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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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 chang- ing the paradigm of cancer research from the development of nonspecific, broadly toxic chemotherapies to the development of highly targeted combi- nations 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 clini- cal 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 can- cer 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 can- cers and some early-stage cancers in adults. Furthermore, the importance of the Cooperative Group Program is growing as industry trials are increas- ingly 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 1

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2 A NATIONAL CANCER CLINICAL TRIALS SySTEM 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 measur- able, 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 assess- ing 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 envi- ronment (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 dis- covery 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 recipi- ents 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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 INTRODUCTION 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 bio- specimens that advance preclinical research, and incorporating a broad range of expertise into trial design, implementation, and statistical analy- ses. 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 occa- sionally result in complete remission of these cancers. Congress appropri- ated $5 million to establish the Cancer Chemotherapy National Service Center, and NCI initiated the Cooperative Group model to test chemothera- peutic 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 Coopera- tive 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 Pro- gram (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 Pro- gram. 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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 A NATIONAL CANCER CLINICAL TRIALS SySTEM 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 clini- cal 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 through- out 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) multimo- dality 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 detec- tion, 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 investiga- tors 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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 INTRODUCTION 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 iden- tification of histologic subtypes of tumors and the recognition of prognostic variables; • development of adjuvant and neoadjuvant chemotherapy and con- current 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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 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX 1-2 A Sampling of Cooperative Group Accomplishments Pediatric cancers •    evelopment  of  effective  treatments  for  childhood  cancers,  including Wilms’  D 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 lympho- blastic 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.  •    he high rate of participation of children in Cooperative Group trials; if a clinical  T trial is available, 50 to 60 percent of children eligible are enrolled and 90 per- cent 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. •    efinition  of  new  risk-based  classification  schemes  that  use  clinical  and  D expanded biological factors for ALL, acute myeloid leukemia (AML), and neu- roblastoma (NBL). These classification schemes are used at the time of diag- nosis to determine therapy on the basis of risk. •   ncorporation of minimal residual disease (MRD) assessments at distinct points  I 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. •   dentification of candidate genes and patterns of gene expression as predictors  I of outcomes in ALL, NBL, and meduloblastoma. •    linical  translation  of  targeted  agents  in  pediatric  cancers.  For  example,  C a   ntibody-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. •    or  Philadelphia  chromosome-positive  (Ph+)  ALL,  the  integration  of  imatinib  F into an aggressive chemotherapy backbone resulted in a significant improve- ment  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 •    evelopment  of  the  framework  for  the  current  therapy  of  patients  with  AML.  D Trials also defined the standard of care for patients with AML, refining classifi- cation of leukemia to include cytogenetic and molecular genetic characteristics  (CALGB).

