Thursday, September 17, 2020

Thalidomide

 

 

On 24 September 1972, The Sunday Times carried an article entitled "Our Thalidomide Children: A Cause for National Shame" : this examined the settlement proposals then under consideration, describing them as "grotesquely out of proportion to the injuries suffered", criticised various aspects of English law on the recovery and assessment of damages in personal injury cases, complained of the delay that had elapsed since the births and appealed to Distillers to make a more generous offer. The article contained the following passage:

 

"... the thalidomide children shame Distillers ... there are times when to insist on the letter of the law is as exposed to criticism as infringement of another’s legal rights. The figure in the proposed settlement is to be £ 3.25 million, spread over 10 years. This does not shine as a beacon against pre-tax profits last year of £ 64.8 million and company assets worth £ 421 million. Without in any way surrendering on negligence, Distillers could and should think again."

A footnote to the article announced that "in a future article The Sunday Times would trace how the tragedy occurred". On 17 November 1972, the Divisional Court of the Queen’s Bench Division granted the Attorney-General’s application for an injunction restraining publication of this future article on the ground that it would constitute contempt of court (see paragraphs 17 to 35 below for a summary of the draft article and particulars of the contempt proceedings).

 

Luckily, the European Court eventually ruled for The Sunday Times :

 

“The newspaper then decided to fight the injunction on its investigation into the origins and testing of the drug. The case went right through the British legal system and up to the European Court of Human Rights, which decided that the injunction violated the right of ‘freedom of expression’. The full story of thalidomide could eventually be told in 1976, revealing that both Grünenthal (the maker) and Distillers had not met the basic testing requirements of the time.”

 

How strange for the “untouchable" British Courts.

But why did Distillers with such a big business in Whisky and Gin decided to go into Pharmacy, you may ask.  Watching the Harold Evans’ film finally gave me a clue.  It was all to do with Huxley and his Brave New World.

One member of the board volunteered that he had read Brave New World in which Aldous Huxley predicted that sedative pills would soon replace alcohol and religion as ‘the opiate of the masses’.  The board of Distillers sat up and the rest is history, saddest history of modern Medicine.

 

Thalidomide & Morality.

A certain Australian doctor, Dr. McBride has often been quoted as being the first to report the abnormalities associated with thalidomide taking and its effect on foetal development.  In fact his reputation rested on a short letter to the Lancet in the early 60s asking if anyone else had noticed the problems he had observed in the babies of mothers who'd taken thalidomide for their nausea during pregnancy.

This was the first published notification of concern but the reality was indeed that a midwife at his hospital, Crown Street Hospital— Sister Sparrow — had noticed a few babies being born with limb defects.

They were mostly, if not all, Dr McBride's patients and the only thing Sister Sparrow could put it down to was that Dr McBride had started prescribing thalidomide as an anti-nausea drug when the other obstetricians hadn't.

Dr. McBride did eventually got the Australian Order for this letter but was struck off the Medical Register for falsifying data on the research of another drug .

 

The link

Dr. Widukind Lenz  of Germany has been credited with working out the link between Thalidomide and malformed extremities. 

In one of his lectures, Lenz described dramatically how he was confronted with this event:

In June 1961, 1 was consulted by the parents of a child who had been born with short arms and only three fingers on each hand. Shortly before, I had received inquiries about two similar cases and had replied that I was not aware of this specific type of malformation syndrome, but it seemed most likely to me to be due to a new mutation of a dominant gene. Shortly thereafter, however, further similar cases were born and other doctors reported similar observations. Hence, it seemed more and more unlikely that these cases were all due to new mutations of a gene that previously mutated extremely rarely.

 

Lenz started to systematically and thoroughly ask the parents about details of the gestational history.  On November 11, 1961, a date he remembered well, he first began to suspect that the sedative Contergan (thalidomide) could be the cause of this ‘new’ malformation syndrome.  Three days later, his suspicion turned into certainty and he communicated these observations to the manufacturer — Grünenthal — and recommended withdrawal of the agent.  Only two weeks later, the company withdrew the drug from the market.

Dr. Widukind Lenz’s father, Fritz A Lenz was a German geneticist, member of the Nazi Party and influential specialist in eugenics in Nazi Germany.

Research into this subject throws up surprises.

