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3
Operations, Oversight, and Funding of Cancer Clinical Trials
Cancer clinical trials are highly complex and represent a major research undertaking. They require hundreds of steps with numerous decision points and there are multilayered and iterative review processes because multiple oversight bodies have jurisdiction over a trial. The primary focus of the Cooperative Group Program is large, definitive, randomized Phase III studies and the development efforts preceding these trials (NCI, 2006). Phase III trials are considered the “gold standard” for changing medical practice because the results of these trials are used to obtain Food and Drug Administration (FDA) approval, establish practice guidelines, and make insurance coverage decisions. They are also the most complex and costly trials to conduct. These large-scale clinical trials necessitate interactions among numerous stakeholders, including multiple governmental agencies, academic medical centers, community practices, patients, and industry. To improve the system as a whole, a revision of the roles of all these stakeholders must be considered.
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. The chapter identifies inefficiencies and limitations of the current system and describes the committee’s recommendations, which aim to improve the speed, efficiency, and effectiveness of cancer clinical trials, especially those that the Cooperative Groups undertake.
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ORGANIZATION OF THE COOPERATIVE GROUP PROGRAM
The Cancer Therapy Evaluation Program (CTEP), which is part of the Division of Cancer Treatment and Diagnosis (DCTD) of NCI, administers the Cooperative Group Program, which represents a major component of DCTD’s extramural research activities. The NCI Cooperative Groups were originally organized by geographic area or, in some cases, by type of disease or therapeutic modality. Each Cooperative Group includes a large network of physicians, statisticians, nurses, clinical research associates, pharmacists, patient advocates, and other affiliated investigators. The Groups operate independently and have their own administrative structures, operating procedures, and committees. Each Group has an operations office and statistical center overseen by the Group chair and Group statistician, respectively. To be involved with a Cooperative Group, institutions must apply for membership and meet that Group’s eligibility criteria, including accrual potential and the ability to comply with Group standards and federal requirements. Each institution participating in a Cooperative Group is represented by a principal investigator, who manages the institution’s activities within the Group (Mauer et al., 2007).
Institutions participate in the Cooperative Groups as main member institutions, affiliates of a main member institution, or members of participating Community Clinical Oncology Programs (CCOPs). The main member institutions are generally academic medical centers or other major medical centers that are centrally involved in Cooperative Group activities. Main member institutions enroll a significant number of patients in clinical trials and also contribute scientific expertise and other resources to Group activities. Affiliate members, designated by the main member institutions, include community-based organizations and physicians’ practices and have lower patient accrual rates.
Created in 1983, “the CCOP network allows patients and physicians to participate in state-of-the-art clinical trials for cancer prevention and treatment while in their local communities,” according to NCI (2009b). The CCOP network can include hospitals, clinics, health maintenance organizations, groups of practicing physicians, or a consortium that agrees to work with a principal investigator through a single administrative unit (Mauer et al., 2007). Each CCOP chooses to join one or more CCOP Research Bases, which are NCI-designated Cancer Centers or Cooperative Groups that design, develop, and conduct clinical trials (NCI, 2009b).
OVERSIGHT OF CLINICAL TRIALS
Cancer clinical trials are highly regulated activities. Multiple agencies of the U.S. Department of Health and Human Services (HHS) review and
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provide oversight of cancer clinical trials, including NCI, FDA, the Office for Human Research Protections (OHRP), and the Office for Civil Rights (OCR). Many reviews are required before a Cooperative Group clinical trial can begin. These include reviews undertaken by the disease site and other scientific committees of the Cooperative Groups, various committees and branches of NCI, institutional review boards (IRBs), comprehensive cancer centers, CCOPs and their affiliates, and, in some cases, FDA and industry sponsors (Table 3-1). Additional oversight is required during the conduct of the trial and at the closure of the trial. The many oversight bodies have different objectives and responsibilities, and thus, they seek similar and overlapping but not identical information and action for compliance. This section provides a brief overview of Cooperative Group clinical tri-
TABLE 3-1 Types of Reviews Required to Develop a Cooperative Group Clinical Trial, by Stakeholder
CTCG
CTEP
CCC
CCOP/Affiliates
Others
Scientific Review
Disease Site Committee
Steering Committee/CRM
Protocol Review
Feasibility Review
Industry Sponsor
Executive Committee
Site Surveys
PRC
Protocol Reviews (2–4)
CTEP Final
Data Management
CRF Reviews (2–4)
CDE Review
Database Review
Safety/Ethics
Informed Consent
Local IRB
Informed Consent
CIRB
Regulatory
Regulatory Review
PMB Review
RAB Review
FDA
Contracts/Grants
Budget Language
Industry Sponsor
Study Start-up
Start-up Review
Start-up Review
Start-up 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.
