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A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program
1
Introduction
Advances in biomedical research have produced significant opportunities to improve cancer prevention, detection, and treatment. Insights about the genomic and molecular mechanisms of disease have enabled basic scientists to identify new therapeutic targets and develop new agents that are changing the paradigm of cancer research from the development of nonspecific, broadly toxic chemotherapies to the development of highly targeted combinations of therapies. However, the ability to translate biomedical discoveries into advances in cancer care remains dependent on the clinical trials system. Clinical trials provide an essential link between scientific discovery and clinical practice. These trials are crucial to the translation of new knowledge into tangible benefits for patients, and the knowledge gained in a clinical trial can also inform and guide further research into the biology of the disease.
Since its inception in the 1950s, the Clinical Trials Cooperative Group Program has been instrumental in establishing the standards for the care of patients with cancer and for clinical research methods. Research undertaken by the Cooperative Groups has contributed to significant advances in cancer treatment and prevention, including the introduction of new treatments and the use of established treatments for new indications that have led to improved survival and increased cure rates, particularly for pediatric cancers and some early-stage cancers in adults. Furthermore, the importance of the Cooperative Group Program is growing as industry trials are increasingly being conducted outside of the United States. The Cooperative Group Program provides a primary mechanism by which the value of therapeutic agents can be assessed within the medical milieu of the U.S. health care system. However, despite these important contributions and a long record
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of accomplishments, the Cooperative Group Program is facing numerous challenges that threaten its ability to continue to undertake large-scale, innovative trials that benefit patient care. Confronting these challenges is essential. A national cancer clinical trials enterprise is necessary “to ensure that the advances in understanding the biological basis of cancer, generated by the past 40 years of research, are harnessed effectively to bring measurable, meaningful benefits to patients” (NCI, 2005).
IMPORTANCE OF CANCER CLINICAL TRIALS
Clinical trials are essential for establishing the evidence base that the oncology community uses to make treatment decisions and to determine the direction of future clinical research. By evaluating the safety and efficacy of new therapies, comparing the effectiveness of existing therapies, and assessing different prevention, screening, and detection strategies, clinical trials are responsible for setting the standard of patient care. In fact, today’s most effective therapies began as hypotheses tested within the clinical trials environment (C-Change and Coalition of Cancer Cooperative Groups, 2006). Clinical trials also provide fundamental information about the biology of cancer, which investigators leverage to advance preclinical research and drug development.
Numerous stakeholders conduct clinical trials with various goals across the spectrum of research. While industry trials primarily focus on drug discovery and development activities with the potential for a substantial return on investment, publicly sponsored trials have a more diverse portfolio, from small, proof-of-concept Phase I and II studies that typically enroll patients with metastatic disease who have already had one or more lines of therapy to large Phase III studies that may focus on adjuvant or neoadjuvant therapy, first-line therapy for metastatic disease, or prevention strategies. Publicly sponsored trials are also more likely to study less common cancers that are not often a focus of industry research and development.
The National Cancer Institute (NCI) supports the largest U.S. network for clinical trials of any type through the use of several different funding mechanisms. NCI supports individual trials through grant mechanisms and research contracts, funds programs that use clinical trial data to advance preclinical research, and also partially funds cancer centers that conduct clinical trials as a component of their overall research and patient care activities. In addition, NCI supports trials through cooperative agreements, such as the Clinical Trials Cooperative Group Program. The various recipients of the funds provided by the use of these different funding mechanisms bring different strengths to the research portfolio.
The largest component of the NCI-supported clinical trials portfolio is the Clinical Trials Cooperative Group Program. The Cooperative Group
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Program is the major mechanism through which large-scale cancer clinical trials are conducted in the public interest. The expansive, multi-institutional clinical trials infrastructure maintained by the Cooperative Group Program is recognized for its fundamental importance in reaching a large, diverse community-based patient population, acquiring high-quality data and biospecimens that advance preclinical research, and incorporating a broad range of expertise into trial design, implementation, and statistical analyses. Within the portfolio of NCI-supported clinical trials, the Cooperative Group Program primarily focuses on late-stage translation activities, such as large Phase II and Phase III clinical trials that may have implications for changing treatment practices directly relevant to patient care. Individual institutions can rarely undertake such trials because it would take too long to accrue a sufficient number of patients to achieve timely results.
