Appendix A
Previous and Ongoing Analyses Undertaken by NCI
In the 50 years of its existence, the Cooperative Group Program has advanced the treatment of cancer and the conduct of clinical research. Despite these successes, the Cooperative Group Program has continued to face a number of challenges that threaten its effectiveness. To further explore the challenges and opportunities confronting the Cooperative Groups, multiple evaluations of the Program have been conducted. Two of the most recent reviews of the Cooperative Group Program include the Armitage report (1997) and a review by the Clinical Trials Working Group (CTWG) in 2005. As a result of the CTWG report, the National Cancer Institute (NCI) established the Operational Efficiency Working Group (OEWG) to provide recommendations for improving the time from concept approval to enrolling patients on a clinical trial. In addition to these specific recommendations aimed at the Cooperative Group Program, the Program has also been influenced by other working group recommendations, including the Translational Research Working Group (TRWG) report recommendations.
REVIEWS OF THE COOPERATIVE GROUP PROGRAM
Armitage Report
In 1996, the NCI director and the chair of the Extramural Board of Scientific Advisors commissioned an external review of the Cooperative Group Program in response to concerns that the clinical trials portfolio had become increasingly inefficient and unresponsive to evolving needs.
The Clinical Trials Review Group was asked to recommend changes to the current system that would (1) take advantage of the most promising opportunities in therapy and diagnosis; (2) prioritize the most important research questions so that they can be explored in the fastest possible time; (3) improve the organization, funding, review, and cooperation in the Cooperative Group Program; and (4) attract both patients and researchers to participate in clinical trials.
The review committee met six times over an 11-month period and included experts from academic research institutions, cancer centers, community oncology practices, cancer patient advocacy groups, and the National Institutes of Health. The committee released its findings, known as the Armitage report, after its chair, James Armitage, in 1997 (NCI, 1997). The report made the recommendations regarding review, funding, design, oversight, and administration of the NCI clinical trials system. A subsequent implementation committee report was completed in 1998.
Clinical Trials Working Group Report
In 2004, the NCI director established the CTWG to advise the National Cancer Advisory Board on the development, conduct, infrastructure, support, and coordination of cancer clinical trials across NCI. The CTWG was asked to develop recommendations to (1) optimize the NCI-supported clinical trials system by improving coordination and research infrastructure, (2) remove institutional and regulatory barriers that inhibit collaboration in clinical trials research, and (3) envision how clinical trials should use the tools of contemporary bioinformatics and molecular medicine.
The review committee conducted 7 face-to-face meetings and 10 group conference calls over a 16-month period and included experts from academic research institutions, community oncology practices, the pharmaceutical and biotechnology industries, cancer patient advocacy groups, NCI, the Food and Drug Administration (FDA), and the Centers for Medicare & Medicaid Services (CMS). The committee released its findings in 2005 (NCI, 2005b).
The committee proposed 22 recommendations to achieve four major goals for designing a more efficient national system for clinical trials conducted or supported by NCI, as follows: (1) better coordination, (2) prioritization based on solid science and the needs of patients, (3) standardized tools and procedures, and (4) improved operational efficiency (NCI, 2005b).
Recommendations
While the Armitage report had a broader focus than the CTWG report, including a focus on issues such as organization, prioritization,
participation, and funding, the CTWG report was more narrowly focused and emphasized coordination, collaboration, and the adoption of new technologies (Box A-1). Table A-1 lists the recommendations of both the Armitage and the CTWG reports, divided into several categories: data collection, standardization, and management; cooperation; process improvement; organizational and structural improvement; accrual; funding; and
BOX A-1 Comparison of the Armitage and Clinical Trials Working Group Committee Charges
SOURCES: NCI, 1997, 2005b. |
TABLE A-1 Comparison of Prior Recommendations for the NCI Cooperative Group Program
|
Armitage Report |
Clinical Trials Working Group |
Data collection, standardization, and management |
|
|
Cooperation |
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|
Process improvement |
|
|
|
Armitage Report |
Clinical Trials Working Group |
Organizational and structural improvement |
|
|
Accrual |
|
|
|
|
|
Funding |
|
|
|
Armitage Report |
Clinical Trials Working Group |
Investigator recruitment |
|
|
aK12 awards support newly trained clinicians appointed by an institution for development of independent research skills and experience in a fundamental science within the framework of an interdisciplinary research and development program. T32 awards enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. K08 awards provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas. SOURCES: NCI, 1997, 2005b. |
investigator recruitment. Interestingly, the Armitage report gave several recommendations on the retention and recruitment of clinical scientists, whereas the CTWG report’s 22 recommendations did not address recruitment and retention issues. Despite the time lapse between the release of the two reports, several themes emerged from both reports, including the importance of data standardization, the need for a comprehensive database of NCI trials, improved public awareness of clinical trials, and the need to reduce the time it takes to initiate a clinical trial.
