numerous high-profile safety scares, clinicians and regulators push to fix
critical weaknesses in the FDA’s monitoring system for approved drugs
was on the market for 5 years before manufacturer Merck voluntarily withdrew
the arthritis medication in 2004 due to an increased risk of heart attacks
and strokes. An estimated 88,000–139,000 Americans had heart attacks
while taking Vioxx, and as many as 55,000 died. Soon after, other painkillers
in the same class of medicines came under scrutiny, including Bextra, which
Pfizer removed from the market in 2005 upon the recommendation of the US
Food and Drug Administration (FDA).
cried out for better oversight of approved drugs. Then, in 2007, a cardiologist
in Cleveland showed that Avandia, a blockbuster antidiabetic drug, increased
the risk of heart attacks. An FDA advisory committee reviewed the evidence
and found the claim to be true, but voted to keep Avandia on the market
because of its efficacy, while mandating that the drug carry the FDA’s
strictest warning label. The cries became louder.
almost a decade since Vioxx was taken off the market and 6 years since Avandia
made headlines, the national system for monitoring approved drugs has not
gotten any better, critics say—despite the 2007 FDA Amendments Act
(FDAAA) that granted the agency more power to oversee drugs once they hit
don’t think there have been any significant changes,” says David
Resnik, a bioethicist at the National Institute of Environmental Health
Sciences. “I don’t think anything has improved at all.”
drug safety is a hot-button issue not only because of high-profile drug
scares, but also because of accelerating efforts to get drugs to market
sooner. Last July, for example, Congress passed the Food and Drug Administration
Safety and Innovation Act, which among other things created a new designation
called a “breakthrough therapy.” Though the details of the new
designation are still being worked out, it is considered one step above
“fast track” status, and mandates that the FDA work closely
with drug developers to expedite a breakthrough drug’s path to the
clinic. A handful of experimental drugs have been granted the status, and
at least one company, Vertex Pharmaceuticals, is launching shorter-than-normal
Phase 3 trials—24 weeks instead of 48—for a combination of two
cystic fibrosis drugs that received the designation in January.
have this push for drugs coming through the pipeline sooner from both market
forces and unmet medical need,” says Ruth Faden, founding director
of the Johns Hopkins Berman Institute of Bioethics.
push, however, has not been balanced with adequate effort to track the safety
of drugs in the marketplace, says Xianglin Du, an epidemiologist at the
School of Public Health at the University of Texas Health Science Center
at Houston. “At the moment, no one is satisfied with the current system.
We need to improve this system for the safety of all people, to identify
risks earlier and in a timely manner.”
number of adverse events reported to the FDA has dramatically increased
over the last decade, from roughly 200,000 reports in 2001 to 900,000 in
2012. But adverse events themselves are not a failure of the drug-approval
system, experts note. “It’s impossible—no matter how good
or how phenomenally careful the system is from the manufacturer to the regulator—[to]
have all the information we need about the benefit-risk ratio of a drug
at the end of the premarket phase,” says Faden. Clinical trials include
only 500 to 3,000 patients, so the full range of a medication’s side
effects is not likely to be revealed until it is used by the general population,
which includes people typically excluded from clinical trials, such as those
with comorbidities, pregnant women, and senior citizens. FDA approval of
a drug is therefore not a gold stamp of safety, Faden emphasizes, but a
point on a continuum when the FDA makes a judgment call that the benefits
of a drug outweigh its risks.
central issue, that we approve drugs based on incomplete information, is
not a flaw,” says Brian Strom, a professor of biostatistics and epidemiology
at the University of Pennsylvania Perelman School of Medicine, “but
it means that inevitably there will be problems that emerge.” The
goal of postmarket drug safety monitoring, therefore, is not to prevent
adverse events from happening, but to detect them early and efficiently,
making adjustments when required.
the current system depends on spontaneous, voluntary reporting—pharmaceutical
companies, consumers, and health-care professionals voluntarily report adverse
events to the FDA through a reporting system called MedWatch—and any
voluntary system is prone to vast underreporting. “[MedWatch] likely
misses over 90 percent of people with concerns,” says Du.
way to more thoroughly detect a drug’s side effects is to go looking
for them—for example, by scouring electronic medical records. In 2011,
Du and colleagues demonstrated the feasibility of this approach using electronic
Medicare claims data. In a study of 19,478 women aged 65 or older, the team
tracked whether women with breast cancer had an increased risk of heart
disease when undergoing chemotherapy that included a class of drugs called
anthracyclines. They found that this type of chemotherapy increased the
risk of heart failure by 25 percent, but had no effect on other types of
heart disease (Cancer, 115:5296-308, 2009). “Electronic data allows
you to do a lot of things that you can’t do with traditional medical
charts,” says Du, such as getting rapid access to real-time health
information and maintaining records even when patients move or switch providers.
(See “Researchers, Hire Hackers,” page 26.)
the FDA’s own project, a national electronic system called Sentinel,
proved useful in investigating whether a new blood thinner, called dabigatran
(Pradaxa), shared the same risk of serious bleeding as the already available
warfarin, or whether the new drug’s risk was higher. Through MedWatch,
the FDA received many reports of bleeding associated with Pradaxa, but was
unable to conclude whether the number of reports was higher than expected.
