Deadly Medicines and Organised Crime

by Peter Gotzsche

  When Pearce et al. found out that the new epidemic mirrored the sales curve for fenoterol, all hell broke loose. They met resistance from all quarters and demands that others should carefully scrutinise their data, not only people with amicable relations to the company; the company itself also requested the data. A lawyer prudently advised them to ignore all legal threats and not show the paper to the company before it was accepted for publication.

  Pressures mounted, also from the Medical Research Council, although it hadn’t funded the study, and the university. They didn’t understand, or chose to ignore, that they had no right whatsoever to interfere with the research. The only way out was therefore to go to the top, the Department of Health, where the researchers learned, however, that Boehringer Ingelheim had been there first.

  All sorts of false rumours were spread, including false allegations that there was no protocol for the study, although this protocol had been seen by the Asthma Foundation and the Medical Research Council that refused to fund the study. Boehringer Ingelheim succeeded in postponing – and almost preventing – publication in the Lancet, which got cold feet after having accepted the paper because of the immense pressure. Lancet received several lengthy faxes every day from the company and had to ask them to stop.

  Boehringer Ingelheim had invested a lot in the physicians and it paid off. Their sympathy was on the company’s side, being concerned that its New Zealand branch might close down; they were not thinking of their patients. The Department of Health also sided with the company and broke the confidentiality by giving the company a copy of the manuscript it had requested from the researchers.

  It was as bad as it could be. The researchers’ first study was unfunded and so was the next one, and Dunedin Hospital refused to allow them access to its records. The Department of Health would not give the researchers any assurance that it would not also show the manuscript from the second study to the company, and when it didn’t get it in the first place from the researchers, it requested it from their university under the Freedom of Information Act. Boehringer gave the researchers’ data to its paid friends so that they could come up with other results even before the original data appeared in print.

  This was an outrageous transgression of the ethical ground rules for science, but despite its dirty methods, Boehringer lost the battle. The market share for fenoterol dropped from 30% to less than 3% in just 3 years and asthma deaths plummeted simultaneously, vindicating the research by Pearce et al.

  Shady marketing and research

  At one time, we visited chest physicians and showed them a film of small white particles that had been placed in the mucus in the windpipe. The movement of these particles towards the mouth was recorded with and without giving the patients terbutaline, and the story was that the cilia moved the particles faster when patients were treated. The idea was to convince the doctors that they should not only use the drug for asthma, but also for smoker’s lungs (chronic bronchitis). These patients cough a lot, which is why a quicker transport of irritants out of the lungs was speculated to be beneficial. But yet again, a simple question would have revealed that the emperor had no clothes. There were no randomised trials that had shown that terbutaline was effective in patients with chronic bronchitis. Even today, terbutaline is only approved for asthma and other bronchospasm, not for chronic bronchitis.

  It is illegal to market a drug for non-approved indications, so-called off-label use. As we shall see in the next chapter, illegal marketing is very common, and it is also routine that the companies circumvent the law. It is not illegal to discuss research results with doctors, and we could therefore show the film without breaking the law as long as we did not suggest to the doctors to use the drug for chronic bronchitis. If they had asked, we could say that we weren’t allowed to recommend the drug for this indication but that the results were interesting, and that the doctors were free to use drugs for whatever purpose they found reasonable. Absurdly, such indirect recommendations are not illegal. In my opinion, they should be. There is no good reason to present preliminary research results to practising clinicians; it is only reasonable to discuss them with academic researchers with the purpose of embarking on a definitive clinical trial hoping the new indication will be approved by the drug regulators.

  We also balanced on the edge of the law with another indication, but before I come to this, I need to explain what The Cochrane Collaboration is. It is a non-profit organisation that was started in 1993 by Iain Chalmers in Oxford, United Kingdom. It built on a common frustration among researchers and others that most medical research is of poor quality and biased, and a realisation that we needed rigorous systematic reviews of the randomised trials that could tell us more clearly what the benefits and harms of our interventions are. Once established, The Cochrane Collaboration grew quickly and currently engages about 30 000 people. The reviews are published electronically in The Cochrane Library, and there are more than 5000 such reviews, which are regularly updated. Half of the world’s population have free access to the full reviews through national subscriptions usually financed by governments; the other half have access to the abstracts.

  Coughing is very common and there is a huge market for over-the-counter cough medicines. A Cochrane systematic review of the randomised trials shows that none of them are effective,9 which means that the huge market is also a huge waste of money. Drugs like terbutaline don’t appear to work either,10 but someone in Astra coined the idea that we should suggest to doctors that terbutaline had an effect on cough, with reference to the study illustrated in the mucosa film.

  I didn’t believe this. Why should a drug used for dilating the airways in patients with asthma work for cough that was not caused by bronchospasm? Whatever the legal technicalities, I regard this as off-label promotion, and there were no witnesses that could testify to which degree the doctors were directly encouraged to try the drug for cough, as most encounters were on a one-to-one basis where only the doctor and the salesperson were present.

  We also did something good. We produced an illustrated guidance for patients with asthma in eight steps about how to use the spray, which also showed how one could estimate the remaining number of doses by immersing the container in water and see whether it floated or went to the bottom.

