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FDA Report
REPORT HIGHLIGHTS
DRUG SAFETY: Improvement Needed in FDA’s
Postmarket Decision-making and
Oversight Process
GAO conducted an organizational review and case
studies of four drugs with safety issues:
Arava,
Rezulin,
Bextra, and
Propulsid.
Bextra
There was sometimes a lack of consensus in our
drug case studies, and we observed that ODS
often performed a series of related analyses
about the same safety concerns for OND over a
significant period of time. As an illustration
of this iterative decision-making process, OND
requested in 2002 that ODS analyze cases of
serious skin reactions associated with the pain
reliever Bextra after the drug’s sponsor had
communicated with OND about this potential risk.
ODS staff searched the AERS database and found
several related cases for review.
They estimated the occurrence of reported cases
of serious skin reactions among Bextra users by
using the cases and drug utilization data. On
the basis of their analysis, ODS recommended
that Bextra’s label be updated to include this
risk, and OND followed the recommendation by
working with the sponsor to update the label in
2002. Between 2002 and 2004, ODS staff conducted
five other analyses of the occurrence of serious
skin reactions associated with Bextra, including
two that were requested by OND. In March 2004,
ODS staff recommended that Bextra carry a boxed
warning about its risks of serious skin
reactions. The ODS staff based their
recommendation on their finding that Bextra’s
risk for serious skin reactions was 8 to 13
times higher than that for other similar drugs
and 20 times higher than the incidence rate in
the population. The ODS Division Directors who
reviewed the analysis and recommendation agreed,
but the OND review division responsible for
Bextra did not initially agree. About 5 months
later, the OND review division decided a boxed
warning was warranted, after ODS performed
another analysis requested by OND, comparing
Bextra’s risk with several other similar drugs,
including Mobic. ODS found no reported cases of
serious skin reactions associated with Mobic. In
2005, a joint meeting of FDA’s Arthritis
Advisory Committee and DSaRM was held to discuss
the postmarket safety of several
anti-inflammatory drugs including Bextra, with a
focus on their cardiovascular risks. The
committees recommended, after presentations by
FDA staff and others, that Bextra should remain
on the market. A few months later, FDA asked the
sponsor to withdraw the drug from the market
because, in part, its risk for serious skin
reactions appeared to be greater than for other
similar anti-inflammatory drugs.
FDA’s postmarket drug safety decision-making
process has been limited by a lack of clarity,
insufficient oversight by management, and data
constraints. We observed that there is a lack of
established criteria for determining what safety
actions to take and when. Aspects of ODS’s role
in the process are unclear, including its role
in participating in scientific advisory
committee meetings organized by OND. A lack of
communication between ODS and OND’s review
divisions and limited oversight of postmarket
drug safety issues by ODS management has
hindered the decision-making process. FDA relies
primarily on three types of data sources—adverse
event reports, clinical trial studies, and
observational studies—in its postmarket decision
making. Each data source has
While acknowledging the complexity of the
postmarket drug safety decision-making process,
we observed in our interviews with OND and ODS
staff and in our case studies that the process
lacked clarity about how drug safety decisions
are made and about the role of ODS. If FDA had
established criteria for certain postmarket drug
safety decisions, then some of the disagreements
we observed in our case studies could have
possibly been resolved more quickly. For
example, in the case of Bextra, as described
earlier, ODS and OND staff disagreed about
whether the degree of risk warranted a boxed
warning, the most serious warning placed in the
labeling of a prescription medication.
Propulsid
As another example, there were differing
opinions over taking stronger actions against
Propulsid, the nighttime heartburn medication
which was associated with cardiovascular side
effects, or whether to modify the label. Between
1995 and 1997, Propulsid’s label had been
modified, including the addition of a boxed
warning, to warn consumers and professionals
about the cardiovascular side effects of the
drug. In June 1997 a task force within FDA,
including OND and ODS staff, was convened to
further evaluate the efficacy and safety of
Propulsid. FDA staff, including task force
members, later met to discuss several regulatory
options, including proposing further label
modifications, presenting the agency’s concerns
to an advisory committee, and proposing to
withdraw approval of Propulsid. According to a
former OND manager, as a result of this meeting,
FDA decided to seek further label modifications.
