MAJOR ONGOING INITIATIVES

Improving the Clinical Trials System

CTEP has undertaken several new projects in response to the recommendations of the Clinical Trials Working Group (http://transformingtrials.cancer.gov/) and some were funded, at least in part, by the American Reinvestment and Recovery Act (ARRA) http://www.cancer.gov/aboutnci/recovery.

• Project to Accelerate Therapeutics Development
• Increasing the Transparency and Expertise of the CTEP Review Process by Engaging External Scientists and Advocates in the Review of All Concepts for Phase 3 Trials
• Expanding Access to Clinical Trials through Continued Growth of the Cancer Trials Support Unit
• Central Institutional Review Boards
• Continuing Improvement of the Informatics Infrastructure

Project to Accelerate Therapeutics Development

• Accelerating Clinical Trials of Novel Oncologic Path Ways
• Re-engineering Protocol Implementation and Development

Accelerating Clinical Trials of Novel Oncologic PathWays

This program, abbreviated ACTNOW, focuses on accelerating progress by speeding the development of 37 new clinical treatment and imaging trials. These trials are testing novel agents (alone, in combination, and with other standard therapies) that target new pathways by which cancer cells grow, metastasize and develop resistance to current treatments. The selected trials have received enhanced resources to enable rapid development and approval of the treatment protocol, such that, 90 days from notification of the award, the trials were either open to enrollment or in review at the local institutional review board (IRB). This timeline is significantly faster than is typically attained using NCI’s standard approach to trial development. This accelerated timeline is possible due to the resources provided by ARRA. These resources allowed more staff to be hired and devoted to protocol writing and statistical plans, and increased personnel available for database and case report form development. This set of trials is also greatly enhanced by ARRA funding, which permits the use of innovative diagnostic scans, specimen sample collection and assay development, and adequate reimbursement for the research costs associated with data management at local sites. http://www.cancer.gov/aboutnci/recovery/recoveryfunding/actnow

Re-engineering Protocol Implementation and Development:

This ARRA initiative, also known as RaPID, is designed to decrease the time it takes to go from conception of a clinical trial to approval by NCI and subsequent activation for patient enrollment. Cooperative Groups, NCI-supported Cancer Centers, and CTEP are working collaboratively to streamline processes and leverage technology to cut the time to protocol approval by half or more. The ARRA funds have permitted the Cooperative Groups and CTEP to hire trial development coordinators who can help the medical staff focus their efforts on meeting the timelines.

Increasing the Transparency and Expertise of the CTEP Review Process by Engaging External Scientists and Advocates in the Review of All Concepts for Phase 3 Trials

The Clinical Trials Working Group (CTWG), established in 2004 to advise on ways to restructure the NCI clinical trials enterprise, recommended that an open and transparent process for the design and prioritization of clinical trials be established. In response to that recommendation, a network of disease-specific Scientific Steering Committees was established to evaluate the design and prioritization of phase 3 trials and large, phase 2 clinical trials. The Scientific Steering Committees (SSC) (http://transformingtrials.cancer.gov/steering/overview) are composed of leading cancer experts and advocates from outside the NCI as well as NCI senior investigators, including representative from CTEP. This process leverages current Intergroup, Cooperative Group, SPORE, and Cancer Center structures and involves representation from the broad oncology community. Disease-specific Scientific Steering Committees have now been established for 12 types of cancer.

Current Disease-Specific Steering Committees

Other Scientific Steering Committees have also been established that focus on clinical imaging, symptom management and quality of life, and patient advocacy.

