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Ensure that NCI's Clinical Trials Program is poised to address the most important medical and scientific questions in cancer prevention, treatment, and quality of life quickly and effectively through state-of-the-art clinical trials.
NCI-supported clinical trials provide a crucial infrastructure for moving new cancer interventions from the laboratory to studies in people with, or at risk for, cancer and then to the health care setting. These clinical trials have always included investigations of a broad set of interventions -- chemoprevention, chemotherapy, radiation, and surgery -- sometimes used alone and sometimes in combination.
With recent advances in deciphering the molecular changes that cause a cell to become cancerous and then metastasize, a new paradigm of cancer treatment and prevention research is emerging and bringing with it the promise of an exponential growth in effective cancer interventions. Increasingly, new anti-cancer agents are directed at distinct molecular targets within cancer cells, leaving healthy cells unharmed.
NCI currently provides leadership, resources, and expertise at all stages of clinical development for molecularly targeted agents.
- In the early stages of research, when candidate drugs are first identified and shown to have promise, NCI forms collaborations and partnerships that help researchers from public, industrial, and academic settings develop anti-cancer agents for a broader array of tumor types and at a faster pace than would otherwise be possible.
- Partners work together to establish "proof-of-principle" in early clinical trials.
- Then they move rapidly to verify the presence of relevant molecular targets in populations of patients and persons at risk for cancer and to test for improvements in outcomes such as prevention, tumor response, and improved quality-of-life and survival.
- For Phase III trials, NCI provides resources to test promising leads in large numbers of patients.
While much has been accomplished to streamline cancer clinical trials, NCI must further accelerate movement of promising research, discoveries into clinical development and delivery to the public. We must:
- Identify the most important questions in prevention and treatment that can be addressed through clinical trials.
- Create flexible mechanisms that allow for easy collaboration among basic scientists, clinicians, industry, academia, and NCI.
- Explore the use of combinations of molecularly targeted agents for treating cancer by targeting several critical points in cancer-causing molecular pathways. See Targeting Signaling Pathways with Drug Combinations.
- Develop surrogate endpoints to improve the efficiency of small translational trials.
- Identify the most promising treatment or prevention agents for movement into large, easily accessible trials.
- Improve support to physician researchers.
- Improve access to clinical trials by physicians, patients, and those at risk of cancer.
- Provide leadership in harmonizing clinical trial regulations.
- Help ensure that treatments are made available to all patients who need them, including minority and underserved populations.
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Building Public-Private Partnerships for Clinical Trials Research
NCI is expanding its role in public-private partnerships as more private-sector companies begin to develop anti-cancer drugs. Because pharmaceutical companies tend to seek FDA approval or licensing of a new agent for one or a few tumor types, NCI can help ensure that new agents are evaluated against a fuller range of cancers (or precancers) and in combination with treatments such as surgery, radiation therapy, or other drugs.
- In one recent success, the collaboration between Novartis and NCI-supported researchers led to the development of Gleevec™ (imatinib mesylate) to treat chronic myelogenous leukemia and now gastrointestinal stromal tumors, in both adult and pediatric patients.
- In an ongoing partnership with Genetech, NCI-supported clinical investigators are testing a promising molecularly targeted drug, Avastin™ (bevacizumab), in patients with advanced colorectal cancer who were previously treated by chemotherapy.
- In a partnership with Searle and Pfizer, Inc., researchers found that the arthritis drug, celecoxib, can reduce the number of precancerous colon polyps in patients with familial adenomatous polyposis, an inherited syndrome that predisposes them to colon cancer. Researchers are also testing celecoxib for prevention and/or treatment of head and neck and other cancers.
Building Collaborations among Laboratory and Clinical Scientists
NCI also recognizes the increasing need for collaboration with laboratory scientists in conducting clinical trials for molecularly targeted agents. The cellular pathways and interactions involved in these molecular targets are extraordinarily complex and interrelated, and they require scientists to develop new techniques and tests to identify patients whose tumors contain the relevant targets and to monitor drug effects during treatment. More than half of NCI-sponsored cancer treatment trials initiated over the last 2 years have included correlative studies with laboratory scientists, and this trend is increasingly seen in cancer prevention trials.
