International Journal of Clinical Pharmacy

https://doi.org/10.1007/s11096-018-0657-1

COMMENTARY

An historical overview over Pharmacovigilance

Giulia Fornasier1 · Sara Francescon1 · Roberto Leone2 · Paolo Baldo1 

Received: 5 January 2018 / Accepted: 12 May 2018

© The Author(s) 2018

Abstract
Pharmacovigilance started about 170 years ago, although it was not yet named as such at that time. It is structured activity
in the professional health field, with important social and commercial implications aimed at monitoring the risk/benefit ratio
of drugs, improving patient’s safety and the quality of life. In this commentary we report the milestones of pharmacovigi-
lance up to the present day, in order to understand all the steps that have characterized the historical evolution; from the
first reports, which were essentially letters or warnings sent by clinicians to publishers of important and famous scientific
journals, up to today’s modern and ultra-structured electronic registries. The historical phases also help us to understand
why pharmacovigilance helped us to achieve such important results for man’s health and for pharmacology itself, and to
identify the challenges that await Pharmacovigilance in future years.

Keywords  Adverse drug reactions · History · Legislation · Pharmacovigilances · Signal detection · Thalidomide

Pharmacovigilance (PV) is defined by the European Com- In this short article, we describe the milestones (as repre-
mission (EU) as the “Process and science of monitoring the sented in Fig. 1) that led to the evolution of Pharmacovigi-
safety of medicines and taking action to reduce the risks lance activities in the last century.
and increase the benefits of medicines”. The international We intentionally excluded a part of scandals (e.g. inhibi-
PV systems aim to monitor the risk/benefit ratio of drugs as tors of cyclooxygenase types 2 because of cardiovascular
well as improve patients’ safety and their quality of life. PV adverse reactions), because they were mainly due to incor-
activities include: collecting and managing data on the safety rect marketing or inappropriate information campaigns by
of medicines, looking at individual case reports to detect pharmaceutical companies [2].
new “signals”, pro-active risk management to minimize any The history of Pharmacovigilance started 169 years ago,
potential risk associated with the use of medicines, commu- on Jan 29, 1848, when a young girl (Hannah Greener) from
nicating and informing stakeholders and patients. This seam- the north of England died after receiving chloroform anes-
less post-marketing surveillance, which is primarily aimed thetic before removal of an infected toenail. Sir James Simp-
at protecting the public, allows CAs (Controlling Authori- son had discovered that chloroform was a safer and powerful
ties) to modify—on the basis of newly discovered signals— anesthetic, and he had introduced it in clinical practice. The
the Summary Product Characteristics (SPC), released by causes of Hannah’s death was investigated to understand
the Marketing Authorization Holder (MAH) for any new what happened to Hannah, but it was impossible to identify
medicinal product at the first boot into the market [1]. what killed her. Probably she died of a lethal arrhythmia or
The etymological roots for the word “pharmacovigilance” pulmonary aspiration [3].
are: Pharmakon (Greek) = medicinal substance, and Vigilia As a result of other deaths and alerts raised by the clini-
(Latin) = to keep watch. cians and the public about the safety of anesthesia, The Lan-
cet Journal established a commission to take on this prob-
lem. The commission exhorted English doctors, including
* Paolo Baldo the doctor in colonies, to report deaths caused by the anes-
pbaldo@cro.it
thesia. The results were published in The Lancet in 1893 [4].
1
Pharmacy Unit, Centro di Riferimento Oncologico CRO The US Federal Food and Drug Act was formed on
Aviano, National Cancer Institute - IRCCS, Aviano, Italy June 30, 1906, and it established that drugs must be pure
2
Pharmacology Unit, Department of Diagnostics and Public and free of any contamination. Furthermore, in 1911, this
Health, University of Verona, Verona, Italy

13
Vol.:(0123456789)
 International Journal of Clinical Pharmacy

Fig. 1  Timeline of the historical evolution of Pharmacovigilance. *ASA: acetylsalicylic acid; **WHO: World Health Orgnaisation; ***EMA:
European Medicines Agency

