformatics grid), will help to standardize clinical trials reporting not only for the Cooperative Groups but for all clinical trials supported by the NCI. The common CDE vocabulary system has also made rapid development of electronic case report forms more feasible. With the increasing availability of electronic data reporting for group trials, speed and data accuracy should improve owing to real-time data queries, thereby reducing time-consuming follow-up queries that currently arise weeks to months later when patient information is less readily retrievable.

The CTSU also manages two additional tasks: auditing and research reimbursement. Trials performed via the CTSU are audited in a fashion similar to other Cooperative Group trials (see the section entitled “Quality Assurance and Audits”) to verify data accuracy and quality by comparing the primary record with the research forms that the site submits. Given that sites may now participate in trials led by multiple groups, the CTSU patient charts are simply added to a scheduled audit when a group is visiting a member site, to avoid burdening sites with multiple Cooperative Group audits. Depending on the number of CTSU accruals at a site, the audit team is sometimes supplemented with members from other groups or CTSU staff to ensure sufficient expertise. Similarly, the CTSU has used existing contractual relationships between groups and their members to forward payments to group members who have participated in trials via the CTSU. Physicians who are not group members are supported via direct contracts and are paid by the CTSU directly.

Cancer Trial Support Unit and Cooperative Group Interactions

The introduction of the CTSU was the first major structural change to NCI's multicenter trials system since its inception more than 50 years ago. The CTSU has assumed a major role as a support structure that complements the work of the Cooperative Groups. The CTSU is not a scientific structure and does not develop or analyze the studies that it supports. Rather, all the data that it receives are passed on to the group that is leading the trial for analysis. By reducing the duplicative administrative work that was traditionally done at each Group Operations Office and by offering more clinical trials to each group member, the CTSU allows the groups to focus on their prime missions: developing important clinical trial questions and analyzing these trials rigorously.



In NCI-sponsored multicenter trials, the identical protocol is carried out at many sites, averaging about 100; each site requires its own local institutional review board (LIRB) to conduct an initial full-board review and subsequent annual reviews, adverse event reviews, and amendment reviews. These multiple IRB reviews create a largely redundant, time-consuming workload at these sites, compounding the ever-mounting pressures on the nation's IRB system, which have been well documented.[8] To provide an idea of the scope of the duplicative effort that occurs, consider that NCI has more than 8000 registered investigators at more than 1500 sites. On average, there are 160 ongoing phase III trials and 30 new trials entering the NCI system annually, resulting in approximately 16,000 IRB reviews (3000 initial reviews) conducted each year.[9] In addition, investigators often mention that the amount of time, paperwork, and (more recently) funding required of them to obtain IRB approval is a serious barrier to opening trials. These factors provided the impetus for the NCI to develop a new, centralized approach to human subjects protection for its large, phase III trials program.

Customarily, central institutional review boards (CIRB) models were instituted when LIRBs were lacking. In these cases, for-profit central IRBs contract their services to institutions without IRBs and maintain close contact with the sites by sending staff for frequent visits, thereby fulfilling the Office for Human Research Protection requirement that the IRB of record have knowledge of the local context. By contrast, LIRBs exist throughout the NCI system, and this fact led NCI to use a model in which responsibility is shared between the CIRB and LIRB. The CIRB provides the initial full-board review and then transmits its decision and detailed minutes of the meeting to the LIRB participants via a confidential Web site. These sites have the option to perform a facilitated review, whereby a LIRB chair (or a designated subcommittee) can review the CIRB documents rapidly, determine whether or not there are local issues that should be addressed, and then expeditiously approve the protocol, without the need for a full-board review at the local level. If facilitated review is accepted by the local site, then the CIRB becomes the IRB of record for that protocol. This means that the CIRB will perform the continuing annual reviews, adverse event reviews from all sites participating in the trial, and the amendment reviews. This process relieves the LIRB of the burden of review for these multicenter trials, but the LIRB still has the responsibility to review adverse events that occur at the local site (but can now view them in the context of the overall adverse event review provided by the CIRB). The LIRB also retains responsibility for the medical and ethical conduct of the investigators and their staffs at their institution. To formalize this division of responsibility, a written agreement is signed by the LIRB when it joins the CIRB Initiative (available at http://www.ncicirb.org).

NCI's CIRB is composed of a distinguished panel of oncology physicians, nurses, and patient representatives and includes a pharmacist, an ethicist, and a lawyer. Recently, a pediatric CIRB was initiated. The two NCI CIRBs review all phase III studies from the Adult Cooperative Groups as well as any phase III trials that have been opened in the CTSU and trials from the Children's Oncology Group. Unlike most LIRBs, the CIRB is focused exclusively on cancer trials and has sufficient time and expertise to review each protocol in detail. In addition, compared with LIRBs, the CIRB by design has more leverage to request changes in the protocol and informed consent, as NCI requires that studies obtain CIRB approval before they can open.

This new model for human subjects protection in multicenter trials is now utilized by over one third of all major NCI-designated Cancer Centers and many other university medical centers. A major goal will be a significant reduction in review workload for LIRBs while preserving their role as the primary overseers of the actual conduct of the research at the local site. Patients and investigators should benefit from the ability to open trials rapidly using this mechanism and from the greater availability of trials that should result.

Clinical Trials Working Group Initiatives

The Clinical Trials Working Group proposed 22 initiatives to improve the NCI's clinical trials system in 2005. Although it is early in the implementation of these recommendations, several activities have already entered into their pilot phase of development. To facilitate coordination of the entire NCI clinical trials enterprise, a new Federal Advisory Committee-approved advisory group reporting to the NCI director, the Clinical Trials Advisory Committee, has been initiated with a specific charge to monitor the implementation of the Clinical Trials Working Group recommendations and to provide oversight for NCI's clinical trials program. This committee has already taken up a review of the funding guidelines for the NCI-supported Cooperative Groups, Cancer Centers, and Specialized Program of Research Excellence program with the goal of providing clear incentives for these major NCI research programs to work harmoniously in the clinical trials arena. To enhance the scientific quality of the clinical trials that are supported by the NCI, the initial disease-specific scientific steering committees called for in this report have been formed. Their function is to coalesce investigators in both translational and clinical science supported by the NCI with community-based clinical trialists and patient advocates to develop a broad consensus around scientifically outstanding clinical trials that are likely to reach their accrual goals in a timely fashion.

To assist in the process of standardizing the clinical trials infrastructure for NCI-supported investigations, the caBIG workspace for clinical trials has been expanded, and the caBIG has begun work on the creation of a comprehensive database of the clinical trials that are funded by all NCI funding mechanisms. A public-private partnership group has also been formed to develop commonly accepted clauses for clinical trial contracts to reduce the lead time that is needed to open studies. Finally, initial studies have been conducted to investigate the major process roadblocks to timely clinical trial initiation.[10]These investigations will undoubtedly lead to additional recommendations to streamline the clinical trials process further.


Although the CTSU, the CIRB, and the national scientific steering committees represent new mechanisms to reduce barriers and facilitate broader clinical trials participation by practicing oncologists, advocates, and translational scientists, a number of other important mechanisms provide additional options for support and participation ( Fig. 23-1 ).


Figure 23-1  Mechanisms for participating in NCI-sponsored clinical trials. *All members (affiliate, CCOP, main) have access to the CTSU menu of trials regardless of whether or not they are members of the group leading the trial.



Clinical Trials Cooperative Groups

Physicians who wish to be more actively involved in the intellectual and scientific aspects of clinical trials and who can commit to accruing at least 5 to 10 patients per year to group studies, should seriously consider joining a Cooperative Group. Most groups have an affiliate program that allows community sites to partner or affiliate with a main member who assumes a number of the management and monitoring responsibilities for the affiliate. Procedures for joining can be found on the groups’ Web sites (see Box 23-1 ). Affiliate members attend the semiannual meetings of the groups and are actively involved in the scientific agenda, protocol development, and publications of the group. In addition to intellectual satisfaction, career development, and networking opportunities, members have access to a broader array of clinical trials for their patients, including phase I, phase II, and pilot trials that are not available on the CTSU menu and therefore are not accessible to nonmembers. Cooperative Groups also provide training and networking opportunities for research staff, including research nurses and clinical research associates, at group meetings and in other venues.