 

Non approval

America is amongst less than a handful of major countries that did not approve thalidomide.  It may be surprising that the notable country that did not was East Germany.

In 1960, America had a stroke of luck. That was when the application to begin mass-marketing the drug thalidomide in the United States landed on the desk of Dr. Frances Oldham Kelsey, a reviewer at the Food and Drug Administration (FDA). 

The application for New Drug Approval (NDA) was by drug manufacturer Richardson-Merrell’s NDA for Kevadon—the U.S. trade name for thalidomide—was only the second NDA Kelsey received, meaning she didn’t yet have a backlog of reviews to get through. For Kelsey and the other reviewers, thalidomide did not pass muster.  

Before the days of the Internet: Kelsey read about a paper was published in the BMJ[1] on December 31, 1960 of 4 patients suffering from symptoms of peripheral neuritis.  This raised an even bigger red flag for Kelsey: “the peripheral neuritis did not seem the sort of side effect that should come from a simple sleeping pill.”  Not only were there pharmacological problems, but Kelsey found the clinical trials to be woefully insufficient in that the physician reports were too few and they were based largely on physician testimonials rather than sound scientific study. She rejected the application.

She asked for more information from Merrell, who responded with another application merely stating that thalidomide was at least safer than barbiturates.  Kelsey then sent a letter directly to Merrell saying that she suspected they knew of the neurological toxicity that led to nerve inflammation but chose not to disclose it in their application.  Merrell grew increasingly upset that Kelsey would not pass their drug, which had been used in over 40 other countries at this point.

If neurological toxicity developed in adults who took thalidomide, Kelsey wondered: What was happening to the foetus of a pregnant woman who took the drug?  In her training she has studied what happened to drugs crossing the placenta barrier.  Her concern hit on what would be the most dangerous effect of thalidomide in other countries.

 

The withdrawal

On November 15, 1961, Dr. Widukind Lenz[2] called Chemie Grünenthal to share his suspicions regarding the drug and the link to limb malformations in newborns. He spoke to Dr. Mückter, Grünenthal’s medical director, and urged him to take the drug off the market immediately. Lenz now had 14 cases of babies born with deformities which he strongly believed were directly connected to Thalidomide. Mückter vehemently refused to withdraw the drug. Luckily Lenz wouldn’t be put off and went public with his suspicions. It was only after the press got hold of the story that Grünenthal decided to withdraw the drug, on November 27, 1961.  But by then over 10,000 infants all over the world were affected, and countless others died in-utero. 

Despite this withdrawal, Merrell did not withdraw the application on their own until April of 1962.  But by then the drug had already been distributed to “more than 1200 physicians, about 15,000-20,000 patients—of whom over 600 were pregnant,” according to Swan.  In the U.S., 17 cases of congenital deformities were reported, but as Swan says via email, “that could have been thousands had the FDA not insisted on the evidence of safety required under the law (despite ongoing pressure from the drug’s sponsor).”

 

A darker past

It has since emerged that the “first” case of foetal defect was born on Christmas Day, 1956 to an employee of Grünenthal.

In the Auschwitz[3] files:

In November 1944, Fritz ter Meer, sent a memo to Karl Brandt, the SS General who ran Hitler’s euthanasia programme, explaining that a drug numbered 4589 (with the same chemical formula as Thalidomide) had “been tested and was ready for use.”

Correspondence was discovered that dealt with the sale of one hundred and fifty female prisoners for experimental purposes, “… With a view to the planned experiments with a new sleep-inducing drug we would appreciate it if you could place a number of prisoners at our disposal…”

There are hints that some Auschwitz prisoners made artificial limbs[4] for some of these deformed babies.

It is now widely believed that this preparation was the forerunner for the preparation that was to become known the world over as Thalidomide.

President Kennedy awarded Kelsey the President’s Award for Distinguished Federal Civilian Service, making her the second woman to receive such a high civilian honour.

In her memoir, Kelsey says that the honour did not belong just to her. “I thought that I was accepting the medal on behalf of a lot of different federal workers,” she writes. “This was really a team effort.” She was quickly promoted to chief of the investigational drug branch in 1963, and four years later, she became director of the Office of Scientific investigation—a position she held for 40 years until she retired at the age of 90. She lived until the age of 101, and passed away in 2015.

There is hope still.

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