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 INTRODUCTION •    irst demonstration of the significant progression-free survival benefit of using  F fludarabine  during  first-line  therapy  in  patients  with  chronic  lymphocytic  leu- kemia (CLL), leading to fludarabine becoming a standard of care for the initial  therapy of CLL (CALGB).  •    linical  development  and  Food  and  Drug  Administration  (FDA)  approval  of  C 5-azacytidine for the treatment of myelodysplastic syndrome (CALGB). •    efinition of the role of all-trans retinoic acid in the induction and maintenance  D of acute promyelocytic leukemia (ECOG). •    rials  to  establish  thalidomide  plus  dexamethasone  as  standard  of  care  for  T 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). •    emonstration  of  three  cycles  of  CHOP  (cyclophosphamide,  doxorubicin,  D v   incristine,  and  prednisone)  plus  involved  field  radiotherapy  as  the  stan- dard  therapy  for  early-stage,  nonbulky,  aggressive  non-Hodgkin’s  lymphoma  (SWOG). Breast cancer •    andmark trials supporting the use of more conservative, less disfiguring treat- L ment of breast cancer, altering the standard of care toward breast-conserving  therapy. These trials demonstrated equivalent survival between patients under- going radical mastectomy and patients undergoing total mastectomy and then  equivalent rates of survival and in-breast recurrence between patients under- going  lumpectomy  and  patients  undergoing  total  mastectomy  when  lumpec- tomy and mastectomy were followed by radiation therapy (NSABP). •    emonstration of a significant survival benefit of adjuvant treatment with trastu- D zumab, a monoclonal antibody, in women with human epidermal growth factor  receptor 2 (HER-2)-positive breast cancer (NCCTG, NSABP). •    evelopment  of  Oncotype  DX,  a  21-gene  assay  that  predicts  the  benefit  of  D 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 associ- ated side effects (NSABP).  •    emonstration by the Breast Cancer Prevention Trial that tamoxifen treatment  D reduced the incidence of breast cancer by nearly 50 percent in women with an  increased risk of developing breast cancer (NSABP). •    emonstration that tamoxifen and raloxifene are equally effective in reducing  D the risk of invasive breast cancer (NSABP). •    evelopment and demonstration of clinical effectiveness of dose-dense adju- D vant therapy for breast cancer (CALGB).  •    efinition  of  the  role  of  adjuvant  paclitaxel  as  part  of  adjuvant  therapy  for  D breast cancer leading to FDA approval of the use of paclitaxel for this indica- tion. 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).  continued

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 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX 1-2 Continued •    emonstration that patients receiving adjuvant tamoxifen for breast cancer with  D 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). •    ssessment of the beneficial role of hormonal therapy plus chemotherapy in  A 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).  •    emonstration that breast cancer patients with positive axillary nodes benefit  D 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). •    omparison  of  the  effectiveness  of  different  imaging  strategies  has  refined  C 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 •    evelopment of combined-modality treatment for Stage III non-small-cell lung  D cancer (NSCLC) as a standard of care (CALGB). •    emonstration that both radiation therapy and chemotherapy are effective in  D elderly  patients  with  lung  cancer  but  that  the  risk  of  toxicity  is  substantially  greater in older patients (NCCTG). •    emonstration  that  bevacizumab  can  improve  the  response  rate,  the  length  D of progression-free survival, and the overall survival rate when it is combined  with chemotherapy for the first-line treatment of NSCLC (ECOG). •    irst  randomized  comparison  of  new  agent-platinum  chemotherapy  regimens  F (vinorelbine-cisplatin versus paclitaxel-carboplatin) for advanced NSCLC, which  found improved tolerability of the paclitaxel-carboplatin combination (SWOG). •    emonstration that healthier patients with inoperable NSCLC had better results  D if they received chemotherapy during their course of radiotherapy rather than  before radiotherapy (RTOG). Gastrointestinal cancer •    emonstration  that  adjuvant  chemotherapy  improves  the  rate  of  survival  in  D patients with Stage III colon cancer (NCCTG).  •    emonstration that bevacizumab (a vascular endothelial growth factor [VEGF]  D 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). •    emonstration that oxaliplatin added to infusional 5-FU as first-line therapy improves  D the rate of survival in patients with metastatic colorectal cancer (NCCTG).

