DEPARTMENT OF MEDICAL HISTORY
150 years of pharmacovigilance
Philip Routledge
150 years ago, on Jan 29, 1848, 15-year-old Hannah
Greener from Winlaton, northeast England, had a
routine general anaesthetic before treatment of an
ingrowing toenail. The anaesthetic agent, chloroform,
had only been introduced into clinical practice a year
earlier by James Simpson, professor of midwifery at
Edinburgh, since it produced less nausea and vomiting
than ether. Unfortunately, Hannah Greener died during
the anaesthetic from what was possibly an episode of
ventricular fibrillation. Because of the continuing
concerns of the public and profession about the safety of
anaesthesia, The Lancet set up a commission, which
invited doctors in Britain and its colonies to report
anaesthesia-related deaths. These findings were
subsequently published in the journal in 1893.1 Thus, the
forerunner of a spontaneous reporting system for
suspected adverse drug reactions (ADRs) was
established, at least for a time.2
Since that episode, advances in drug regulation often
seem to be provoked by misfortune, or even disaster.3 In
1906, the US Federal Food and Drugs Act was passed;
this act required drugs to be pure and free from
contamination, but there was no requirement for them to
be efficacious. Nonetheless, there were 107 deaths in the
USA in 1937 from the use of diethylene glycol as a
solvent for sulfanilamide.4 Although the toxicity of
diethylene glycol was known at the time, it was not
known to the manufacturer, and an amendment to the
original act was passed in 1938 to outlaw misbranding of
ingredients or false advertising claims.
However, the most pivotal event in pharmacovigilance
occurred in 1961 when an Australian obstetrician,
William McBride reported a 20% increase in fetal
malformation and the appearance of an hitherto rare
malformation, phocomelia (literally “seal limbs”), in
association with the use of the hypnotic thalidomide in
pregnancy.5 This drug had not been adequately screened
for teratogenic effects, but similar malformations were
subsequently shown in the rabbit and (at high dose) in
the rat. The impact was especially devastating in West
Germany (4000 affected individuals), where the drug had
been sold over the counter.6 Licensing of the drug had
been delayed in the USA because of concerns over
hypothyroidism and peripheral neuropathy, although
there were a few cases of phocomelia in the children of
mothers who had taken part in clinical trials. In the USA,
the Kefauver-Harris amendment to the US Federal Food
and Drugs Act, requiring premarketing submission of
both efficacy and safety data to the Food and Drug
Administration (FDA), was passed in 1962. The
thalidomide disaster also stimulated the development of
Lancet 1998; 351: 1200–01
Department of Pharmacology, Therapeutics and Toxicology,
University of Wales College of Medicine, Heath Park, Cardiff CF4
4XN, UK (Prof P Routledge MD)
1200
spontaneous reporting pharmacovigilance systems and
legislation in Europe, such as the UK’s “yellow card”
system (1964) and legislation to regulate medicines in the
UK (Medicines Act 1968) and Europe (EC Directive
65/65). Before the Medicines Act came into force in
1971, the Dunlop Committee, the forerunner of the UK
Committee on Safety of Medicines, provided
independent advice on the safety of medicines.
In 1974, 4 years after the cardioselective beta-
adrenoceptor blocking drug practolol was first marketed
in the UK, reports of an unusual oculomucocutaneous
syndrome and sclerosing peritonitis were reported in
association with the drug, and a warning was issued a
year later. In 1976, the manufacturers withdrew the drug
from chronic oral use. Skegg and Doll7 reported minor
eye complaints in 14 (14%) of 71 patients in clinical trials
of practolol compared with 4 (6%) during an equal
period before the drug was prescribed. They argued that
early recognition of the mild and relatively common
effects of practolol would have led to earlier diagnosis of
the more severely affected patients, some of whom lost
their sight. They also suggested that recording of all
adverse events rather than just suspected ADRs during
clinical trials might prevent investigators from
overlooking drug toxicity.8
The non-steroidal anti-inflammatory drug
benoxaprofen was marketed in 1980. A year later,
photosensitivity and serious hepatotoxicity were reported
in association with the drug, and it was withdrawn in
1982. The UK Committee on Safety of Medicines set up
the Grahame-Smith Working Party, which made 29
recommendations in 1983, most of them to address the
problem of under-reporting of suspected ADRs. They
concluded that increased publicity should be given to the
spontaneous suspected adverse drug reaction (yellow
card) reporting system, and that yellow cards should be
made more easily available to potential reporters.9 In
1982, the biguanide oral hypoglycaemic agent
phenformin hydrochloride was also withdrawn from the
UK market after 50 deaths from lactic acidosis were
reported in association with this drug. In fact, a
significant (around 10%) incidence of reduction of alkali
reserve and one death from metabolic acidosis had been
reported in association with this drug in 1959, 10 years
before it was even marketed.10 The Grahame-Smith
Working Group was reconvened and recommended that
premarketing drug-safety studies should be of adequate
size, and that companies should be encouraged to
undertake postmarketing surveillance studies on issues
identified in the premarketing stage on all new medicines
intended for widespread long-term use. It also
recommended that patients should be given more
information about the drugs they use, including possible
ADRs.9
In 1993, almost 20 years after Skegg and Doll’s
comments on the importance of scrutinising all adverse
THE LANCET • Vol 351 • April 18, 1998

events, the nucleoside analogue fialuridine was
associated, in the USA, with worsening liver function,
severe lactic acidosis, and the deaths of several patients
with hepatitis B in clinical trials of the drug.11 An FDA
task force subsequently commented that in all instances
in which drug toxicity might have been suspected, none
was attributed by the sponsors to a toxic effect of the
drug, and worsening liver function seemed always to have
been attributed to worsening of the hepatitis.