Community Clinical Oncology Program

For practices or groups or networks of practices that already have research experience and that can commit to enrolling significant numbers of patients in clinical trials, NCI grant funding through the Community Clinical Oncology Program (CCOP) mechanism offers many opportunities. CCOPs must document the ability to enroll 50 patients in cancer treatment studies plus 50 to 75 patients in prevention studies and/or trials focused on symptom management and cancer control. The grants provide important up-front funding to enable sites to hire critical staff from the start to support the substantial patient accrual that is required. In addition, special minority-based CCOPs are funded and provide additional support for groups or networks that serve predominantly minority populations. Minority-based CCOPs strive to increase cancer prevention and control activities in minority and underserved communities in addition to increasing access to clinical trials for minority patients. The CCOP program, funded by the NCI's Division of Cancer Prevention, has been in existence since 1983 and now funds over 50 research sites in 34 states. Details on these programs can be found on the Division of Cancer Prevention's Web site (http://www3.cancer.gov/prevention/ccop/).

Children's Oncology Group

Tremendous strides have been made over the past 50 years in the treatment of childhood cancers, transforming a once-fatal disease of children into a highly curable one. This success has been due in large part to the participation of large numbers of children with cancer in clinical trials. It is estimated that some 70% of children who are diagnosed are entered into clinical trials, and this has been a key factor in the rapid progress that has been made. In March 2000, four NCI-sponsored pediatric groups—the Children's Cancer Group, the Pediatric Oncology Group, the Intergroup Rhabdomyosarcoma Study Group, and the National Wilms’ Study Group B—agreed to consolidate their efforts and formed the Children's Oncology Group. The Children's Oncology Group has more than 230 member institutions, which include all major U.S. universities and teaching hospitals, as well as sites in Europe and Australia. Individual practices seeking affiliate membership can receive information athttp://www.childrensoncologygroup.org.

National Cancer Institute Cancer Centers Program

NCI-designated Cancer Centers exist in nearly every state and are funded by NCI to support a broad research infrastructure, including the personnel and physical resources to conduct a variety of clinical trials. While serving as tertiary referral centers, the Cancer Centers increasingly have recognized the desirability of forging links with community practitioners. The resultant research networks enable Cancer Centers to complete trials more quickly while providing practitioners and their patients with access to new drugs and techniques at an early stage of their development. These partnerships are flourishing in some areas of the country, and the model is likely to be replicated widely. For more information about Cancer Centers in your area, consult http://www3.cancer.gov/cancercenters.

Phase I and II Early Therapeutics Development Networks

The NCI supports a network of individual academic institutions and academic consortia to support the conduct of phase I and early phase II clinical trials, often performed with pharmacokinetic and correlative pharmacodynamic studies. These institutions enroll approximately 2000 patients per year in clinical trials, often first-in-human studies, that often set the standard for the further investigation of individual new agents or combinations of investigational agents by the Cooperative Groups or by industry. A major feature of this network is the expertise of the investigators and their institutions in blood and tumor sample acquisition, pharmacokinetic assay development and monitoring, and the development of pharmacodynamic assays.

National Community Cancer Centers Program

The NCI has very recently launched a new pilot program, the National Community Cancer Centers Program, to encourage collaboration between private practice medical, surgical, and radiation oncologists and large community hospital systems to explore ways to share information related to cancer care and expand and standardize the collection of blood and tissue specimens for cancer research. The program will also extend other NCI initiatives in the area of clinical trials and reduction of health care disparities. The major goal of this program is to provide access to research-based cancer care to a broader range of hospitals and clinics where most patients are treated.


During the first decades of the development of the field of medical oncology, there was relatively little industry participation in cancer therapeutics development. In part, this was a reflection of the complexity of therapeutics development in the field during a period when the lack of a sufficiently detailed understanding of cancer biology prevented a fully rational basis for new drug development. This relative lack of industry involvement, coupled with the significant public health problem presented by cancer, was responsible for the development of the large NCI-sponsored clinical trials apparatus described in detail in this chapter. The past decade, however, has seen a significant increase in biopharmaceutical investment in cancer discovery research and a parallel increase in both the extent and sophistication of industry sponsorship of clinical trials for the development of new cancer therapeutics. Hundreds of new agents are currently in different stages of clinical evaluation by the industry, either alone or in cooperation with the National Cancer Institute or similar organizations in other parts of the world.

Purpose and Nature of Industry-Sponsored Clinical Trials

The primary goal of therapeutic agent investigation by the biopharmaceutical industry is the evaluation of promising agents for eventual registration and commercialization. Because registration of a new cancer drug requires the demonstration of safety and efficacy for the new agent in the context of currently available therapy for the cancer being treated, the spectrum of clinical trials sponsored by industry often overlaps with the range of trials conducted by the Cooperative Groups. Furthermore, there is a long tradition of industry providing investigational agents for the conduct of clinical investigations through NCI-sponsored mechanisms, and there are many examples of new agents or indications that have received FDA approval on the basis of NCI-sponsored clinical trials. Ethical considerations regarding human investigation and expectations regarding adherence to standards for the conduct of clinical trials do not differ between NCI-sponsored and industry-sponsored clinical trials; therefore, the fundamental processes of conducting clinical trials are similar in both cases. Despite these similarities, however, there are some differences between industry trials and those sponsored by NCI.

Particular Characteristics of Industry-Sponsored Trials

Biopharmaceutical development proceeds in a heavily regulated environment, with detailed regulations from various government agencies covering the spectrum of activities ranging from those related to preparing an agent for first entry into humans, through the years of clinical investigation in patients, to postapproval restrictions on public discussion regarding possible uses of the agent for indications other than those for which the drug was approved. As a result of the requirements of working in such an environment, corporate clinical investigations tend to be focused on the “clinical development plan,” the specific plan of clinical trials that will produce an appropriate evidentiary base to allow for regulatory review of the safety and efficacy profile of the agent. During the investigational phase of an agent's life cycle, therefore, companies might restrict the general availability of the agent to individual investigators for clinical study. This perceived need for containment and control can lead to tension between the investigative community and the industrial sponsor. Other potential sources of tension in the interaction between companies and investigators relate to the investigators’ perceptions of the need for independence and objectivity in the conduct of multicenter trials. Historically, for example, many companies have generated phase III protocols internally, although usually with considerable input from both external advisors and regulatory bodies. The trial would be conducted by company personnel, and authorship would be conferred on the principal investigator of the largest accruing site. Increasingly, a new model is emerging in which a recognized expert is appointed as the principal investigator; this individual has a much greater role in the design, monitoring, and eventual analysis and publication of the trial than might have been the case historically. Similarly, recent years have seen the almost universal adoption of independent Data and Safety Monitoring Committees for late-stage clinical trials to oversee safety-related information as it emerges from the ongoing trial and to make recommendations to company staff about appropriate actions.

Impact of Globalization on Pharmaceutical Development

Pharmaceutical products increasingly are marketed globally, and large multinational pharmaceutical companies, therefore, need to conduct clinical development from a global perspective. Clinical trials with investigational agents with which the FDA is involved are being conducted in over 75 countries. This tendency toward global development has been greatly accelerated by the International Committee on Harmonization process, which facilitated standardization of many of the activities that are involved in preparing agents for clinical investigation, conducting those investigations, and then preparing the information for registration. Now a single set of standards exists for the conduct of industry-sponsored trials worldwide. Attempts are therefore made to harmonize the development process to produce a globally accepted drug registration package to the greatest extent possible.

