Clinical Trials
A strong clinical research structure
including a comprehensive program of clinical trials in treatment, early
detection, and prevention is a critical component of the NCI research program.
The components of the program include the Cancer Centers described above
and the Cooperative Groups described in the following section. The Community
Clinical Oncology Program (CCOP) is also a crucial component, extending
the opportunity for participation in clinical trials to communities across
the country. Hundreds of clinical trials are supported through these and
other research mechanisms, such as individual research grants, program project
grants, cooperative agreements, and contracts. Our ability to conduct clinical
trials is in danger of being compromised by changes in the health care system.
In the past, institutions have used surplus revenues from patient care services
to supplement government research support. The growth of managed care has
all but eliminated those discretionary funds. As a result, institutions
can no longer sponsor research activities requiring capital expenditures
and cannot support essential training for young investigators. These changes
pose a very real danger for the continuation of cancer research and our
ultimate success against cancer.
Cooperative Group Clinical Trials Program
The nationwide Cooperative Groups program promotes and supports clinical
trials in cancer treatment, prevention, and early detection. More than 1,400
institutions and 8,500 investigators participate in these Cooperative Group
studies.
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Examples of Cooperative Group Clinical Trials
The NCI Role in the Development of Paclitaxel (Taxol®)
Paclitaxel is a plant-derived drug originally identified through the
NCI's natural products screening program and brought into clinical trials
by the NCI in the mid 1980s. The drug has been found to have important anti-tumor
activity in patients with ovarian and breast cancers. For example, protocol
GOG 111 by the Gynecologic Oncology Group, one of the NCI Cooperative Groups,
recently demonstrated a 50 percent increase in median survival time among
women with advanced ovarian cancer who were treated with the combination
of paclitaxel and cisplatin compared with the standard approach of cisplatin
with cyclophosphamide. The NCI has collaborated with Bristol-Myers Squibb
in the clinical development of paclitaxel under a CRADA (Cooperative Research
and Development Agreement).
The NCI Role in the Development of All-trans Retinoic Acid ("Vesanoid")
for Acute Promyelocytic Leukemia
Acute promyelocytic leukemia (APL) is a form of acute leukemia affecting
more than 500 individuals in the United States annually. The disease is
treated with aggressive chemotherapy associated with risks of fatal infections
and bleeding. Once initial chemotherapy approaches--sometimes including
bone marrow transplantation--have failed, the disease is frequently fatal.
Following research results from China showing complete disappearance of
malignant cells in patients receiving all-trans retinoic acid, an orally
administered modification of Vitamin A, the NCI moved rapidly to make the
drug available to patients with APL in whom initial chemotherapy had failed.
In collaboration with the pharmaceutical company Hoffman LaRoche, the NCI
obtained a clinical supply of all-trans retinoic acid. Over the last three
years more than 1,600 patients with relapsed APL have received the drug,
shipped overnight by the NCI after request by the treating hematologist
or oncologist. Information gathered from this experience was critical in
the FDA evaluation of the agent, and Vesanoid was approved by the FDA for
general availability in December of 1995. Meanwhile, an NCI-sponsored randomized
clinical trial involving the major adult and pediatric Cooperative Groups,
and evaluating the role of Vesanoid combined with chemotherapy in the initial
treatment of APL, has been recently completed. The results clearly demonstrate
the benefits of combining Vesanoid with available best chemotherapy, and
represent a major advance in the treatment of malignancy.
The sheer number of different types of cancer and the biological complexity
of individual cancers present extraordinary challenges to the efficient
clinical investigation of new anti-cancer agents or new treatment strategies
suggested by laboratory and animal experiments. To more rapidly test potential
treatment advances in patients, the NCI maintains a standing funded clinical
trials program to conduct such investigations. In this way, new clinical
trial organizations do not have to be created each time a potential new
cancer treatment emerges. Nine NCI-sponsored Cooperative Groups annually
place approximately 20,000 new patients onto cancer treatment protocols,
principally large randomized Phase III clinical trials that have been responsible
for establishing the current state of the art for cancer treatment worldwide.