Simplifying Administration of Clinical Trials
NCI continues to simplify the administration of NCI-supported clinical trials to make it easier for physicians and their patients to participate. In 2000, we launched the online Cancer Trials Support Unit (CTSU) Website to centralize the common administrative, financial, and data collection activities of NCI's clinical trials cooperative groups. Since May 2002, CTSU physicians outside NCI cooperative groups have also been able to enroll patients into these NCI-sponsored clinical trials.
Making Strides in Cancer Treatment through Clinical Trials
NCI's focused investment in clinical trials is paying off with increased survival and better quality of life for patients with a variety of cancers. Just a few of the advances emerging from recent clinical trials are listed here:
In breast cancer patients who have experienced metastasis to at least one lymph node, adding the drug paclitaxel to standard adjuvant chemotherapy of adriamycin and cytoxan (AC) improved disease-free survival by 17 percent. Furthermore, patients treated with a dose-dense chemotherapy regimen, where treatments are given over shorter intervals, received the most benefit from paxlitaxel (82 percent versus 75 percent disease-free survival compared to standard administration). As a result of this discovery, 4,000 more women could be alive and disease-free 4 years after diagnosis. These and other recent clinical trial data provide firm evidence for the role of paclitaxel in adjuvant therapy. NCI-supported investigators conducting a Phase III clinical trial demonstrated, for the first time, that adjuvant chemotherapy can improve survival in women with endometrial cancer. Following hysterectomy, staging, and tumor debulking (surgical removal of as much of the tumor as possible) in women with advanced endometrial cancer, one group of patients received the standard treatment of pelvic and abdominal radiation and a second group received systemic chemotherapy with the drugs cisplatin and doxorubicin. The women given chemotherapy survived, on average, 33 percent longer than those treated with radiation. Approximately 4,000 to 5,000 women per year may benefit from this new treatment approach. In follow-up studies, researchers are evaluating possible benefits of combining chemotherapy with tumor-reducing radiation therapy. In partnership with Millennium Pharmaceuticals, Inc., NCI has been studying the use of Velcade™ (bortezomib) in patients with refractory or relapsed myeloma. In a recently completed Phase II clinical trial, 30 percent of patients responded well to Velcade over the course of about a year. In May 2003, the FDA gave accelerated approval to Velcade for treatment of relapsed myeloma patients who do not respond well to standard therapy. NCI-sponsored clinical investigators are now conducting follow-up studies to the Phase II trial, and have begun evaluating Velcade in newly diagnosed multiple myeloma patients. Other clinical investigators are discovering anti-tumor effects of Velcade in breast, non-small cell lung, neuroendocrine, and renal cancers, as well as in melanoma, sarcoma, chronic myelogenoius leukemia, and non-Hodgkin's lymphoma. Velcade is the first in a new class of molecularly targeted anti-cancer agents known as proteasome inhibitors.
Making Strides in Cancer Prevention through Clinical Trials
From years of scientific research, we know that cancers are not caused by a single, catastrophic event, but result from a complex and long-evolving process. Since many cancers take decades to develop, we have the time and opportunity to intervene to stop or reverse their progress. NCI's clinical trials for cancer prevention seek to determine which person is at risk for cancer, define ways to prevent or reduce that risk, detect cancer at its earliest stages, and actively intervene to prevent invasive cancer. The following represent a small sampling of the progress in these areas:
In June 2003, researchers of the NCI-sponsored Prostate Cancer Prevention Trial presented the first-ever findings that prostate cancer can be prevented, at least in part, by drug intervention:
- Men in the study who took the drug finasteride for 7 years were 25 percent less likely to develop prostate cancer than men taking a placebo.
- However, those trial participants who did develop prostate cancer while taking finasteride experienced a slightly higher incidence of potentially aggressive tumors.
- Further study is needed to determine whether there is a difference in survival of patients who developed prostate cancer while taking finasteride versus taking a placebo.
Daily aspirin may be an appropriate supplement to regular surveillance procedures for many men and women at increased risk for colorectal cancer.
- Through two large randomized trials, NCI-supported investigators confirmed earlier observational studies that daily aspirin can reduce the development of colorectal polyps.
- On average, patients at increased risk for colorectal cancer who took daily aspirin for as few as 3 years reduced their colorectal polyp development by 35 percent.
Because colon polyps often become cancerous over time, their prevention may reduce the incidence of colorectal cancer. Long-term aspirin therapy is not appropriate for everyone. People considering aspirin therapy should consult their physician to discuss risks and benefits.