Models for the Conduct of Industry Clinical Trials

Biopharmaceutical industry sponsors usually produce the investigational agent in their own facilities, as they anticipate eventually being responsible for the commercial production and distribution of the agent. They also can conduct the series of required clinical trials directly using their own clinical trials personnel, which may include internal company physicians, statisticians, monitors, data managers, quality assurance auditors, and the rest of the required infrastructure, such as company standard operating procedures, company information system support, and drug distribution apparatus. Alternatively, drug sponsors may utilize a contract research organization to perform the actual clinical trials. In fact, for large development programs, it is not unusual for large companies to coordinate clinical trials programs using a mixture of both internal and externally acquired resources. Contract research organizations are companies in the business of conducting clinical trials. Over the last decade, following the explosion in growth of biopharmaceutical clinical investigation, a large number of such companies have been created, some capable of conducting global trials. The actual arrangement—direct or indirect—that a drug sponsor uses for a particular clinical trial is important to the investigator and staff at the clinical trial site, because it determines the predominant source of interactions and contact during the actual conduct of the trial.

Different models exist, as well, for investigator participation in clinical trials with industry. Traditionally, pharmaceutical sponsors have dealt either with individual investigators or with individual institutions, as in the case of academic centers. Clinical trial contract budgets have included direct trial-related costs such as performing additional laboratory studies that are not being done as part of usual medical care plus direct site-related costs associated with the time spent on the trial by the various participating staff and indirect costs for institutional overhead. Recent years have seen the emergence of consortia of investigators (sometimes under the rubric of a Site Management Organization) or consortia of institutions presenting themselves to companies as clinical trial entities, often linked by a single central IRB and often offering the advantage of working under a single negotiated contract. In addition, individual academic centers sometimes have formed networks of oncologists within their referral area for the purpose of presenting themselves as more efficient entities for interaction. New models continue to evolve. These new models make it easier for companies to engage the several hundred sites that are required to conduct major phase III registration-directed trials in a much more efficient manner.

Good Clinical Practice and Other Issues

One area of drug development that has been the focus of International Committee on Harmonization activities is the development of good clinical practice guidelines for the conduct of clinical trials. Good clinical practice describes international ethical and scientific quality standards for designing, conducting, recording, and reporting trials that involve the participation of human subjects. The very useful and informative document “ICH E6 Consolidated Guidance for Good Clinical Practice for Industry” (available at http://www.fda.gov/cder/guidance/index.htm) represents a summary of good clinical practice guidance for the generation of clinical trial data that are intended for submission to regulatory authorities. This document comprehensively summarizes the responsibilities of IRBs, investigators, and sponsors, as well as issues regarding the clinical protocol, investigator's brochure, and the documents that are essential in the conduct of a trial. Although investigators participating in an industry-sponsored clinical trial can expect help in the preparation of the required documents, it is important that they understand their responsibilities both to their patients and to the industry sponsor within the context of a global registration program.

Recent concerns regarding investigator conflict of interest in new drug development have led many institutions to develop policies regarding the extent of financial involvement by investigators in companies sponsoring trials in which the investigators are participating. Industry sponsors have also developed conflict-of-interest policies. In addition, as part of drug approval submissions in the United States, companies must now provide financial disclosure statements from individual investigators who are participating in the registration-directed trials.

Changing Nature of Oncology Trials: Impact on Infrastructure

The same explosion in understanding cancer biology that has led to the increase in the number of new agents under development brings with it a realization that the most appropriate tests of those biologically targeted agents are clinical trials in which the patients who participate have tumors that are biologically appropriate for the agent. For example, imatinib administered to all newly diagnosed patients with any form of leukemia would have a response rate much lower than that in the biologically appropriate group of newly diagnosed patients with chronic myelogenous leukemia; selection of patients with chronic myelogenous leukemia allows for a focused development program leading to rapid initial registration. The same considerations can logically be extended to matching any biologically directed agent with any cancer patient population and argues strongly for more complete biologic characterization and continued monitoring of patients entering cancer clinical trials. Regardless of whether such characterization is prospective or retrospective in clinical trial design and analysis, it can be expected that the increased need for collection of peripheral blood for germline DNA studies; plasma for proteomics studies; fresh tumor tissue for DNA, RNA, and/or protein studies; and tumor tissue blocks for DNA or immunohistochemical studies or for specialized imaging studies will all place new demands on the infrastructure that is required to conduct trials. These requirements will also introduce new challenges for quality control on sample collection and storage and will increase the resource requirements for trials. It is also likely, however, that such clinical trials will become much more informative. The potential exists in the future for smaller, more definitive trials in more biologically homogeneous groups of patients than is possible with the classic histopathology that is currently used to characterize patients; this potential should lead to more effective and well-tailored treatments.

Challenges to the Conduct of Industry Oncology Clinical Trials

Numerous challenges exist both to the oncologist who wants to participate in the clinical trials process and to the corporate sponsor that wishes to conduct such registration-directed trials. From the individual oncologist's perspective, the bureaucratic hurdles that are associated with the clinical trials administration process can appear daunting, particularly when added to the responsibilities of using investigational agents in patients. Acquiring sufficient trained personnel to conduct such trials is a challenge. Unless participation in a particular trial is part of a broader commitment to the clinical trials process with supportive infrastructure in place and experience in the conduct of several simultaneous ongoing trials, successful participation is unlikely. For these reasons, oncologists who are already participating in Cooperative Group trials through one or another mechanism already have in place some of the required infrastructure for the local conduct of industry-sponsored clinical trials. The corporate sponsors of oncology drugs that are undergoing development face their own challenges and uncertainties. Cancer drug development traditionally has been a high-risk field. Many agents fail in late-stage development, a time when significant time and resources have already been expended. Although it is hoped that the kind of increased linkage of biologic study with therapeutics development will eventually make this whole process more predictable, the development of new cancer drugs remains an expensive and high-risk activity. Development is carried out through a clinical trials process that remains highly inefficient and lacking in standardized information collection, systems, and processes and without many biological markers to aid in decision making early enough in the clinical trials process to decrease risks in development. Continued improvements in efficiency and productivity of the clinical trials system remain a high priority in order to accelerate the delivery of effective new agents to patients.


Staffing is foremost among the critical components for an effective research practice listed in Box 23-2 . The number and precise composition of the necessary staff depend on the number of patients who are enrolled in clinical trials and the nature of the practice. In some settings, in which the number of patients in studies is small, one good research nurse can perform many of the required functions. At more active sites, research nurses, clinical research associates, and research pharmacists perform separate functions. For budgeting purposes, for example, it is often estimated that one full-time clinical research associate can handle 25 new patients and up to 50 patients in follow-up in a year. Some of the structures that support clinical trials participation, such as the CCOP program, provide substantial up-front funding to support salaries for the necessary staff in return for a commitment to substantial accrual. Many others, including the CTSU and the Cooperative Groups, provide a small amount of funding when each patient is accrued. The latter approach allows sites to introduce clinical research into their practices at a more gradual pace.

Box 23-2 




The presence of committed physicians who are willing to devote the time and energy necessary to conduct clinical research and to accept conscientiously the significant responsibility inherent in the conduct of human research.



The availability of suitably trained staff (preferably an experienced research nurse) with enough time to assist in screening patients for protocol eligibility and for following patients on protocol treatment.



The availability of suitable staff to administer the required treatments in the protocol-prescribed manner; increasingly, this might include administration of a wide range of potential therapeutics including, but not limited to, more conventional intravenous chemotherapy and, in some cases, radiation.



Adequate and committed pharmacy capabilities to handle and account for investigational agents if these are part of the protocol treatment.



Adequate data management staff to handle the data-reporting requirements for patients who are being treated on protocols.



Access to an Institutional Review Board (IRB) with Office for Human Research Protections assurances to approve the protocol and monitor the progress of the research.



Access to suitable laboratory facilities to complete the studies that the protocol requires.