  During my 2 years with Astra, from 1975 to 1977, we launched a new product, zinc lozenges, which was approved for treatment of venous and ischaemic leg ulcers and a very rare zinc deficiency disease, acrodermatitis enteropathica, which affected the uptake of zinc. I still have the 20-page brochure I wrote for the launch, which was based on a similar brochure in Swedish.

  It is revealing to compare the brochure with the Cochrane review on zinc for leg ulcers.11 The first study in the brochure is also the biggest and it was published in a prestigious journal, the Lancet, which is very attractive for marketing purposes. The results were impressive.12 According to the brochure, the ulcers in the 52 patients treated with zinc were healed after 32 days whereas it took 77 days for the 52 placebo-treated patients. However, the trial was unreliable. The brochure stated that because the results for the first 16 patients clearly showed which group was treated with zinc, it was not possible to continue the study in a double-blind fashion. The study was excluded from the Cochrane review because it wasn’t randomised, which we usually expect blinded studies to be.

  The brochure reported positive effects from the randomised trials, but the Cochrane authors interpreted the same trials differently. They included six small trials of mediocre quality and found no evidence of a beneficial effect of zinc. Like Globacillin, zinc disappeared from the market.

  In 1977, I was offered a job at Astra-Syntex, a new joint-venture company between Astra and the California-based Syntex. My task was to establish a medical department and to be responsible for clinical trials and registration applications for new drugs and indications. I was very happy to leave marketing but also had concerns about the research the industry did and wanted to leave. I chose the most arduou
s way out and started to study medicine in 1978 while I continued to work for the company. I qualified 6 years later and left the company to work at different hospitals in Copenhagen.

  Astra-Syntex’s survival hinged on just one drug, naproxen (Naprosyn), a nonsteroidal anti-inflammatory drug (NSAID) used for arthritis. I performed several trials with the drug and discovered along the way that I wasn’t immune to company influence. There were many NSAIDs on the market, but somehow you get so used to the idea that your drug might be better than the others that you end thinking it is better, just as if it had been your child. One of the reasons why marketing of medicines is so effective is that the salespeople believe they are selling a very good drug.

  A clear indication of my naïvety was that I asked the European headquarters in London why we didn’t perform a trial comparing naproxen with a simple analgesic such as paracetamol, for example in sports injuries. The medical director kindly explained that they were not interested in such a trial but never said why, although I asked on more than one occasion. The reason was of course that such a trial might show that a much cheaper analgesic was equally effective, and on top of that we already knew that paracetamol was much safer than naproxen. In order to lure people into preferring naproxen for paracetamol, it was therefore necessary to give the doctors the impression – without having any data to support it – that naproxen was more effective.

  The trick was done using theoretical arguments. This is a very powerful marketing tool, although the arguments rarely hold water. In textbooks of pharmacology, naproxen is described as having anti-inflammatory properties and the hyped argument goes somewhat like this: When you have a sports injury, there is tissue injury and inflammation with oedema, and it is important to dampen the inflammation to speed up the recovery.

  It is very easy to lure doctors into doing wrong things by making them listen to the songs of the sirens while paying many of them, both for singing and for listening (see Chapter 8). As I shall explain in detail later, NSAIDs are dangerous drugs and many thousands of people are killed every year because of bleeding stomach ulcers and heart attacks, to mention just the two worst harms. But marketing is all that is needed. A couple of years ago, Danish TV focused on the liberal use of NSAIDs in professional football clubs for all sorts of pain. The prescription status of the drugs wasn’t a hindrance, as the sports doctors provided large supplies of the drugs, letting the footballers take as many as they wanted without even asking. There was a scandal, but as is usual with scandals, it quickly died out and I suppose it is now business as usual.

  Around 1980, I was approached by a rheumatologist who looked after the Danish national football team. He wanted to find out whether naproxen was better than aspirin for sports injuries. Aspirin is also an NSAID – the oldest one in existence and very cheap – but it is often used in low doses where it is assumed to have no anti-inflammatory effects, only an analgesic effect. We did the trial, using low-dose aspirin despite the concerns of my superiors in London, and just as they had predicted, there were no significant differences between the two drugs. However, the results were analysed by our statistics department in Sweden, which went on a ‘fishing expedition’ that eventually found something that could lessen the company’s pains that naproxen wasn’t any better than aspirin. The abstract of the published paper says:13

  ‘Fresh injuries were over-represented in the acetylsalicylic acid group (p<0.01), and when all patients were analyzed together [i.e. from both treatment arms], a significantly better treatment result was obtained the shorter the interval between injury and start of treatment. This might have influenced the results from this study.’

  Oh boy. I have contributed to this as an author. In principle, there is nothing wrong with reservations in an abstract, but imagine if naproxen had been significantly better than aspirin and there had been more fresh injuries in the naproxen group. Would this reservation about the good news for the company then have made it into the abstract? Hardly, and I doubt there would have been anything about this in the main text of the article either.

