The pharmacovigilance timeline

The Pharmacovigilance Timeline

1780 BC The Babylonian Code of Hammurabi details the punishments of medical harm.

“If a physician make a large incision with the operating knife, and kills him, or open a tumor with the operating knife, and cut out the eye, his hands shall be cut off.”

950 BC Homer’s Odyssey:

“Such useful medicines, only borne in grace
Of what was good, would Helen ever have.
And this juice to her Polydamna gave
The wife of Thoon, all Ægyptian born,
Whose rich earth herbs of medicine do adorn
In great abundance. Many healthful are,
And many baneful.
Every man is there
A good physician out of Nature’s grace,
For all the nation sprung of Paeon’s race.

460-377 BC Hippocrates’ Primum non nocere, “First do no harm”

131-201 BC The Greek physician Galen “warned against badly written and obscure prescriptions”. Galen paid careful attention to the precise quantities of the various ingredients used in his remedies, and to the doses which had to be given. Galen argued that all medicines were capable of mild, strong, harmful or even fatal effects on the patient, based on the dose given.

864-930 AD The renowned Persian physician Abu Bakr Mohammad Ibn Zakariya al-Razi, also known as Rhazes, made important advances in many areas, including drug safety. He attacked charlatans and fake doctors who selling their nostrums and ‘cures’. He was instrumental in making Arabian authorities appoint a “mutasib”, whose duties included the supervision of the makers of drugs and syrups to ensure the purity of their wares.

“It is essential that the mutasib make them fearful, try them, and warn them against imprisonment. He must caution them with punishment. Their syrups and drugs must may be inspected at any time without warning after their shops are closed for the night”

10th century Salerno medical school was empowered to inspect drugs for adulteration, with dire penalties for transgressors: “whosoever shall have or sell any poison or noxious drug not useful or necessary to his art, let him be hanged”

1224 The Hohenstaufen Emperor Frederick II, ordered the regular inspection of the drugs and mixtures prepared by apocatharies, and ruled that the life of the seller of a poison, magic elixir, or love potion would be forfeit if the consumer died.

13th century Oath for apothecaries in Basle Switzerland published; it included the line that drugs should be “of such good quality and of such usefulness that he knows, upon his oath, that it will be good and useful for the confection what the physician is making"

Mez-Mangold, L. (1971). A history of Drugs, p’83. F Hoffman-La Roche and Co., Basle.

1509-1547 The reign of King Henry VIII led to controls on the quality of medicines. He empowered The Royal College of Physicians of London to appoint four fellows of the College as inspectors of apothecaries’ wares. These inspectors had the power to destroy defective stock within the London area. In the early seventeenth century the Society of Apothecaries also supplied inspectors.

1599 King James VI of Scotland issued a charter making provisions for the supervision of the sales of drug and poisons. The first inspector appointed was William Spang, who was responsible for
approving “droggis” (drugs) offered for sale in the city of Glasgow.

1618 The London Pharmacopoeia’s
preface discussed “the very noxious fraud and deceit of those
people who are allowed to sell the most filthy concoctions… under
the name and title of medicaments”

17th century The Paris
Faculty of Physicians forbid antimony use by physicians.

1785 William Withering sets out his
classical description of the toxicity of digoxin.

“The foxglove, when given in very large and quickly
repeated doses, occasions sickness, vomiting, purging, giddiness,
confused vision, objects appearing green or yellow, increased
secretion of urine with frequent motions to part with it, and
sometimes inability to retain; slow pulse, even as low as 35 in a
minute, cold sweats, convulsions, syncope, and death”

18th century Calomel (mercurous
chloride) was used widely in American states suffering outbreaks of
yellow fever.  Clinical
mercurialism including intense salivation, loosening of the teeth,
ulceration, gangrene of the mouth and cheeks, osteomyelitis of the
mandible became common.  Despite this calomel became a cure-all for many physicians,
but laymen had a more sceptical view of the medicine: 

Since calomel’s become their boast,
How many patients have they lost,

How many thousands they make ill,

Of poison with their calomel.

It remained in fashion for many years.

1848 America passed the first statue to
control the quality of drugs, after quinine imported for the US army
was found adulterated.

