Testing Drugs in People
By Ken Flieger
Most of us understand that drugs intended to treat people have to be tested in people.
These tests, called clinical trials, determine if a drug is safe and effective, at what
doses it works best, and what side effects it causes--information that guides health
professionals and, for non prescription drugs, consumers in the proper use of medicines.
Clinical testing isn't the only way to discover what effects drugs have on people.
Unplanned but alert observation and careful scrutiny of experience can often suggest drug
effects and lead to more formal study. But such observations are usually not reliable
enough to serve as the basis for important, scientifically valid conclusions. Controlled
clinical trials, in which results observed in patients getting the drug are compared to
the results in similar patients receiving a different treatment, are the best way science
has come up with to determine what a new drug really does. That's why controlled clinical
trials are the only legal basis for FDA to conclude that a new drug has shown
"substantial evidence of effectiveness."
Does It Work?
It's important to test drugs in the kind of people they're meant to help. It's also
important to design clinical studies that ask, and answer, the right questions about
investigational drugs. And that's no easy task.
The process starts with a drug sponsor, usually a pharmaceutical company, seeking to
develop a new drug it hopes will find a useful and profitable place in the market. Before
clinical testing begins, researchers analyze the drug's main physical and chemical
properties in the laboratory and study its pharmacologic and toxic effects in laboratory
animals. If the laboratory and animal study results show promise, the sponsor can apply to
FDA to begin testing in people.
Once FDA has seen the sponsor's plans and a local institutional review board--a panel
of scientists, ethicists, and non-scientists that oversees clinical research at medical
centers throughout the country--approves the protocol for clinical trials, experienced
clinical investigators give the drug to a small number of healthy volunteers or patients.
These phase 1 studies assess the most common acute adverse effects and examine the size of
doses that patients can take safely without a high incidence of side effects. Initial
clinical studies also begin to clarify what happens to a drug in the human body--whether
it's changed (metabolized), how much of it (or a metabolite) gets into the blood and
various organs, how long it stays in the body, and how the body gets rid of the drug and
its effects.
If phase 1 studies don't reveal major problems, such as unacceptable toxicity, the next
step is to conduct a clinical study in which the drug is given to patients who have the
condition it's intended to treat. Researchers then assess whether the drug has a favorable
effect on the condition.
Usually, No Miracles
Again, the process appears straightforward--simply recruit groups of patients to
participate in a clinical trial, administer the drug to those who agree to take part, and
see if it helps them. Sounds easy enough, and sometimes it is. In what may be medicine's
most celebrated clinical trial, Louis Pasteur treated patients exposed to rabies with an
experimental anti-rabies vaccine. All the treated patients survived. Since scientists knew
that untreated rabies was 100 percent fatal, it wasn't hard to conclude that Pasteur's
treatment was effective.
But that was a highly unusual case. Drugs do not usually miraculously reverse fatal
illness. More often they reduce the risk of death, but don't entirely eliminate it. They
usually accomplish this by relieving the symptoms of the illness, such as pain, anxiety,
heart failure, or angina. Or a drug may alter a clinical measurement--reduce blood
pressure or lower the cholesterol level, for example--in a way that physicians hope will
be valuable. Drug effects like these can be a good deal harder to detect and evaluate than
a result as dramatic as Pasteur's rabies cure.
This is mainly because diseases don't follow a predictable path. Many acute illnesses
or conditions--viral ailments like colds or the flu, minor injuries, insomnia--can usually
be counted on to go away spontaneously without treatment. Some chronic conditions like
arthritis, multiple sclerosis, depression, or asthma often follow a varying course--better
for a time, then worse, then better again, usually for no apparent reason. And heart
attacks and strokes, for example, have widely variable death rates depending on treatment,
age, and other factors, so that the "expected" mortality for an individual
patient can be hard to predict.
A further difficulty in gauging the effectiveness of an investigational drug is that in
some cases measurements of disease are subjective, relying in part on what is essentially
a matter of interpretation by the physician or patient. Such measurements can be
imprecise, influenced by a patient's or physician's expectations or hopes. In those
circumstances, it's difficult to tell whether treatment is having a favorable effect, no
effect, or even an adverse effect. The way to answer this critical question about an
investigational drug is to subject it to a controlled clinical trial.
New Drug Development Timeline
The phases of new drug development, from preclinical testing, research, and development
through postmarketing surveillance are illustrated in a 6K PDF chart.
Understanding Controls
In a controlled trial, patients in one group receive the investigational drug. Those in a
comparable group--the controls--get either no treatment at all, a placebo (an inactive
substance that looks like the investigational drug), a drug known to be effective, or a
different dose of the drug under study.
Usually the test and control groups are studied at the same time. In fact, usually the
same group of patients is divided in two with each subgroup getting a different treatment.
That is the best way to be sure the groups are similar.
In some special cases, a study uses a "historical control," in which patients
given the investigational drug are compared with similar patients treated with the control
drug at a different time and place. "Historical control" can also refer to a
comparison of groups of patients treated at about the same time but at different
institutions.
