Generating New Ideas

Broadening Access for Physicians and Patients

Educating & Communicating

Streamlining Procedures

Automating Data Systems

Further Information

Clinical Trials Plan Generating New Ideas Broadening Access for Physicians and Patients Educating & Communicating Forming Partnerships-- Collaborations with Advocacy and Voluntary Groups Forming Partnerships with Industry Forming Partnerships with Payers and Providers Streamlining Procedures Automating Data Systems

Cancer Clinical Trials - Building a New National System

A fundamental change is under way in how the National Cancer Institute (NCI) develops, reviews, conducts, and supports clinical trials.

The revitalized system is more flexible and more inclusive, inviting input from basic and clinical researchers, community and research oncologists, patients and families, and all groups with a commitment to improving cancer care.

The new system will speed new ideas from lab to clinic, increase physician and patient participation, and streamline administration and data reporting.

Several pilot projects are under way, and several more will soon be launched. Like a puzzle, each piece is equally important, and each piece interconnects with the others.

The NCI's efforts to build the new clinical trials system fall into five categories: generating new ideas, broadening access for physicians and patients, educating and communicating, streamlining procedures, and automating data systems.

Why Revamp?

The overall goal of the new system is to accelerate the pace of clinical research, and therefore rapidly answer important research questions.

Increasing the number of patients on clinical trials is essential. While 20,000 cancer patients take part in NCI-sponsored clinical studies each year, many patients who would be eligible never have the opportunity and most do not know that a clinical trial may be a treatment option for them. In addition, barriers prevent many physicians from participating in clinical research. In the new system any qualified oncologist in the U.S. will be able to offer patients NCI-sponsored clinical trials.

For physicians who already participate in trials, paperwork and procedural workloads are being reduced by standardizing data collection and by online reporting systems. The process of informed consent is being simplified and projects are underway to centralize the Institutional Review Board (IRB) process.

To assure that promising treatment ideas move quickly from the lab into the clinic, the NCI is committed to stimulating and funding innovative approaches. New meeting forums are bringing together basic and clinical scientists from academia and industry, thus expanding the pool of research ideas, and a new scientific review process has been designed to ensure that the best ideas are evaluated in clinical trials.

Through these and other changes, the NCI and its partners will be able to streamline the national clinical trials system, which in turn will improve cancer care for everyone.

Background Information

Report of the National Cancer Institute Clinical Trials Program Review Group ¹--Also known as the Armitage Report, this 1997 report from the NCI's Clinical Trials Program Review Group launched the planning for the new clinical trials system. Dr. James O. Armitage from the University of Nebraska served as the group's chair.

Clinical Trials Implementation Committee ²--This committee translated the Armitage Report's recommendations into a working plan. It was co-chaired by Dr. John Glick of the University of Pennsylvania and Dr. Michaele C. Christian of the NCI.

Generating New Ideas

Recognizing the need to be more responsive to suggestions from all groups with an investment in clinical trials, the new system provides avenues for ideas from an array of academic and industry-related basic and clinical researchers. The goal is to speed the best ideas from the laboratory into the clinic through the clinical trials system. New meetings and review processes will allow wider collaboration and provide streamlined approval for the most promising trial concepts.

State-of-the-Science (SOTS) Meetings ³

The traditional source of ideas for new clinical trials has been the NCI-sponsored Clinical Trials Cooperative Groups. The SOTS meetings augment this approach by adding clinical and basic scientists from outside the Cooperative Groups, along with industry and patient advocate representatives. The goal is to have both Cooperative Group and non-Group leaders discuss and debate obstacles to translating basic research into clinical practice and the resulting implications for the eventual design of phase III trials.

• Using a workshop format, the SOTS meetings invite a dialogue among researchers, clinicians and patient advocates to address key questions.
• Recommendations from the meetings are disseminated widely to the scientific community and interested public via a Web-based audio-visual presentation.
• Slides, presentations and discussions from these meetings can be accessed at the SOTS Web site ³.

Rapid Access to Intervention Development ⁴ (RAID)

Recognizing that most academic institutions cannot support the long list of tasks involved in the pre-clinical development of drugs and biologics, the NCI has set up RAID to provide funds and expertise for researchers working with promising new agents. Researchers who win RAID grants will receive help with tasks (such as toxicology screening, assay development, and dose optimization) to show "proof-of-principle" of the agents' anti-cancer potential.