1861 Oliver Wendall Holmes, with
calomel in mind, “if the whole material medica, as it is used
now, could be sunk to the bottom of the sea, it would be all the
better for mankind – and all the worse for the fishes”

1880  The Glasgow Commission Inquiry
into the deaths due to chloroform anaesthesia was appointed by the British Medical Association.
The British Medical Association appointed the Glasgow committee in 1880
which concluded that “Chloroform was injurious to the heart and in
comparison more dangerous than ether”. In 1888 Edward Lawrie in
Hyderabad claimed that he had administered chloroform anaesthesia to
40,000 people without a single fatality and formed the “First Hyderabad
Chloroform Commission”. 141 animal experiments were done and it was
concluded “Chloroform may be given with perfect safety and without any
fear of accidental death, if only respiration is carefully attended
to”. This was not accepted in England and so the “Second Hyderabad
Chloroform Commission” was formed to which a representative from Lancet
was sent. The Nizam of Hyderabad offered £ 1000 for a commission
consisting of Lauder Bruntor, F.R.S. U.K., Surgeons Lawrie and
Rustomji. Experiments were carried out on 430 animals (dogs, monkeys,
horses, goats, rats, rabbits and cats) and a clinical study on 54
humans. They concluded that the Edinburgh School was right.

Divekar VM, Naik LD. Evolution of anaesthesia in India. J Postgrad Med 2001;47:149-52

1881 The first book on Adverse Drug Reactions published.

Lewin L: Die nebenwirkungen der
. Published: Berlin A. Hirschwald 1881.

Translated as The untoward effects of drugs. A
pharmacological and clinical manual. By Mulheron JJ. Geo S Davis,
Medical Publishers, Detroit, 1883.

1899 First bottle of aspirin sold.

1922 Inquiry into arsenical treatment of
syphilis causing jaundice.

1929 Formation of the Food, Drug and
Insecticide Administration (later the Food and Drug Administration).

1929: Leake ”many drug firms make
the mistake of believing that their chemists can furnish trustworthy
pharmacological opinion, Indeed some eminent chemists impatient with
careful pharmacological technic have ventured to estimate for
themselves the clinical possibilities of their own synthetics…
There is no short cut from the chemical laboratory to the clinic
except one that passes too close to the morgue.”

1937107 people die as a result of poisoning with an elixir of
containing as a solvent diethylene glycol.

1938 Aspirin noted to be a cause of
gastric haemorrhage,39 years
after its first use.

1952 First edition of Meyler’s Side Effects of Drugs published.

1954 One hundred deaths in France caused
by poisoning with Stalinon, an inorganic compound of tin, in a
treatment for boils.

1958 Knowledge of aspirin’s gastric
side effects becomes widely known.

1960 FDA begin to collect reports of
adverse reactions and sponsor hospital drug monitoring.

1961 Thalidomide disaster. (To be

McBride’s famous letter to The Lancet.
McBride WG. Thalidomide and Congenital Abnormalities.Lancet December 16th 1961

Dr. Widukind Lenz also played an important part in the recognition of thalidomide’s adverse effects, and gives a brief history of his experiences in a lecture he delivered in 1992.

1960s Oral contraceptives linked to
thromboembolism in young women.

1964 Yellow Card Scheme started in the

1966 Adverse Drug Reaction Bulletin

1968 Medicines Act passed by UK
Parliament, bringing in new and comprehensive safeguards covering
most aspects of drug development.

1970s Practolol linked to syndrome
involving the skin and eyes.

1972 Thirty-six French infants are killed by a manufacturing error.

“in 1972, 204 children in Paris, aged 3 months to 3 years, developed severe diaper rash and neurologic abnormalities after use of an infant powder that accidentally contained 6.3% HCP when there was supposed to be none. Thirty-six children died. The talc was prepared in the same area that HCP was kept, and 38 kg of HCP contaminated 600 kg of infant powder that went into 2898 cans.”

RW Miller. How Environmental Hazards in Childhood Have Been Discovered: Carcinogens, Teratogens, Neurotoxicants, and Others. Pediatrics 2004;113(4):945-951. [PDF]

Eighteen of the cases were described in the BMJ, four of whom died.

“Intracranial hypertension seems to be responsible for a major part of the symptoms – for example, papilloedema, suture diastasis, sixth-nerve palsy, tense fontanelles, and probably, dsiturbances of consciousness. Attacks of cerebration and sudden cardiorespiratory areest may also result from increased intracranial pressure.”

Goutieres F, Aicardi J. Accidental percutaneous hexachlorophane intoxication in children. Goutieres F. Aicardi J. Accidental percutaneous hexachlorophane intoxication in children. BMJ 1977: 10(2):663-5.

The FDA Milestones page.

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