Sometimes patients are followed for a time after treatment with an investigational
drug, and investigators compare their status before and after treatment. Here, too, the
comparison is historical. It is based on an estimate of what would have happened without
treatment. The historical control design is particularly useful when the disease being
treated has high and predictable death or illness rates. Then investigators can be
reasonably sure what would have happened without treatment.
It's important that treatment and control groups be as similar as possible in
characteristics that can affect treatment outcome. For instance, all patients in specific
groups must have the disease the drug is meant to treat or same stage of the disease. In a
clinical trial of a drug to treat angina (chest pain associated with cardiovascular
disease), for example, if one group of patients being studied actually had sore ribs
rather than angina, their differing response to the drug could not be assumed to be due to
its effectiveness or lack thereof.
Treatment and control groups should also be of similar age, weight, and general health
status, and be similar in other characteristics that could affect the outcome of the
study, such as other treatment being received at the same time.
Two principal methods have been used to achieve this all-important comparability. One
is to carefully pair each person in the treatment group with a control patient who has
closely matching characteristics. This method is rarely used today because even in the
best of circumstances, it's difficult to match pairs of patients for the myriad factors
that could have a bearing on results.
In the more common approach, called randomization, patients are randomly assigned to
either the treatment or control group, rather than deliberately selected for one group or
the other. When the study population is large enough and the criteria for participation
are carefully defined, randomization yields treatment and control groups that are similar
in important characteristics. Because assignment to one group or another is not under the
control of the investigator, randomization also eliminates the possibility of
"selection bias," the tendency to pick healthier patients to get the new
treatment.
When It Helps to Be 'Blind'
In clinical trials, bias (a "tilt" in favor of a treatment) can operate like a
self-fulfilling prophesy. The hope for a good outcome can skew patient selection so that
the treatment group includes a disproportionate number of patients likely to do well
whatever their treatment. The same kind of inadvertent bias can lead both patients and
investigators to overrate positive results in the treatment group and negative findings
among controls, and cause data analysts to make choices that favor treatment. Clinical
trials that include such biases are likely to be incapable of assessing drug effect.
In conjunction with randomization, a design feature known as "blinding" helps
ensure that bias doesn't distort the conduct of a study or the interpretation of its
results. Single-blinding consists of keeping patients from knowing whether they are
receiving the investigational drug or a placebo. In a double-blind study, neither the
patients, the investigators, nor the data analysts know which patients got the
investigational drug. Only when the closely guarded assignment code is broken to identify
treatment and control patients do the people involved in the study know which is which.
Ethical Questions
Testing experimental drugs in people inevitably presents ethical questions. For example,
is it ethical to give patients a placebo when effective treatment is available? Not all
authorities agree on the answer. But the generally accepted practice in the United
States--and one increasingly being adopted abroad--is that well and fully informed
patients can consent to take part in a controlled-randomized-blinded clinical trial, even
when effective therapy exists, so long as they are not denied therapy that could alter
survival or prevent irreversible injury. They can voluntarily agree to accept temporary
discomfort and other potential risks in order to help evaluate a new treatment.
In any trial in which a possible effect on survival is being assessed, it's important
to monitor results as they emerge. That way, if a major effect is seen--positive or
negative--the trial can be stopped. This happened in the first clinical study of the AIDS
drug zidovudine (AZT), when a clear survival advantage for patients receiving zidovudine
was seen well before the trial was scheduled to end. The trial was then ended early, and
within a week FDA authorized a protocol allowing more than 4,000 patients to receive
zidovudine before it was approved for marketing under the brand name Retrovir. This is an
example of the ethical principle that if a lifesaving or life-extending treatment for a
disease does exist, patients cannot be denied it.
In some cases, a new treatment can be compared with established treatment, so long as
the effectiveness of the latter can readily be distinguished from placebo and the study is
large enough to detect any important difference.
It is also possible to evaluate new drugs in this situation in "add-on"
studies. In this kind of trial, all participants receive standard therapy approved for
treating the disease, but those in the treatment group also get the investigational drug.
The control group gets either no added treatment or placebo. Any difference in results
between the treatment and control groups can be attributed to the investigational drug. It
is common to study new anti-seizure drugs in this way, as well as new agents intended to
reduce mortality after a heart attack.
Testing in Women and Children
In recent years there has been growing interest at FDA and by the public in drug testing
in patient populations that have been relatively neglected in clinical trials, especially
women and children. Children are generally not included in trials at all until the drug
has been fully evaluated in adults, unless the drug is intended for a pediatric disease,
such as acute lymphocytic leukemia. When children are not likely to use drugs frequently
(for example, drugs to treat high blood pressure), they often have not been included in
clinical trials at all. (See "Why FDA Is Encouraging Drug Testing in Children.")
Without pediatric studies or other sources of scientific information, labeling cannot
include guidance about dosage, side effects, and when a drug should or should not be used
in children. In October 1992, FDA proposed changes in its regulations governing drug
labeling for "pediatric use." The proposal is aimed at encouraging drug sponsors
to develop pediatric information--through clinical trials in children or by extrapolation
of findings in adults--that can be included in drug labeling.
Although both sexes now are generally represented in clinical trials in proportions
that reflect gender patterns of disease, FDA and women's health advocates agree that less
care has been taken to develop information about significant differences in the ways men
and women respond to drugs.