THE CLINICAL TRIALS COOPERATIVE GROUP PROGRAM
The Clinical Trials Cooperative Group Program began in 1955. At that time, the U.S. Congress was interested in developing a more systematic and planned program for the study of chemotherapy in cancer treatment because studies had shown that the treatment of leukemia and lymphoma with alkylating agents, steroids, antifolate, and mercaptopurine could occasionally result in complete remission of these cancers. Congress appropriated $5 million to establish the Cancer Chemotherapy National Service Center, and NCI initiated the Cooperative Group model to test chemotherapeutic agents in clinical trials. By 1958, 17 Cooperative Groups had been organized and operated under research grants from NCI. Federal funding for chemotherapy research continued to climb: in 1958 alone, Congress appropriated $25 million (Zubrod, 1984).
In the beginning, the primary objective of the Clinical Trials Cooperative Group Program was to test new anticancer agents from NCI’s drug development program. However, between 1955 and 1966, NCI underwent an internal reorganization. In recognition of the importance of clinical trials as an independent research activity, the Cooperative Group Program was separated administratively from the drug screening program and transferred to the Cancer Therapy and Evaluation Branch of the Chemotherapy Program (Keating and Cambrosio, 2002).
During the following decades, NCI implemented some organizational changes to the Program. In 1980–1981, the mechanism of support for the Cooperative Group Program was converted from a grant to a cooperative agreement, which had a profound effect on the Cooperative Group Program. A cooperative agreement enabled NCI to have a considerable role in Cooperative Group activities, including trial concept selection, protocol development, and trial operations (CTEP, 2006) (these are described fur-
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BOX 1-1
NCI Cooperative Group Program 2010
The NCI Cooperative Group Program is composed of 10 Groups:
American College of Radiology Imaging Network (ACRIN)
American College of Surgeons Oncology Group (ACOSOG)
Cancer and Leukemia Group B (CALGB)
Children’s Oncology Group (COG)
Eastern Cooperative Oncology Group (ECOG)
Gynecologic Oncology Group (GOG)
National Surgical Adjuvant Breast and Bowel Project (NSABP)
North Central Cancer Treatment Group (NCCTG)
Radiation Therapy Oncology Group (RTOG)
Southwest Oncology Group (SWOG)
ther in Chapter 3). In 1983, the Community Clinical Oncology Program (CCOP) was established to ensure that community physicians and cancer patients not treated in academic medical centers had access to cancer clinical trials and to boost the rates of accrual to clinical trial protocols. NCI established the Minority-Based CCOP in 1990 to increase the involvement of racial and ethnic minority patients in clinical trials research and to improve access to the latest advances in cancer treatment, prevention, and control (NCI, 2003).
Cooperative Group membership has evolved over time (Hoogstraten, 1980), and the Program currently includes 10 Cooperative Groups (the names of the 10 Groups and the abbreviations for the groups used throughout the remainder of this chapter are presented in Box 1-1). The focus of each Group varies, but there are four main types of groups: (1) disease-oriented Groups (e.g., GOG); (2) Groups that focus on high-technology, single-modality studies (e.g., RTOG); (3) Groups in which investigators focus on a particular patient population (e.g., COG); and (4) multimodality Groups. Over time the Cooperative Groups have expanded their research mission beyond testing new anticancer agents from NCI’s drug development program to include cancer treatment, prevention, early detection, quality of life issues, rehabilitation, and comparative effectiveness. Each year more than 25,000 patients participate in multi-institutional clinical trials involving more than 3,100 institutions and 14,000 investigators within the 10 Cooperative Groups.1
1
Some funds from the Cooperative Group Program also support the European Organisation for Research and Treatment of Cancer and the NCI of Canada—Clinical Trials Group.
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ACHIEVEMENTS OF THE COOPERATIVE GROUP PROGRAM
The Cooperative Groups have been responsible for numerous advances in cancer research, treatment, and prevention and in the training of investigators. Over the five decades since its inception in the 1950s, the high-quality research conducted by the Cooperative Groups has been instrumental in establishing the standards of cancer patient care and clinical research methods (Mauer et al., 2007), and research undertaken by the Cooperative Groups leads to more than 200 peer-reviewed publications annually. Cooperative Group accomplishments can be organized by influential trials that have, over the 50 years of the Groups’ existence, incrementally provided practitioners with evidence to guide the treatment of patients with cancer (see Box 1-2 for a list of some of these accomplishments). Likewise, Cooperative Group accomplishments can be organized thematically by clinical objective and type of disease. Cooperative Group research has led to the
development of new standards for the management of patients with cancer;
development of sophisticated investigative techniques;
collection of data to obtain regulatory approval for new drugs or new drug indications;
refinement in diagnosis and treatment of cancer based on the identification of histologic subtypes of tumors and the recognition of prognostic variables;
development of adjuvant and neoadjuvant chemotherapy and concurrent chemoradiotherapy for solid tumors through studies that combine modalities;
refinement of the use of chemotherapy through the study of new agents and different dosing schedules;
comparison of new cancer treatments against the best available treatments; and
development of novel therapeutic agents in Phase I and II trials (Mauer et al., 2007).
