IOM Goal 1: Improve the speed and efficiency of the design, launch, and conduct of clinical trials

Goal 1 / Recommendation 1: Consolidate Cooperative Group "front-office" operations to strengthen productivity; rank Groups at disease-site committee level and fund based on quality and success of clinical trial concepts, record of developing new investigators, and strength of multidisciplinary focus on disease sites.

Recommendation 1 Progress:

• Engaged in ongoing discussions with the Group Chairs concerning how best to address the IOM recommendation to consolidate to a maximum four adult Cooperative Groups and one pediatric Cooperative Group. This initial presentation to Cooperative Group Chairs is a starting point for discussion about potential consolidation as well as other aspects of transforming the Program.

Goal 1 / Recommendation 2: Consolidate Cooperative Groups’ offices and personnel to improve operational and organizational management in patient registration, data collection and management, case reporting, data queries and reviews, image storage and retrieval, and other "back office" operations.

Recommendation 2 Progress:

• Instituted a comprehensive "back-office" consolidation procedure for the Cooperative Group system that involves a centralized patient registration system for all Cooperative Group treatment trials via the Oncology Patient Enrollment Network (OPEN) under the Cancer Trials Support Unit (CTSU). The CTSU also provides centralized regulatory support for site participation in Group trials.
• Currently working with the Cooperative Groups to institute a single, electronic, clinical trials data management system (CDMS) across the Program. Planning for the CDMA is ongoing, and it is anticipated that new trials will begin to be developed using the new CDMS starting in 2011. The full implementation of a common CDMS will include:
  • Establishment of standard procedures for data collection
  • Development of electronic case report forms that use common data elements
  • Implementation of a common electronic protocol authoring tool
  • Development of a common Group credentialing system for investigators and sites
  • Standardization of key aspects of protocol development across the Group system
• Currently working with the Groups to address standardizing of other key procedures and processes for both operations as well as statistical and data management across the system.
• Implemented Operational Efficiency Working Group (OEWG) recommendations for tracking and metrics related to clinical trial development and activation.
• Created and enhanced the Clinical Trials Reporting Program for registering NCI-supported trials on Clinicaltrials.gov.
• Developed standardized clauses for clinical trial contracts in collaboration with the CEO Roundtable on Cancer.
• Developing new processes to enhance collaboration among Cooperative Groups, NCI, and other stakeholders on trial development.

Goal 1 / Recommendation 3: Coordinate with FDA for trials involving an IND or IDE under a HHS-led transagency effort involving NCI, FDA, and the Office of Human Research Protections (OHPR) to streamline government oversight and regulation of cancer clinical trials.

Recommendation 3 Progress:

• Established an interagency agreement with FDA for early review of approved Cooperative Group Phase 3 treatment trials that are identified as licensing trials, allowing for 21-day review of trial concepts prior to protocol development.
• Developed coordinated protocol development and review processes with the Groups for phase 3 trials developed for FDA's Special Protocol Assessment.
• Coordinated the development of adult and pediatric NCI Central IRBs with the Office for Human Research Protections (OHRP) for Group treatment trials.

Goal 1 / Recommendation 4: Facilitate collaboration among cancer clinical trial stakeholders, including public-private partnerships and precompetitive consortia, and reward innovation leading to increased efficiency.

Recommendation 4 Progress:

• In collaboration with CEO Roundtable on Cancer, developed Standard Terms of Agreement for Research Trials (START) clauses for company and academic collaborations.
• Assessing the feasibility of developing standardized Material and Transfer Agreements (MTAs) that cover Intellectual Property (IP) considerations.
• Working with stakeholders to revise IP option on all CTEP Cooperative Research and Development Agreements relating to drug development and specimen/correlative sciences interactions.

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IOM Goal 2: Incorporate innovative science and trial design into cancer clinical trials

Goal 2 / Recommendation 5: Mandate submission of annotated biospecimens from patients in Cooperative Group trials to high-quality standardized central biorepositories; implement new funding mechanisms and policies to support management and use of those resources for retrospective correlative science.

Recommendation 5 Progress:

• Developed U24 mechanism to support central biorepositories with common/centralized operating procedures for samples collected from patients in Cooperative Group trials.
• Currently working with the Cooperative Groups on consolidating biorepositories to create a public resource within a national banking system that supports NCI-supported clinical trial networks.
• Developed policy to cover intellectual property issues related to biospecimen use and clinical trials for Collaborative Research and Development Agreements (CRADAs).

Goal 2 / Recommendation 6: Lead development and assessment of innovative designs for clinical trials that evaluate cancer therapeutics and biomarkers, including combinations of therapies.

Recommendation 6 Progress:

Worked with the Investigational Drug Steering Committee (IDSC) on evaluation of innovative clinical trial designs as well as other key issues related to cancer therapeutics. See below for examples of some of the recent work in these areas by the IDSC.

