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Implementing a National Cancer Clinical Trials System for the 21st Century An American Society of Clinical Oncology and Institute of Medicine Workshop INTRODUCTION Clinical trials enable scientific discoveries to advance patient care, and they also inform and guide subsequent research. The National Cancer Insti- tute (NCI) supports the largest U.S. network of clinical trials of any type, of which the largest component is the Clinical Trials Cooperative Group Pro- gram (informally known as the Cooperative Group Program). It currently comprises 10 Groups that involve more than 3,100 institutions and 14,000 investigators who enroll more than 25,000 patients in clinical trials each year. Since its inception in the 1950s, the Cooperative Group Program has been instrumental in establishing the standards for cancer patient care and clinical research methods. Research performed by the Cooperative Groups has significantly advanced cancer treatment and prevention (IOM, 2010). However, despite its many and important accomplishments, the Coop- erative Group Program faces several challenges that threaten its ongoing productivity. Stagnant and declining funding, inefficient processes, exten- sive and complex government oversight, and a lack of resources to pursue cutting-edge research hinder the Cooperative Group Program’s ability to translate research discoveries into timely clinical applications (IOM, 2010). Recognizing the importance of maintaining an effective publicly funded clinical trials system, the director of NCI at the time, John Niederhuber, requested that the Institute of Medicine (IOM) conduct a consensus study of cancer clinical trials and the Cooperative Group Program and develop 1

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2 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM recommendations as to how to improve the current system. In April 2010, the consensus committee’s report, entitled A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Pro- gram (IOM, 2010) was released to the public.1 The report’s recommenda- tions are summarized in Box 1. The authoring committee of the report concluded (IOM, 2010): Collectively, the implementation of [the committee’s] recommendations would reinvigorate the Clinical Trials Cooperative Group Program for the 21st century and strengthen its position as a critical component of the trans- lational pathway from scientific discovery to improved treatment outcomes for patients with cancer. Modifying any particular element of the Program or the clinical trials process will not suffice; changes across the board are urgently needed. All participants and stakeholders, including physicians, patients, and health care insurers, as well as NCI, other federal agencies, academia, founda- tions, and industry, must reevaluate their current roles and responsibilities in cancer clinical trials and work together to develop a more effective and efficient multidisciplinary trials system. To discuss how best to achieve the aims underlying the recommen- dations in the IOM consensus report and to summarize progress to date toward addressing these recommendations, the IOM’s National Cancer Policy Forum and the American Society of Clinical Oncology (ASCO) convened a workshop on March 21, 2011, in Washington, DC. The goals of the workshops were to 1. Establish a venue to promote a collaborative approach by all stake- holders to implement recommended changes; 2. Provide a forum to ensure public involvement; 3. Document changes that take place; and 4. Facilitate progress toward the IOM committee’s goal of ensuring the continued viability and increased productivity of an NCI-funded clinical trials system with widespread academic involvement and community outreach. This workshop included four panel discussions, which focused on (1) the roles of NCI and the Cooperative Groups; (2) the role of payors; (3) interactions between industry, the Food and Drug Administration, and the publicly funded cancer clinical trials system; and (4) the role of clinical 1 The Executive Summary from the Institute of Medicine consensus report appears in Appendix B of this workshop summary.

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3 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM BOX 1 Summary of the IOM Consensus Recommendations Goal I. Improve the speed and efficiency of the design, launch, and conduct of clinical trials 1. Review and consolidate some front office operationsa of the Cooperative Groups on the basis of peer review 2. Consolidate back office operations of the Cooperative Groups and improve processesb 3. Streamline and harmonize government oversight 4. Improve collaboration among stakeholders Goal II. Incorporate innovative science and trial design into cancer clinical trials 5. Support and use biorepositories 6. Develop and evaluate novel trial designs 7. Develop standards for new technologies Goal III. Improve the means of prioritization, selection, support, and completion of cancer clinical trials 8. Reevaluate the role of NCI in the clinical trials system 9. Increase the accrual volume, diversity, and speed of clini- cal trials 10. Increase funding for the Cooperative Group Program Goal IV. Incentivize the participation of patients and physicians in clinical trials 11. Support clinical investigators 12. Cover the cost of patient care in clinical trials a Front office operations refer primarily to the Cooperative Group scientific committees and statistical offices, which are responsible for activities such as trial design, prioritization, and data analysis. b Back office operations refer to administrative structures and activities that include such things as data collection and management, data queries and reviews, patient registration, audit functions, case report form processing, image storage and retrieval, drug distribution, credentialing of sites, and funding and reimbursement for patient accrual. SOURCE: IOM, 2010.