Significant advances derived from Cooperative Group research include improvements in the treatment of childhood cancer, the treatment of solid tumors and hematologic malignancies in adults, adjuvant therapy, and combined-modality treatment. Additionally, trials of cancer prevention and the publication of negative findings from Cooperative Group research greatly contribute to ensuring the use of evidence-based treatment and prevention strategies.
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BOX 1-2
A Sampling of Cooperative Group Accomplishments
Pediatric cancers
Development of effective treatments for childhood cancers, including Wilms’ tumor, leukemia, and rhabdomyosarcoma, which have improved the cure rates for childhood cancers from less than 10 percent when the Cooperative Groups were first founded to nearly 80 percent today. The outcome of acute lymphoblastic leukemia (ALL) has progressed from a 6-month median survival to an 80 percent overall cure rate. There has also been substantial improvement in the 5-year cancer survival rates; between 1960 and 2000, the 5-year rate of survival for children with solid tumors increased from 27 to 80 percent.
The high rate of participation of children in Cooperative Group trials; if a clinical trial is available, 50 to 60 percent of children eligible are enrolled and 90 percent of children under age 5 years are enrolled. With high participation rates, the results of clinical trials performed by COG define the standard of care for children with cancer in the United States and elsewhere.
Definition of new risk-based classification schemes that use clinical and expanded biological factors for ALL, acute myeloid leukemia (AML), and neuroblastoma (NBL). These classification schemes are used at the time of diagnosis to determine therapy on the basis of risk.
Incorporation of minimal residual disease (MRD) assessments at distinct points in therapy into trial design to ascertain the impact of an earlier intervention on the basis of this surrogate marker, given the degree of correlation between the early outcome, the response to therapy, and the presence of MRD in patients with ALL, AML, and NBL.
Identification of candidate genes and patterns of gene expression as predictors of outcomes in ALL, NBL, and meduloblastoma.
Clinical translation of targeted agents in pediatric cancers. For example, antibody-based immunotherapy (chimeric anti-glycoprotein D2 antibody ch 14.18) in NBL improved the rate of event-free survival by 20 percent after stem cell transplantation for these high-risk patients.
For Philadelphia chromosome-positive (Ph+) ALL, the integration of imatinib into an aggressive chemotherapy backbone resulted in a significant improvement in the rate of overall survival for children with Ph+ ALL. The rate of event-free survival after treatment with imatinib and aggressive chemotherapy appears to be superior to that obtained historically by the use of stem cell transplantation. Whereas stem cell transplantation provided the best curative option for children with Ph+ ALL, prolonged follow-up has demonstrated that superior outcomes are achieved with imatinib treatment plus chemotherapy. This also has significant ramifications for the treatment of adults, given the high incidence of Ph+ ALL in adults with ALL.
Hematologic malignancies
Development of the framework for the current therapy of patients with AML. Trials also defined the standard of care for patients with AML, refining classification of leukemia to include cytogenetic and molecular genetic characteristics (CALGB).
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First demonstration of the significant progression-free survival benefit of using fludarabine during first-line therapy in patients with chronic lymphocytic leukemia (CLL), leading to fludarabine becoming a standard of care for the initial therapy of CLL (CALGB).
Clinical development and Food and Drug Administration (FDA) approval of 5-azacytidine for the treatment of myelodysplastic syndrome (CALGB).
Definition of the role of all-trans retinoic acid in the induction and maintenance of acute promyelocytic leukemia (ECOG).
Trials to establish thalidomide plus dexamethasone as standard of care for patients with newly diagnosed myeloma. Trial E1A00 was the basis for the approval of thalidomide for the treatment of myeloma by the FDA in 2006 (ECOG).
Demonstration of three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus involved field radiotherapy as the standard therapy for early-stage, nonbulky, aggressive non-Hodgkin’s lymphoma (SWOG).
