Cancer Clinical Trials
The In-Depth Program
National Institutes of Health
National Cancer Institute

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The National Cancer Institute Clinical Trials
Education Series
Cancer Clinical Trials Books
Cancer Clinical Trials: The Basic Workbook
The self-modulated workbook, with its accompanying activities,
will help readers understand why cancer clinical trials are
important, how they work, how participants' safety is protected,
as well as some of the reasons so few adults participate in these
trials. It is designed for individuals who want to develop a basic
understanding of clinical trials.
Cancer Clinical Trials: The In-Depth Program
The textbook expands on the subjects outlined in The Basic
Workbook. It features additional information on clinical trial design,
resources for physician participation, and referral of individuals to
studies. It is designed for health care professionals and others
who seek a more in-depth understanding of clinical trials.
Cancer Clinical Trials: A Resource Guide For Outreach, Education,
and Advocacy
The interactive workbook provides direction and guidance for
individuals and organizations interested in developing specific
clinical trial outreach and education activities. This guide can also
be used along with either or both of the texts listed above.
Trainer's Guide for Cancer Education
A manual for planning and conducting educational sessions on
cancer-related topics, including clinical trials.
Cancer Clinical Trials Resources
The following resources will help support cancer clinical trials
education and outreach efforts.
Publications
Low literacy brochures on cancer clinical trials for potential
participants:
· If You Have Cancer...What You Should Know About Clinical Trials

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· If You Have Cancer and Have Medicare...What You Should Know
About Clinical Trials
Clinical trial participant booklets:
· Taking Part in Clinical Trials: What Cancer Patients Need to Know*
· Taking Part in Clinical Trials: Cancer Prevention Studies--What
Participants Need to Know*
*Also available in Spanish
Videos
· A clinical trial awareness video and speaker's guide, "Cancer
Trials...Because Lives Depend on It"
· A video and discussion guide on deciding to take part in a
clinical trial, "Cancer Clinical Trials: An Introduction for
Patients and their Families"
Slide Programs
Three slide programs are available in PowerPoint on CD-ROM and
on the www.cancer.gov Web site:
Cancer Clinical Trials: The Basics
Provides background on why cancer clinical trials are important,
how they work, and how participants' safety is protected.
Cancer Clinical Trials: The Way We Make Progress Against Cancer
A brief community awareness presentation.
Cancer Clinical Trials: In-Depth Information
Expands on the subjects outlined above, featuring additional
information on clinical trial design with resources for physician
participation and referral of individuals to studies.
Ordering Information
To order these publications, contact the Cancer Information Service
at 1-800-4-CANCER or log onto www.cancer.gov/publications. Most
materials are available as PDF files on the Web site.
The Cancer Information Service
NCI's Cancer Information Service (CIS), with regional offices throughout the
United States, may work with organizations and professionals to plan,
implement, and evaluate culturally appropriate clinical trials education
programs using the Clinical Trials Education Series. Contact the CIS at
1-800-4-CANCER.

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Table
of
Contents

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Table of Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Introduction: An Overview of Clinical Trials . . . . . . . . . . . . . . . . .3
1. The Clinical Trial Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
The Drug Development and Approval Process . . . . . . . . . .5
Types and Phases of Clinical Trials . . . . . . . . . . . . . . . . . . . . .7
Special Access Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
2. Clinical Trial Design and Interpretation of Results . . . . . . . . .21
Research Team Members . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
Components of a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . .23
Using Statistics to Interpret Results . . . . . . . . . . . . . . . . . . .29
3. Advancing Cancer Care Through Clinical Trials . . . . . . . . . . .33
FDA Approval Requirements . . . . . . . . . . . . . . . . . . . . . . . . .33
Releasing the Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35
Improving Cancer Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
Speeding Up Drug Development . . . . . . . . . . . . . . . . . . . . .39
4. Participant Protection in Clinical Trials . . . . . . . . . . . . . . . . . . .41
Evolution of Participant Protection . . . . . . . . . . . . . . . . . . . .41
Government Oversight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43
Protecting Participants Before a Clinical Trial Begins . . . .45
Protecting Participants During a Clinical Trial . . . . . . . . . .49
5. Barriers to Clinical Trial Participation . . . . . . . . . . . . . . . . . . . .53
Barriers for Health Care Professionals . . . . . . . . . . . . . . . . .54
Barriers for the General Population . . . . . . . . . . . . . . . . . . .55
Barriers for Diverse Populations . . . . . . . . . . . . . . . . . . . . . .57
Cost Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59
6. Conducting, Referring to, and Locating Clinical Trials . . . . .63
Sponsorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63
Making Referrals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67
Cancer Information and Clinical Trial Resources . . . . . . . .69

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7. Case Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
The Clinical Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Finding a Clinical Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Sample Points to Discuss With the Patient
Considering a Clinical Trial: Randomization,
Patient Protection/Myths, and Insurance . . . . . . . . . . . . 75
Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

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Preface

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Preface
Research supports that the public understands very little about
clinical trials. Some people are fearful of being "guinea pigs," even
though participants in clinical trials receive high-quality care.
Other people are not aware of clinical trials as an option, do not
understand how they work, or do not have access to them.
Likewise, health care professionals may be unaware of appropriate
clinical trials, may not want to refer people out of their practice, may
believe that standard therapy is best, or may think that getting involved
in clinical trials will add an undue administrative burden to their work.
Today's standard cancer treatments were yesterday's clinical trials.
Successful clinical trials have:
· Increased survival rates of participants with testicular cancer,
breast cancer, leukemia, and lymphoma
· Decreased morbidity associated with the surgical treatment of
many cancers
· Resulted in the development of new compounds and techniques
to reduce the side effects of cancer therapies
This guide is designed to familiarize health care professionals and
others with the ins and outs of clinical trials. It describes how:
· The clinical trial process works
· Trials are designed to obtain particular information
· Clinical trials advance standard cancer treatment
· Trial participants are safeguarded
· People might face obstacles to participating in clinical trials
· To find a local clinical trial
After reading the guide and reviewing the case study, the reader
will be better able to manage issues related to clinical trials. The
reader should be able to:
· Discuss clinical trials as potential treatment or preventive options
· Answer people's questions and allay their fears about clinical trials
· Locate and refer people to accessible clinical trials
· Ultimately help advance the early detection, treatment, and
eventual prevention of cancer
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Clinical
Introduction:
Trials
An
Overview
of

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Introduction:
An Overview of Clinical Trials
Approximately 555,550 people in the United States are expected to
die of cancer each year--an average of more than 1,500 people a
day. As the second leading cause of death after heart disease,
cancer accounts for one in four deaths each year. Moreover, about
1,284,900 new cancer cases are expected to be diagnosed in 2002.
As widespread as the threat of cancer is among all Americans, its
impact is felt disproportionately by racial and ethnic minorities,
the medically underserved, and people over age 65.
Scientific research continues to provide valuable insights into the
causes of cancer. But research is an incremental process, moving
forward in small, carefully planned steps. Advances typically begin
with basic research in the laboratory. After years of testing in cells
and tissues, promising leads are tested in animal models of human
cancers. Only after treatments or techniques prove successful in
animals can they be evaluated in people through clinical trials.
Well-designed, well-run clinical trials are the only way to
determine the true effectiveness of a promising new agent
or intervention being investigated.
Clinical trials are designed to answer specific questions about the
effects of a therapy or technique designed to improve human
health. The trials are planned in advance, follow a rigorous
scientific process, and the findings are analyzed. The scientific
process has built-in safeguards for participants, who are selected
carefully from volunteers. Clinical trials are usually conducted
in a progressive series of steps, called phases. The process starts
with small trials testing the safety of an intervention and moves
to progressively larger trials. The larger trials compare the
effectiveness of the new intervention given to the investigational
group to the currently accepted standard care given to the
control group.
Clinical trials are mechanisms for developing better methods of
detecting, treating, and eventually preventing diseases like cancer.
The enormous strides made in treating childhood cancer, for
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example, are the direct result of clinical trials. In the United States
today, more than 70 percent of children with cancer live at least 5
years after diagnosis, as opposed to only 55 percent in the mid-1970s.
More than 60 percent of children with cancer participate in clinical
trials, yet only 3 percent of adults with cancer do. To answer the
most pressing questions about cancer--and to do so quickly--
many more adults must participate in clinical trials. To encourage
participation, the National Cancer Institute (NCI) and other
organizations provide information to ensure that health care
professionals and the people they treat understand clinical trials,
consider them as an option, and can easily locate them in their
communities. Clinical trials should not be considered only in
terms of caring for people who have cancer. They may also present
prevention and early detection options for people at high risk
of developing cancer.
For more basic information about clinical trials, see
"Facts and Figures about Cancer Clinical Trials" at
http://www.cancer.gov/clinicaltrials/facts-and-figures.
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1.
The
Clinical
Trial
Process
7