Expanding Access to Clinical Trials through Continued Growth of the Cancer Trials Support Unit

www.ctsu.org

• Incorporating the Children’s Oncology Group (COG) into the Cancer Trials Support Unit (CTSU) provides regulatory and administrative support for all COG and COG phase 1 consortia trials

• Addressing adolescent/young-adult (AYA) disparities by supporting COG and adult group collaborations

• Accruing over 51,000 patients to trials on CTSU menu

• Expanding CTSU Support Beyond NCI Cooperative Groups to Include other NCI/NIH Programs
  • National Hearth Lung and Blood Institute: two active trials for the Bone and Marrow Transplant Clinical Trials Network

  • Phase 2 studies involving CTEP-sponsored cancer centers: 7 active trials, 1 in development

  • Division of Cancer Prevention cancer control trials: 8 active trials, 7 trials closed to patient accrual, and 2 trials in development

• Novel collaborations: NCI Phase 2 Contractors; AIDS Malignancy Consortium; Adult Brain Tumor Consortium; International Breast Cancer Study Group; US Military Cancer Institute; Bone and Marrow Transplant Clinical Trials Network

Central Institutional Review Boards

Streamlining processes for review of human subjects protection for clinical trials by developing Central Institutional Review Boards (CIRBs) that facilitate communication with local IRBs in multi-center cancer trials.

CIRB Initiative: The CIRB provides an innovative approach to human subjects protection through a facilitated review process that streamlines local IRB review of adult and pediatric national multi-center cancer treatment trials. The initiative consists of two CIRBs, one for adult trials and one for pediatric trials. The adult CIRB reviews all phase 3 adult Cooperative Group studies. The pediatric CIRB reviews all Children’s Oncology Group phase 2, phase 3, and pilot studies. Under this model, the CIRB conducts full board review of a new study; a local IRB chair or an IRB subcommittee at participating institutions reviews CIRB materials for local context; and if approved, the CIRB becomes the IRB of record for the life of that study. (www.ncicirb.org)

Continuing improvement of the informatics infrastructure that supports clinical trials by continuing development of clinical trials standards, including the common toxicity criteria and common data elements, and by the development and implementation of a remote data capture system for the collection of clinical trial data

• ADOPTion of New Technologies for Remote Data Capture and Protocol Authoring (ADOPT)
• Participation in ADOPT Sub-tasks

ADOPTion of New Technologies for Remote Data Capture and Protocol Authoring (ADOPT)

To rapidly bridge the gap between the expanding array of preclinical opportunities and the existing approaches to patient care, increased attention must be devoted to the numerous processes underlying clinical trial development and management. Significant groundwork has been laid to reconfigure the NCI trials infrastructure. For these initiatives to achieve their full potential, NCI and the extramural clinical investigator community must now direct their attention and energies to improving the process by which clinical trials are developed and conducted if the goal of more rapid progress against cancer is to be realized. In keeping with both the numerous stakeholders involved and the complexities of the various processes, NCI is proposing a multi-pronged approach to address the barriers that must be overcome if clinical trials are to provide patients the answers they so desperately need. These initiatives include the integration of standardized information-technology (IT) tools or operational processes for:

• electronic Protocol Authoring (ePA)
• electronic Case Report Forms (eCRF)
• Clinical Data Management System (CDMS)

electronic Protocol Authoring (ePA)

The ePA project goal is to streamline the clinical trial development process and broaden investigator participation on clinical trials through provision of a Commercial off the Shelf (COTS) protocol authoring package. This task has been broken into phases (requirements gathering, COTS analysis, selection, procurement, integration and implementation); to assure project success. As of the spring 2011, the ePA vision document and project plan, business and technical requirements, and architecture design are complete. The NCI posted a Request for Information (RFI) to validate and reassess the ePA requirements. A project plan for potential procurement and deployment of an ePA tool is in development.

electronic Case Report Forms (eCRF)

This program will include implementation of a core library of standardized phase 2 and 3 eCRF modules currently being developed by NCI to enhance data collection efficiency and to accelerate the cancer clinical trial development process used by CTEP’s trial mechanisms/networks. The purpose of this ADOPT sub-initiative is to integrate all of the NCI developed eCRF modules into the IT systems and business practices of CTEP, Cooperative Groups, Consortia, and the CTSU. Although the ADOPT eCRF initiative will incorporate all NCI developed eCRF modules, there are two specific subcomponents that will require specific attention:

• Oncology Patient Enrollment Network (OPEN) — OPEN is the CTSU portal for sites to register and enroll trial participants and shall be expanded in functionality and purpose to more broadly support NCI clinical trials. OPEN is being utilized by all of the adult Cooperative Groups for trials activated after Jan 1, 2011. In addition several groups have elected to use OPEN for many of their trials that were activated prior to that date. Finally, OPEN is being utilized to support patient registration for several non-cooperative Group trials.