SOURCE: Dilts, 2008.
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als oversight, with emphasis on issues that the committee considered most relevant to improving the clinical trials system.
NCI Oversight of Cooperative Group Trials
The cooperative agreements that provide funding to the Cooperative Groups stipulate NCI review and oversight at each step of the clinical trial process, including selection of trials to be conducted, protocol development, and trial operations (NCI, 2006). The role of CTEP staff, as described in the NCI clinical trials Cooperative Group Program Guidelines (NCI, 2006), is to “assist, facilitate, and assure optimal coordination of Group activities. CTEP staff have very specific and well-defined responsibilities for the oversight and review of Group clinical trials and for investigational agent development.” Given this central position of NCI in the clinical trials system, the committee recommends that the current roles of NCI as well as the Cooperative Groups be reevaluated.
The 2005 report by the Clinical Trials Working Group (CTWG) recommended several ways to improve NCI oversight of cancer clinical trials (NCI, 2005b; see also Appendix A). In response to the recommendations of the CTWG, NCI created a number of offices, committees, and subcommittees, as indicated in Table 3-2 and Figure 3-1.
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). However, all trial concepts that the Groups generate must be reviewed and approved by CTEP before they are launched. Because an excess of trials with poor enrollment raised concerns that prioritization of the trials was inadequate, the CTWG recommended the creation of a network of scientific steering committees (Box 3-1) that would leverage Cooperative Group, inter-Group, Specialized Programs of Research Excellence, and Cancer Center structures to work with NCI staff on the design and prioritization of Phase III trials to better allocate resources, increase scientific quality, and reduce duplication (NCI, 2005b; see also Appendix A). With this new organizational setup, principal investigators submit the concept for a clinical trial to CTEP for review and approval by the appropriate steering committees, with the goal of prioritizing them.
This approach to concept review remains inefficient and is not sufficiently effective in prioritizing trials. Since the steering committees were formed, the lengths of concept proposals have increased significantly (they
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TABLE 3-2 NCI Oversight of Cancer Clinical Trials
Office, Committee, or Subcommittee
Role
NCI Office, Coordinating Center for Clinical Trials
Established in 2006; supports the implementation of the initiatives of the CTWG and the Translational Research Working Group (TRWG)
NCI Committees
Clinical and Translational Research Operations Committee (CTROC)
Established in 2005; an internal committee that provides strategic oversight for NCI clinical trials and translational research
Clinical Trials and Translational Research Advisory Committee (CTAC)
Established in 2007; provides extramural oversight for implementation of the CTWG and TRWG initiatives, including steering committees
CTAC Subcommittees/Working Groups
Investigational Drug Steering Committee (IDSC)
Provides strategic input into the clinical development (early phase) plans for new agents for which the Cancer Therapy Evaluation Program holds the investigational new drug application
Disease-Specific Scientific Steering Committees (SCs)
Prioritize concepts for Phase III and selected Phase II therapeutic clinical trials; refine and collaborate on concepts by the use of task forces, when appropriate
Patient Advocate Steering Committee
Develops and shares best practices for patient 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 System (CTMS) Steering Committee
Provides strategic advice for the CTMS work space, advising on project selection, prioritization, and oversight
Ad Hoc Coordination Subcommittee
Provides advice on how to foster collaboration among the various components of the NCI-sponsored clinical trials infrastructure, to develop a fully integrated clinical trials system
Ad Hoc Public/Private Partnership Subcommittee
Provides advice on how to enhance NCI-sponsored clinical trials through collaborative interactions with the private sector
Cooperative Group Clinical Trials Funding Model/Complexity Model Working Group
Charged with developing a model for aligning reimbursement of Phase III treatment trials with complexity, to compensate the additional costs
Correlative Science Working Group
Charged with developing validation standards and prioritization criteria of correlative science studies associated with Phase III trials
Operational Efficiency Working Group
Charged with developing approaches to cut timelines in half
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FIGURE 3-1 Integrated management of NCI cancer clinical trials.
