Therapie (2016) 71, 129—134

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PHARMACOVIGILANCE

The history of pharmacovigilance

Jacques Caron , Michaël Rochoy , Louise Gaboriau ,
Sophie Gautier ∗

Centre régional de pharmacovigilance, CHRU de Lille, 1, place de Verdun, 59045 Lille cedex,
France

Received 23 July 2015; accepted 10 December 2015

Available online 16 February 2016

KEYWORDS Summary This article reviews the main historical events before the 21st century and
Pharmacovigilance; explained their consequences in the current pharmacovigilance legislation.
History © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson
SAS. All rights reserved.

Abbreviations

AFSSAPS French Agency for the Safety of Health Products (Agence française de sécurité
sanitaire des produits de santé)
CAST Cardiac Arrythmia Suppression Trial Study
DES diethylstilbestrol
FDA Food and Drug Administration
PVC Premature ventricular contractions

Unlike the history of medicine, the history of pharmacovigilance is fairly recent. Even
if it is important to point out physicians’ bygone preoccupations with adverse drug reac-
tions, illustrated in Hippocrates’ ‘‘primum non nocere’’, the birth and development of
pharmacovigilance occurred at a later stage and progressively. This evolution came about

DOI of original article: http://dx.doi.org/10.1016/j.therap.2016.02.026.

∗ Corresponding author.
E-mail address: sophie.gautier@chru-lille.fr (S. Gautier).