• An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics.
  LoRusso PM, Boerner SA, Seymour L. Clin Cancer Res. 2010 Mar 15;16(6):1710-8.
• Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the National Cancer Institute investigational drug steering committee.
  Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin Cancer Res. 2010;16:1726-36.
• Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents.
  Dancey JE, Dobbin KK, Groshen S, Jessup JM, Hruszkewycz AH, Koehler M, Parchment R, Ratain MJ, Shankar LK, Stadler WM, True LD, Gravell A, Grever MR; Biomarkers Task Force of the NCI Investigational Drug Steering Committee. Clin Cancer Res. 2010;16:1745-55.
• Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors
  Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott WJ, Ivy SP, Leier CV, Lindenfeld J, Liu G, Remick SC, Steingart R, Tang WHW. J Natl Cancer Inst, 2010; 102: 596-604.
• Novel designs and end points for phase II clinical trials.
  Adjei AA, Christian M, Ivy P. Clin Cancer Res. 2009; 15:1866-72.
• Randomized Clinical Trials With Biomarkers: Design Issues.
  Freidlin B, McShane LM, Korn EL.  J Natl Cancer Inst 2010; 102: 152-160.
• REporting recommendations for tumor MARKer prognostic studies (REMARK).
  McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM for the Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics.  J Natl Cancer Inst, 2005; 97: 1180-4. (a new version is pending in 2011).
• The design of phase II clinical trials testing cancer therapeutics: consensus recommendations from the clinical trial design task force of the National Cancer Institute investigational drug steering committee.
  Seymour L, Ivy SP, Sargent D, Spriggs D, Baker L, Rubinstein L, Ratain MJ, Le Blanc M, Stewart D, Crowley J, Groshen S, Humphrey JS, West P, Berry D. Clin Cancer Res. 2010; 16:1764-9.

Goal 2 / Recommendation 7: In cooperation with other agencies, develop national unified standards for new technologies, tools, and methods and include consistent operating procedures and updates.

Recommendation 7 Progress:

• Supported development of therapeutic biomarkers for NCI-sponsored clinical trials and instituted the Biomarker, Imaging, and Quality of Life Studies Funding Program (BIQSFP) to ensure that critical biomarkers, imaging and quality of life studies for selected, prioritized clinical trials are incorporated into phase 3 Cooperative Group trials and large, multi-institutional phase 2 Group treatment trials.

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IOM Goal 3: Improve prioritization, selection, support, and completion of cancer clinical trials

Goal 3 / Recommendation 8: Evaluate NCI role in the clinical trials system: file more IND applications for agents to be tested in high-priority trials; support high-priority trials when NCI does not hold IND application; strengthen and streamline peer review process for trial concepts; operate steering committees administered by NCI independently of NCI staff.

Recommendation 8 Progress:

• Implemented the NCI Experimental Therapeutics Program (NexT) to offer a single pipeline to industrial partners and academic researchers who wish to partner with NCI in developing their treatment or diagnostic agents. It is hoped that this program will increase the number of IND agents in the NCI portfolio.
• Revamped the prioritization process for large phase 2 and phase 3 treatment and control trials by creating disease- and modality-specific steering committees to ensure that the most important trials are given highest priority. While NCI has a voice on the steering committees, its primary role is to facilitate the implementation of important trials.
• Convene Clinical Trials Planning meetings to identify critical clinical trial issues for future studies.

Goal 3 / Recommendation 9: Increase the speed, volume, and diversity of patient accrual to ensure high-quality performance at all sites participating in Group trials; use electronic health records to cue physicians about potential trials for patients; encourage eligibility criteria that allow broader patient enrollment in high-priority trials, regardless of where the trial originates; encourage greater participation of patient advocates in trial concept development and accrual planning.

Recommendation 9 Progress:

• Modernizing the clinical trials IT infrastructure by procuring a single clinical trials data management system that can be used across the entire NCI clinical research enterprise.
• Enhancing trial participant diversity through support for Minority-based Community Clinical Oncology Programs, Patient Navigator Research Program, and other NCI programs.
• Working with patient advocates in concept development and accrual planning, along with Cooperative Groups, Disease Steering Committees, and Patient Advocate Steering Committee.

Goal 3 / Recommendation 10: Allocate a larger portion of NCI's research portfolio to the Clinical Trial Cooperative Group Program to ensure sufficient resources to achieve the unique mission of the Program; increase per case reimbursement rate and adequately fund highly ranked trials; reduce number of Cooperative Group trials if adequate funding is not available; and expand role of external advisory boards (e.g., National Cancer Advisory Board and Board of Scientific Advisors) in advising NCI on fund allocation.

Recommendation 10 Progress:

• Although funding for the Cooperative Group has remained fairly stable over the past 10 years, in real dollars this has translated into a decrease in resource availability. NCI has developed some smaller targeted initiatives to try to increase reimbursement to participating sites from $2,000 to $5,000 per enrolled patient for phase 2 studies and additional funding beyond the standard $2,000 per patient for selected phase 3 trials based on their complexity. In addition, funding for critical biomarkers, imaging and quality of life studies incorporated into selected, prioritized clinical trials has been provided through the BIQSFP program.
• Transformation of the clinical trials system will require a comprehensive approach to both funding as well as shared strategic management to maximize resources and enhance collaboration.

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IOM Goal 4: Incentivize the participation of patients and physicians in clinical trials

Goal 4 / Recommendation 11: Work to ensure that clinical investigators have adequate training and mentoring, paid protected research time, necessary resources, and recognition; reward Cooperative Group efforts in Cancer Center Support Grant site visits; fund site and trial principal investigators to cover time to develop and oversee trials; work with a nonprofit foundation to develop a certification program and registry.

Recommendation 11 Progress:

• Working across divisions to harmonize guidelines for clinical trial programs to provide appropriate incentives for collaboration.
• Created a Clinical Investigator Team Leadership Award to promote collaborative science and recognize outstanding clinical investigators.

Goal 4 / Recommendation 12: Lead initiatives to encourage coverage of patient care costs (except for study-related costs paid for by the manufacturer) in NCI-supported clinical trials and work with providers to inform patients about availability, coverage, and value of clinical trials.

Recommendation 12 Progress:

• Worked with Centers for Medicare & Medicaid Services (CMS) to establish pilot program for reimbursement for clinical trials care under a CMS national coverage decision for agents used for colorectal cancer as well as on data collection to evaluate use of imaging and other clinical modalities.
• Participation with NIH and across HHS to help shape national policy on clinical trials reimbursement and to educate patients and payors regarding the benefit of clinical trials.

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