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4 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM trials investigators and patient advocates. This document summarizes the content of each workshop session, which included presentations by panel members and open discussion. The views expressed in this summary are those of the speakers and discussants, as attributed to them, and are not the consensus views of the workshop participants or members of the National Cancer Policy Forum. Key Challenges Discussed at the Workshop adult Groups into fewer Groups. derived from those changes. - cles to conduct cutting edge clinical trials that are likely to advance patient care. is adequately evaluated and appropriately allocated. to participate in clinical trials. PANEL I: NCI AND THE COOPERATIVE GROUPS The first session of the workshop opened with accounts from represen- tatives of NCI and leaders of the Cooperative Groups about the responses of their respective organizations to the IOM consensus report. Their five presentations were followed by a panel discussion involving additional Cooperative Group leaders. NCI Perspective and Current Activities Overview of the NCI Response Dr. James Doroshow, director of NCI’s Division of Cancer Treatment and Diagnosis, opened the session with an account of that agency’s multi- faceted efforts to address the IOM consensus report. “NCI is implementing

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5 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM a comprehensive approach to transforming its clinical trials system to cre- ate a highly integrated network that can address rapid advances in cancer biology,” he stated, noting that this process has been informed not only by recommendations from the IOM report, but by several others—most notably those of the Clinical Trials and Operational Efficiency Working Groups (CTWG and OEWG, respectively; NCI, 2005, 2010)—as well as by input from stakeholders. Focusing on the four overarching goals and twelve recommendations put forth in the IOM consensus report (see Box 1), Dr. Doroshow provided detailed documentation of progress in these areas, which is summarized in Table 1. Efforts to consolidate “front office” operations among the Cooperative Groups (in response to Recommendation 1 of the IOM consensus report) were especially visible at the time of the workshop, which closely followed announcements to voluntarily consolidate the Radiation Therapy Oncology Group (RTOG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP); the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN); as well as ongoing efforts to consolidate the American College of Surgeons Oncology Group (ACOSOG), the Cancer and Leukemia Group B (CALGB), and the North Central Cancer Treatment Group (NCCTG). NCI’s initial approach has focused on supporting up to four adult Groups and one pediatric Group, according to Dr. Doroshow. He added that NCI intends to implement a new Funding Opportunity Announcement (FOA)2 over the course of the next year that will call for a simultaneous external peer review of all parties, so as to “look at organizations one against another and try to facilitate the allocation of the resources that we have in the most appropriate way.” The timeline for that initiative is shown in Box 2. The cancer clinical trials network is ripe for transformational, systemic change for the following reasons, Dr. Doroshow noted: to define subgroups for study necessitate that NCI-supported clini- cal research groups function as a coordinated network. 2 A Funding Opportunity Announcement is a publicly available document by which a federal agency makes known its intentions to award discretionary grants or cooperative agreements, usually as a result of competition for funds. FOAs may entail program announce- ments, requests for applications, notices of funding availability, or solicitations, depending on the agency and type of program.

