By Kathy Wren
Officials at the Food and Drug Adminis- tration (FDA) must wrestle with a dif- ficult paradox. Since the early 1960s, after the thalidomide tragedy, the agency has been charged with protecting the public from unsafe and ineffective
medical products. At the same time, across
society, the demand for faster access to new
therapies has risen. As patients exhaust treatment options for serious or life-threatening
conditions, their tolerance for risk may grow.
In an effort to balance prudence and innovation, the FDA has implemented a variety
of new regulatory pathways to expedite the
approval of new drugs and medical devices
that meet certain conditions. But the benefits of these accelerated approaches must be
weighed against their drawbacks, speakers
cautioned at a 13 June event at AAAS headquarters in Washington, DC. The meeting
was cosponsored by AAAS; the Program on
Regulation, Therapeutics, and Law within
the Division of Pharmacoepidemiology and
Pharmacoeconomics of Brigham and Women’s Hospital/Harvard Medical School; and
the National Center for Health Research.
Scientific evidence is paramount to balancing the multiple demands on the Obama
Administration, according to FDA Commissioner Margaret Hamburg. “At the end of
the day, we have to be guided by science in
everything we do. It has to be our compass,”
she said in a keynote address.
Several of these speedier approval pathways are specifically designed to allow FDA
validation based on studies measuring “
surrogate end points.” Certain cholesterol levels,
for example, have been proven to adequately
reflect a patient’s risk of having a heart attack,
so a drug that reduces those levels may be
presumed to lower cardiovascular mortality.
Forty-nine percent of the drug approvals
by the FDA from 2005 to 2012 were based
on surrogate end points, according to a
study by Joseph Ross, an assistant profes-
sor of medicine and of public health at the
Yale University School of Medicine. The
numbers varied by medical specialty, with
a full 80% of cancer drug approvals relying
on these measurements.
As speedier approval pathways allow the
use of surrogate measures in a wider variety
of conditions, fewer of these measures are
subject to the rigorous validation required
of earlier FDA-authorized surrogates such as
cholesterol levels or systolic blood pressure.
“We need to do better studies to validate
whether these surrogates are as good as we
think, and not just assume things about
them,” said Jerry Avorn, a professor of medicine at Harvard Medical School and chief
of the Division of Pharmacoepidemiology
and Pharmacoeconomics at Brigham and
Speakers at the meeting cited study design as another area of concern. While randomized, controlled clinical trials are the
gold standard in medical research, this type
of study is not always used when testing
new medical products for FDA approval.
And it is particularly rare for new devices,
which are subject to different regulatory
procedures from prescription drugs.
More than 90% of all new medical de-
vices are not tested in clinical trials at all,
according to Diana Zuckerman, president
of the National Center for Health Research.
And, when Rita Redberg, a cardiologist at
the University of California, San Francisco,
School of Medicine, investigated the ap-
proval of cardiovascular devices in the high-
est-risk category over an 8-year period, she
found that only one-third were approved on
the basis of a randomized clinical trial.
In some cases, bypassing a controlled trial
may cost lives. An intracranial stent called
the Wingspan Stent System was approved
for use in stroke prevention on the basis of
a 45-person study, according to Redberg. Instead of using a randomized control group,
the researchers compared the patients’
outcomes to those in a previous study. The
FDA approved the Wingspan stent via the
“humanitarian device exemption,” which is
intended to encourage the development of
devices for treating rare diseases.
Later, a larger, randomized, controlled
trial known as the SAMPRISS trial determined that 1 out of every 11 patients who
received the Wingspan stent experienced a
stroke or died. An FDA committee agreed
that these data did not support the stent’s
use for stroke, and the agency recommended narrowing the official list of ways
that the device should be used.
The SAMPRISS trial was able to gather
data effectively because it required anyone
using the device to be enrolled in the trial,
and it may thus be a good model for future
postmarket studies, Redberg suggested.
EDITED BY KATHY WREN
At FDA, speedier
In 1988, days after AIDS activists protested at the FDA for greater access to experimental drugs, the agency
announced new regulations to speed up approval for certain medical products.
View the 2013 AAAS Annual Report