Some staff, from both OND and ODS, however,
supported stronger actions at this time,
including proceeding with proposing a withdrawal
of approval. According to several FDA officials,
in the absence of established criteria,
decisions about safety actions are often based
on the case-by-case judgments of the individuals
reviewing the data.
Our observations are consistent with previous
FDA reviews. In 2000, two internal CDER reports
based on interviews that FDA conducted with
staff indicated that an absence of established
criteria for determining what safety actions to
take, and when, posed a challenge for making
postmarket drug safety decisions. The reports
recognized the need to establish criteria to
help guide such decisions. In a review of the
safety issues concerning Propulsid, CDER staff
recommended that a standardized approach to
postmarket drug safety issues be established, by
addressing various issues such as how to
determine when to incorporate safety issues into
labeling and when stronger actions should
supersede further labeling changes. According to
the report, several staff noted frustration with
the numerous changes made to Propulsid’s label
that were mostly ineffective in reducing the
number of cardiovascular adverse events.
Rezulin
Similarly, after the diabetes drug Rezulin was
removed from the market in 2000 because of its
risk for liver toxicity, a CDER report focused
on Rezulin also recommended that a consistent
approach to postmarket drug safety be developed,
including what regulatory actions should occur
to address postmarket drug safety concerns, and
when they should occur.
Arava
In addition to a lack of criteria for safety
actions, we observed a lack of clarity related
to ODS’s recommendations. In practice, ODS often
makes written recommendations about safety
actions to OND but there is some confusion over
this role, according to several ODS managers,
and there is no policy that explicitly states
whether ODS’s role includes this responsibility.
The case of Arava illustrates this confusion. In
2002, the OND review division responsible for
Arava, a drug used to treat rheumatoid
arthritis, requested that ODS review postmarket
data for cases of serious liver toxicity
associated with its use. The ODS staff who
worked on this analysis recommended that Arava
be withdrawn from the market because they
concluded that the risk for serious liver
toxicity exceeded its benefits. The OND Division
Director responsible for Arava felt that ODS
should not have included a recommendation in its
consult because he argued that this was the
responsibility of OND, not ODS. Some of the
confusion may be the result of ODS’s evolving
role in postmarket drug safety. A current and a
former ODS manager told us that in the past,
ODS’s safety consults were technical documents
summarizing adverse events with minimal data
analysis and few recommendations. Over time the
consults have become more detailed with
sophisticated data analyses and more
recommendations about what safety action is
needed (for example, label change, medication
guide, drug withdrawal).
One staff member noted that the numerous
labeling changes made it increasingly difficult
to use Propulsid as labeled because of the
numerous contraindications.
ODS’s role in scientific advisory committee
meetings is also unclear. According to the OND
Director, OND is responsible for setting the
agenda for the advisory committee meetings, with
the exception of DSaRM. This includes who is to
present and what issues will be discussed by the
advisory committees. For the advisory committees
(other than DSaRM) it is unclear when ODS staff
will participate. While ODS staff have presented
their postmarket drug safety analyses during
some advisory committee meetings, our case study
of Arava, and another case involving
antidepressant drugs, provide examples of the
exclusion of ODS staff. For example, in March
2003, the Arthritis Advisory Committee met to
review the efficacy of Arava, and its safety in
the context of all available drugs to treat
rheumatoid arthritis. The OND review division
responsible for Arava presented its own analysis
of postmarket drug safety data at the meeting,
but did not allow the ODS staff—who had
recommended that Arava be removed from the
market—to present their analysis because it felt
that ODS’s review did not have scientific merit.
Specifically, the OND review division felt that
some of the cases in the ODS review did not meet
the definition of acute liver failure, the
safety issue on which the review was focused.
The OND division also believed that in some of
the cases ODS staff inappropriately concluded
that liver failure resulted from exposure to
Arava. After the meeting, ODS epidemiologists
and safety evaluators asked the ODS and OPaSS
Directors to clarify ODS’s role involving
postmarket drug safety issues, including its
role at advisory committee meetings. According
to an FDA official, there was no written
response to this request.
