Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
What are Clinical Trials?
Clinical trials carry out tests on people to see whether a candidate
therapy is safe and works to counter the effects of a disease.
Before human patients are the subjects, therapy is tested in cells or tissue
grown in the lab, and then in animals, to provide the best possible assurance
that a drug will be safe for people to take.
How Do Clinical Trials Proceed?
A pilot trial is a very first look at a candidate therapeutic in people,
a study that may be observational with too few patients to allow a formal
statistical analysis. Pilot testing must be able to inform further testing of a
candidate therapy. A pilot study paves the way for subsequent full scale
clinical trials. Therefore, a pilot trial should establish the number of
participants needed for a formal clinical trial and criteria to include or
exclude certain people. This will protect participants and provide the best
judgment of safety and effectiveness.
Clinical testing Is Divided into Four Phases:
Phase I testing looks at the safety of a candidate treatment, often in
just a few people. Participants are examined for any adverse reactions or side
effects. If any appear that are judged to be too dangerous, testing is halted
and the drug will not advance any further in the clinical trials process.
A Phase I trial enrolls perhaps ten or twenty subjects. For candidate
therapeutics in many diseases, this stage of testing can be in healthy
volunteers. But in ALS, the lack of effective treatment makes it likely that any
new candidate is tested in patients.
In ALS, a therapeutic will need to enter the nervous system. Also, ALS
compromises the ability to maintain nutrition and adequate tissue oxygenation as
breathing and swallowing weaken. Any new ALS therapeutic must be shown safe even
in the context of altered nutritional status and oxygenation common in ALS.
Thus, even initial testing must determine safety in patients who have the
disease, when it comes to new therapies for ALS.
Phase II testing attempts to determine the optimal dose, route (by mouth, by
injection) and timing of doses of the candidate treatment. Information about a
drug’s ability to help in the disease may be obtained in the course of Phase II
testing, but such findings are not able to reliably predict a candidate’s
effect. Usually less than a hundred patients are involved.
The therapeutic effect of the candidate is specifically sought in Phase III
testing, once Phase I and II trials show safety and yield the optimal dose. This
is the stage of testing that enrolls enough patients to allow a statistical
judgment that a treatment is effective. Phase III trials usually require
hundreds to thousands of participants.
Phase IV testing is for drugs already approved for sale to treat a specific
disease or diseases (termed a treatment’s indications). This stage of clinical
trial allows further gathering of data on large groups of people who are taking
the treatment for a prolonged period of time. Often a rare adverse effect only
becomes evident after a drug is marketed simply because there has been enough
exposure to the drug to reveal the rare occurrence.
Who Can Participate in a Clinical Trial?
There may be limits on who can volunteer to be part of a clinical trial.
The design of a trial ensures that the most reliable measures possible are
collected to best judge a treatment’s effects.
Due to requirements for producing reliable data, patients may have to be of a
certain age, gender, stage of disease, or even race, to participate for many
clinical trials. Studies must address any anticipated risk of a drug for
patients of a certain age, gender, race, or physical condition, or interaction
with other drugs being taken and protect participants from being exposed to
undue risk.
For ALS, restrictions are often looser to participate in clinical trials than
for other conditions that are not so devastating or rapidly fatal. Nevertheless,
ALS patients in clinical trials are required to fulfill certain criteria of the
disease or disease severity (“Inclusion criteria”) and might be ineligible if
they show certain other characteristics (“Exclusion criteria”).
How are Clinical Trials Designed?
Phase II and Phase III trials are usually randomized, placebo controlled,
double blind studies that include a statistical analysis.
Statistics:
Clinical trials can only test relatively few patients and must make
predictions from a few people that will most likely hold for the patient
population as a whole. Statistics provide the means to judge if a change induced
by drug treatment is likely to be a real, reproducible change, and that what
doctors see in a restricted set of patients is likely to hold true for the
entire population of patients with that disease.
So the patients must be as clearly characterized and represent the disease
picture as closely as possible. That allows researchers to take data from
clinical trials and predict that the entire population of patients will show the
same results if given the same treatment.