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1
The Clinical Trial Process
Learning Objectives
· Identify the steps in the drug development process
· Name the various types and phases of clinical trials
· Describe special access programs
The Drug Development and Approval Process
Clinical trials are a key part of the drug development and
approval process. The entire process takes place under the
watchful eye of the Food and Drug Administration (FDA). As a
consumer protection agency of the U.S. Department of Health and
Human Services, FDA is required by law to review all test results
for new drugs to ensure that they are safe and effective for specific
uses. "Safe" does not mean that the product is free of possible
adverse side effects; rather, it means that its potential benefits
outweigh any known risks. The FDA approval process is focused
on drugs, but similar processes exist for the approval of:
· New devices (e.g., infusion pumps)
· Agents (e.g., vitamins and medications)
· Biologics (e.g., vaccines)
For purposes of illustration, the process outlined in this text
focuses on drug approval.
Before a new drug or biologic agent that shows promising results
in the lab can be tested in people, its sponsor must submit an
Investigational New Drug (IND) application to FDA. Once the
application is approved, the sponsor can begin testing the drug in
clinical trials with human participants. If these trials demonstrate
that the new drug is safe and superior to standard treatment, the
sponsor can file a New Drug Application (NDA) or a Biologics
The Clinical Trial Process
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Steps in the Drug Development Process
1. Early research and preclinical testing. During early
research and preclinical testing, drugs undergo basic
laboratory investigation and animal model testing for
efficacy and toxicity. This step takes about 4 years.
2. Investigational New Drug application. The trial sponsor
files an IND application with FDA. If FDA approves the
application, clinical trials begin.
3. Phase 1 clinical trial. Phase 1 trials determine the safety
and appropriate dosage of the drug for humans. It might
take about 2 years before enough participants enroll in the
trial. If phase 1 trials are successful, researchers design
phase 2 trials.
4. Phase 2 clinical trial. Phase 2 trials evaluate the effectiveness
of the drug and look for side effects. It might take up to 2
years to enroll participants for these trials. If phase 2 trials
are successful, researchers design phase 3 trials.
5. Phase 3 clinical trial. Phase 3 trials evaluate the effectiveness
of the new treatment, compared with standard treatment. It
might take 3 to 4 years to enroll enough participants for these
trials. Researchers report trial results in peer-reviewed
scientific journals and at professional meetings.
6. New Drug Application. The trial sponsor files an NDA or
BLA with FDA. The sponsor submits this application to FDA
once it has adequate data to support a certain indication for a
drug (usually by finding that the drug is safe and superior to
standard treatment in a definitive phase 3 trial).
7. FDA approval. FDA approves the claim that is being made
about the drug, which takes about 11 2 years. After approval,
it can be marketed to the public. FDA approval allows the
drug to be "labeled" for a specific use. This label includes
information on the drug's dosage, indications, safety, and
side effects.
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License Application (BLA) to FDA. Only after FDA approves
the drug can it be marketed.
For an overview of the drug approval process from start to finish,
see FDA's From Test Tube to Patient: New Drug Development in the
United States. This book tells the story of new drug development
in the United States and highlights the consumer protection role
of FDA. Call 1-888-INFO-FDA or see the Web site http://www.fda.gov.
Types and Phases of Clinical Trials
Cancer clinical trials focus on developing new strategies for the
prevention, detection, treatment, and overall improvement of the
care and quality of life of people with cancer or people at high risk
for developing cancer. In cancer research, a clinical trial is
designed to show how a particular anticancer strategy affects the
people who receive it.
Clinical trials differ by type and phase, but they all involve
rigorous scientific testing. Each type of clinical trial attempts to
answer different research questions:
· Prevention trials: What kinds of interventions--such as lifestyle
modifications, dietary supplements, or drugs--can prevent
cancer from occurring?
· Screening and early detection trials: What tests can find cancer
as early as possible in healthy people?
· Diagnostic trials: How can new tests or procedures identify a
suspected cancer earlier or more accurately?
· Genetics trials: Can gene-transfer therapy be used to treat cancer?
· Treatment trials: What new interventions (e.g., drugs, biologics,
surgical procedures, radiation) can help people who have cancer?
· Quality-of-life and supportive care trials: What kinds of
interventions can improve the comfort and quality of life of
people who have cancer?
The Clinical Trial Process
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Clinical trials occur in four phases, each of which is designed to
answer different research questions:
· Phase 1: How does the treatment affect the human body? How
should the treatment be given? What dosage is safe?
· Phase 2: Does the treatment do what it is supposed to do for a
particular cancer? How does the treatment affect the human body?
· Phase 3: Is the new treatment (or new use of a treatment) better
than current practice?
· Phase 4: What are the effects of an approved treatment?
The phases of clinical trials are explained in the context of drug
treatment trials on the pages that follow. But the same concepts
apply to most types of clinical trials, which are described after
treatment trials.
Phase 1
Phase 2
Phase 3
Phase 4
Number of
15­30 people
Fewer than 100
Generally,
Several
participants
people
from 100 to
hundred to
thousands of
several
people
thousand
people
Purpose
· To find a
· To determine
· To compare
· To further
safe dosage
if the agent or
the new
evaluate the
intervention
agent or
long-term
· To decide
has an effect
intervention
safety and
how the
on a
(or new use
effectiveness
agent
particular
of a
of a new
should be
cancer
treatment)
treatment
given
with the
· To see how
· To observe
current
the agent or
how the
standard
intervention
agent
affects the
affects the
human body
human body
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Treatment Trials
Treatment trials are designed to test the safety and effectiveness of
new drugs, biological agents, techniques, or other interventions in
people who have been diagnosed with cancer. These trials evaluate
the potential clinical usefulness of a therapy or compare an
investigational treatment against standard treatment, if there is one.
Phase 1
Phase 1 trials are the first step in transforming laboratory data into
clinical care. While the primary goal of a phase 1 trial is to
determine the toxic effects, pharmacological behavior, and
recommended dosage of a therapy or technique for future trials,
these trials are conducted with therapeutic intent.
In a phase 1 trial, the study participants (usually less than 30
people) are divided into cohorts of three to six participants. Each
cohort of participants is treated with an increased dose of the new
therapy or technique. Results in early participants greatly
influence the dose subsequent participants receive. Initial dosage
is based on preclinical testing and is usually quite conservative. If
no serious side effects are seen in the initial group after a period of
time, usually 3 to 4 weeks, the next group of participants receives
a higher dose. This pattern is repeated until a certain percentage of
participants experience dose-limiting toxicity--that is, side effects
strong enough that the next group of participants should not get a
higher dose. The highest dose with acceptable toxicity is
determined to be appropriate for further testing.
Phase 1 trials are not limited to "first in human" studies.
Subsequent phase 1 trials often evaluate new schedules or
combinations of established drugs or radiation. Later phase 1 trials
may also be conducted to evaluate toxicity, response, and
pharmacokinetics in populations that might not have been
included in prior trials, such as children or the elderly. Some
phase 1 trials are pilot trials for larger trials designed to determine
the interaction of a drug with another treatment or substance.
The Clinical Trial Process
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Who Participates
Almost all phase 1 trials of new anticancer drugs involve
participants with a cancer that lacks or does not respond to
standard treatment. People with many types of cancer can
participate in the same phase 1 trial. Participants are generally
required to have organ function capable of metabolizing and
excreting the drug and a 1- to 2-month life expectancy, in order to
evaluate the drug's effects and the body's response to it.
Possible Benefits
· If the new agent under study has an effect on the cancer,
participants may be among the first to benefit.
Possible Risks
· Because phase 1 trials are often the first studies involving
humans, unpredictable side effects can occur.
Phase 2
Phase 2 trials are designed to evaluate the effectiveness of the drug in
a somewhat larger group of participants (usually less than 100), using
the dosage determined to be safe in phase 1 trials. On the basis of their
findings in phase 1 trials, researchers often focus phase 2 trials on
cancers for which no effective treatment exists and/or that are most
likely to show a response to therapy. In choosing which type of cancer
to study, researchers may also take into account effective alternatives
and choose a cancer that has none. Some anticancer compounds being
developed target molecular pathways in specific cancers, a
development that may affect the cancers chosen for phase 2 trials.
In most phase 2 trials, all participants receive the same dose of the
drug (or undergo the same intervention). The new treatment is
assessed for effectiveness, and additional safety information is
noted. Even if the new treatment seems effective, it usually requires
further testing before entering widespread use. Because the
treatment has not been compared with any other therapy or
technique, its relative value is unclear, and it is impossible to
rule out other factors that may have influenced its effectiveness.
In addition, phase 2 trials are often too short to determine
long-term benefits; larger and longer phase 3 trials are more
suited to this purpose.
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Some phase 2 trials compare different schedules of administering
the same drug. At the end of such trials, the most promising
regimen is chosen to move into phase 3 trials. Participants in this
type of phase 2 trial are assigned at random to either the
investigational group, which is given the new treatment, or the
control group, which receives the standard treatment. Neither the
participants nor their doctors choose which group individual
participants will be in.
Who Participates
Generally, people who take part in phase 2 trials have not found
the current standard of care effective or have cancers for which
there is no standard treatment. Participants are generally required
to have adequate organ function, a 3-month life expectancy, and a
limited number of prior treatments.
Possible Benefits
· If the new agent has an effect on the cancer, participants may be
among the first to benefit.
Possible Risks
· Unpredictable side effects may occur.
Phase 3
Phase 3 trials are large trials (usually involving more than 100
participants) designed to determine whether a new therapy or
technique is more effective or less debilitating than a standard
treatment. These trials are conducted at multiple institutions
around the country, including community settings. Because the
results of phase 3 trials guide health care professionals and people
with cancer in making treatment decisions, their results should
apply to aspects such as survival time and quality of life.
Like phase 2 trials, phase 3 trials usually focus on specific types of
cancer. Participants enrolling in a phase 3 trial are assigned at
random to an investigational group, which is given the new
treatment, or a control group, which receives the current standard
treatment. Some trials can also include more than two study
groups, depending on the research questions being asked.
The Clinical Trial Process
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Who Participates
Many people with cancer get their first treatment in a phase 3 trial.
Eligibility requirements vary with the disease stage or other
factors being studied. Phase 3 trials typically involve large
numbers of participants in order to determine true effectiveness.
Possible Benefits
· Regardless of the group a participant is assigned to, he or
she will receive at a minimum the best widely accepted
standard treatment.
· If a participant is taking the new treatment and it is shown to work,
he or she may be among the first to benefit.
Possible Risks
· New treatments under study are not always better than, or even
as good as, standard treatment.
· New treatments may have side effects that are worse than those
of standard treatment.
· Despite phase 1 and 2 testing, unexpected side effects may occur.
· If the new treatment has benefits, it still may not work for every
participant (just as standard treatments do not help everyone).
· Participants receiving the standard treatment may not benefit as
much as those receiving the new one.
Finding Out About Standard Cancer Care
Standard cancer care is the accepted and widely used
treatment for a certain type of cancer. It is based on the results
of past research. The National Cancer Institute's Web site
www.cancer.gov contains a database of the latest information
about cancer and clinical trials. Specialists review current
literature from more than 70 medical journals, evaluate its
relevance, and synthesize it into clear summaries for the public
and health professionals. Many of the summaries are also
available in Spanish.
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Phase 4
Phase 4 trials are used to further evaluate the long-term safety and
effectiveness of a treatment. Less common than phase 1, 2, and 3
trials, phase 4 trials usually take place after the new treatment has
been approved for standard use.
Other Types of Trials
Adjuvant and Neoadjuvant Treatment Trials
Adjuvant trials are additional therapy after standard treatment. They
are designed to prevent the recurrence of cancer in people who no
longer show clinical evidence of disease. Adjuvant trials attempt to
treat the subclinical or microscopic disease thought to be responsible
for cancer recurrence and therefore improve disease-free and overall
survival. The combination of standard and adjuvant treatments is
initially tested in a small feasibility or pilot study similar to a single-
agent phase 2 trial. This is followed by a randomized phase 3 trial if
the combination proves safe and effective.
Neoadjuvant trials are additional therapy before standard
treatment. These trials evaluate treatments designed to reduce
tumor size to a point where it can be definitively treated by
therapies that are considered the best standard treatment. For
example, clinical trials have shown that chemotherapy can reduce
an inoperable breast cancer to a size that can be removed surgically.
Both adjuvant and neoadjuvant trials are phased like other
treatment protocols, with the phase dependent on the major
objective of the trial.
Who Participates
People who have no clinical evidence of disease after primary
treatment, but who are at high risk of recurrence, participate in
adjuvant trials. People whose cancer, once reduced, could be
effectively treated by therapies considered the best standard
treatment participate in neoadjuvant trials.
The Clinical Trial Process
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Prevention Trials
Cancer prevention trials are designed for people at risk of
developing cancer. The trials evaluate the safety and effectiveness
of various risk-reduction strategies. The two types of prevention
trials answer the following questions:
· Action trials: Can a person's actions--such as exercising more
or quitting smoking--prevent cancer?
· Agent trials: Can taking certain medicines, vitamins, minerals,
or food supplements lower the risk of certain types of cancer?
(Agent trials are also known as chemoprevention trials.)
Chemoprevention trials compare a promising new prevention
agent or technique with a standard agent or technique, or placebo.
The investigational group takes the agent being studied; the
control group takes either the standard agent that is being
compared with the study agent or--because there may be no
standard agent--a look-alike agent that contains no active
ingredient, called a placebo.
Who Participates
Prevention trials seek participants from various age groups and
socioeconomic backgrounds or people who have combinations of
cancer risk factors. Participants in prevention trials are otherwise
healthy individuals who are at risk for cancer.
Possible Benefits
· If the intervention being studied is found to be effective,
participants may be among the first to benefit.
Possible Risks
· New cancer prevention interventions may have unknown side
effects or risks.
· The drug intervention may have worse side effects or be less
effective than standard preventive measures.
· Even if a new drug or intervention is effective, it may not work
for every participant.
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Screening Trials
Screening trials assess the effectiveness of new means of detecting
the earliest stages of cancer. In addition, these trials examine
whether early treatment improves overall survival or disease-free
survival. Screening tools include imaging tests and laboratory tests.
Who Participates
Participants are healthy and may be chosen to represent particular
age groups or socioeconomic backgrounds. Screening trials also
seek participants with certain cancer risk factors, such as
belonging to a family that has a genetic predisposition to cancer.
Possible Benefits
· For many types of cancer, detecting the disease at an early stage
can result in earlier treatment and an improved outcome.
· Screening trials often encourage participants to continue screening
on a regular basis, which can lead to improved health overall.
· Screening trials for people with a genetic predisposition to
cancer can alert other family members to begin regular cancer
screening, aid in early detection, and help in the diagnosis and
treatment of potential cancers.
Possible Risks
· Some of the imaging procedures used in screening may be
uncomfortable or require participants to be in confined spaces
for some period of time.
· If an imaging technique is being studied, participants may be
exposed to x-rays or radioactive substances.
· Tests can be time consuming.
The Clinical Trial Process
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Diagnostic Trials
Diagnostic trials develop better tools for physicians to use in
classifying types and phases of cancer, and in managing the care of
people with cancer. Some trials compare the ability of two
diagnostic techniques to provide information about a suspected
cancer. Genetic tests are being evaluated as diagnostic tools to
classify cancers further, thus helping physicians direct cancer
therapy and improve treatments for people with specific genetic
mutations. Diagnostic trials may also evaluate techniques
designed to measure and monitor cancer response more accurately
or less invasively, such as using a new imaging tool that eliminates
the need for surgery.
Who Participates
Participants include people with cancer or symptoms
suggesting cancer.
Possible Benefits
· The diagnostic test under investigation may be better and less
invasive than current tests.
· A new diagnostic tool may help detect cancer recurrence, which
could lead to improved outcomes.
Possible Risks
· Participation in a diagnostic trial may require people to take
multiple tests.
Genetics Trials
Actual genetic intervention (such as gene-transfer) trials are few in
number, however trials are under way where actual cellular
manipulation at the gene level occurs. Most genetics research
involves looking at tissue or blood samples from large populations
of people in order to determine how genetic make-up can
influence detection, diagnosis, prognosis, and treatment. This
genetic epidemiologic research does not involve any actual
intervention. Rather, it is designed to broaden understanding of
the causes of cancer. Genetics research is also being used to
develop targeted treatments based on the genetics of a tumor.
Genetics research is a critical component of cancer research
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because it helps scientists understand the causes of cancer and can
lead to developing clinical trials for the prevention, detection, and
treatment of cancer.
Quality-of-Life and Supportive Care Trials
Quality-of-life and supportive care trials test interventions
designed to improve quality of life for people with cancer and
their families. They seek better therapies or psychosocial
interventions for people experiencing nutrition problems,
infection, pain, nausea and vomiting, sleep disorders, depression,
and other effects of cancer or its treatment. Some supportive care
trials target families and caregivers to help them cope. The
effectiveness of supportive care trials may be measured either:
· Subjectively: Is the person's pain reduced?
· Objectively: Are the white blood cell counts improved?
Who Participates
Participants include:
· People who are interested in relief from the effects of cancer
or its treatment
· Family members or others who want support in caregiving or
meeting their own needs
Possible Benefits
· If the intervention is found to be effective, a person with cancer
and his or her family may be among the first to benefit.
Possible Risks
· People may not benefit from participating in the trial.
The Clinical Trial Process
17

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Special Access Programs
Investigational drugs may be made available for use outside of
a clinical trial. Working with NCI and other sponsors, FDA has
established special conditions under which a person with cancer can
receive unapproved cancer drugs that have shown clinical benefit.
Group C
In the 1970s, NCI researchers became concerned about the time
it took to bring to market investigational drugs found to have
antitumor activity. Working with FDA, NCI established the "Group
C" classification to allow access to drugs with reproducible activity.
Group C agents are investigational drugs provided by the National
Cancer Institute to properly trained physicians for the treatment
of individual patients who meet specific eligibility criteria within
this category and are treated according to a protocol.
Each Group C drug protocol specifies eligibility, reporting
methodology, and drug use. Group C designation speeds new drugs
to people who need them most. The process allows NCI to gather
important information on the safety as well as activity of the drugs
in the settings where they will be most used after FDA approval.
Drugs are placed in the Group C category by agreement between
FDA and NCI. Group C drugs are always provided free of charge,
and the Centers for Medicare and Medicaid Services (formerly the
Health Care Financing Administration) provides coverage for its
beneficiaries for care associated with Group C therapy.
Treatment IND
In 1987, FDA began authorizing the use of new drugs still in the
development process to treat certain seriously ill people. In these
cases, the process is referred to as a treatment Investigational New
Drug (IND) application. Clinical trials of the new drug must
already be under way and have demonstrated positive results.
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FDA sets guidelines about:
· What serious and life-threatening illnesses constitute
· How much must be known about a drug's side effects and benefits
· Where physicians can obtain the drug for treatment
For many seriously ill people, the possible benefits outweigh the
risks associated with taking an unapproved drug.
Less common ways that people can receive investigational drugs
are through expanded access protocols or mechanisms known as
special or compassionate exception.
Expanded Access Protocols
Expanded access protocols are available for a limited number of
well-studied investigational drugs awaiting final FDA approval.
Expanded access allows a wider group of people to be treated
with a drug. The purpose is to make investigational drugs that
have significant activity against specific cancers available before
the FDA approval process has been completed.
The IND sponsor must apply to FDA to make the drug available
through an expanded access protocol. There must be enough
evidence from completed trials to show that the drug may be
effective to treat a specific type of cancer and that it does not have
unreasonable risks. FDA generally approves expanded access only
if no other satisfactory treatments are available for the disease.
Special or Compassionate Exception
People who do not meet the eligibility criteria for a clinical trial of
an investigational drug may be eligible to receive the drug. The
person's doctor contacts the trial sponsor and provides the
person's medical information and treatment history; requests are
evaluated on a case-by-case basis. FDA must approve each request
to provide the drug outside a clinical trial. There should be
reasonable expectation that the drug will prolong survival or
improve quality of life.
The Clinical Trial Process
19

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Considerations when determining whether a person may receive
an investigational drug as a special exception include:
· Is the person ineligible for a clinical trial?
· Have standard therapies been exhausted?
· Is there objective evidence that the investigational agent is
effective for the person's type of disease?
· Can the drug potentially benefit the person?
· What is the risk to the person?
In some cases, even people who qualify might not be able to
obtain the drug if it is in limited quantity and high demand.
Refer to the case study in section 7, page 73, for a review and summary
of content covered in this workbook.
20
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2.
Clinical
Interpretation
Trial
Design
of
Results
and

---

2
Clinical Trial Design and
Interpretation of Results
Learning Objectives
· Define key members of the research team
· Review key components of a clinical trial
· Describe the purpose of the randomization, stratification,
and blinding in clinical trial protocols
· Name common statistical methods used to interpret clinical
trial results
Clinical trials follow strict scientific guidelines that dictate how a
study is designed and who participates in it. The reasons for these
guidelines may not be immediately clear to a person urgently
seeking treatment, but they protect people and provide
scientifically sound results that can lead to truly effective therapies
and techniques.
Research Team Members
Designing and implementing a clinical trial requires the many
talents of a multidisciplinary research team. Each team may be set
up differently, depending on an institution's policy and resources.
Typical team members and their responsibilities include:
· Principal investigator--oversees all aspects of a clinical trial,
specifically, concept development; protocol writing; protocol
submission for institutional review board (IRB) approval;
participant recruitment; informed consent; and data collection,
analysis, interpretation, and presentation.
Clinical Trial Design and Interpretation of Results
21

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· Research nurse--coordinates the clinical trial and educates
staff, participants, and referring health care providers. This
nurse acts as an information conduit from the clinical setting to
the principal investigator and vice versa, and assists the
principal investigator with toxicity and response monitoring,
quality assurance, audits, and data management and analysis.
· Data manager--handles the management of clinical trial data,
including electronic data entry. Collaborates with the principal
investigator and research nurse to identify what participant
data will be tracked. The data manager also provides data to
monitoring agencies and prepares summaries for interim and
final data analysis.
· Staff physicians and nurses--administer treatment to
participants as specified in the protocol; assess and record
toxicity, drug tolerance, and adverse events; collaborate with
the principal investigator and research nurse in observing and
reporting clinical trends; and provide clinical management and
participant education.
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Components of a Clinical Trial
Protocol
Every trial has a written, detailed action plan called a protocol. The
protocol provides the background, specifies the objectives, and
describes the design and organization of the trial. Every site
participating in the trial uses the same protocol, ensuring consistency
of procedures and enhancing communication. This uniformity
ensures that results from all sites can be combined and compared.
The clinical trial protocol answers the following questions:
· What is the scientific rationale or basis for conducting the trial?
· What are the objectives?
· How many participants will be in the trial?
· Who is eligible to participate? (This is determined on the basis
of factors such as age and disease status.)
· What is the intervention, and what is its duration or schedule?
· What side effects might there be?
· What medical tests or followup visits will participants
have? How often?
· What information will be gathered about participants?
· What are the endpoints of the trial?
Clinical Trial Design and Interpretation of Results
23

