Deadly Medicines and Organised Crime

by Peter Gotzsche

  In 1965, a Swiss veterinarian published findings that dogs treated with clioquinol developed acute epileptic convulsions and died. Guess what Ciba’s response was to this. Ciba inserted a warning in the drug’s packaging in England that it should not be used in animals!

  In 1966, two Swedish paediatricians studied a 3-year-old boy who had been treated with clioquinol and suffered severely impaired vision. They reported their findings in the medical literature and also informed Ciba that clioquinol was absorbed and could damage the optic nerve. These events, including the catastrophe in Japan, had no visible effect on the company that continued its marketing efforts worldwide. In 1976, clioquinol was still widely available as an over-the-counter drug for the prophylaxis and treatment of travellers’ diarrhoea despite the lack of evidence that it was effective.3 Package inserts from 35 countries showed wide variation in dosage, duration of treatment, contraindications for use, side effects and warnings; a complete mess.

  By 1981, Ciba-Geigy had paid out over $490 million to Japanese SMON victims, but the company didn’t take the drug off the market until 1985, 15 years after the catastrophe struck. In contrast, the Japanese Ministry of Health banned the drug 1 month after it became known in 1970 that clioquinol was behind the SMON tragedy.

  The story also illustrates an all-too-common gross failure of drug regulatory agencies, which should have taken action but did nothing.

  A third of my childhood memories about the drugs my grandfather used is about corticosteroids. When the newly synthesised cortisone was first given to 14 patients with rheumatoid arthritis in 1948 at the Mayo Clinic in Rochester, Minnesota, the effect was miraculous.5 The results were so striking that some people believed a cure for rheumatoid arthritis had been discovered. Corticosteroids are highly effective for many other diseases, including asthma and eczema, but the initial enthusiasm evaporated quickly when it was discovered that they have many serious adverse effects, too.

  In the mid-1960s, my grandfather broke his hip and the fracture wouldn’t heal. He spent 2 years in hospital, lying immobilised on his back with his leg in a huge plaster. It must have been some sort of a record for a hip fracture. I have difficulty remembering exactly what he told me, but the reason for his troubles was that he had abused corticosteroids for many years. It was something about the drug having so many good effects that he thought it worth taking even if you were healthy, to increase your strength and to be cheered up. As I shall explain in later chapters, it seems that the dream of a ‘quick fix’, whether by a legal or an illegal drug, that improves our natural physical performance, mood or intellectual capacity, never dies.

  Back then, I found it very likely that my grandfather had been persuaded by a drug salesperson to take the corticosteroid, as salespeople rarely say much about the harms of their drugs while they routinely exaggerate their benefits and recommend the drugs also for non-approved indications. In terms of sales, nothing beats persuading those who are healthy to consume drugs they don’t need.

  All my childhood memories about drugs are negative. Drugs that were supposed to be beneficial harmed me. I suffered from motion sickness and my grandfather gave me a drug against this, undoubtedly an antihistamine, which made me so drowsy and uncomfortable that I decided after a few tries that it was worse than the disease and refused to have any more of it. Instead, I asked him to stop the car when I needed to vomit.

  Young people are volatile and it can be hard to choose an occupation. When I was 15, I left school to become a radio mechanic because I had been a radio amateur for some years and was fascinated by it. In the middle of the summer, I changed my mind and started in the gymnasium, now convinced I would become a graduate electrical engineer, but that didn’t last long either. I switched my interest to biology, which was one of the most popular subjects in the late 1960s; the other was psychology. We knew there weren’t many jobs in either discipline but didn’t care about such a trivial issue. After all, we became students in 1968 when the traditions were turned upside down and the world laid at our feet. We bubbled with optimism and what was most important was to find a personal philosophy of life. After having read Sartre and Camus, I subscribed to the idea that one should not follow routines, traditions or other people’s advice but should decide for oneself. I changed my mind again and now wanted to become a doctor.

  As it happened, I ended up taking both educations. I spent many vacations with my grandparents, and one of these visits convinced me that I should not waste my life on being a doctor. My grandfather had invited me into his surgery during my final year at school. It was situated in a wealthy part of Copenhagen and I couldn’t avoid noticing that many of the problems the patients presented with weren’t really anything to bother about, but a reflection of boredom. Many women had very little to do, didn’t have a job and had servants who helped them look after the house. So why not pay the gentle and handsome doctor a visit, like in the joke about the three women who met regularly in the waiting room. One day, one was missing, and one of the others asks the last one what happened. ‘Oh,’ she replied, ‘she couldn’t come as she is ill.’

  The study of animals seemed more meaningful and I rushed through the education as if it were a sporting contest only to realise that I still didn’t know what to do with my life. My chances of getting a job were small, as I had not done any research during my studies or had taken other initiatives that would make employers more interested in me than in 50 others.