Willingness to comply with certain federal regulatory requirements, including adequate privacy procedures and training in human subjects protection (available as an online course through NIH at http://cme.cancer.gov/c01/).

Quality Assurance and Audits

Because the accuracy of the data that are collected on clinical trials is critical to the validity of the conclusions from the trials, all clinical trials organizations include quality assurance and audit programs. Although these are structured somewhat differently depending on the mechanism of participation (industry conducting the most frequent and extensive audits), all such programs have certain features in common. All send queries to the site when discrepancies or suspected errors are noted in submitted information, and all compare data that are submitted from the sites to the primary medical or research record for verification at on-site audits. NCI audits are typically conducted every 3 years and review a sample of patients enrolled on a variety of protocols. In addition to verifying data accuracy and protocol adherence, informed consents are reviewed, as are adverse event reporting compliance, pharmacy practices, and timeliness of required IRB submissions and approvals. Preparation for audits is time consuming for the sites, as all relevant records, including laboratory studies and films (computed tomography, magnetic resonance imaging, etc.) required to document tumor measurements and response verification, must be gathered for the audit team. Some participants consider this work onerous; however, audits fulfill an important educational role in addition to ensuring the quality of the data and clinical trial procedures at participating sites. Data quality initially became a concern when clinical trial participation moved beyond academic sites to community practices. A number of evaluations in the 1980s, however, documented the ability of community sites to perform at a level comparable to that of academic institutions in terms of data quality, protocol adherence, and patient outcome. [11] [12]Indeed, over 30% of the accrual to adult Cooperative Group trials now comes from community practices in the CCOP, and additional accrual comes from Cooperative Group affiliates, predominantly community sites.

As was noted previously, although regulatory standards regarding the conduct of clinical trials impose similar overall expectations, for its own reasons industry monitoring is both more extensive and frequent than the usual cooperative group monitoring. The basic tenet of monitoring for both industry-sponsored and NCI-sponsored clinical trials is similar: the need to verify data accuracy by comparing case report forms, whether submitted by paper or electronically, with source data in the patient's medical record. The sponsor-assigned clinical trial monitor will visit the site regularly, educate the involved staff about the goals and particular details of the protocol, and then track the progress of protocol-related activities throughout the conduct of the trial. Monitoring responsibilities include confirmation of appropriate local IRB review, investigator registration via completion of the FDA 1572 form, the existence of timely informed consent documents for each patient, inspection of drug accountability records, confirmation of timely and complete submission of serious adverse events reports, and ensuring appropriate and timely handling of amendments. These activities all fall within the responsibility of the clinical trial monitor, whether the monitor is provided directly from the company sponsor or through a contract research organization. Furthermore, regardless of whether the clinical trial is conducted directly by its own organization or by a contract research organization, biopharmaceutical companies often conduct their own quality assurance audits and monitoring associated with the trial, to further ensure the integrity of the submitted data. The intensity of clinical trial monitoring tends to increase as clinical trials mature and the data management group prepares to officially “lock” the database before the conduct of prespecified analysis and reporting activities. The intensity of quality assurance auditing also increases for a particular clinical trial when it has been identified as part of a New Drug Application or Biologic Licensing Application for drug registration with the FDA. Monitoring and data management activities are evolving with the widespread introduction of electronic data collection and submission systems that are replacing traditional paper-based case report form approaches.

Educational and Training Tools

As has been described previously, participation in clinical trials adds many complexities to care of cancer patients and can require that physicians, nurses, and other office staff acquire new and different skills. Fortunately, because of the widespread interest in clinical trials in the cancer community, there are many resources for gaining information about clinical trials and for acquiring the necessary skills. Professional societies are a good source for educational programs and materials, and some, such as the Oncology Nursing Society (http://www.oncc.org/), the Society of Clinical Research Associates (http://www.socra.org/), and the American Society of Health-System Pharmacists (http://www.ashp.org/), actually offer certification programs that can serve as important career development incentives to office staff. The American Society of Clinical Oncology (http://www.asco.org) also has a very useful Web site with links to a variety of sites that provide information about available clinical trials and detailed information about chemotherapy agents for physicians and nurses. NCI-sponsored Cooperative Groups provide regular educational activities for physicians, statisticians, nurses, and data managers who participate in their trials. Furthermore, the biopharmaceutical industry sponsors a wide range of educational activities that are conducted by both academic institutions and professional societies (e.g., the American Society of Clinical Oncology and the American Association of Cancer Research) about the clinical trials process in general and about the responsibilities of the individual clinical investigator.

The NCI's home page (http://www.cancer.gov/) provides a gateway to the many Web sites at the NCI and provides links to many other useful sites. It contains extensive information about cancer in general and cancer statistics, as well as detailed information about clinical trials with direct links to the Physician Data Query (PDQ). PDQ (http://cancer.gov/cancerinfo/pdq/) is a database maintained by the NCI that provides a comprehensive listing of NCI-sponsored clinical trials, along with extensive and detailed listings of trials (including international trials) that are submitted voluntarily by cancer centers, private hospitals, and the pharmaceutical and biotechnology industries. The PDQ search engine allows searches by geographic location and site or investigators, as well as by tumor type, stage, and other relevant categories, and it provides contact information to facilitate patient referral when appropriate. In addition, PDQ provides detailed information about the treatment of many cancers, as well as information on screening, prevention, genetics, and supportive care. Useful information on insurance coverage for patients on clinical trials, including the coverage offered by specific insurance carriers, can also be obtained from www.cancer.gov.

The NCI site also provides a link to the Cancer Therapy Evaluation Program, which coordinates NCI-funded clinical trials in treatment across the country. The Cancer Therapy Evaluation Program Web site contains detailed information related to the conduct of clinical trials, including the following:



Human research protections and the required online course for all research teams conducting NIH-funded research



The Investigators’ Handbook and other tools for protocol development



Information on data-reporting requirements and on the monitoring and auditing of clinical trials

The Web site of the Division of Cancer Prevention (http://www3.cancer.gov/prevention/) provides similar information on the conduct of cancer prevention and control studies. Other NCI resources include the Cancer Information Service (1-800-4-CANCER), a telephone service that provides information in both English and Spanish, answers many patient questions, and refers callers to other resources when appropriate.


Although the involvement of oncologists in clinical trials introduces additional complexities to their practice of oncology, it also provides substantial benefits to all participants and ultimately contributes to the goals of improving cancer treatment and prevention. A growing number of clinical practices have been able to integrate active clinical research into their activities successfully. To help facilitate this participation, the NCI began a small pilot in 2002 to allow sites without Cooperative Group affiliation to join Group-led trials directly via the CTSU.[13] A number of sites became involved successfully, and the NCI developed a number of tools that are now available through the CTSU. These tools include IRB submission packets, protocol calendars, and summaries, among others ( Box 23-3 ). It is envisioned that the availability of a central IRB nationally and an electronic data reporting system will eliminate critical barriers and will make it easier for community physicians to participate. Similarly, the biopharmaceutical industry continually seeks interested, conscientious physicians to participate in its trials. The shortage of such physicians creates a potentially serious limitation on the rate of development of new treatments for cancer. Surveys that have been done under the auspices of the Coalition of National Cooperative Groups suggest that the attitude of the treating physician is perhaps the most critical factor in patient enrollment in clinical trials. [2] [5] With the right attitude, an increasing number of resources and tools are now available to make access to clinical trials a reality for many more patients, with the potential to benefit both themselves and future patients with cancer.

