A National Cancer Clinical Trials System for the 21st Century Reinvigorating the NCI Cooperative Group Program (2010) / Chapter Skim
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3 Operations, Oversight, and Funding of Cancer Clinical Trials
3 Operations, Oversight, and Funding of Cancer Clinical Trials
Pages 121-190
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This chapter describes the organization, oversight, and funding of the National Cancer Institute (NCI) Cooperative Group Program, as well as the processes and collaborations needed to develop, launch, and complete a large-scale cancer clinical trial.
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. OvERSIGHT OF CLINICAL TRIALS Cancer clinical trials are highly regulated activities.
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Data CRF Reviews CDE Review Management (2–4) Database Review Safety/Ethics Informed Local IRB Informed CIRB Consent Consent Regulatory Regulatory PMB Review FDA Review RAB Review Contracts/ Budget Industry Grants Language Sponsor Study Start-up Start-up Start-up Start-up Review Review Review NOTES: CCC = Comprehensive Cancer Centers; CCOP = Community Clinical Oncology Program; CDE = Common Data Element; CIRB = central institutional review board; CRF = case report form; CRM = Concept Review Meeting; CTCG = Clinical Trials Cooperative Group; CTEP = Cancer Therapy Evaluation Program; FDA = Food and Drug Administration; PMB = Pharmaceutical Management Branch; PRC = Protocol Review Committee; RAB = Regulatory Affairs Branch.
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Trial Concept Selection Investigators within the Cooperative Groups develop ideas for new cancer clinical trials, and these suggestions percolate through Cooperative Group committees to the Group leadership. Funding for the Cooperative Groups is based on past accomplishments but is not provided on a per trial basis or on the basis of specific trial proposals (see the section on funding for cancer clinical trials)
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therapeutic clinical trials; refine and collaborate on concepts by the use of task forces, when appropriate Patient Advocate Steering Develops and shares best practices for patient Committee advocate participation in steering committees; identifies common concerns and needs and proposes potential solutions; disseminates information from steering committees to the appropriate communities; ensures that the concept evaluations consider the patient community at large and includes a special focus on minority and underserved populations The Clinical Trials Management Provides strategic advice for the CTMS work space, System (CTMS) Steering advising on project selection, prioritization, and Committee oversight Ad Hoc Coordination Provides advice on how to foster collaboration among Subcommittee the various components of the NCI-sponsored clinical trials infrastructure, to develop a fully integrated clinical trials system Ad Hoc Public/Private Partnership Provides advice on how to enhance NCI-sponsored Subcommittee clinical trials through collaborative interactions with the private sector Cooperative Group Clinical Trials Charged with developing a model for aligning Funding Model/Complexity Model reimbursement of Phase III treatment trials with Working Group complexity, to compensate the additional costs Correlative Science Working Charged with developing validation standards and Group prioritization criteria of correlative science studies associated with Phase III trials Operational Efficiency Working Charged with developing approaches to cut timelines Group in half
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Clinical and Translational Research Operations Committee (CTROC) Divisions, Centers, and Offices FIGuRE 3-1 Integrated management of NCI cancer clinical trials.
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In addition, there is little interaction among the disease-specific steering committees to determine trial priorities across disease categories, nor is there consideration of how the trial portfolio should be balanced with regard to Phase II or Phase III trials, although 3 Personal communication, Margaret Mooney, National Cancer Institute, December 9, 2009.
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The emphasis should be on scientific strength and opportunity, innovation, feasibility, and importance to improving patient outcomes. In addition, steering committees should operate independently from NCI staff, with NCI taking a more traditional role of facilitating the review process rather than actively participating in it; and they should have a primary focus on the prioritization of clinical needs and scientific opportunities and on facilitating communication and cooperation among the Cooperative Groups.
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staff assesses Cooperative Group compliance with NCI-established policies on data and safety monitoring boards for all Cooperative Group Phase III trials. At the request of CTEP, the BRB staff also review mechanisms established by the Cooperative Group for data management and analysis.