  What most people did in this situation was to become a school teacher. I tried, but it didn’t work out. I had barely left school before I was back again, the only difference being that I was now on the other side of the teacher’s desk. I wasn’t much older than my pupils and felt I belonged more to this group than to my new tribe of teachers who, moreover, smoked to an unbelievable extent. Although I could learn to smoke a pipe, I wasn’t mature for such a job and also had difficulty accepting that this was what I was going to do for the next 45 years. Like life being over before it had started.

  Two things particularly annoyed me during the 6 months where I tried to learn how to teach, being supervised by another teacher. In biology, we didn’t use textbooks much, although wonderful textbooks were available. We were now in the dark 1970s where our universities and academic life at large were heavily influenced by dogmas, particularly Marxism, and it was not healthy to raise too many questions that things could perhaps be done differently. My supervisor required of me that, instead of using textbooks, I should produce the educational material myself because it needed to be relevant for the time we were living in. Some have aptly called these years the history-free period. I found myself cutting newspaper articles about the oil industry and pollution and spent endless hours at the photocopying machine putting my ‘breaking news’ compendia together. I don’t wish to imply that such issues are not interesting or relevant, but my subject was biology, which goes back billions of years, so why this restless emphasis on something that happened yesterday?

  The other problem was the prevailing fashion in pedagogy, which dictated that I needed to write down a detailed plan before each lecture outlining what learning goals I wanted to achieve, subgoals at that, how I would achieve them, etc., etc. After each lecture I was expected to analyse my performance and discuss with my supervisor whether I had achieved all these goals. Thinking through what you wish to achieve beforehand and evaluating it afterwards is very reasonable of course, but there was so much of it that it drained me, as I am not the bookkeeping type. I also lectured in chemistry, and particularly in that subject the rigid template felt like overkill. To teach people why and how chemical substances react is straightforward. Like in mathematics, there are some facts and principles people need to learn, and if they don’t want to learn them, or cannot learn them, there isn’t much the teacher can do. Imagine if a piano teacher was expected to construct similarly elaborate schemes before every music lesson she gave and evaluated herself afterwards. I am sure she would run away quickly.

  Th
e séances with my supervisors reminded me of the Danish lessons at the gymnasium where we were asked to interpret poems. I was quite bad at this type of guesswork and was irritated that the authors hadn’t written more clearly what was on their mind if they wanted to communicate with us mortals. The lecturer was in a much better position, as he possessed a gold standard, which was a handbook written by a scholar who had interpreted the poems the teachers used. This is actually amusing. I have heard art critics interpret paintings, and when the artist was later asked whether they were right, he laughed and exclaimed that he didn’t mean anything with his paintings, he just painted and had fun while doing it. Pablo Picasso painted in many different styles over the years and was once asked what he was searching for. Picasso replied: ‘I don’t search, I find.’

  I did well according to my pupils but not according to my supervisors. I was told they could let me pass but with an evaluation that could make it difficult for me to get a job as a teacher. They preferred to fail me to give me a chance of thinking about whether I really wanted to be a teacher. This is the only time I have failed an exam, but I am immensely grateful that they made this wise decision. I had invested far too little effort in my new profession. My university years had been so easy that I hadn’t dreamed about working in the evenings, in contrast to those teachers who were more successful than me. I had no idea that it was considered so difficult to teach. Later, I lectured at the university in the theory of science for more than 20 years.

  After having applied for and not getting a few jobs as a chemist or biologist, my grandfather suggested I went into the drug industry. I sent three applications and was called for two interviews. My first experience was really weird. I could almost smell the vitamin pills of my childhood when I entered the office. The man who interviewed me had a dusty appearance and was partly bald-headed with long whiskers that would have made him a perfect character in a Western movie, selling snake oil or whiskey – someone whose used car you wouldn’t buy. He was also the type of salesman I associated with one who sold ladies’ underwear or perfume. Even the name of the company was old-fashioned. It was pretty clear that we both felt uncomfortable in each other’s presence.

  The second company was modern and attractive. It was the Astra Group, with headquarters in Sweden. I got the job and spent 7 weeks in Södertälje and Lund on various courses, which mostly dealt with human physiology, diseases and drugs. There was also a course in ‘Information technique’, which I suggested to the course leader should more appropriately be called ‘Sales technique’. He didn’t comment on my suggestion, but the course was about manipulating doctors into promising to use the company’s products rather than those of its competitors, and to use even more of the company’s drugs, to new types of patients, and in increased doses. It was all about increasing the sales, which we learned through role plays where some of us played various types of doctors, ranging from the sour to the forthcoming ones, and others tried to penetrate the palisades and ‘close the deal’.

  When I learned about drug usage, my first thought was: ‘Gosh, it’s amazing that there are so many drugs around and that they are used so much, for all kinds of ailments. Can it really be true that they are so effective that it justifies such massive use?’

  I toured my district as a drug salesman, officially called a drug representative, and visited general practitioners, specialists and hospital doctors. I didn’t like it. I had a full academic education with high marks behind me but felt inferior when I talked to doctors who sometimes treated me badly, which I fully understand. It must have been a nuisance to spend time with salespeople and I often wondered why they didn’t say no. There were so many companies that it was common for a general practitioner to have more than one visit a week.

