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Strategic Options for Cancer Care
Clinical Trials
An Overview
Lee P. Shulman, MD
We do not yet know how to eradicate breast cancer. Groundbreaking
research in the past several years has begun to offer breast cancer
researchers fascinating insights into the biology of breast cancer,
helping focus research on the areas that hold promise as well as
build on the knowledge already gained.
Clinical trials represent one of the final stages of this long
and complex research process where the efficacy and safety of a
health care intervention is tested. Each trial has several phases:
- Phase I primarily tests the safety of an experimental drug
on a few patients;
- Phase II tests some short-term effectiveness but mainly tests
the drug's safety and identifies effective dosages using greater
numbers of patients
- Phase III tests safety, effectiveness, and dosage amounts in
a large number of patients;
- Phase IV addresses safety and marketing concerns after a drug
or device has been approved by the US Food and Drug Administration
(FDA) and is on the market. (A Phase IV study may also be undertaken
to establish that a drug works better for a certain population.)
In most situations, only after completing at least two pivotal
Phase III trials will the FDA consider approving a drug or device
for human use.
Investigators need to accrue sufficient numbers of individuals
in order to conduct a clinical trial. While 70% to 80% of pediatric
cancer patients participate in clinical trials (a number thought
by many to be higher), currently only 3% of adult cancer patients
participate in clinical trials. Many trials never accrue a sufficient
number of patients and must close. It is estimated that at least
10% to 15% of adult cancer patients must participate in trials to
move research forward rapidly.2
To meet the need for high-quality breast cancer research, including
clinical trials, the National Breast Cancer Coalition Fund (NBCCF),
a grassroots organization formed in 1991 and dedicated to ending
breast cancer through the power of action and advocacy, has focused
a significant portion of its resources on the following efforts:
- increasing federal funding for breast cancer research
- collaborating with the scientific community to implement new
models of research
- improving access to high-quality health care, including access
to clinical trials
- expanding the influence of breast cancer advocates in all aspects
of the decision-making process.
The success of NBCCF's work is evidenced by the eightfold increase
in federal spending on breast cancer research. To further influence
breast cancer research, NBCCF launched its Clinical Trials Project
in 1996 to help move clinical research in breast cancer on a fast
track, without compromising scientific integrity. The Clinical Trials
Project focuses on participating in research collaborations, improving
access to quality trials, and training advocates to influence clinical
trials. NBCCF is committed to helping to create and support more
high-quality clinical trials (Table).
TABLE. NBCCF Guidelines on High-Quality
Clinical Trials
- Trials should be designed to answer new and/or important
questions about breast cancer, be well designed, scientifically
rigorous, and employ appropriate outcome measures.
- A trial is defined as well designed on the basis of many
factors, one of which is the way in which the intervention
is allocated. Phase I trials, in which the safety and dosage
of an intervention are examined, are not randomized. Phase
II trials, which look at safety and preliminary efficacy,
do not have to be randomized. Any trial attempting to establish
the efficacy of a standard treatment, prevention, or diagnostic
strategy, however, should be controlled and randomized.
- Trials should be conducted in an ethical manner. There
must be sufficient data supporting efficacy and safety that
lead reasonable people to believe the trial should proceed.
Participants must have sufficient information to provide
meaningful informed consent, and the trial should be reviewed
and approved by each participating institution's institutional
review board (IRB). IRBs should generally adhere to the
policies set forth by the Office for Protection of Research
Risks within the Public Health Service. The same board should
review the trial progress and be kept informed of new developments
or protocol changes.
- A data and safety monitoring committee must monitor the
trial progress at regular intervals. This committee is responsible
for informing participants of unforeseen risks, modifications
to the protocol and consent forms as needed, stopping the
trial if necessary, and ethical issues related to the study.
- Those planning and carrying out the research should include
a collaborative team of individuals, including: those who
are trained and proficient clinicians, those who have had
formal training in clinical research, and a minimum of one
consumer advocate.
- Neither the research team nor institution needs to be
part of an established cancer center. The trial's merit
should be decided on the basis of the strength of the hypothesis
being tested, the planning and design of the trial, the
capabilities of the research team, the resources for carrying
out the research, the adequacy of the statistical power,
and the manner in which ethical issues have been addressed.
NBCCF = National Breast Cancer Coalition
Fund.
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Research Collaborations
As part of the Clinical Trials Project, NBCCF works with research
organizations to improve trial design and monitoring, increase access
and accrual, educate the medical community and consumers, and promote
initiation of high-quality breast cancer trials. Before forming
a partnership on a clinical trial with any research organization,
NBCCF carefully evaluates the proposed clinical trial and research
organization to determine if they meet NBCCF's rigorous guidelines.
NBCCF designed this new model of research collaboration to bring
meaningful input of trained advocates to every phase of decision-making
about selected clinical trials. By developing intensive curricula
and training advocates in the science of breast cancer and the different
aspects of clinical trials, and then partnering with research organizations
on a clinical trial, NBCCF is changing the way clinical trials are
being conducted.