SOURCE: Doroshow, 2008.
are now about 25 pages long), making the review process more arduous. Multiple layers of review still slow the process, and trial concepts are still not ranked against each other, as is usually done in peer review. Steering committees review and vote up or down on trial concepts as they are submitted, and NCI staff actively participate in the review process, unlike other NCI peer review groups. As of January 1, 2010,1 62 percent of concepts for Phase III trials reviewed by the steering committees had been approved,2 whereas the historic approval rate was about 65 percent before
1
The various steering committees have been phased in gradually, with start dates as follows: Gastrointestinal Cancer, January 2006; Gynecologic Cancer, June 2006; Head and Neck Cancer, January 2007; Genitourinary Cancer, February 2008; Breast, September 2008; Lung, Fall 2008; Hematologic Malignancies, December 2009.
2
Of 45 concepts, 28 (62 percent) were approved, 15 (33 percent) were disapproved, and 2 (4 percent) were pending.
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BOX 3-1
Clinical Trials and Translational Research Advisory Committee Steering Committees
Investigational Drug Steering Committee (IDSC) for Early-Phase Trial Prioritization
Membership includes principal investigators of NCI’s early-phase U01 grants and N01 contracts and representatives from Cooperative Groups and other content experts. The committee has nine task forces in the areas of signal transduction, biomarkers, angiogenesis, clinical trial design, pharmacology, immunotherapy, PI3K/Akt/mTOR (PAM), cancer stem cells, DNA repair, and programmed cell death. The Group has developed recommendations for:
Toxicity management of antiangiogenic agents
Novel Phase I and Phase II clinical trial designs
Prioritization of agents for immunotherapy trials
Guidelines for the incorporation of biomarkers into early-phase trials
Disease-Specific Scientific Steering Committees
NCI established disease-specific scientific steering committees with the goal of increasing information exchange at an early stage of trial development; increasing the efficiency of clinical trial collaboration; reducing trial redundancy; and developing, evaluating, and prioritizing trial concepts. These committees are charged with prioritizing, refining, and collaborating on concepts for Phase III and selected Phase II therapeutic clinical trials. The committees use task forces when appropriate, convene planning meetings to identify the critical issues and questions about the disease to be studied, and periodically review accrual and unforeseen implementation issues.
The initial committees included the Gastrointestinal Cancer, Gynecologic Cancer, and Head and Neck Cancer Committees. Subsequent committees included the Genitourinary Cancer, Breast Cancer, and Thoracic Malignancy Committees and three committees for adult Hematologic Malignancies (Leukemia, Lymphoma, and Myeloma). Committees on brain cancers and pediatrics are in development. The full transition to disease-specific steering committees is expected in 2010.
SOURCES: NCI, 2009a,f.
the implementation of the committees.3 The approval rate for Phase II trial concepts was 53 percent. 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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they are charged with guiding the development of “strategic priorities” (NCI, 2005b). A possible alternative approach might be for the steering committees to identify research priorities and then issue requests for proposals to address them. However, the trial concept review process should be strengthened and streamlined, and it should entail the evaluation of concise proposals (including the intended statistical design) that are ranked against each other. 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.
Protocol Development
After CTEP approval for a trial concept is achieved, the principal investigator and other key staff develop a full study protocol that must again be reviewed and approved by various branches within CTEP (Table 3-1). Although the Cooperative Group guidelines state that protocols can be “approved with recommendations,” in which investigators are requested to give serious consideration to any recommendation included in the consensus review but are not obligated to amend the study, reviewers generally do not distinguish between major and minor review concerns. The committee recommends that all review bodies distinguish between major review concerns (concerns regarding patient safety and critical scientific flaws, which must be addressed) and minor concerns (which should be considered, but are not obligatory).
Moreover, if changes are made before activation of the study, the investigators must send CTEP a revised protocol for review that details any changes in the previous CTEP-approved document. This policy includes changes to the protocol that are requested by an IRB subsequent to CTEP approval (see also the section on oversight of trials by IRBs). Similarly, minor changes requested by NCI can trigger iterative reviews by IRBs. Additional duplicative and iterative reviews can further slow the process when a trial involves an investigational new drug (IND) or an investigational device exemption (IDE), as both FDA and NCI are involved in protocol review and development (see also the section on FDA oversight). The committee recommends that federal oversight be more flexible in allowing minor amendments to the protocol or consent form to fast-track the chain of reapprovals.
In sum, the protocol development process is arduous and time-consuming.
