The response of the ABPI to misconduct by pharmaceutical companies

Bayer and Adalat

On 11th September 1986, James Erlichman reported in the Guardian newspaper that Bayer UK Pharmaceutical Co bribed doctors with money, colour televisions and trips to the USA in return for them prescribing its drug Adalat Retard (nifedipine) for patients in “bogus” research. The more patients a doctor started on Adalat the greater their reward. A company employee revealed that doctors were asked to collect data on the patients they recruited for so-called “research”, but no scientific analysis of data collected was performed. Even by the standard of the pharmaceutical industry, the bribery was so blatant that its UK trade body, the Association of the British Pharmaceutical Industry (ABPI), suspended Bayer UK from membership on 17th December 1986. The ABPI recognised that Bayer had been conducting “bad marketing practices” which they had tried to disguise as genuine research. It later became known that in 1985 the ABPI had been informed that Bayer had been engaged in unethical marketing practises but the ABPI took no action until James Erlichman exposed it. Bayer UK showed its contempt for the ABPI’s sanction by immediately changing its name to Bayer UK Ethical Pharmaceutical Co.

Financial inducements to doctors from pharmaceutical companies were then so common that they were regarded as the norm. They continue today, but doctors and pharma are more careful about concealing them.

Bogus research that pharmaceutical companies called post market surveillance was very common. Doctors were paid to start patients on a company’s drug and follow the patients up for a set period of time. The follow up might involve making measurements (such as blood pressure) at set intervals. If it were genuine research it would have ethics committee approval, patients would be required to consent to being subjects in the research, the results would be published in medical journals and the pharmaceutical company would provide the medication used. None of those applied. The drugs were supplied on NHS prescriptions completed by the doctors who received payments from the company according to how many patients they enrolled. As a result, the NHS funded the “research” by paying the pharmaceutical company for the drugs prescribed and the kick-backs to doctors came from the company’s profits from the drug sales to the NHS.

For a pharmaceutical company, so-called post market surveillance had three purposes: 1) to get patients, particularly those who needed long term treatments for chronic illnesses, switched to their drug; 2) to get doctors accustomed to prescribing the company’s drug; and 3) to instil a sense of indebtedness in doctors.

Sterling-Winthrop and Amrinone

Shortly after the Guardian published James Erlichman’s article in September 1986, an employee of Oxfam suggested that I speak to him about my experiences of illegal and unethical conduct by another pharmaceutical company.

Five years earlier I had started a research fellowship in cardiology at St Thomas’ Hospital in London conducting research on Amrinone. Amrinone was made by Sterling-Winthrop, which was subsequently taken over by Sanofi-Aventis. It was hoped that Amrinone would be beneficial for the treatment of heart failure. At the time, there were few effective drugs for heart failure treatment. We informed Sterling-Winthrop that we were unable to find evidence that Amrinone injections increased cardiac contractility in patients with heart failure and we reported our experience of serious side effects with the oral preparation of the drug.

It is important to understand that everybody has small changes in biological parameters such as blood pressure, heart rate and cardiac contractility from minute to minute. Therefore in order to determine whether a drug alters contractility it is necessary to perform statistical analyses to see whether the drug produces consistent effects in groups of patients. When there is no statistically significant effect some patients will show slight increases in a parameter measured purely as a result of normal biological variation while others show slight decreases, but in the group overall increases and decreases cancel each other out. In addition, proof of a true pharmacological effect requires demonstration of a dose-response effect, so that larger doses have greater effects than smaller doses over the therapeutic range. Amrinone did not increase contractility of the heart and there was no dose-response effect.

Senior company employees met us the week after we had sent them details of our findings. They initially asked us to exclude some patients from the analysis. They were the patients in whom there was a downward trend in contractility after they were given the drug. The effect of excluding them would have been to entirely alter the statistical analysis by producing an apparent but spurious increase in contractility in the remainder. My supervisor, Dr Michael Webb-Peploe and I refused because that would be research fraud. We were then offered money if we did not publish any of our findings. I would have received the equivalent of two year’s salary. The company representatives could not conceal their surprise when we refused their money. Next they threatened us with litigation. When we did not back down, they asked whether we would be willing to speak to an American professor of cardiology about our findings before publishing. We agreed to hold off publication until they had brought him to speak to us.

