Children whose development was impaired by their mother's use of thalidomide in a swimming pool. Photo: via Luciana Christiante / Flickr (CC BY-NC-ND).
Dr Frances Kelsey: thalidomide and the precautionary principle
Helena Paul & Philip Bereano
25th August 2015
We owe a deep debt of gratitude to Dr Frances Kelsey, write Helena Paul & Philip Bereano. In 1960, she defied her bosses at the FDA to prevent the licensing of thalidomide in the USA, saving thousands from being born with serious deformities. Her tough approach to minimising the risk from new drugs contains lessons we ignore at our peril.
The case of thalidomide shows how vital it is not to ignore early warning signals or be hurried into premature approvals of innovations, with serious and often irreversible consequences at a later date.
Back in the 1950s, the precautionary principle had not yet been developed in Europe but did exist in all but name in US law.
One consequence was that the drug thalidomide was licensed in the UK and mainland Europe, leading to terrible malformations in newborn babies. But reliance on precaution in the US avoided such occurrences.
Subsequently, the EU enshrined the principle of precaution in its own laws and fought alongside countries of the global south to include precaution in noteworthy international agreements such as the Convention on Biological Diversity, the Cartagena Protocol on Biosafety and the UN's Codex Alimentarius guidelines for assessing 'Foods from Modern Biotechnology'.
Now, however the idea of precaution and the precautionary principle itself are under attack in Europe, accused of hampering innovation in science. Given this clear evidence in the thalidomide case of the importance of precaution, the EU should certainly not contemplate abandoning or diluting it as an underlying principle.
Thalidomide is known around the world as the drug that caused thousands of women to give birth to children with serious malformations of their limbs. It was developed in the 1950s by a German company as an anti-convulsive drug that also seemed like the perfect tranquilliser and pregnant women found it useful against morning sickness.
It was licensed in 1956 without looking at the effects on foetuses and sold over the counter without prescription.
So why did the US not approve thalidomide?
The first application for approval was made in the US in September 1960 and a former family doctor, Dr Frances Oldham Kelsey, who had just taken the job of reviewing requests to license new drugs at the Federal Drug Administration.
The rules at that time set a limit of just 60 days to decide on the application and a failure to respond left the company free to market the drug. However, the US did have regulations dating from the 1930s that, although they did not mention precaution, nevertheless allowed Kelsey to use it as her legal basis for requesting more information from Merrell.
She and her two colleagues agreed they all had reasons not to be satisfied with the information provided by the William S. Merrell Company and had several questions, so they asked for more detail.
The company complained about her to the FDA but she refused to budge, insisting that she and her colleagues did not have sufficient proof to enable her to approve the drug. The company was determined to go ahead and re-applied for approval in January 1961.
Of course by this time thalidomide had already been in use for four years in Europe and in February 1961 Kelsey read a letter in the British Medical Journal from the drug's owners, Distillers Ltd, which revealed that some patients had suffered numbing effects on the arms and legs in connection with thalidomide.
Apparently this information on 'peripheral neuritis' had already been known in Europe, but the company was not required to include it in their submissions to the FDA.
Clear evidence emerges of the link between thalidomide and malformation
Then in November 1961 conclusive evidence was reported on the link between thalidomide and phocomelia, the condition in foetuses in which the limbs are absent or severely malformed and the hands and feet are attached directly to the body. This led to Merrell withdrawing their application for approval, and the FDA actively tried to track down samples that had been circulated.
This meant that only a handful of cases of malformations resulted in the US, unlike the thousands in Europe. Dr Kelsey's insistence on information and her refusal to yield to pressure and rush into approving thalidomide spared the US a terrible experience.
As she wrote in 1965, "objectively designed clinical studies should have detected both the neuropathy and the embryopathy long before these side effects caused such widespread damage. The clinical studies submitted in support of the application for thalidomide in this country did not record either side effect.
"Retrospective inquiries, however, disclosed several cases of both neuropathy and phocomelia that had not been reported, the investigators having considered the effects to be unrelated to the drug under test. While it is not known exactly what percent of mothers taking the drug during the critical period of pregnancy did give birth to deformed babies, the figure generally cited is 20 percent. Such a high incidence would have been readily determined by properly designed clinical studies."
In 1962, the Kefauver Harris Amendment or 'Drug Efficacy Amendment' to the Federal Food, Drug, and Cosmetic Act was passed. This means that the Food and Drug Administration still employs a precautionary approach, requiring new drugs to be tested before they are put on the market. Also the burden of proof for actually being effective, as well as only presenting acceptable risks remains on the industry, not the agency or consumer groups.
Dr Kelsey also recommended the establishment of a new system at both national and international levels to make sure that never again would so many people suffer needlessly from adverse drug side effects - which exists today in the form of the FDA's Adverse Event Reporting System:
"An additional safeguard would be the establishment of a national or international adverse reaction program based on a register of medical case histories which would permit an independent observer to detect correlations between drug intake and toxicity that might elude the indi- vidual clinical investigator or attending physician.
"Certainly it should not take many thousands of deformed children to establish the degree of hazard that is associated with thalidomide. It would indeed add inestimably to the tragedy of the thalidomide episode if we shut our eyes to the fact that it could have been largely averted."
Precaution does not stifle but stimulates innovation
Since the Reagan administration elevated the interests of corporations above public health and safety, however (a position followed by all subsequent administrations, Democratic as well as Republican), the US has largely abandoned application of precaution at home. In addition, US delegates have relentlessly attacked other governments invoking this approach in international negotiations.
The death of Dr Kelsey on 7th August 2015 at 101 is a good moment to reflect on her work and remind ourselves here in Europe of the importance of precaution and rigour in the assessment of not only new drugs, but all new developments in technology.
The case of thalidomide shows how vital it is not to ignore early warning signals or be hurried into premature approvals of innovations, with serious and often irreversible consequences at a later date. Nicholas Taleb and colleagues mention the warning given by the thalidomide case in their analysis of the nature of risk in the context of GMOs.
A vital set of case studies where we have failed to heed such warnings may be found in 'Late Lessons from Early Warnings: Science, Precaution, Innovation' from the European Environment Agency. The impact on knowledge and on ecosystems from the power of vested interests emerges again and again as central, especially as we reach planetary boundaries.
It also shows that the application of precaution can stimulate innovation rather than suppressing it in particular "when supported by smart regulation or well-designed tax changes."
Helena Paul has worked for 25 years on issues including indigenous peoples' rights and tropical forests; oil exploitation in the tropics; biodiversity, including agricultural biodiversity; patents on life and genetic engineering (GE); and corporate power. She helped co-found GM Freeze and Genetic Engineering Network in 1999 and has been chair of the former ever since.
Philip Bereano is an attorney and Professor Emeritus in Technology and Public Policy at the University of Washington. He participated as an NGO representatives in the negotiations of the Cartagena Biosafety Protocol, the Supplemental Protocol on Liability and Redress, and the development of the UN's Codex Alimentarius Guidelines on Food from Modern Biotechnology.
Books: Helena has co-authored a number of papers on agriculture, climate change and biodiversity, and the book 'Hungry Corporations: Transnational Biotech Companies Colonise the Food Chain' (Helena Paul and Ricarda Steinbrecher, Zed Books 2003).
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