• RAID helps academic institutions bridge the gap between discovery and clinical testing in phase I and phase II trials, speeding entry of promising discoveries into the clinic.
• The program provides funds and expertise to assist researchers needing help with a few specific tasks or with the entire new drug application process.
• RAID also serves as a model for the development of similar initiatives, such as Rapid Access to Preventive Intervention Development ⁵ (RAPID), which is directed toward prevention agents.

Quick Trials for Novel Cancer Therapies ⁶

Quick Trials is a new initiative that NCI developed to provide support for investigator inititated trials and patient monitoring. This initiative uses the exploratory/developmental grants (R21) mechanism and it also has shortened the time from submission to funding to approximately five months. NCI supports early clinical trials testing of new theraputic approaches and agents through a variety of funding mechanisms. This includes support for phtase 1 and 2 cooperative agreements and plans for phase 2 contracts (FY01) to test NCI-sponsored agents.

Clinical Oncology Special Emphasis Panel (SEP) ⁷

The Clinical Oncology SEP provides the clinical oncology community with its own National Institutes of Health (NIH) study section. All phase I, II, and III clinical trials can be reviewed, as can translational research linked to a clinical trial.

Correlative Science Studies

Additional NCI funding is now available for clinical correlative science studies. The goal is to deepen the understanding of the relationship between tumor characteristics and clinical outcomes, including responses to specific therapies. Investigators can apply to work with clinical material from Cooperative Group studies. In addition, the Cooperative Groups will be provided with developmental funds to support the generation of pilot correlative studies (R01 and R21 applications). online resources include:

• Funding opportunities such as Exploratory Studies in Cancer Diagnostics ⁸ ; Exploratory Grants for Correlative Studies and Clinical Trials ⁹; and Correlative Studies Using Specimens from Multi-Institutional Treatment Trials ⁹.
• A list of specimen resources that gives researchers access to human tissues ¹⁰.
• The NCI Tissue Expediter ¹¹.
• The NCI Clinical Trials Cooperative Group Human Tissue Resources ¹².
• The AIDS and Cancer Specimen Bank (ACSB) ¹³.

Broadening Access for Physicians and Patients

Each year, thousands of physicians enroll approximately 20,000 patients in NCI-sponsored clinical treatment trials. However, the large phase III studies can take 4 years or longer to accrue patients, delaying answers to important treatment questions. The new system will speed completion of studies and increase clinical trials access for both physicians and patients.

National Network of Physician Partners

Eventually, any interested, qualified physician--whether at a small community clinic, HMO, or large academic hospital--will have access to a broad range of NCI-sponsored clinical trials via the Cancer Trials Support Unit (CTSU). This nationwide network will increase the number of oncologists participating in clinical trials. Patients will benefit by having a broader range of clinical trials available through their local oncologist compared to what can be found currently.

• Patient enrollment and data entry will be streamlined and online, via the CTSU ¹⁴.
• A Web-based menu of open studies via the CTSU will simplify the search process, reducing the time it takes physicians to find appropriate clinical trials for their patients.
• Complete protocol information, in language appropriate for both patients and physicians, will be linked to the CTSU. This information will help both physicians and patients make informed decisions about participating in clinical trials.
• Initially, Cooperative Group members will belong to the Network and will co-develop the informatics systems. Expansion is planned to non-Group members once the CTSU systems are tested.

Special Populations Networks ¹⁵

The SPN is a new $60 million program addressing the unequal burden of cancer within certain special population groups. The networks are intended to build relationships between large research institutions and community-based programs. In addition to other key activities, these cooperative relationships will be used to foster cancer awareness, including support for minority enrollment in clinical trials.

• By encouraging minority participation in clinical trials, the NCI hopes to understand why cancer disproportionately affects special populations.
• Ongoing NCI efforts have raised the proportion of minority participation in treatment clinical trials to nearly 20 percent.

Physician Communication Module (PCM)

The NCI's Cancer Therapy Evaluation Program (CTEP) and Howard University Cancer Center (HUCC) have expanded their collaborative effort to involve underrepresented populations in clinical trials and to broaden access to patients and physicians who have not previously participated in clinical trials.