Mammography often finds what turns out to be benign breast diseases such as hyperplasia, fibroadenomas, and fibrosis, triggering the need for follow-up biopsies to determine if the abnormality is cancer. Data from the landmark Breast Cancer Prevention Trial show that women at high risk for breast cancer who received tamoxifen, especially women under age 50, developed fewer cases of benign breast disease and, consequently, were better able to avoid invasive follow-up biopsies.
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| 1. | Identify and accelerate development of the most promising new agents for cancer treatment and prevention. | $84.70 M |
- Expand partnerships and create flexible collaborations with industry, the FDA, and other public, private, and academic organizations to speed development of promising agents and to bring together the best laboratories, institutions, and investigators (including surgeons, pathologists, and radiologists, in addition to traditional participants) for early translational research. $4.00 M
- Expand resources for the Rapid Access to Intervention Development (RAID) and Rapid Access to Prevention Intervention Development (RAPID) programs. (See Molecular Targets of Prevention, Diagnosis, and Treatment, Objectives)
- Facilitate early proof-of-principle clinical trials by expanding capacity to file Investigational New Drug Applications and New Investigational Technology Applications. $0.70 M
- Create broadly-based working groups to identify clinically relevant surrogate endpoints. Develop resources and standardize assays, approaches, and clinical trial designs to validate these endpoints. $2.00 M
- Expand translational research capacity to use correlative studies more extensively. $8.00 M
- Develop resources to assess the effects of promising agents on their molecular targets through increased funding of Interdisciplinary Research Teams for Molecular Target Assessment. $20.00 M
- Develop molecular assays required to characterize/classify tumors, and make them widely available Support a national tissue resource to facilitate rapid evaluation of new assays and relevant clinical correlations as new targets are identified. (See Molecular Targets of Prevention, Diagnosis, and Treatment, Objectives)
- Increase the pace of development and clinical testing of promising new therapeutic and preventive agents. $35.00 M
- Substantially increase the number of promising agents entering NCI-sponsored clinical trials over the next 2 to 3 years as well as the number of pivotal early clinical trials.
- Triple annual patient accrual to early clinical trials of promising agents.
- Provide financial incentives for timely initiation of clinical trials and adherence to developmental milestones.
- Expand the rapid grant review process, Quick Trials, for mechanism-based clinical trials.
- Support the NCI intramural clinical trials program by increasing the number of data managers, research nurses, biostatisticians, and clinicians available to support a critical mass of clinical investigators, and continuing the Tissue Array Research Program to identify key molecular alterations in cancers. $15.00 M
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| 2. | Strengthen scientific planning and leadership for the large, definitive clinical trials that evaluate and define the efficacy and clinical benefit of new treatments and prevention strategies. | $25.00 M |
- Identify and address compelling clinical questions confronting physicians and their patients under treatment for cancer or at high risk of cancer. $17.00 M
- Expand state-of-the-science meetings to identify important research questions and develop scientific strategic plans to address them in disease settings not currently covered, including pediatric tumors. Continue to include broad representation from the scientific community, both basic and clinical, as well as the advocacy community. $1.00 M
- Expand clinical trials planning to address critical questions across the major types of conditions experienced by patients. $1.00
- Integrate cross-disciplinary input (e.g., oncology and diagnostic imaging) and project teams into scientific strategic planning, and involve patient advocates in this planning.
- Support appropriate multidisciplinary scientific leadership for the clinical trials, including radiation oncology, pathology, and imaging, in addition to medical, surgical, or gynecological oncology.
- Incorporate evaluation of relevant biomarkers as well as behavioral, epidemiologic, outcomes, and other research into existing treatment and prevention trials to address a broader array of relevant clinical questions utilizing this standing infrastructure.
- Provide additional research funds for leadership support of scientists who are responsible for writing, monitoring, and analyzing NCI-sponsored, high-priority Phase III trials, including researchers who chair studies in addition to caring for patients, and study statisticians. $5.00 M
- Enable correlative studies and long-term follow-up for future evaluation of new assays and biomarkers by increasing funding for tissue banks (collection and storage of patient tissues from large clinical trials with accompanying patient data). $1.00 M
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| 3. | Double the rate at which Phase III trials are completed. | $223.50 M |
- Increase the number of patients accrued to national trials, and shorten the duration of accrual, to substantially increase the number of new treatments or interventions that can be evaluated.
