Introduction

The National Cancer Institute’s Cooperative Group Program for clinical research was established in 1955 and has grown to include 12 cooperative groups, representing 1,700 institutions and the collective recruitment of roughly 22,000 patients to cancer clinical trials each year. Cooperative groups are made up of comprehensive cancer centers, cancer centers, academic medical centers, community hospitals, and private research institutions, and they are supported by 10 biostatistics centers and a clinical trial support unit at the National Cancer Institute (NCI). The Cooperative Group Program enables pooling of public resources available for the study of cancer prevention, detection, and treatment. Because of the public and academic nature of the collective groups, it has been possible for them to conduct clinical trials that extend beyond the usual focus and capacity of pharmaceutical companies, including trials on methods of cancer prevention and early detection, the comparative effectiveness of treatments, and how treatments affect patients’ quality of life or long-term health, as well as trials that use new trial designs for combination therapies and proof-of-concept studies. In addition, the cooperative groups’ infrastructure provides a valuable resource for industry to use for the clinical evaluation of commercial drug candidates.

In the first 50 years of their existence, the cooperative groups contributed to substantial gains in the quality of treatment for many types of cancer, including breast, ovarian, colorectal, and childhood cancers. Cooperative group research has been instrumental in establishing nearly all of today’s standard adjuvant therapies as well as combined-modality



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Introduction The National Cancer Institute’s Cooperative Group Program for clini- cal research was established in 1955 and has grown to include 12 coopera- tive groups, representing 1,700 institutions and the collective recruitment of roughly 22,000 patients to cancer clinical trials each year. Cooperative groups are made up of comprehensive cancer centers, cancer centers, academic medical centers, community hospitals, and private research institutions, and they are supported by 10 biostatistics centers and a clini- cal trial support unit at the National Cancer Institute (NCI). The Coop- erative Group Program enables pooling of public resources available for the study of cancer prevention, detection, and treatment. Because of the public and academic nature of the collective groups, it has been possible for them to conduct clinical trials that extend beyond the usual focus and capacity of pharmaceutical companies, including trials on methods of cancer prevention and early detection, the comparative effectiveness of treatments, and how treatments affect patients’ quality of life or long-term health, as well as trials that use new trial designs for combination thera- pies and proof-of-concept studies. In addition, the cooperative groups’ infrastructure provides a valuable resource for industry to use for the clinical evaluation of commercial drug candidates. In the first 50 years of their existence, the cooperative groups con- tributed to substantial gains in the quality of treatment for many types of cancer, including breast, ovarian, colorectal, and childhood cancers. Cooperative group research has been instrumental in establishing nearly all of today’s standard adjuvant therapies as well as combined-modality 

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 MULTI-CENTER PHASE III CLINICAL TRIALS treatments. Despite this record of success, cooperative group trials today are facing a number of issues that limit their effectiveness. The trials must deal with cumbersome and complex processes, including trial planning and start-up; scientific, regulatory, and ethics review; staff participation; patient accrual; trial monitoring; and financial management. Inefficiencies in these processes, which greatly prolong the period of trial design and approval as well as erode financial support and increase regulatory bur- dens, have hampered the ability of the cooperative group Phase III trials program to achieve its goals. Many clinical research programs and indi- vidual cancer patients choose not to participate in the program or to par- ticipate modestly. For example, while the Cooperative Groups Program recruits around 22,000 patients every year, this represents only a small fraction of cancer patients eligible to participate in trials. 1 To compound the problems of lack of institutional and patient participation, the results of some cooperative group trials are never published after many years of hard work and patient participation. There is great concern that the process of moving new cancer treat- ments into Phase III trials and then into regulatory approval within the NCI Cooperative Group Program has become inefficient, underfunded, and underutilized by oncologists and cancer patients. Despite NCI- sponsored internal and external reviews, the NCI Cooperative Group Program has remained largely unchanged over its existence, except for the gradual increase of regulations and oversight. Thus, the National Cancer Policy Forum (NCPF) chose to convene a workshop entitled “Multi-Cen- ter Phase III Clinical Trials and NCI Cooperative Groups,” which was held in Washington, DC, July 1–2, 2008. As explained by the workshop chair, Dr. John Mendelsohn, president of M. D. Anderson Cancer Cen- ter, the purpose of the workshop was to outline the challenges faced by the public clinical cancer research enterprise and to identify potential approaches for addressing these challenges. He opened the conference by throwing out what he called a “big, audacious goal.” This goal is to slash in half the amount of time that it takes to progress from the conception of a clinical trial to actually starting the trial. The agenda for the workshop can be found in Appendix A. At the confer- ence, experts and major stakeholders offered presentations in four sessions: • rganization of the NCI clinical trials system and operation of O Phase III clinical trials; 1 The American Cancer Society estimates that there will be 1,437,180 new diagnoses of can- cer in the United States in 2008 (ACS, 2008). Of these individuals, not all would be eligible to participate in clinical trials, but the percentage eligible would be estimated to be higher than the 1.5 percent that currently participate.