As another example of ODS’s unclear role in
scientific advisory committees, in February 2004
an ODS epidemiologist was not allowed to present
his analysis of safety data at a joint meeting
of the Psychopharmacologic Drugs Advisory
Committee and the Pediatric Subcommittee of the
Anti-Infective Drugs Advisory Committee that was
held to discuss reports of suicidal thoughts and
actions in children with major depressive
disorder during clinical trials for various
antidepressant drugs. According to statements by
FDA officials at a congressional hearing, OND
believed that the ODS staff member’s analysis,
which showed a relationship between the use of
antidepressants and suicidal thoughts and
behaviors in children, was too preliminary to be
presented in detail. The analysis was based on
pediatric clinical trial data that FDA requested
from the sponsors of several antidepressant
drugs. FDA had asked the sponsors to identify
suicide-related events using specific methods,
and then ODS was asked to analyze all of the
submitted data. OND later decided that the
sponsors may have been inconsistent in their
classification approaches and asked outside
experts to perform additional reviews of all the
cases by rating whether particular events could
be classified as suicidal. The staff member who
performed the ODS review, however, believed that
the available data were sufficient to conclude a
relationship between the use of antidepressants
and suicidal thoughts and behaviors in
pediatrics and to recommend further safety
actions. In his consult, the ODS staff member
also concluded that while additional analyses
would yield valuable information, they would
also take several more months to complete. In
light of this delay, he recommended an interim
plan to discourage the use of all but one
antidepressant in the treatment of pediatric
major depressive disorders. In December 2004,
ODS epidemiologists communicated to the CDER
Director their position that ODS’s role should
include the responsibility of presenting all
relevant ODS data at advisory committee
meetings. According to an FDA official, there
was no written response to this request.
However, in our interviews, the Directors of
CDER and OND told us that in retrospect they
felt it was a mistake for FDA to have restricted
the ODS epidemiologist from presenting his
safety information at the meeting.
Several ODS managers that we interviewed told us
that there is also a lack of clarity regarding
the role of the epidemiologist in postmarket
drug safety work. Despite the fact that ODS’s
epidemiologists have some defined
responsibilities, there appears to be some
confusion about the scope of their activities
and a lack of understanding on the part of OND
about their role and capabilities. A prior
review of postmarket drug safety identified
similar issues. For example, in that review some
epidemiologists indicated that they should be
able to maintain an independent approach to
their research and the publication of their
research. However, some OND review division
directors indicated that the work of the
epidemiologists should be considered within the
context of CDER’s overall regulatory mission.
Further, the epidemiologists’ research
conclusions do not necessarily reflect the
conclusions of FDA but may be perceived as such
by the medical community. ODS managers indicated
that a current challenge for FDA is to determine
how it should use its epidemiologists and what
their work products should be. According to the
current ODS Director, efforts are needed to help
OND better understand what epidemiologists can
do. The epidemiologists themselves have asked
for greater clarity about their role and a
stronger voice in decision making.
A lack of communication between ODS and OND’s
review divisions and limited oversight of
postmarket drug safety issues by ODS management
have also hindered the decision-making process.
The frequency and extent of communication
between ODS and OND’s divisions on postmarket
drug safety vary. ODS and OND staff often
described their relationship with each other as
generally collaborative, with effective
communication. But both ODS and OND staff said
sometimes there were communication problems, and
this has been an ongoing concern. For example,
according to some current and former ODS staff,
OND does not always adequately communicate the
key question or point of interest to ODS when it
requests a consult, and as ODS works on the
consult there is sometimes little interaction
between the two offices. After a consult is
completed and sent to OND, ODS staff reported
that OND sometimes does not respond in a timely
manner or at all. Several ODS staff
characterized this as consults falling into a
“black hole” or “abyss.” OND’s Director told us
that OND staff probably do not “close the loop”
in responding to ODS’s consults, which includes
explaining why certain ODS recommendations are
not followed. In some cases CDER managers and
OND staff criticized the methods used in ODS
consults and told us that the consults were too
lengthy and academic.