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 INTRODUCTION •    emonstration  that  the 3-year disease-free  survival  rate  is  a  valid  surrogate  D of  the  5-year  overall  survival  rate  in  patients  receiving  adjuvant  5-FU-based  chemotherapy for resected colon cancer (NCCTG). •    emonstration that laparoscopic resection of colon cancer is as effective as  D open colectomy for the treatment of localized colon cancer (NCCTG). •    hange of the standard of care for adjuvant therapy for Stage II and III colon  C cancer.  Over  time,  trials  evaluating  different  adjuvant  approaches  found  sig- nificant 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). •    alidation of the utility of combined-modality therapy for localized esophageal  V cancer. Investigators observed a 4.5-year median survival rate and a 39 per- cent 5-year survival rate for patients randomized to induction chemoradiother- apy 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). •    revention trials, such as one demonstrating that aspirin reduced the risk of  P development of colon adenoma in patients with colon cancer treated by com- plete resection of the colon (CALGB). •    emonstration that adjuvant chemotherapy plus radiation improves survival in  D patients with Stage II and III rectal cancer (NCCTG). •    ignificantly  improved  survival  for  patients  with  advanced  pancreatic  adeno- S carcinoma when they received the drug gemcitabine, in addition to standard  therapy, after surgery (RTOG). Genitourinary cancer •    emonstration that finasteride can significantly alter the risk of prostate cancer  D in men over 55 years of age (SWOG). •    etermination that radiotherapy combined with long-term hormone suppres- D sion significantly improves the survival rate for men with high-grade prostate  cancer (Gleason Score 8 to 10). However, men with locally advanced pros- tate cancer (Gleason Score 2 to 6) benefit most from hormonal suppression  before radiotherapy (RTOG). •   dentification  of  several  prognostic  biomarkers  from  specimens  of  patients  I 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). •    emonstration  of  the  utility  of  bacillus  Calmette-Guérin  (BCG)  for  the  treat- D ment  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 indica- tion (SWOG). continued

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0 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX 1-2 Continued BOX 1-2 Continued Brain cancer •    emonstration  that  lower-dose  radiation  therapy  is  as  effective  as  and  less  D toxic  than  higher-dose  radiation  therapy  for  patients  with  low-grade  glioma  (NCCTG). •    stablishment of proof of principle that chemotherapy is effective for the treat- E ment of patients with low-grade oligodendroglioma (NCCTG). •    etermination  that  chromosome  arm  1p  and  19q  deletions  in  gliomas  are  D associated with a longer period of survival in patients (NCCTG, RTOG). •    irst  U.S.  research  organization  to  coordinate  an  international  brain  tumor  F 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.  •   mprovement  in  survival  by  more  than  33  percent  for  patients  with  a  single  I brain metastasis obtained by the use of whole-brain radiotherapy followed by  stereotactic radiosurgery instead of whole-brain treatment alone (RTOG). Gynecologic cancer •    etermination of the standards for multiagent chemotherapy for all gynecologic  D 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). •    onfirmation  of  the  value  of  cytoreductive  surgery  in  patients  with  ovarian  C cancer (GOG). •    emonstration  that  the  combination  of  cisplatin  and  cyclophosphamide  was  D 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 partici- pates 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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1 INTRODUCTION •    efinition of the value of chemoradiation for the treatment of cervical cancer.  D 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). •    efinition of the pattern of spread of endometrial carcinoma and defined risk  D groups (GOG). •  Identification of the limited value of reassessment laparotomy (GOG). •    onfirmation  of  the  value  of  intraperitoneal  therapy.  Intraperitoneal  cisplatin  C and  paclitaxel  were  associated  with  significantly  better  progression-free  sur- vival and overall survival, but they were also more toxic and had more compli- cations (GOG).  Head and neck cancer •    efinition  of  the  role  of  taxanes  in  the  treatment  of  head  and  neck  cancers  D (ECOG).  •    iscovery that patients who received chemotherapy together with radiotherapy  D after surgery were far less likely to have a recurrence of cancer for patients  with high-risk head and neck cancer (RTOG).  Skin cancer •    stablishment  of  the  role  of  high-dose  interferon  alpha-2b  as  the  first  FDA- E 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 Coopera- tive 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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 A NATIONAL CANCER CLINICAL TRIALS SySTEM 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 nonstandard- ized, 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 can- cers. 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, phy- sician or patient preference for standard therapies, excessive regulatory bur- dens, 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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 INTRODUCTION of expertise to conduct clinical trials is questionable. Without the conduct of clinical trials in the United States, patients could lose access to promis- ing 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 Clini- cal Trials, held on October 4 and 5, 2007, focused on the science underpin- ning 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 con- veyed 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 agree- ment 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 poten- tial 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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 A NATIONAL CANCER CLINICAL TRIALS SySTEM 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 rel- evant 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 commit- tee 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, man- agement 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. Atten- tion 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; •    educe the prolonged period of time currently spent moving from initial concept  r to final approval; •  prioritize trials and trial sites based on scientific merit and past performance; •  increase participation of both clinicians and patients; •    ake  greater  use  of  technologies  such  as  imaging  and  other  biomarkers  to  m select therapies for development and testing, to match patients and therapies,  and to monitor patient responses; •    efine standards for minimal data requirements to establish safety and efficacy  d of experimental therapies; •  reduce costs and ensure adequate funds for high-quality trials; and •  promote greater collaboration among various stakeholders.