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6 TABLE 1 Progress by NCI Toward Goals and Recommendations of the IOM Report A National Cancer Clinical Trials System for the 21st Century (2010) Goal Recommendation NCI Response as of March 2011 1: Improve speed and efficiency 1: NCI should facilitate some Current focus on supporting up to four adult Cooperative Groups of the design, launch, and consolidation of Cooperative Group with continued funding of one pediatric Cooperative Group conduct of clinical trials “front office” operations by reviewing and ranking the Groups with defined Planning for NCI external peer review of all Groups in the same metrics on a similar timetable and by review cycle with new review criteria emphasizing collaboration and linking funding to review scores evaluating Groups as partners in a National Clinical Trials Network Engaged in ongoing discussion with the Cooperative Group Chairs about potential consolidation activities, with some Groups already taking first steps to consolidate (RTOG-NSABP; ACOSOG- CALGB-NCCTG; ECOG-ACRIN) 2: Require or facilitate consolidation Instituted comprehensive, centralized 24/7 patient registration of Group “back office” operations for all Group trials, with regulatory and site verification of trial and, working with the extramural participation by the Cancer Trials Support Unit (CTSU) community, make process improvement in operations and Implemented Operational Efficiency Working Group (OEWG) organizational management a priority timelines for concept evaluation, protocol development, and trial activation Working with Groups on a single, harmonized approach to clinical trial management, including protocol authoring, case report forms, and standardized data collection and management

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3: The U.S. Department of Health Established an interagency agreement with the Food and Drug and Human Services (HHS) should Administration (FDA) for early review of approved Cooperative lead a trans-agency effort to streamline Group Phase III treatment trials, allowing for 21-day review of a and harmonize government oversight concept if it has been identified as a licensing trial and regulation of cancer clinical trials Developed coordinated protocol development and review processes with Groups for Phase III trials developed under FDA Special Protocol Assessment (SPA) Developed adult and pediatric NCI Central Institutional Review Boards with the HHS Office for Human Research Protections (OHRP) for Group trials with recent major improvement in review time lines and plan for accreditation by the Association for the Accreditation of Human Research Protection Programs Working with the Center for Devices and Radiological Health (CDRH) of the FDA to coordinate early review of investigational devices (e.g., biomarker assays, genomic signatures) used in treatment trials 7 continued

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8 TABLE 1 Continued Goal Recommendation NCI Response as of March 2011 4: NCI should take steps to facilitate NCI is working across divisions to harmonize guidelines for more collaboration among the various programs engaged in the conduct of clinical trials so that the stakeholders in cancer clinical trials appropriate incentives are in place for collaboration among Cooperative Groups, Cancer Centers, and Specialized Programs of Research Excellence (SPOREs) In collaboration with the CEO Roundtable on Cancer, developed Standard Terms of Agreement for Research Trials (START) clauses for company and academic collaborations; accelerated clinical trials negotiations Assessing feasibility of developing standardized Material Transfer Agreements (MTAs) that cover intellectual property (IP) considerations for industry and academic institutions Revised IP option on all Cancer Therapy Evaluation Program (CTEP) Cooperative Research and Development Agreements (CRADAs) relating to drug development and specimen use for correlative science; published in Federal Register March 11, 2011 (CTEP, 2011)

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5: NCI should mandate submission Revising Requests for Application (RFAs) for Resource-Related of annotated biospecimens to Research Project-Cooperative Agreement (U24) grants by the high-quality, standardized central National Institutes of Health (NIH) for National Specimen Banks biorepositories when samples are to include common operating procedures for samples collected from collected from patients in the course patients enrolled in Cooperative Group and other NCI-supported of Group trials and should implement trials and to reflect consolidation of the Group system new funding mechanisms and policies to support the management and use Working with Groups to develop a common review process and of those resources for retrospective procedures for requests for biospecimens banked from clinical trials correlative science Identified the need to develop shared information technology (IT) infrastructure to enhance specimen inventories 9 continued