• HUCC is participating in the Expanded Participation Project (EPP), utilizing a point-of-care technology called iKnowChart (iKC), software that provides clinical trial management.
• HUCC staff enter characteristics of patients whom they see in practice into the system, and iKC returns information on NCI EPP trials for which the patient might be eligible. Physicians can utilize iKC to work-up the patient for full inclusion/exclusion, enrollment, and follow-up.
• Last year CTEP extended the PCM to include Meharry Medical College (MMC), part of the Meharry-Vanderbilt Alliance and the MMC/Vanderbilt-Ingram Cancer Center (VICC) Partnership.
• MMC is also participating in the EPP, utilizing iKC to increase the research activities at Meharry, increase the accrual of minority patients to NCI clinical trials, and substantially further NCI's informatics initiatives.

Educating & Communicating

In addition to an improved clinical trials program, it is essential that physicians and patients are aware of the value of trials and know how to access the system. As part of the new national system, an extensive set of communication programs will deliver tailored information about clinical trials, including Web-based education for health professionals and patients.

Cancer.gov ¹⁶

The National Cancer Institute's Web site provides online access to cancer information for patients and physicians, and serves as the primary cyber-gateway to all of the NCI's programs and divisions. Included are peer-reviewed state-of-the-art summaries on treatment, screening, prevention, supportive care, genetics, and complementary and alternative medicine, as well as NCI's searchable clinical trials database. The Web site also provides contextual information about clinical trials and integrates related resources for patients and physicians. This information will be increasingly important as the clinical trials program evolves and more people participate.

• The site offers extensive information about the "what and how" of clinical trials participation, including a discussion of the patient protections that are in place.
• Timely reports about clinical research advances and features about new areas of clinical investigation are linked to the NCI's cancer information system.
• The site houses information on 1,800 active clinical trials and an archive of 11,000 closed trials, many of which are linked to their resulting publications.
• Cancer information summaries and clinical trial abstracts are available in patient and health professional versions.
• Improvements in search capabilities have made clinical trials abstracts easier to find.

Cancer Information Service (CIS) ¹⁷

The NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) assists cancer patients and their families with the latest, most accurate information in English and Spanish. CIS staff can assist callers in locating clinical trials, treatment centers and local resources.

Education Programs

An immediate way to increase awareness of the importance of clinical trials is through health professionals who have direct contact with patients, patient advocates and the public. A new clinical trials education series is scheduled for fall 2001. The first program in the clinical trials series focuses on the basics of clinical trials education for the interested public and is written in lay language. The second program focuses on educating primary physicians, specialty physicians and nurse practitioners. The third program focuses on outreach opportunities for the interested public and cancer-related organizations. This series will inform the learner about:

• Understanding clinical trials.
• Ensuring protection for patients in clinical trials.
• Participating in clinical trials.
• Communicating information about clinical trials.

A Web-based program, Human Participant Protections Education for Research Teams ¹⁸, provides information about the rights and welfare of human participants in research, and enables physicians, biomedical and behavioral researchers, nurses and data managers to:

• Learn with interactive modules, case studies and exercises.
• Satisfy NIH requirements for obtaining federal research funds.
• Receive continuing medical education (CME) credit or contact hours.
• The program is located at: http://cme.nci.nih.gov.

As these programs become available, information will be posted on NCI's Web site, http://cancer.gov.

New Training Grants ¹⁹

Training the next generation of clinical researchers is vital to the ongoing success of the national cancer clinical trials program. The NCI provides a continuum of opportunities as individuals proceed through career tracks. New sources of training money include:

• Institution-based predoctoral and postdoctoral mentoring programs (K12).
• Individual postdoctoral mentoring programs (K23).
• Junior faculty transition awards to support researchers during the crucial transition from mentored to independent status (K22).
• Programs for established researchers (K24).
• Enhancements to the Comprehensive Minority Biomedical Branch ²⁰ (CMBB) address the particular needs of minority trainees.

Forming Partnerships

The clinical trials system is linked to government agencies, public and private organizations, institutions, and health care plans and providers committed to cancer research and cancer care. Partner organizations include:

• Advocacy and Voluntary Groups.
• Industry.
• Payers and Providers.

