In May 2011 I boarded an early morning flight from London. I was headed to Düsseldorf to have a firsthand look at the documents deposited forty years earlier by the team that had tried (and failed) to convict senior Grünenthal executives involved in the thalidomide disaster. The large English gent wedged into the budget flight seat beside me felt compelled to warn me about the culinary treats awaiting me. ‘Worse than the crap we eat. Cabbage, spicy sausage and pickled pig’s trotter,’ was his ungenerous summation of German food.
It was not my first visit to Germany. Coincidentally, as a toddler I had spent a year in Uerdingen, a town just outside Düsseldorf. My father had been sent to Germany by his American employer to supervise the start-up of a Bayer chemical plant. My brother Simon was born at the maternity hospital in Düsseldorf where not many years earlier thalidomide babies were being born. I was eighteen months old when Simon was born and some of my first words were in German, thanks to the neighbours with whom we had become close friends. I had visited Germany as an adult and had studied German at university so I had some basic language skills. But I knew, of course, that my German would be far from adequate for the documents at the archive. So help was at hand. We had arranged for a number of German-speaking consultants to meet me in Düsseldorf.
Nina Stähle had been recommended to us after doing the archival research in Germany and the UK for the Australian inquiry into the fate of the HMAS Sydney, the Australian cruiser sunk by a German raider off the coast of Western Australia during World War II. Stähle, who spoke French and flawless English in addition to her native German, did an enormous amount of important work for us. She brought to bear not just her language skills but also a detailed appreciation of our case theory and a precise, forensic approach to the prosecutor’s material. The other consultants, who prefer not to be named, also played important roles in unravelling the Grünenthal story.
The archive—Landesarchiv Nordrhein-Westfalen—was located in a quiet residential street. Close by was a synagogue, in front of which two bored policemen appeared to be permanently stationed. The archive was welcoming but strict. No pens, only archive-approved pencils. No cameras. Complete silence. Among Stähle’s talents was negotiating German bureaucracy, so the first volumes of thalidomide material we had requested were waiting for us. The files emerged in irregular-shaped folders, yellowed with age but perfectly and precisely catalogued. And as a bonus for me and my rudimentary German, there was a great deal of material in English—letters between Grünenthal and its UK, US and Canadian licensees, journal articles and witness statements.
In a few critical respects the German prosecution team had a tougher job in the 1960s than we were facing five decades later. The German prosecutor had tried to secure convictions against the Grünenthal executives for negligent manslaughter and other serious criminal charges. That meant he had to prove his case according to the criminal standard, usually expressed as beyond all reasonable doubt. By contrast we had to establish Grünenthal’s responsibility for Lyn Rowe’s injuries only on the balance of probabilities, the civil law standard. That was a much lower bar for us to get over. In plain terms, the difference is between ‘all but certain’ and ‘more likely than not’.
Also, the German prosecution team was trying to prove the guilt of individuals. Only that person’s own knowledge, actions and omissions could be held against him. It was a restriction that did not apply to us because we were focused on the company as a whole. So the behaviour and negligence of any number of Grünenthal executives and staff could help us establish the overall negligence of the company.
To succeed in proving Grünenthal’s (or Distillers’) negligence, we did not have to prove that Grünenthal actually knew there was a risk to the foetus in giving thalidomide to pregnant women. That would be a bonus. It would be enough to show that a reasonable, careful pharmaceutical company, by the standards of the time, should have foreseen a risk of harm—even if Grünenthal did not.
So we were looking for warning signs in the Düsseldorf archive. Were there any flashing lights that should have alerted Grünenthal to the potential danger of thalidomide? Were they ignored? Had Grünenthal properly tested the drug? Had Grünenthal responded appropriately to reports of side effects? The answers would emerge during long sessions with the prosecutor’s documents.
There is no doubt that the thalidomide experience scarred Grünenthal. The massive death and injury toll has left a shadow over the company and Grünenthal spent years and vast sums defending the criminal charges against its executives. Even today, fifty years on, Grünenthal is bitterly accused by thalidomide groups of hopelessly negligent behaviour in the 1950s and ’60s, followed by a failure to front up to its obligations to victims. These charges are hotly denied by Grünenthal.