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An expanded support role for NCI would help Group investigators gain access to more experimental therapeutic agents and reduce the time that the Groups spend in negotiation with industry to acquire agents before the launch of a trial and also ensure the availability of the agent during the trial. NCI could facilitate the more timely completion of clinical trials in other ways as well.
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. Another analysis found that of 20 multicenter clinical trials reviewed, 17 experienced inconsistencies both in the IRBs' review processes and in their recommendations (Greene and Geiger, 2006)
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A subcommittee or the chair can therefore perform the local IRB review, so there is no need to wait for the next meeting of the full local IRB. Such facilitated reviews should allow local sites to open studies within days, making it easier to conduct trials of treatments for rare diseases and for patients nearing the end of the eligibility window to participate in clinical trials.
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trials. The NCI CIRB has been sanctioned by OHRP, which helped NCI develop its CIRB, and is officially endorsed by the American Society of Clinical Oncology.
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. As noted above, multiple agencies within HHS review or have regulatory jurisdiction over cancer clinical trials, including NCI, 10 Personal communication, Jeffrey Abrams, National Cancer Institute, September 23, 2009.
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. For example, the Common Rule allows patients to provide consent for future research to be performed with the biosamples collected from the patient in a clinical trial, whereas the Privacy Rule does not.
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The committee thus recommends that OHRP develop guidance that clearly establishes the accountability of the NCI CIRb to encourage its wider use and acceptance by local institutions. Informed Consent Two HHS regulations14 require researchers supported by HHS funding to obtain and document informed consent from patients participating in their clinical trials.
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At a recent IOM workshop, one clinical researcher noted that because of the increasing complexity of cancer clinical trials, his average ICF is between 30 and 35 pages long, which is too long for patients to digest without medical staff devoting a considerable amount of time to verbally summarize them (IOM, 2009c)
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fied summaries of consent forms would improve patient communication and decision making. FDA Oversight of Cancer Clinical Trials Part of FDA's mission is to ensure the safety and effectiveness of therapeutics and diagnostics on the market.
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More than one FDA unit is often involved in reviewing Cooperative Group cancer clinical trials. Although the Office of Oncology Drug Products was recently established within the Center for Drug Evaluation and Research to review most oncology drugs, some cancer therapeutics and diagnostics may be reviewed by several offices of the Center for Biologics Evaluation and Research,17 or the Office of In Vitro Diagnostic Device Evaluation and Safety within the Center for Devices and Radiological Health (FDA, 2009)
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of imaging to assess tumor progression in randomized clinical trials has been advocated to control the bias that might result from errors in progression assessments. A review of the literature for studies of breast, colorectal, lung, and renal cell cancer using retrospective BICR found high rates of discrepancy between the local and the central reviews, but these differences did not lead to different conclusions about treatment efficacy.
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In a poll of several Cooperative Group and industry trial sites, more than 85 percent noted that data optimization would moderately or significantly impact the resources of the trial site, allowing the collection of higher-quality, targeted data and greater participation in clinical trials (Abrams et al., 2009)
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, as well as the steps and timing required for CTEP and the CIRB to evaluate and approve Phase III clinical trials (Dilts et al., 2009)
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. The ultimate inefficiency is a clinical trial that is never completed because of insufficient patient accrual, and this happens far too often.
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, who reported that 59 percent of the clinical trials performed by NCI-supported clinical trials networks had been published during a similar time period. A computer model that was developed on the basis of those analyses found that if individual Cooperative Groups or CTEP singly tried to improve its processes, each would cut only a few days off the trial development timeline, but if they worked together to improve the entire process, the timeline could be substantially shortened.
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Timeline pauses if industry negotiations cause delay Feedback on major challenges If registration trial, FDA in 5 days review in 30 days Protocol Concept Concept revision/ Protocol Protocol revision/review review review cycles review cycles development Forms development 0 30 90 180 210 300 Time (days) FIGuRE 3-3 The target timeline for Phase III clinical trials proposed by the NCI's Operational Efficiency Working Group.