RESPONSE TO THE CTWG REPORT
NCI has launched several initiatives in response to the CTWG report, as delineated in Box A-2. In addition, NCI has launched an evaluation plan in response to the CTWG recommendation for a quantitative and qualitative, evidence-based evaluation to assess measures of the program management process, the system performance process, and system outcomes.1 The evaluation plan consists of a baseline feasibility analysis, an interim evaluation of specific initiatives related to these measures, and final evaluations at specified intervals after implementation of the initiatives. A goal is to develop a structured framework for continuous monitoring and feedback to accommodate midcourse corrections.
The evaluation aims to compare the baseline to the future on the basis of system outcome measures (overall output) and system performance measures (performance of individual CTWG initiatives). The system outcome measures are intended to gauge the quality and impact of clinical trials and the efficiency of both trial development and initiation and trial conduct. NCI has engaged evaluation specialists to assist with development of the definitions, survey instruments, statistical adjustments, and other tools; to conduct the evaluations; and to determine the appropriate timing for examining the various measures in the context of the implementation timelines and the nature of the impacts envisioned.
The baseline evaluation of the current system was completed in 2008 to provide a basis for ascertaining the value of the restructuring effort. The results of that baseline evaluation are being analyzed by a Working Group of the Clinical Trials and Translational Research Advisory Committee (formerly the Clinical Trials Advisory Committee [CTAC]), which will propose which elements of the recommended evaluation system should be implemented and establish a timeline for follow-up evaluations.
BOX A-2 NCI Initiatives in Response to the CTWG Report NCI has launched initiatives in six categories in response to the CTWG report. The objectives and current status of those initiatives are briefly described below. Many of these activities are also described in Chapter 3. Enterprise-wide initiatives aim to enhance coordinated leadership of the clinical trials enterprise by addressing ongoing National Cancer Advisory Board oversight of clinical trials and an integrated NCI organizational structure for clinical trials management. NCI established the Clinical Trials Advisory Committee (CTAC; since renamed the Clinical Trials and Translational Research Advisory Committee) so that a broad range of stakeholders could provide advice on NCI-supported national clinical trials (both extramural and intramural) to the NCI director, deputy directors, and division directors. NCI also established the Clinical Trials and Translational Research Operations Committee (CTROC) as an internal NCI advisory committee responsible for review of ongoing clinical trials and prioritization of proposed NCI-supported clinical trials, correlative science programs, and translational research. CTROC members include the directors of all NCI divisions, offices, and centers that have clinical trials or translational science portfolios. The Coordinating Center for Clinical Trials was established to oversee implementation of the 22 initiatives recommended by the CTWG in 2005, as well as 15 initiatives recommended by the TRWG in 2007. The center, which resides within the NCI’s Office of the Director, facilitates and manages the operations of CTAC and CTROC in conjunction with all NCI divisions, offices, and centers. Coordination initiatives aim to improve coordination and cooperation among the functionally diverse components of the current system, including industry and federal regulatory agencies. Currently, NCI is working to establish a comprehensive database containing regularly updated information on all NCI-funded interventional clinical trials. Grantees will be requested to enter specific information about each clinical trial into the database. Prioritization and scientific initiatives aim to improve prioritization and scientific quality by developing a more open and transparent process for the design and prioritization of clinical trials that are science driven and that meet the needs of patient care. NCI has established an Investigational Drug Steering Committee and several disease-specific steering committees, as described in Chapter 3. Standardization initiatives aim to improve standardization of the tools and procedures used for trial design, data capture, data sharing, and administrative functions to minimize duplication of effort and to facilitate the development of a shared infrastructure to support an integrated national cancer clinical trials network. Working with the CEO Roundtable on Cancer, NCI developed the Standard Terms of Agreement for Research Trials clauses to help cut the time spent on contract negotiations between pharmaceutical or biotechnology companies and academic medical centers. |