- Increase funding for nursing, data management, and other infrastructure costs at local clinical trial sites, and for operations, data management, and statistical offices.
- Increase the number and capacity of existing Community Clinical Oncology Programs.
- Facilitate participation of new clinical trials investigators through a "start-up" loan program (repayable by reduced future reimbursements) for training, research nurse support, and data management.
- Facilitate greater investigator participation in clinical trials.
- Continue to reduce the administrative burdens associated with clinical trials participation.
- Further reduce the lead time required to develop and activate new clinical trials through broader implementation of the Central Institutional Review Board, more rapid protocol development and review, and other mechanisms.
- Provide extensive information about treatment and prevention clinical trials to enable patients and physicians to make informed choices.
- Incorporate NCI educational materials into marketing and communications strategies to inform patients and physicians about clinical trials by working with the NCI Offices of Communications and Education, patient advocacy groups, professional societies, and others.
- Develop novel strategies, including the use of alternative media, for working with minority and underrepresented patient populations and their primary care physicians.
- Consolidate administrative tasks and provide a single interface for investigators to enroll patients by expanding the Cancer Trials Support Unit. Develop uniform electronic case report forms and data reporting systems. Ensure continued high quality, accurate data from new sites, and increased accrual to clinical trials through expansion of NCI's audit program.
- Facilitate efficient collection, analysis, and sharing of clinical trials data for current and future use in association with tissue specimens in tissue repositories and banks, by maintaining state-of-the-art informatics systems.
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| 4. | Ensure that clinical trials are broadly accessible to cancer patients, populations at risk for cancer, and the physicians who care for these groups. | |
- Increase access for minority and underserved populations to state-of-the-art clinical trials (See Reducing Cancer-Related Health Disparities, Objective 3).
- Provide funding directly to patients with special needs to cover costs associated with travel, childcare, and other relevant expenses that might limit participation. Address barriers to access for patients dependent on state and Federal health agencies for healthcare coverage by working with state and local government agencies, the Indian Health Service, and other gatekeepers.
- Encourage local sites to identify existing resources to help minority and underserved patients receive appropriate follow-up care and ensure that follow-up care is offered.
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| Management and Support | $1.70 M |
| Total | $334.90 M |
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"The collaboration will help our two agencies take full advantage of our combined knowledge base at a time when many new kinds of anti-cancer agents are in the pipeline. Molecularly targeted drugs and other novel agents offer great promise, but they also present new challenges that require more collaboration."
- Andrew C. Von Eschenbach, M.D., Director, NCI |
"FDA is committed to finding better ways to get safe and effective treatments to patients with life-threatening diseases as quickly as possible. At a time when the opportunities to reduce the burden of cancer are greater than ever, sharing tools and resources with our colleagues at the National Cancer Institute will help us fulfill that mission."
- Mark B. McClellan, M.D.
Commissioner, FDA |
In May 2003, NCI and the Food and Drug Administration (FDA) announced a joint effort to streamline cancer drug development. Under a multi-part Interagency Agreement, the two agencies will share knowledge and resources to enhance the efficiency of clinical research and the scientific evaluation of new cancer medications. Federal researchers and regulators will be working more effectively than ever before to facilitate the development of new cancer drugs and speed their delivery to patients.
This new partnership will broaden existing and create new joint programs to:
Develop biomarkers for use as surrogate markers in clinical trials. Create a cancer bioinformatics infrastructure to improve data collection, integration, and analysis for preclinical, pre-approval, and postapproval research. Address joint technology development issues in proteomics and other areas. Advance the process for developing and evaluating cancer chemoprevention agents, including the development of clinically meaningful endpoints. Improve consumer awareness of the consequences of their choices about diet and nutrition for cancer prevention. Enhance staff capabilities through collaborative training, joint rotations, and joint appointments. Conduct a systematic review of current policies to identify other ways in which NCI-FDA collaborations can enhance the development and regulatory process for cancer technologies.
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Cancer is caused by mutations in genes that in turn alter the structure of proteins that regulate molecular pathways for cell growth and other important functions. To improve patient outcomes, researchers hope to develop and test in the clinic, therapies that use combinations of drugs to target several critical points in cancer-causing molecular pathways. This diagram shows how three drugs might be used in combination to shut down a pathway with multiple proteomic changes.
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