Box 23-3 




National Cancer Institute: http://www.cancer.gov



Cancer Trials Support Unit (including links to cooperative groups): http://www.ctsu.org



Cancer Therapy Evaluation Program (CTEP): http://ctep.info.nih.gov



Community Clinical Oncology Program (CCOP): http://www3.cancer.gov/prevention/ccop



Cancer Centers Program: http://www3.cancer.gov/cancercenters



Central IRB: http://www.ncicirb.org



Physician's Data Query (PDQ): http://cancer.gov/cancerinfo/pdq


  1. Taylor K, Feldstein M, Skeel R, et al: Fundamental dilemmas of the randomized clinical trials process: results of a survey of the 1,737 Eastern Cooperative Oncology Group Investigators.  J Clin Oncol1994; 12:1796-1805.
  2. Fleming ID: Barriers to clinical trials: Part I B. Reimbursement problems.  Cancer1994; 74:2662-2665.
  3. Schain WS: Barriers to clinical trials: Part II. Knowledge and attitudes of potential participants.  Cancer1994; 74:2666-2671.
  4. Mansour EG: Barriers to clinical trials: Part III B. Knowledge and attitudes of health care providers.  Cancer1994; 74:2672-2675.
  5. Comis RL, Aldige CR, Stovall EL, et al: A quantitative survey of public attitudes towards cancer clinical trials [cited 2003 Jul 10].  Available at http://www.cancertrialshelp.org/static_binary/308.pdf
  6. Clinical Trials : A Blueprint for the Future,  Bethesda, MD, National Institutes of Health Publication No. 99-4524, 1999.
  7. Abrams JS, Cummings C: Implementing clinical trials in your practice: getting started and what's new.   In: Perry MC, ed. American Society of Clinical Oncology 2002 Educational Booklet,  Alexandria, VA: American Society of Clinical Oncology; 2002:273-282.
  8. Sung NS, Crowley Jr WF, Genel M, et al: Central challenges facing the national research enterprise.  JAMA2003; 289:1278-1287.
  9. Christian MC, Goldberg JL, Killen J, et al: Sounding board: a central institutional review board for multi-institutional trials.  N Engl J Med2002; 346:1405-1408.
  10. Dilts DM, Sandler AB, Baker M, et al: Processes to activate phase III clinical trials in a cooperative oncology group: the case of Cancer and Leukemia Group B.  J Clin Oncol2006; 24:4553-4557.
  11. Koretz MM, Jackson PM, Torti FM, Carter SK: A comparison of the quality of community affiliates and that of universities in the Northern California Oncology Group.  J Clin Oncol1983; 1:640-644.
  12. Begg CB, Carbone PP, Elson PJ, Zelen M: Participation of community hospitals in clinical trials: analysis of five years of experience in the Eastern Cooperative Oncology Group.  New Engl J Med1982; 306:1076-1080.
  13. Denicoff AM, Hopkins JR, Riordan SE, et al: Expanding participation to non-group members in phase III cooperative group treatment trials.  Proc Am Soc Clin Oncol2007; 25:6533.


Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Abeloff: Abeloff's Clinical Oncology, 4th ed.

Copyright © 2008 Churchill Livingstone, An Imprint of Elsevier

Chapter 24 – Economic Analysis of Cancer Treatment

Charles L. Bennett,Karen A. Fitzner




Cancer care accounts for the largest number of dollars spent on any medical condition in the United States.



Cancer accounts for 10% of all Medicare expenditures.



Fewer than half of the states have passed legislation mandating coverage of clinical trials.



Cost-benefit, cost-effectiveness, cost-utility, and cost-identification analyses are the main methods for evaluating the economics of clinical interventions.



Empirical studies have found that results of cost-effectiveness studies are associated with pharmaceutical versus not-for-profit funding, although quality is not.



Few economic studies have been incorporated into clinical trials sponsored by the National Cancer Institute (NCI).



To date, only seven NCI-sponsored clinical trials have included economic assessments.


The costs of treating patients with cancer contribute substantially to the United States’ $1.6 trillion annual health care spending. In fact, the economic burden of cancer is the largest imposed by any medical illness. The high expense associated with cancer is related to a number of factors, including an increase in the prevalence of cancer as people live longer, the high rate of comorbid medical illness in cancer patients, and high costs associated with diagnosis, treatment, and end-of-life and palliative care as new, more expensive treatments become available. The direct costs of cancer care (spent for prevention, screening, diagnosis, treatment, and palliation) accounted for $61 billion in 2002. [1] [2] Pharmaceutical costs, which have been growing rapidly, account for a large amount of cancer-related expenditure.[3]

Cost is a major determinant of the type and intensity of cancer care, particularly related to reimbursement of high-tech and high-cost procedures and pharmaceutical products for cancer patients.[4] The physician has a large role in determining the medical costs incurred by individual patients. Medical costs are categorized as (1) direct medical costs; (2) direct nonmedical costs, that is, amounts spent for caregivers and travel; (3) indirect costs, that is, the economic value of lost productivity due to illness, disability, and death (mortality); and (4) intangible costs, that is, costs associated with pain, suffering, and grief. Although several studies have evaluated the direct costs of various types of cancers, few include estimates of direct nonmedical, indirect, and intangible costs. Pilot studies indicate that these costs may be as high as 75% of the total cost of cancer care. [5] [6]

In 2006, the most costly cancers for men were prostate cancer followed by lung and colorectal cancer; for women, the most costly cancers were breast cancer followed by colorectal and lung cancer.[7] In addition to considering total costs, it is important to consider the benefit (or value) provided by the intervention in exchange for the amount expended. The number of articles addressing cost-effectiveness of cancer treatments has increased dramatically in the past few years, a large number of these studies addressing supportive care agents. [8] [9] [10] Oncologists, insurers, and policymakers increasingly are addressing questions of costs, cost-effectiveness, and quality of life. Many changes have been made in this area since the late 1990s, particularly in relation to the costs of clinical studies. Previously, the national mandate to evaluate the effectiveness of health care, including cancer care, was designed to incorporate cost-effectiveness assessments. The U.S. Healthcare Research and Quality Act of 1999 gave a mandate to the Agency for Healthcare Research and Quality to focus on evidence-based technology assessments, which could then be incorporated by relevant people in the medical community into guidelines produced by physicians or medical societies. Unfortunately, cost considerations are not addressed explicitly in the current mandate. A few of the assessments will, however, provide information that may be applicable to cost-effectiveness analyses that can be conducted by others.

Clinical Trials and Their Reimbursement

The costs of cancer clinical trials have become an important issue related to cancer treatment over the past decade. Findings from pilot studies of about 1300 patients in phase II/III clinical trials estimate that costs ranged from 10% lower to 23% higher for clinical trials in comparison to control groups that received standard medical care. [8] [9] [10] [11] [12] [13] [14] On the basis of these findings, nearly half of U.S. states, Medicare, and several private insurers now cover the costs of patient care in “qualifying” clinical trials. Because of economic and other considerations, federal policies were not supportive of clinical trial reimbursement during the 1990s; Medicare excluded coverage of routine costs of care associated with clinical trial participation on the basis that such treatment was experimental or investigational.[10] However, a 1993 review found that Medicare was being billed millions of dollars for patients who received care in clinical trials.[12] The U.S. General Accounting Office estimated that Medicare had paid 50% to 90% of routine patient care costs in clinical trials because fewer than 4% of claims for clinical trial costs incurred by Medicare beneficiaries were denied and oncologists often submitted bills for components of complex treatments without specifying the procedure itself.[14]

In the late 1990s, there were several unsuccessful proposals, such as the Medicare Cancer Clinical Trial Coverage Act and the Medicare Cancer Clinical Trial Demonstration Act, that would have allocated considerable funds to cover cancer clinical trials sponsored by the National Institutes of Health, the Department of Defense, and the Department of Veterans Affairs. Following years of lobbying by individuals, patient groups, health care workers, and organizations who were concerned about reimbursement denials of clinical trial costs and the low rates of accrual to clinical trials, a 2000 executive order authorized Medicare to cover the costs of any cancer clinical trial that satisfied qualifying criteria. Medicare has paid routine care costs (e.g., office visits and lab tests) for patients enrolled in federally funded clinical trials since 2000. The Centers for Medicare and Medicaid Services revised its National Coverage Determination for off-label use in cancer clinical trials in early 2005. Medicare now pays for both routine and nonroutine costs associated with the patient's care as well as the off-label use of some anticancer drugs. [15] [16] [17]