  The academic challenges were very small and I realised that my university education would wither pretty quickly if I didn’t move on to another job. The job also threatened my self-esteem and identity as a person. To be an effective salesman, you need to behave like a chameleon, adapting your own personality to the person in front of you. The risk of playing so many roles and pretending to agree with doctors you disagree with is that you lose yourself. I had read some of Søren Kierkegaard’s works and knew that losing yourself was the worst mistake you could make. If you deceive not only the doctors but also yourself, it becomes too painful to look in the mirror and accept what you see. It is easier to be living a lie and it moved me deeply when I saw Arthur Miller’s 1949 play, Death of a Salesman, years later at a theatre in London. I knew exactly what this was about.

  The doctors listened to my sales pitches without asking uncomfortable questions, but on a couple of occasions they told me I was wrong. Astra had developed a new type of penicillin, azidocillin, which it had given a catchy name, Globacillin, as if it were effective against everything. In one of our campaigns, we tried to sell the drug for acute sinusitis. We informed the doctors about a study that showed that the drug penetrated into the mucosa in the difficult-to-reach sinuses where the bacteria were located and indicated that this was an advantage over usual penicillin. An ear, nose and throat surgeon told me that it wasn’t possible to take biopsies and measure the concentration of an antibiotic in the mucosa, as one would inadvertently include capillaries in the sample where the concentration was higher. It was very humiliating for me to be told by a specialist that my company had cheated me. Academics are trained to think for themselves, but I lacked the skills to do so in a medical context.

  Another argument for using the new, more expensive drug was that its effect on a particular bacterium, Haemophilus influenzae, was 5–10 times better than penicillin. This claim resulted from laboratory experiments in a Petri dish. The right questions to ask would have been:

  Were these studies performed by the company and have the results been replicated by independent researchers?

  What is the effect of treating acute sinusitis with penicillin or azidocillin, compared with placebo? And if there is an effect, is it then large enough to justify routine treatment of sinusitis with antibiotics, considering the adverse effects of the drugs?

  Most important, has azidocillin been compared with penicillin in randomised trials of acute sinusitis, and was the effect any better?

  Such questions would have made it clear that there was no rational basis for using azidocillin. We nevertheless succeeded to sell the drug with our doubtful arguments to some doctors for some time, but it is no longer on the market.

  After only 8 months as a salesman, I left the roads and became a product manager with responsibility for written materials and for our 3-yearly sales campaigns, in collaboration with the sales manager. It doesn’t make me proud to recollect what we were doing. We sold a drug against asthma, terbutaline (Bricanyl), and in one of the campaigns we tried to convince the doctors that the patients needed not only constant treatment with pills but also with a spray. Again, we didn’t give the doctors the relevant information, which would have been the results of randomised trials of the combination treatment versus treatment with either spray or pills.

  Asthma deaths were caused by asthma inhalers

  Today, regular treatment with inhalers containing drugs like terbutaline is not recommended; in fact, such treatments have been proscribed in most guidelines because of safety concerns. Epidemiologist Neil Pearce from New Zealand has written a most disturbing account of the powers of the drug industry and its paid allies among doctors in relation to asthma.6 When the inhalers came on the market in the 1960s, asthma death rates went up in the same way the sales did, and after the regulators had warned about overuse, they both went down again. Pearce wanted to study one of the drugs in detail, isoprenaline from Riker, and received data from the company that expected his research would show that the theory about the drugs causing the deaths was wrong. However, he confirmed the theory and when he sent his manuscript to the company (which one should never do), they told him he would be sued. His university promised to make its lawyers available in case of litigatio
n and he published the paper, but now became fiercely attacked by asthma specialists.

  Doctors tend to become very angry if you tell them they have harmed their patients, even when they have done that in good faith. I have written a whole book about my experiences after I demonstrated in 1999 the harmful consequences of mammography screening, which converts many healthy women to cancer patients unnecessarily.7

  This was in 1972. But, although Pearce’s findings were supported at the time, asthma experts told him 16 years later when he entered asthma research again that the theory had been proven wrong. No one was able to tell him how or what the explanation then was for the increase and fall in asthma deaths in the 1960s. The misconception seemed to have been created and fuelled by the doubt industry, i.e. drug companies commissioning substandard research to their hired consultants among the asthma specialists. ‘Doubt is our product’ a tobacco executive once said,8 and this smokescreen always seems to work. Create a lot of paid noise and confuse people into disbelieving the original, rigorous study and believing the noise instead.

  In 1976, a new epidemic of asthma deaths began in New Zealand. When Pearce’s colleagues suggested it might be caused by overtreatment, they were met by extremely hostile reactions from the official Asthma Task Force that believed the problem was undertreatment. This is a standard industry position, and indeed the major funder of asthma research in New Zealand was Boehringer Ingelheim, the maker of fenoterol (Berotec).