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Alone against Thalidomide

· ​Frances Oldham ·

Between 1957 and 1962 we witnessed on an international scale a dramatic increase in serious malformations in the newborn of which phocomelia (a more or less extensive reduction of the long bones, even to the point of their total absence), was the most frequent phenomenon.

The cause of this disaster would be traced back to Thalidomide, an anticonvulsive drug with sedative properties, used as an anti-epileptic, recommended in pregnancy to combat morning sickness and deemed so safe and effective as to deserve the nickname “wonder drug”.

Thalidomide was produced in Germany in 1954 and was marketed from 1957 in more than 40 countries including many European countries (among them Italy) and in Africa, Canada and Australia.

On the basis of laboratory tests on experimental animals by the pharmaceutical firm that produced it, Chemie Grünenthal, the drug was not lethal at any of the doses used and for this reason was launched on the market as a safe alternative to barbiturates, of which, on the contrary, an overdose was known to be lethal.

By a bitter paradox, in England the advertisement for the medical press of Distaval (the brand name under which Thalidomide was sold in that country) showed a lovely little boy holding a bottle of the drug with the slogan “this child’s life may depend on the safety of Distaval”.

Five years passed and about 20,000 cases of adverse events (miscarriages, still births, malformations) were required before it was possible to prove the teratogenicity of Thalidomide – namely, its ability to induce malformations in the foetus – if the mother was exposed to the drug during the first three months of pregnancy.

The history of Thalidomide is one of the most lamentable in modern pharmacology and it is not by chance interwoven with the birth of modern regulations in the area of drug security. It is estimated that throughout the world between 8,000 and 12,000 children were born with abnormalities associated with Thalidomide and of these only 5,000 survived childhood.

In the United States, however, the tragedy of Thalidomide was avoided thanks to the professionalism and moral integrity of a woman, the pharmacologist and doctor Frances Oldham Kelsey.

Frances Oldham was born in 1914 in Canada and obtained a first degree in pharmacology at McGill University in Montreal in 1934. She was subsequently admitted for her doctorate to the University of Chicago, at the Pharmacology Department directed by Dr Eugene Geiling.

President John Kennedy presents the President’s Award for Distinguished Federal Civilian Service (1962)

In an interview in 2001 Frances Oldham Kelsey herself recounted a curious mistake which in her opinion might have favoured her candidacy for the PhD: Dr Geiling, in all likelihood deceived by the name of Frances, pronounced in the same way as the male name Francis, thought that the candidate was a man and had communicated his determination to offer her a scholarship with a letter addressed to Mr Oldham. In those times the scientific world did not look favourably on the presence of women in laboratories and, showing a great sense of humour, Frances Oldham Kelsey commented in the interview that she had always been left with the doubt as to whether she would ever have obtained the doctorate had her name been Elizabeth or Mary Jane.

After obtaining her doctorate in 1938, Frances continued to collaborate with the University of Chicago and in 1950 she also obtained a degree in medicine. In the meantime she had married her colleague Fremont Ellis Kelsey and had had two children.

It was in order to follow her husband, who had been appointed to an office at the National Institutes of Health (nih), thatFrances Oldham Kelsey arrived at the Food and Drug Administration (fda), the American government body for the regulation of food and pharmaceutical products, where she remained until 2005.

In September 1960, Dr Kelsey had just been taken on by the fda when, as her first task, considered easy and thus suitable for an employee still unfamiliar with bureaucratic procedures, she was assigned to examine the request forwarded by the pharmaceutical company Richardson-Merell for the authorization to put a new drug on the market, Kevadon, the brand name of Thalidomide. The drug’s presence on the world market and its excellent credentials were in favour of its rapid approval.

Kelsey’s answer was not long in coming and it was a refusal, motivated by the incompleteness of experimental and clinical data to support the request and by the lack of any indication of the drug’s side effects.

Frances Oldham Kelsey demanded in particular greater clinical evidence on the drug’s safety, data on its toxicity in the long term and, given its use in pregnancy, a study of its effects on the foetus.

This first refusal was followed by 18 months of litigation, during which Richardson-Merrell sent in a further six requests and tried by every possible means to force the drug’s approval, while Kelsey, despite the pressures, did not retreat and continued to ask for further in-depth studies in support of its safety.

The thick dossier of correspondence between the two parties shows how the company responded to Kelsey’s requests, providing data which were regularly deemed insufficient.

Throughout this period Richardson-Merrell’s executives publicly accused her of pedantry and incompetence, while in private, as Kelsey declared to a reporter of Life Magazine, they bombarded her with insults “which were not fit to be published by the magazine”.

In the meantime the world medical community was beginning to wonder about the increase in the births of infants with serious malformations, in particular those of newborn babies affected by the until then rare condition of phocomelia. Yet it was only in November 1961 that a German paediatrician showed that 50 per cent of mothers with malformed children had taken Thalidomide in the first three months of their pregnancies. Subsequently the drug was gradually withdrawn in the various countries in which it was regularly on the market, and in March 1962 Richardson-Merrell cancelled (almost secretly) its request to market Thalidomide in the United States too.

In the few years when Thalidomide was on the world market it caused the birth of thousands of babies with deformities; in the United States, however, thanks to Frances Oldham Kelsey, only 17 cases of babies with deformities associated with Thalidomide were documented, all of whom were affected during the clinical trials preceding its application for approval. Indeed, during this period Richardson-Merrell had distributed more than 2.5 million Thalidomide pills to more than 1,000 doctors who had then provided about 20,000 patients with them, several hundred of whom were pregnant women.

These numbers suffice to make clear the extent of the tragedy which came very close but was avoided thanks to Frances Oldham Kelsey, who in 1962 received the President’s Award for Distinguished Federal Civilian Service from President John F. Kennedy. In the long life of FOK – the acronym of Frances who was to die at the age of 101 in 2015 – this was certainly a turning point. From being a woman strongly committed and competent in her work, appreciated by her superiors but behind the scenes, awkward and timid in public, thanks to President Kennedy’s words she became an icon of professionalism for all doctors. That same year a Gallup Poll designated her as one of the 12 most admired women in the world and in 2000 she was inducted into the National Women’s Hall of Fame. Kelsey worked for fda until she was 90, and personified what the Agency wished to be for the protection of citizens.

The human and professional life of Frances Oldham Kelsey, now unfortunately remembered by few, has a special fascination, that of an intelligence oriented to good which does not let itself be led astray by prejudices or worn down by routine, or be attracted by personal advantage. 

Mariella Balduzzi

PRINTED EDITION

 

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