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The following FDA-required protocol elements help investigators
answer the questions above and assist participants and health care
professionals in understanding the goals of a clinical trial:
· General information
· Background information (with relevant references from
the scientific literature)
· Trial objectives and purpose
· Trial design
· Participant selection and withdrawal
· Participant treatment
· Efficacy assessment
· Safety assessment
· Statistics
· Direct access to source data and documents
· Quality control and quality assurance
· Ethics
· Data handling and record keeping
· Financing and insurance
· Publication policy
· Supplements
Eligibility Criteria
Participant eligibility criteria can range from general (age, sex,
type of cancer) to specific (prior treatment, tumor characteristics,
blood cell counts, organ function). Eligibility criteria may also vary
with trial phase. In phase 1 and 2 trials, the criteria often focus on
making sure that people who might be harmed because of
abnormal organ function or other factors are not put at risk.
Phase 2 and 3 trials often add criteria regarding disease type
and stage, and number of prior treatments.
Eligibility criteria might be very detailed if researchers think that a
drug will work best on a specific type of cancer or population.
Trials with narrow eligibility criteria might be complicated to
conduct and might produce less widely applicable results.
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Researchers therefore attempt to include as many types of people
as possible in a clinical trial without making the study population
too diverse to tell whether the treatment might be as effective on a
more narrowly defined population. The more diverse the trial's
population, the more useful the results could be to the general
population, particularly in phase 3 trials. Results of phase 3 trials
should be as generally applicable as possible in order to benefit the
maximum number of people.
The trend today is toward broadening eligibility criteria for
phase 3 clinical trials. Less restrictive criteria may enable more
researchers and people with cancer to participate in these trials.
With more participants, the disadvantages of having a more
diverse population will be outweighed by the results applying
more generally to the population.
Endpoints
An endpoint is a measurable outcome that indicates an
intervention's effectiveness. Endpoints differ depending on the
phase and type of trial. For instance, a treatment trial endpoint
could be tumor response or participant survival. Quality-of-life or
supportive care trial endpoints could include participants' welfare
and control of symptoms.
Examples of endpoints include:
· Tumor response rate--the proportion of trial participants
whose tumor was reduced in size by a specific amount, usually
described as a percentage. If 7 of 10 patients responded, the
response rate is 70 percent.
· Disease­free survival--the amount of time a participant
survives without cancer occurring or recurring, usually
measured in months.
· Overall survival--the amount of time a participant lives,
typically measured from the beginning of the clinical trial until
the time of death.
Tumor response rate is a typical endpoint in a phase 2 treatment
trial. However, even if a treatment reduces the size of a participant's
Clinical Trial Design and Interpretation of Results
25

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tumor and lengthens the period of disease-free survival, it may not
lengthen overall survival. In such a case, side effects and failure to
extend overall survival might outweigh the benefit of longer
disease-free survival. Alternatively, the participant's improved
quality of life during the tumor-free interval might outweigh other
factors.
Because tumor response rates are often temporary and may not
translate into long-term survival benefits for the participant,
response rate is a reasonable measure of a treatment's effectiveness
in a phase 2 trial, whereas participant survival and quality of life
are better endpoints in a phase 3 trial.
Randomization
In phase 3 trials (and some phase 2 trials) participants are assigned
to either the investigational or control group by chance, via a
computer program or table of random numbers. This process,
called randomization, gives each person the same chance of being
assigned to either group. Randomization ensures that unknown
factors do not influence the trial results.
5
Control Group
9
8
7
3
5
4
1
3
2
Randomization
6
10
9
7
8
2
1
10
6
4
Investigational Group
Randomization is a method used to prevent bias in research. A computer or a table
of random numbers generates treatment assignments, and participants have an
equal chance to be assigned to one of two or more groups (e.g., the control group
or the investigational group).
26
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If physicians or participants themselves chose the group, assignments
might be biased. Physicians, for instance, might unconsciously assign
participants with a more hopeful prognosis to the experimental group,
thus making the new therapy seem more effective than it really is.
Conversely, participants with a less hopeful prognosis might pick the
experimental treatment, leading it to look less effective than it really is.
Randomization tends to produce comparable groups in terms of
factors affecting prognosis and other participant characteristics. In
this way, randomization guarantees the validity of the conclusion
concerning the effectiveness of the treatment.
Stratification
Stratification is used in randomized trials when factors that can
influence the intervention's success are known. For instance,
participants whose cancer has spread from the original tumor site
Control Group
7
10
4
2
10
Randomization
12
9
12
8
Investigational Group
1
Stratification
7
5
2
Control Group
9
8
1
6
Randomization
6
5
11
3
11
Investigational Group
4
3
Stratification is a process used in randomized trials when factors that can influence
the intervention's success are known. Assignment of interventions within the two
groups is then randomized. Stratification enables researchers to look in separate
subgroups to see whether differences exist.
Clinical Trial Design and Interpretation of Results
27

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can be separated, or stratified, from those whose cancer has not
spread. Assignment of interventions within the two groups is
then randomized. Stratification enables researchers to look at
factors in both groups.
Blinding
Trials set so that participants do not know which intervention they
are receiving are known as single-blinded trials. Those in which
neither researchers nor participants know who is in the
investigational or control group are called double-blinded trials.
Double-blinded trials ensure that people assessing the outcome
will not be influenced by knowing which intervention a
participant is receiving and also that ancillary followup treatment
will be the same.
Data Collection and Management Tools
Most research teams use standardized and newly created tools to
collect, process, analyze, and audit data. Tools vary in format from
visual analog scales to open-ended questionnaires. Examples of
tools for participants to use to self-report data include diaries,
calendars, logs, and surveys.
The case report form is the basic tool of data abstraction. Many
reports use a Web-based format, others are paper-based. NCI is
constructing an informatics system that will reduce the extensive
paperwork often associated with clinical trials. For example, the
Common Toxicity Criteria (CTC), a Web-based, interactive
application, uses standardized language to identify and grade
adverse events in cancer clinical trials. Forms are also available for
rapid reporting of adverse events, electronically or by telephone,
to alert researchers to potential safety issues. The Adverse Event
Expedited Reporting System (AdEERS) is a Web-based program
that enables researchers using NCI-sponsored investigational
agents to expedite the reporting of serious and/or unexpected
adverse events directly to NCI and FDA.
28
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Using Statistics to Interpret Results
Researchers use statistical methods to determine whether an effect
observed in a clinical trial is real (statistically significant) or caused
by chance (not statistically significant). Although the examples
included here use terminology and illustrations from treatment
trials, these statistical techniques apply to all types of clinical trials.
Key Terms
Familiarity with the following terms is useful in understanding
how researchers use statistics to interpret clinical trial results:
· p-values reflect the likelihood that the results of a clinical trial
are because of chance rather than due to a real difference
between the tested treatments. The smaller the value of p, the
greater the likelihood that the results are not because of chance.
A p-value of 0.05 (that is, 1 in 20) or smaller is widely accepted
as an indication that the results are statistically significant.
· Confidence intervals reflect a range of values of the true value
that would be obtained if everyone with a particular cancer
were treated with the treatment under study. The wider the
interval, the more variable the result and the less likely it is to
be close to the true value. Confidence intervals are typically
thought of as the approximate bounds or limits of the true
value. Researchers frequently use either a 95 or a 99 percent
confidence interval.
· Sample size is the number of people participating in a trial.
· Statistical power refers to the chance of finding a statistically
significant result when there is one. Ideally, statistical power
should be 0.80 or 0.90--reflecting an 80 to 90 percent chance of
detecting that the true difference in treatment effectiveness is
the smallest size considered medically important to detect.
· Relative risk is the likelihood that cancer will occur within a
specific timeframe in one group versus another.
Clinical Trial Design and Interpretation of Results
29

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Statistical Significance
The result of a clinical trial can be statistically significant (not due
to chance) without being clinically significant (medically
important). Suppose, for instance, that a group receiving an
experimental treatment has a 2 percent higher survival rate than
the group receiving the standard treatment. This difference could
be statistically significant, but if participants who survive longer
experience serious side effects, it may not be medically important.
In this case, the side effects might be worth tolerating only if the
experimental treatment group has a 10 percent higher survival
rate. Good trial planning and interpretation take into consideration
both medical importance and statistical significance.
The results of a trial are usually considered statistically significant
when data comparison results in a p-value of 0.05 or smaller. If the
p-value is 0.01 or even 0.001, the results are considered even more
significant because there is less likelihood that the results are due
to chance.
Confidence intervals are often useful data for researchers because
they enable researchers to generalize the results of the trial to
the population.
For example, in a treatment trial with an investigational and a
control group, the mean (average) values of the endpoints (e.g.,
survival for 5 years after treatment) are calculated separately for
each group. Then the standard error--how far the values extend
on either side of the mean--is calculated for each group. The less
overlap between the confidence interval for the standard treatment
group and the experimental treatment group, the more likely the
difference between the groups is statistically significant. Research
reports typically include confidence intervals, for example:
The rate of 5-year survival for group A was 73 percent
(95% confidence interval, 65.7% to 80.3%). The rate of 5-year
survival for group B was 58 percent (95% confidence
interval, 49.8% to 66.2%). p = 0.004.
30
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In this case, the confidence intervals come close to each other--
65.7 percent and 66.2 percent--but do not overlap. The p-value is
definitely statistically significant.
Confidence intervals can give an indication of whether the results
of small-sized trials that are not statistically significant are
nevertheless medically significant. They can be particularly
important tools when the trial size is limited because the type of
cancer is rare.
Trial Size
The number of participants in a clinical trial greatly influences its
statistical significance. With too few participants, a trial does not
generate enough information to draw a conclusion, and important
results may be missed. On the other hand, by testing more people
than needed to obtain statistically significant results, a trial takes
longer to produce results and may give ineffective or unsafe
therapy to more people than necessary.
When planning a clinical trial, researchers first decide how large a
difference between treatment groups is medically important. Next,
they calculate sample size, or how many people should be enrolled
in the trial. The sample should include enough participants to get a
statistically significant result (a p-value of 0.05 or smaller).
Sample size also influences the statistical power of the research
and is calculated before the trial begins. As sample size increases,
statistical power increases. Ideally, power should be 0.80 or 0.90.
Calculating statistical power helps a researcher decide how many
people to enroll in a trial.
Relative Risk
Relative risk usually describes the risk of getting cancer based
on lifestyle, environmental exposure to cancer-causing agents,
or family history of disease. However, when used in cancer clinical
trial reports, relative risk usually indicates the likelihood that
cancer will occur within a specific timeframe in one group
versus another.
Clinical Trial Design and Interpretation of Results
31

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Intention to Treat
Phase 3 trials are often analyzed on an intention-to-treat basis--
that is, all participants who were initially admitted into the trial
and randomized are included in the primary analysis. Intention-
to-treat analysis therefore includes people who:
· Did not follow instructions
· Can no longer be located or contacted
· Withdrew from the trial
· Did not receive treatment
Including data from the groups above may weaken the results of a
trial, but excluding the data would bias the trial. For instance, if
half of the people in a treatment group withdrew because they
thought the drug they were taking was ineffective and had severe
side effects, and if the other half of the group had a 50 percent
response rate, then excluding the data from the participants who
withdrew makes the drug appear to be 50 percent effective. The
actual response rate is 25 percent. Intention-to-treat analysis
typically excludes participants who were ineligible to be included
in the trial but were randomized.
Refer to the case study in section 7, page 73, for a review and summary
of content covered in this workbook.
32
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3.
Advancing
Clinical
Trials
Cancer
Care
Through
37

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3
Advancing Cancer Care
Through Clinical Trials
Learning Objectives
· Describe the FDA drug approval process
· Describe how clinical trial results are released
· Describe clinical trials that have led to advances in cancer
prevention, detection, and treatment
· Discuss the importance of professional referral and patient
participation in the research process
Once phase 1 and 2 treatment trials are completed, the data are
analyzed and, if the treatment shows promise, it moves into phase 3
trials. As soon as the treatment sponsor thinks that phase 3 data
show it is safe and superior to standard treatment, the sponsor may
submit a New Drug Application (NDA) or a Biologics License
Application (BLA), to FDA for approval. At this stage, FDA
approves only the claim being made about the drug or intervention,
not the drug or intervention itself.
FDA Approval Requirements
A New Drug Application includes:
· The exact chemical or biological makeup of the therapy and the
mechanisms by which it is thought to be effective
· Results of animal studies
· Results of clinical trials
· How the drug or therapy is manufactured, processed,
and packaged
· Quality control standards
· Information about drug or intervention samples of the product
in the form(s) in which it is to be administered
Advancing Cancer Care Through Clinical Trials
33

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FDA assesses applications in order of importance, giving first
priority to interventions with the greatest potential benefits. All
drugs that offer significant medical advances are considered
priority drugs in the approval process.
Independent advisory committees of professionals from outside
the agency give expert advice and guidance in making decisions
about drug approval. By law, these committees include both a
patient representative and a consumer representative. One such
committee is the Oncologic Drugs Advisory Committee, which
meets regularly to consider most cancer-related treatments and
preventive drugs. The committee assesses the safety, effectiveness,
and appropriate use of products considered for approval.
As FDA looks at the sponsor's data and its own review results, it
applies two questions to each application:
1. Do the results of well-controlled clinical trials provide
substantial evidence of effectiveness?
2. Do the results show that the product is safe under the proposed
conditions of use? (In this context, "safe" means that potential
benefits outweigh any known risks.)
Once FDA has approved a new drug, the drug is "labeled" for a
specific use. This label includes information on eligibility, dose,
safety, and adverse effects. The agency's responsibility for new
treatments does not stop with final approval. FDA also:
· Implements and tracks programs to make sure manfacturers
comply with standards and practice regulations
· Monitors new drug advertising to make sure it is truthful
and complete
· Handles feedback from health professionals and consumers
about effectiveness, adverse reactions, and potential problems in
labeling and dosage
CANCER CLINICAL TRIALS: THE IN-DEPTH PROGRAM
34

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Releasing the Results
The results of a clinical trial are usually reported first in peer-
reviewed scientific journals. If the results appear to have significant
medical importance, researchers make a public announcement
when the formal report is submitted for publication, ensuring that
people benefit from the new treatment as soon as possible.
Particularly important results are featured by the media and widely
discussed at scientific meetings and within advocacy groups.
Clinical trial results are not available to the public as the trial
progresses because:
· Knowing interim results could influence medical personnel and
participants in the trial, biasing the results
· Statistical analysis might be less meaningful, compromising the
accuracy of the findings
In the absence of very clear evidence that a trial should be stopped
early for medical reasons, trials are completed before reporting
results. Interim results are unavailable to the public, and often
to the research teams. Independent data and safety monitoring
boards track phase 3 trial data. These boards alert researchers
about any safety or effectiveness issues that arise during the trial.
Data and safety monitoring plans are also in place for many
phase 1 and 2 trials.
Research progresses in small steps, and sometimes publishing the
results of a trial is not as important as taking what was learned from
the trial and building on it in a new trial. To find the results of a
clinical trial, search a medical literature database, like Medline or
PubMed, available online through the National Library of Medicine
(www.nlm.nih.gov) and at medical institutions' libraries. The "closed
protocol" file in NCI's PDQ® (Physician Data Query) may contain
related studies (see section 6 for more information on PDQ).
It often takes more than a year for a scientific paper to be written,
submitted, reviewed, edited, and published. If an initial literature
search turns up nothing, try again after some time has passed.
Advancing Cancer Care Through Clinical Trials
35

