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1. The Clinical Trial Process
The Drug Development and Approval Process
Types and Phases of Clinical Trials
Special Access Programs
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Learning Objectives
Identify the steps in the drug development process
Name the various types and phases of clinical trials
Describe special access programs
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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 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. For more information call 1-888-INFO-FDA
or visit the FDA's Web site.
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Steps in the Drug Development Process
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. Investigational New Drug application. The trial
sponsor files an Investigational New Drug (IND) application
with FDA. If FDA approves the application, clinical trials
begin. 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. 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. Phase 3 clinical trial. Phase 3 trials evaluate the
effectiveness of the new treatment, compared to 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. 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). FDA approval. FDA approves the claim that is
being made about the drug, which takes up to about 1
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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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?
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.
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filler
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Phase
1
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Phase
2
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Phase
3
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Phase
4
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Number of participants
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15-30 people
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Less than 100 people
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Generally, from 100 to thousands of people
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Several hundred to several thousand people
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Purpose
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*To find a safe dosage
*To decide how the agent should be given
*To observe how the agent affects the human body
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*To determine if the agent or intervention has an
effect on a particular cancer
*To see how the agent or intervention affects the
human body
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*To compare the new agent or intervention (or new
use of a treatment) with the current standard
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*To further evaluate the long-term safety and
effectiveness of a new treatment
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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.
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
Possible Risks
Phase 2
Phase 2 trials are designed to evaluate the effectiveness of the
drug in a somewhat larger group of participants (usually under 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 to 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.
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
Possible Risks
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.
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.
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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.
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 to 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
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.
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.
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
Genetics Trials
Actual genetic intervention (such as gene-transfer) trials are few
in number, however trials are underway 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
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:
Who Participates
Possible Benefits
Possible Risks
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 underway and have demonstrated positive results.
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.
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 for a review and summary of content covered in this workbook.
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