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TABLE 1 Continued 10 Goal Recommendation NCI Response as of March 2011 2: Incorporate innovative 6: Cooperative Groups should lead Initiated the Biomarker, Imaging, and Quality of Life Studies science and trial design into the development and assessment of Funding Program (BIQSFP) to ensure that critical correlative studies cancer clinical trials innovative designs for clinical trials could be incorporated in a timely manner into Phase III and large, that evaluate cancer therapeutics and multi-institutional Phase II trials during the process of concept biomarkers (including combinations development of therapies) From mid-2008 to 2010, 14 of 40 concepts incorporating predominantly integral and some integrated markers were supported for a total commitment to date of $22.5 million Children’s Oncology Group Trial AAML0531 incorporating biomarkers completed (>1,000 pts): FLT3/ITD (fms-like tyrosine kinase receptor-3/internal tandem duplication) high allelic ratio (Integral) and CEBP (CCAAT/Enhancer Binding Protein) (Integrated) 7: NCI, in cooperation with Under auspices of the Clinical and Translational Research Advisory other agencies, should establish a Committee (CTAC), developed definitions of integral and integrated consistent, dynamic process to oversee studies for biomarkers, imaging, and quality-of-life investigations development of national unified associated with Group trials and priorities for support thereof standards Working with the NIH National Library of Medicine (NLM) and the Association of American Cancer Institutes (AACI) to develop the Cancer Trials Reporting Program database to provide accrual information related to all NCI-supported clinical trials

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8: NCI should reevaluate its role in Initiated CTAC, the first new federally chartered NCI advisory the clinical trials system group in a decade, which has operated for more than three years assuming specific responsibilities for NCI’s clinical trials programs. It is currently engaged in evaluating the implementation of the Clinical Trials Working Group (CTWG) recommendations; developing an extramural group to provide strategic input for clinical trials network, under CTAC guidance Revamped prioritization process for large Phase II and Phase III treatment and control trials by creating disease- and modality-specific steering committees to ensure that the most important trials are given highest priority. Note that facilitate trial implementation, rather than to direct the primary review identify critical clinical trials issues for future studies 11 continued

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80 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM Research Foundation Perspective Shelley Fuld Nasso, of the Susan G. Komen for the Cure Foundation, concurred with Mr. Katz’s comments. Ms. Nasso directs patient advocates, many of whom are involved with the Cooperative Groups, who volunteer within the foundation’s science program. These advocates—who are pas- sionate and more than willing to dedicate their time to advancing cancer research—want to be part of the discussion of revitalizing cancer clinical trials, she observed. “They have so much to offer,” she said. “We work with them to train them and place them in peer review and IRBs and working in the Cooperative Groups and other avenues for research advocacy.” Ms. Nasso also pointed out that patient volunteers for Komen raise sig- nificant funds to support cancer research. “We have invested $610 million cumulatively, $65 million last year . . . [in] Cooperative Group efforts,” she stated. “We know we have benefited from the Cooperative Groups in terms of practice-changing results for breast cancer patients.” In the last several years, the Komen Foundation has shifted its research portfolio away from basic studies and toward more translational research, Ms. Nasso reported. The foundation is “really trying to look at the key challenges in breast cancer and prioritizing our research to focus on some of those key issues, giving larger grants for collaborative efforts,” she said. “There has been a lot of talk about prioritization in the Cooperative Group trials . . . but not a lot of discussion about how that’s going to happen,” she observed. “I think it’s really important to make sure that patients are at the table when that prioritization happens.” Building on the point made by Mr. Katz about the importance of metrics to judging the success of revitalization efforts, Ms. Nasso noted that the Komen Foundation is developing metrics to evaluate its own research portfolio, “to see that we are making a difference and that we are funding research that really changes clinical practice and isn’t just validating some- thing that we already knew.” For example, she said, “we have made a goal in our research to decrease incidence or mortality within ten years. That’s a criterion that we look at in funding research.” Regarding the issue of educating patients—and potential patients— about cancer trials, Ms. Nasso observed that “when you are faced with that diagnosis, it really doesn’t matter what you know before that; it’s what your doctor says to you.” She offered the example of a physician, recently diag- nosed with stage IV renal cell carcinoma, who—despite his education and experience—was overwhelmed by the treatment decisions that confronted

