Before a new drug, surgical procedure, or therapy becomes available to the
public, it must go through a rigorous testing process and be evaluated by the US
Food and Drug Administration (FDA). This testing process consists of a series of
clinical trials that are designed to test the safety and usefulness of the new
drug compared to the current standard treatment.
The clinical trials that make headlines are usually what are called phase III
trials. These are large-scale tests with hundreds or thousands of patients. They
are the culmination of earlier phase I and phase II trials that include many
fewer people and still earlier preclinical experiments with animals. They are
also the final tests in humans before the FDA is asked to authorize sale of new
medicines.
Why Are Large-Scale Trials
Needed?
Clinical trials are designed to test whether a drug is safe for humans, and
whether the drug is effective in treating human diseases or conditions. Although
the drug has generally gone through extensive animal testing before the trial
begins, animal trials cannot always predict how new medicines will affect
humans. Even the most painstaking tests with animals give only approximate
indications of how people will respond to drugs. At some point, after thorough
study in animals (and when the FDA is convinced human experimentation will
probably be safe), tests with humans become necessary.
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Not only is it necessary to test new drugs in humans, but they need to be
tested in a large number of humans in order for the results of the trial to be
clear. The reason so many volunteers are required is that people are highly
variable in how they respond to drugs. It is not unusual, for example, for a
drug be somewhat effective in only 30 percent of those who take it. For medical
researchers to prove such a slight benefit requires testing the drug in as many
as several thousand patients.
This extensive testing is part of what drives up the cost of new drugs – the
average development time is over 10 years and costs from 500 to 700 million
dollars.
What Goes on Prior to a Large-Scale
Phase III Trial?
An enormous amount of testing has gone on by the time a drug is ready for
phase III. In general, a new drug or treatment goes through preclinical testing
in animals, then small phase I and phase II trials in humans before being ready
for large-scale testing.
Preclinical testing
When a drug is discovered that seems to have medical potential, a drug
company will test it exhaustively in animals, looking for signs it may be
poisonous, cause cancer, or cause birth defects. Animal studies will also be
used to estimate the initial drug doses to be tested in humans.
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When animal experiments are finished, the company asks the FDA for permission
to begin clinical trials. The FDA only grants approval once they are satisfied
that the animal experiments are sound and that clinical trials are likely to be
safe.
Phase I
The first test of the drug in humans is known as phase I. It is designed to
find out if the drug is safe rather than whether the drug is effective. Phase I
is also used to learn what drug doses to use in later trials, how the drug is
broken down in the body and excreted, and study short-term side effects.
A phase I trial rarely has more than 100 participants. Often healthy people
are enrolled in phase I trials rather than patients on the assumption that if
the drug has unexpected side effects, healthy people have the best chance of
escaping permanent harm. But on other occasions, as with a drug treating a
serious disease like cancer, phase I subjects may be patients who have failed
standard treatments.
Phase II
If a drug passes the safety tests of phase I, it advances to a phase II trial
with up to 200 participants. The goal of a phase II trial is to learn more about
safety and side effects, sharpen estimates of proper doses, and get an early
appraisal of whether the drug is going to work. This trial is often the first
time a drug is tested in actual patients.
What Are the Different Types of Phase III
Trials?
The phase III trial consists of hundreds or thousands of people. Commonly,
phase III will be conducted at several medical centers to see if people treated
in different locales have similar experiences. The central question of a phase
III trial is whether the drug works. Phase III will also give doctors an
extensive look at the drug’s side effects. There are many different ways of
conducting a phase III trial.
Blinded, randomized trials
Many Phase III trials are randomized, double-blind trials. Randomized means
people are assigned at random either to receive the new drug, the standard
treatment for that disease, or a nonfunctional substitute (such as a sugar
pill). This last group is often called the control group, or the placebo group.
Because phase III must answer definitively whether the drug works, it’s
important to compare people who receive it with others who do not.
A good example of how people are randomly assigned to study groups is the
phase III trial for Herceptin, which treats a form of breast cancer. In this
trial women either received the standard breast cancer treatment with Herceptin
or the standard treatment without Herceptin. In this case, there was no control
group who received just a sugar pill because to do so would be to not treat
women with a potentially fatal illness. In this trial, the women who received
Herceptin with the standard treatment became the test group; the others, the
controls.
Women were assigned at random to the two groups. This means that the average
age of the two groups was roughly similar as was the severity of their cancer so
the results can be compared. If the two groups had differed considerably in age
or health, researchers would not be able to tell if the drug itself was
effective, or if the women in that group were just younger or healthier.
Herceptin’s trial was also considered double-blind, which means that neither
the women nor their doctors knew who was receiving Herceptin. Of course, it is
natural for doctors to want to know what treatments their patients are getting,
and in single-blind trials they do. There, only the trial participants are
unaware of which group they are in. But double-blind trials are considered
better because they prevent doctors from acting on preconceived notions they may
have about whether or not the drug works.
For example, a doctor in the Herceptin trial might have been tempted to offer
extra treatment to participants that weren’t getting Herceptin. But the
physician’s attempt to compensate for the fact that the participant wasn’t
receiving the study drug would have collided with the requirement to keep groups
comparable in everything except who received the new drug. Unintentionally, the
doctor might have interfered with the trial, casting doubt on its conclusions.
This is why it is considered good practice for phase III trials to be
double-blind.
Open trials
Not every trial is blind. In unblinded trials, often described as open
trials, both doctors and participants know what treatments are being given.
Trials of surgical procedures and comparisons of medical devices are often by
nature open. One of the problems with an open drug trial is that many
participants may not want to take placebos, because they presume the drug will
be better. Open trials, like single