FDA Postmarket Drug Safety
ODS management has not effectively overseen
postmarket drug safety issues, and as a result,
it is unclear how FDA can know that important
safety concerns have been addressed and resolved
in a timely manner. According to a former ODS
Director, the small size of ODS’s management
team has presented a challenge for effective
oversight of postmarket drug safety issues.
Another problem is the lack of systematic
information on drug safety issues. According to
the ODS Director, ODS currently maintains a
database of consults that can provide certain
types of information such as the total count,
the types of consults that ODS staff conducted,
and the ODS staff that wrote the consults. But
it does not include information about whether
ODS staff have made recommendations for safety
actions and how the safety issues were handled
and resolved, including whether recommended
safety actions were implemented by OND. For
example, ODS was unable to provide us with a
summary of the recommendations for safety
actions that its staff made in 2004 because it
was not tracking such information.
Data constraints—such as weaknesses in data
sources and limitations in requiring certain
studies and obtaining data—contribute to FDA’s
difficulty in making postmarket drug safety
decisions. OND and ODS use three different
sources of data to make postmarket drug safety
decisions. They include adverse event reports,
clinical trial studies, and observational
studies. While data from each source have
weaknesses that contribute to the difficulty in
making postmarket drug safety decisions,
evidence from more than one source can help
inform the postmarket decision-making process.
The availability of these data sources is
constrained, however, because of FDA’s limited
authority to require drug sponsors to conduct
postmarket studies and its resources.
While decisions about postmarket drug safety are
often based on adverse event reports, FDA cannot
establish the true frequency of adverse events
in the population with AERS data. The inability
to calculate the true frequency makes it hard to
establish the magnitude of a safety problem, and
it makes comparisons of risks across similar
drugs difficult.
In addition, it can be difficult to attribute
adverse events to particular drugs when there is
a relatively high incidence rate in the
population for the medical condition.
For example, ODS staff analyzed adverse event
reports of serious cardiovascular events among
users of the anti-inflammatory drug Vioxx in a
2001 consult. However, because Vioxx was used to
treat arthritis, which occurs more frequently
among older adults, and because of the
relatively high rate of cardiovascular events
among the elderly, ODS staff concluded that the
postmarket data available at that time were not
sufficient to establish that Vioxx was causally
related to serious cardiovascular adverse
events.
With AERS data it is also difficult to attribute
adverse events to the use of particular drugs
because the AERS reports may be confounded by
other factors, such as other drug exposures. For
example, one AERS report described a patient who
developed cardiac arrest after he was given the
drug hyaluronidase with two local anesthetics in
preparation for cataract surgery. Because local
anesthetics can lead to cardiac events, the ODS
safety evaluator who reviewed this case
concluded that the causal role of hyaluronidase
alone could not be established.
FDA may also use data from clinical trials and
observational studies to support postmarket drug
safety decisions, but each source has weaknesses
that constrain the usefulness of the data
provided. Clinical trials, in particular
randomized clinical trials, are considered the
“gold standard” for assessing evidence about
efficacy and safety because they are considered
the strongest method by which one can determine
whether new drugs work.
However, clinical trials also have weaknesses.
Clinical trials typically have too few enrolled
patients to detect serious adverse events
associated with a drug that occur relatively
infrequently in the population being studied.
They are usually carried out on homogenous
populations of patients that often do not
reflect the types of patients who will actually
take the drugs, including those who have other
medical problems or take other medications. In
addition, clinical trials are often too short in
duration to identify adverse events that may
occur only after long use of the drug.48 This is
particularly important for drugs used to treat
chronic conditions where patients are taking the
medications for the long term. Observational
studies, which use data obtained from
population-based sources, can provide FDA with
information about the population effect and risk
associated with the use of a particular drug.
Because they are not controlled experiments,
however, there is the possibility that the
results can be biased or confounded by other
factors.
Despite the weaknesses of clinical trials and
observational studies, evidence from both types
of studies helps inform FDA’s postmarket drug
safety decision-making process. For example,
clinical trials conducted by drug sponsors for
their own purposes sometimes provide information
for FDA’s evaluation of postmarket drug safety
issues. For instance, drug sponsors sometimes
conduct clinical trials for drugs already
marketed in order to seek approval for a new or
expanded use. These studies may also be
conducted to support claims about the additional
benefits of a drug, and their results sometimes
reveal safety information about a marketed drug.
