3. Advancing Cancer Care Through Clinical Trials
FDA Approval Requirements
Releasing the Results
Improving Cancer Care
Speeding Up Drug Development
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
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
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:
Do the results of well-controlled clinical trials provide
substantial evidence of effectiveness?
Do the results show that the product is safe under the proposed
conditions of use? (In this context, "safe" means that
potentialbenefits 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
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.
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 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 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.
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. 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 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.
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 them--and
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.
The
Drug Development and Approval Process in the
1990s
|
|
Preclinical Testing
|
Clinical Trials
|
Post-Clinical Trials
|
Total Years for Drug Approval
|
|
Step 1
Laboratory / Preclinical
Testing
|
Step 2
File IND1 application with
FDA2
|
Step 3
Phase 1
|
Step 4
Phase 2
|
Step 5
Phase 3
|
Step 6
File NDA3 or BLA4 with
FDA
|
Step 7
FDA Approval
|
|
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
|
Determine what dosage is safe,
how treatment should be given
|
Evaluate effectiveness, looks
for side effects
|
Determine whether the new
treatment (or new use of a treatment) is a better
alternative to current standard
|
Inform the FDA of Phase 3 data which supports drug safety and better
performance over standard treatment
|
Review
process/ approval
|
All anticancer drugs
(average number of years)
|
4.4 years
|
|
8.6 years
|
|
1.4 years
|
14.4 years
|
All drugs*
(average number of years)
|
3.8 years
|
|
10.4 years
|
|
1.5 years
|
15.7 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 for a review and summary of content covered in this workbook.
Back to Top
< Previous Section | Next Section > |