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81 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM him. “No matter how much you may know beforehand, it’s when you are faced with that diagnosis and you are talking to your doctor that you need to hear the message that clinical trials are there for you to participate in,” she said. It’s important to recognize, as part of any attempt to conserve resources allocated to clinical trials, that patients be regarded as a particularly precious resource, Ms. Nasso added. “When a patient agrees to participate in a clini- cal trial, it’s really a gift that they are giving to science,” she said. “We have to make sure that we are using that effectively.” Panel Discussion Maintaining Engagement of Cooperative Group Investigators Noting that the question of how to keep investigators at the academic and community levels engaged in the Cooperative Group process had been raised in this and in prior sessions, Dr. Buckner turned the question over to the panel. Dr. Michael Caligiuri, of Ohio State University (OSU), who described the OSU Cancer Center as “very, very active in the Cooperative Groups,” focused on the importance of leadership. He concurred with the points made earlier by Drs. Thomas and Baker regarding the importance of recognition for participation in the Cooperative Groups and rewarding researchers through promotion, tenure, and pay. “It’s very important that we promote them into, first, committee and then leadership participation in the Cooperative Groups,” he said. However, Dr. Caligiuri added, it is the Cancer Center that currently foots the bill for advancing and rewarding Cooperative Group researchers. “We at the Cancer Center pay for a lot of people, for travel, for their partici- pation, for opening trials where there is insufficient funding,” he said. Dur- ing his opening remarks in the panel discussion, in his capacity as president of the Association of American Cancer Institutes (AACI),38 Dr. Caligiuri noted that Cancer Centers provide faculty, staff, infrastructure for early 38 The Association of American Cancer Institutes comprises 95 leading cancer research centers in the United States. AACI’s membership roster includes NCI-designated centers and academic-based cancer research programs that receive NCI support. AACI is dedicated to promoting the nation’s leading research institutions’ efforts to eradicate cancer through a comprehensive and multidisciplinary program of cancer research, treatment, patient care, prevention, education, and community outreach. See http://www.aaci-cancer.org/about.asp, http://www.aaci-cancer.org/mission.asp.

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82 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM discovery, clinical scientific review of early concepts, early-phase clinical tri- als, core labs for correlative science, and funding for patient accrual to the Cooperative Groups, as well as much of their leadership. He also observed that some institutional hosts provide “extraordinary” financial support to Cancer Centers, while others can offer little more than a “paltry sum.” Dr. Grubbs stressed the importance to clinical trials physicians of establishing—through institutional leadership—an environment in which treating a patient on a clinical trial is considered a standard of care above and beyond the usual evidence-based medicine we have available today. “You just have to instill in your physicians that you are better physicians and your patients are getting better care [for doing clinical trials],” he said. This attitude has a positive ripple effect that affects even those patients that are not in trials, he added. One participant emphasized Dr. Grubbs’ earlier point that partici- pating in the Cooperative Groups enables community physicians to col- laborate with their academic counterparts, noting that academic Cancer Centers have been encouraged to apply for joint grants to increase accruals of minorities to surgical clinical trials. These funds facilitate increased col- laboration between academic and community clinical centers, which in turn encourages clinical investigators by allowing them to publish their research and attend academic meetings, the participant said. Noting that regulatory “red tape” frustrates community physicians involved in clinical trials, Ms. Gonzalez urged simplification of the IRB process as a key incentive for their continued participation. Community physicians would also welcome the implementation of previously suggested improvements in CPT codes, recognition, and external research collabora- tions, she said. Mr. Katz suggested that investigators’ engagement in the Cooperative Groups be defined in terms of specific, measurable outcomes. “We don’t really know, I think, where we are today in terms of [how many] young investigators are participating [in the Cooperative Groups] and how many are opting out and how many might come in,” he stated. “I think if we are serious about this, we ought to figure out where we are, set a target, and figure out what we need to do to get there.” Measuring Success Echoing the suggestion (by Mr. Katz and Ms. Nasso) that metrics for the success of Cooperative Group consolidation be defined and monitored,