In addition, new anti-cancer agents being
studied for the first time in patients are entered into Phase I and Phase
II clinical trials; many of these early treatment clinical trials are conducted
under NCI Investigational New Drug (IND) sponsorship in institutions funded
by NCI cooperative agreements. More than 200 investigational agents or treatment
strategies, ranging from new chemotherapy drugs and cancer vaccines to agents
that prevent tumor blood vessel development, are being studied under NCI
INDs. Many of these agents are being developed clinically as a result of
active NCI cooperation with biotechnology and pharmaceutical companies,
accelerating the clinical testing of scientific advances emerging from these
sources. Others come from the scientific laboratories and discovery programs
of the NCI itself. Examples of important new anti-cancer agents that have
emerged from NCI development include paclitaxel (Taxol®) for ovarian
and breast cancers, interferon alpha for malignant melanoma and chronic
myelocytic leukemia, fludarabine for chronic lymphocytic leukemia, and all-trans
retinoic acid for acute promyelocytic leukemia.
Science is increasingly delineating the distinct biological bases for many
tumors. As a result, many clinical trials of new treatments are linked to
particular laboratory studies, and many NCI trials now include laboratory
components in addition to the clinical evaluations. For example, clinical
studies of new acute leukemia treatments now routinely include the analysis
of genetic changes in the malignant leukemia cells of the individual patient.
The NCI has funded small clinical trials groups especially to evaluate potential
new treatments for patients with brain tumors, malignancies occurring in
the setting of AIDS, and pediatric tumors, due to the very specialized nature
of these cancers. A similar program has very recently been established to
develop new therapies for breast cancer. Furthermore, recognition of gender,
age-related, and ethnic differences in individual responses to cancer therapy
has led to initiatives to make such evaluations a routine part of the clinical
development of new anti-cancer agents. A recent NCI evaluation shows that
minority populations participate in treatment clinical trials in proportion
to their cancer incidence. Minority participation in clinical research is
a high priority for the Institute. Two new grant programs are designed to
draw more women and minority participants into cancer
prevention and screening studies.
Greater patient access to advanced therapeutic approaches
has been a chief goal of the NCI clinical trials program. The field of childhood
cancers is one of the success stories in medicine in the twentieth century.
About 70 percent of children who develop cancer in the United States annually
are treated in the NCI-sponsored Cooperative Groups clinical trials. While
the percentage of adults with tumors treated on protocols is much smaller
(on the order of one percent), more than 8,500 oncologists participate in
NCI trials, allowing patients to benefit from advanced treatment approaches
whether they are seen at the largest comprehensive cancer center or the
smallest community hospital.
Community Clinical Oncology Program
The Community Clinical Oncology Program (CCOP) is a mechanism that links
community cancer specialists and primary care physicians with clinical Cooperative
Groups and Cancer Centers to conduct cancer treatment, prevention, and control
clinical trials.
There are 52 CCOPs in 30 states, with 300 participating hospitals where
approximately 3,000 physicians cooperate to enter patients and individuals
at risk for cancer on NCI-approved clinical trials. An additional 10 minority-based
CCOPs are funded to enhance the participation of minority populations in
clinical trials research. These programs are located in nine states and
Puerto Rico, bringing an additional 42 hospitals and 350 physicians into
the clinical trials network. Through this network, individuals can access
state-of-the-art clinical research trials while remaining in their home
communities.
Each year the CCOPs enter over 4,000 patients onto cancer treatment clinical
trials (accounting for about one-third of all patients on NCI Phase III
treatment efficacy trials). An additional 4,000 participants are entered
onto cancer prevention and control clinical trials from the CCOP communities.
Support is also provided for university members and affiliates to participate
in prevention and control research. The CCOP covers the spectrum from testing
new combinations of anti-tumor drugs in cancer patients to testing the ability
of new agents to prevent first occurrences of cancer. Examples of the latter
are the Breast Cancer Prevention Trial (box on page 41) and the Prostate
Cancer Prevention Trial. CCOPs have also demonstrated successful interventions
for symptom management and continuing care of cancer patients, including
treatment for mucositis and hot flashes, common side effects of chemotherapy.
The program is rapidly evolving to include interventions for individuals
with specific molecular alterations associated with genetic cancer susceptibilities.
Linking the community, university researchers, and the NCI, the CCOP has
proven to be one of the critical paths for the dissemination of state-of-the-art
cancer treatment and prevention information. The CCOP research network is
well positioned to conduct the research of the future that will move oncologic
practice from the treatment of established disease to the management of
cancer risk.