Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 3 ADVERSE DRUG REACTIONS
to excipients (for example, the change in excipient
in phenytoin tablets from calcium sulfate to lactose
led to an epidemic of toxicity in humans due to increased
bioavailability of the active substance; the use of
ethylene glycol as a solvent infamously led to the Elixir
Sulphanilamide tragedy) and some may be due to
degradation products formed during storage (for
example, tetra-ethyl pyrophosphates in some organophosphate
preparations).
Even though all new drugs are intensively evaluated
before release onto the market, evaluation before registration
cannot assure the safety of a drug. Premarketing
clinical trials, although examining up to several thousand
animals, are usually too small, conducted for too
short a period of time and conducted in a select and
nonrepresentative population to detect rare or delayed
ADRs. It is sobering to realize that the upper boundary
of the 95% confidence interval in a study in which no
adverse drug reactions are observed in 10,000 treated
patients is 3/10,000. Clearly, the absence of detectable
ADRs does not mean that no ADRs can be expected. If
the clinical signs caused by the drug reaction also occur
spontaneously in the untreated population, then a larger
number of patients must be observed in order to attribute
the reaction to the drug. In addition, it is difficult
to include in trials all groups of animals including different
breeds, the aged, the young, diseased animals and
others that may have a high risk of developing an ADR.
Hence, postmarketing surveillance or pharmacovigilance
of drug ADRs is very important in assuring drug
safety, detecting unusual and uncommon ADRs and
identifying individuals or populations at higher risk.
Postmarketing drug surveillance
(pharmacovigilance)
Postmarketing surveillance of adverse drug reactions
occurs in various forms: phase IV clinical trials, spontaneous
reporting schemes, intensive monitoring within
hospitals (uncommon in veterinary medicine), analysis
of health registers (more relevant to human medicine)
and prospective studies. ADR reports rarely indicate the
need to remove the drug from the market but such
reports may lead to changes in dose rate, additional
labelling or further clarification of labelling, additional
warnings, precautions and contraindications and formulation
changes.
Phase IV clinical trials may be conducted by the manufacturer
after marketing approval, take place under
usual clinical use of the drug and usually do not include
a control group. However, it has been demonstrated in
human medicine that despite the relatively large size of
the cohorts monitored in phase IV studies, spontaneous
reporting methods were more likely to detect previously
unsuspected ADRs.
Spontaneous ADR reporting schemes can involve
reporting of suspected ADRs by practitioners and
animal owners through a variety of mechanisms: case
reports in the literature, submissions to ADR reporting
centers (which may or may not involve regulatory
authorities, depending on the country) and reporting
directly to the manufacturer. In many countries, manufacturers
are now required to report ADRs to appropriate
regulatory authorities. Spontaneous reporting
schemes are relatively inexpensive and potentially draw
data from all patients taking the drug. However, underreporting
is a serious disadvantage – it is estimated that
more than 95% of ADRs go unreported.
The ADR reporting rate is low within the medical
profession and almost certainly even lower within the
veterinary profession. Even in countries where ADR
reporting is mandatory, the reporting rate by medical
practitioners remains low. An analysis of the attitudes
of medical practitioners in South Africa to ADR reporting
revealed that there were differences in reporting
rates between groups within the profession (a larger
number of medical specialists reported ADRs compared
with general practitioners). Surgical specialists did not
report any ADRs during the study (Robins et al 1987).
The major reasons identified for failure to report ADRs
were: the belief of the medical practitioners that unusual
or serious reactions were infrequent; common or trivial
ADRs did not warrant reporting; apathy; being too busy
to fill in the paperwork. Fear of personal consequences
(criticism and medicolegal action) was not deemed to be
an important impediment to reporting. The authors
concluded somewhat pessimistically that ‘the prognosis
is poor (for improved ADR reporting) and it appears
that, like all else which passes between doctors and their
patients, ADRs will continue to remain largely outside
the reach of an external agency’.
Similar studies have not been undertaken within the
veterinary profession but there is no reason to assume
that the attitudes of veterinarians to ADR reporting are
radically better than those of their medical colleagues.
While complacency in reporting is widespread, an
examination of those factors associated with an
increased rate of reporting reveals that the likelihood of
reporting is related to:
● novelty of the reaction
● severity of the reaction
● limited time of the drug on the market, often called
the Weber effect (Weber 1984) after a study of
NSAID ADRs in the UK which revealed that ADR
reports peaked within 2 years and thereafter
declined
● media coverage, also known as the Panorama effect
from the effect of coverage by the BBC Panorama
program on increases in ADR reports (Martin et al
2005). Certainly media attention to reported carpro-
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