To understand the competing views we have to go back to the events that led up to the launch of the drug in 1957. Grünenthal was established immediately after World War II and focused on the booming antibiotics market. In 1954, with the company looking to expand into synthetic drugs, Dr Heinrich Mückter (the former army doctor who did typhus experiments in occupied Poland) set two of his staff, Wilhelm Kunz, a chemist, and Dr Herbert Keller, a pharmacologist, to work developing new antibiotics. The story goes that, as part of this hunt, Kunz heated a commercially available chemical and created a new compound. Its name would be N-Phthalyl glutamic acid imide: more commonly, thalidomide. Keller is said to have thought that the compound appeared to be a ‘structural analogue’ of the barbiturates, which then dominated the sedative and hypnotic (sleeping pill) market. This apparent similarity persuaded the Grünenthal men to check whether the drug would have a barbiturate-like sleep inducing or sedative effect. Rats were the chosen test subject.
Around this time Grünenthal was developing something of a name for making inflated efficacy and safety claims for its products—including a tuberculosis drug and a variant on penicillin. But the criticism it had attracted appears not to have led to a more cautious approach. Instead Grünenthal charged headlong into a much bigger and vastly more damaging controversy. To test thalidomide Grünenthal used a ‘jiggle cage’, which in a convoluted fashion tried to measure the amount of movement (or jiggle) in drugged and un-drugged rats. The tests led to a published paper claiming that thalidomide had a pronounced sedative effect on the rats.
This finding has always been somewhat mysterious. Widukind Lenz, the German paediatrician who forced the withdrawal of thalidomide in late 1961, described the jiggle-cage paper as possessing ‘so little scientific value’ that it should not have been accepted for publication. ‘The authors claim to have shown a sleep-inducing effect, though no sleep was observed,’ Lenz noted. Other pharmaceutical companies were later unable to replicate thalidomide’s claimed sedative effect in animals and wondered what the Grünenthal men had done.
This question mark over the early testing has contributed to some speculation that perhaps the first test subjects were humans, in whom thalidomide certainly does have a sedative effect. Allied with this speculation is a theory that the early testing was done by Nazi doctors during World War II, and that thalidomide later made its way to Grünenthal via one of these doctors. We never saw any persuasive evidence for this theory, which has been given some media coverage in part through the efforts of Martin Johnson, the former director of the UK Thalidomide Trust. Johnson holds firm to this view and has some adherents, but Lyn Rowe’s lawyers were not among them. In any event, the questions over the Grünenthal tests are never likely to be resolved as Grünenthal long ago destroyed a large part of its early research.
In the wake of its testing, Grünenthal decided its drug held promise as a rival to the barbiturates as a sedative/sleeping pill. And even better, Grünenthal had the perfect sales pitch for its drug: complete safety. By feeding increasing amounts of a drug to test animals, researchers can establish its lethal dose or, more precisely, its LD50—the dose at which the drug kills fifty per cent of the test animals. The Grünenthal testers found that no matter how much of the drug they forced into test animals it was almost impossible to kill them. Thalidomide thus has a startlingly high LD50, which sparked a very compelling (though horribly wrong) super-safe sales pitch. In a marketplace crowded with barbiturates which carried serious overdose risks and had contributed to an epidemic of accidental deaths and suicides, an ‘ultra-safe’ sleeping pill held great appeal.
But safely stuffing large amounts of a drug into an animal—or even a human—in one-off experiments proves little. Any medically trained person (then and now) knows that all sorts of side effects can emerge from the long-term use of a drug, even in low doses. This was not a consideration that appeared to cause Grünenthal and Distillers much concern. So keen were they on the safety claims that they later used reports of failed suicide attempts with thalidomide to further ramp up the sales pitch.
Next for Grünenthal after the animal tests were human trials. This has led some critics to observe that it took less than twelve months for Grünenthal to move from invention (or synthesis) of thalidomide to tests in humans, with relatively little animal testing in between. Further criticism arises because the clinical trials on which Grünenthal embarked frequently amounted to small-scale use by doctors, many of them friendly to Grünenthal.
One bizarre—or, to modern eyes, brutally primitive—study took place in Bonn. Dr Konrad Lang treated forty children, many of them brain damaged, over extended periods with extremely high doses of thalidomide: up to twenty times the recommended dose for an adult. None of the children’s parents had been informed of the trial. Lang had never before performed pre-market testing on a drug, and he later conceded that his experiments with thalidomide did not amount to a proper trial. No doubt many of the children were effectively sedated by these massive doses. In addition, one child with a congenital heart defect died, a three-month-old baby suffered heart failure and died, and another child temporarily lost her sight. Dr Lang decided that the deaths and other side effects had not been caused by the drug and reported to Grünenthal that thalidomide was a rapid-acting sedative ‘particularly suited for children’.