Breast cancer
Landmark trials supporting the use of more conservative, less disfiguring treatment of breast cancer, altering the standard of care toward breast-conserving therapy. These trials demonstrated equivalent survival between patients undergoing radical mastectomy and patients undergoing total mastectomy and then equivalent rates of survival and in-breast recurrence between patients undergoing lumpectomy and patients undergoing total mastectomy when lumpectomy and mastectomy were followed by radiation therapy (NSABP).
Demonstration of a significant survival benefit of adjuvant treatment with trastuzumab, a monoclonal antibody, in women with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer (NCCTG, NSABP).
Development of Oncotype DX, a 21-gene assay that predicts the benefit of chemotherapy and the 10-year risk of a recurrence of breast cancer, using clinically annotated Cooperative Group tumor blocks. Oncotype DX testing enables some women to safely forgo chemotherapy treatment and its associated side effects (NSABP).
Demonstration by the Breast Cancer Prevention Trial that tamoxifen treatment reduced the incidence of breast cancer by nearly 50 percent in women with an increased risk of developing breast cancer (NSABP).
Demonstration that tamoxifen and raloxifene are equally effective in reducing the risk of invasive breast cancer (NSABP).
Development and demonstration of clinical effectiveness of dose-dense adjuvant therapy for breast cancer (CALGB).
Definition of the role of adjuvant paclitaxel as part of adjuvant therapy for breast cancer leading to FDA approval of the use of paclitaxel for this indication. Correlative science studies found that the benefit of adding paclitaxel was limited primarily to women with estrogen receptor-negative and HER-2-positive tumors (CALGB).
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Demonstration that patients receiving adjuvant tamoxifen for breast cancer with reduced cytochrome P-450 2D6 (CYP2D6) activity or those receiving CYP2D6 inhibitors have shorter lengths of disease-free survival compared to those with highly active CYP2D6 (NCCTG).
Assessment of the beneficial role of hormonal therapy plus chemotherapy in premenopausal women with hormone receptor-positive, node-positive breast cancer. Before the trial, the combination of hormonal therapy and adjuvant chemotherapy was of uncertain benefit in this patient group (ECOG).
Demonstration that breast cancer patients with positive axillary nodes benefit more (significantly superior rates of disease-free and overall survival) from 1 year of combination chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) compared with the benefit achieved from 2 years of therapy with a single agent (melphalan). Additional trials built on this combination chemotherapy (SWOG).
Comparison of the effectiveness of different imaging strategies has refined imaging usage. For example, a trial demonstrated that digital mammography is superior to film-screen mammography for a subset of women (e.g., women with dense breasts, such as those who are younger and pre- or perimenopausal) (ACRIN).
Lung cancer
Development of combined-modality treatment for Stage III non-small-cell lung cancer (NSCLC) as a standard of care (CALGB).
Demonstration that both radiation therapy and chemotherapy are effective in elderly patients with lung cancer but that the risk of toxicity is substantially greater in older patients (NCCTG).
Demonstration that bevacizumab can improve the response rate, the length of progression-free survival, and the overall survival rate when it is combined with chemotherapy for the first-line treatment of NSCLC (ECOG).
First randomized comparison of new agent-platinum chemotherapy regimens (vinorelbine-cisplatin versus paclitaxel-carboplatin) for advanced NSCLC, which found improved tolerability of the paclitaxel-carboplatin combination (SWOG).
Demonstration that healthier patients with inoperable NSCLC had better results if they received chemotherapy during their course of radiotherapy rather than before radiotherapy (RTOG).
Gastrointestinal cancer
Demonstration that adjuvant chemotherapy improves the rate of survival in patients with Stage III colon cancer (NCCTG).
Demonstration that bevacizumab (a vascular endothelial growth factor [VEGF] inhibitor) significantly improved the rate of overall survival when it was used in combination with a regimen of oxaliplatin, fluorouracil (5-FU), and leucovorin (FOLFOX4) in patients with advanced colorectal cancer, expanding the FDA-approved indication for bevacizumab (ECOG).
Demonstration that oxaliplatin added to infusional 5-FU as first-line therapy improves the rate of survival in patients with metastatic colorectal cancer (NCCTG).
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Demonstration that the 3-year disease-free survival rate is a valid surrogate of the 5-year overall survival rate in patients receiving adjuvant 5-FU-based chemotherapy for resected colon cancer (NCCTG).
Demonstration that laparoscopic resection of colon cancer is as effective as open colectomy for the treatment of localized colon cancer (NCCTG).