At the state level, the question put before some state legislatures has been whether insurance barriers to clinical research are best removed through voluntary action of health insurers or formal legislation. As of December 2006, 22 states had passed laws mandating coverage of patient care costs associated with treatment provided in specified categories of cancer clinical trials.[18] In the mid-1990s, Rhode Island became the first state to legislate insurance coverage for phase II clinical trials. Since then, Georgia mandated insurance for selected pediatric cancer trials in 1998, and Maryland and Virginia mandated insurance for cancer trials conducted in in-state academic institutions in 1999. Maine requires managed care organizations and private insurers to cover trials approved and funded by the NIH, a NIH-sponsored cooperative group or center, or the U.S. Department of Health and Human Services. Louisiana requires coverage of Phase II, III, and IV clinical trials that are approved by entities such as the Food and Drug Administration (FDA), the Department of Defense, the Veterans Administration, and the Coalition of National Cancer Cooperative Groups. The New Jersey Association of Health Plans agreement is unique in that all private insurers in a single state have voluntarily agreed to provide cancer clinical trial coverage. These coverage mandates are important because without third-party coverage, most patients are unable to bear the cost of participating in a clinical trial.

Today, public payers and several large private health insurers reimburse for medical care costs associated with clinical trials. Concern over variable scientific quality has led many state legislatures to limit reimbursement to trials funded by federal agencies. Moreover, many states have mandated clinical trial coverage by private and public payers for cancer trials but not for other medical conditions. This is in part due to the national infrastructure surrounding cancer trials, which is the most established and comprehensive of any disease clinical trials.

Economic Assessments in Cancer Care

Economic issues in cancer care are paramount in planning for optimal use of scarce resources and in responding to the increased economic pressures faced by the health care system. Physicians and health policymakers need to make judgments on the effectiveness and cost-effectiveness of cancer care based on explicit assessments of the costs and benefits of alternative management strategies. In other words, payers want assurance that expensive treatments are cost-effective. To understand the financial impact of alternative cancer management strategies more clearly, it is essential to understand the basic terminology of economic studies in health care: costs, benefits, cost-effectiveness, cost utility, and cost minimization. It also is important to explain the methods that policymakers and oncology researchers use when they evaluate the costs of cancer care.

When Are Economic Assessments Likely to Be Helpful (or Unhelpful)?

Assessments of the costs of cancer care can be considered when significant resources are being used, when resource considerations have a direct impact on patient care, and when resource allocation decisions are likely to be made.[19] Economic analyses also help to identify the most efficient option when two or more clinically efficacious interventions are available. Examples of situations in which a large amount of resources are used include use of supportive care agents such as antiemetics, erythropoietin, granulocyte colony-stimulating factor (GCSF), and genetic predictors. Resource considerations played a prominent role in the decision to support high-dose chemotherapy with stem cell transplantation for breast cancer before reports of unfavorable results were received from several randomized clinical trials. Economic analyses are unlikely to be helpful in cases in which a treatment works well but only a small number of individuals are affected, thereby limiting the overall cost impact. For example, advanced testicular cancer routinely is treated with chemotherapy. The cure rate is high, but the number of cases is fewer than 10,000 per year. Similarly, data have been collected on the economic implications of high-dose chemotherapy with stem cell transplantation for breast cancer, but they will not be useful to policymakers because this procedure has not been found to be clinically effective.

Types of Economic Analyses

Economic evaluations provide information on the value of an intervention or therapy in relation to its costs when compared to a competing alternative when, ideally, the alternative is the current standard of care. Economic evaluations of cancer interventions can range from decision analytic models to retrospective database comparisons to analyses conducted alongside clinical trials. However, all of the economic analyses of clinical interventions can be grouped into four categories based on the measure of effectiveness used in the analysis: cost-benefit (costs and benefits are measured in the same terms, usually monetary), cost effectiveness (costs measured in monetary terms, effectiveness in clinical terms), cost utility (costs measured in monetary terms, utility measured in terms of utility), and cost identification (costs measured in monetary terms, no effectiveness measurement).[20]

Cost-benefit analysis compares the incremental cost of a medical intervention with its incremental benefit, with both terms measured in monetary units. Therefore, interventions with positive net benefits, in which the value of the incremental benefits is greater than the incremental costs, are cost-beneficial compared to the alternative. In theory, cost-benefit analysis allows for the comparison of health interventions with other programs or interventions from non–health care sectors that may be competing for the same dollars. That is, with a cost-benefit analysis, a government could compare whether to spend monies on a new after-school program for children or use the same monies to fund a breast cancer screening program. However, difficulties in valuing all the relevant factors (e.g., years of life lost and quality of life) in monetary terms limit the use of cost-benefit analysis.

More commonly, economic evaluations in cancer care involve cost-effectiveness analysis. Cost-effectiveness analysis provides information about the value of an intervention or therapy in relation to its costs compared to a competing alternative when effectiveness is measured in clinical terms. The analysis compares two or more interventions and provides information about the differences in costs and effects between comparators. The results are summarized into a ratio that provides the results in terms of the costs per unit of effect. This ratio is referred to as the incremental cost-effectiveness ratio, because it is assessing incremental differences between alternative treatments. Because it is a cost-effectiveness analysis, the denominator of the ratio is valued in natural units, such as years of life, and is calculated by finding the difference in the effectiveness measure between the alternatives. For example, many cost-effectiveness analyses in cancer treatments report the incremental cost per year of life saved.

Cost-utility analysis is a subset of cost-effectiveness analysis in which the measure of effectiveness is a utility or value. Utilities provide a measure of overall quality of life and are applicable across different types of cancer. The measure is intended to incorporate both positive and negative aspects of treatment. The utility is combined with information on survival to estimate quality-adjusted life years, which are used as the measure of effectiveness in cost-utility analyses. Thus, cost-utility analyses provide an estimate of the cost per quality-adjusted life year gained. In principle, this method can be used to compare the value of screening programs to new chemotherapeutic agents to gauge the relative value of an alternative.

The final type of clinical economic analysis used in cancer studies is cost identification. This technique reports the total types and amounts of resources used in providing medical care, without formal assessments of the clinical benefits of the treatment. This technique is an integral part of the other economic evaluations in that it provides the cost estimate used in the numerator. However, with this method, the benefits are not compared formally among alternatives.

It is important to emphasize that in all types of economic analyses, the way monetary units are assigned to treatments can make important differences. Specifically, costs differ markedly from charges.[21]Costs represent the true opportunity cost of a resource, whereas charges represent the amount that is billed for that resource. There might be little connection between costs and charges, charges typically being much greater than the actual costs. Therefore, it is important to be aware of whether costs or charges are being used to derive the economic estimates.


Total medical care expenditures for oncology account for 10% of all Medicare expenditures.[22] Medicare Part A covers inpatient cancer care. Cancer-screening services are covered for cervical, breast, colorectal, and prostate cancer, and many types of chemotherapy and related treatments are covered under Part B. As of 2006, Medicare Part D provides a drug benefit that covers cancer drugs but requires significant financial contribution from patients who have prescription expenses more than $2,250.[23] In the future, prescription drug data will also be captured via Medicare part D.

Recent studies have incorporated economic analyses for various cancers experienced by the Medicare population. [1] [2] [24] Costs have been evaluated for the initial phase, the primary course of therapy, and any adjuvant therapy, continuing care, including surveillance activities for detecting recurrences and new cancers, and the terminal care phase. Data for these analyses derive from the linked Surveillance Epidemiology and End Results (SEER) and Medicare database that includes detailed financial and clinical data elements for cancer patients who received care in 11 geographic regions of the country (seehttp://seer.cancer.gov). The database provides detailed information for inpatient services (Part A) and payments for outpatient services (Part B). The Medicare-SEER cost files were generated by reviewing monthly cost files for each cancer patient identified in the SEER database. Prices are adjusted using the Medicare per capita index and Medicare-based price indices that account for differences in health care purchasing power over time and location. These data are used to provide estimates of national expenditures according to type of cancer and gender.