Operational efficiency initiatives aim to improve operational efficiency by increasing the rate of patient accrual and reducing operational barriers so that trials can be initiated and executed in a timely, cost-effective manner. NCI funded a study to identify institutional barriers to the initiation of clinical trials by documenting and analyzing the steps needed to activate clinical trials (Dilts and Sandler, 2006; Dilts et al., 2006, 2008). In addition, since 2006, selected grantees have received administrative supplements to increase funding for the recruitment of minority and medically underserved patients to NCI clinical trials. In 2008, nine continuation supplements totaling $830,000 and four new supplements totaling $399,000 were awarded. Informatics initiatives aim to define, design, build, and deliver a comprehensive clinical trials informatics infrastructure that will serve all of the critical stakeholders. NCI plans to rely on the NCI Center for Bioinformatics to provide program management and infrastructure through caBIG to achieve these aims. SOURCE: See http://restructuringtrials.cancer.gov/initiatives/overview. |
Results of the Baseline Feasibility Study
The baseline measures of system performance for the CTWG initiatives included incentives for collaboration among investigators, the extent of multisite Phase II and multi-Cooperative Group Phase III trials, the extent of collaboration between industry and NCI, the nature and quality of clinical trial prioritization processes, and the distribution and cost-effectiveness of accrual across sites (Doroshow, 2008). The baseline measures did not consider initiatives in which there was little or no activity ongoing prior to the CTWG report, such as a comprehensive clinical trials database, the level of caBIG (cancer Biomedical Informatics Grid)-compatible clinical information technology, the value added by the Investigational Disease Steering Committee and Scientific Steering Committee processes, the impact of correlative science funding and standardization, the value and use of standardized clinical trial tools, and the cost savings achieved by shifting patient accrual to highly accruing, more efficient sites.
Multiple sources of data were used for the baseline feasibility analysis, including interviews, database analyses, and reviews of factual information in documents. Baseline interviews were held in 2007 with 81 stakeholders (investigators conducting Phase I, II, and III trials; principal investigators of the Community Clinical Oncology Program, investigators conducting
industry trials, and NCI staff). The questions were mostly open-ended, and some questions were designed to elicit perceptions of specific facts or events. Two CTEP databases (the Clinical Data Update System and the Division of Cancer Prevention Enterprise System Knowledgebase) have been analyzed, and the analysis includes all clinical trials, letters of intent (LOIs) for the conduct of clinical trials, and clinical trial concepts that were active between January 1, 2000, and December 31, 2005. However, no current database captures all clinical trials performed at the cancer centers.
The baseline document review covers NCI program guidelines, cancer treatment guidelines, and academic medical center tenure and promotion guidelines. An expert panel, composed of nine individuals who conduct NCI-funded clinical trials, an individual from industry who conducts clinical trials, and a patient advocate, participated in the development of measures and interview guides and reviewed the key findings at the end. Plans for future evaluations include the refinement of baseline measures and the development of new measures; incorporation of additional information into clinical trials databases to strengthen future evaluation efforts; and the development of an initiative-specific timeline.
For the system outcome measures, the analysis of the quality of trials focused on early closure and publications. Recommendations were made to include fields in clinical trials databases to indicate early closure and the reason for closure, as well as to report the publications that resulted from the clinical trial. Suggestions were also made to include Phase II and III linkages in clinical trials databases, as well as measures to evaluate the strength of evidence for dose and toxicity criteria in Phase I trials and outcome in Phase II and III trials. In addition, the group recommended that the databases include earlier time points in concept development, as well as fields for trial complexity and patient eligibility criteria to facilitate the interpretation of the accrual data.