organization forbade false therapeutic indications of drugs of thalidomide brought to light many problems and criti-
[4]. In 1937, there were 107 deaths in the USA, because cal issues, in particular, the reliability of animal tests, the
of the use of sulfanilamide elixir, containing diethyl gly- behavior of the industrial company, and the importance of
col as the solvent. This solvent was considered the cause of monitoring the drugs after their marketing. In particular, this
deaths, but the manufactory companies were not aware about tragedy changes the system of Pharmacovigilance, because
its toxicity at that time [3, 5, 6]. Consequently, the Federal the spontaneous reporting of adverse drug reactions became
Food, Drug and Cosmetic Act was established in 1938; its systematic, organized, and regulated. This letter already con-
aim was to renovate the public health system. Indeed, the tained all of the elements needed to generate a spontaneous
new system foresaw that the safety of drugs should be dem- reporting and to establish a cause-effect relationship between
onstrated before their market approval, and introduced the the adverse event and the drug (Fig. 2) [13]. In 1964, the
possibility of conducting factory inspections [7]. In 1938, “Yellow card” (YC) was structured in the UK. YC is a spe-
Douthwaite supposed that acetylsalicylic acid (ASA) could cific form to compile a spontaneous report of drug toxicity
cause melena [8]. The study of the gastrointestinal toxic- [14]. In USA (1962), the amendment, requiring safety and
ity of ASA showed different outcomes. However, in 1955, efficacy data of drugs before premarketing submission, was
it was proved that ASA can cause gastrointestinal diseases approved. As a result of this amendment, the safety data have
and therefore it is currently contraindicated in patients with to include also teratogenicity test in three different animals
gastrointestinal ulcers [9]. [5]. In Europe (1965), the disaster of thalidomide stimu-
In 1961, a big change of European Pharmacovigilance lated the development of a European legislation with the
happened following the tragedy of Thalidomide. Dr. EC Directive 65/65 [15]. In 1966, a pilot study of Boston
McBride, an Australian doctor, wrote a letter to the editor Collaborative Drug Surveillance Program started. It was the
of the Lancet Journal, in which he suggested a connection first group to conduct epidemiologic researches to quantify
between congenital malformation of babies and thalidomide. the potential adverse effects of drugs utilizing in-hospital
In fact, he observed that the incidence of congenital malfor- monitoring and had an essential role in the development
mations of babies (1.5%) had increased up to 20% in women and application of methods in drug epidemiology [16]. In
who had taken thalidomide during pregnancy [10]. At the 1968, the WHO Programme for International Drug Moni-
same time, during a Pediatric Convention in Germany Dr. toring was instituted and ten members participated in this
Lenz suggested a correlation between malformations and program (Australia, UK, USA, Germany, Canada, Ireland,
thalidomide and his suspect was published in a German Sweden, Denmark, New Zealand, and Netherlands). Italy
Journal (Welt am Sonnatag) [11]. In 1973, a retrospective participated in this program in 1975 [17]. Many studies of
study showed the correlation between the congenital malfor- observed adverse drug reactions were conducted between
mations of babies and the ingestion of thalidomide during 1968 and 1982 [3]. In 1992, the European Society of Phar-
pregnancy [12]. In USA, the tragedy of thalidomide was not macovigilance (ESoP) was funded, turned into the Interna-
observed, because Dr. Kelsey showed strong doubts about tional Society of Pharmacovigilance (IsoP). The aims of this
the safety of thalidomide during pregnancy [5]. The tragedy society were to promote Pharmacovigilance, and enhance

13
International Journal of Clinical Pharmacy

Fig. 2  McBride’s letter and

important elements for generat-
ADR
ing spontaneous reporting

Risk group

Increased
frequency
Confluence of data

all aspects of the safe and proper use of medicines [18]. In Pharmacovigilance Practices (GVP). The guideline on GVP
1995, the European Medicines Agency (EMA) was set up is divided into two categories: modules covering major Phar-
[19]. In 2001, EudraVigilance was funded. It is the official macovigilance processes and product- or population-specific
European database for managing and analyzing information considerations. This last category is available for vaccines
on suspected adverse reactions to medicines which have and biological medicinal products. In this guideline there
been authorized for the market or being studied in European are also special chapters dedicated to special areas, namely
clinical trials [20]. A major change in European Pharma- pregnancy and breast-feeding (P III) and geriatric popula-
covigilance was observed with the new legislation (Directive tion (P V) [22].
2010/84/EU), in 2012 [20]. The main changes in the new In November 2017, the new EudraVigilance format was
legislation were [21]: launched; in particular, the marketing authorizations will
have extended access to the EudraVigilance database to
• Modification of the definition of adverse drug reactions support the fulfillment of their Pharmacovigilance obliga-
(ADR); tions. These obligations include the continuous monitoring
• Greater involvement of patients and citizens in Pharma- of EudraVigilance data and the communication of validated
covigilance activities; signals to the Agency and national regulatory authorities, as
• Strengthening of the Eudravigilance database containing outlined in Commission Implementing Regulation (EU) N.
reports of suspected reactions reported by all EU Mem- 520/20121 [19].
ber States;
• Increasing transparency and timeliness of important Acknowledgments  The authors thank the Editor of The Lancet Journal
for permission to use McBride’s letter (1961) to explain the basic ele-
information on Pharmacovigilance problems; ments of Pharmacovigilance.
• Obligation of “additional monitoring” for the products
contained in the specific list kept by the EMA; Funding  This study was funded by Agenzia Italiana del Farmaco
• Possibility to impose further safety and/or efficacy stud- (AIFA) and Regione Autonoma Friuli Venezia-Giulia (Number:
ies on the certificates of marketing authorization at the H25E11000000005).
time of granting the trust; Conflicts of interest None.
• Establishment within the EMA of the Pharmacovigilance
Risk Assessment Committee (PRAC). Open Access  This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creat​iveco​
In particular, the most relevant change consists in the mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
new definition of ADR: “A response to a medicinal product credit to the original author(s) and the source, provide a link to the
which is noxious and unintended”. In fact, with this defini- Creative Commons license, and indicate if changes were made.
tion were covering any adverse event following the use of a
medicine, also medication errors and uses outside the terms
of the marketing authorization, including the misuse and References
abuse of the medicinal product.
Furthermore, the new legislation set-up measures 1. Pharmacovigilance Risk Assessment Committee: PRAC strategy
to facilitate the performance of PV, called the Good on measuring the impact of Pharmacovigilance activities. 2016.