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83 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM Dr. Deborah Bruner, of the University of Pennsylvania, suggested that such measurements be conducted on a single consolidation, before other Groups follow suit. For example, she asked, do rates of accrual rise for a new Group formed from three former Groups? “We have no articulation or plan for that kind of pilot testing,” she noted with concern. “Accruals are critical and important, and we can’t do trials without get- ting patients,” Dr. Murphy acknowledged. “But if you will remember from Dr. Reaman’s presentation this morning, immediately after we merged the four pediatric groups, we actually had a dip in accruals. We were so busy finishing the legacy trials, trying to get our act together, writing new grants, getting the finances in order, that we didn’t have the uninterrupted scientific progress, because we were also merging the science.” She therefore predicted that it will be difficult to maintain even current accrual levels in the adult groups until consolidation is truly complete. Dr. Hohneker agreed with this point, and Dr. Buckner noted that since April 2010, only five Phase III trials have been approved throughout the Cooperative Groups. Moreover, Dr. Murphy observed, “suppose we could double accruals in the Cooperative Groups. We don’t have the capacity for that . . . so be careful what you wish for.” Nevertheless, she continued, it is important to define what consolidation is meant to accomplish and ways to measure progress toward such goals. Adopting a business model to describe consolidation of the Coopera- tive Groups, Dr. Hohneker stated that corporate mergers tend to be defined as successful within specific time frames. He said you have to get to the so- called 80-20 rule,39 which states that for many events, about 80 percent of the effects come from 20 percent of the causes, and move expediently for change to work. “The idea is to improve speed and efficiencies and to look at metrics for that and targets for that that you would expect,” he stated. Such time frames must be appropriate to the disease being studied, Dr. Thomas observed. For example, she said, “in pancreatic cancer, there have been 10 years of negative clinical trials, but we only have those because the Cooperative Group pushed to get them done. Many of those studies wouldn’t have been done and completed if it weren’t for the Cooperative Group.” She explained that all the Groups that study gastrointestinal cancers convene twice a year to examine their collective clinical trials port- folio, which offers the possibility of judging the quality of the portfolio that emerges from that process, rather than the number of accruals or number of 39 See http://en.wikipedia.org/wiki/Pareto_principle.

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84 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM trials. In fact, the number of trials for such intractable diseases may decline, but the quality of studies may improve as a result of Group consolidation, she concluded. An NCI committee is examining metrics to be used to judge future Cooperative Group performance, Dr. Grubbs reported; he added that many workshop participants have been involved with this effort. While objec- tive measurements such as numbers of people enrolled in trials, or length of time to begin and conduct a trial, are easy to obtain, measurements of quality—such as whether a study significantly changed patient care—are very difficult to define, he observed. “There aren’t that many events to look at when it comes to the comple- tion of trials,” Mr. Katz responded. “It’s not like trying to look at every patient. You can review all the trials that actually changed the standard of care, and you wouldn’t have a desk full of papers.” “What’s very important in terms of resource utilization is, Did the study answer the question?” Dr. Buckner asserted. “Too often in the cancer field, the study was well done; unfortunately, it didn’t turn out to be an advance, but that still enhances our collective knowledge of what works and what doesn’t work,” he continued. Thereafter, translational research can address the question of why something didn’t work, or only sometimes works, he added. “To expand on the metric, it’s not only what changed prac- tice, but what we learned and, importantly, whether we learned anything,” he concluded. “The worst trial is one in which we don’t get an answer of any kind.” Dr. James Dignam, of the University of Chicago and RTOG, asserted that the 40 percent trial failure rate due to low accrual in cancer clinical trials, which was cited in the IOM consensus report (Cheng et al., 2009; Schroen et al., 2009), is not the most accurate measurement available. He called participants’ attention to a recent article by Korn and colleagues (2010), published after the IOM report, which estimates that rate at 22 per- cent and concludes that only about 2 percent of patients will be enrolled in such failed trials. “Often these trials that are smaller than we like are still orders of magnitude larger than other studies and serve as the best informa- tion about a given disease situation,” he observed. Open Trial Enrollment Based on a question from Dr. Go, who was unable to enroll an inter- ested patient in a trial conducted by a Cooperative Group of which he