To assess the impact of the changes on fostering collaboration, the group suggested that future interviews examine collaboration in trial design and that NCI develop a way to track collaborative trial efforts in the clinical trials databases. Collaboration in accrual and accrual through the Cancer Trials Support Unit (CTSU) also was considered, and repeat analyses at regular intervals were suggested (Doroshow, 2008).
Operational Efficiency Working Group
As discussed in Box A-2, the CTWG report called for an analysis of the institutional barriers that prolong the time from concept approval to accrual of the first patient onto a trial. In response, CTAC established the OEWG to recommend strategies and implementation plans based on the findings of its analysis. Sixty-three clinical trial stakeholders participated in the OEWG, including 10 Cooperative Group chairs, 8 cancer center
directors, clinical investigators, statisticians, protocol and trial specialists, a community oncologist, NCI clinical trials leadership and staff, representatives of the pharmaceutical and biotechnology industries, patient advocates, representatives of the FDA, CMS, and the CTSU.
OEWG deliberations focused on identification of the key barriers to the timely activation of clinical trials and a commitment to achieve new target timelines for the steps in trial activation. In these discussions, the OEWG developed new process maps for trial activation and established firm dates to terminate the development of a trial protocol if all issues were not resolved. To achieve the targeted timelines, the OEWG developed recommendations and associated implementation plans (Box A-3). The OEWG target timeline for Phase III Cooperative Group trials is 300 days to complete steps under CTEP and Cooperative Group control (including concept review, protocol development, protocol review, and forms development). The 300-day timeline excludes contract and drug supply negotiations with industry partners as well as institutional review board (IRB) approval; however, if the protocol is not activated in 2 years, it will be terminated. For cancer center investigator-initiated trials, the target timeline is 90 days to complete protocol review and revision, forms development, IRB review, and ancillary committee review, and 180 days to complete all steps from protocol submission to trial activation. The Investigational Drug Branch (IDB) early drug development Phase II target timeline is 210 days to complete steps under CTEP/IDB and extramural control, including letter of intent review, protocol development, protocol review, and forms development. This timeline excludes industry negotiations, arranging drug supply, and IRB and FDA approval; however, if the protocol is not activated within 18 months, it will be terminated.
TRANSLATIONAL RESEARCH WORKING GROUP REPORT
The TRWG was established in June 2005 under the auspices of the National Cancer Advisory Board and was charged with evaluating the current status of the NCI’s investment in translational research, envisioning its future, and developing recommendations and implementation plans to realize that vision. The work of the TRWG was intended to complement and extend the work of the CTWG. While the CTWG report primarily focused on late translation (Phase III trials), the TRWG’s focus was on early translation activities, including partnerships and collaborations among government, academia, and industry; intervention development; and early-stage trials.2
BOX A-3 Operational Efficiency Working Group Recommendations Cooperative Group Process Improvement
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Early Drug Development Phase II Trial Activation Process Improvement
Cancer Center Process Improvement
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Standardization of Tools and Templates
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Recommendations
In developing its recommendations, the TRWG outlined the current challenges confronting early translational research at the NCI (Box A-4). To address these challenges, the TRWG developed 15 recommendations in three categories: coordinated management, tailored funding programs, and operational effectiveness (Table A-2). In addition, the TRWG constructed six developmental pathways to describe the decision-making points and processes along which translational research occurs for six domains: bio-specimen-based risk assessment devices, image-based risk assessment agents
Enhanced Biomarker Funding and Capabilities
Cancer Center Trial Prioritization
SOURCE: Doroshow and Hortobagyi, 2010. |
and techniques, anticancer agents (drugs or biologics), immune response modifiers, interventive devices, and lifestyle alterations (Cheever et al., 2008; Dorfman et al., 2008a,b; Hawk et al., 2008a,b; Schilsky et al., 2008; Srivastava et al., 2008).