What lessons have been learned from the events in the
150 years since Hannah Greener’s death? Clearly,
although efficient regulatory systems are necessary to
protect the consumer, they will always depend upon the
support and cooperation of all health-care professionals.
Most drugs have been tested on about 2500 people
before marketing. Therefore, effective postmarketing
surveillance, especially spontaneous reporting of
suspected toxicity by all prescribers, is the most sensitive
way to detect the relatively rare but often serious non-
dose-related (type B) ADRs. In practice, only a small
proportion of even serious suspected ADRs are reported
to the regulatory authorities, and there is concern, at least
in the UK, that reporting rates are falling from the peak
levels of 1992. The recent involvement of pharmacists in
reporting in the UK (they have long been able to report
in many other European countries) does not relieve the
prescribing physician from continuing responsibility to
report.
New approaches to encourage spontaneous reporting
of suspected ADRs are urgently needed, and new
methods of drug-safety monitoring should also be
considered. The pharmaceutical industry can help by
funding such initiatives in pharmacovigilance. The
European Union has set an example by supporting
pharmacovigilance research in the recent DGXII
(BIOMED) programme. Drug safety and
THE LANCET • Vol 351 • April 18, 1998
DEPARTMENT OF MEDICAL HISTORY
pharmacovigilance should be included in the
undergraduate medical curriculum and postgraduate
educational programmes, and undergraduates and
postgraduates should have training in the best way of
communicating drug-safety issues to patients.12 Journals
can provide the forum for debate on these matters, as The
Lancet did more than 100 years ago.1 Finally, surveillance
must continue during the drug-development process and
throughout the life-span of the drug as a therapeutic
agent. In this respect, eternal pharmacovigilance may well
be the price of freedom, at least from potentially major
adverse drug reaction disasters in years to come.
References
1 Commission on Anaesthetics. Lancet 1893; i: 629–38.
2 Rawlins MD. Pharmacovigilance: paradise lost, regained or
postponed? J R Coll Physicians Lond 1995; 29: 41–49.
3 Goldberg A. Introduction. In: Mann RD, ed. Adverse drug reactions:
the scale and nature of the problem and the way forward. Carnforth:
Parthenon Publishing, 1987:1–3.
4 Geiling EMK, Cannon PR. Pathogenic effects of elixir of
sulfanilamide (diethylene glycol) poisoning. JAMA 1938; iii: 919.
5 McBride WG. Thalidomide and congenital abnormalities. Lancet
1961; ii: 1358.
6 Taussig HB. A study of the German outbreak of phocomelia. JAMA
1963; 180: 1106–14.
7 Skegg DCG, Doll R. Frequency of eye complaints and rashes among
patients receiving practolol and propranolol. Lancet 1977; ii: 475–78.
8 Skegg DCG, Doll R. The case for recording events in clinical trials.
BMJ 1977 b; 2; 1523–24.
9 Mann RD. The yellow card data: the nature and scale of the adverse
drug reactions problem. In: Mann RD, ed. Adverse drug reactions: the
scale and nature of the problem and the way forward. Carnforth:
Parthenon Publishing, 1987: 5–66.
10 Walker RS, Linton AL. Phenethyldiguanide: a dangerous side-effect.
BMJ 1959; 2: 1005–06.
11 McKenzie R, Fried MW, Sallie R, et al. Hepatic failure and lactic
acidosis due to fialuridine (FIAU), an investigational nucleoside
analogue for chronic hepatitis B. N Engl J Med 1995; 333: 1099–105.
12 McNamee D. Communicating drug-safety information. Lancet 1997;
350: 1646.
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