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Improving Cancer Care
Once an intervention is proven safe and effective, it may become
the new standard of care. Thus, current cancer care is based on
the results of past clinical trials. Recent clinical trials have
resulted in the following treatment benefits for people with
chronic myelogenous leukemia, cervical cancer, breast cancer,
and melanoma.
Chronic Myelogenous Leukemia--A New
Treatment Option
In 2001, FDA approved GleevecTM, offering a new treatment option
for many people with chronic myelogenous leukemia (CML). Until
then, bone marrow transplantation in the initial chronic phase of
the disease was the only known effective therapy for CML.
However, this is not an option for many people, and the procedure
can cause serious side effects or death. Another option, treatment
with the drug interferon alfa, may produce remission (a decrease
in or disappearance of signs and symptoms of cancer) for many
people. But if the drug is ineffective or people stop responding to
it, their prognosis is generally bleak.
In three short-duration, early-phase clinical trials with Gleevec,
researchers found that people with CML either had higher
remission rates than expected or they had few side effects.
Gleevec was designed to target an abnormal version of a
cellular protein present in nearly all people with CML. The
abnormal protein is much more active than the normal version
and probably causes the disease. By blocking the abnormal
protein, called BCR-ABL, Gleevec kills the leukemia cells.
Gleevec represents a new class of cancer drugs, which target
abnormal proteins that are fundamental to the cancer itself.
Cervical Cancer--Improved Survival Rates
For many years, the standard therapy for invasive cervical cancer
was surgery or radiation alone. Five large clinical trials showed
that women with invasive cervical cancer have improved survival
CANCER CLINICAL TRIALS: THE IN-DEPTH PROGRAM
36

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rates when they receive a cisplatin-containing chemotherapy
regimen plus radiation therapy.
Breast Cancer
Less Extensive Surgery, Same Survival Time
For many years, the standard therapy for all breast cancers was a
modified radical mastectomy with radiation or chemotherapy.
Clinical trials showed that for women with early-stage disease,
long-term survival after lumpectomy with axillary lymph node
dissection plus radiation therapy is similar to survival after
modified radical mastectomy.
Reduced Risk for Women at High Risk
Traditionally, women seeking to reduce their risk of breast cancer
had no clear option. A large phase 3 clinical trial assessed risk
reduction in women taking the drug tamoxifen. The trial found
that high-risk women who took the drug for up to 5 years (an
average of 4 years) had 49 percent fewer diagnoses of invasive
breast cancer than those taking a placebo.
Melanoma--Improved Survival
According to the findings of a large, randomized clinical trial,
compared with low-dose interferon or no therapy, high-dose
interferon alfa-2b (Intron-A) significantly prolongs disease-free
survival for people at high risk for melanoma recurrence.
Biological Therapy
Biological therapy (sometimes called immunotherapy, biotherapy,
or biological response modifier therapy) uses the body's immune
system, either directly or indirectly, to fight cancer or to lessen the
side effects that some cancer treatments might cause.
The immune system is a complex network of cells and organs that
work together to defend the body against attacks by "foreign," or
"nonself," invaders. This network is one of the body's main
defenses against disease. It works against disease, including
cancer, in a variety of ways. For example, the immune system may
recognize the difference between healthy cells and cancer cells in
the body, and work to eliminate those that become cancerous.
Advancing Cancer Care Through Clinical Trials
37

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Biological therapies are designed to repair, stimulate, or enhance
the immune system's responses. Many clinical trials are testing the
use of biological therapies, such as monoclonal antibodies and
vaccines, to treat cancer.
Monoclonal Antibodies
Monoclonal antibodies (MOABs) are a form of biological therapy
now being studied in the laboratory and in clinical trials.
MOABs are designed to fill a critical gap in the body's immune
system. Although the human body naturally produces antibodies
to identify and fight off viral and bacterial infections, the immune
system may not always recognize cancer cells as harmful. This is
because some cancer cells do not possess an antigen on their cell
membrane that is capable of eliciting an immune response.
Therefore, cancer is able to grow and spread unchecked. MOABs
are being developed to supplement the body's immune system by
recognizing and attacking specific proteins that cancer cells
express. These specific antibodies may be active on their own, or
they may be linked to a drug to allow specific delivery of the drug
to the cancer cell.
Basic immunologic research identified a molecule specific to the
surface of B-lymphocytes that also is highly expressed on the
surface of most lymphomas. An antibody directed against this
molecule was shown to be capable of killing cells. Over several
years, researchers tried to engineer the antibody and succeeded.
In 1997 FDA approved rituximab, now used to treat people with
low-grade lymphoma.
Cancer Vaccines
Cancer vaccines are another form of biological therapy being
studied in the laboratory and in clinical trials. Researchers are
developing vaccines that may promote the recognition of cancer
cells by a person's immune system. These vaccines may help the
body reject tumors and prevent cancer from recurring. In contrast
to vaccines against infectious diseases, cancer vaccines are
designed to be injected after the disease is diagnosed, rather than
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38

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before it develops. Vaccines given when the tumor is small may be
able to eradicate the cancer. Cancer vaccines being tested in clinical
trials are designed to treat cancer by getting the immune system to
attack existing cancerous cells. Many vaccines are not used alone,
but in combination with surgery, chemotherapy, or other
interventions that help stimulate the immune response in general.
Early attempts to vaccinate people with cancer against the disease
have been directed largely at melanoma, a potentially deadly skin
cancer with easily accessible tumors. Researchers are also
conducting studies that may lead to the development of vaccines
for lymphoma, prostate, lung, breast, colon, and other cancers.
Speeding Up Drug Development
In the recent past, it has taken 15 years, on average, for an
experimental drug to travel from the laboratory to U.S. consumers.
Often the longest part of the process is finding people to
participate in each clinical trial phase. With increased public
awareness about clinical trials, more people may be willing to
participate, and more professionals may refer people into
appropriate trials. This awareness would ultimately reduce the
time it takes for researchers to enroll participants in trials and
complete them­­and speed up the movement of new drugs or
treatments into standard care.
Decisions to Advance Drug Development
Investigators make decisions about how to proceed with further
research based on scientific evidence and promising basic research
leads. Even if some participants in a clinical trial had a positive
response to a new treatment, researchers must look at the global
experience of all participants when deciding whether or not to
continue or expand trials. In some trials, more participants treated
with standard therapy may have better results than those treated
with the experimental therapy, and the investigator may decide to
continue research in a different direction.
Advancing Cancer Care Through Clinical Trials
39

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The Drug Development and Approval Process
Total Years for
Preclinical Testing
Clinical Trials
Post-Clinical Trials Drug Approval
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Step 7
Laboratory/
1
File IND
Phase 1
Phase 2
Phase 3
File NDA3
FDA
preclinical
application
or BLA4
approval
testing
with FDA2
with FDA
Assess
Obtain FDA
Determine
Evaluate
Determine
Inform the
Review
safety and
approval to
what dosage
effective-
whether
FDA of Phase
process/
biological
begin clinical
is safe, how
ness, look for
the new
3 data which
approval
activity
testing in
treatment
side effects
treatment
supports
in the
humans after
should be
(or new
drug safety
Purpose
promising
given
use of a
and better
laboratory
results in
treatment)
performance
and in
laboratory
is a better
over current
animal
alternative
standard
models
to current
treatment
standard
All
anticancer
drugs
4.4 years
8.6 years
1.4 years
14.4 years
(average
number
of years)
All drugs*
(average
3.8 years
10.4 years
1.5 years
15.7 years
number
of years)
1IND = Investigational New Drug
2FDA = Food and Drug Administration
3NDA = New Drug Application
4BLA = Biologics License Application
* Classified as "new chemical entities," which exclude diagnostic agents, vaccines, and other biological compounds.
Sources: DiMasi, J.A. (2001). New drug development in the United States 1963-1999. Clinical Pharmacology and
Therapeutics, May; 69(5); Tufts Center for the Study of Drugs Development, Tufts University; adapted from Pharmaceutical
Research and Manufacturers of America.
Refer to the case study in section 7, page 73, for a review and summary of content covered in
this workbook.
CANCER CLINICAL TRIALS: THE IN-DEPTH PROGRAM
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4.
Participant
Clinical
Trials
Protection
in

---

4
Participant Protection
in Clinical Trials
Learning Objectives
· Recognize historical events and their influence on the
development of safeguards for participants in clinical trials
· Identify Government regulations and agencies related to
patient protection
· Describe current methods of participant protection that are
implemented throughout the research process
Evolution of Participant Protection
The strong national and international safeguards in place today to
protect research participants evolved from notorious abuses of
human rights in the past. The first formal statement of medical
ethics regarding research in humans emerged from the 1946 trial
and conviction in Nuremberg, Germany, of Nazi physicians and
scientists who conducted experiments on concentration camp
inmates during World War II. The Nuremberg Code outlined broad
concepts for the protection of human subjects and forms the basis
of today's international code of ethics for the conduct of research.
In the United States, three infamous clinical trials called attention
to the need for participant protection:
· The Tuskegee syphilis study, held from 1932 to 1972, followed--but
did not treat--poor black men who had syphilis. During the
trial, the men were offered "special free medical care" and were
told that they would be treated for "bad blood." Instead, more
than 400 men with syphilis and 200 men without the disease
who served as controls were enrolled in an observational clinical
trial without their knowledge or consent. By 1963, it was apparent
that many more infected men than controls had developed
complications, and 10 years later a report on the trial indicated that
Participant Protection in Clinical Trials
41

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the death rate among those with syphilis was roughly double that
of the controls. In the 1940s, penicillin was found to be effective in
the treatment of syphilis, but researchers in the trial, which
continued for almost 30 years after the discovery, neither informed
nor treated subjects with the antibiotic.
· From 1963 to 1966, researchers deliberately infected newly
admitted "mentally defective" children at the Willowbrook
School, a State school in New York, with the hepatitis virus in
order to study the natural history of the disease under
controlled circumstances. In some cases, parents were not
allowed to admit children to the institution unless they agreed
to let them participate in the trials.
· In 1963, physician-investigators at the Jewish Chronic Disease
Hospital in Brooklyn, New York, injected cancer cells grown in
the lab into people hospitalized with various chronic diseases
without informing the people or gaining their consent. In
review proceedings, the Board of Regents of the State University
of New York found that the trial had not been presented to the
hospital's research committee; the researchers were found guilty
of fraud, deceit, and unprofessional conduct.
In 1974, in response to these tragedies, the President established
the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research. In 1979, the commission
issued the Belmont Report, which delineated the ethical principles
upon which today's regulations regarding research participants in
the United States are based:
· Respect for persons--recognition of the personal dignity and
autonomy of individuals, as well as special protections for
people with diminished autonomy
· Beneficence--the obligation to protect people from harm
by maximizing unanticipated benefits and minimizing possible
risk of harm
· Justice--fairness in the distribution of research benefits
and burdens
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In addition, the commission concluded that "a permanent board
with the authority to regulate at least all federally supported
research involving human subjects" should be formed.
In response, Congress passed the National Research Act, which
mandated the establishment of IRBs to review all U.S. Department
of Health and Human Services (DHHS)-funded research. The
procedures established for IRBs were further delineated and
revised in 1981.
For more details on the history of participant protection, the role of
the IRB, and patient confidentialy, see http://cme.cancer.gov.
Government Oversight
Two similar sets of regulations--enforced by HHS's Office for
Human Research Protections (OHRP) and FDA--are in place to
ensure the protection of clinical trial participants. If a trial is
Government-supported and it involves an FDA-regulated drug or
device, then it is subject to both sets of regulations. The basic
requirements for IRBs and informed consent are congruent in the
two sets of regulations.
Office for Human Research Protections
The Office for Human Research Protections (OHRP), formerly
called the Office of Protection from Research Risks, safeguards
participants in federally funded research and provides unity and
leadership for 17 Federal departments and agencies that carry out
research involving human participants. OHRP enforces an
important regulation called the Common Rule (Title 45 CFR Part
46, Subpart A). The Common Rule sets standards for:
· Informed consent process
· Formation and function of IRBs
· Involvement of prisoners, children, and other vulnerable
groups in research
· Many other protective measures
Researchers must provide written statements describing the
Participant Protection in Clinical Trials
43

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organization of the IRB, its procedures for approving trials, and
how clinical trial participants are protected.
Although breaches in participant protection seldom occur, recent
discoveries of inadequate protection have prompted the
restatement of oversight goals and the addition of some new
requirements by OHRP and the National Institutes of Health
(NIH) to strengthen enforcement of the Common Rule, including:
· Aggressive efforts to improve the education and training of
clinical research staff, IRB members, and staff research
administrators regarding protection
· Guidelines to reaffirm the need to audit informed consent
records for evidence of full compliance and confirmation of
consent by investigators
· Submission of monitoring plans for all phase 1 and 2 clinical
trials and the presence of a data and safety monitoring board
for phase 3 trials
· Additional information to clarify regulations regarding conflict
of interest
For a detailed proposal of the Government oversight goals set
forth by former HHS Secretary Donna Shalala, see "Protecting
Research Subjects--What Must Be Done" in the September 14,
2000, issue of the New England Journal of Medicine (343: 808-810).
Food and Drug Administration
FDA has its own regulations and policies on IRB review, informed
consent, and participant protection (Title 21 CFR Parts 50 and 56).
The regulations apply to any clinical trial that involves an
investigational drug, biological product, or other device regulated
by FDA, regardless of whether the trial receives Federal funding.
FDA periodically inspects IRB records and operations to certify the
adequacy of approvals, human subject safeguards, and the
conduct of business.
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Protecting Participants Before a Clinical
Trial Begins
Scientific Review by Sponsor
Clinical trials that are sponsored by NCI are reviewed through
different types of panels, including experts who review the
scientific and technical merit of the proposed research. Many other
clinical trial sponsors, such as pharmaceutical companies, also
seek expert advice on the merits of their studies. Typical issues
addressed by members of expert panels include:
· Significance: Does the trial address an important problem? If its
aims are achieved, how will scientific knowledge be advanced?
What effect will the trial have on current concepts or methods in
the field?
· Approach: Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and
appropriate? Does the applicant acknowledge potential problem
areas and consider alternative tactics?
· Innovation: Does the project employ novel concepts,
approaches, or methods? Are the aims original and innovative?
Does the project challenge existing paradigms or develop new
methodologies or technologies?
· Investigator: Do the principal investigator and other researchers
have sufficient training and experience to carry out the project?
· Environment: Does the scientific environment in which the
work will be done contribute to the probability of success? Do
the proposed experiments take advantage of unique features of
the scientific environment or employ useful collaborative
arrangements? Is there evidence of institutional support?
Institutional Review Board (IRB) Approval
An IRB functions as both a clearinghouse and a monitor of clinical
trials. It determines whether the risks involved in a clinical trial
are reasonable with respect to the potential benefits, and it must
approve any clinical trial before it begins. The IRB also monitors
the ongoing progress of the research.
Participant Protection in Clinical Trials
45

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Federal regulations require that an IRB include at least five people
from diverse occupations and backgrounds. In addition, one
member must be outside the sponsoring institution--that is, not
connected to it by employment or relatives. To meet these
requirements, IRBs are usually made up of a mix of medical
specialists, nurses, other health care professionals, ethicists, and
lay members from the community.
Most institutions that carry out clinical trials have their own
review boards (there are roughly 3,000 IRBs in the United States).
In some cases, a small institution might arrange for its research to
be reviewed by another IRB rather than set up its own. All trials
that are federally funded or evaluate a new drug or medical device
regulated by FDA must be submitted to an IRB. However, many
institutions require that all clinical trials conducted in their
facilities, regardless of funding source, be IRB-approved. Before a
trial can begin, the principal investigator submits an application to
an IRB. The board reviews it on the basis of the following criteria:
· Risks to participants are minimized as much as possible
through sound research design
· Risks to participants are reasonable in relation to the anticipated
benefits and the knowledge that may result
· Participant selection is equitable
· Informed consent is sought in accordance with 45 CFR Part 46.116
· Informed consent is documented in accordance with 45 CFR
Part 46.116
· Provisions are made for monitoring the data collected to ensure
the safety of participants
· Provisions are made to protect the privacy of participants and
the confidentiality of data collected during the trial
· Additional safeguards are in place if any participants are likely
to be vulnerable to coercion or undue influence (e.g., children,
prisoners, people with mental disabilities, or people with low
income or education levels)
The IRB decides whether to approve the clinical trial and notifies
the researcher and the institution in writing. The IRB may specify
changes the researcher must make in order to gain approval.
CANCER CLINICAL TRIALS: THE IN-DEPTH PROGRAM
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After approving a trial, the IRB must decide how frequently to
monitor it--usually on the basis of the risk involved. At the very
least, the trial's progress must be reviewed yearly.
Informed Consent
Informed consent, as a legal, regulatory, and ethical concept, is an
integral part of research. In clinical trials, informed consent is the
process of providing all relevant information about the trial's
purpose, risks, benefits, alternatives, and procedures to a potential
participant, who then, consistent with his or her own interests and
circumstances, makes an informed decision about whether or not
to participate. Before agreeing to take part in a clinical trial,
participants have the right to:
· Learn everything that is involved in the trial--including all
details about treatment, tests, and possible risks and benefits
· Both hear and read the information in language they
can understand
Informed Consent Documents
The informed consent form or document provides a summary of the
clinical trial and explains a participant's rights. It is designed to
begin the informed consent process. The participant acknowledges
that he or she is entering a study, has been told what it involves,
and understands the potential risks and benefits of participating.
Although reputable researchers do not try to fool people or sign
them up against their will, individuals sometimes have difficulty
understanding the information about a trial before agreeing to
participate. Individuals may not understand the medical
terminology and/or clinical requirements of a study, and they
should be encouraged to ask questions until they understand all
aspects of treatment. For many people it is important to ask a
friend or family member to come with them when they receive
information about medical options to be sure all important
questions are raised. Some people may want to take notes or bring
a tape recorder to assist them with questions and recall.
Participant Protection in Clinical Trials
47