http://dx.doi.org/10.1016/j.therap.2015.12.007
0040-5957/© 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.
130
Figure 1. Extract from Ormsby’s article, published in the British
Medical Journal in 1877, showing the incidence of deaths in pres-
ence of chloroform and ether. With courtesy British Medical Journal
[2].
through problems of pharmacovigilance, debates and
‘‘scandals’’ that appeared in the 19th century, some of
which led to legislation in order to protect patients whilst
reinforcing the prerogatives and demands, in terms of
safety, of national or supranational agencies that had been
set up. Outlining the history of pharmacovigilance requires
certain issues representative of the main stages in the his-
tory of drug safety to be broached, whilst other problems,
mentioned here very briefly but often not even mentioned
at all, were nonetheless major events in terms of human
consequences.
The first example of a safety issue that led to coordi-
nated and rational pharmacovigilance reflection is provided
by chloroform, discovered in France by Eugène Soubeiran
in 1831 (this authorship has however been contested by the
Germans). While the very first general anaesthetic was car-
ried out publicly with ether by William Morton in Boston in
1846, chloroform was first used as an obstetrical anaesthetic
in Edinburgh in 1847 by James Young Simpson. Chloroform
shot to fame a few years later when Queen Victoria under-
went anaesthesia with the substance for the birth of her
eighth child in 1853. The use of chloroform spread and even
supplanted ether, especially in Britain and France. How-
ever, from the first years following its use, attention was
drawn to fatal accidents in the form of syncope, known
as ‘‘chloroform-induced syncope’’. Because deaths had also
been reported with ether and because of the growing con-
cern of both the general public and physicians, The Lancet
set up a commission inciting doctors from the United King-
dom and its colonies to report any deaths related to general
anaesthesia, collecting the data and publishing the results
in 1893 [1]. This first example of a requested notification,
associated with incidence estimations [2] which gave chlo-
roform a clear disadvantage compared to ether (Fig. 1), led
to the first descriptions, forty years later, of deaths linked to
chloroform and ultimately to its demise in favour of ether.
The second significant problem occurred later and
stemmed from acetylsalicylic acid. We know that Felix
Hoffman (Fig. 2), a German chemist working for Bayer, syn-
thesised acetylsalicylic acid on August 12th 1897, which was
better tolerated when ingested than sodium salicylate, and
was given the name Aspirin (the French have fought for its
authorship against the Germans, which is only fair after
what was mentioned earlier). What is less known is that
J. Caron et al.
within two weeks, in August 1897, Felix Hoffman synthe-
sized Aspirin and (re)synthesized diacetylmorphine (a.k.a.
Heroin), the discovery of which went unnoticed, and was
attributed in 1874 to a British chemist, Charles Adler Wright
(with no authorship dispute to this day, neither by the
French nor by the Germans). The Bayer Laboratory stud-
ied the effects of diacetylmorphine on an experimental
level as well as on patients with tuberculosis, who found
the drug remarkably efficacious and powerful. No addictive
potential was found at that time. Enthused by the results,
the managers of Bayer Laboratories thought that diacetyl-
morphine should be medically ranked alongside ‘‘heroic
remedies’’; they therefore gave it the name Heroin® and
marketed it in 1898, one year before Aspirin, as an anti-
tussive and analgesic drug. Commercial success was fast
(we can well imagine), especially as it was supported by
a large advertising campaign. However, the addictive power
of Heroin unavoidably came to be recognized. In the end,
hundreds of thousands of people were found to have become
dependant on the drug at the beginning of the 1910s (a
number of 500,000 dependant patients was reported in
the US!). The first steps to limit the medical use of this
drug were taken in 1912 and Bayer Laboratory stopped its
production of heroin in 1913. However, the recreational
use of heroin, which has been well established since that
time, unfortunately continues to wreak havoc across the
world.
Leaving the 19th century behind, we can now look at what
happened in the 20th century. Sulfanilamide has been syn-
thesized since 1908 but it was not until 1935 that a team
from the Institut Pasteur demonstrated that this product
was actually the active, colourless sulfonamide metabolite,
sulfamidochrysoïdine (Prontosil® ), a sulfonamide azoic dye,