Placebo:
The placebo effect is well known in medicine as a temporary improvement
in pain or other symptoms of a disease that follows a fake pill. It is a real
effect. But it is not due to the active properties of a drug. So testing of any
new treatment must insure that the effect is due to the drug and not to the
power of positive thinking or to the extra attention from the medical staff that
comes with participation in a clinical trial.
Patients in clinical trials have more doctor visits and tests than those who are
not in trials. This also must be taken into account, and placebo treatment with
blinding (see below) does so.
For diseases such as cancer, where effective treatments exist, new drugs can be
tested against the standard of care. But in ALS, with only one approved drug
that does not have a strong effect to prolong life or slow progression, many
argue that candidate therapies should still be compared to a placebo.
Blinding:
Clinical trials often are double blinded, meaning neither the clinicians
nor the patient knows which drug is taken: placebo (or standard treatment) or
candidate treatment. Unconscious bias can creep in when an investigator looks at
data knowing which treatment generated the numbers or records symptoms from
patients on the test drug. And patients can give more attention to perceived
changes if they think active drug may have created them. In a blinded clinical
trial, only a central office knows the treatment assignment until the study ends
but can unblind a patient or the entire study if needed. Randomization:
Often trials will assign patients to two or three treatment groups at random.
This prevents any bias from influencing what patient gets which treatment. As
patients enroll in a trial that is randomized, they are assigned by computer
(kind of like drawing numbers from a hat) to a treatment group.
It is better to pick from a hat than to inadvertently pick those people with a
milder form of the disease or a slower course of progression to receive the test
drug. When a study is analyzed and the results presented, the researchers are
always careful to consider if the groups of patients were indeed well randomized
as to characteristics such as age, gender, stage of disease, and so forth.
Control:
Control refers to a control group intended for comparison to the group of
patients receiving the candidate treatment. The control group is the patients
who are taking a placebo or the standard of care treatment. If a control group
is not included, researchers would be less certain that the patients taking the
candidate therapy were not getting better by chance fluctuations in their
illness, as opposed to a direct effect of the drug.
Fluctuations in disease progression are documented for many illnesses including
ALS. Simple hope that a new treatment will work can color expectations and
perceptions. A patient’s speech can appear clearer. A patient can gather
strength to sit up unassisted or take a few steps unaided. Decline in abilities
can slow or plateau. These are real effects of positive thinking. A control
group helps to balance effects of the mind against effects of a drug.
What are Outcome Measures?
These are the measurements that are defined at the outset of a trial as
the sought for action of the drug candidate. For ALS, survival time is an
example of an outcome measure that an effective treatment should change. Other
outcome measures that are useful in ALS are tests of muscle strength or measures
of breathing. Quality of life, measured by self report or caregiver report, is a
desirable measure to include in ALS clinical trials. Rating scales are available
that rate various aspects of life with ALS including ability to move and to
carry out activities of daily living, as well as problems with breathing and
eating. An example is the ALS functional rating scale (ALS-FRS).
What are Surrogate Markers?
Some disorders have known signs that imply the disease process is
interrupted. These measures can serve as a surrogate for the actual desired
outcome. In heart disease, lowering blood pressure or cholesterol would be valid
surrogate markers as these changes are accepted to lower the risk of heart
attack and death. In ALS, surrogate markers are as yet unproven but are
suggested. For instance, breathing capacity appears to predict survival.
Improved and accelerated clinical testing in ALS will surely follow once good
surrogate markers of disease progress are identified.
Where are Clinical Trials Carried Out?
Many clinical trials are at medical centers of teaching hospitals linked
to a medical school. But private practice physicians can also be part of a
clinical trial and be able to enroll his or her patients.
Different organizations may sponsor a clinical trial. These can include federal
agencies, private charitable organizations such as The ALS Association, or drug
or biotech companies.
What is an IRB?
An Institutional Review Board (IRB) is required to safeguard patients
participating in clinical trials. This is a committee of experts convened by an
institution to review biomedical research involving humans as subjects. An IRB
will approve the initiation of the research and then reviews its progress to
ensure the safety of the participants. The board includes health professionals,
clergy, and members of the public. Every institution that oversees clinical
testing must have an IRB.
The IRB meets regularly to follow the progress of a trial. It can call a halt to
a trial if unanticipated risks appear, or if a treatment is showing such clear
evidence of beneficial effect that it would be unethical to not make it widely
available.
