Introduction - Uppsala Monitoring Centre

perhaps even stranger that there were no further reports of purpura and that fixed
drug eruptions, not previously reported with Sedormid despite 65 years on the
market, started occurring. Sedormid is a good example of a drug with an important
ADR that was not restricted or removed from the market but was allowed to wither in
a competitive market.
Discussion
The many factors involved in a decision to remove a drug from the market make it
unlikely that there will be any pattern to the regulatory authorities’ decisions.
However, it is clear that those countries with an active pharmaceutical research
industry will tend to be those who first perceive a problem with toxicity and who will
be the most likely to remove a drug from the market. There was a steady decrease
in the lifespan of the drugs over the years, probably due to improving technology
leading to improved pharmacovigilance and the increasing availability of alternative
drugs.
The problem remains as to how to follow up hypotheses generated by
substantiated individual cases. Clinical trials tend to be unethical, unless the ADR is
not serious and is reversible, and prospective studies require time during which
more patients will be exposed to a possible danger. Cohort studies without control
groups are very poor at discovering new ADRs.
The 50 drugs examined here include three where there is an unknown factor:
insoluble bismuth salts, clioquinol and Phenacetin.
In several cases the decision whether to withdraw a drug has hung on the
incidence of a very rare adverse effect, e.g. agranulocytosis and hepatotoxicity and
in this case, different studies tend not to replicate the same frequency. Different
regulatory authorities will interpret these incidences according to how relevant they
consider it is to extrapolate the findings to their own situation. Carcinogenicity has
depended, in most cases, on extrapolating from animal studies without waiting for
corroboration in humans. The exceptions to this have been diethylstilboestrol and
thorium, where, despite evidence in animals, the drugs were not withdrawn.
The most common form of toxicity requiring withdrawal from the market is
hepatotoxicity and animal studies are not very effective in predicting the human
response as far as idiosyncratic reactions are concerned. The serious
haematological ADRs are so rare that discovery is late and require large studies in
order to reveal them. Most drugs having central effects are candidates for drug
dependency, but there is rarely a specific time when a new drug’s addictive powers
reach a threshold when action has to be taken. Neurological tissue is very
unforgiving and once damaged may never be repaired, so although fairly rare they
are important because of their potential irreversibility.
Dr Judith Jones, speaking of the ‘epidemic’ of drug withdrawals in 1989 said that
such withdrawals suggested several possibilities: