Pharmacovigilance is the cornerstone of postmarket-ing drug safety activities in the United States and will likely remain so for the foreseeable future.
THE VALUE AND FUTURE OF
PHARMACOVIGILANCE IN THE UNITED STATES
Pharmacovigilance
is the cornerstone of postmarketing drug safety activities in the United
States and will likely remain so for the foreseeable future. Nearly all
postmarketing labeling changes related to drug toxic-ity are based on
spontaneous case reports. The same holds true for drug withdrawals. Since 1980,
there have been 22 major prescription drug withdrawals in the United States
(Wysowski and Swartz, 2005). Of these, spontaneous case reports and their
analysis were a critical informational component contributing to the withdrawal
decision in 20. The two exceptions were encainide and flosequinan, where
randomized clinical trials identified the increased mortality risk conferred by
these approved drugs (Echt et al.,
1991; Massie et al., 1993). This
should not be a surprise because patients
with cardiac arrhythmias under treatment of those arrhythmias will sometimes
experience sudden death due to arrhythmias, and death is not infrequent among
patients with congestive heart failure. In situ-ations where the underlying
disease being treated and the ADR resulting from treatment are the same, only a
well-conducted randomized trial will convincingly establish the drug–ADR
association.
As
mentioned earlier, data mining is emerging as a potential means of generating new
safety signals using existing ADR databases (Lindquist et al., 2000; Almenoff et al.,
2005). A variety of methods have been developed, each of which compares every
poten-tial drug–ADR combination in the database for statis-tical evidence of a
discrepancy from an ‘expected’ number derived from all case reports in the
database. The hope, as yet unrealized, is that such screening will help
pharmacovigilance practitioners to identify and respond to previously
unrecognized safety problems, and to do so with a shorter lag time. The
integra-tion of data mining into routine business practices is beginning to
occur at a number of national and international pharmacovigilance centers.
However, to data, data mining has not been shown prospectively to improve overall
signal detection.
In
another recent development, ‘active’ surveillance for ADRs has emerged as a
potential comple-ment to the traditional so-called ‘passive’ surveil-lance
afforded by voluntary case reports, such as those collected by national
pharmacovigilance centers (Food and Drug Administration, 2005). The inten-tion
here is to search prospectively and proactively for ADR signals. Suggested
methods include setting-, drug- and outcome-based approaches. Setting-based
active surveillance has been pilot tested in emergency rooms and blood banks
(Bennett et al., 2000; Budnitz et al., 2005) while outcome-based
surveillance has been applied to the
problem of drug-induced acute liver failure (Ostapowicz et al., 2002; Larson et al.,
2005). The principle of drug-based active surveillance was demonstrated
recently in a study of the associ-ation between rotavirus vaccine and
intussusception (Davis et al., 2005).
These authors applied sophisti-cated statistical methods to automated,
longitudinal claims data from a large healthcare organization and showed that
it might be possible to detect impor-tant safety signals prospectively in real
time. The use of longitudinal healthcare data for active surveillance requires
much additional work but offers the prospect of a significant advance for
pharmacovigilance.
While
the utility of case reports is undeniable, there is much that might be done to
improve and expand their value. Strategies to improve the level of reporting of
serious ADRs need to be developed The proverb about ‘strength in numbers’ also
applies to pharmacovigilance. A few reports may provide a sufficient basis upon
which to modify a prod-uct’s label. However, important information regarding
the magnitude and duration of risk as well as risk factors for ADR occurrence
is more easily and reli-ably discovered through careful analysis of a larger
series of cases. Hand in hand with the value of a larger number of serious case
reports is improved quality and completeness of those reports. The more
clinically detailed a series of reports is, the greater the range of analytic
possibilities. The value of this for regulatory decision-making and risk
management efforts cannot be overstated. How to achieve these goals in an
envi-ronment of immense time constraints and litigation fear is an important
challenge for the future.
Another
area of potentially great public health value is the expansion of current
pharmacovigilance prac-tice to include other venues and types of ADRs. In the
United States, the focus of pharmacovigilance has been on the rapid
identification of serious unlabeled
events. Many, if not most of these, fall into the cate-gory of ‘unexpected’ or
‘idiosyncratic’ and have been referred to as type B reactions (Meyboom et al., 1997). This is an important
endeavor but from a population perspective, the bulk of drug-related morbidity
and mortality is because of type A reactions, i.e. those that represent an
extension of the drug’s pharmacol-ogy. The problem is great enough to represent
one of the leading causes of mortality in the United States (Lazarou, Pomeranz
and Corey, 1998). Pharmacovig-ilance strategies in this arena might lead to the
iden-tification of ‘problem areas’ and provide the basis for more effective
intervention and prevention.
Finally,
advances in technology in the 1990s and the advent of the ICH process have
created an environ-ment where global pharmacovigilance is now conceiv-able. A
remaining challenge is to make this a reality.
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