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 INTRODUCTION THE COMMITTEE’S vISION FOR CANCER CLINICAL TRIALS IN 2015 The committee recognized that the numerous reviews of the Coop- erative 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 cur- rent 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 envi- sions 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 thera- pies that reflect patient preferences and that are appropriately reimbursed. This list of ideal characteristics laid the groundwork for the commit- tee deliberations to develop goals and specific recommendations to achieve them. The committee concluded that the academic, governmental, and com- mercial sectors must join with the public to develop a 21st-century clinical trials system to more effectively leverage scientific advancements and trans- late 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 sup- port 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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0 A NATIONAL CANCER CLINICAL TRIALS SySTEM 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 •    ollaboration among stakeholders, with effective and timely communication, in  C developing the most promising treatments •    treamlined  procedures  for  rapid  planning,  approval,  and  launch  of  clinical    S trials, with accountability for meeting timelines and rewards for productivity •    fficient  incorporation  of  new  technologies  and  scientific  questions,  such  as  E the  identification  and  application  of  biomarkers  and  molecular  imaging,  into  clinical trials A strong publicly supported clinical trials system in the United States that comple- ments commercial trials to develop drugs and devices •     highly efficient and flexible system for innovative, rigorously prioritized clinical  A trials •    dequate funding for well-designed, high-quality trials A •  Patient access to promising therapies as they develop •    ddresses questions and collects data that are relevant and meaningful to the  A 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 •    ublicly  accessible  tissue  repositories  with  high-quality,  fully  annotated,  and  P 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 devel- opment 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 col- laborative nature of cancer clinical trials.

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1 INTRODUCTION •    road  use  of  those  samples  in  retrospective  studies  as  new  hypotheses  B evolve •     consistent and dynamic process for rapidly setting national standards and  A unified procedures for new technologies such as diagnostics, with reproduc- ibility and effective incorporation into clinical trials  Harmonized  and  synchronized  rules  and  guidelines  across  federal  regulatory  agencies  •    uidance  grounded  in  an  understanding  of  contemporary  science  as  new  G paradigms  develop  for  therapeutic  approaches  as  well  as  for  clinical  trials  methodology Support for clinical investigators •    raining and retention of professionals to efficiently and swiftly carry out impor- T tant clinical research •  Adequate paid protected research time for active clinical investigators •    ecognition  and  appropriate  rewards  for  collaborative  clinical  research  in  R academic advancement and community practice careers •    dequate  reimbursement  of  costs  for  actively  participating  institutions  and  A physicians Broad patient involvement in clinical trials  •    hird-party payor coverage of nonexperimental costs of patient care to ensure  T that patients do not forgo participation in trials because of financial hardship •    articipation in the design, implementation, and conduct of trials, and in the  P 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 Work- ing Group. REFERENCES ACS (American Cancer Society). 2008. Cancer Facts & Figures 200. Atlanta, GA: American Cancer Society. Agres, T. 2005. Clinical trials trickling away. Drug Discovery and Development 2005 Quarter 3(7), http://www.dddmag.com/clinical-trials-trickling-away.aspx (accessed January 22, 2010).

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