Change of the standard of care for adjuvant therapy for Stage II and III colon cancer. Over time, trials evaluating different adjuvant approaches found significant survival advantages for first 5-FU plus levamisole, then for 5-FU plus leucovorin, and finally 5-FU plus leucovorin plus oxaliplatin, improving patient outcomes (NSABP).
Validation of the utility of combined-modality therapy for localized esophageal cancer. Investigators observed a 4.5-year median survival rate and a 39 percent 5-year survival rate for patients randomized to induction chemoradiotherapy followed by surgery but a 1.8-year median survival rate and a 16 percent 5-year survival rate for those randomized to surgery alone. Although this trial had limited accrual, it is unlikely that a more robust trial will be undertaken as a result of these findings and the direction of the field (CALGB).
Prevention trials, such as one demonstrating that aspirin reduced the risk of development of colon adenoma in patients with colon cancer treated by complete resection of the colon (CALGB).
Demonstration that adjuvant chemotherapy plus radiation improves survival in patients with Stage II and III rectal cancer (NCCTG).
Significantly improved survival for patients with advanced pancreatic adenocarcinoma when they received the drug gemcitabine, in addition to standard therapy, after surgery (RTOG).
Genitourinary cancer
Demonstration that finasteride can significantly alter the risk of prostate cancer in men over 55 years of age (SWOG).
Determination that radiotherapy combined with long-term hormone suppression significantly improves the survival rate for men with high-grade prostate cancer (Gleason Score 8 to 10). However, men with locally advanced prostate cancer (Gleason Score 2 to 6) benefit most from hormonal suppression before radiotherapy (RTOG).
Identification of several prognostic biomarkers from specimens of patients with androgen-independent prostate cancer (AIPC) obtained in a CALGB trial. These biomarkers, including plasma and urine VEGF levels, were inversely related to the rate of survival and were independent prognostic factors. This research provided a rationale for the trial of bevacizumab in combination with docetaxel chemotherapy in patients with AIPC (CALGB).
Demonstration of the utility of bacillus Calmette-Guérin (BCG) for the treatment of superficial bladder cancer. Immunotherapy with BCG reduces the risk of recurrence of superficial bladder cancer, establishing BCG as standard therapy and leading to a new drug approval for the use of BCG for this indication (SWOG).
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Brain cancer
Demonstration that lower-dose radiation therapy is as effective as and less toxic than higher-dose radiation therapy for patients with low-grade glioma (NCCTG).
Establishment of proof of principle that chemotherapy is effective for the treatment of patients with low-grade oligodendroglioma (NCCTG).
Determination that chromosome arm 1p and 19q deletions in gliomas are associated with a longer period of survival in patients (NCCTG, RTOG).
First U.S. research organization to coordinate an international brain tumor trial. This landmark study used high-dose temozolomide after radiotherapy for patients with newly diagnosed glioblastoma and is a joint effort between RTOG and the European Organisation for Research and Treatment of Cancer.
Improvement in survival by more than 33 percent for patients with a single brain metastasis obtained by the use of whole-brain radiotherapy followed by stereotactic radiosurgery instead of whole-brain treatment alone (RTOG).
Gynecologic cancer
Determination of the standards for multiagent chemotherapy for all gynecologic sites. For example, the trial evaluating treatment with paclitaxel-cisplatin in ovarian cancer demonstrated that paclitaxel adds further treatment benefits, including a significantly better response rate, progression-free survival, and overall survival, leading to a new standard of care (GOG).
Confirmation of the value of cytoreductive surgery in patients with ovarian cancer (GOG).
Demonstration that the combination of cisplatin and cyclophosphamide was not superior to carboplatin and cyclophosphamide in patients with suboptimal Stage III and IV ovarian cancer and that the combination of carboplatin and cyclophosphamide was significantly less toxic. These findings led to a new drug approval for carboplatin in 1989 (SWOG).
Childhood Cancer
One of the major accomplishments in research on and the treatment of pediatric cancer is the high rate of participation of children in Cooperative Group clinical trials. In the United States, 90 to 95 percent of all children with a newly diagnosed malignancy are seen at an institution that participates in COG (O’Leary et al., 2008). If a clinical trial is available, more than half of these children participate; for young children (less than 5 years of age), the rates of participation in a clinical trial are closer to 90 percent. The collective achievements of Cooperative Group research over the past four decades have led to effective treatments for childhood cancers and improved cure rates (Mauer et al., 2007). The age-adjusted mortality rate for
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Definition of the value of chemoradiation for the treatment of cervical cancer. Five Cooperative Group trials found that radiation therapy combined with platinum-based chemotherapy conferred mortality rate reductions of 30 to 50 percent compared with the mortality rate after radiation therapy alone for women with locally or regionally advanced cervical cancer or localized cervical cancer with poor prognostic indicators (GOG, RTOG, and SWOG).
