Introduction - Uppsala Monitoring Centre

1. The diagnostic techniques had not been developed:
a) Abuse liability testing in animals: chloral hydrate, phenobarbitone, datura,
sodium arsenate and glutethimide
b) Carcinogenicity testing in animals: chloroform, piperazine, phenolpthalein,
thorium dioxide, methapyrilene, diethylstilboestrol and dantron
c) Laboratory testing had not been developed: Phenacetin, amidopyrine,
dipyrone, pyrithyldione, chloramphenicol, phenylbutazone,
oxyphenbutazone, thenalidine, sulfamethoxydiazine and
sulfamethoxypyrazine.
d) The disease entity had not been discovered: SMON, Reye’s syndrome,
SIDS and tetracycline tooth problem.
2. Failure to carry out known precautionary studies: dinitrophenol,
diiododiethyltin, phenformin and buformin.
3. A clear symptom complex was known but the association with the drug was
not recognised: bismuth insoluble salts, mercury amide HCl and thalidomide.
4. Prior to 1960 there were no spontaneous reporting systems, other than the
American Medical Association’s registry for cases of drug-induced blood
dyscrasias instigated in 1952.
There was frequently more than one factor that was responsible for the ADR
with some of these drugs. These are dealt with in detail below….
Delay in regulatory 183 action (Time from first case to first regulatory
action)
After the first case had produced a hypothesis one would expect, these days, that
further investigation would take place. This might be a prospective epidemiological
investigation (clinical trial, cohort study) or a retrospective investigation (inspection of
spontaneous reports, case control studies, cohort studies). Pharmaceutical
companies have often undertaken their own cohort study, but without a control
group and these have not resulted in published accounts of the ADRs found
(Stephens, 1995). In the USA the FDA, when it has decided that a change in
product information is required, will request the action from the manufacturer. In
most situations, drugs are voluntarily withdrawn by the market authorization holder
(Wysowski et al., 2005).
Prior to 1960, other than the AMA registry, the only other body that took action
was the BMA in 1877 when it set up the committee for the investigation of the
chloroform deaths. The only other source of new ADR data was the publication in
books and journals of interesting cases, but the journals have always been more
reluctant to publish reports of ADRs that have already appeared in print rather than
183 Regulatory = An official body, not an individual, which had the power to take some action