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 INTRODUCTION • Patient recruitment and physician participation; • Data collection standards to establish safety and efficacy; and • Costs and payments within clinical trials. Across the various sessions, many of the presentations touched on similar issues, with speakers identifying shared problems and potential solutions for improving the quality and efficiency of trials undertaken by the cooperative groups. At the end of this document is a section titled “Summary and Wrap-Up.” This section spells out the common themes heard at the workshop, as summarized by Dr. Mendelsohn. This document will serve as one input to the deliberations of an Institute of Medicine committee that will develop consensus-based rec- ommendations for improving cancer clinical trials and the operation of the NCI Cooperative Group Program. The committee will also consider other issues that may warrant exploration and analysis. Some of these were mentioned by the NCPF chair, Dr. Harold Moses of the Vanderbilt- Ingram Comprehensive Cancer Center. He pointed out that a number of other topics relevant to the discussion on how to improve the Coop- erative Group program had been addressed at a complementary work- shop, “Improving the Quality of Cancer Clinical Trials,” that was held by the NCPF in October 2007. This workshop covered clinical trial design, molecular imaging, predictive markers, clinical trial costs, and regulatory issues. The workshop summary has been published and will also be used as input to the deliberations of the committee (IOM, 2008). In general, this workshop summary follows the order of the speakers at the conference, although some speaker comments have been grouped to maintain the summary’s primary organization by topic. The views expressed in this summary are those of the speakers and discussants, as attributed to them, and are not the consensus views of workshop partici- pants or NCPF members. ADAPTING THE COOPERATIVE GROUPS IN A CHANGING CLINICAL ENVIRONMENT Dr. John Niederhuber, director of the NCI, focused his introductory remarks on the recent paradigm shift in cancer treatment from “search and destroy” nonspecific and broadly toxic treatments to “target and con- trol” combinations of therapies that are specifically targeted to the genetic or molecular defects that underlie a patient’s cancer. Using lung cancer as an example, he noted that researchers discovered specific genetic muta- tions of the epidermal growth factor receptor that are linked to how well a patient responds to the targeted cancer treatments gefitinib and erlotinib; researchers have also identified the mechanisms of resistance

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 MULTI-CENTER PHASE III CLINICAL TRIALS to these treatments (Paez et al., 2004; Kobayashi et al., 2005; Yun et al., 2008). These findings have led to promising clinical results in a cancer that is traditionally difficult to treat. “It represents that transition we are making to identify more specifically a target and match that patient in a much more specific way to that target,” Niederhuber said. He then said that the main focus of the NCI’s Cooperative Group Program has been to test new anticancer agents from the NCI’s drug development program (Dignam, 2004). For most of the program’s dura- tion these agents have been toxic, nonspecific chemotherapies, used singly or in combination. “In an era of targeted therapy, the system is geared toward the testing of nonspecific regimens,” he said. “It lacks the capac- ity to highly characterize each patient and carefully match that patient profile to targeted therapeutic combinations.” As he noted in his cover letter to forum members and workshop participants, “the clinical trials system must be structured today to meet the challenges and requirements of tomorrow” (Appendix C). The main challenge in this regard will be to design a trial structure that can obtain drug approval and demonstrate safety and benefit in this new kind of environment—an environment in which patients can be characterized according to the molecular defects that underlie their cancers so as to better match them to the experimental therapies under evaluation. Such characterization may be done within the cancer genome characterization centers, which are currently part of the Cancer Genome Atlas pilot project of the NCI and the National Human Genome Research Institute, or within a similar setup, Dr. Niederhuber suggested.2 He also referred attendees to two relevant documents published by the NCI. One is on restructuring the NCI’s clinical trials enterprise, and the other is on overhauling the process whereby biomedical discoveries are translated into useful interventions for patients.3 Dr. David Parkinson, president and chief executive officer of Nodality, Inc., concurred with Dr. Niederhuber’s comments: “We have enormous opportunity related to biology and technology around cancer therapeutic solutions. We also have very significant inefficiencies in translating those opportunities into clinical reality.” 2 See http://www.cancer.gov/newscenter/pressreleases/TCGAcancertypes. 3 See http://spores.nci.nih.gov/public/ctwg_finrpt_June2005.pdf and http://www.cancer .gov/aboutnci/trwg/executive-summary.pdf.