• Director's Consumer Liaison Group (DCLG) ²¹. As NCI's all-consumer advisory body, the Director's Consumer Liaison Group makes recommendations to the Director of NCI from the consumer advocate perspective on a wide variety of issues, programs, and research priorities.
• Office of Liaison Activities (OLA) ²². NCI's Liaison Activities supports the Institute's research and related programs by fostering strong communications and relationships with the cancer advocacy community, professional societies, scientific organizations and federal agencies.
• The Cancer Information Service Partnership Program ²³ works with organizations that reach minority and medically underserved audiences that have limited access to health information and services to increase the public's awareness of and understanding about cancer. The Cancer Information Service can be reached at 1-800-4-CANCER (1-800-422-6237).
• Consumer Advocates in Research and Related Activities (CARRA) ²⁴ is a new NCI program designed to increase the involvement of people affected by cancer in NCI activities, including clinical trials
• A community-based pilot project, "Cancer Trials...Because Lives Depend on It," tested a new approach to clinical trials accrual in 2000-2001. Partner organizations recruited community leaders who attended training programs and encouraged their communities to consider participating in clinical trials. Evaluation is ongoing. In addition, NCI is developing a new series of clinical trial education and outreach materials based on the lessons learned in the pilot campaign. Materials will be available in fall 2001.

• The Office of Technology and Industrial Relations ²⁵ encourages research and development of new technologies, and promotes and facilitates collaborations between the NCI and the private sector.
• The Technology Transfer Branch ²⁶ facilitates collaborative efforts between the NCI and the private sector by negotiating technology transfer agreements, such as Cooperative Research and Development Agreements (CRADAs). These agreements contribute to the commercialization and distribution of federally-developed technologies.
• The Developmental Therapeutics Program ²⁷ evaluates new agents, many from private companies, at the pre-clinical level.
• The Cancer Therapy Evaluation Program ²⁸ assists industry collaborators with the clinical development of new drugs.

• Centers for Medicare & Medicaid Services (CMS) ²⁹, through its Medicare program ³⁰, now reimburses providers for the cost of routine patient care associated with beneficiaries' participation in clinical trials.
• An agreement between United Health Care and the Coalition of National Cancer Cooperative Groups, Inc. ³¹, which covers costs for medical care in multi -institutional clinical trials.
• Studies on the patient care costs ³² for clinical trials participants. These have shown that costs for patients on clinical trials are comparable to those receiving standard treatment. This information is pivotal in encouraging more health plans to help pay for clinical trials.
• For more information on these initiatives, contact the Office of Education and Special Initiatives at cancertrials-r@mail.nih.gov.

Streamlining Procedures

Among the barriers to physician participation in clinical trials are the time-consuming tasks of constructing protocols, having them reviewed, and enrolling patients. One of the goals of the new system is to provide tools that will simplify these tasks and at the same time improve the quality of the research.

Cancer Trials Support Unit (CTSU) ¹⁴

The CTSU is designed to streamline and centralize many administrative, financial, and data collection tasks associated with clinical trials. The CTSU will provide participating physicians with a single access point to the NCI's entire phase III clinical trials system, facilitating access to protocols, training, and educational information. Highlights of the fully developed system will include:

• Cross-Group registration of patients. Physicians can register patients on adult Cooperative Group trials in lung, genitourinary, colorectal, and breast cancers and leukemia, even if they are not members of the Group conducting the trial.
• Online patient registration, eligibility assessment, and reporting of data that will use a common format and state-of-the-art data management systems.
• A coordinated auditing system that will eliminate multiple quality assurance audits for research personnel participating in more than one Cooperative Group.
• Centralization of administrative tasks, including credentialing and verification of Institutional Review Board approval for all investigators participating in the Cooperative Groups and the CTSU.
• The CTSU opened in July, 2000, for Cooperative Group members. If the initial experience is successful, oncologists not affiliated with a Group will be encouraged to participate as well.

Informed Consent ³³

New recommendations for informed consent documents have been developed to improve patients' understanding of cancer clinical trial participation. The recommendations were developed by a group that included research physicians and nurses, patient advocates, IRB members, communications and legal experts, ethicists, representatives of the pharmaceutical industry, as well as the staff of the NIH and the FDA. The guidelines package includes:

• Specific recommendations for information to be included in informed consent documents for cancer clinical research.
• A guide for the provision of supplemental materials.
• A template form that investigators can use to develop informed consent documents.
• Sample completed informed consent documents using the template.