13
 International Journal of Clinical Pharmacy

http://www.ema.europ​a.eu/docs/en_GB/docum​ent_libra​ry/Other​ 13. ICH guideline. https​://www.ich.org/filea​dmin/Publi​c_Web_Site/

/2016/01/WC500​19975​6.pdf. ICH_Produ​cts/Guide​lines​/Effic​acy/E2D/Step4​/E2D_Guide​line.
2. Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing with- pdf. Accessed 22 Dec 2017.
drawal of analgesic medications because of adverse drug reac- 14. YellowCard. https​://yello​wcard​.mhra.gov.uk/monit​oring​safet​y/.
tions: a systematic review. Expert Opin Drug Saf. 2018;17:63–72. Accessed 22 Dec 2017.
3. Routledge P. 150  years of pharmacovigilance. Lancet. 15. Council Directive 65/65/EEC. http://www.echamp​ .eu/eu-legisl​ atio​
1998;351:1200–1. n-and-regul​ation​-docum​ents/direc​tive_65-65-eec__-__conso​lidat​
4. Commission on Anaesthetics. Lancet. 1893; i:629–38. ed_versi​on.pdf. Accessed 22 Dec 2017.
5. Woolf AD. The Haitian diethylene glycol poisoning tragedy: a 16. Boston Collaborative Drug Surveillance Program. http://www.
dark wood revisited. JAMA. 1998;279:1215–6. bu.edu/bcdsp​/. Accessed 22 Dec 2017.
6. FDA Consumer Magzine. https ​ : //www.fda.gov/downl ​ o ads/ 17. WHO Pharmacovigilance. http://www.who.int/medic​ines/areas​
About​FDA/WhatW​eDo/Histo​ry/Origi​n/ucm12​5604.doc (1981). /quali​ty_safet​y/safet​y_effic​acy/pharm​vigi/en/. Accessed 22 Dec
Accessed 22 Dec 2017. 2017.
7. Food and Drug Administration (FDA). History. https​://www.fda. 18. ISoP - ESOP/ISoP History. http://isopo​nline​.org/about​-isop/esopi​
gov/About​FDA/WhatW​eDo/Histo​ry/. Accessed 22 Dec 2017. sop-histo​ry/. Accessed 22 Dec 2017.
8. Douthwaite AH. Some recent advances in medical diagnosis and 19. EMA Histor y. http://www.ema.europ ​ a .eu/ema/index​
treatment. Br Med J. 1938;1:1143. .jsp?curl=pages​/about​_us/gener​al/gener​al_conte​nt_00062​8.jsp.
9. Levy M. The epidemiological evaluation of major upper gastroin- Accessed 22 Dec 2017.
testinal bleeding in relation to aspirin use. In: Kewitz H, Roots I, 20. EudraVigilance history. http://www.ema.europ​a.eu/ema/index​
Voigt K, editors. Epidemiological concepts in clinical pharmacol- .jsp?curl=pages​/regul​ation​/gener​al/gener​al_conte​nt_00063​3.jsp.
ogy. Berlin: Springer; 1987. p. 100–4. Accessed 22 Dec 2017.
10. McBride WG. Thalidomide and congenital abnormalities. Lancet. 21. Directive 2010/84/EU. https​://ec.europ​a.eu/healt​h/sites​/healt​
1961; ii:1358. h/files​/files​/eudra​lex/vol-1/dir_2010_84/dir_2010_84_en.pdf.
11. Lenz W, Knapp K. Foetal malformations due to Thalidomide. Accessed 22 Dec 2017.
German Med. 1962;7:253–8. 22. EMA Pharmacovigilance. http://www.ema.europ​a.eu/ema/index​
12. Kajii T, Kida M, Takahashi K. The effect of thalidomide intake .jsp?curl=pages ​ / regul ​ a tion ​ / gener ​ a l/gener ​ a l_conte ​ n t_00181​
during 113 human pregnancies. Teratology. 1973;8:163–6. 9.jsp&mid=WC0b0​1ac05​80024​1de. Accessed 14 Mar 2018.

13