Using the Sentinel system, the FDA determined there was no higher rate of
bleeding than warfarin, but did put out a safety announcement in December
2012 that Pradaxa should not be used by patients with mechanical heart valves,
who were more likely to experience strokes, heart attacks, and blood clots
on Pradaxa than on warfarin.
olden days, we would have had to launch a full-blown epidemiologic study
to do this,” says Gerald Dal Pan, director of FDA’s Office of
Surveillance and Epidemiology (OSE). “What we were able to do with
Sentinel was query the system and use population-based data . . . to find
out who had bleeds or hemorrhage.”
in 2008, FDA’s pilot version of Sentinel, Mini-Sentinel, now includes
data from 110 million individuals collected from numerous health-care sources
and compiled by the Harvard Pilgrim Health Care Institute, a research arm
of the not-for-profit insurance provider. But so far, Sentinel has only
been used to track suspected adverse events, not to identify new ones. Indeed,
this seems to be a general limitation of such reporting systems. In 2010,
a team at Brigham and Women’s Hospital in Boston developed a system
to send automated reports straight from a doctor’s note entered into
an electronic medical chart to the FDA. A group of 26 clinicians, who had
submitted no adverse event reports in the prior year, filed 217 reports
in 5 months using the electronic reporting system (Pharmacoepidemiol Drug
Saf, 19:1211-15, 2010). Yet when Dal Pan and his team at the FDA reviewed
those reports, the data within them were often conflicting or lacking, and
most reported events were not serious and were already noted in labels for
the associated drugs (Pharmacoepidemiol Drug Saf, 21:565-70, 2012). “We
felt it was a good proof of principle, but can these systems be used to
tell us new things, things we don’t already know?” Dal Pan asks.
the 2004 withdrawal of the widely prescribed Vioxx, the FDA asked the Institute
of Medicine of the National Academies (IOM) to evaluate the US postmarket
safety-monitoring system. The resulting IOM report called for increased
FDA staff and organization on the postapproval side. “The FDA spends
an enormous amount of effort and resources on approvals and getting drugs
out,” says Strom. “It needs to spend more on doing studies of
drugs after marketing.”
the FDA launched the Safety First initiative, which instituted internal
operational frameworks to give premarketing and postmarketing safety equal
focus, and Dal Pan grew the OSE staff from about 130 in 2005 to 250 today.
“We’ve been making a lot of changes in postmarket drug safety
for the last several years,” he says.
hearings about a postmarket clinical trial of Avandia spurred the agency
to request a second assessment from the IOM, which subsequently produced
a second set of recommendations in May 2012. This time, a key suggestion
was that the FDA create a better system for tracking individual drugs. “There’s
no single place you can go, on the FDA website or otherwise, to find out
all the relevant safety and efficacy data on a particular drug at a particular
moment in time,” says Steven Goodman, associate dean for clinical
and translational research at the Stanford University School of Medicine
and cochair of the IOM panel.
IOM recommended that the FDA create a benefit-and-risk assessment and management
plan, or BRAMP, for every approved drug: a single, publicly accessible document
that would detail safety issues and postmarketing studies as a way to continually
weigh the drug’s benefits against its risks. “If the FDA itself
was doing this, it could stay on top of things, instead of waiting for a
fire to break out,” says Goodman.
the FDA has not instituted such a system. “For us to prepare all those
documents would be quite a lot of work, and we’re using our resources
in different ways,” Dal Pan says. It might be possible, he notes,
for drug manufacturers to take on such a task, but such company-prepared
reports would be confidential, not publicly available.
major recommendation from the 2012 IOM report was for the FDA to require
more and earlier postmarket studies. “Right now, [the FDA] mounts
studies when a crisis occurs, which is too late anyway,” says Strom.
In 2007, the FDA ordered the TIDE trial, a randomized postmarket clinical
trial comparing Avandia with Takeda Pharmaceutical’s rival drug Actos,
after the initial evidence of Avandia’s potential dangers was published.
The trial was halted in 2010 after additional studies confirmed Avandia’s
risks, which raised ethical concerns about knowingly giving patients a potentially
a postmarketing study doesn’t need to be randomized trials like the
TIDE trial, which are costly and raise ethical questions, says Goodman.
Instead, the FDA could simply require that companies start gathering data
on the outcomes of patients taking their new drugs right after approval,
increasing the chances of catching adverse events early. These observational
studies should at least be done for drugs of heightened concern, such as
those with demonstrated risk factors during clinical trials or those likely
to be widely used for common, chronic conditions, says Goodman.
the FDA should require more long-term observations of drugs’ effects,
says Resnik. The current postmarketing system is geared toward detecting
acute drug reactions, yet some adverse reactions don’t show up until
5, 10, even 20 years later.
a human system in the end, and we’re not going to be able to make
it perfect,” says Faden. From voluntary reports to electronic health-care
records, from randomized trials to observational studies, adds Dal Pan,
“there’s no one-size-fits-all for what we need to do.”