Definition of the pattern of spread of endometrial carcinoma and defined risk groups (GOG).
Identification of the limited value of reassessment laparotomy (GOG).
Confirmation of the value of intraperitoneal therapy. Intraperitoneal cisplatin and paclitaxel were associated with significantly better progression-free survival and overall survival, but they were also more toxic and had more complications (GOG).
Head and neck cancer
Definition of the role of taxanes in the treatment of head and neck cancers (ECOG).
Discovery that patients who received chemotherapy together with radiotherapy after surgery were far less likely to have a recurrence of cancer for patients with high-risk head and neck cancer (RTOG).
Skin cancer
Establishment of the role of high-dose interferon alpha-2b as the first FDA-approved adjuvant therapy for high-risk malignant melanoma (ECOG).
SOURCES: Coltman, 2008; Dignam, 2004; Giantonio et al., 2008; Green et al., 2008; Grothey et al., 2008; Hillman and Gatsonis, 2008; Mauer et al., 2007; O’Leary et al., 2008; Omura, 2008; RTOG, 2009; and Wickerham et al., 2008. For further information on additional Cooperative Group achievements, see CTEP, 2002.
children with cancer has decreased since 1950 (Figure 1-1), and cure rates have increased from less than 10 percent when the Cooperative Groups were founded to nearly 80 percent at present (O’Leary et al., 2008).
Adult Solid Tumors and Hematologic Malignancies
Cooperative Group research has been instrumental in providing data on the treatment of specific tumors and hematologic malignancies. For example, landmark trials from NSABP first demonstrated equivalent rates of survival between patients undergoing a radical mastectomy and patients undergoing a total mastectomy and then between patients undergoing a
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times of 600 to 800 days (Dilts and Sandler, 2006; Dilts et al., 2006, 2008, 2009). In addition to inefficiencies within the concept development process, extensive and overlapping oversight by NCI, institutional review boards, and FDA contributes to delays in activating trials. Collaborations among Cooperative Groups and industry sponsors largely remain nonstandardized, which also increases the time and complexity of clinical trial planning. Because science can change rapidly, the time that it takes to activate a new trial may render obsolete the research question that the clinical trial was designed to answer and threatens the relevance of Cooperative Group trials (see Chapter 3).
Inadequate Patient and Physician Involvement in Cancer Clinical Trials
Few patients and physicians participate in clinical trials for adult cancers. Of the 1.4 million patients with a new diagnosis of cancer in 2008 (ACS, 2008), it is estimated that no more than 5 percent of patients enrolled in clinical trials,4 with some estimates suggesting that less than 3 percent of patients enrolled in clinical trials (reviewed by ENACCT-CCPH, 2008). Likewise, reimbursement concerns, a lack of awareness of clinical trials, physician or patient preference for standard therapies, excessive regulatory burdens, and time constraints prevent many physicians from enrolling patients in clinical trials (C-Change and Coalition of Cancer Cooperative Groups, 2006; Mansour, 1994; Somkin et al., 2005). Because of the trend toward the use of targeted therapy and personalized medicine, clinical trials increasingly rely on stratified populations (see Chapter 2), which require large numbers of patients willing to participate. The low rate of involvement of physicians and patients in clinical trials slows accrual and prevents the Cooperative Groups from efficiently translating new knowledge into better patient care. Many trials never reach their accrual goals and thus generate no meaningful results to guide treatment (see Chapter 4 for more details).
Movement of Industry Trials Overseas
In part because of the difficulty of activating and conducting clinical trials in the United States, there is a growing trend for industry to conduct clinical trials overseas (Getz, 2007; Glickman et al., 2009; IOM, 2009). Cost savings and recruitment efficiencies are cited as the primary drivers of the globalization of clinical trials (Agres, 2005; Normile, 2008). With the movement of clinical trials, clinical investigators, and resources away from the United States, the ability of the United States to maintain a critical mass
4
This is in stark contrast to rate of enrollment for children with cancer, the majority of whom are enrolled in clinical trials.
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of expertise to conduct clinical trials is questionable. Without the conduct of clinical trials in the United States, patients could lose access to promising new therapies as they develop, and in some cases, the results of clinical trials may have less relevance to U.S. patient populations (see Chapter 4).