In 1996, Genentech, a biotechnology company, approached NBCCF
because it was having difficulty accruing a sufficient number of
patients for its Phase III clinical trial of the drug trastuzumab
(Herceptin). NBCCF worked with Genentech on all aspects of the trial,
from protocol design, to outreach, to oversight. NBCCF helped design
an expanded access program for the drug, served on the Data Monitoring
Committee, and served on the Steering Committee of the trial. Advocates
reviewed and helped revise the trial protocol and attended all major
investigator meetings. Additionally, study investigators in specific
communities partnered with trained NBCCF advocates who used their
networks in the breast cancer community to raise awareness about
the trial and to facilitate patient accrual.
NBCCF is currently active in the implementation of three clinical
trials:
- Biomira's Phase III clinical trial of Theratope, a vaccine
that potentially stimulates the body to develop an immune response
directed against breast cancer. Enrollment in this trial is now
closed. The accrual phase of this trial was also completed ahead
of schedule with the help of NBCCF.
- Genentech's Phase III clinical trial of Avastin, a potential
new anti-angiogenic therapy. With the help of NBCCF advocates,
Genentech has met its accrual goal ahead of schedule. It has decided
to accrue an additional 50 patients in selected areas.
- BCIRG (Breast Cancer International Research Group) 006's Phase
III clinical trial of docetaxel (Taxotere) and carboplatin as
an adjuvant therapy. NBCCF is working with BCIRG to accrue patients
in approximately 130 clinical trial sites in the United States;
BCIRG is adding additional trial sites based on the recommendations
and contacts of NBCCF advocates.
Access to Quality Trials
Part of the difficulty in conducting clinical trials is being able
to accrue a sufficient number of patients willing to participate.
In order to accrue enough patients, a number of approaches need
to be simultaneously undertaken. The following are particularly
important: physician support, insurance coverage for routine medical
costs, inclusion of diverse populations where appropriate, and trial
designs that take into account the patient's quality of life.
Patients need to be given information about all of their treatment
options, including information about all clinical trials for which
they are eligible, in order to make meaningful choices about the
treatment they wish to pursue. (With the number of clinical trial
databases available on the Internet, it is no longer such a cumbersome
task for a physician to find out for which trials his or her patients
would be eligible.) NBCCF is working to get word out to more doctors
about the importance of clinical trials in finding the answers needed
to eradicate breast cancer.
No one should be excluded from research trials because they cannot
afford the standard care costs associated with a trial. NBCCF is
working at the federal Medicare level to require insurance companies
to pay these costs. Lastly, accrual in clinical trials would also
be improved by designing trials that address important patient interests
and concerns. Involving trained advocates in the trial design helps
researchers to incorporate quality-of-life issues into the design,
thus making it more likely that patients will want to participate.
Trained Advocacy
NBCCF empowers advocates to collaborate with the breast cancer research
and health care communities to help find answers, to critically
analyze information, and to ensure access to high-quality breast
cancer treatment. The trainings are conducted through our Project
LEAD seminar, a four-day intensive curriculum on the science of
breast cancer held four times a year, and the annual Advocacy Conference.
In addition, information is published through position papers, fact
sheets, analyses, and newsletters. In July 2001, NBCCF held its
first Project LEAD Clinical Trials Training, an advanced course
for Project LEAD graduates, to train them to participate in all
levels of the clinical trials process-from evaluating trial design
to serving on Institutional Review Boards and Data Safety Monitoring
Boards. As NBCCF partners with more industry clinical trials, it
will need a fleet of advocates who are trained to participate in
all aspects of the clinical trial process.
NBCCF advocates work with members of Congress to pass legislation
that will improve the quality of clinical trials and patient access
to them. Thanks, in part, to the hard work of NBCCF members, President
Clinton issued in June 2000 and Executive Memorandum requiring Medicare
to reimburse all routine patient-care costs for those participating
in clinical trials.
Conclusion
As stated at the beginning, currently only 3% of adult cancer patients
in the United States are in clinical trials. If that number does
not increase dramatically, the cure for and prevention of cancer
will be light years away. With clinical trials and new models of
research, the stunning results in animals that have recently been
in the news could have more meaning for human beings, which is of
course the goal. As laboratory scientists discover more about cancer,
the entire scientific community must embrace the new models of research
that welcome the participation of advocates. Only then will clinical
trials be accelerated to turn those discoveries into interventions
that will help eradicate breast cancer.
NBCCF does not accept any compensation from
industry for any of its work in its Clinical Trials Project.
References
- American Cancer Society. Cancer Facts and Figures, 2001. Atlanta,
GA, 2001.
- Coalition of National Cancer Cooperative Groups, Inc. Report
from Summit II on Clinical Trials: Patient Care Costs and High
Quality Clinical Trials. February 24, 1999.
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