2. Advancing Cancer Care through Clinical Trials
Evaluating Clinical Trial Results
Approving New Drugs
Once a new drug or intervention is proven safe and effective in a
clinical trial, it may become the new standard of practice.
Everything we can tell people with cancer today about their treatment
options is based on the results of clinical trials. Members of the
interested public can help speed up the research process.
Learning Objectives
By reading this section and completing the exercises, you
will be able to:
Explain the process of evaluation of clinical trial
results
Describe the steps by which the U.S. Food and Drug
Administration (FDA) approves a new drug
Name some examples of clinical trials that have led
to advances in cancer prevention, detection, and
treatment
Explain how members of the public can help speed up
the research process
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After a clinical trial is completed, researchers look carefully at
the collected data before making decisions about further testing and
what their findings mean.
After a phase 1 trial is completed, researchers decide
whether:
There are enough data to support further study
with a phase 2 trial
Further research will be discontinued because the agent
was not safe
After a phase 2 trial is completed, researchers decide
whether:
There are enough data to support further study
with a phase 3 trial
Further research will be discontinued because the agent
was not safe or effective
After a phase 3 trial is completed, the researchers must look at
the data and decide whether the results have medical importance. When
the analysis is complete, the researchers will inform the medical
community and the public of the trial results.
In most cases, a trial's results are first reported in
peer-reviewed scientific journals. But if a trial's results have
significant medical importance, a public announcement may be made
while the formal report is being submitted to ensure that people can
quickly benefit from the new advance. Particularly important results
are likely to be featured by the media and widely discussed at
scientific meetings and by advocacy groups.
Peer review is a process by which experts
critique a study's report before it is published to make
sure that the analysis and conclusions are sound.
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Once a new drug or technique is proven safe and effective in a
clinical trial, it may become the new standard of practice for
physicians.
By law, the Food and Drug Administration (FDA), an agency of the
U.S. Department of Health and Human Services (HHS), must review all
test results for new agents to ensure that products are safe and
effective for specific uses.
Once a new agent proves promising in the laboratory, the drug
company or research sponsor, such as NCI, must apply for FDA approval
through an Investigational New Drug (IND) application. Once FDA gives
approval to the sponsor, clinical trials may begin.
Once a trial sponsor feels there are adequate data from the
results of the trial to support a certain use for a drug, the sponsor
submits a New Drug Application (NDA) or a Biologics License
Application (BLA) to FDA.
The
Drug Development and Approval Process in the
1990s
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Preclinical Testing
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Clinical Trials
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Post-Clinical Trials
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Total Years for Drug Approval
|
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Step 1
Laboratory / Preclinical
Testing
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Step 2
File IND1 application with
FDA2
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Step 3
Phase 1
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Step 4
Phase 2
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Step 5
Phase 3
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Step 6
File NDA3 or BLA4 with
FDA
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Step 7
FDA Approval
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Purpose
|
Assess safety and biological
activity in the laboratory and in animal
models
|
Obtain FDA approval to begin clinical testing in humans after promising
results in laboratory
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Determine what dosage is safe,
how treatment should be given
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Evaluate effectiveness, looks
for side effects
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Determine whether the new
treatment (or new use of a treatment) is a better
alternative to current standard
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Inform the FDA of Phase 3 data which supports drug safety and better
performance over standard treatment
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Review
process/ approval
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All anticancer drugs
(average number of years)
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4.4 years
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|
8.6 years
|
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1.4 years
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14.4 years
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All drugs*
(average number of years)
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3.8 years
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10.4 years
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1.5 years
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15.7 years
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1IND = Investigational New Drug
2FDA = Food and Drug Administration
3NDA = New Drug Application
4BLA= Biologics License Application
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*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.
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How FDA Makes Decisions
FDA uses independent advisory committees of professionals and
consumers from outside the agency for expert advice and guidance in
making decisions about drug approval. By law these committees include
both a patient representative and a consumer representative.
As FDA looks at all the data submitted and the results of its own
review, it addresses two key questions:
1. Do the results of well-controlled studies provide substantial
evidence of effectiveness?
2. Do the results show the product is safe under the proposed
conditions for use? (In this context, "safe" means that potential
benefits have been determined to outweigh any risks.)
For an overview of the drug approval process from start
to finish, see FDA's book 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 www.fda.gov/cder/about/whatwedo/testtube.pdf.
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How Can the Public Influence the Drug Development
Process?
As shown on the Drug Development and Approval Process chart, it takes 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 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 ultimately reduces the time it takes for researchers to
enroll participants in trials and complete them-and speeds the
movement of new drugs or treatments into standard care.
Most of the ways we treat cancer today are based on the results of
earlier clinical trials. Recent clinical trials have resulted in the
following treatment benefits for people with chronic myelogenous
leukemia, cervical cancer, breast cancer, and melanoma, for
example.
Chronic Myelogenous Leukemia-A New Treatment Option
In 2001, FDA approved Gleevec, 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 the drug, their prognosis is generally poor.
In three short-duration, early-phase clinical trials with
Gleevec, researchers found higher remission rates among people
with CML than they would have expected, and the people had few
side effects. Gleevec was designed to target an abnormal version
of a normal cellular protein present in nearly all people with
CML. The abnormal protein is much more active than the normal
version and is probably the cause of 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
the 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. The results of
five large clinical trials showed that women with invasive
cervical cancer have improved rates of survival when they receive
a cisplatin-containing chemotherapy regimen plus radiation
therapy.
Breast Cancer
Less Extensive Surgery, Same Survival Rate
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
For many years, there was no clear option for women seeking to
reduce their risk of breast cancer. A large study was designed to
see if the drug tamoxifen could reduce the risk of developing
breast cancer in women who were already at high risk for
developing the disease. The study found that those 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 who took a
placebo.
Melanoma-Improved Survival Rates
According to the findings of a large, randomized clinical
trial, compared to 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
(reappearance).
Finding Clinical Trial Results
To find trial results, look up the official name of the
study and search medical publication databases, such as PDQ
(www.cancer.gov)
or PubMed from the National Library of Medicine (www.nlm.nih.gov).
If you have trouble locating the study or searching for it,
the research librarian at a university or medical library
may be able to help. It often takes over a year for a
scientific paper to be written, submitted, reviewed, edited,
and published. If an initial search turns up nothing, try
again after some time has passed.
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How Clinical Trials Advance Cancer Care
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Apply what you've learned about clinical trials to respond to
the following questions. You may wish to print these questions for
a reference.
A. What happens to clinical trial results?
__________________________________________________________
__________________________________________________________
__________________________________________________________
B. Clinical trials answer research questions. How does this help
people?
__________________________________________________________
__________________________________________________________
__________________________________________________________
C. Sometimes researchers decide not to continue studying an agent
or to seek FDA approval. How do scientists decide when to move from
one clinical trial phase to the next?
__________________________________________________________
__________________________________________________________
__________________________________________________________
D. How can public awareness about clinical trials influence the
research process?
__________________________________________________________
__________________________________________________________
__________________________________________________________
Answers to Exercise 2
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