He was an opinion leader in the treatment of heart failure and a consultant to Sterling-Winthrop. He assured us that we alone were getting the results we had reported. He said that if we published, other cardiologists would think that we could not do the research properly and our department would be discredited. That troubled my boss more than me – he had spent years building up a reputation for research. Nevertheless we went ahead and published. As soon as we did, I was contacted by professors of cardiology at three different universities in the USA. They each said that they had got results similar to us and when they told Sterling-Winthrop, the company had brought the same professor of cardiology to see them. He told them exactly what he told us. He said that they alone were getting those results and if they published their departments they would be discredited. As a result they did not publish.

One of my colleagues, Alex Crowther and I were each scheduled to give presentations on our research on Amrinone at a meeting in Luxembourg. We had informed Sterling-Winthrop of the presentations because it was a condition of our agreement that we inform the company of presentations and publications. We had also informed Sterling-Winthrop of our travel arrangements. We were due to fly from London on the evening before the conference. Alex’s presentation was scheduled for the second day but mine was on the first day. When we arrived at Heathrow airport, we discovered that Alex was no longer booked on the flight. He suggested that he would come out the next day, but I was keen to have his support when I presented on the first day. We managed to get him onto the flight. It was a well that we did. When we arrived at the conference on the first day, we discovered that Alex’s talk had been brought forward from the second day. The organisers had received a forged letter purporting to be from Alex asking for his talk to be brought forward to the first day. If he had missed the flight the night before the conference, he would have missed his presentation. As it was, after I presented a Sterling-Winthrop employee accused me of fabricating my results. I pointed out that I was an independent investigator with no reason to fabricate negative data, whereas the accuser was a company employee. I asked the chairman to appoint two people to check the veracity of our data. Days later I received an apology from Sterling-Winthrop, but the hundreds of doctors who heard the Sterling-Winthrop employee accuse me of presenting false data remained unaware of Sterling-Winthrop’s apology.

Subsequently Sterling-Winthrop used various tricks to try to discredit our finding. Often when I presented our findings at medical meetings, a professor of cardiology that I knew was a consultant to Sterling-Winthrop would claim that he had tried to replicate our findings and failed. After that had happened repeatedly over two years, I responded at a meeting by saying that he had been claiming that he had failed to replicate our findings for two years but he had not published his findings. I suggested that as a result of his failure to publish his claims, some people might wonder whether he had been lying all the time. He never challenged me again. Forty years later, he has still not published his failure to replicate.

In 1983, after we published a paper on the side effects of Amrinone, I was contacted by Dr Leo Offerhaus of the Netherlands Committee for the Evaluation of Medicines.1 They had spotted that there were major discrepancies between the side effects reported in our paper and the clinical record cards submitted by the company on our patients. I had copies of my clinical record forms and was able to prove that the company had sent the Netherlands Committee forged clinical records for our patients with the information on side events deleted. Dr Offerhaus ensured that Sterling-Winthrop’s application for a product licence for Amrinone was rejected by most European countries. Dr Offerhaus later told me that for his efforts in protecting patients and ensuring that a crime was exposed, he suffered detriment in his work.

When I realised that Sterling-Winthrop had submitted false documents in the Netherlands, I notified the UK Committee on Safety of Medicines (CSM) and discovered that Sterling-Winthrop had also failed to notify the CSM of the side effects experienced by our patients. During discussions with the CSM, I discovered that contrary to statements made to us at the outset of our research, Sterling-Winthrop had not obtained a Clinical Trials Certificate for oral Amrinone, though they had got a Clinical Trials Certificate for Amrinone injection. This meant that the research with oral Amrinone conducted by us as well as by doctors in the National Heart Hospital in London, in Newcastle-upon-Tyne and in Birmingham had been illegal.

I assumed that Sterling-Winthrop would be prosecuted for breaches of UK laws, including breaking the Medicines Act 1968. Dr Monroe Trout, the senior vice president of Sterling-Winthrop, told us that they were telling the UK Department of Health that if the company was prosecuted it would close down drug manufacturing in the UK. It had a large factory in the North East of England. The company was not prosecuted.

I tried unsuccessfully to get sanctions against the company and its employees. The ABPI and the Faculty of Pharmaceutical Medicine of the Royal College of Physicians refused to take any action. The General Medical Council refused to take action against the doctors employed by Sterling-Winthrop who had lied to us about the drug’s approval, had offered us bribes and had made threats in order to get us to conceal the fact that the drug was ineffective and dangerous.

I spoke to editors of major journals, including BMJ, Lancet and Nature. I was taken to lunch by two BMJ editors and by John Maddox of Nature. None disputed the facts but all were afraid to take on a multinational pharmaceutical company with enormous financial and legal resources. One editor mentioned the possibility of loss of advertising revenue from the company. (In fairness to Dr Ian Munro of the Lancet, I should say that over afternoon tea he told me that he had cancer and thought it unfair to start a legal case that his successor would have to fight.)