ORIGIN OF THE STUDY
Recognizing the value of publicly sponsored cancer clinical trials and the challenges that currently confront the U.S. clinical trials system, the Institute of Medicine’s (IOM’s) National Cancer Policy Forum held two workshops to examine these issues and to obtain input from a diverse group of stakeholders. The first workshop, Improving the Quality of Cancer Clinical Trials, held on October 4 and 5, 2007, focused on the science underpinning clinical trials; collaborations among Cooperative Groups, industry, and academia; and the regulatory issues affecting clinical trial development, especially the early stages of development. The second workshop, Multi-Center Phase III Clinical Trials and NCI Cooperative Groups, held on July 1 and 2, 2008, explored the organization and operations of the Cooperative Group Program, patient and physician involvement in Cooperative Group research, and data collection requirements, as well as clinical trial cost and reimbursement issues. The proceedings of both workshops were published by the IOM as workshop summaries (IOM, 2008, 2009).
Invited speakers represented a diverse group of stakeholders, including NCI, FDA, the Centers for Medicare & Medicaid Services, Cooperative Group leadership, clinical investigators from academia and community practice, preclinical research scientists, biostatisticians, bioimaging and biomarker experts, industry participants, insurers, patient advocates, and cancer center administrators. Throughout the workshops, speakers conveyed the importance of Cooperative Group clinical trials in setting the standard of care for cancer treatment, prevention, and detection. However, speakers voiced a number of concerns over the current system, prompting the workshop chair, John Mendelsohn, to note that there was general agreement among workshop participants that the Cooperative Group Program is approaching a state of crisis (IOM, 2009). Other presenters discussed ways in which innovative trial designs, therapeutic combinations, drug-diagnostic codevelopment, molecular imaging, and correlative science have the potential to significantly improve cancer care if the barriers are appropriately addressed.
Based on the input received from these workshops, the director of NCI, John Niederhuber, requested that the IOM conduct a consensus study of cancer clinical trials and the Cooperative Group Program. Funding was obtained from NCI, the Centers for Disease Control and Prevention, the
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American Cancer Society, the American Society of Clinical Oncology, the Association of American Cancer Institutes, and C-Change.
COMMITTEE APPOINTMENT AND CHARGE
The NCI asked the IOM to examine a broad a number of topics relevant to cancer clinical trials and the organization and operation of the Cooperative Group Program and to make recommendations that could improve the quality of cancer clinical trials conducted through the program (Box 1-3). To address the charge, the IOM appointed a 17-member committee whose members had a broad range of expertise and experience. Among these individuals were experts in biomedical research, clinical investigation in academia and community practice, statistics, radiology, research and development in the biotechnology and pharmaceutical industries, management research, systems engineering, the health insurance industry, and patient advocacy.
BOX 1-3
Committee Statement of Task
An IOM committee will review the organization and operation of the National Cancer Institute (NCI) Clinical Trials Cooperative Group Program and recommend ways to improve the quality of cancer clinical trials conducted by the groups. Attention will be focused on how to improve, modernize, and streamline the process, with special consideration given to the recent emphasis on targeted therapies due to an improved understanding of the biology of cancer. Given the limits on funding for cancer clinical trials, there is a particular need to improve efficiency and make efficient use of time, effort, and resources. Specifically, the committee will recommend ways to
improve the design, review, and operation of clinical trials;
reduce the prolonged period of time currently spent moving from initial concept to final approval;
prioritize trials and trial sites based on scientific merit and past performance;
increase participation of both clinicians and patients;
make greater use of technologies such as imaging and other biomarkers to select therapies for development and testing, to match patients and therapies, and to monitor patient responses;
define standards for minimal data requirements to establish safety and efficacy of experimental therapies;
reduce costs and ensure adequate funds for high-quality trials; and
promote greater collaboration among various stakeholders.
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THE COMMITTEE’S VISION FOR CANCER CLINICAL TRIALS IN 2015
The committee recognized that the numerous reviews of the Cooperative Group Program have not resulted in transformative programmatic change. Indeed, a recently published commentary stated that “[i]ts awkward present form evolved because of decades of tinkering with administrative structures at NCI and the National Institutes of Health, reactions to specific events or perceived risks, and changing needs of various governmental and nongovernmental stakeholders” (Steensma, 2009).
