Taking the Medicine: A Short History of Medicine’s Beautiful Idea, and our Difficulty Swallowing It

by Burch, Druin

  This was wonderful, given Grünenthal’s desire to see their drug as being a safe version of a barbiturate. Armed with these reports, they went back to their animal experiments and managed to create one that showed an apparent effect. They put mice in a cage and recorded that they moved about a little bit less after being given the drug. It was not a recognised way of measuring a sedative, but the intention was not to hold the drug up to the highest standards of testing. The intention was to get it licensed. Performing a test is not the same thing as performing a reliable test. Not all evidence is equal. Give people sugar pills as though they are drugs and they report a range of effects and side effects. Tell them the pills are like barbiturates but safer, and you get some people coming back and saying that they slept better after taking them. Record enough different measures of an animal’s movements and, eventually, one of them will correlate with whatever drug you want it to. Science, like a hammer, is only useful if you know what you are doing with it.

  On Christmas Day 1956, in Stolberg where Grünenthal was based, a child was born without ears. The father had brought home drug samples from Grünenthal, where he worked, and given them to his wife during her pregnancy. Ten months later, on the first day of October 1957, three days before Sputnik took to the heavens, Grünenthal commercially released thalidomide. It spent heavily on advertising, buying space in fifty medical journals, sending out 50,000 circulars and writing directly to a quarter of a million doctors.

  The drug, released under the brand name of Contergan, was a massive success. Grünenthal showed a willingness to recommend it for whatever reason people were saying they found it helpful. In 1958, after reports that it subdued vomiting, Grünenthal wrote to doctors stating it was ‘the drug of choice’ for treating morning sickness in pregnant women. The British company selling the drug thought this sounded like an excellent recommendation, and told their customers that thalidomide ‘can be given with complete safety to pregnant women and nursing mothers, without adverse effect on mother or child’. Sales were enormous. In some countries they were second only to aspirin.

  In 1959, a German neurologist wrote to Grünenthal reporting that one of his patients had developed nerve damage while taking the drug. Were they aware, he asked, of other such cases? They said no. It was a lie. Other reports were already coming in. By 1960, Grünenthal had received information describing around a hundred cases of nerve damage in people taking thalidomide. They instructed their sales representatives to deny the link, and undertook no extra research to investigate it. When their representative in Cologne was asked about thalidomide causing nerve damage, he described his response: ‘I did my best to foster confusion.’

  It is very hard to explain the behaviour of Grünenthal as the reports of side effects mounted. ‘If I were a physician,’ said Heinrich Mückter in 1961, still the company’s head of research and development, ‘I would not now prescribe Contergan. Gentlemen, I warn you – I do not want to repeat an earlier judgement – I see great dangers.’ That was when speaking at a private company meeting. Six weeks later, at a public medical one, he described Contergan as ‘the best sleeping pill in the world’.

  From September the previous year, the Ohio-based company Richardson-Merrell had begun seeking approval to sell thalidomide in America. As a routine application, for a drug already accepted worldwide, the paperwork was given to the Food and Drug Administration’s latest reviewer. An ex-academic, Frances Oldham Kelsey had previously worked on the fatal elixir of sulphonamide, helping to prove that it was the diethylene glycol that killed over a hundred people. She joined the FDA after a post became unexpectedly available. Her predecessor, demanding evidence of a drug’s effectiveness, had abruptly lost her job – in order, it was said, ‘to placate a pharmaceutical company’.

  Kelsey was ‘a short, slim, unpretentious woman with a sweet smile and a slight overbite’. Both her manner and her cooking were described as being rather British, an equally pejorative description whether it referred to food or to clothes. She did not seem likely to disturb the easy relationship between the drug companies and the FDA.

  To the great surprise of Richardson-Merrell, Kelsey turned their application down. She was not satisfied that either the safety or the effectiveness of thalidomide was actually proven. Standards of proof were lax, but they were also barely defined. That left Kelsey free to decide on them herself. She did, and in her view the previous investigations of thalidomide did not fulfil them.

  Richardson-Merrell was submitting not only thalidomide, but also an anti-cholesterol drug named MER/29. It hoped the two together would prompt its entry into ‘the truly big time’ of emerging American pharmaceutical companies. The anti-cholesterol drug caused blindness and other side effects in primate trials – information that the company knew about and concealed. (It was later sued by some of those damaged by the drug, paying out $200 million in compensation.) When Kelsey rejected the application, Richardson-Merrell rewrote and resubmitted it. She rejected it again, pointing out that it contained no new information. The expert opinion that supported it, thought Kelsey, was less like scientific evidence than a series of purchased testimonials.

  The company grew increasingly desperate to start marketing thalidomide, directly hounding both Kelsey and her FDA superiors. At the same time, it carried on providing the drug to American doctors. FDA approval was required to market and sell a drug, but not to distribute it as part of a trial. And the proper nature of a trial was not specified. Richardson-Merrell’s was not run by their researchers or pharmacists. Their trial was directed by their Sales and Marketing division. It organised the sending out of samples to doctors, reassuring them that there was no obligation to report back any results.