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Months are often consumed by multiple re-reviews that sometimes address only minor changes. Given the funding limits and voluntary nature of the Cooperative Group Program, it can be difficult for the Groups to devote sufficient staff time to rapidly develop and amend a protocol as the process proceeds, further compounding delays due to expectations for revisions and re-review (IOM, 2009c). The provision of funds for professional project managers could ease the workloads of principal investigators and greatly facilitate a rapid review process and adherence to timelines. As described in subsequent sections of this chapter, improved processes are also needed to reduce the time required for protocol development and trial launch. For example, use of standardized templates for some portions of the protocol might result in fewer iterative reviews and speed the review process.
Trial Operations
Once a trial is launched, NCI takes a direct role in overseeing quality control, data and safety monitoring, data management and analysis, and compliance with federal regulatory requirements (NCI, 2006). For example, an NCI program director assisted by the Biometric Research Branch (BRB) 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. BRB staff make recommendations with the goal of ensuring that data collection and management procedures are adequate for quality control and analysis yet are sufficiently simple to encourage maximum participation of physicians entering patients into studies and to avoid unnecessary expense. Data must be made available for external monitoring as well, as required by NCI’s agreement with FDA relative to NCI’s responsibility as sponsor of a therapeutic agent (NCI, 2006).
The Clinical Trials Monitoring Branch (CTMB) of CTEP provides direct oversight of each Cooperative Group’s monitoring program, which includes on-site auditing. CTMB is responsible for establishing guidance for the conduct of quality assurance audits and for overseeing and monitoring the compliance of the Groups, the CCOP research bases, and the Cancer Trials Support Unit (CTSU) with NCI’s monitoring guidelines. CTMB also monitors compliance with applicable federal regulations. CTMB staff may attend certain on-site audits, and they review audit reports and findings and assess the adequacy and acceptability of any corrective actions. CTMB staff also review and provide advice regarding the mechanisms established by the Group for quality control of the therapeutic and diagnostic modalities that it uses in its trials (NCI, 2006).
In addition to overseeing the conduct of Cooperative Group clinical
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trials, NCI also provides some logistical support (NCI, 2006). For example, the Pharmaceutical Management Branch provides for the distribution of investigational new agents for which DCTD is the sponsor. However, NCI does not provide those services for other agents. Faster trials could be fostered through more active and consistent support from NCI. Thus, the committee recommends that NCI file more IND applications for agents to be tested in approved protocols and that NCI devote more funds to the distribution of drugs for approved protocols to ensure an adequate drug supply for high-priority studies. These tasks entail time- and resource-intense activities. 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. NCI should provide resources and technical assistance to facilitate the rapid adoption of a common patient registration system. For example, the Oncology Patient Enrollment Network4 would provide a standardized Internet-based environment for the enrollment of all patients in all Cooperative Group trials. NCI should also provide a common remote data capture system.5 The availability of such a system would permit sites to enter patient-level data into a clinical database over the Internet. The implementation and adoption of these structured electronic tools would increase consistency across trials, Groups, and sites; conserve resources by reducing the workload associated with patient enrollment and follow-up; allow more timely data review; and enhance the knowledge gained from a trial. However, these transitions can be costly and temporarily disruptive, so support from NCI to facilitate rapid implementation is important.
NCI should also facilitate the establishment of more efficient and timely methods for ensuring that trial data are complete and accurate while the trial is ongoing. Many Groups wait until completion of a trial before beginning the necessary steps to ensure data quality because they lack the resources to check the data more frequently, but this can result in significant delays in analyzing and publishing the results. NCI should also develop standardized case report forms that meet regulatory requirements. The language for most clinical data elements in NCI-sponsored trials has been standardized by the NCI Common Data Elements,6 but standardized report formats would also simplify the reporting across multiple trials and multiple sites.
4
See https://open.ctsu.org.
5
See https://www.ctsu.org/RDC_project_page.asp.
6
See https://wiki.nci.nih.gov/display/caDSR/CTEP+Common+Data+Elements.
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Oversight of Trials by IRBs
In the 1970s, concern about the inadequate protection of human subjects in research led to federal regulations and the establishment of IRBs7 (Beecher, 1966; HEW, 1979). At that time, most clinical research was done at single sites by single investigators. Since then, the increasing emphasis on evidence-based clinical practice has greatly increased the number of clinical trials. There has also been substantial growth in the number of multicenter trials as well as an increase in the complexity of clinical trials. In addition, the purview of IRBs has been expanded as additional regulations regarding human subjects research have been developed, such as the Privacy Rule promulgated under the provisions of the Health Insurance Portability and Accountability Act (HIPAA). These combined changes have overburdened IRBs and have fostered long delays in the review of study protocols and informed-consent forms (ICFs) (IOM, 2002).