With the goal of providing recommendations that result in systemic change, the committee took a broad view of the clinical trials process rather than simply focusing on NCI’s role. The committee defined the current system’s inadequacies in terms of missed opportunities, misaligned incentives, and collective challenges. Many aspects of the clinical trials infrastructure have not changed dramatically since the 1950s, whereas biomedical discoveries and technology development have been advancing rapidly in recent years. The collective environment in which clinical trials are conducted influences the pace of clinical advances.
The committee then described the needs of an ideal cancer clinical trials system of the near future, circa 2015 (see Box 1-4). The committee envisions a dynamic system that could efficiently respond to emerging scientific knowledge, involve the broad cooperation of stakeholders, and leverage evolving technologies that could provide high-quality, practice-changing research. Clinical trial participation would be the preferred option for patients and physicians because it would provide access to innovative therapies that reflect patient preferences and that are appropriately reimbursed.
This list of ideal characteristics laid the groundwork for the committee deliberations to develop goals and specific recommendations to achieve them. The committee concluded that the academic, governmental, and commercial sectors must join with the public to develop a 21st-century clinical trials system to more effectively leverage scientific advancements and translate them into public health benefits by improving the science, technology, efficiency, and timely completion of the very best cancer clinical trials.
THE COMMITTEE’S CONCLUSIONS AND RECOMMENDATIONS
The committee reviewed the available published literature and obtained input from experts in the field, interested individuals, and institutions to formulate its recommendations. The committee’s recommendations support four main goals for achieving the ideal vision of cancer clinical trials: (1) improve the speed and efficiency of clinical trial design, launch, and conduct, (2) incorporate innovative science and trial design in cancer clini-
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BOX 1-4
Needs for Cancer Clinical Trials in 2015
Rapid translation of scientific discoveries into public health benefit
Trials that address questions with significant implications for patient care
Collaboration among stakeholders, with effective and timely communication, in developing the most promising treatments
Streamlined procedures for rapid planning, approval, and launch of clinical trials, with accountability for meeting timelines and rewards for productivity
Efficient incorporation of new technologies and scientific questions, such as the identification and application of biomarkers and molecular imaging, into clinical trials
A strong publicly supported clinical trials system in the United States that complements commercial trials to develop drugs and devices
A highly efficient and flexible system for innovative, rigorously prioritized clinical trials
Adequate funding for well-designed, high-quality trials
Patient access to promising therapies as they develop
Addresses questions and collects data that are relevant and meaningful to the diverse U.S. patient population
A robust, standardized, and accessible clinical trials infrastructure
A complete database of active and planned trials
Standardized electronic data capture
Publicly accessible tissue repositories with high-quality, fully annotated, and inventoried samples collected and stored in a standardized fashion
cal trials, (3) improve selection, support, and completion of cancer clinical trials, and (4) incentivize participation of patients and physicians in clinical trials.
ORGANIZATION OF THE REPORT
Chapter 2 provides an overview of the science underpinning the development of cancer therapies and the challenges that must be overcome to achieve the goals of personalized medicine for cancer.
Chapter 3 provides an overview of the structure, organization, and funding of cancer clinical trials and the Cooperative Group Program. It also delineates the inefficiencies in the current system and discusses the collaborative nature of cancer clinical trials.
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Broad use of those samples in retrospective studies as new hypotheses evolve
A consistent and dynamic process for rapidly setting national standards and unified procedures for new technologies such as diagnostics, with reproducibility and effective incorporation into clinical trials
Harmonized and synchronized rules and guidelines across federal regulatory agencies
Guidance grounded in an understanding of contemporary science as new paradigms develop for therapeutic approaches as well as for clinical trials methodology
Support for clinical investigators
Training and retention of professionals to efficiently and swiftly carry out important clinical research
Adequate paid protected research time for active clinical investigators
Recognition and appropriate rewards for collaborative clinical research in academic advancement and community practice careers
Adequate reimbursement of costs for actively participating institutions and physicians
Broad patient involvement in clinical trials
Third-party payor coverage of nonexperimental costs of patient care to ensure that patients do not forgo participation in trials because of financial hardship
Participation in the design, implementation, and conduct of trials, and in the communication and dissemination of clinical trial results
Chapter 4 examines the incentives and disincentives for participation in cancer clinical trials, for both patients and clinicians.
Appendix A reviews the recommendations from past evaluations of the Cooperative Group Program and ongoing changes in response to those recommendations. It also includes a summary of the recommendations made in March 2010 by the NCI-appointed Operational Efficiency Working Group.
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