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85 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM was not a member, participants discussed whether the cancer clinical trials system should be more open in order to allow any Cooperative Group inves- tigator to enroll patients into any Group’s trials. Most Phase III trials accrue many patients and are available across the country, Dr. Buckner explained, but even large Phase II trials accrue no more than 250 patients, and they tend to be relatively popular with patients. Therefore, he asked, What is gained by opening such a trial—at greater expense—to accrue patients at multiple sites? An institution that enrolls lots of people in clinical trials, but does not belong to a particular Group, should nonetheless have access to that Group’s trials, Mr. Katz responded. Some institutions accrue very few patients to trials, he noted; nevertheless they incur costs associated with having trials open. Dr. Grubbs agreed and noted that individual sites can determine whether it makes sense to assume the cost of opening a given trial. “I’m not going to open a trial that costs money and not accrue. . . . If institutions are seriously participating in the research, then they ought to have access to all the trials,” he asserted. Moreover, he added, “if you have a great trial, people are going to want to do it and it will get done fast. Isn’t that the final point here, that we want to get trials done quickly and get the answer and move on?” Selection of Trial Sites Following a question from Dr. Cross, the panel considered which types of trials should be opened broadly across the country at all institutions and which should be opened primarily at referral centers (e.g., community hos- pitals). Dr. Cross said that as a payor, he would prefer to have as many trials as possible conducted in community settings, where routine costs are lower. (Patients who lack insurance are often unable to enroll in trials conducted in tertiary centers, Ms. Gonzalez pointed out.) Mr. Katz remarked that this issue has recently been discussed at a steering committee meeting and that it may be an accrual barrier when experimental agents must be given in a tertiary center. In some cases, he said physicians are not even allowed to give the pills to patients at the local community cancer center; they have to be certified as investigators and there are regulatory issues. He suggested that a hybrid approach could solve this issue. “The trial should be done where it can be done,” Dr. Caligiuri insisted. In a given trial, there may be a device or an agent or a treatment for a par- ticular tumor type that might be most efficiently administered in a tertiary

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86 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM center, but might also be provided at certain community sites, he said. “It’s not a black-and-white issue.” “This is a perfect question for comparative effectiveness research,” Dr. Murphy observed. “Are the results in Cancer Centers better than in the communities, or vice versa? The groups and the CCOPs are positioned to answer those kinds of questions,” she said. “It’s a matter of delivery of cancer services, basically, and optimum outcomes. . . . These are important issues for payors, as well as patients—convenience, impact on quality of life,” she continued. “These could all be studied.” Dr. Grubbs responded that CCOPs had excellent audit reports, just as the Cancer Centers did. “So I think we have shown there is equivalency there. . . . It’s not unusual that in the Phase II trial, the leaders in accruals are the CCOPs, not the main member institutions,” he said. Dr. Bertagnolli remarked that clinical trials offer the best way to dis- seminate novel findings to the community, and therefore research should not be confined within tertiary centers if at all possible. When a clinical trial is performed in a research center, she said, “it allows the quality of the entire health care system to be expanded in probably the most efficient and best-controlled way.” Dr. Buckner noted that while critical evaluations of some patients may require expertise and technology available only at tertiary centers, they often can still receive care at community centers close to their homes. “It depends on what the disease is, what the comfort level is of the patient, what the comfort level is of the physician or provider who is treating the patient, and the expertise available at a convenient referral center,” he explained. Funding Clinical Trials Dr. Schilsky noted that an analysis presented at the March 2011 CTAC meeting determined that annual funding for the entire NCI clinical trials portfolio amounts to nearly $1 billion, of which approximately $250 mil- lion supports the Cooperative Groups and the CCOPs. “Where is the other $750 million going?” he asked. “What are we getting for that investment of resources?” Dr. Doroshow said that the analysis40 of the Fiscal Year 2006 NCI bud- get was undertaken by Judy Hautala of the Science and Technology Policy Institute. A total of nearly $975,000,000 was devoted to interventional 40 See http://deainfo.nci.nih.gov/advisory/ctac/0311/Hautala.pdf.