---

The following elements of informed consent are required under
the Common Rule (Title 45 CFR Part 46, Subpart A):
· Statement that the trial involves research
· Explanation and description of the nature of the trial, purpose
of the trial, duration of participation, procedures to be followed,
and which procedures are experimental
· Description of foreseeable risks and discomforts
· Benefits to the participant and others
· Alternative procedures or treatments
· Description of the confidentiality of records
· Explanation of procedures if the project involves more than
minimal risk (e.g., compensation, availability of medical treatment)
· Contact person for questions
· Statement that participation is voluntary, that there will be no
loss of benefits on withdrawal, and that the participant may
withdraw at any time
· Statement that the participant's signature indicates a decision to
participate, having read and discussed the information presented
Any research trial, regardless of whether it is federally funded,
should provide this information to participants in an informed
consent document.
NCI has issued recommendations designed to help research
institutions and clinical centers write comprehensive, user-friendly
informed consent documents. Its Working Group on Informed
Consent also developed a template and sample forms that serve as
models for covering all of the information that Federal regulations
require. To view the template or other documents related to
informed consent, see the clinical trials section of www.cancer.gov.
Pediatric Assent to Participate
Children and adolescents are not deemed capable of giving true
informed consent, so they are asked for their assent to (or dissent
from) participation in a clinical trial. The trial must be explained
in age-appropriate language or using visual aids. Parents or
guardians are asked to give informed permission for their child to
participate in a trial.
CANCER CLINICAL TRIALS: THE IN-DEPTH PROGRAM
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Assent must be obtained from all children and young people over
age 7 unless:
· The child is found to be incapable of assenting
· The clinical trial offers a treatment or procedure that "holds out
a prospect of direct benefit that is important to the health or
well-being of the child and is available only in the context of the
research" (in other words, if the trial offers a treatment that is
thought to be better than those currently available or if it offers
the only alternative to those available)
Even in these cases, permission from the parent or guardian is
required. For more information, see the clinical trials section of
www.cancer.gov.
Protecting Participants During a Clinical Trial
Informed Consent Process
The informed consent process provides people with ongoing
explanations that will help them make educated decisions about
whether to begin or to continue participation in a clinical trial. The
process does not end with the signing of informed consent
documents. If new benefits, risks, or side effects are discovered
during the trial, researchers must inform participants. Participants
are encouraged to ask questions at any time.
Institutional Review Board Role
During the initial review process, the IRB establishes how often a
clinical trial should be monitored. Monitoring occurs at least
yearly but sometimes more frequently. During these review
sessions, the IRB examines a progress report provided by the
clinical researcher in charge of the project. The report describes:
· How many people are enrolled in the trial
· How many have withdrawn
· Participants' experiences, including benefits and adverse effects
· Progress to date
Participant Protection in Clinical Trials
49

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Based on this information, the IRB decides whether the project
should continue as described in the original research plan and, if
not, what changes need to be made. An IRB can decide to suspend
or terminate approval of a clinical trial if the researcher is not
following requirements or if the trial appears to be causing serious
harm to participants.
Data and Safety Monitoring Board (DSMB) Role
NIH requires that all phase 3 clinical trials undergo monitoring by a
DSMB, and that all phase 1 and 2 clinical trials have a data and
safety monitoring plan. A DSMB may also be appropriate and
necessary for phase 1 and 2 clinical trials that are blinded, take place
at multiple clinical sites, or employ particularly high-risk
interventions or vulnerable populations.
The DSMB is an independent committee whose membership
includes, at a minimum, a statistician and a clinical expert in the
area being studied. Other members are experts in all scientific
disciplines needed to interpret the data and ensure participant
safety. Members may also be clinical trial experts, statisticians,
bioethicists, or other clinicians knowledgeable about the trial's
subject matter.
The objectives of data and safety monitoring plans are to:
· Ensure that risks associated with participation are minimized to
the extent practical and possible
· Ensure the integrity of data
· Stop a trial if safety concerns arise or if its objectives are met
Ending Trials Early
There can be compelling reasons for halting a trial early. If
participants experience severe side effects, or if there is clear
evidence that risks outweigh benefits, the IRB and DSMB will
recommend that the trial be stopped early. A trial might also be
stopped if there is clear evidence that the new intervention is
effective--in order to make it widely available.
CANCER CLINICAL TRIALS: THE IN-DEPTH PROGRAM
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Breast Cancer Prevention Trial
The Breast Cancer Prevention Trial, conducted by NCI's National
Surgical Adjuvant Breast and Bowel Project, was designed to
evaluate whether taking the drug tamoxifen could prevent breast
cancer in women considered to be at high risk of developing the
disease. In March 1998, interim data showed that tamoxifen cut the
chance of getting breast cancer almost in half. Instead of
continuing the trial for the full 5 years, as planned, researchers
stopped the trial after about 4 years.
Women in the trial who were taking tamoxifen were offered the
opportunity to continue treatment for the remaining 14 months of
the trial. Women receiving the placebo were invited to participate
in the Study of Tamoxifen and Raloxifene, or STAR trial, designed
to determine whether the osteoporosis prevention drug raloxifene
is as effective as tamoxifen in reducing the chance of developing
breast cancer. The women's other option was to seek tamoxifen
from a physician on their own, outside a clinical trial.
B-14 Trial
Another trial involving tamoxifen and conducted by the National
Surgical Adjuvant Breast and Bowel Project, the B-14 trial, was
also halted early--but for a different reason. This trial, which
started in 1982, enrolled women who had had surgery for cancer
that was limited to the breast. After surgery, the women took
either tamoxifen or a placebo for 5 years to determine whether
tamoxifen would prevent recurrence of the cancer. Five years into
the trial, significantly more of the women taking tamoxifen
remained disease-free, so the trial was extended another 5 years.
Women who had been taking tamoxifen were given the
opportunity to reenroll in the trial and be randomly assigned to
take tamoxifen or placebo for an additional 5 years.
The extended trial was cut short when several interim data
analyses showed that the tamoxifen group had a slightly higher
rate of cancer recurrence than the placebo group. Statistical
analysis showed that no additional benefit was to be gained by
continuing tamoxifen for more than 5 years. The trial was halted,
and the women stopped taking tamoxifen beyond 5 years.
Participant Protection in Clinical Trials
51

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Before taking part in any clinical trial, health care
professionals and their patients should make sure it is
reputable by getting answers to these important questions:
· What is the purpose of the study or therapy?
· Who has reviewed and approved it?
· What are the credentials of its researchers and personnel?
· What information or results is it based on?
· How are study data and patient safety being monitored?
· How will the results be shared?
Quality Assurance Monitoring
NCI has several ways of ensuring the quality of data collected
during clinical trials. Many trials, for example, have committees
that review major elements of the study for accuracy, such as:
· Pathology
· Radiotherapy
· Surgery
· Administration of investigational drugs
In addition, data management and statistical centers use quality
control measures to help identify and correct or clarify
inconsistencies and inaccuracies in submitted data.
Another part of NCI's quality assurance program is onsite
monitoring, or audits, of trial procedures, documents, and data.
Institutions are audited at least once every 3 years. Auditors
review three main areas:
1. Conformance to IRB and informed consent requirements
2. Shipping, storage, and use of drugs and other agents
3. Individual participants' cases
Adverse Event Reporting
An adverse event is any unanticipated problem involving risks to
clinical trial participants or others. For more information on
adverse event reporting, see the clinical trials section of the Web
site www.cancer.gov.
Refer to the case study in section 7, page 73, for a review and summary
of content covered in this workbook.
52
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5.
Barriers
Participation
to
Clinical
Trial

---

5
Barriers to Clinical
Trial Participation
Learning Objectives
· Compare and contrast benefits and risks of participating in
cancer clinical trials
· Identify barriers that deter health care professionals from
referring patients to clinical trials
· Identify barriers for low participation in cancer clinical trials
· Identify barriers that deter special populations (ethnic
minorities, people with limited proficiency in English,
elderly persons) from participating in clinical trials
· Recognize cost and insurance issues related to participation
in clinical trials
A 1999 press release from the American Society of Clinical
Oncologists revealed that only 3 percent of adults with cancer
participate in clinical trials--far fewer than the number needed to
answer the most pressing cancer questions quickly.
The reasons so few adults participate in clinical trials are complex
and involve both participant and professional issues. Ideas to
address these problems can be found in Cancer Clinical Trials: A
Resource Guide for Outreach, Education, and Advocacy, also available
from NCI.
Barriers to Clinical Trial Participation
53

---

Barriers for Health Care Professionals
· Lack of awareness of appropriate clinical trials. Physicians are
not always aware of available clinical trials. Some may not be
aware of the local resources, or some may assume that none
would be appropriate for their patients.
· Unwillingness to "lose control" of a person's care. Most
doctors feel that the relationship they have with their patients is
very important. They want what is best for the patient, and if
the person must be referred elsewhere to participate in a trial,
doctors fear they may lose control of the person's care.
· Belief that standard therapy is best. Many health care
providers may not adequately understand how clinical trials are
conducted or their importance. Some believe that the treatment
in clinical trials is not as good as the standard treatment. They
also might be uncomfortable admitting that there is uncertainty
about which treatment is best in a phase 3 clinical trial.
· Belief that referring and/or participating in a clinical trial
adds an administrative burden. The length and details of most
research protocols may deter providers from participating in clinical
trials. The possibility of incurring additional costs and expenses that
might be inadequately reimbursed is a deterrent for many.
· Concerns about the person's care or how the person will react
to the suggestion of clinical trial participation.
Strategies for Addressing Barriers
· Provide checklists on patient charts with eligibility criteria, placing
posters with open protocols listed, or using abridged "protocol
pocket cards" with key inclusion and exclusion criteria.
· Dedicate one research nurse or research assistant to identifying and
screening participants, coordinating pre-enrollment tests, educating
participants about the protocol and process, and initiating the
informed consent and enrollment process.
· Access funding for clinical trial support. See the www.cancer.gov site
section on clinical trials, the CTSU site (www.ctsu.org), and the NCI
Cooperative Group sites for information.
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Barriers for the General Population
· Lack of awareness of clinical trials. Research has consistently
shown that most people with cancer are not aware of the option
to participate in clinical trials.
· Lack of access to trials. The reality or the perception that there
are no trials nearby deters many potential participants. In
addition, seeking care at a distant trial site presents time and
travel barriers.
· Fear, distrust, or suspicions of research. For many people, the
loss of control (not choosing their treatment) that comes with
entering a randomized trial is too great. Many also fear being
treated like "guinea pigs" or being "experimented upon," as
well as not receiving treatment for their cancer. People may
have a general lack of trust in the medical profession based on
past negative experiences or the knowledge of historical abuses
of research participants.
· Practical or personal obstacles. Costs of being away from work
and family may be deterrents for some people. Others may not
wish to leave the care of their own physician. People from
certain racial or ethnic groups or who are medically
underserved may feel that care within a trial will not be
sensitive to their needs. Others may feel that recruitment
strategies are not sensitive to their needs. Still others may
believe that standard care is better than the treatment available
in a trial.
· Insurance or cost problems. Another deterrent is the fear of being
denied insurance coverage for participation in a clinical trial. If a
person is uninsured, the cost of trial participation is an issue.
· Unwillingness to go against personal physician's wishes.
Barriers to Clinical Trial Participation
55

---

A Survey on Clinical Trial Barriers
A survey of almost 6,000 people with cancer conducted in
2000 took a look at why so few adults participate in cancer
clinical trials. Some of the highlights included:
· About 85 percent of people with cancer were either
unaware or unsure that participation in clinical trials
was an option, though about 75 percent of these people
said they would have been willing to enroll had they
known it was possible.
· Of those who were aware of the clinical trial option,
most declined to participate because they believed
common myths about clinical trials. They either
thought that:
­ The medical treatment they would receive in a clinical
trial would be less effective than standard care
­ They might get a placebo
­ They would be treated like a "guinea pig"
­ Their insurance company would not cover costs
· People who received treatment through a clinical trial
found it to be a very positive experience:
­ Ninety-seven percent said they were treated with
dignity and respect and that the quality of care they
received was "excellent" or "good"
­ Eighty-six percent said their treatment was covered by
insurance
Source: Harris Interactive. Health Care News 1(3) [Poll].
(Available from www.harrisinteractive.com/about/healthnews/
HI_HealthCareNews2001Vol1_iss3.pdf)
Supported by the Coalition of National Cancer Cooperative Groups, the
Cancer Research Foundation of America, the Cancer Leadership Council, and
the Oncology Nursing Society.
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Barriers for Diverse Populations
Additional barriers exist for people who are from certain
ethnic/racial backgrounds or who are medically underserved. The
following is not meant to be a comprehensive overview of all
barriers associated with clinical trials, and what is outlined should
not be generalized to all diverse populations.
Diverse U.S. Populations­­Definitions
Diverse populations include minority ethnic and racial groups
designated by the U.S. Government, including:
· American Indian or Alaska Native
· Asian American
· Black or African American
· Hispanic or Latin American
· Native Hawaiian or other Pacific Islander
Ethnically diverse populations are growing rapidly; in the 2000
Census, about 25 percent of the U.S. population reported their race
as something other than White.
The National Cancer Institute's working definition of diverse
populations also includes medically underserved populations.
Medically underserved populations are those that lack easy access
to, or don't make use of, high-quality cancer prevention, screening
and early detection, treatment, or rehabilitation services. These
may include people of any racial or ethnic group who live in rural
areas, or who have low income or literacy levels. Medically
underserved groups are generally characterized as experiencing
higher cancer mortality rates and insufficient participation rates in
cancer control programs.
Specific Barriers
· Long-standing fear, apprehension, and skepticism exist among
some minority populations about medical research because of
abuses that have happened in the past (e.g., the legacy of the
Tuskegee syphilis study). Among these populations, there is often
Barriers to Clinical Trial Participation
57

