Author: Jon Merz
Date: 01-06-06 10:18
Source: Washington Post
URL: http://www.washingtonpost.com/wp-dyn/content/article/2006/01/01/AR2006010100749.html?sub=AR
Date published: January 2nd 2006
from Michael Goodyear:
Superfluous Medical Studies Called Into Question
By David Brown
Monday, January 2, 2006; A06
In medical research, nobody is convinced by a single experiment.
A finding has to be reproducible to be believable. Only if different scientists
in different places do the same study and get the same outcomes can physicians
have confidence the finding is actually true. Only then is it ready to be put
into clinical practice.
Nevertheless, one of medicine's most overlooked problems is the fact that some
questions keep being asked over and over. Repeated tests of the same diagnostic
study or treatment are a waste -- of time and money, and of volunteers' trust
and self-sacrifice. Unnecessary clinical trials may also cost lives.
All this is leading some experts to ask a new question: "What part of 'yes'
don't doctors understand?"
Two papers dramatically illustrated this problem last year and may have helped
nudge the medical establishment toward doing something about it.
One article examined 18 years of research on aprotinin, a drug used to reduce
bleeding during heart surgery. The other looked at studies on the relationship
between a baby's sleeping position and sudden infant death syndrome. Both
concluded that research on these subjects went on long after the answers were
known -- namely, that aprotinin worked and that babies sleeping on their backs
were less likely to die of SIDS.
The odyssey of aprotinin, which is derived from the lung tissue of cows, was
recounted in the journal Clinical Trials.
Dean Fergusson and his colleagues at the Ottawa Health Research Institute found
64 randomized, controlled trials -- the most authoritative type of study -- on
the use of aprotinin in heart surgery. They were done in half a dozen countries
over 18 years, starting in 1987.
Two-thirds were little more than variations on each other. And nearly all showed
the same thing: Patients who received aprotinin during surgery bled less. They
had only one-third the chance of needing a blood transfusion of patients who
did not get the drug.
What was surprising was that this advantage was clear by June 1992, after the
12th of the 64 studies. If researchers after that time had familiarized
themselves with previous studies -- and especially if they had analyzed
summaries of those studies, called "meta-analyses" -- they might not have
considered it necessary to run their own.
But it appears that very few of them studied closely what had been published
previously about aprotinin. On average each new paper listed only one-fifth of
the previous studies in its references. Only two research teams mentioned the
two published "overviews" of aprotinin research, one from 1994 and the other
from 1997. Both of them demonstrated the unquestionable advantage of giving the
drug.
In all 64 studies, the patients were randomly assigned to get aprotinin or a
placebo. In general, mortality did not differ between the two groups. But some
of the patients receiving a placebo had bleeding and needed transfusions that
they might have avoided had they been given aprotinin.
Being given a placebo long after aprotinin's value had been proved probably did
not cost lives. The same cannot be said of medicine's failure to pay attention
to studies of infant sleep position.
Last April, in the International Journal of Epidemiology, Ruth Gilbert of the
Institute of Child Health in London examined 40 studies of SIDS and sleep
position going back to 1965.
Gilbert found that if researchers had pooled the results of the oldest studies
and analyzed them, they might have gotten a big hint by 1970 that putting
babies to sleep on their stomachs raised the risk of SIDS. Instead, that
observation did not become convincing until the late 1980s.
Researchers now know that sleeping on the stomach raises the risk of SIDS
sevenfold. That realization led to "Back to Sleep" campaigns in Britain in 1991
and in the United States in 1994.
Between 1970 and the unveiling of that advice, 11,000 British infants -- who
might have survived if sleeping on the back had been the norm -- died of SIDS.
In the United States, Europe and Australia, "at least 50,000 excess deaths were
attributable to harmful health advice," Gilbert and her colleagues wrote.
The problem is evident even in research on the highest-profile diseases.
In 1992, Joseph Lau, then at the Department of Veterans Affairs hospital in
Boston and now at Tufts University, published a paper that has become a classic
in epidemiology. He examined 33 clinical trials of streptokinase, a drug that
dissolves clots in the coronary arteries of people having heart attacks.
The trials were conducted from 1959 to 1988. Lau conducted a "cumulative
meta-analysis" of the results. This is done by adding each trial's patients and
their outcomes to all the preceding ones. The result was a running scorecard of
streptokinase's performance.
Lau determined that by the end of the eighth trial in 1973, the evidence was
clear that heart attack patients who got streptokinase had 25 percent lower
death rates than those who did not. That conclusion, and the percentage, did
not budge while 34,542 more patients were enrolled in 25 more trials of
streptokinase over the next 15 years.
There are lots of reasons this kind of thing happens.
In many of the aprotinin studies, the researchers tested the drug in subgroups
of patients or altered variables to see if outcomes changed. The drug is very
expensive, so they tried different doses. Sometimes they added it to the blood
in the heart-lung machine; sometimes they injected it directly into the
patient. Some studies examined not only aprotinin's effects on bleeding, but
also on the function of artery bypasses to restore blood flow to the heart
muscle.
Additionally, surgical culture and practices differ somewhat from country to
country, and apparently surgeons in some nations felt they needed to study the
drug themselves before adopting its use.
Even given these justifications, however, there was much repetition. Two studies
of aprotinin's effects on patients taking aspirin were published in 1994,
another in 1998, and another in 2000. All showed the same thing: Aprotinin
worked for those patients, too.
The reason for the plethora of SIDS studies was different. The evidence that
stomach-sleeping was hazardous arose from observational studies, which are
inherently less authoritative than controlled trials where people are randomly
assigned to do one thing or another. It takes more observational studies to
persuade doctors to change something as important as advice to new parents.
The number of unnecessary studies that occur is an open question.
Nobody requires that medical scientists review previous research to make sure
the question they are asking has not already been answered. This may change,
though.
The Lancet, a British journal, announced last summer that it will require that
authors submitting papers show they performed a meta-analysis of previous
research or consulted an existing one.
"In 10 years we are going to look back on this time, and we won't believe this
wasn't done as a matter of course," said Steven N. Goodman, a physician and
biostatistician at Johns Hopkins University who edits Clinical Trials.
The current state of affairs, in his opinion, is indefensible.
When a patient volunteers for a randomized clinical trial, he or she strikes an
implicit bargain with the researcher. The patient may benefit, but even if he
does not, others will. That is because the study will produce new knowledge.
But if the question is already settled, then the patient's sacrifice and
altruism are for naught.
"In the ethical world, two things need to be considered -- harms and wrongs,"
Goodman said. "People in unnecessary trials are sometimes harmed, but I would
say they are always wronged. And in the world of clinical research, wrongs are
almost worse than harms."
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