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provide an international ethical and scientific quality standard for designing, conducting, recording, and reporting on the results of clinical trials that involve the participation of human subjects, there is currently no mechanism for the systematic identification of best management and administrative practices that can be used as benchmarks by a clinical trials office in a Cancer Center or a Cooperative Group, nor can such best practices be used to aid up-andcoming Cancer Centers. Furthermore, there are few standard processes or metrics of what constitutes operational quality in the development or management of clinical trials.
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For example, NCI recently created a parallel approval process for initial IRB review for adult clinical trials. Once CTEP approves a study protocol, the CIRB review can be done concurrently while the Cooperative Group Operations Office makes final study arrangements and submits the protocol to local IRBs that do not use the CIRB.
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The committee recommends that the Cooperative Groups be reviewed and ranked using defined metrics on a similar timetable and that funding be linked to the review scores. The key planning and scientific evaluations should be at the disease site committee level, with a focus on the quality and success of the clinical trial concepts developed and on the committee's record of developing new investigators.
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. The goal of that merger was to consolidate talent and resources to minimize duplication, make better use of dwindling funds, and increase the efficiencies of conducting clinical trials (Benowitz, 2000; Murphy, 2009)
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10 A NATIONAL CANCER CLINICAL TRIALS SySTEM BOX 3-2 Overview of Creation of Children's Oncology Group The first pediatric cancer clinical trials group was the Children's Cancer Group (CCG) , one of the original Groups formed in the 1950s, previously known as CCGA or Group A, to distinguish it from Group B, the forerunner of Cancer and Leukemia Group B (CALGB)
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11 OPERATIONS, OVERSIGHT, AND FUNDING with the pharmaceutical industry, which was necessary to gain access to promis ing new agents for testing. This process of working with industry was inherently challenging because the pharmaceutical industry had relatively little interest in developing and licensing drugs for childhood cancers due to the small market. Fourth, the Group leaders believed that by working together, they could articu late a stronger case to the public for pediatric cancer clinical trials. Parents, the public, and philanthropic foundations and individuals were often confused about why there were multiple Groups and what the differences were. The merger took 3 years and proved to be very challenging, with perhaps the biggest challenge being the merging of the very different cultures of the Groups. A transition team was created and consisted of the Group chairs, vice chairs/executive officers, administrators, and Group statisticians; the heads of the committees in surgery, pathology, radiation therapy, and nursing; and clinical research associates. The merger was labor-intensive, entailing the development of a memorandum of understanding, the creation of an interim governing council, the creation of a new constitution, the development of transitional committees for every disease and discipline, a new membership committee to review the performance and qualifications of each institutional member, new rosters, greatly increased communications, and many additional interim meetings. NCI provided some additional funding to cover some of the additional travel costs associated with interim meetings, but no extra staff was hired, and it was difficult to retain valued staff who were concerned that their jobs would be eliminated by the merger (many ultimately were)
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. COST OF CANCER CLINICAL TRIALS It has been difficult to accurately document the costs of all the various components and procedures of clinical trials.
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. FDA Clinical Trials Transformation Initiative The recently created FDA Clinical Trials Transformation Initiative (CTTI)
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Center for Management Research in Healthcare The Center for Management Research in Healthcare was designed with the focus of providing advances in management disciplines for health care-related applications by integrating theory founded on academic principles and industry best practices. The goals include the transfer of management knowledge to health care settings and the dissemination of findings that arise between the intersection of health care and management. Sensible Guidelines for the Conduct of Clinical Trials In 2007 several clinical trials groups from McMaster, Duke, and Oxford Univer sities in the United Kingdom organized an international meeting called "Sensible Guidelines for the Conduct of Clinical Trials" to discuss the difficulties involved in initiating and running randomized trials efficiently. The organizers concluded that solutions to many of the problems would require a coordinated response from academic trialist groups, regulatory agencies, pharmaceutical companies, and health care providers worldwide. A follow-up meeting of the Sensible Guidelines group took place in Oxford on September 5–6, 2009. The principal aims were to (1)
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. Startup costs for clinical trials include staff training, IRB approval, time for reviews, and staff time for startup visits and the completion of forms (C-Change and Coalition of Cancer Cooperative Groups, 2006)
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This focus on personalized medicine increases the complexity and cost of clinical trials, as there is a greater need for the documentation of patient characteristics, imaging, and biomarker tests (see also Chapter 2)
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One study estimated that 30 to 40 percent of all funding for cancer clinical trials is used to cover the costs of local regulatory compliance (C-Change and Coalition of Cancer Cooperative Groups, 2006)
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FuNDING FOR CANCER CLINICAL TRIALS Overview of Federal Funding for Cancer Research The U.S. Congress determines the total funding allotment for NCI each year, but the NCI director is responsible for proposing a budget and for allocating the available funds among the various programs and funding mechanisms within NCI.