A new FDA guideline on the study and evaluation of gender differences in clinical drug
trials, issued in July 1993, encourages drug companies to include appropriate numbers of
women in drug development programs and to pay particular attention to factors that can
affect drug behavior, such as phases of the menstrual cycle, menopause, and the use of
oral contraceptives or estrogens. Another focus is discovering gender-related differences
in how a drug is absorbed, metabolized or excreted, and how it works.
The guideline also does away with an FDA policy dating from 1977 that excluded women of
childbearing potential from participation in early clinical studies. The agency believes
that institutional review boards, as well as clinical investigators and women themselves,
can gauge whether women's participation in clinical trials is appropriate and make sure
that fetuses are not unduly exposed to potentially toxic agents. Studying drugs in people
will probably never be an exact science. But steady progress in the methodology and, in a
way, the philosophy of clinical trials is making the process more productive, more
reliable, and more beneficial for us all.
Key Components
The key components of FDA's review of marketing applications include:
- detailed and properly analyzed results of clinical trials
- information about how the trials were planned, designed, conducted, and assessed
- data on studies in animals
- information about how the drug is made.
A Skeptic's Guide to Medical 'Breakthroughs'
Everyone is gratified by news of a major drug breakthrough, especially if it promises help
for people who are desperately or terminally ill or severely disabled. And if you or a
loved one has been praying for such a drug, the news may seem like a miracle.
But can you accept the good news at face value? All too often you can't, because many
such reports are either exaggerated or seriously inaccurate interpretations of scientific
findings. Really significant advances in drugs and drug therapy are all too rare. They
don't happen nearly as often as the tabloids and magazines at the supermarket checkout
might lead you to believe. Sober skepticism is a good attitude to have when evaluating
news about drug "breakthroughs." Here are a few guidelines:
- Where did the news report appear? Is it in a newspaper, magazine, or broadcast news
service that regularly covers health and medical affairs and assigns specialized reporters
to the subject? Or is it part of a publication or broadcast that emphasizes sensational
stories that seem, and probably are, too good to be true?
- Is the reporter someone whose coverage of health and medicine you believe to be accurate
and cautious? If you are doubtful about the news medium in which the report appears, it's
probably best to take the story with a grain of salt.
- News stories about drugs producing complete cures, especially in patients with cancer,
AIDS, severe arthritis, or other grave illness, are likely to be cruelly wrong. Aside from
antibiotics for a few infections, drugs that make a disease disappear totally and
permanently are almost unknown.
- What's being reported? The results of one study in a small number of patients are
seldom, if ever, conclusive.
- This kind of preliminary information is presented at scientific meetings or published in
scientific journals whose editors and readers know how to interpret such findings. News
stories may place undue importance on these reports and jump to conclusions that the
researchers themselves know are unjustified.
- Ask your doctor what he or she knows about the story. While physicians can't know
everything, there's a good possibility that they would know about a truly important
medical advance. A negative answer should make you even more than usually skeptical.
Most medical science writers and reporters try diligently to provide accurate and
authoritative information. They avoid unfounded speculation, and they strive to put
exciting discoveries in perspective. Their stories don't often grab front page headlines
or lead off the evening news, but they can be trusted to give you solid information. And
that's a great deal better than false hope.
Personal Participation
Anyone interested in participating in a clinical trial should discuss the idea with his or
her physician. Doctors are generally aware of investigational drugs that might be of
benefit to their patients and of clinical trials involving these drugs. They can obtain
detailed information from a variety of sources, including drug sponsors.
Clinical trials are carried out at major medical research centers such as teaching
hospitals, at specialized clinics for people with AIDS, Alzheimer's disease or other
conditions, and even in doctors' offices. Although they often involve hospitalized
patients, many clinical trials are conducted on an outpatient basis, with participants
more or less going about their normal activities. The center or institution where a study
is to be carried out often runs newspaper ads recruiting potential participants for
clinical studies that tell readers where to call or write for further information.
Although investigational drug studies vary widely, some things should be expected by
participants in virtually any clinical trial. For example, participants might have to give
blood samples more often than during ordinary care. Tests to assess disease status might
be more frequent. Participants are often required to keep detailed records of their
symptoms and follow strict schedules.
It's also important to understand that volunteering for a clinical trial does not
guarantee that an individual patient will receive the drug under investigation. Control
patients may get a placebo, a drug already approved for their condition, or perhaps no
treatment at all.
These and other aspects and implications of taking part in a clinical trial must be
fully explained in advance by the people conducting the trial, and patients must agree to
the conditions before they can participate. The hope of personally benefiting from a new
drug--or the desire to take part in research that might one day benefit millions--is what
makes people volunteer for clinical trials. But it shouldn't prevent them from finding out
all they can about being a part of the process.
Source: Food and Drug Administration (FDA)
"Testing Drugs in People" originally appeared in the July-August 1994 FDA
Consumer . The companion article "Skeptic's Guide to Medical Breakthroughs"
was taken from the November 1987 FDA Consumer. FDA Consumer Special Report on New Drug
Development in the United States (January 1995).
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