  In Germany and Australia, doctors were already growing concerned about thalidomide. Other worries were emerging besides its ability to cause nerve damage. In the autumn of 1961 a German paediatrician named Widukind Lenz wrote to the national Welt am Sonntag (‘World on Sunday’) newspaper. He described 150 children born with severe and terrifically unusual birth defects. He linked the defects to maternal consumption of thalidomide during pregnancy. William McBride, an Australian obstetrician, wrote to the Lancet having reached the same conclusion in his own patients.

  Lenz wrote to Grünenthal and asked them to withdraw the drug. ‘Every month’s delay’, he wrote, ‘means that fifty to one hundred horribly mutilated children will be born.’ The company declined to withdraw thalidomide. Lenz’s request for it to be taken off the market was followed up by one from the German government.

  Later in 1961, in response to public pressure, Grünenthal withdrew the drug – although only from Germany, and only in response to what Heinrich Mückter called the ‘sensationalism of the Welt am Sonntag story’.

  A lack of records makes it impossible to accurately assess the damage caused by thalidomide. Estimates suggest that around 10,000 children were severely deformed by the drug, of whom only about half survived to be adults. In America, Richardson-Merrell’s ‘investigating’ sales department handed out around 2.5 million tablets. It was a large number, but tiny compared to the sales elsewhere. Thanks to Kelsey’s continuing refusal to approve thalidomide, fewer than twenty American children were born deformed as a result of the drug.

  The pharmacologist at Grünenthal, the man whose mistake it was to believe that thalidomide resembled a barbiturate, was sickened. The thought of his drug having had such toxic effects had not occurred to him. Now it was clear what his work had led to. ‘I felt like a bus driver who has run into a group of children and has killed and injured many of them,’ he said.

  Heinrich Mückter felt differently. When, along with eight other company executives, he faced criminal charges brought by the West German Ministry of Justice in May 1968, Mückter began with a declaration of outrage. ‘I would first like to say that I still regard the charge as a gross injustice to me personally.’ Chemie Grünenthal seemed to feel similarly. They fought the charges ferociously, attacking the character and the
knowledge of Widukind Lenz, threatening journalists with legal action, and refusing to acknowledge any responsibility. After the third year of the trial, an out-of-court settlement of $43 million was accepted by the families of those affected. Grünenthal executives never came to judgement.

  Reading the account of thalidomide on the company website you are left with the feeling that an unforeseen and unavoidable tragedy was handled with compassion and generosity by a caring corporation. Having avoided a final judgement over its legal responsibility, Grünenthal seems happy declaring itself innocent of any moral wrongdoing. The British company that sold thalidomide, Distillers, behaved in a similar manner, denying all legal and moral responsibility. Only the disgust of individual Distillers shareholders and dogged publicity in the Sunday Times (starting in 1972, but coming after considerable research over a ten-year period in which the British press were legally barred from discussing thalidomide) forced the company into paying compensation.

  In the USA the thalidomide scandal brought Senator Kefauver’s drug hearings back to life. The resulting Kefauver–Harris Amendments became law on 10 October 1962. Effectiveness and safety now needed to be proved somewhat more stringently before the FDA would license a drug. At the same time the notion of what was called ‘informed consent’ also passed into American law. Pharmaceutical companies were required to honestly inform people about the side effects of their products. Estes Kefauver believed that his Amendment was his ‘finest achievement’ when it came to keeping Americans safe.

  ‘I do not think we need to be particularly proud’, said John F. Kennedy at the time, ‘that it took an international catastrophe to make us realise that the first thing with drugs is safety.’ He was proud, however, of the actions he took in response. Having become President and signed Kefauver’s Amendment into law, he told Congress that ‘the physician and consumer should have the assurance that any drug or therapeutic device on the market today is safe and effective for its intended use’.

  It is the sort of language that politicians are elected for using. Expressing doubt or uncertainty or caution is not the way to get into office. Kennedy’s and Kefauver’s confidence in the benevolence of their actions, however, was misplaced.

  The point of the thalidomide story is the fragility of knowledge. What brought the drug’s ill-effects to people’s attention was not that it killed and maimed, but that it did so in a strikingly unusual way. It was the nature of the abnormalities that brought them to attention, not their numbers. If the deaths had been through pneumonia, or some other common disease, the fatal nature of the drug would have taken very much longer to uncover. Doctors, even the best of them, were still using drugs without the information that they needed to understand what their medicines did.

  In the aftermath, this was the realisation that was missing from the world’s response. Governments gave regulatory bodies new powers. The notion that medications mix an unpredictable balance of harms and benefits, whose overall sway is often not immediately apparent, was largely lost. There was very little open-minded thoughtfulness about the way in which effectiveness and safety were best assessed. Instead there was the triumphal passing of legislation.

  In Germany people were struck by the fact that thalidomide was not removed by government action, or the careful compassion of pharmaceutical companies, but purely as a result of bad publicity in the press. New regulation was introduced worldwide, almost all of it following the pattern of America’s FDA. Some of it helped, some made things worse.