Central Institutional Review Board (IRB)

In the case of multi-center studies, each local IRB--these can number in the dozens or hundreds--must review and approve the same protocol. To reduce this burden, the NCI and the Office of Human Research Protections (OHRP) are jointly undertaking a pilot project to develop a centralized model of human subjects protection for cancer patients participating in multi-center clinical trials. This pilot involves the establishment of an NCI central IRB (CIRB) working in tandem with local IRBs to protect human subjects.

• During 2000, NCI appointed a diverse and expert group of consumer advocates, ethicists, oncology professionals and others to serve as CIRB members, and also enlisted the participation of 22 local IRBs into the pilot. SOPs were developed. OHRP and NCI signed a Cooperative Project Assurance.
• The CIRB began reviewing protocols in January 2001. Plans are underway to expand both the menu of protocols for CIRB review and the number of sites participating in the pilot.
• For more information, e-mail: goldbergj@mail.nih.gov.

Protocol Assembly ³⁴

The NCI has created a series of electronic forms, templates, and databases to make it easier for investigators to submit and develop ideas for protocols and streamline the review process. Some of these serve investigators directly by eliminating paperwork and speeding up the protocol development process. Others help the NCI staff track information about trials and contribute to the overall efficiency of protocol management. Resources available for investigators include:

• A template for a letter of intent for phase I or II trials.
• A template for submitting a concept for a phase III trial.
• A template to guide the writing of protocols.

Clinical Trials Monitoring Branch Audit Information System (CTMBAIS)

Implemented in January 1999, CTMBAIS is a Web-based information system which permits online submission of all data collected during quality assurance audits of NCI-sponsored Cooperative Group clinical trials. The system links the Cooperative Groups, CTMB, and the Clinical Trials Monitoring Service to coordinate audit-related activities. It includes:

• Maintenance of comprehensive membership rosters for each Cooperative Group.
• Submission of audit schedules.
• Acknowledgment of preliminary audit reports and transmission of final reports.
• Tracking and follow-up of responses to audit findings.
• For more information, e-mail: ncictephelp@ctep.nci.nih.gov.

Automating Data Systems

One of the major goals of the new clinical trials framework is to construct an informatics system that will reduce the extensive paperwork often associated with clinical trials. Electronic data systems now make it easier for clinical researchers to record and report data and adverse events.

Common Toxicity Criteria (CTC) ³⁵

The CTC is a standard language for reporting adverse events occurring in cancer clinical trials. Developed in 1984, the CTC was revised in 1998 to improve the comprehensiveness and accuracy of reporting and to standardize reporting across the Cooperative Groups and therapeutic modalities. CTC Version 2.0 was initially implemented for NCI treatment trials begun on and after March 5, 1998. It has been adopted by other organizations, including the EORTC and pharmaceutical companies. It includes:

• Mapping of adverse event names to preferred terms in MedDRA (Medical Dictionary for Drug Regulatory Reporting), the standard language for drug regulatory reporting globally.
• A Web-based interactive application for identifying and grading events electronically, creating reports, and saving them in local databases.
• An index with cross references to other medical and lay terms.
• Mapping of the original CTC to version 2.0.
• A user's manual and a Web-based tutorial.

Adverse Event Expedited Reporting System (AdEERs) ³⁶

AdEERS is a Web-based system designed to allow Cooperative Groups, Cancer Centers, and single institutions to submit expedited reports for serious and/or unexpected events to the NCI for all trials using an NCI-sponsored investigational agent. AdEERS is integrated with existing CTEP applications, including the CDUS and the CTC, to promote data reuse. It includes:

• Lists of values for adverse event terms, disease names, prior therapies, and pre-existing conditions, mapped to MedDRA (Medical Dictionary for Drug Regulatory Reporting), the standard language for drug regulatory reporting globally.
• Links to the NCI guidelines for reporting adverse events and the Agent Specific Adverse Event List.
• Interactive Computer Based Training (CBT) designed to assist users in the completion of an actual report, with simultaneous access to the CBT and AdEERS.