Many reports to Grünenthal from its ‘testers’ were glowing. Doctors reported a pronounced sedative and hypnotic effect and no hangover. Amid the good news, though, questions emerged. One doctor reported he had dropped the drug because of ‘absolute intolerability’. Among the side effects he noted was slight paraesthesia, a tingling or burning sensation often caused by nerve damage. Responding to this report, Grünenthal’s Heinrich Mückter conceded in a letter on 3 April 1956 that thalidomide seemed ‘a very strong sedative’ which if used in high doses over a long period could cause ‘disturbance in the nervous system’. Mückter was right about that. Thalidomide would soon damage the nervous systems of many thousands of Germans, in addition to killing and malforming thousands of babies.
Throughout its testing and into the sales period, there were significant gaps in Grünenthal’s understanding of thalidomide. Why the drug caused sedation and sleep was simply not known. Grünenthal did not know the details of where in the body thalidomide acted, or how it was broken down and absorbed. Even Keller, one of the inventors, thought that the trials had ‘not been very impressive’ and the testers had not been ‘particularly enthusiastic’. But the uncertainties did not get in the way. Dubious testimonials and commercial ambition would suffice as the drug’s launching pad.
Rushing a drug to market had very recently been shown to be a poor idea. In 1953 a French company had started selling a treatment for boils called Stalinon, after grossly inadequate testing. A tin-based compound, Stalinon proved horribly toxic in humans. It caused more than one hundred deaths, most commonly from cardiac or respiratory failure, and many serious injuries. Some survivors suffered aftereffects for years. In December 1957 a French court awarded the victims 643 million francs and the pharmacist responsible received a two-year jail sentence. In 1958 an examination of the ‘worst disaster ever caused by a drug’ found that had Stalinon been properly tested in animals, its toxicity would have been evident and it would never have been trialled in humans. Grünenthal, clearly, was paying insufficient heed to the cautions underlined by the Stalinon events.
In October 1957 Contergan, Grünenthal’s main thalidomide product, was launched with a huge splash. Advertisements and pamphlets promoted the drug as completely non-toxic and totally safe. The market was swamped with promotional material. During 1958 alone, Grünenthal placed fifty advertisements for thalidomide in medical journals and sent more than 200,000 letters to doctors, plus further mail-outs to 50,000 doctors and pharmacists. Sales started slowly but Contergan would soon become the success story Grünenthal had been hoping for: by early 1960 it was the best-selling sleeping pill in Germany.
Grünenthal, of course, received some negative reports about the new medication, including dizziness, vomiting and agitation. Some complaints were strident. ‘Once and never again,’ one Swiss doctor declared. ‘This was a horrible preparation.’
But eventually one particular side effect of thalidomide began to stand out. Peripheral neuritis is a condition in which the peripheral nerves are damaged. It usually starts in the hands and feet, and causes numbing, tingling, itching or burning. Peripheral neuritis (also often referred to in various thalidomide documents as polyneuritis or neuropathy) can vary in seriousness and persistence, but at its most extreme it is an agonising torment. Thalidomide, it became clear, could cause a horrible brand of peripheral neuritis. There was no effective treatment and much of the damage persisted for long periods. Sometimes it was permanent.
It was this nerve-damage side effect, not the capacity of the drug to harm foetuses, which came to light first and it did so in great numbers. Grünenthal later estimated the number of nerve-damage victims in Germany at four thousand—a gross underestimate but still a terrible toll. Others have put the figure many times higher.
Many doctors argued that the nerve damage alone justified the removal of thalidomide from sale. The injuries were serious and the drug was, after all, only a sedative or sleeping pill: there was no shortage of alternatives available. Yet Grünenthal’s response to the nerve-damage reports, detailed later, was to suppress, spy, deny, lie and mislead.
But a revelation far worse than nerve damage lay ahead. Thalidomide was wreaking havoc on unborn babies in Germany, Spain, Brazil, Syria, Australia, New Zealand, Canada, Japan, Sweden, Ireland, the United Kingdom, Norway, Italy and many other countries across the world.