Fifty years ago, Frances Kelsey revolutionised the regulation of prescription drugs. As a new FDA employee, she reviewed Kevadaon, known as thalidomide. She questioned the drug's safety: "It just came with so many extravagant claims that I didn't believe," she said.
Kelsey took a stance against inadequate testing and corporate pressure, refusing to approve thalidomide’s release in the US. Her stance came in the first month of her job at the FDA; it was her first assignment. In 1960, Kelsey was concerned by data suggesting dangerous side effects in those who took the drug repeatedly.
"We were concerned about the non-absorption," said Kelsey.
"That you could give enormous amounts, both to animals and humans, without toxicity. We felt that there might be conditions, illnesses, or other drugs that might change the absorption, and toxic effects might appear."
"The clinical reports were more on the nature of testimonials, rather than the results of well-designed, well-executed studies,"
But Kelsey persisted in asking the company for further data:
"I think I always accepted the fact that one was going to get bullied and pressured by industry," said Kelsey. "It was understandable that the companies were very anxious to get their drugs approved."
The Richardson-Merrell company that submitted the FDA application were eager to get the drug to market before Christmas.
"They were particularly disappointed because Christmas is apparently the season for sedatives and hypnotics (sleeping pills). They kept calling me, and then just came right out and said, 'We want to get this drug on the market before Christmas, because that is when our best sales are, " said Kelsey.
In December of 1960, the BMJ published a letter from a UK doctor who reported cases of peripheral neuritis in patients taking the drug for a long time.
Kelsey asked for further data: she suspected nerve damage could also affect the developing foetus. She was right: European doctors began reporting severely deformed babies with a condition known as phocomelia.
By November 1961, a German paediatrician determined the cause as thalidomide. In March 1962, Richardson-Merrill withdrew its application.
Kelsey actions were vital in preventing the severe adverse consequences of thalidomide.
The effect in America was stunning: It was no surprise, therefore, that in 1962, President John F. Kennedy awarded Kelsey the President's Award for Distinguished Federal Civilian Service.
It prompted JFK to increase funding for drug regulation, require clinical trials for drug approval, and establish administrative safeguards to prevent such actions from happening again.
The new regulations required that drugs be shown to be both safe and effective, informed consent be obtained when used in clinical trials, and adverse reactions be reported to the FDA.
We and other researchers have shown repeated breaches of these principles from devices such vaginal mesh to “miracle” drugs such as Tamiflu/oseltamivir or Sodium Valproate, and we are currently aghast at regulatory inaction on claims or use of Comirnaty in pregnant women, immunosuppressed folk or those at micro risk of anything. The latter under the guise of saving granny from little Jane passing on Covid.
Where are the modern-day Kelseys when you need them? Her diligence and persistence in the face of pressures to stand aside - and JFK's recognition of her work - are the opposite of the impotence of today's regulators.
This post was written by two old geezers who think regulation to protect you has ceased to exist but cannot agree on an alternative. Carl says reform, and Tom says to abolish patents and show of hands.
Both old geezers admire courage: taking the right stance is hard
There are several other examples of toxic drugs and several reasons why the toxicity goes unnoticed for a while:
1. Exclusion of specific groups. Benoxaprofen was never trialled in the elderly.
2. Side effect is too rare to be picked up in a trial. If you have a trial of 1000 people, a side-effect that occurs at 1 in 500 or less will not be seen out of the background. It's not until it gets widely used that it will emerge. Benoxaprofen again.
3. Side-effect is not considered a side-effect because it is an unknown. You require a critical mass to identify cause and effect, and with a rare side-effect that accumulation takes time.
4. The side-effect is unreported, because it's not thought to be one. Thus a wider body of evidence takes time to emerge.
5. Drug trial managers conceal side-effect data. This might have been the case with rofecoxib and cardiac toxicity.
6. Drug testing is subject to subjective data analysis. Suppose you run a pharmacokinetic study of a drug on 12 people, and find a well-defined half-life in 11 but with one significant outlier (representing 8%). Because it's an outlier it's excluded from the analysis, but 8% of the population might have the same anomalous metabolism. If, as in the case of auranofin, the half-life in that one patient is prolonged substantially any dose schedule based on a shorter one runs the risk of accumulation and thus toxicity. Benoxaprofen as well.
6. Indirect effects are not observed because of (1). Thalidomide and valproate were never tested in pregnant women. One cannot assume that no harm might accrue if you haven't tested for it - though in these cases one might argue that testing is unethical - in which case it should never be used in these groups. I might add that the high incidence of neuropathy would have scuppered thalidomide in the end. My mother got that (fortunately not being pregnant at the time!).
7. The public trumpeting of some "new hope" drives public expectation that they can have it. This happened with benoxaprofen, which was pushed by the mainstream media and doctors (including me) pressurised to prescribe despite reservations. Interestingly in that particular case my department wrote a letter to a well-known medical magazine "World Medicine" expressing our reservations and stating explicitly that there might be unknown risks. The letter was rejected because the editor was convinced enough by then existing science.
The "Yellow Card" reporting system is inadequate. It is underused and overused at the same time. The side-effects list of the Covid vaccine as listed from the system contains numerous non-specific occurrences that are highly unlikely to be side-effects at all, but as per (3) above real side-effects may go unreported.
What can be done? Perhaps a new independent surveillance system, one which has access to all the trial data, is required. Certainly the Internet and FoI system have greatly enhanced the wider critical analysis of data, but as with the attempts to analyse statin trials such an approach is hampered or completely obstructed by Big Pharma refusing to release raw data for external review, usually on the grounds of commercial confidentiality. And current regulators are often supported financially by drug companies. That has to end.
There is also the question of whether some companies and individuals try to downplay developing evidence of harm to protect themselves. As a possible example - why was the AstraZeneca vaccine withdrawn? Because it was commercially non-viable? Or because the side-effect profile was shown to be unacceptable? Or did the first arise because of the second? Maybe we will never know, but if individuals are found to have been deceitful in matters as significant as this then they should be prosecuted for fraud. The very knowledge that that might happen could well discourage future evasion and dissembling.
Kelsey was indeed a heroine. Apparently she wanted tests on 2 different animals before approving Thalidomide.
My Dad had handover notes as a Houseman in 1961 from his predecessor. In the notes Thalidomide was listed as one of the standard drugs to be used on the ward in Bart's. The vade mecum was annotated by his predecessor 'Very safe'!
Stories like that made me suspicious of the vaccines for Covid from the start.
However, Kelsey's decision has made it very hard to get FDA approval for some other very good medications and treatments,so Americans have been denied many treatments for years Americans now go outside the US to test eg Mexico.
Science is never settled and is messy with swings and roundabouts along the way.