IRB Oversight of Multicenter Trials
In many cases, each site participating in a multicenter trial will have its own IRB review of a study, which causes “unnecessary duplication of effort, delays and increased expenses in the conduct of multi-center trials,” as noted in a recent FDA guidance (FDA, 2006). For example, one study (Greene and Geiger, 2006) found that one-quarter of the 20 trials reviewed experienced delays (of up to 8 months) because of multiple IRB negotiations.
Multiple IRB reviews do not necessarily improve patient protection, as evidenced by the numerous inconsistencies in the rulings of local IRBs reviewing the same study (Gold and Dewa, 2005; Greene and Geiger, 2006). One survey of participating sites in a multicenter genetic epidemiology study found that the participating local IRBs used different evaluation criteria, which resulted in requirements for the use of different numbers of consent forms at each institution participating in the trial (McWilliams et al., 2003). 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). McWilliams and colleagues concluded, “Lack of uniformity in the review process creates uneven human subjects protection and incurs considerable inefficiency” (McWilliams et al., 2003). The lack of consistency in consent requirements among IRBs can also lead to selection bias and decrease statistical power (Jamrozik, 2000).
In addition, the bulk of the changes that IRBs request are often minor changes to ICFs that increase the reading level of the forms, thus making
7
45 C.F.R. § 46.103.
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High-priority trials must be adequately funded to efficiently and effectively attain results that can move the field forward. NCI has an obligation to adequately fund trials identified as being of high priority. NCI should increase the total funding allocation for the Cooperative Group Program to ensure the effective translation of discoveries made with public funding to improved clinical care. Thus, NCI should allocate a larger portion of its research portfolio to the Clinical Trial Cooperative Group Program to ensure that the Program has sufficient resources to achieve its unique mission. The allocation of NCI funds among the competing needs of its various programs is a major challenge for the NCI director, who must take many factors into consideration. Greater input from the broad expertise and experience of external advisory boards would be helpful to ensure the most rational distribution of funds across the major NCI programs, in light of such factors as scientific opportunity and clinical need. External advisory boards, such as the National Cancer Advisory Board and the Board of Scientific Advisors, should have a greater roles in advising NCI on how it allocates its funds to support a national clinical trials program. These high-level boards should not be involved in the oversight of individual trials or in concept review, which would further slow the process, but rather, they should have a greater influence on how much funding is allocated to the overall Cooperative Group Program.
Given the limits of the NCI budget, the total number of NCI-funded trials undertaken by the Cooperative Groups should be reduced to a quantity that can be adequately supported, to ensure sufficient funding for high-priority trials. Compromising the science to launch more trials than the available funding can support is detrimental to progress. However, even in the absence of a substantial increase in the overall funding of the Program, the funds saved by launching fewer but higher-priority trials could be allocated for increased per case reimbursement rates to trial sites, which has been set at $2,000 since 1999, well below the estimated median costs per patient. The many duties required of clinicians and other key research staff to participate in clinical trials are costly in terms of both time and resources. These voluntary contributions constitute a substantial value and strength of the Program. However, when the discrepancy between the per case reimbursement and the actual cost of participation is excessive, as it is now, it becomes a major disincentive to participation. 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. Thus, NCI should increase the per case reimbursement and adequately fund highly ranked trials to cover the costs
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of the trial, including the costs of biomedical imaging and other biomarker tests that are integral to the trial design.
Given the limited funding capacity of NCI, it would also be beneficial to leverage the resources of industry to support the work of the Cooperative Groups in a transparent way to benefit patients, for example, in comparison trials or for secondary indications. Two recent reports from PCAST acknowledge the importance and value of strengthening public-private collaborations to enhance innovation, particularly for discovery and translational research in personalized medicine. However, industry funding for Cooperative Group trials has been limited for a variety of reasons, including concern about the inherent inefficiencies in the Program and the groups’ concern about maintaining independence in study design and execution. These concerns may contribute to the increasing tendency of pharmaceutical companies to conduct trials in other countries.
Thus, NCI should facilitate the creation of more public-private partnerships and precompetitive consortia, guided in part by successful models. NCI should also facilitate the development of appropriate hybrid funding models, in which NCI and industry support clearly defined components of trials that are of mutual interest. Commercial firms might be more interested in collaborations with the Cooperative Groups if the review and operational procedures of the Program were streamlined, as recommended in this report. 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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