• Common Terminology Criteria for Adverse Events (CTCAE) — The CTCAE will be reviewed and updated on a periodic basis to assure that safety data remains consistent with the current state of the science. The CTCAE will be monitored, maintained and updated by the NCI through separate (non-ADOPT) mechanisms. Through ADOPT, Groups and Consortia will develop best practices to assure IT systems, protocols and business operations remain current with the latest CTCAE version. As of the fall 2011, all CTEP trials have been converted and harmonized to use the latest version of the CTCAE.

Clinical Data Management System (CDMS)

To strengthen the infrastructure of its clinical trial networks, NCI has purchased licensing rights for a commercial Clinical Data Management System (CDMS) software product that allows for remote electronic data capture, along with the related installation, support, and maintenance services, to support the conduct of cancer clinical research. ADOPT initially focused on generic issues related to the adoption of a common CDMS tool across the NCI infrastructure. Through a separate initiative, NCI is working with its multi-center clinical trial organizations, such as the Cooperative Groups, to deploy a specific CDMS methodology. Currently the multi-center programs use a variety of tools and methodologies to collect, monitor, and assess clinical trial data, which contributes to significant inefficiencies in the clinical trial process. The potential benefits of deploying a common CDMS technology across NCI multi-center programs include improved speed, quality, and security of clinical trial data, reduction in data discrepancies, and access to data in real time for more immediate review of adverse events as well as for interim analyses/review. The Groups began implementing the common CDMS in 2011. It is anticipated that all groups will be utilizing the common CDMS application by the fall 2012.

Participation in ADOPT Sub-tasks

The NCI Cooperative Groups and Consortia will participate in all three ADOPT sub-tasks (ePA, eCRF and CDMS). The Cancer Centers will focus on CDMS activities. Standardization and common infrastructure, provided through ePA, eCRF, and CDMS, will improve the efficiency and effectiveness of NCI clinical trial networks while simultaneously providing an opportunity to reduce clinical trial costs and timelines.

• The Common Toxicity Criteria for Adverse Events (CTCAE)
• CTEP and the Center for Bioinformatics and Information Technology (CBIIT)
• Patient-Reported OutcomesVersion of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

The Common Toxicity Criteria for Adverse Events (CTCAE)

This has been used by CTEP to provide a standardized vocabulary for the reporting of Adverse Event terms. Submission of adverse event information using the CTCAE into the CTEP Enterprise System (CTEP-ESYS) allows for the systematic assessment and analysis of reported events, so CTEP can direct investigators and ensure that patient safety is protected. Version 4 of the CTCAE is Medical Dictionary for Regulatory Activities (MedDRA) compliant, meaning that the CTCAE terms are in sync with the international medical community and serve to enhance the reliability of reported events.

CTEP and the Center for Bioinformatics and Information Technology (CBIIT)

Together these organizations have been working on the Cancer Adverse Event Reporting System (caAERS) which will serve as a tool for the reporting of routine and serious adverse events for all trials funded by the NCI. caAERS is now being piloted within the extramural community to ensure the reporting pathways are accessible by investigators.

Patient-Reported OutcomesVersion of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

The purpose of the PRO-CTCAE project (http://outcomes.cancer.gov/tools/pro-ctcae.html) is to develop an electronic-based system for patient self-reporting of symptom adverse events (AEs) listed in the CTCAE in an effort to improve the accuracy and precision of grading of this class of AEs. CTEP is participating in this project collaboratively as support and oversight for this contract is provided by representatives from NCI's Division of Cancer Control and Population Sciences, Division of Cancer Prevention’s Community Oncology and Prevention Trials Research Group, DCTD, and the Center for Bioinformatics. NCI is working collaboratively with the Food and Drug Administration (FDA) to develop the PRO-CTCAE and to assure that it will be compliant with MedDRA. Next steps include the testing and integration of the PRO-CTCAE system in phase 2 and phase 3 clinical trials.