Clinical Data Update System (CDUS) ³⁷

The CDUS is the primary data reporting mechanism for all NCI-sponsored clinical trials. It was developed with the goals of standardizing and streamlining data reporting and reducing the administrative burden of cancer research. Benefits include:

• Elimination of duplicate reporting mechanisms and other annual reports required by the NCI.
• Integration with other NCI databases, reducing investigators' data entry burden.
• Revision and validation of NCI and Group databases (e.g., protocol numbers and status).
• Immediate and automated error checking.
• Rapid transactions allowing investigators to find source data and make corrections before the data matures.

Common Data Elements (CDE) ³⁸

CDEs are terms that medical providers may use to collect and report patient information for clinical trials. The purpose of the CDE Dictionary is to promote a common nomenclature and vocabulary across various organizations performing cancer research. This project is a continuing collaborative effort between the NCI and partners who represent a variety of clinical and basic science disciplines. At present, the CDE Dictionary:

• Includes an extensive listing of data elements that could be required by a cancer treatment trial for lung, breast, prostate, and colorectal cancers.
• Contains a repository of detailed information pertaining to each standard element for clinical trial data collection.
• Offers templates of case report forms that can be used to create forms that are specific to a protocol.
• Evolves as new terms for additional cancers are identified and defined.

Further Information

The Web sites listed below lead to various components of the New National System for Cancer Clinical Trials.

Clinical Trials Plan

Armitage Report ³⁹ -- Launched plans for the new system.
Clinical Trials Implementation Committee ² -- The NCI committee that molded the Armitage Report into a working plan.

Generating New Ideas

State of the Science Meetings (SOTS) ³
Rapid Access to Intervention Development (RAID) ⁴
Rapid Access to Preventive Intervention Development (RAPID) ⁵
Quick Trials for Novel Cancer Therapies ⁴⁰
Clinical Oncology Special Emphasis Panel ⁷
Correlative Science Studies--Description of funding opportunities. ⁴¹
List of projects that give researchers access to human tissue ¹⁰
The AIDS and Cancer Specimen Bank (ACSB) ¹³
Cooperative Human Tissue Network ¹²

Broadening Access for Physicians and Patients

Special Populations Networks ¹⁵

Educating & Communicating

Cancer.gov ⁴² -- NCI's Web site includes general cancer information, clinical trials background and information, and links to many other NCI resources and programs.
Cancer Information Service (CIS) ¹⁷ -- Personalized information for patients 1-800-4-CANCER (1-800-422-6237).
New Training Grants ¹⁹ -- Overview of programs and links to information on how to apply.

Forming Partnerships--Collaborations with Advocacy and Voluntary Groups

Director's Consumer Liaison Group (DCLG) ²¹ -- Advises the NCI Director.
Cancer Information Service Partnership Program ²³

Forming Partnerships with Industry

Technology Transfer Branch (TTB) ²⁶
Office of Technology and Industrial Relations (OTIR) ²⁵
Developmental Therapeutics Program (DTP) ²⁷
Cancer Therapy Evaluation Program (CTEP) ²⁸

Forming Partnerships with Payers and Providers

Medicare coverage for clinical trials. ⁴³
The Department of Defense ⁴⁴ Cancer Clinical Trials Agreement with the NCI.
The NCI and the Department of Veterans Affairs ⁴⁵ Clinical Trials Agreement.
Agreements between United Health Care and the Coalition of National Cancer Cooperative Groups, Inc. ³¹ provide access to cancer clinical trials.
Summaries of studies on costs of clinical trials ⁴⁶
For more information on these initiatives, contact the Office of Education and Special Initiatives, e-mail: cancertrials-r@mail.nih.gov

Streamlining Procedures

Cancer Trials Support Unit (CTSU) ¹⁴
Simplification of Informed Consent Documents ⁴⁷
Central Institutional Review Board (CIRB) e-mail: goldbergj@mail.nih.gov
Protocol Assembly Forms and Procedures ⁴⁸

Automating Data Systems

Common Toxicity Criteria (CTC) ³⁵
Adverse Event Expedited Reporting System (AdEERs) ³⁶
Clinical Data Update System (CDUS) ³⁷
Common Data Elements (CDE) ³⁸