initially intended for carpet dyes, but for which Gerhard
Domagk (Nobel Prize for Medicine in 1939) identified anti-
streptococcal properties. Although it was put on the market
in the form of pills or capsules in the US, the commercial
development of sulphanilamide led a small Tennessee com-
pany (SE Massengil & Co.) to solubilize the product into
diethylene glycol and to market Elixir Sulfanilamide® in
1937, without any toxicological testing being carried out.
Very quickly a link was established between a series of
deaths from kidney failure and the marketing of this new
pharmaceutical form of sulfanilamide involving the respon-
sibility of a solvent.
A batch recall campaign was organised on a large scale
by the Food and Drug Administration (FDA), created in 1906,
thus minimizing the consequences of this tragedy, respon-
sible however for the deaths of 105 people, including 34
children [3]. What is important to remember is that the FDA
did not have the power at that time to recall products for
safety reasons, and that the only legal leverage they had
was that the brand name ‘‘Elixir’’ was only used for special-
ity products containing alcohol, which was not the case for
Elixir Sulfanilamide® . Without this expedient, which enabled
the recovery of 228 gallons of Elixir out of 240 before distri-
bution (Fig. 3), the number of deaths would have been much
greater. A year later, in 1938, President Franklin Roosevelt
signed the ‘‘Federal Food, Drug and Cosmetics Act’’, which
included in the law the necessity for pharmaceutical com-
panies to submit a report to the FDA concerning the safety
of all medicinal drugs. It was the first time that safety data
The history of pharmacovigilance
Figure 2. Félix Hoffmann’s discoveries in august 1897. With courtesy Rolf Ackermann (Corporate Media Relations, Bayer, Leverkussen,
Germany).
Figure 3. One-gallon bottle of Sulfanilamide Elixir® .
was required for medication before it was put on the mar-
ket! A first step had been taken towards the evaluation of
the risk-benefit of drugs.
If we return to Europe, and more precisely to France at
the beginning of the 1950s, although several examples could
be used, there is one in particular, namely that in 1954 of
Stalinon® [4]. A year earlier, a chemist from a small labora-
tory decided to combine, in ‘‘pearl’’ form (an old-fashioned
galenic form), an organic by-product derived from tin (di-
iododiethyl of tin, 15 mg/pearl) used for anti-staphyloccocal
purposes with vitamin F (Fig. 4). In order to obtain the
‘‘visa’’ (former marketing authorization) for Stalinon® to
treat furunculosis, the laboratory bought the rights to an
earlier tin-based product, the manufacture of which had
ceased (Stalonex® ), thus enabling Stalinon® to be presented
as a modified formula and not as a new product. Prob-
lems of instability of tin, which were known at the time,
were deliberately hidden by colouring the pearls in order to
make them more opaque. The quality control of the raw
131
Figure 4. Vitamin F Stalinon® and its pharmaceutical form,
pearls. With courtesy Laurence Leprêtre (Agence France Presse,
Paris, France).
materials and of the finished product was neglected and
during the court case that followed, it was demonstrated
that the quantity of tin salts in each pearl could vary con-
siderably from one batch of Stalinon® to the next. Finally,
the data on clinical efficacy, limited to a few patients, was
apparently established following an error in the product
preparation, with one fifth of the dosage of diiododiethyl
of tin per pearl, and the preparation was finally marketed in
France [5]. The dangers of Stalinon® were quickly identified
after its marketing, especially in the Niort area where three
suspicious deaths led a clinician to denounce the neurotoxic-
ity of the product. The Préfet (government representative)
of the Deux-Sèvres region immediately banned Stalinon®
from his county. Because the number of cases was on the
increase, the laboratory suspended the sale of the product
in France. The final death toll rose to 102, mainly resulting
from encephalopathy, and over a hundred patients devel-
oped severe, irreversible, neurological after-effects. The
story of Stalinon® , beside the obvious responsibility of the
laboratory that had developed the product, had the virtue of
showing in France the dysfunctioning of the system and the
responsibility of the government (which was not taken into
account during the trial), and therefore led to a reform of
the visa legislation, which was published by ordonnance on
February 4th 1959 [6], making the conditions for obtaining
drug visas tougher.
132 J. Caron et al.