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widespread fear and distrust of the medical care system as a result
of discrimination, indifference, and disrespect. Many feel that they
do not want to give up rights or lose power in order to be
"experimented on." Others may be skeptical about the quality of
care that would be provided in a clinical trial. Some may find that
trial recruitment strategies are not sensitive to their needs.
· Doctors may not mention clinical trials as an option for cancer
care. As noted above, many physicians do not refer people to
clinical trials. Some physicians may avoid suggesting a clinical
trial to people who belong to racial or ethnic minorities out of
concern that people would see them as insensitive. Moreover,
some physicians may inadvertently discriminate against older
people or those from certain ethnic or cultural backgrounds.
· People from various cultural or ethnic backgrounds hold
different values and beliefs that may be different than
principles of Western medicine. Many people have cultural
beliefs that Western medicine cannot address their health
concerns. Different ethnic and cultural views of health and
disease (e.g., fatalism, family decisions about treatment, use of
"traditional healers," prayer, herbal medicines, or use of
complementary/alternative health practices) may make clinical
trials a less attractive treatment option. For prevention trials,
many may feel that the risk of a potential disease and its
consequences may be less important than meeting daily needs.
· Language or literacy barriers may make it difficult for some
people to understand and consider participating. The
complexity of forms, including informed consent documents,
may also be a barrier to those considering participation.
Translation can also be difficult if the person translating
information has not had specialized training.
· Additional access problems confront many people. Depending
on where they live or their access to transportation, people may
have difficulty getting to a clinical trial site. Those with low
incomes may find it difficult to take time off work or find
appropriate childcare. Other barriers, such as a lack of health
insurance or a source of health care, clearly present difficulties in
accessing trials.
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For some solutions to barriers for diverse populations, see NCI's
Cancer Clinical Trials: A Resource Guide for Advocacy, Education, and
Outreach.
Cost Barriers
The costs associated with clinical trials can be a barrier for many
professionals and the public. Physicians are often concerned about
reimbursement related to the expense of either caring for people
enrolled in trials or offering trials within their practice. Potential
trial participants often fear that their insurance company will not
cover participation. Those who are uninsured will need to know
how their participation in a trial will be covered.
There are two types of costs associated with clinical trials:
participant care costs and research costs.
Participant Care Costs
Participant care costs include:
· Usual care costs, such as doctor visits, hospital stays, clinical
laboratory tests, and x-rays, occur whether someone is
participating in a trial or receiving standard treatment.
· Extra care costs are those associated with clinical trial
participation, such as additional tests that may be required.
These costs may or may not be covered by a participant's health plan.
Research Costs
Research costs include costs associated with conducting the trial,
such as:
· Data collection and management
· Research physician and nurse time
· Analysis of results
· Clinical laboratory tests and x-rays
· Cost of the agent being tested
Most of the time, research costs are covered by the sponsoring
organization.
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Health Plan Coverage
Health insurance companies and managed care plans do not
always cover all care costs in a clinical trial. What they do cover
varies by plan and by trial. Now that Medicare has developed a
policy explicitly covering the routine care costs of diagnostic and
treatment clinical trials, other insurers may follow suit.
Insurance companies often claim that paying for clinical trials
would be too costly. But recent studies (Bennet et al., 2000;
Fireman et al., 2000; Wagner et al., 1999) found that costs for
participants in clinical trials are not appreciably higher than costs
for people not enrolled in trials.
For coverage strategies for participants and professionals, see the
clinical trials section of www.cancer.gov. Some insurance carriers
that cover clinical trials will even help health care professionals
locate appropriate trials.
Established vs. Investigational Therapies
In general, the most important factor determining coverage of a
treatment is the health plan's judgment as to whether the therapy
is "established" or "investigational." Health plans usually consider
a treatment established if sufficient scientific data exist to show it
is safe and effective. If a health plan does not think sufficient data
exist, it may consider the service investigational. Thus, some
health plans, especially smaller ones, will not cover any costs
associated with a clinical trial. Policies vary widely, but in most
cases it helps to have someone from the research team initiate
discussions with the health plan.
Other Criteria
Health plans may specify other criteria a trial must meet in order
to be covered, for example:
· Sponsorship: The trial must be sponsored by an organization
whose review and oversight procedures meet the health plan's
standards of scientific rigor.
· Trial type and phase: The trial must be judged "medically
necessary" by the health plan; this determination is made on a
case-by-case basis. In some cases, the trial must be in phase 3.
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While a plan may be willing to cover costs associated with
phase 3 trials, it may require documentation of known benefits
before covering a phase 1 or 2 trial. Participants may have more
difficulty getting coverage for costs associated with prevention
and screening trials because health plans are currently less
likely to have a review process in place for them.
· Cost neutrality: The trial must be cost-neutral--that is, it must
not be significantly more expensive than treatments the health
plan considers standard.
· Lack of standard therapy: The trial must offer treatment of a
cancer for which no standard therapy is available.
· Facility and personnel qualifications: The facility and medical
staff must meet specific health plan qualifications for
conducting unusual services, especially intensive therapy such
as a bone marrow transplant (high-dose chemotherapy with
bone marrow/stem cell rescue).
Legislation and Policies
Despite interest at the Federal level, as of 2002, no legislation has
been passed to require private health plans to uniformly cover all
clinical trial costs. However, there have been several important
developments at the Federal level regarding clinical trial coverage:
· Medicare reimburses for all routine participant care costs for its
beneficiaries participating in clinical trials.
· Beneficiaries of TRICARE, the Department of Defense's health
program, are covered for NCI-sponsored phase 2 and phase 3
prevention and treatment clinical trials.
· The Department of Veterans Affairs (VA) allows eligible
veterans to participate in a broad range of NCI clinical trials
across the country. The agreement covers all phases and types
of NCI-sponsored trials.
Many States have also passed legislation or developed policies
that require health plans to cover clinical trial costs. For an
updated legislation listing, see the clinical trials section of the
NCI Web site www.cancer.gov.
Refer to the case study in section 7, page 73, for a review and summary
of content covered in this workbook.
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6.
Conducting,
Locating
Clinical
Referring
Trials
to,
and

---

6
Conducting, Referring to, and
Locating Clinical Trials
Learning Objectives
· Describe the types of sponsorship of cancer clinical trials
· Define the role of the National Cancer Institute in
conducting clinical trials throughout the United States
· Identify methods of referring patients to clinical trials
· Demonstrate ways of locating clinical trial resources
Sponsorship
In order to find a clinical trial, it is helpful to understand who
sponsors trials. Clinical trials are sponsored by both Government
and private organizations including the National Cancer Institute
and pharmaceutical companies. Clinical trials take place all over
the United States, in locations as diverse as a rural community
clinic or a cancer center in a large urban area.
National Cancer Institute
NCI sponsors hundreds of clinical trials around the country
through six major programs, which are discussed below.
Clinical Trials Cooperative Group Program
The Clinical Trials Cooperative Group Program supports a large
network of organizations that continually generate and conduct
new clinical trials consistent with national priorities in cancer
treatment research. Member organizations carry out large,
randomized phase 3 trials, as well as phase 2 trials.
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Members conduct clinical trials in locations nationwide, while
administration and data are handled at a central location.
Members of the groups include:
· Academic institutions
· NCI-designated cancer centers
· Physicians in the Community Clinical Oncology Program and
the Minority-Based Community Clinical Oncology Program
(described below)
· Community physicians and community hospitals
Each year, the groups enroll some 20,000 new people in treatment
trials, evaluate some 12,000 new participants in ancillary studies, and
follow the progress of many times that many participants in ongoing
trials. Thousands of individual investigators participate in these
studies. The cooperative groups have been instrumental in
developing both new standards of care for people with cancer and
sophisticated clinical investigation techniques.
There are 12 groups in the Clinical Trials Cooperative Group Program:
1. American College of Surgeons Oncology Group (ACOSOG)
2. Cancer and Acute Leukemia Group B (CALGB)
3. Children's Cancer Study Group (CCSG)
4. Eastern Cooperative Oncology Group (ECOG)
5. Gynecologic Oncology Group (GOG)
6. Intergroup Rhabdomyosarcoma Study Group (IRSG)
7. National Surgical Adjuvant Breast and Bowel Project (NSABP)
8. National Wilms Tumor Study Group (NWTSG)
9. North Central Cancer Treatment Group (NCCTG)
10. Pediatric Oncology Group (POG)
11. Radiation Therapy Oncology Group (RTOG)
12. Southwest Oncology Group (SWOG)
For more cooperative group information, see http://ctep.info.nih.gov.
Cancer Trials Support Unit
NCI and the Clinical Trials Cooperative Group Program are
collaborating in a pilot project--the Cancer Trials Support Unit
(CTSU)--to reduce administrative burdens and recruit more
physicians to become involved in clinical trials.
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CTSU is designed to streamline and centralize many
administrative, financial, and data collection tasks. CTSU will
provide participating physicians with a single access point to
NCI's entire phase 3 clinical trial system, facilitating access to
protocols, training, and educational information. Highlights of the
fully developed system will include:
· Cross-group registration enabling physicians to register people
on adult cooperative group trials in leukemia, lung,
genitourinary, colorectal, and breast cancers, even if they are not
members of the group conducting the trial
· Online 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 IRB approval for all investigators
participating in cooperative groups and CTSU
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.
For more information about CTSU, see www.ctsu.org.
Community Clinical Oncology Program
The Community Clinical Oncology Program (CCOP) enables
community physicians to work with investigators conducting
NCI-supported clinical trials. The program increases the number
of participants and physicians who can take part in clinical trials
operated simultaneously in major research centers and in the
community. It benefits investigators by giving them an
opportunity to conduct large-scale cancer prevention and control
studies at the community level.
Facilities participating in the program must be affiliated with an
NCI-supported clinical cooperative group or cancer center and use
research protocols developed by these groups.
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Minority-Based Community Clinical Oncology Program
The Minority-Based Community Clinical Oncology Program
(MBCCOP) was initiated in 1990 to provide people with cancer
who belong to minority groups access to state-of-the-art treatment,
prevention, and control technology. The minority-based program
was begun because 40 percent of the people with cancer referred to
CCOP physicians each year are from a minority group. Each
MBCCOP pledges to accrue more participants from minority
groups than other CCOPs do.
Since funding began, participant enrollment in the minority-based
program has grown to account for approximately 10 percent of all
ethnic minorities enrolled in NCI-approved clinical trials.
Cancer Centers Program
The Cancer Centers Program consists of more than 50 NCI-
supported research centers. Each cancer center also belongs to at
least one cooperative group.
NCI supports three types of centers:
1. Comprehensive cancer centers, which conduct basic, clinical,
and preventive research programs, as well as community
outreach and education programs
2. Clinical cancer centers, which conduct primarily clinical
research programs but may have programs in other research
areas as well
3. Cancer centers (formerly called Basic Science Cancer Centers),
which conduct basic or preventive research programs and do not
have clinical programs
Please refer to http://cancer.gov/cancercenters for a comprehensive list
of cancer centers.
Clinical Grants Program
The Clinical Grants Program supports clinical researchers through
various types of grants, all of which are peer reviewed.
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Pharmaceutical and Biotech Companies
Pharmaceutical and biotech companies also conduct clinical trials,
both locally and nationally. They may conduct these trials in
collaboration with universities, hospitals, NCI, and local
physicians. These trials are subject to the companies' own review
panels and to an IRB, which may be local or national in scope.
Making Referrals
When a person is first diagnosed with cancer, his or her physician
may suggest several possible options for treatment, possibly
including a clinical trial. Likewise, a person at high risk of
developing cancer may be offered prevention options that include
a clinical trial.
Decisions concerning eligibility for cancer clinical trials are often
complicated, requiring very specific information regarding a
person's medical condition and prior treatment. For that reason, it
is preferable to have a provider who is familiar with the person's
case make the initial contact with clinical trial staff. A person who
calls a researcher directly may have insufficient medical
information, thereby making a decision about eligibility difficult
and frustrating for both the potential participant and the
researcher. Once contact is made, a referral coordinator may accept
telephone, mail, or e-mail inquiries from physicians, potential
participants, and others about the availability of clinical trials.
Preliminary eligibility can be evaluated over the phone, and
appointments with the clinical trial team can be scheduled if the
person decides to proceed.
The informed consent process begins as soon as a potential
participant begins to explore the trial with the clinical research team.
The research team discusses the trial's purpose, procedures, risks,
potential benefits, and participants' rights. After this dialogue, the
person may wish to speak to his or her referring provider to review
the information and help determine the best course.
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If the person opts to enter the trial, the research team should send
the referring provider relevant updates and followup information
until the person returns to the provider's care.
Deciding to refer a person to a clinical trial is easier if the health care
professional has adequate information regarding the trial's objectives
and eligibility criteria. Before discussing a trial as an option, the
professional should learn as much as possible about the trial.
Discussing Clinical Trials with Patients
Health care professionals may be able to assist potential trial
participants in their decision by considering the following benefits
and risks to clinical trial participation with their patients.
Possible Benefits of Clinical Trial Participation
· Participants will receive, at a minimum, the best standard
treatment. This may be as good as, or better than, the new
approach being tested.
· If a participant is taking the new treatment and it is shown to
work, he or she may be among the first to benefit.
· By examining the benefits and drawbacks of clinical trials and
other treatment choices, participants are taking an active role in
a decision that affects their health care and life.
· Some participants feel good about helping advance medical
knowledge that will improve cancer care and help others.
· Even when they don't lead to new therapies, clinical trials often
answer important questions and help move research forward.
Possible Risks of Clinical Trial Participation
· New treatments are not always better than standard care.
· New treatments may have unexpected side effects that are
worse than those of standard treatment.
· Although a new treatment is beneficial, it may not work for every
participant. Even standard treatments do not help everyone.
· If a participant receives standard treatment instead of the
new treatment being tested, it may not be as effective as
the new approach.
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· Participants may have additional patient care costs that are not
covered by the study sponsor or by their health insurance or
managed care plan.
· Participants may have to incur the costs of travel, childcare, lost
work hours, hotels, and meals.
· Participation in a clinical trial may require increased patient
responsibility, such as going to more appointments or self-
monitoring for side effects.
Cancer Information and Clinical Trial
Resources
NCI Resources
NCI's Web site, www.cancer.gov, provides access to a wealth
of information on clinical cancer care. The site contains
information from PDQ® (Physician Data Query), including the
latest information about cancer treatment, screening, prevention,
genetics, supportive care, and complementary and alternative
medicine, as well as a registry of cancer clinical trials. Clinical
oncology specialists review current literature from more than
70 medical journals, evaluate its relevance, and synthesize it into
clear summaries, which are then reviewed monthly and updated
as needed based on new information. Most cancer information
summaries appear in two versions: 1) a technical version for the
health professional and 2) a nontechnical version for patients,
their families, and the public. Many of the summaries are also
available in Spanish.
The NCI Web site also includes approximately 100 fact sheets on
various cancer-related topics, information on ordering NCI
publications, and educational features and news summaries
concerning the latest results from cancer clinical trials.
NCI also has a Web-based continuing education tutorial on
implementing clinical trials into your practice. This tutorial
provides information for health care professionals interested in
referring patients to trials, and more detailed information for
health care professionals interested in actually implementing
clinical trials into their practice. The series is available at
http://cme.cancer.gov.
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The clinical trials registry PDQ contains more than 1,800 ongoing
clinical trials, with information about trials around the world. All
clinical trials undergo review prior to inclusion. Although no
single resource lists every cancer clinical trial being conducted in
the United States and abroad, PDQ is the most comprehensive
cancer clinical trials registry, and contains information about trials
sponsored by NCI, the pharmaceutical industry, and some
international groups. Users can narrow their search by multiple
parameters, such as stage of disease, phase of trial, treatment
modality, and geographic location. PDQ also contains an archival
file of more than 11,000 clinical trials that are no longer accepting
participants, including contact information for principal
investigators of trials that may not yet be published in the
biomedical literature.
Accessing NCI's Clinical Trial and Cancer Information by Phone
NCI's Cancer Information Service--NCI's Cancer Information
Service is a national information and education network for
patients, the public, and health professionals. From regional offices
covering the entire United States, Puerto Rico, and the U.S. Virgin
Islands, trained staff provide the latest cancer information through
a toll-free telephone service. Staff can respond to calls in either
English or Spanish. The Cancer Information Service, with regional
offices throughout the United States, may work with organizations
and professionals to plan, implement, and evaluate culturally
appropriate clinical trials education programs using the Clinical
Trials Education Series.
Access: The toll-free number is 1-800-4-CANCER (1-800-
422-6237). For deaf and hard of hearing callers with TTY
equipment, the number is 1-800-332-8615. Hours of
operation are Monday through Friday, 9:00 a.m. to 4:30 p.m.,
local time. Callers also have the option of listening to recorded
information about cancer 24 hours a day, 7 days a week.
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NIH Web Site
No single resource lists every cancer clinical trial being conducted
in the United States and abroad. However, in 2000 the National
Institutes of Health launched a new Web site, www.clinicaltrials.gov,
that aims to be a complete listing of all U.S. Government- and
industry-sponsored clinical trials, including cancer trials.
The site contains approximately 7,200 clinical trials, most of them
Government-sponsored. However, additional trials from the
pharmaceutical industry are being added.
Other Web Sites
The Internet includes a variety of clinical trial databases and
matching services. The owners of these sites can be:
· Not-for-profit organizations, that might:
­ Use volunteers to provide content
­ Be supported by an academic institution or foundation
· For-profit organizations, that might:
­ Receive a fee from pharmaceutical companies every time a
person signs up for a trial
­ Give some of its profits back to the cancer community
Anyone interested in using online services to find a clinical trial
should ask questions and evaluate the information before submitting
personal information or calling an investigator from the service:
· Who owns/runs the site?
· Where does the financial backing come from?
· How does the service get paid? By matching people to trials? By
clinical trial submission to the database? Other?
· Does anyone make money on this site? If so, who?
· What is the source of clinical trial information?
· Does the site include all clinical trials? All Government-
supported trials? All pharmaceutical trials?
People may wish to look at information from many sites and
consider the source of the information before making important
health-related decisions.
Refer to the case study in section 7, page 73, for a review and summary
of content covered in this workbook.
Conducting, Referring to, and Locating Clinical Trials
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Guide To Finding Clinical Trial Resources
What is it?
How do I access it?
What will it provide?
National
Database produced by NCI
Go to www.cancer.gov
Summaries about
Cancer
clinical trials
Go to the clinical trials area
Institute's PDQ
Registry of approximately
conducted by NCI-
1,800 active cancer clinical
and follow the search
sponsored
trials
directions
researchers, the
OR
pharmaceutical
industry, and some
Call 1-800-4-CANCER
international groups
National
Database produced by NIH
Go to www.clinicaltrials.gov
Summaries about
Library of
clinical trials for a
Registry now lists 4,000
Medicine
Can browse by disease or
wide range of
primarily NIH-supported
sponsor or insert key words
conditions--most of
clinical studies on many
the trials listed are
conditions, and more will
sponsored by NIH
be added
All trials on PDQ are listed in
this database
Food and Drug
A list of sources prepared by
Go to www.fda.gov/oashi/
Web addresses and
Administration's FDA's Office of Special Health
cancer/trials.html#table
telephone numbers
Cancer Clinical
Issues
Can browse by disease for
Trials Directory
Information listed
Guides user to other Web
different sources
on the Web sites in
locations for institutions that
this directory varies
conduct or list cancer clinical
widely
trials
Local Cancer
Locally produced Web sites
Different sites can be found
Information that varies
Center Web
that include listings for trials
through:
from center to center
Sites
sponsored by NCI and some
· www.cancer.gov
pharmaceutical companies
· Local institutions
· Call 1-800-4-CANCER for a
Good supplementary
center near you
resources for locating clinical
Information on trials taking
trials; a cancer center may
place at NCI's Clinical Center in
begin participating in an
Bethesda, Maryland is available
NCI-sponsored trial before the
at http://ccr.nci.nih.gov then
center's information is listed in
select "clinical trials"
CancerNet/PDQ
Some centers may also have
telephone information centers
Examples of
Pharmaceutical Research
PhRMA
Descriptions, sites,
Pharmaceutical and Manufacturers of America Go to http://www.phrma.org
telephone numbers,
Resources/
(PhRMA) publishes a list of
Click on "New Medicines in
and investigator
new cancer drugs in
Development" and search by
names by State
Internet Clinical development
disease. The drugs are listed
Trial Matching
by cancer type. Or call
Sites
CenterWatch's Clinical Trials
202-835-3400.
Listing Service and Emerging
Med.com's clinical trials
CenterWatch
matching service list many
Go to www.centerwatch.com
industry- and Government-
Click on "Trial Listings" and
sponsored trials
then "CenterWatch Trial
Listings by Medical Areas" or
call 617-856-5900.
EmergingMed.com
Go to http://www.emergingmed.com
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7.
Case
Study