  19 Syphilis, Leprosy and Head Injuries

  ALBERT NEISSER WENT to school with Paul Ehrlich. Neisser, too, became a doctor, and by the time he was twenty-one, in 1878, he discovered the germ that causes gonorrhoea. A common sexually transmitted disease, without antibiotics it was capable of spreading beyond the sexual organs and causing a range of complications. It could kill. Having found its cause, Neisser went on to help discover the germ that gave rise leprosy, to found the German Society for the Fight Against Venereal Diseases, and to conduct experiments on prostitutes.

  Neisser’s idea was that serum therapy could be used to protect women from syphilis. He took blood from patients suffering from the disease, removed the cells and injected the remaining serum into prostitutes under his care. Some of the women whom he injected with serum later developed syphilis. Neisser concluded that his therapy had failed. When he published his findings in 1898, others added the suggestion that his serum had infected the women. The press expressed outrage. Neisser, they pointed out, had neither explained to the women what he was doing nor asked their permission.

  Had Neisser’s treatment worked, it would have been celebrated. Jenner is famous for having discovered the smallpox vaccine, and his human trials of it were done with exactly the same lack of consent. Neisser’s therapy, however, did not work. He was fined and his actions were discussed in the Prussian parliament. A report was commissioned. It emphasised the importance of patients being fully informed about what was done to them, and being able to give or withhold their consent. In 1900 the government issued guidelines based on the report. They required ‘unambiguous consent’ and a ‘proper explanation of the possible negative consequences’ of what was proposed. The paradox was clear. If you were experimenting, you did not know exactly what an intervention’s outcomes might be. That was the nature of an experiment, and it made it difficult to satisfy the demand that those participating be fully informed of all possible consequences.

  By 1931, the Reich government issued clarified guidelines. Novel medical treatments required consent, ‘given in a clear and undebatable manner following appropriate information’. That could be overlooked, if the situation was desperate and consent impossible – a patient unconscious and slipping towards death, for example, with no relatives available to give or refuse consent on his or her behalf.

  Another problem was clearly apparent to the German authorities. Doctors had technical knowledge that patients did not. ‘Informed consent’ was a problematically subjective term. Patients varied immensely in the sort of information they were capable of understanding. There seemed no clear solution to this, no absolute level of comprehension required. All that was reasonable was for doctors and patients both to do the best they could; the former to explain and the latter to understand.

  What was not apparent in these debates was the huge weight of inherited medical ignorance. Almost everything that doctors did, from their recommendations about diet and rest to the operations and drugs that they prescribed, had been decided on without reliable trials. As a result, only a very small proportion of what was known was actually correctly known – usually those minority of interventions that changed a situation beyond all possibility of misinterpretation. The loss of all five litres of a patient’s blood, for example, was clearly accepted as fatal. The loss of half of it was still seen by some as therapeutic.

  The majority of medical beliefs were guesses, yet the German government was suggesting that doctors carefully warn their patients whenever their treatment was experimental. Neither governments nor doctors could yet see that most of their treatments were worse than experimental: they were untesting, as well as untested.

  Despite these failings, Germany was making creditable efforts to develop ideas about the way in which an admission of ignorance could be worked into the relationship between a doctor and a patient. It was a society with a good health care system, where the welfare state made patients confident that they would not be put in the position of having to accept openly experimental care purely because their financial means were limited. The deal was that doctors should try to be open about what they did not know, and in return recruit their patients to help them improve. A patient should be free to decide whether to agree, and whether to submit himself or herself to an unproven medical therapy.

  It was also in Germany that those ideas curdled. The Nuremberg trials following the Second World War showed the extent to which doctors were eager participants – and leaders – in Nazi atrocities. Res
ponding to the murders and vivisections carried out by Josef Mengele, Karl Brandt and others, the 1947 Nuremberg code set out ten principles for medical research. Consent was number one, and here the wording made an effort to describe what was meant by ‘informed’. The consenting patient ‘should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision’. Rather than an experimental treatment, the patient should, if they wished, be able to choose a proven one.

  Two other points from the Nuremberg code are worth dwelling on. The eighth said that ‘the highest degree of skill and care should be required through all stages of the experiment’. Incompetent experiments, in other words, breach the code. The skill and care needed to get reliable results are not ornamental extras, they are essential.

  The tenth point is similarly sensible, and put into words what people wished to do already. It said that those running an experiment must be willing to bring it to an end whenever they had reason to believe that continuing it was harmful. That was the principle that the cardiologists had wanted to put into action, when Cochrane gave them the false data suggesting their heart attack patients did better in hospital than at home. This point of the Nuremberg code said trials should potentially be stopped early, but added nothing at all about how certain of harm you needed to be before stopping one.

  The temptation is to halt a trial the moment one treatment seems better than another. An American paediatrician, William Silverman, has pointed out that this is a bit like stopping a race the moment the horse you’ve backed is a nose in front. Finishing lines sometimes matter. If a trial is stopped before the difference it shows is conclusive, you can be in a worse position than before you started. Not only do you still not really know the answer, but the opportunity for finding out may be gone for good. Drugs are not ignored while evidence about them accumulates; doctors make up their minds about them regardless, wedding themselves to an opinion that it becomes very difficult to shake them out of.