The second half of the 1950s and the 1960s were high-
lighted by the most disastrous event in the history of
pharmacovigilance. Marketed in 1956 by Chemie Grünen-
thal in Western Germany, thalidomide was mainly used as
a hypnotic/sedative drug and later used in order to manage
nausea in pregnant women. Tests, complying with require-
ments at the time, had been carried out on animals and
had shown ‘‘reassuring’’ results with no proof of terato-
genic effects. Besides, the notion of the ‘‘placental barrier’’
seemed to indicate at the time that the foetus was protected
from xenobiotics present in the bodies of pregnant women.
Marketing success was prompt, and thalidomide was com-
mercialised in many countries under various speciality brand
names (Contegan® in Western Germany, Distaval® in the UK),
with a reputation for efficacy and safety, which made the
drug an interesting alternative to barbiturates, very widely
used at the time and for which adverse effects and risks of
overdose were a real concern. The first safety warning signs
appeared in 1960 when cases of neuropathy were observed.
Then, very quickly, cases — usually rare — of congenital
malformation appeared, including cases of phocomelia and
agenesis of the limbs among new-borns and were initially
attributed to the nuclear trials that were taking place in
the same period. The link to the use of thalidomide was
first established in October 1961 by the German geneti- Figure 5. Presidential distinction (President’s Award for Dis-
cist Widukind Lenz during a congress in Düsseldorf, and was tinguished Federal Civilian Service), awarded to Doctor Frances
later confirmed in December of the same year by a letter to Oldham Kelsey. With courtesy Christopher Kelly (Office Media
the editor of The Lancet from an Australian doctor, William Affairs, Office of External Affairs, Food and Drug Administration,
McBride, who claimed an increase of 20% in malformation United States).
occurrences when the product was used during pregnancy
[7]. Product recall of thalidomide began in November 1961
but unfortunately for some countries the process took a
few months. Tests on animal tetarogenesis, which were first
carried out on rodents, were completed by tests on other
animals, rabbits in particular, which clearly showed the ter-
atogenous potential of the product. Over 12,000 cases of
malformation, not only of abnormality in the limbs (among
which phocomelia was the most characteristic example),
were recorded, mainly in Europe, Australia and Canada.
Thalidomide was never marketed in the US; in 1960, Doctor
Frances Oldham Kelsey, a recently arrived expert member of
the FDA, was asked as her first task to examine the registra-
tion papers of the product. This Canadian pharmacologist,
who later was granted American citizenship, blocked the
registration for thalidomide despite pressure from the lab-
oratory that had made the request. She argued her case by Figure 6. Signing of the Kefauver-Harris amendment by Presi-
pointing out examples of paresthesia in the limb extremities dent John Fitzgerald Kennedy in 1962 (in the presence of Docteur
among certain patients and by the fact that the innocu- Frances Oldham Kelsey). With courtesy Christopher Kelly (Office
ousness of the substance for the foetus remained, to her Media Affairs, Office of External Affairs, Food and Drug Adminis-
mind, to be demonstrated. This led her to demand fur- tration, United States).
ther scientific data. There is no doubt that her insight and
determination, which were rewarded by one of the high- but the visa was withdrawn at the last minute in December
est presidential distinctions (Fig. 5), protected the American 1961 for safety reasons, which had by then become obvi-
population from the dangers of thalidomide and contributed ous. Ironically this tragedy was almost certainly avoided in
to an amendment of the legislation, namely the Kefauver- France because of the Stalinon® scandal, which had caused a
Harris amendment of the Federal Food, Drug and Cosmetic backlog of paperwork to process and delays for the delivery
Act in 1962 (Fig. 6) which, among other things, reinforced, of numerous new drugs, including thalidomide!
defined and made compulsory the main rules concerning the The shock wave triggered by thalidomide brought about
modern assessment of drug efficacy (which was new) and numerous reactions throughout the world, with the appear-
safety before marketing. France was also spared, but only ance in particular of new national drug registration and
just. A visa had indeed recently been granted to a pharma- monitoring agencies, the development of pharmacovigilance
ceutical company wishing to market thalidomide in France, departments within pharmaceutical companies and the start
The history of pharmacovigilance
Figure 7. Description of Distilbene® (DES), in Vidal’s 1973 medical dictionary: the indication ‘‘repeated spontaneous miscarriages’’ was
always present and only disappeared in France in 1976. In 1977, the use of DES became a contraindication during pregnancy. With courtesy
Caroline Ferrenbach (Vidal France).
of international cooperation concerning adverse drug reac-
tions; exchange of information was implemented in 1963 by
the World Health Organisation in its 16th assembly, with the
creation of a world centre of pharmacovigilance, initially
based in Geneva and then transferred to Uppsala in Sweden
from 1978.
Ten years after the thalidomide affair, in 1970, the drug
diethylstilbestrol (DES) changed the perspective on medi-