Quality Assessment of Economic Analyses

Controversy exists over the quality of economic analyses of medical treatments and has led to the development of grading systems for economic evaluations. [25] [26] The quality of the data and the models that are used in these analyses are the major determinants of the results. Additional items that are considered in the quality of economic evaluations include the objective and perspective of the analysis, data sources, type of comparison, handling of uncertainty, the time horizon of the analysis, and the discount rate. Other important considerations are the outcome measure that are used in the analysis, measurement of costs, measurement of effectiveness, and the overall transparency of the analysis (i.e., were the assumptions explicitly stated?).

Study sponsorship is gaining attention as concern has been raised over the potential for conflict of interest to bias the research, affect the design, and skew the interpretation of economic analyses of medical therapies. [27] [28] [29] The newness of pharmacoeconomics research and its potential effects on pharmaceutical company revenue make it particularly vulnerable to financial conflicts of interest. Researchers have examined the effects of conflict of interest on pharmacoeconomic research in breakthrough areas in oncology, such as hematopoietic colony-stimulating factors, antiemetics, and taxanes oncology. Published articles were classified according to qualitative conclusion, quantitative result, timing of study initiation, and funding source.

The first study found correlations between funding source and qualitative cost assessment, timing of study initiation, and discrepancies between qualitative conclusions and quantitative results. Favorable conclusions were reached by 81% of the pharmaceutical company-sponsored studies and 48% of the nonprofit-sponsored studies (P < 0.009). All of the studies that reached unfavorable conclusions had been sponsored by nonprofit organizations. Although nearly one fourth of the studies gave qualitative conclusions that overstated their quantitative results, this was not significantly greater for pharmaceutical company-sponsored studies than for nonprofit-sponsored studies.[27] More than 80% of economic studies funded by all sources were conducted after favorable clinical trial results were known. The findings of the study demonstrated a strong association between pharmaceutical company sponsorship and favorable economic assessments. Although there is no evidence of bias in individual articles, the results raised concerns about potential bias in pharmacoeconomic studies. Unfavorable cost profiles probably are underreported, and qualitative overstatements about the cost-effectiveness of new agents are not uncommon.

The second study addressed variations in study quality when the 44 pharmaceutical and not-for-profit-funded cost-effectiveness studies of the six breakthrough drugs in oncology were compared.[28]Investigators rated specific aspects of study reporting based on criteria from the U.S. Public Health Service Panel on Cost-effectiveness in Health and Medicine. Dissemination strategies were evaluated by using impact factor scores from the Science Citation Index. Operational aspects of pharmaceutical manufacturer–sponsored study reporting were better overall than were those associated with nonprofit-sponsored studies with respect to the following criteria: The results were more likely to be reported based on data obtained from randomized clinical trials or detailed cost models (90% versus 70%); to include descriptions of the source of cost differences (90% versus 79%); to state whether the study was carried out from a societal, governmental, or insurer perspective (70% versus 42%); and to indicate clearly the time period over which costs were evaluated (65% versus 50%). Nonprofit-sponsored studies were more likely than pharmaceutical-sponsored studies to report the generalizability of the findings to other clinical settings (58% versus 35%), to include statements on the statistical significance of the findings (38% versus 20%), and to clearly outline the cost per unit and data sources for the cost analyses (67% versus 45%). Most studies were published in low-impact-factor, peer-reviewed journals, and journal impact factor scores were similar between pharmaceutical- and nonprofit-sponsored studies. Overall, the study found differences in study reporting but not in types of journals where studies were published. These results, particularly with respect to differences in generalizability, may account in part for the finding that pharmaceutical manufacturer-sponsored studies were less likely to report unfavorable conclusions.

Strategies for Conducting Economic Analyses in Oncology

Because economic assessments are potentially useful as secondary endpoints in clinical trials of new cancer therapies or technologies,[19] cost analyses have been proposed alongside pivotal trials or new technologies. These are appropriate when investigational therapies are resource-intensive or when new technologies or treatments are likely to be used by large numbers of cancer patients. In most cases, these analyses are associated with phase III clinical trials, although inclusion in phase II trials can facilitate the collection of pilot data that can assist in study design for phase III trials. Phase IV studies also are possible sources of data for clinical and economic analyses. Estimates of the potential difference in costs between treatment arms can be helpful to coverage determinations.

The perspective of the economic analysis varies in many of the reported cost-effectiveness analyses. Most commonly, the perspective is that of the third-party payer; however, the societal perspective should also be considered.[21] Many clinical trials report economic data that are based on a “modified” societal perspective; that is, direct medical costs are quantified as societal costs, while direct nonmedical and productivity costs are not evaluated. Data collection can be prospective or retrospective. Prospective studies allow for timely assessment of clinical and economic outcomes at the end of the study. Detailed information on direct medical, direct nonmedical, productivity, and intangible costs can be obtained if careful planning is done before the study begins. Retrospective economic assessments are far less costly to conduct, but they include information on only a limited perspective (generally the third-party payer perspective).

The time interval from randomization to follow-up can influence the findings of the economic analysis, if follow-up is short. Ideally, the time horizon should be the same for the clinical and the economic analysis and should allow for realistic outcome measurement. Some economic analyses consider intermediate outcomes (e.g., response rate); other cost analyses are based on a review of final outcomes (e.g., survival in months or years). In either case, the outcomes should be identified prospectively. Despite increasing discussion about methodologies and practical approaches to including economic analyses in randomized clinical trials, remarkably few of these assessments have been reported in the literature. The National Cancer Institute (NCI)–sponsored Cooperative Trials Groups reported only one prospective and six retrospective economic analyses. [30] [31] [32] [33] [34] [35]

One can argue that cost data should be considered as important as clinical data and should be subjected to quality control assessments. Most of the literature related to cost analyses in cancer has been based on retrospective assessments of clinical trials, and these retrospective reviews generally have been funded by the pharmaceutical industry. Combining economic studies and clinical trials requires targeted funding, staff, and cooperation between clinical and economic researchers and analysts. Few independent nonprofit groups have the funds to supported economic analyses. Hence, concerns exist about researcher independence. One privately funded economic assessment of autologous stem cell transplant studies for breast cancer, for example, did not reveal the economic findings until after the clinical trial results were reported as negative. The savvy reader of economic analyses needs to think about the sponsor of a study and that group's motivation for undertaking a study and reporting its findings.

Economic Analyses Conducted by Cancer Clinical Trials Groups

During the 1990s, the NCI supported efforts to integrate economic analyses into cancer clinical trials. [19] [20] In 1994, the NCI sponsored a conference with representatives of cancer centers and cooperative groups that addressed the importance, appropriateness, and complexity of these evaluations. The next year, the American Society of Clinical Oncology (ASCO) established a Health Outcomes Working Group, which was charged with developing specific guidelines for implementing economic evaluations in cancer clinical trials.[20] In 1996, the NCI and ASCO convened a second meeting, attended by experts from the NCI-sponsored cooperative groups, NCI staff, and experts in the field of health economics, to consider the practical implementation of economic evaluation in cancer clinical trials. In 1998, a workbook that served as a developing guide designed to be used as practical reference for subsequent economic analyses of cancer clinical trials was published.[17] The first articles describing economic analyses alongside clinical trials conducted by the NCI-sponsored cooperative groups were published in 1997.