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. Furthermore, the clinical trials program supported by NCI is multifaceted, with the Cooperative Group Program being just one of several clinical research endeavors that NCI supports (Figure 3-5)
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The allocation for the NCI Cooperative Group Program represents approximately 3 percent of the total NCI budget. Figure 3-5 SOURCE: See http://www.cancer.gov/aboutnci/servingpeople/snapshot.
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The committee recommends that these external advisory boards have a greater role in advising NCI on how it allocates its funds to support a national clinical trials program. This would help to ensure the most rational distribution of funds, in light of such factors as scientific opportunity and clinical need.
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There is considerable variability across the NIH with regard to the balance between oversight and support of trials by the sponsoring institution, and unlike many other NIH clinical trials arrangements, funding for the Cooperative Groups is not linked to specific clinical trials but, rather, to the infrastructure that supports the trials. The U10 award supports the operations, statistical offices, and committees of the Cooperative Groups (CTEP, 1996; IOM, 2009c)
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NCI also recently introduced the Biomarker, Imaging, and Quality of Life Supplemental Funding Program to support correlative science and quality-of-life studies that are integral to Phase III clinical trials, with $5 million being allocated for this program in 2009 (NCI, 2008)
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The costs linked to treatment within cancer clinical trials are substantial and include physician visits, blood work, and X rays (IOM, 2009c)
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COLLAbORATION AMONG STAkEHOLDERS As noted throughout this chapter, cancer clinical trials often necessitate effective collaboration among diverse stakeholders, but numerous challenges to achieving such collaborations remain (NCI, 2005a)
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. Collaborative Funding Mechanisms Inadequate funding of the Cooperative Groups combined with the growing interest by industry in developing and clinically testing new therapeutics and diagnostics for cancer has also led to more industry-Cooperative Group collaborative cancer clinical trials in the past decade.
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Cooperative Groups use.25 In the United Kingdom, for instance, a government agency (the Depart Department of Health) covers the costs of laboratory and imaging services and the administration of therapeutic agents at no charge for approved clinical trials, and provides the required national infrastructure in the form of salaries for research staff and clinical research associates at National Health Service hospitals.
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A costing template ensures appropriate reimbursement. This system provides value to the public/taxpayer because the resultant trials are considered scientifically of interest and potentially beneficial for improving patient care, but are less likely to be conducted by industry on its own.
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Similarly, if the core funding provided by NCI adequately supported the clinical trials infrastructure, industry and foundations would be more willing participants, as they could just cover the costs of individual studies. The committee recommends that NCI facilitate more public-private partnerships and precompetitive consortia, guided in part by successful models.
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. To expedite the negotiations required between industry and the publicly funded investigators before the launch of a collaborative trial, NCI and the CEO Roundtable on Cancer27 recently reviewed copies of 78 clinical trial agreements from participating organizations and identified 45 key concepts related to intellectual property, study data, subject injury, indemnification, confidentiality, and publication rights.
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. More private-public collaboration in a precompetitive environment could facilitate the development and use of biomarkers in cancer therapeutics, and the codevelopment of a biomarker diagnostic with a targeted cancer drug.
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The potential for impact can often be a strong motivator to good science, and competition can foster both innovative solutions and rapidity in their discovery, much like what occurred with the sequencing of the human genome. Thus, one promising novel approach would be to develop a major, influential grand challenge to improve cancer clinical trials.