For example, to support the addition of a claim
for the lower risk of gastrointestinal outcomes
(such as ulcers and bleeding), Vioxx’s sponsor
conducted a clinical trial that found a greater
number of heart attacks in patients taking Vioxx
compared with another anti-inflammatory drug,
naproxen. This safety information was later
added to Vioxx’s labeling. In addition to
relying on sponsors, ODS partners with
researchers outside of FDA to conduct postmarket
observational studies through cooperative
agreements and contracts. For example, several
cooperative agreements supported a study of
Propulsid using population-based databases from
two managed care organizations and one state
Medicaid program, before and after warnings on
contraindications were added to the drug’s label
in 1998. The cooperative agreement researchers,
which included ODS staff, measured the
prevalence of contraindicated use of Propulsid,
and found that a 1998 labeling change warning
about the contraindication did not significantly
decrease the percentage of users who should not
have been prescribed this drug.
FDA’s access to postmarket clinical trial and
observational data, however, is limited by its
authority and available resources. As described
previously, FDA does not have broad authority to
require that a drug sponsor conduct an
observational study or clinical trial for the
purpose of investigating a specific postmarket
safety concern. One senior FDA official and
several outside drug safety experts told us that
FDA needs greater authority to .require such
studies. Long-term clinical trials may be needed
to answer safety questions about risks
associated with the long-term use of drugs, such
as those that are widely used to treat chronic
conditions. For example, during a February 2005
scientific advisory committee meeting, some FDA
staff and members of the Arthritis Advisory
Committee and DSaRM indicated that there was a
need for better information on the long-term use
of anti-inflammatory drugs and discussed how a
long-term trial might be designed to study the
cardiovascular risks associated with the use of
these drugs. As another example, FDA approved
Protopic and Elidel, both eczema creams, in
December 2000 and December 2001, respectively.
Since their approval, FDA has received reports
of lymphoma and skin cancer in children and
adults treated with these creams. In March 2005,
FDA announced that it would require label
changes for the creams, including a boxed
warning about the potential cancer risk. An ODS
epidemiologist told us that FDA has been trying
for several years to get the sponsor to do
long-term studies of these drugs, but that it
has been difficult to negotiate.
In the absence of specific authority, FDA often
relies on drug sponsors voluntarily agreeing to
conduct such postmarket studies. But the
postmarket studies that drug sponsors agree to
conduct have not consistently been completed.
For example, one study estimated that the
completion rate of postmarket studies, including
those that sponsors have voluntarily agreed to
conduct, rose from 17 percent in the mid-1980s
to 24 percent between 1991 and 2003.54 FDA has
little leverage to ensure that these studies are
carried out, for example, by imposing
administrative penalties.
In terms of
resource limitations, several FDA staff
(including CDER managers) and outside drug
safety experts told us that in the past ODS has
not had enough resources for cooperative
agreements to support its postmarket drug
surveillance program. Annual funding for this
program was less than $1 million from fiscal
year 2002 through fiscal year 2005. In October
2005 FDA awarded four contracts to replace the
cooperative agreements, and FDA announced that
these contracts would allow FDA to more quickly
access population-level data and a wider range
of data sources. The total amount of the
contracts, awarded from 2005 to 2010, is about
$5.4 million, which averages about $1.1 million
per year, a slight increase from fiscal year
2005 funding. The new contracts will provide
access to data from a variety of health care
settings including health maintenance
organizations, preferred provider organizations,
and state Medicaid programs.
According to an
FDA official, FDA does not conduct its own
clinical trials because of the high cost
associated with carrying out such studies and
because FDA does not have the infrastructure
needed to conduct them. It was recently
estimated that clinical trials designed to study
long-term drug safety could cost between $3
million and $7 million per trial.55 The
estimated cost of just one such trial would
exceed the amount FDA has currently allocated
($1.1 million) for its contracts with
researchers outside of FDA.
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