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7
Case Study
The Clinical Case
Mr. Joe Smith, a 59-year-old African American male, presents to
his primary care physician, Dr. Bob Brown, in rural Wisconsin. He
has been complaining of difficulty with initiating urination and
frequency. He presents clinically with an abnormal rectal exam
and an elevated prostate-specific antigen (PSA) of 8 ng/ml
(normal in a 59-year-old Black male is less than 4 ng/ml). Mr.
Smith's mass is biopsied and the results reveal a prostatic tumor.
The nearest comprehensive cancer center is 100 miles away, and
Mr. Smith wants to be treated by Dr. Brown. He says he wants to
stay close to his home and family, and does not want to be cared
for by "those big city doctors."
Mr. Smith decides to undergo a radical prostatectomy at his
community hospital. Surgery reveals a 1.5 cm tumor with clear
margins, negative pelvic node involvement, and unilateral seminal
vesicle involvement, which puts Mr. Smith at high risk for eventual
tumor spread. To complete his clinical staging, a bone scan and CT
scan are completed. Mr. Smith's tumor is formally staged. At his 3-
month followup visit, post-operatively, his PSA is 0.2 (undetectable).
Dr. Brown closely follows Mr. Smith. Three years after his surgery
his PSA has slowly risen to 11, but his bone scan and CT scans
remain negative. Dr. Brown informs Mr. Smith that there are many
clinical trials for men with prostate cancer at all stages. He
explains that these trials are being conducted to try to find the best
methods for cancer prevention, early detection, and treatment. At
this point in his disease, Mr. Smith does not wish to consider a
clinical trial, so he continues to receive standard care. Dr. Brown
recommends starting standard treatment with hormone therapy
injections monthly. The patient's PSA drops to less than 0.2 again.
Case Study
73

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Two years later, the PSA begins to rise to 15 and a bone scan now
shows abnormal uptake in multiple ribs and the thoracic spine.
Mr. Smith is started on an anti-androgen drug and his PSA drops
to 10 at his 3-month followup visit. One year later his PSA has
risen to 40, and he now says he has mild rib pain. Dr. Brown
explains to Mr. Smith that he needs to consult with an oncologist
from the cancer center, Dr. Mary Jones, and that Mr. Smith may
need to see her. Mr. Smith somewhat reluctantly agrees to see Dr.
Jones. Dr. Jones recommends exploring available clinical trials
because Mr. Smith is young, is in good health with mild
symptoms, and has a tumor that now appears to be progressing.
Finding a Clinical Trial
How can Dr. Brown or Dr. Jones find an appropriate clinical trial
for Mr. Smith?
Dr. Jones decides to check NCI's PDQ system, because her center
has no active trials for prostate cancer. The PDQ system will allow
her to see current active clinical trials and their eligibility criteria.
(For a further review of PDQ, please see section 6.)
Dr. Jones uses the NCI PDQ system to assess what, if any, clinical
trials are available for Mr. Smith. Using the Internet, she accesses
the site as follows:
· Enters the clinical trials section of www.cancer.gov
· Selects "Finding Clinical Trials"
· Selects PDQ Search Form
· Enters the relevant data; hits search (appropriate studies
will be retrieved)
· Reviews the trials
If a physician does not have Internet access, how can he or she
find a trial?
Clinical trial information is always available through NCI's Cancer
Information Service (CIS) at 1-800-4-CANCER (1-800-422-6237).
74
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After reviewing available trials, Dr. Jones selects a phase 2 trial
entitled: A Phase II Randomized Study of High­Dose Ketoconazole With
or Without Alendronate Sodium in Patients With Androgen Independent
Metastatic Adenocarcinoma of the Prostate (2001) to discuss with
Dr. Brown and Mr. Smith.
Mr. Smith is clinically eligible for the study. Participants are
randomized to one of two arms: 1) a single oral dose of
ketoconazole on day 1, and then 3 times daily oral dose beginning
on day 8, versus 2) a single oral dose of alendronate sodium on
day 1 and a single oral dose of ketoconazole on day 3 and then
daily alendronate sodium and 3 times daily ketoconazole
beginning on day 8. Participants who experience a clinically
complete remission (CR) receive treatment for an additional
60 days beyond CR. Mr. Smith would have to be willing to have
followup visits at NIH in Bethesda, MD, every 2 months and be
seen in the NIH Cancer Center every 2 weeks for evaluation of
toxicity and drug tolerance.
Sample Points to Discuss With the Patient
Considering a Clinical Trial: Randomization,
Patient Protection/Myths, and Insurance
Randomization
As a health care professional it is often challenging to discuss the
concept of randomization with patients. Patients can feel threatened
knowing that neither they, nor their doctor, can choose what
treatment they will get if they enter a randomized trial. They may feel
that the arm of the study that is standard care or closest to standard
care, is the best option. People may also be concerned that if they
enter a randomized clinical trial they will not receive treatment; they
may receive just a "sugar pill." How can they be sure?
Case Study
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Dr. Jones began her discussion of randomization with Mr. Smith,
his wife, and their two grown sons by explaining that this study
has an objective group of professionals who monitor the study
called a data and safety monitoring board (DMSB). The DMSB
evaluates the data from the clinical trial to interpret if the therapy
or technique being studied appears to be better (more beneficial)
or worse (more harmful) than standard therapy. A trial can be
halted early to allow all participants access to a clearly more
beneficial intervention, or to protect participants from harm.
Dr. Jones explained that there are three phases for clinical trials and
that randomization is generally seen in phase 3 studies where
researchers are unsure whether a new intervention is better than the
currently accepted standard therapy for a specific cancer type. She
discussed how patients entering a phase 3 trial (and, as in this case,
some phase 2 trials) are randomly assigned to groups (called
randomization) and that neither the patients nor their doctors
choose which therapy or technique they will receive. This is done
because if physicians determined which therapy participants would
receive, there could be an unconscious bias in their assignments.
They could tend to assign patients with a more hopeful prognosis to
the experimental therapy group and make the new therapy seem
more effective than it really is. Similarly, if patients were allowed to
choose which therapy they would receive, the results could also be
influenced. Patients with a less hopeful prognosis could tend to pick
the experimental treatment, for example, which may lead that
treatment to look less effective than it really is.
Myths
Mr. Smith and his family have many questions regarding what
they have heard and read about clinical trials. How would you
answer these questions?
1. How do I know I am really safe if I enter this trial? You
and I both know there are bad feelings in our community
about research.
Fact: Tragedies have occurred in the past related to clinical trials.
The African American community most notably remembers the
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infamous Tuskegee syphilis study, which followed, but did not
treat, African American men with syphilis. There are now strong
safeguards in place to protect research participants from the
notorious human rights abuses of the past which include:
· Government oversight and regulations
· Institutional review board (IRB) review and approval
of a clinical trial before it begins and annually while
it is in progress
· An informed consent process which gives potential participants
the information they need to decide about participation,
including foreseeable risks and benefits
· Data and safety monitoring boards which ensure minimization of
risks, integrity of trial data, and oversight to end a trial early if
clear benefit or harm arises from the intervention being studied
(usually used in phase 3 studies)
2. Aren't these clinical trials only for dying cancer patients?
Fact: Clinical trials are not just for patients with the most advanced
disease. In fact, many newly diagnosed cancer patients participate
in clinical trials. If only the sickest patients participated in
treatment trials, researchers would not know how to treat patients
with earlier stages of cancer. Phase 3 treatment includes all stages
of cancer, from the most advanced to the most localized. These
trials enroll hundreds or thousands of patients. Phase 1 and 2
cancer clinical trials, which enroll fewer than 100 patients, seek
people with few treatment options or people who have exhausted
all the current treatment options, which is Mr. Smith's case.
3. Aren't people who join clinical trials just "guinea pigs"
for research?
Fact: People who decide to take part in a clinical trial are called
participants, and strict guidelines are in place to ensure that these
volunteers are treated as such:
· A participant has the right to withdraw from a trial at any time.
The participant's decision does not jeopardize his or her future
treatment and he or she may discuss further treatment options
with the study physician or be referred back to a primary care
provider for standard care.
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· Although people fear that trial participants are treated like
guinea pigs, reports from actual trial participants disagree.
According to a Harris Poll conducted in 2000, the vast majority
of trial participants said their overall experience was positive.
Ninety-seven percent said they were treated with dignity and
respect and that the quality of care they received was
"excellent" or "good." More than 80 percent said they did not
receive more tests than they felt were necessary and 86 percent
said their treatment was covered by insurance.
4. Mr. Smith's wife is very concerned that cancer patients who
join clinical treatment trials get a sugar pill (placebo) instead
of really being treated. Will my husband really get treatment?
Fact: In phase 3 cancer treatment trials, participants with cancer
get either a new treatment or the best standard treatment. In phase
2 trials, like the one Mr. Smith is considering, different schedules
and combinations of two drugs are being evaluated for their
effectiveness. It is unethical to deprive any person with a serious
illness or condition of the best available treatment. There would be
no placebo involved in Mr. Smith's treatment.
5. His oldest son is wondering if only people who have cancer
can participate in a clinical trial. Aren't my brother and I at
higher risk now?
Fact: Treatment and diagnostic trials are designed for people who
already have cancer; however, genetics, prevention, and screening
trials are designed for persons at risk of developing cancer. This is
relevant for Mr. Smith's sons who now have an increased risk for
prostate cancer. Dr. Jones suggests that the sons make an
appointment to discuss a cancer prevention clinical trial.
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Insurance
Dr. Brown is wondering whether participating in this cancer
clinical trial will cost Mr. Smith more than standard treatment.
Will insurance cover the costs?
The costs of new treatments for different cancers vary. Some
treatments under study cost no more than standard therapies.
Others, such as bone marrow transplants, are very expensive.
There are hundreds of insurance companies and managed care
organizations in the United States and each has a different policy
about covering clinical trial costs. In general, most companies have
contract language that prohibits coverage for "experimental
therapies." However, decisions are often made on a case-by-case
basis, and costs for patient care in clinical trials are often covered.
The best way to evaluate each situation is to ask questions such as
the following:
· What will the total patient care costs be?
· What parts of the treatment, if any, does the study provide free
of charge?
· What parts of treatment must be paid for by the participant or
the participant's insurer?
· What is the situation for people who have no health insurance?
· Will total patient charges be higher for a clinical trial
than for standard care?
· How often have insurers reimbursed all costs of the new therapy?
· Are there other resources or organizations that might help cover
the fees or provide services, such as free transportation?
Another option is to discuss reimbursement issues with the
insurance company ahead of time. The company is unlikely to
promise coverage before the fact, but it may give information
about general policies and trends. In considering costs of out-of-
town treatment or follow-up care, patients should remember to
include travel-related costs. The research team conducting the
study will know how many times participants will need to visit,
for how long, whether housing or stipends will be provided, and
whether participants will be hospitalized during their stay.
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Conclusion
After meeting with Dr. Jones and discussing their concerns, the
Smith family met with Dr. Brown to discuss his view of the trial.
Mr. Smith decided to enter the trial. After four months and his
second evaluation, his PSA has decreased to 14 ng/ml, and he has
no bone pain. He will continue for another cycle of therapy and be
reevaluated in 2 months. After his initial apprehension eased and
treatment began, Mr. Smith was able to verbalize satisfaction in
both his decision to enter the trial and in the level of care and
attention he received.
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Glossary