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The committee concluded that a robust, standing cancer clinical trials network is essential to effectively translate discoveries into clinical benefits for patients. Multi-institutional collaborations are necessary to conduct large Phase III trials for indications such as adjuvant therapy, first-line therapy of metastatic disease, and prevention; single institutions are not capable of undertaking such large-scale trials.
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NCI should facilitate front office consolidation by reviewing and ranking the Groups by the use of defined metrics on a similar timetable and by linking funding to review scores. key planning and scientific evaluations should be at the level of multidisciplinary disease site committees, with a focus on the quality and success of the clinical trial concepts developed and the committee's record of development of new investigators.
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Compliance with regulatory requirements for the conduct of clinical trials is another major challenge for clinical investigators. Multiple agencies and institutional bodies of HHS review and provide oversight for cancer clinical trials, including NCI, FDA, OHRP, OCR, and IRBs.
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Harmonizing, coordinating, and streamlining the oversight and review processes could significantly improve the speed and efficiency of clinical trials, ease the burden on investigators, and better protect patients. Changes within individual agencies would also be beneficial.
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A recent report on such incentive prizes, which spur innovation by tapping into competitive and entrepreneurial spirits rather than directly funding research, concluded that they are unique and powerful tools that can produce change not only by identifying new levels of excellence and by encouraging specific innovations but also by changing wider perceptions, improving the performance of communities of problem solvers, building the skills of individuals, and mobilizing new talent or capital. Cancer clinical trials often necessitate effective collaboration among diverse stakeholders, but there are numerous challenges to achieving such collaborations.
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Since the funding mechanism for the Cooperative Group Program was changed from grants to cooperative agreements in 1980, NCI has exercised oversight of every aspect of the clinical trials process, including trial selection, protocol development, and trial operations. But this is not the best use of NCI's limited funds.
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Prioritization alone, however, is not sufficient. At present, only about 60 percent of cancer clinical trials supported by NCI are completed and published.
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The existing system also often does not provide the resources required to thoroughly characterize each patient's tumor and carefully match that profile to targeted therapeutics. Biomedical imaging and other biomarker tests are commonly becoming integral components of modern cancer clinical trials, but supplemental funding for these tests must be obtained by the Cooperative Groups through other support mechanisms.
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However, novel hybrid funding mechanisms, as well as new efforts to establish public-private partnerships and precompetitive consortia would further aid progress toward effective collaboration, to the benefit of patients, who desire access to new and promising cancer therapies. Maintaining a critical mass of clinical trials in the United States via appropriate collaborations is important to ensure that patients in this country gain access to promising therapies as they develop, that trials address questions and generate data that are relevant and meaningful to patients in the United States, and that the nation retains a sufficient number of properly trained clinical trial specialists.
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Presentation to the National Cancer Policy Forum Workshop on Multi-Center Phase III Clinical Trials and the NCI Cooperative Groups, July 1, 2008, Washington, DC. Abrams, J., and M
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2006. Enhancing Cancer Treatment Through Improved Understanding of the Critical Components, Economics and Barriers of Cancer Clinical Trials.
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Presented to the Committee on Cancer Clinical Trials and the NCI Cooperative Group Program, December 16, 2008, Washington, DC. Doroshow, J., and Hortobagyi G
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2006. Guidance for Industry: Using a Centralized IRB Review Process in Multicenter Clinical Trials.
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2001. Quality of informed consent in cancer clinical trials: A cross-sectional survey.
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Washing ton, DC: Committee on Cancer Clinical Trials and the NCI Cooperative Group Program. http://www.iom.edu/~/media/Files/Activity%20Files/Disease/NCPF/2009-Coop-Groups Study/Murphy_On_the_Merger_of_the_Pediatric_Cancer_Clinical_Trials_Cooperative_ Groups.ashx (accessed March 9, 2010)
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2009. Challenges to accrual predictions to phase III cancer clinical trials: A survey of study chairs and lead statisticians of 248 NCI sponsored trials.
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Presented to the Committee on Cancer Clinical Trials and the NCI Cooperative Group Program, April 23, 2009, Washington, DC. Woodcock, J., and R
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