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87 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM clinical trials that year, with about 17 percent going to intramural studies, about 82 percent going toward extramural studies, and the remaining 1 percent going to research management support. The extramural portion includes many different programs, but only three constitute more than 10 percent of the total: the Cooperative Group Program (21 percent), the Cancer Centers (13 percent), and the Clinical Grants and Contracts Branch of the NCI Division of Cancer Treatment and Diagnosis (13 percent). As a result, Dr. Doroshow said, “it’s easy to look at the Group budgets because they are the biggest line, but it is much harder to evaluate all of these other pieces broken up across a large playing field. One of the things that I think is very clear from the last CTAC meeting is that we should do such an analy- sis.” We need to know “what we get for that amount of money,” he added. “I would suggest that you could double the $250 million spent on the Cooperative Groups, which would be transformative for the Cooperative Group Program, and still have $500 million to spend on other clinical trials sponsored by the NCI,” Dr. Schlisky suggested. “If there’s $1 billion being invested by NCI in clinical trials every year, we really need to look at how to make sure that that money is being really well spent.” CLOSING REMARKS As the workshop drew to a close, Dr. Schilsky offered the following reflections, based on the day’s presentations and discussions. “Surely everybody here would agree that it’s vitally important to this country that we have a publicly funded clinical trials system,” he began. “It’s really only a question of how much we invest in it and what it looks like, to make it optimally functional.” He noted several ways to improve the current clinical trials system as expressed by workshop participants: new treatments; and As emphasized in the IOM consensus report and reflected in work- shop discussions among diverse stakeholders, everyone can do something to improve the cancer clinical trials system, Dr. Schilsky observed. “The system will not improve if only the Cooperative Groups change, or if only

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88 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM the NCI changes, or if only pharma develops a new attitude, or if only the FDA puts in place different approval criteria,” he said. Clearly, increased funding for the Cooperative Group Program is cru- cial to its revitalization, Dr. Shilsky asserted. “The budget for the Coopera- tive Groups today is essentially the same, in real dollars, as it was more than a decade ago, yet the work is more complicated and the challenges are at least as great, and the opportunities are greater than they have ever been,” he stated. “If more money is not put into the system, the only possible result is that there will be fewer trials and lower accrual,” he continued. “That’s not necessarily a bad thing, if the trials can be launched more quickly, com- pleted more quickly, and ask and answer high-impact questions. But I think that’s the inevitable result of a system that is essentially being strangled by inadequate funding.” Under such circumstances, priority setting is critical, he added—and again, something all stakeholders must face and to which they should contribute. It will also be important—particularly given such resource limitations— to preserve volunteerism in the Cooperative Groups, Dr. Schilsky noted. Recalling Dr. Grubbs’ comment that his Cooperative Group is his profes- sional “home,” Dr. Schilsky observed that many people in the Cooperative Group system feel similarly and, because they do, invest considerable time, energy, and money in the work of their Group. He reminded participants of the previously discussed NCI portfolio analysis showing that NCI supports only about half of the Cooperative Groups’ total operating budget and that most of the remainder is provided by institutions that value their participa- tion in the Cooperative Group Program. The Cooperative Groups play an important role in developing the next generation of clinical researchers, Dr. Schilsky added. Many leaders in clini- cal cancer research “grew up, made their reputations, and learned how to do clinical trials in the Cooperative Group Program,” he said. “There really is no other venue anywhere in the world where young investigators can get the experience of working with experienced clinical trialists, disease experts, laboratory scientists, expert biostatisticians, people who know how to con- struct databases, and so on like in the Cooperative Group program,” he continued. “If the program downsizes and the younger generation perceives fewer opportunities to participate in the Cooperative Group program, I fear that we are going to lose some of them as time goes by.” Dr. Schilsky closed by reiterating Mr. Katz’s remarks: “Let’s remember to be bold, but to be careful in our attempts to make the system better, and let’s be sure we know what constitutes success before we start making whole-

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89 IMPLEMENTING A NATIONAL CANCER CLINICAL TRIALS SYSTEM sale changes to the system.” Anticipating another such workshop in 2012, Dr. Schilsky said he looked forward to seeing how the new Cooperative Group alliances have been forged and how the cancer clinical trials system was changing as a result of these actions.

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