cation risks during pregnancy, by showing that the adverse
effects of drugs used by the mother and affecting the daugh-
ter in the womb could surface a long time after exposure.
DES, a non-steroid oestrogen synthesized in 1938, was widely
used from 1948 right up to the 1970s in the prevention of
the risks of miscarriage. The advantage of this product in
this particular indication was however challenged and, as
early as 1958, Dieckmann had demonstrated its inefficacy in
a rigorous, control vs. placebo clinical trial [8]. From 1967 to
1970, Herbst et al. saw 7 cases of vaginal adenocarcinoma in
young women aged 15—22 in their Boston gynaecology care
unit. The suggestion by one of the women’s mothers that
DES taken during pregnancy might be the culprit, together
with the rarity of such cancers at this age and the link with
vaginal adenosis, incited the gynaecologists to carry out a
case-control study on 8 cases of vaginal adenocarcinoma and
32 control subjects for whom 7 matching factors were taken
into account. The link of these cancers to the use of diethyl-
stilbestrol was clearly established in the study (P < 0.00001)
since 7 out of 8 mothers whose daughters were suffering
from adenocarcinoma, had been treated with DES during
pregnancy, compared to none in the control group [9]. The
delayed risks were later studied more in depth, and besides
cancer, a risk of malformation of the uterus and fallopian
133
tubes was identified, which made women exposed in the
womb to DES more prone to sterility, extra-uterine preg-
nancies and repeated miscarriages; some risks were even
identified in third generation patients, and did not only con-
cern girls since abnormalities were also possible in boys’
genital-urinary system.
In 1971, the FDA reacted very quickly in the US where
a contraindication for DES during pregnancy was decided
and an American register of vaginal adenocarcinoma cases
was set up. Unfortunately this was not the case in France,
where reactivity was slow (Fig. 7) and where it was esti-
mated that there had been 160,000 cases of exposure to
DES in the womb. The story of DES was one of the first to
enable pharmaco-epidemiology — backing up spontaneous
notification — to make a quick decision. It was not until ten
years later that pharmaco-epidemiology was recognized in
the field of pharmacogivilance [10].
At the end of the 20th century, an affair caused a big
stir in the US but surprisingly not in Europe [11]. Until
1989, class I antiarrhythmic agents were used in cases of
ventricular arrhythmia after a heart attack. It had indeed
been shown that the number of premature ventricular con-
tractions (PVC) after a heart attack was linked to the
mortality rate in the two years following. It was naively
believed that the mortality rate could be reduced by remov-
ing the PVCs. The Cardiac Arrhythmia Suppression Trial
(CAST study) tested this hypothesis, comparing placebo
effects with those of antiarrhythmic treatment, for which
the ‘‘efficacy’’ had been tested on ventricular arrhythmia
disorders (showing few or no symptoms) after a heart attack.
The antiarrhythmic agents used in CAST belonged mainly
(but not exclusively) to class Ic (encainide and flecainide),
134
new at that time. These products, for which development
was coming to an end, had the reputation of being very
efficient in terms of quantitatively reducing ventricular
arrhythmia (they were rather ineptly given the nickname
‘‘PVC killers’’). The CAST study was stopped prematurely
for safety reasons two years after it had been started.
Its first results, published in the New England Journal of
Medicine in August 1989, revealed that class Ic antiarrhyth-
mic agents compared to placebos significantly increased the
overall mortality rate by 2.5, the risk of death from arrhyth-
mia and the risk of non-fatal cardiac arrest by 3.6 [12].
The CAST study, which naturally led to the withdrawal of
class I antiarrhythmic agents in coronary diseases, above
all highlighted the difficulty, in the field of pharmacovigi-
lance, of distinguishing between what is attributable to a
frequent pathology and what is attributable to a drug or
a pharmaceutical class that can induce the same pathol-
ogy. In these circumstances, the study also emphasized the
importance of resorting to randomized clinical trials in order
to come to a conclusion. Other examples, such as cox-
ibs and hormone replacement therapy for the menopause
and its cardio-vascular risks, are illustrations of the same
scenario.
This history of pharmacovigilance terminates at the
beginning of the 21st century. It can be noted that there are
already affairs and scandals, for instance, the coxib affair
for the FDA, or the benfluorex affair for French Agency for
the Safety of Health Products (Agence française de sécu-
rité sanitaire des produits de santé [AFSSAPS]) in France.
There is no doubt that the risk and risk-benefit assessment
of medicinal drugs will continue to evolve in the future, at
the cost of shake-ups, polemics and challenges of the exist-
ing systems. But let us not forget that pharmacovigilance
is built day by day, joining forces with everyone involved,
including patients and their associations, since the objec-
tive is to ensure patients the optimal safety that they have
the right to expect from medicinal drugs that have obtained
marketing authorization.
J. Caron et al.
Disclosure of interest
The authors declare that they have no competing interest.
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