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Glossary
adjuvant therapy: One or more anticancer drugs used in
combination with surgery or radiation therapy as part of the
treatment of cancer. Adjuvant therapy is given before or after the
primary treatment to increase the chances of a cure. Adjuvant
usually means "in addition to" initial treatment.
adverse effect: See side effects.
Adverse Event Expedited Reporting System: AWeb-based
program that enables researchers using NCI-sponsored
investigational agents to expedite the reporting of serious
and/or unexpected adverse events directly to NCI and FDA.
agent: In a cancer clinical trial, an agent is a substance that researchers
believe might be capable of producing an effect that fights cancer.
assent: Children and adolescents are not deemed capable of giving
true informed consent, so they are asked for their assent, or
agreement, to participation in a clinical trial.
audit: In clinical trials, the onsite monitoring of trial procedures,
documents, and data.
Belmont Report: A 1979 report by the National Commission for
the Protection of Human Subjects of Biomedical and Behavioral
Research that delineated the ethical principles upon which today's
regulations regarding research participants in the United States are
based: respect for persons, beneficence, and justice.
bias: Human choices, beliefs, or any other factors besides those being
studied that affect a clinical trial's results. Clinical trials use many
methods to avoid bias because biased results may not be correct.
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biological therapy: Treatment to stimulate or restore the ability of
the immune system to fight infection and disease. Also used to
lessen side effects that may be caused by some cancer treatments.
Also known as immunotherapy, biotherapy, or biological response
modifier (BRM) therapy.
cancer: A term for diseases in which abnormal cells divide without
control. Cancer cells can invade nearby tissues and can spread through
the bloodstream and lymphatic system to other parts of the body.
cancer vaccine: A form of biological therapy, which may
encourage a person's immune system to recognize cancer cells.
These vaccines may help the body reject tumors and prevent
cancer from recurring.
chemoprevention: The use of drugs, vitamins, or other agents to try to
reduce the risk of, or delay the development or recurrence of, cancer.
chemotherapy: Treatment with anticancer drugs.
clinical trial: Aresearch study that tests how well new medical
treatments or other interventions work in people. Each study is
designed to test new methods of screening, prevention, diagnosis,
or treatment of a disease.
combination chemotherapy: Treatment using more than one
anticancer drug.
combination therapy: The use of two or more modes of
treatment--surgery, radiotherapy, chemotherapy,
immunotherapy--in combination or alternately to achieve
optimum results against cancer.
Common Toxicity Criteria: AWeb-based, interactive application
that uses standardized language to identify and grade adverse
events in cancer clinical trials.
confidence intervals: These reflect a range of values surrounding the
true score that would be obtained if everyone with a particular cancer
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were treated with the treatment under study. The wider the interval,
the more variable the result and the less likely it is to be close to the
true score. Confidence intervals are typically thought of as the
approximate bounds or limits surrounding the true score. Researchers
frequently use either a 95 or a 99 percent confidence interval.
control group: In a clinical trial, the group that receives the
accepted standard treatment being studied. In cases where no
standard treatment yet exists for a particular condition, the control
group would receive no treatment. No patient is placed in a
control group without treatment if there is any beneficial treatment
known for that patient. This group is compared to the group that
receives the investigational treatment. See also investigational group.
cooperative groups: Networks of institutions that jointly carry out
large clinical trials following the same protocols.
data and safety monitoring board (DSMB): An independent
committee whose membership includes, at minimum, a statistician
and a clinical expert in the area being studied. Members may also
include bioethicists or other clinicians knowledgeable about the
trial's subject matter. The National Institutes of Health requires
DSMB review of all phase 3 clinical trials. A DSMB might also
review phase 1 or 2 trials that are blinded, take place at multiple
locations, or employ particularly high-risk interventions or
vulnerable populations.
diagnostic trial: Aresearch study that evaluates methods of
detecting disease.
disease-free survival: The amount of time a participant survives
without cancer occurring or recurring, usually measured in months.
double-blinded: Aclinical trial in which neither the medical staff
nor the person knows which of several possible therapies the
person is receiving.
eligibility criteria: Participant eligibility criteria for clinical trials
can range from general (age, sex, type of cancer) to specific (prior
Glossary
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treatment, tumor characteristics, blood cell counts, organ function).
Eligibility criteria may also vary with trial phase. In phase 1 and 2
trials, the criteria often focus on making sure that people who
might be harmed because of abnormal organ function or other
factors are not put at risk. Phase 2 and 3 trials often add criteria
regarding disease type and stage, and number of prior treatments.
endpoint: What researchers measure to evaluate the results of a
new treatment being tested in a clinical trial. Research teams
establish the endpoints of a trial before it begins. Examples of
endpoints include toxicity, tumor response, survival time, and
quality of life.
Food and Drug Administration (FDA): A consumer protection
agency of the U.S. Department of Health and Human Services,
FDA is required by law to review all test results for new drugs to
ensure that they are safe and effective for specific uses.
gene: The functional and physical unit of heredity passed from
parent to offspring. Genes are pieces of DNA, and most genes
contain the information for making a specific protein.
gene therapy: Treatment that alters a gene. In studies of gene
therapy for cancer, researchers are trying to improve the body's
natural ability to fight the disease or to make the cancer cells more
sensitive to other kinds of therapy.
genetic: Inherited; having to do with information that is passed
from parents to offspring through genes in sperm and egg cells.
genetic epidemiologic research: Research that involves looking at
tissue or blood samples from large populations of people in order
to determine how one's genetic make-up can influence detection,
diagnosis, prognosis, and ultimately, treatment.
genetics trials: Clinical trials that examine whether gene transfer
therapy can be used to treat cancer, or whether genetic
epidemiology research improves the understanding of cancer at
the cellular level. Actual genetic intervention (such as gene
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transfer) trials are few in number, however trials are underway
where actual cellular manipulation at the gene level occurs.
imaging: Tests that produce pictures of areas inside the body.
immunotherapy: See biological therapy.
informed consent: The process of providing all relevant
information about the trial's purpose, risks, benefits, alternatives,
and procedures to a potential participant, who then, consistent
with his or her own interests and circumstances, makes an
informed decision about whether to participate.
institutional review board (IRB): A board designed to oversee the
research process in order to protect participant safety. Made up of
researchers, ethicists, and laypeople from the community, the
board must review the trial protocols and the informed consent
forms participants sign.
intervention: The study agent or method that is being tested in a
clinical trial or clinical study. The intervention is usually given to
the investigational group while the control group receives
standard treatment.
investigational group: In a clinical trial, the group that receives
the new agent being tested. See also control group.
investigational new drug (IND): Adrug that the Food and Drug
Administration (FDA) allows to be used in clinical trials but that
the FDA has not approved for commercial marketing.
metastasis: The spread of cancer from one part of the body to
another. In cancer, metastasis is the migration of cancer cells from the
original tumor site through the blood and lymph vessels to produce
cancers in other tissues. Tumors formed from cells that have spread
are called "secondary tumors" and contain cells that are like those in
the original (primary) tumor. The plural is metastases.
metastatic cancer: Cancer that has spread from the place in which
it started to other parts of the body.
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monoclonal antibodies: Laboratory-produced substances that can
locate and bind to cancer cells wherever they are in the body. Many
monoclonal antibodies are used in cancer detection or therapy; each
one recognizes a different protein on certain cancer cells.
Monoclonal antibodies can be used alone, or they can be used to
deliver drugs, toxins, or radioactive material directly to a tumor.
multimodality therapy: Therapy that combines more than one
method of treatment.
National Cancer Institute (NCI): Part of the National Institutes of
Health, of the United States Department of Health and Human
Services, is the Federal Government's principal agency for cancer
research. NCI conducts, coordinates, and funds cancer research,
training, health information dissemination, and other programs
with respect to the cause, diagnosis, prevention, and treatment of
cancer. Access the NCI Web site at www.cancer.gov.
NCI-designated Cancer Centers: There are 3 kinds of NCI-
designated cancer centers:
1. Comprehensive cancer centers, which conduct basic, clinical,
and preventive research programs, as well as community
outreach and education programs
2. Clinical cancer centers, which conduct primarily clinical
research programs but may have programs in other research
areas as well
3. Cancer centers (formerly called Basic Science Cancer Centers),
which conduct basic or preventive research programs and do
not have clinical programs
New Drug Application (NDA): The application filed with FDA by
the trial sponsor once a trial has generated adequate data to
support a certain indication for a drug.
Office for Human Research Protections (OHRP): Safeguards
participants in federally funded research and provides unity and
leadership for 17 Federal departments and agencies that carry out
research involving human participants. OHRP enforces an
important regulation called the Common Rule, which sets
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standards for the informed consent process; formation and function
of IRBs; involvement of prisoners, children, and other vulnerable
groups in research; and many other protective measures.
oncologist: A doctor who specializes in treating cancer. Some
oncologists specialize in a particular type of cancer treatment.
For example, a radiation oncologist specializes in treating
cancer with radiation.
p-value: A statistics term. A measure of probability that a
difference between groups during an experiment happened by
chance. For example, a p-value of .01 (p = .01) means there is a 1 in
100 chance the result occurred by chance. The smaller the p-value,
the more likely it is that the difference between groups was caused
by a difference between the tested treatments.
peer review: Scientific review by a panel of experts. The primary
responsibility of these experts is to assess the scientific and
technical merit of research proposals.
pharmacokinetics: The activity of drugs in the body over a period
of time, including the processes by which drugs are absorbed,
distributed in the body, localized in the tissues, and excreted.
phase 1 trial: Small groups of people with cancer are treated with
a certain dose of a new agent that has already been extensively
studied in the laboratory. During the trial, the dose is usually
increased group by group in order to find the highest dose that
does not cause harmful side effects. This process determines a safe
and appropriate dose to use in a phase 2 trial.
phase 2 trial: Phase 2 trials continue to test the safety of the new
agent and begin to evaluate how well it works against a specific
type of cancer. In these trials, the new agent is given to groups of
people with one type of cancer or related cancers, using the dosage
found to be safe in phase 1 trials.
Glossary
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phase 3 trial: Phase 3 trials are designed to answer research
questions across the disease continuum. Phase 3 trials usually have
hundreds to thousands of participants, in order to find out if there
are true differences in the effectiveness of the treatment being tested.
phase 4 trial: Phase 4 trials are used to evaluate the long-term
safety and effectiveness of a treatment. Less common than phase 1,
2, and 3 trials, phase 4 trials take place after the new treatment has
been approved for standard use.
Physician Data Query (PDQ®): PDQ is an online database
developed and maintained by the National Cancer Institute.
Designed to make the most current, credible, and accurate cancer
information available to health professionals and the public, PDQ
contains peer-reviewed summaries on cancer treatment, screening,
prevention, genetics, and supportive care; a registry of cancer
clinical trials from around the world; and directories of physicians,
professionals who provide genetics services, and organizations
that provide cancer care.
placebo: An inactive substance that looks the same as, and is
administered in the same way as, a drug in a clinical trial. A
placebo may be compared with a new drug when no one knows if
any drug or treatment will be effective.
preclinical testing: Aprocess in which scientists test promising new
cancer treatments in the laboratory and in animal models. This is
done to find out whether agents have an anticancer effect and are
safely tolerated in animals. Once an agent proves promising in the
lab, the sponsor applies for Food and Drug Administration approval
to test it in clinical trials involving people.
prevention trials: Trials involving healthy people who are at high risk
for developing cancer. These trials try to answer specific questions about
and evaluate the effectiveness of ways to reduce the risk of cancer.
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principal investigator: The person responsible for overseeing all
aspects of a clinical trial, specifically, for developing the concept and
writing the protocol; submitting the protocol for institutional review
board approval; recruiting participants; obtaining informed consent;
and collecting, analyzing, interpreting, and presenting data.
protocol: A written, detailed action plan for a clinical trial. The
protocol provides the background, specifies the objectives, and
describes the design and organization of the trial. Every center
participating in the trial uses the same protocol, ensuring consistency
of procedures and enhancing communication among everyone
working on the trial. This uniformity ensures that participant
information from all centers can be combined and compared.
quality of life: The overall enjoyment of life. Many clinical trials
measure aspects of an individual's sense of well-being and ability
to perform various tasks to assess the effects of cancer and its
treatment on the overall quality of life.
radiation therapy: The use of high-energy radiation from x-rays,
gamma rays, neutrons, and other sources to kill cancer cells and
shrink tumors. Radiation may come from a machine outside the
body (external-beam radiation therapy), or it may come from
radioactive material placed in the body in the area near cancer
cells (internal radiation therapy, implant radiation, or
brachytherapy). Systemic radiation therapy uses a radioactive
substance, such as a radiolabeled monoclonal antibody, that
circulates throughout the body. Also called radiotherapy.
randomization: A method used to prevent bias in research. A computer
or a table of random numbers generates treatment assignments, and
participants have an equal chance to be assigned to one of two or more
groups (e.g., the control group or the investigational group).
randomized clinical trial: A study in which the participants are
assigned by chance to separate groups that compare different
treatments; neither the researchers nor the participants can choose
which group. Using chance to assign people to groups means that
the groups will be similar and that the treatments they receive can
Glossary
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be compared objectively. At the time of the trial, it is not known
which treatment is best. It is the patient's choice to be in a
randomized trial.
recurrence: The return of cancer, at the same site as the original
(primary) tumor or in another location, after the tumor had disappeared.
regimen: Atreatment plan that specifies the dosage, the schedule,
and the duration of treatment.
regression: A decrease in the size of a tumor, or in the extent of
cancer in the body.
relative risk: In cancer treatment trials, the likelihood that cancer
will recur within a specific timeframe in one intervention group
versus another.
remission: A decrease in or disappearance of signs and symptoms
of cancer. In partial remission, some, but not all, signs and
symptoms of cancer have disappeared. In complete remission, all
signs and symptoms of cancer have disappeared, although there
still may be cancer in the body.
risk/benefit ratio: The relation between the risks and benefits of a
given treatment or procedure. An institutional review board, usually
located where the clinical trial is to take place, determines whether
the risks in the trial are reasonable with respect to the potential
benefits. It is up to individual potential participants to decide
whether it is reasonable for them in particular to participate.
sample size: In clinical trials, the number of people participating
in a trial.
screening trials: Clinical trials that assess the effectiveness of new
means of detecting cancer early in healthy people, especially the
earliest stages of cancer. For many types of cancer, early detection
results in improved outcomes. In addition, these trials examine
whether early treatment, as a result of early detection, actually
improves overall survival or disease-free survival.
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side effects: Problems that occur when treatment affects healthy
cells. Common side effects of cancer treatment are fatigue, nausea,
vomiting, decreased blood cell counts, hair loss, and mouth sores.
single-blinded: Describes clinical trials set up in such a way
that participants do not know which therapy or intervention
they are receiving.
stage: The extent of a cancer, especially whether the disease has spread
from the original site to other parts of the body. Numbers with or
without letters are used to define cancer stages (e.g., stage IIb).
standard treatment: A currently accepted and widely used treatment
for a certain type of cancer, based on the results of past research.
statistical power: The chance of getting a statistically significant result
when there is one. Ideally, in clinical trials statistical power should be
.80 or .90­­in other words, there is an 80 to 90 percent chance that the
true difference in effectiveness between the treatments is the smallest
size considered medically important to detect.
statistically significant: Describes a mathematical measure of
difference between groups. The difference is said to be statistically
significant if it is greater than what might be expected to happen
by chance alone.
stratification: A separation process used in randomized trials
when factors that can influence the intervention's success are
known. For example, participants whose cancer has spread from
the original tumor site can be separated, or stratified, from those
whose cancer has not spread. Assignment of interventions within
the two groups is then randomized. Stratification enables
researchers to look in separate subgroups to see whether
differences exist.
toxicity: Harmful side effects from an agent being tested.
treatment group: See investigational group and control group.
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treatment trials: Treatment trials are designed to test the safety
and effectiveness of new drugs, biological agents, techniques, or
other interventions in people who have been diagnosed with
cancer. These trials evaluate the novel treatment against standard
treatment, if there is one.
tumor: An abnormal mass of tissue that results from excessive cell
division. Tumors perform no useful body function. They may be
benign (not cancerous) or malignant (cancerous).
vaccine: A substance or group of substances meant to cause the
immune system to respond to a cancer or to microorganisms, such
as bacteria or viruses.
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The printing of this publication was supported by an educational gift from
Novartis Oncology.
This booklet was written and published by the National Cancer Institute (NCI), 9000
Rockville Pike, Bethesda, Maryland 20892.
NCI is the U.S. Government's main agency for cancer research and information about
cancer. To inquire about copyright and use of NCI materials, contact: Clearance Officer,
National Cancer Institute.

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Public Health Service
National Institutes of Health
NIH Publication No. 02-5051
Printed October 2001
Reprinted September 2002
P920

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