The process of being rejected by all the official bodies that I believed should have dealt with the issues took nearly 5 years. While this was going on, in 1984, Sterling-Winthrop told a hearing of the Food and Drugs Administration in the USA that there had been over 1400 life-threatening adverse events in 1200 patients given Amrinone in clinical trials and the company announced that they would cease trials and applications for product licences worldwide. Officially the drug was unsafe to take even on a doctor’s prescription. Two years later, in 1986, I discovered that the company was still marketing Amrinone in parts of Africa and Asia. In those countries it was being sold as an over the counter treatment for heart failure without the requirement for a doctor’s prescription. I approached Oxfam, which had workers in the developing countries where this was happening. They collected evidence of proof of purchase, which was presented at a meeting of the World Health Organisation in Geneva. Sterling-Winthrop was finally embarrassed into withdrawing Amrinone worldwide in 1986.

It was a contact at Oxfam who put me in touch with James Erlichman at the Guardian. He and the Guardian’s editor, Peter Preston, were convinced by the evidence I provided and so were the Guardian’s lawyers. They said that the evidence was so good that defending a legal claim would be easy. Supporting statements came from my research supervisor, Dr Michael Webb-Peploe, and another consultant cardiologist at St Thomas, Dr Stephen Jenkins. (By the time that I went to James Erlichman, Jenkins had become the Lambeth Health Authority District General Manager.) The Guardian covered the story on the front, back and the whole of an inside page of one issue and in follow-up stories in other issues of the Guardian in November 1986. Sterling-Winthrop did not take any legal action.

The response by the Association of the British Pharmaceutical Industry

The two articles by James Erlichman that were published in the Guardian in a few months in 1986 caused people to question the practises of pharmaceutical companies. The response of the ABPI was not to correct the ethical practises of its members. Instead the ABPI decided that they would demonstrate that they took research misconduct seriously by reporting to the General Medical Council (GMC) doctors who fabricated the clinical records of patients that they were paid for enrolling in industry-sponsored “research”.

Dr Frank Wells was the medical director of the ABPI from 1986 to 1996. In 1996, he described that since 1988 the ABPI had reported to the GMC 14 doctors, who were found guilty of serious professional misconduct: seven were erased from the medical register (i.e. barred from medical practice), five were suspended from the medical register for between six and 12 months, and two were admonished.2

I have found information on the seven who were erased from the medical register but on only two of the other seven. The names of the seven erased (followed in brackets by the place they obtained their medical qualifications, if I have found it, and the year that they appeared before the GMC) were Uzair Siddiqui (University of Sind, 1988), Lakshmi Pandit (Punjabi University, 1991), Ramnikgiri Gonsai (Gujarat University, 1991), David Latta (Glasgow University, 1991), Chatru Chandnani (1994), Christopher Vishin (1994) and Paul Chaiyavat Daengsvang (1994). Dr Wells did not mention that the Privy Council (which was then the appeal court for the GMC) restored Gonsai and Daengsvang to the medical register. It overturned the findings on Daengsvang and reduced the sanction on Dr Gonsai to a ban from conducting research for 3 years. I found that subsequently Siddiqui, Pandit and Latta also returned to the medical register because they were recorded as practising in the UK in 2005 when the medical register went online.

I have also found that Kollannur Francis (Kerala University, 1990) was suspended for six months and Sheo Kumar (1990) was admonished.

Dr Siddiqui was a consultant psychiatrist and the other eight doctors that I have information about were general practitioners.

In my experience, genuine research misconduct is much more frequent in universities and in teaching hospitals than in general practice. That may be because a minority of medical research occurs in general practice. Amongst the doctors reported by the ABPI, the proportion who were not white and the proportion who trained in the South Asia were unusually high and not typical of my experience.

During the 1980s and 1990s, I reported a number of doctors to the GMC, but until 1998 the GMC repeatedly refused to take action against any of them. In 1998, I reported Dr Anjan Kumar Banerjee. He was the first doctor that I reported to the GMC that was not white and he was the first that the GMC agreed to investigate. In 2000, Banerjee was suspended from the medical register for one year and, after I reported him a second time, he was erased from the medical register in 2002. I have absolutely no doubt that Banerjee deserved the sanctions imposed on him, because he was a dishonest doctor who harmed patients.

I have reported more than 25 doctors to the GMC. Other than Banerjee, all were white. In my opinion, some doctors that I reported and who the GMC refused to investigate were a greater risk to patients than Banerjee.

