Dolores Kong, The Boston Globe
When migraine sufferers enroll in a study of a potential new
medication, is it ethical to give some of them a placebo, or dummy
sugar pill, rather than a drug that is already known to be
effective? How about patients with high blood pressure? Or
depression? Or schizophrenia?
In all those situations, the US research ``gold standard'' calls
for new drugs under study to be compared with a placebo, an
inactive sugar pill.
But a growing and vocal minority of critics -- ethicists,
scientists, and patient advocates -- say the US method is outmoded
and unethical, violating the spirit of international codes designed
to protect human research subjects after the horrors of the Nazi
experiments.
With so many medications available, therapies should be judged
against each other, not against inactive pills, the critics say.
They point to European and Canadian regulatory agencies that call
for an alternative to the placebo-controlled trial -- a so-called
active-controlled trial -- in which patients who don't get the
potential new drug instead receive a medication already shown to be
effective.
What doctors and patients really want to know, critics say, is
how the potential new drugs compare with existing medications, not
a placebo.
``The placebo is just an easy out. It's an intellectually lazy
approach to the evaluation of drug efficacy,'' said Kenneth J.
Rothman, professor of epidemiology at Boston University School of
Public Health, who co-authored a 1994 study in the New England
Journal of Medicine that helped spur the debate. ``We cannot
deprive patients of effective treatment and live up to our ethical
guidelines.''
Agreed Harvard epidemiologist Karin B. Michels, Rothman's
co-author: ``It is just not necessary to put patients into the
position of having to suffer for science.''
The ``placebo effect'' -- derived from the Latin word placere,
meaning to please -- describes the well-known but inexplicable
phenomenon in which a patient often feels better after getting an
inert sugar pill or undergoing a sham procedure. Amazingly, in some
cases, up to 30 percent of patients who get a placebo experience a
reduction in symptoms.
But because of this, most researchers say that the
placebo-controlled trial is the most rigorous way to test new drugs
because it establishes whether a medication works at all.
For example, if 25 percent of research volunteers who get a
placebo feel better, while 60 percent of those taking the active
pill get relief, only then could researchers conclude that the
active pill really works.
``If there are no placebo controls, we would put ineffective
drugs in the marketplace. Nobody wants that,'' said Dr. Robert
Temple of the US Food and Drug Administration's Center for Drug
Evaluation and Research.
The debate over the ethics of placebo-controlled trials has
taken on international proportions, with the World Medical
Association, the International Conference on Harmonization, and the
Council for International Organizations of Medical Sciences now
considering new policy statements or revisions to existing ones.
The latest volley appeared in last Thursday's New England
Journal of Medicine, with opposing views aired over proposed
revisions to the World Medical Association's Declaration of
Helsinki, an international set of guidelines on medical ethics.
Currently, the declaration recommends the use of placebo in a
study only if there are no proven therapies for the condition and
states that physicians should ``obtain the subjects' freely-given
informed consent, preferably in writing.''
The proposed revisions would call for a placebo whenever
``justified by a scientifically and ethically sound research
protocol'' _ even if there are already proven therapies for the
condition under study _ and would allow a waiver of written
informed consent if a research ethics committee found the risks
slight, or if the procedures used are routinely used in medical
care without consent.
Dr. Troyen A. Brennan of Harvard Medical School opposed the
revisions, saying they ``weaken the principle of the researcher's
moral commitment to the research subject.''
But Dr. Robert J. Levine of Yale University School of Medicine
favored the changes because the document, as currently written, is
``seriously out of touch,'' considering that the placebo-controlled
trial is standard scientific practice.
While the debate rages on, there is broad agreement that
placebo-controlled trials are unethical in the case of bacterial
infections, which can be treated with antibiotics, or cancer, which
can be slowed or stopped with chemotherapy and other methods.
Nowhere were the sides of the debate more clearly drawn than at
a scientific symposium held a few months ago by the US Food and
Drug Administration.
On one side were Drs. Sidney Wolfe and Peter Lurie of Public
Citizen's Health Research Group, who believe that a placebo should
not be used in clinical trials when there are medications already
proven to be effective, and that the Declaration of Helsinki should
not be changed.
``First and foremost, we need to protect patients,'' Wolfe said.
On the other side was Temple of the FDA, saying that the use of
placebo was ethically justifiable in the study of drugs for
everything from panic disorder to a form of chest pain known as
angina. Temple acknowledged that ``there's a debate'' over the
current use of placebo in patients with schizophrenia. Medications
that work for all these conditions are on the market.
Although the FDA has not changed its stance on
placebo-controlled trials in a major way, it has moderated it in
some cases, according to Dr. Janet Woodcock, director of the FDA's
Center for Drug Evaluation and Research.
For instance, in February, the FDA issued guidelines to
researchers stating that patients with ``mildly active'' rheumatoid
arthritis, who are doing poorly on nonsteroidal anti-inflammatory
drugs (NSAIDs) and other therapies, ``are usually not appropriate
candidates for placebo-controlled trials.''
The FDA is also reviewing previous studies, involving a total of
about 100,000 patients with high blood pressure, to assess whether
people on a placebo suffered higher rates of adverse events than
normally expected, said the FDA's Temple during the symposium.
But Public Citizen's Lurie said he has already found in a
separate analysis of high blood pressure studies that patients
given a placebo had an additional 1 out of 1,000 risk of stroke.
While that may seem small, Lurie said during the FDA symposium, an
extra 1 out of 1,000 risk of cancer as a result of long-term
exposure to workplace chemicals would prompt action by occupational
health and safety officials.
But supporters of placebo-controlled trials point out that such
research is scientifically necessary and can be ethically designed.
``My opinion is that before we can test one drug against
another, we have to be sure that each one works,'' said Dr. Steven
C. Schachter, medical director of the office of clinical trials for
Beth Israel Deaconess Medical Center.
``The only way to do that is through a placebo-controlled study.
The challenge is to design (one) that is ethically sound and does
not put patients at unreasonable risk,'' he said.
In a trial of a potential new epilepsy drug, published by
Schachter and colleagues in a recent issue of the journal
Neurology, he said they only enrolled patients who needed to go off
of existing medications as part of a pre-surgical work-up. Hospital
staff continuously monitored the patients' safety, and patients
gave informed consent, said Schachter, who is chairman of the
advisory board for the Epilepsy Foundation of America.
But those circumstances don't convince critics that the placebo
trial should continue to be used. An editorial that criticized
Schachter's study design in the same issue of Neurology was
pointedly titled: ``Placebo-controlled studies in neurology: Where
do they stop?''
While the editorial welcomed the safety measures taken by
Schachter and colleagues, it questioned the researchers' argument
that the study was ethical because it only enrolled patients who
went off medications for a pre-surgical work-up.
In fact, according to the editorial by Dr. David Chadwick of the
University of Liverpool and Dr. Michael Privitera of the University
of Cincinnati, some patients have been known to die after being
taken off medications for such a work-up.
In an interview, Privitera, a professor of neurology, said,
``Scientifically, these studies are very good and tell you exactly
what you want to know.'' But he added, ``No one is asking, `Is this
the right thing for the patient in the trial'?''