Some TRWG recommendations are outgrowths of the CTWG initiatives, such as the Clinical and Translational Advisory Committee (CTAC; previously the Clinical Trials Advisory Committee, created in response to the CTWG recommendations). The TRWG report expanded the scope of the CTAC committee to include translational research, noting that CTAC
BOX A-4 Translational Research Working Group Assessment of Current Challenges in Translational Research
SOURCE: NCI, 2007. |
was already responsible for early-stage trials and correlative science studies. The TRWG report also indicated that integrated oversight would facilitate the coordination and prioritization process for both early- and late-stage translational research. Other report recommendations focused on prioritizing translational research activities at NCI, providing better project management of translational research activities, establishing enhanced bio-specimen repositories and analytical methods, and ensuring the provision of training and career incentives for early translational research.
TABLE A-2 Summary of TRWG Recommendations and Implementation Status
Category |
Specific Recommendations |
Implementation Status |
Coordinated management |
• Establish a flexible, integrated organizational approach that coordinates early translational research across NCI. |
• Expansion of CTAC to include translational research expertise; expansion of the Clinical Trials Operations Committee (and name change to Clinical Trials and Translational Research Operations Committee) to include translational research responsibilities; expansion of Coordinating Center for Clinical Trials to include Translational Research Support Team |
• Designate a specific portion of the NCI budget for early translational research. |
|
|
• Develop a set of award codes that accurately capture the nature and scope of the early translational research portfolio. |
• Pilot project with NCI’s Division of Extramural Activities to code grants for translational research on the basis of the TRWG pathways; comparison with principal investigator’s assessment of projects to look for consistency and interpretation of pathways |
|
• Establish a distinctive prioritization process for early translational research. |
• Two-day NCI translational science meeting (NCI Translates) held in November 2008 and 2009 to explore potential of translational research prioritization and acceleration, as recommended by the TRWG report |
|
|
• Pilot project to prioritize cancer antigens within the immune response modifier pathway; project expanded to prioritize translational research opportunities within the immune response modifier pathway |
Category |
Specific Recommendations |
Implementation Status |
Tailored funding programs |
• Modify multiproject collaborative award guidelines, as appropriate, to facilitate early translational research. |
• CTAC Coordination Subcommittee Guideline Harmonization Working Group mission: promote collaborative team science and ensure that guidelines for different clinical trials funding mechanisms are aligned, eliminate redundancy and duplication while proactively encouraging collaboration, harmonize program guidelines and develop incentives to foster collaboration among all components of the clinical trials infrastructure, including cancer centers, Specialized Programs of Research Excellence, and Cooperative Groups |
• Improve processes and mechanisms for funding investigator-initiated early translational research. |
|
|
• Establish a special translational research acceleration project (STRAP) to advance prioritized early translational research opportunities. |
• Pilot project to establish a STRAP for the immune response modifier pathway |
|
• Establish a funding program for early translational research that requires academia and industry collaboration involving resource sharing or cofunding. |
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|
• Integrate access to manufacturing and other preclinical development services according to good manufacturing practices and good laboratory practices more effectively with milestone-driven early translational research projects. |
• Development of the NCI Experimental Therapeutics Program, a new drug discovery and development pipeline that can partner with researchers to bring new cancer treatments to patients |
Operational effectiveness |
• Establish a formal project management system for early translational research. |
• New Project Management Office established within the NCI Division of Cancer Treatment and Diagnosis |
• Establish a system to coordinate core services essential for early translational research. |
• CTAC Coordination Subcommittee is developing criteria for regional cores and guidelines to encourage sharing and reduce redundancy |
|
• Enhance quality and accessibility of annotated biospecimen repositories and associated analytical methods. |
• Enhancement of NCI’s Office of Biorepositories and Biospecimen Research |
|
• Develop enhanced approaches for negotiation of intellectual property agreements and agent access. |
• NCI and the Life Sciences Consortium of the CEO Roundtable on Cancer have jointly developed a set of common clauses, the Standard Terms of Agreement for Research Trial clauses, that are accessible for use by any party initiating a trial. These standard clauses provide common language for use as a starting point in the contract agreements that govern clinical trials. |
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• Enhance interactions and collaborations with foundations and advocacy groups to advance early translational research. |
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• Enhance training and career incentives for early translational research. |
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SOURCES: Cheever et al., 2009; Clinical Trials Advisory Committee, 2008; Hawk et al., 2008b; NCI, 2007. |
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