Table 24-1 provides information on seven NCI-sponsored studies that have been published to date. The following summary considers some of these real-life examples of the methods and operational considerations researchers face when conducting cancer clinical trials. The first cost-effectiveness study of an NCI-sponsored cooperative group trial was reported in 1997 by investigators who were affiliated with the Children's Cancer Study Group.[32] The clinical trial evaluated the clinical and cost-effectiveness of GCSF as an adjunctive therapy for children with acute lymphoblastic leukemia. The study randomized 164 children and found a reduction in the duration of neutropenia (5.3 versus 12.7 days) and duration of hospitalization (6 versus 10 days). Cost-minimization analyses indicated that GCSF did not add additional costs. Clinical and economic data were obtained directly from the clinical trial participants.

Table 24-1   -- Completed Economic Analyses Conducted by National Cancer Institute-Sponsored Clinical Trials Groups


Treatment Arms

Effectiveness Time Frame

Economic Time Frame



Radiation Therapy Oncology Group 90-03 and 91-04[37]

Brain metastases; head and neck cancer

Not measured


Cost estimation

90-03 costs estimated well; 91-04 costs not estimated very well

Eastern Cooperative Oncology Group 1490[35]

GM-CSF vs placebo for older



Cost minimization

GM-CSF was cost saving, and adults with AML decreased infections

Southwest Oncology Group 9031[33]

GCSF vs placebo for adults with AML



Cost minimization

GCSF did not add additional costs and decreased hospital stay

Southwest Oncology Group 9509[30]

Vinorelbine + cisplatin vs paclitaxel + carboplatin for non–small cell lung cancer


24 months

Cost minimization

Cisplatin + vinorelbine is less costly

Children's Cancer Study Group[32]

GCSF vs placebo for children with leukemia



Cost minimization

GCSF did not add additional costs and was associated with shortened duration of neutropenia

Pediatrics Oncology Group[36]

GCSF vs control for children with leukemia



Cost minimization

GCSF did not add additional costs and was associated with shortened duration of neutropenia

Children's Cancer Study Group 1881, 1882, 1891, 1901, 1922, 1941[31]

Acute leukemia—various treatments



Cost effectiveness

Delayed intensification, augmented therapy, and dexamethasone therapy cost-effective vs treatment of first relapse

AML, acute myelogenous leukemia; GCSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor.




The second economic analysis of an NCI-sponsored cooperative group trial was reported in 1999 by investigators who were affiliated with the Eastern Cooperative Oncology Group.[35] The randomized clinical trial evaluated the clinical effectiveness of the hematopoietic cytokine, granulocyte macrophage colony-stimulating factor (GM-CSF), as an adjunctive therapy for people 55 years of age or older who were receiving induction chemotherapy for acute myeloid leukemia. Patients receiving GM-CSF experienced a 72% reduction in severe infections, four fewer days with an absolute neutrophil count lower than 500 cells/mL, but no significant difference in the duration of hospitalization compared to the group taking the placebo. Decision analytic modeling was used to analyze the costs of GM-CSF use during induction therapy. Clinical probabilities of acquiring an infection were obtained from the clinical trial data; hospital costs per day for infected and uninfected patients were obtained from billing data from seven sites participating in the clinical trial. The significant improvements in rates of severe infections were associated with an estimated $2310 in cost savings per patient. The reduction in costs was particularly evident among individuals who received two cycles of induction chemotherapy. The study was conducted over a six-month period, with funding for the study provided by the pharmaceutical manufacturer.

A retrospective economic analysis of a randomized clinical trial conducted by the former Pediatrics Oncology Group[36] compared the costs of inpatient supportive care for pediatric patients (age 1 to 22 years) with T-cell leukemia and advanced lymphoblastic lymphoma. Patients received either GCSF (n = 45) or no GCSF (n = 43) following induction and two cycles of maintenance therapy. During maintenance therapy, the patients receiving GCSF had significantly fewer days to an absolute neutrophil count above 500 cells/mL and a trend toward fewer days of hospitalization. The study found that the total median costs of supportive care were similar for all patients in the study. Data on resource utilization were tabulated from case report forms, and costs were derived from national data on hospitalization costs, average wholesale prices of pharmaceuticals, and patient billing information from a single institution. The four-month study was conducted with support from the Cooperative Clinical Trial Group and the pharmaceutical supplier of the study drug.

In 2001, the Radiation Therapy Oncology Group (RTOG)[37] initial pilot study addressed four aims: (1) measurement of radiation therapy treatment costs for patients treated in different arms of two randomized controlled clinical trials, (2) comparison of measured costs to those predicted by an economic model, (3) examination of the distribution of costs among patients treated on the same arm, and (4) assessment of the feasibility of retrospective data collection effort. The RTOG selected two phase III clinical trials to evaluate in this pilot effort. The first study, RTOG 91-04, compared standard treatment to a total dose of 30 Gy with a second arm of accelerated hyperfractionation to a total dose of 54.4 Gy for cancer patients with brain metastases. The second study, RTOG 90-03, was a phase III study of patients with squamous cell carcinomas of the head and neck who received either standard fractionation to a dose of 70 Gy, hyperfractionation to a dose of 81.6 Gy, accelerated fractionation with a split to a total dose of 67.2 Gy, or accelerated fractionation with a concomitant boost to a total dose of 72 Gy. Expected quantities of procedure codes and relative value units associated with Medicare billing efforts were modeled. The median and mean relative value units were within the range predicted by an economic model for all arms of the head and neck cancer study but were above the predicted range for the brain cancer study. Some of the researchers encountered considerable difficulties in collecting the retrospective economic data, suggesting that prospective data collection might be the better strategy for economic analysis of RTOG studies. Clinical trials with complex treatment protocols, such as the head and neck cancer study, appeared particularly difficult to include in retrospective economic analytic efforts.

Nonfinancial metrics can be reported. One study, for example, reported on the feasibility of using duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate cost-effectiveness ratios of various treatment regimens evaluated in clinical trials of children with acute lymphoblastic leukemia.[26] Metrics included marginal cost-effectiveness estimates of the number of days per patient for delayed intensification and for augmented therapy and relapse-adjusted “savings” associated with augmented therapy (16 days) and with dexamethasone-based therapy (82 days). The study was supported by grants to the office of the cooperative group's chairman and indicated that retrospective economic analyses were feasible, provided that the economic analyses focused on duration of hospitalization.

Researchers affiliated with the Southwest Oncology Group conducted the first prospective economic analysis of a randomized clinical trial conducted by an NCI-sponsored cooperative clinical trial group.[30] The clinical trial included patients who were randomized to receive cisplatin plus vinorelbine versus carboplatin plus paclitaxel. The findings from this study indicated that prospective economic analyses could be conducted alongside randomized clinical trials, although these efforts did require external funding and committed resources from the statistical operations center of the cooperative clinical trial group.

This review of the design, outcome metrics used, and sponsorship of these studies is instructive in identifying potential opportunities and obstacles for future research. Most studies were based on retrospective economic analyses. Funding sources were diverse, most of the analytic efforts being supported by pharmaceutical suppliers.


U.S. health care expenditure on cancer care is greater than expenditure for any other illness. It is important to consider both the clinical benefit and the economic value provided by cancer treatment interventions, particularly during their development. Economic tools (cost-benefit, cost-effectiveness, cost-utility, and cost-identification analyses) can provide such information. Despite increases in coverage for patients in “qualifying” clinical trials by Medicare, several private insurers, and many U.S. states, few robust economic analyses have been conducted in trials sponsored by the NCI. Clinical trials that incorporate cost analyses can contribute to an understanding of the value of an intervention and can do so from a variety of perspectives.

Costs of cancer care can be evaluated in a variety of clinical settings. Economic considerations have important practical implications for oncologists and should be addressed for most new cancer treatments and procedures. Continuing economic pressures facing the health care system in the United States serve as an important reminder of the importance of unbiased cost analyses, particularly for cancer treatments. Despite nearly universal support for economic information, the paucity of cost-effectiveness analyses, especially studies that are not funded by the pharmaceutical industry, is particularly worrisome. Policymakers and physicians strive to make informed decisions about rational allocations of cancer resources. Economic data, if properly obtained, can assist in these decisions.


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