Dr Wells also wrote that the contracting pharmaceutical company made the final decision whether the ABPI should report a doctor to the GMC. One of the investigators used by the ABPI told me that if there was evidence of research fraud by a senior doctor who was an opinion leader that the company used for promoting its drug, the investigators were in some cases told to drop their investigations. This may be part of the reason why hospital doctors and white doctors are a low proportion of those reported by the ABPI to the GMC.

There are more recent examples of pharmaceutical companies failing to report doctors who falsified research. For example, Dr Andrew Dowson (who is white and works in King’s College Hospital, London, which is a large hospital affiliated to a medical school) was chief investigator and site principal investigator for a multi-centre clinical trial of botulinum toxin injections for treatment of migraine sponsored by Allergan Pharmaceutical Co. In 2004, Dowson was discovered to have entered false clinical observations (such as blood pressure) in the clinical records forms of patients that he had not seen. He signed to certify that they were a true record. Allergan allowed Dowson to continue in the trial and did not report him to the GMC, but the Northern and Yorkshire Multicentre Research Ethics Committee, which gave ethical approval, learned of Dowson’s misconduct and removed him from the trial and reported him to the GMC, which sanctioned him in 2006. Despite being sanctioned for research misconduct, Dowson continued to work as the director of headache services at King’s College Hospital. In 2015, another GMC hearing found Dowson guilty of multiple counts of misconduct including dishonesty in an unrelated clinical trial sponsored by NMT medical. NMT did not report Dowson to the GMC – I did. The GMC suspended Dowson from the medical register, but after his period of suspension he returned to his job at King’s College Hospital. Despite the GMC twice finding Dowson guilty of misconduct in migraine research, he remained on the medical advisory board of a migraine charity even during his period of suspension from the medical register. I phoned the charity because I presumed that they were unaware of the GMC findings and was verbally abused by a member of the charity’s executive. I asked the GMC if they were concerned that Dowson was on the medical advisory board of a migraine charity when suspended from the medical register and I was told that the GMC had no concerns.

Over the years, I have learnt that there is clear racial bias in dealing with dishonest doctors. Non-white doctors receive severe punishments, while senior white doctors who commit egregious misconduct often get away without a sanction.

James Erlichman

James Erlichman’s Guardian article “A Cow Disease to Beef About” on 11th July 1988 was the first article in Britain to expose government incompetence and culpability in the Bovine Spongiform Encephalopathy (BSE) scandal.3 He traced people with the human variant of the disease, CJD. His coverage was a turning point in attitudes to the BSE crisis and the public’s trust in mass production of food.

Erlichman also gave a witness statement for the McLibel trial. In that case, McDonald’s sued Dave Morris (a postman) and Helen Steel (a gardener) for allegations in a leaflet that they and other members of London Greenpeace distributed outside a branch of McDonald’s in London. One of the allegations in the leaflet was that McDonald’s food is unhealthy. Erlichman’s statement said that McDonald’s had admitted to him that contrary to claims that they used only prime beef in their burgers, McDonald’s used meat from elderly dairy cows that were being killed because they no longer produced enough milk.

The leaflet that resulted in the libel claim from McDonald’s was partly written by an undercover Metropolitan policeman who had infiltrated London Greenpeace. He became the sexual partner of Steel for two years until he suddenly disappeared. Steel was concerned for his safety and when trying to trace him she discovered that he had assumed the name of a dead child. She eventually found and confronted him 24 years after he disappeared. McDonald’s did not sue the Metropolitan Police for its role in producing the leaflet.

The McLibel case was Britain’s longest running trial. It lasted seven years with another three years of appeals. McDonald’s was represented by Richard Rampton QC and Timothy Atkinson. When NMT Medical sued me for libel and slander for concerns I expressed about the MIST trial, NMT also instructed Rampton and Atkinson, but NMT’s case collapsed after just under four years when NMT went into liquidation.

It was during my libel case that I last met James Erlichman over lunch. He had contacted me to ask whether he could help with the libel case.

James died on 6th December 2018.

References

  1. Wilmshurst PT, Webb-Peploe MM. Side effects of amrinone therapy. Br Heart J 1983;49:447-451.
  2. Wells F. The British pharmaceutical industry’s response. In Fraud and misconduct in medical research. Second edition. Eds Lock S, Wells F. BMJ Publishing Group, London. 1996, pp 90-113.
  3. Choi C. James Erlichman obituary. The Guardian. 11 December 2018. https://www.theguardian.com/media/2018/dec/11/james-erlichman-obituary

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