  We first submitted our paper to British Journal of Sports Medicine. The editor was keenly aware of the commercial priorities in the industry; he said he was surprised that we posted our study from Syntex, as our work contradicted the claims the company had made about naproxen being more effective than paracetamol and aspirin. We were startled that an editor so frankly sided with a company’s commercial interests and his next remark made us laugh. He noted that 18 patients received aspirin during the first 3 days of injury compared to only 2 on naproxen. He then suggested that a more fair comparison could be made if we were to treat another group of patients, at least 16 in number, with naproxen during the first 3 days following the injury. If we were willing to do this, he would reconsider our paper seriously. My goodness! How did he imagine we could include another 16 patients on only one of the drugs in a randomised double-blind trial? It cannot be done. We effectively buried the trial – although it wasn’t our intention – by publishing it in a fairly unknown journal that stopped coming out 5 years later.13

  I always wondered how it was possible to say that NSAIDs have anti-inflammatory effects, or whether it was only a marketing ploy. If a drug has an analgesic effect, it will lead to faster mobilisation, which would be expected to decrease the oedema. How could one then postulate that there was also a separate anti-inflammatory effect? NSAIDs had some effect in rats that had been treated in such a way that their paws were swollen and tender, but what did that prove? I often raised this issue with rheumatologists, but I never received a satisfactory answer.

  However, one day I was contacted by a group of orthopaedic surgeons who wanted to study the effect of naproxen in ankle distorsions. I grabbed the opportunity to study also the effect on the oedema, which we measured by immersing the foot in water and comparing its volume with that of the other foot. It was a highly interesting study. We randomised 173 patients twice: to crutches or no crutches (mobilisation), and to naproxen or placebo. This so-called factorial design is much underused despite its elegance, which is that it can provide answers to two questions without needing more patients than if only one question was asked. The results surprised us.14 The patients recovered faster when they were mobilised, which also decreased the oedema, whereas naproxen had no effect on the oedema. Our marketing-oriented bosses in Sweden interfered again with our research, and there were no numerical data on either of these outcomes in our published paper. However, I have kept the more comprehensive internal study report and the effect of mobilisation was dramatic. At the first follow-up visit after 2–4 days, 30 of 68 patients had recovered, compared to only 10 of 63 patients in the group using crutches, and the difference in volume between the two feet was only 28 mL when the patients were mobilised, compared to 71 mL when crutches were used.

  It was a beautiful study that had implications for practice. Years later, after a serious ankle distorsion, I stumbled along in great pain during a trip to London to attend the British Medical Journal’s (BMJ) advisory board meeting and I moved with immense difficulty. One of the other members of the board asked me why I didn’t use crutches and I replied that I had shown in a trial that patients recover faster if they don’t. Our trial inspired him to do a systematic review of bed rest for all diseases and he identified 39 trials (5777 patients) with 15 different conditions.15 He found that it is harmful to immobilise people in a bed; not a single outcome improved significantly whereas several outcomes worsened.

  We submitted our trial to Acta Orthopaedica, a humble Nordic journal, but its editors didn’t understand how important it was and rejected it. We had also tried the BMJ and my co-authors now just wanted to get the trial out. I couldn’t convince them that it was too important to publish in Danish, but that’s what happened after we had translated the paper. Years later, I was approached by a researcher working on a systematic review of treatment of soft tissue injuries, and he told me that our study was not only the largest but also the best, so he asked
me to translate our Danish paper into English!

  In 1990, I defended my doctoral thesis, Bias in Double-Blind Trials,16 which consisted of six papers. I had analysed 244 reports of trials in depth that had compared one NSAID with another. It was the first time a whole therapeutic area had been so thoroughly investigated and I uncovered an overwhelming amount of bias favouring the sponsoring company’s drug over the control drug. The trial reports were generally so unreliable that they should be seen not as scientific publications but as advertisements for the drugs.

  I had also assembled trials that compared an NSAID with placebo, which I used to study whether there is any anti-inflammatory effect with NSAIDs. In some trials, the researchers had used jeweller rings to measure if the drugs had an effect on swollen finger joints in patients with rheumatoid arthritis. They hadn’t.17 I therefore believe the idea of an anti-inflammatory effect of NSAIDs is a hoax, like so many other myths about drugs that the drug companies have invented and marketed.

  It is highly unfortunate that the drug companies define for us how we should think about drugs, as their manipulations are so massive. For example, it is common to talk about second-generation or even third-generation drugs, e.g. second-generation antipsychotics. This gives you the impression that they are better than old drugs, which is rarely what independent, publicly funded researchers find when they compare them in large randomised trials.

  Like Astra, Astra-Syntex also engaged in unethical marketing. The standard dose of naproxen was 500 mg daily, but the salespeople were asked to persuade the doctors to use 1000 mg, equipped with dose-response studies that had been written up by the company. I reviewed such studies as part of my thesis,18 and they were terribly flawed. In the naproxen studies, the patients received placebo and two or three different doses of naproxen in a crossover design where all patients tried each treatment in random order. The doses varied between 250 mg and 1500 mg daily. Many of the outcomes were not reported and with a British understatement I called the statistical methods ‘rather unusual’.18