In addition to the IRB, clinical trials in the Phase I - III category have a
Data and Safety Monitoring Board (DSMB) of scientists, statisticians, and other
experts that watches for adverse effects. It ensures that the data collected are
as complete as possible and can halt a trial if risks appear, or if the
objectives of a trial are met.
What is a Protocol?
Each clinical trial has a detailed description of how the trial will be
carried out, what parameter is being tested, and what measurements will be taken
at what times. Details of patient characteristics are also stated beforehand
(eligibility criteria). Each center or physician enrolling patients follows the
same study protocol. The first step to initiate a trial is having the IRB
approve the protocol.
What is Informed Consent?
Clinical trials are entirely voluntary and patients can withdraw at any
point. Participants in clinical trials learn of and must read and sign a
statement listing clearly the risks and benefits of taking an experimental drug.
Informed consent is a process and not a piece of paper. It must continue
throughout a clinical trial. Patients have the right to understand what is
happening throughout the trial, if risks and benefits change.
Risks and Benefits to Participating in Clinical Trials
Setting eligibility criteria defines the characteristics of the patient
who can most safely participate in a clinical trial. For instance, if a
candidate drug is known to be broken down by the liver, patients will be tested
for their liver function, which must be adequate to participate. Otherwise,
potentially dangerous levels of drug might accumulate in the bloodstream if the
liver cannot detoxify properly.
Risks to patients include effects of the candidate treatment that are yet
unknown, for instance, if the drug indeed affects liver metabolism and this only
becomes evident during testing. This kind of potential problem is why drugs are
tested extensively in animals before use in people. But sometimes interactions
with particular patients are not revealed until clinical trial.
By contrast, approved drugs have been taken by many patients for years, so risks
are usually known.
Other risks to patients participating in clinical trials include increased cost
as well as increased risk. Health insurance does not usually cover experimental
treatment.
Another adverse aspect to clinical trials is participants may have to give more
frequent blood samples and keep a detailed record of symptoms than if receiving
usual care for their illness.
Benefits include the chance that a new drug is more successful at treating the
participant’s disease than existing treatments. Also, as mentioned, clinical
trials involve more frequent doctor visits and more frequent testing which can
help patients. Patients in clinical trials who do not receive the candidate
treatment do receive the best standard of care for their disease.
A benefit to participating in a clinical trial is that the questions answered
can benefit all patients with the disease. Even if a candidate treatment fails
to hold promise, the results of any clinical trial give new insight and
direction to those working to solve the disorder.
What is the role of the FDA?
The Federal Food, Drug, and Cosmetic Act of 1938 set up the Food and Drug
Administration to ensure that any new drug to be sold is safe and effective. The
FDA staff reviews preclinical results that the testing parties are required to
submit to demonstrate that a new drug can be tested safely in people (see IND
below). If testing shows that a drug is safe and effective, the FDA must approve
the drug for sale and state what information is to be provided with the drug to
physicians and patients (in the package insert) so it can be used properly.
The FDA also inspects IRBs to help protect the rights and safety of human
research subjects.
What is an IND?
An Investigational New Drug Application must be submitted to the FDA
before testing begins of a new drug in people. The IND application consists of
the plans for the study and details of the composition of the drug, how it is
manufactured, and results of tests in animals.
What is Compassionate Use?
The FDA allows people to be treated with promising drugs still in
clinical testing, provided an illness is life threatening and has no other
effective treatment. These “expanded access protocols” are allowed while
clinical researchers are still in the process of formal clinical trials that are
supplying information that the drug is safe and likely to be effective. Programs
for expanded access to experimental drugs include the treatment IND for people
for whom there are no other treatment options.
The FDA also designates drugs for priority review that supply a real advance in
treatment, as opposed to drugs that merely make available another option to ones
already on the market. The agency will mobilize personnel and resources to plan
for a streamlined review when a priority drug is first put into clinical
testing. The special “accelerated approval” process is also available with
expedited FDA review for new treatments for otherwise life threatening
illnesses.
Who Pays for Patient Costs in Clinical Trials?
This will vary according to the clinical trial and a patient’s insurance.
Be sure to ask this very important question when considering whether to
participate.
MGM
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