Inside the World of Pharmaceutical Research - Dr Wilmshurst, consultant cardiologist

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Dr Wilmshurst, a consultant cardiologist, has spent the last two decades

trying to expose research misconduct and has reported more than twenty doctors

to the General Medical Council. In recognition of his dogged and selfless

pursuit of the truth, Dr Wilmshurst was presented with the HealthWatch Award

2003.

I feel greatly honoured to receive the Health Watch Annual Award and I am

grateful for the opportunity to speak to you about obstacles to honesty in

medical research.

I have been interested in this subject for 20 years, since I first experienced

research misconduct when I was a research registrar. I hope that a personal

account of my experiences may explain why I believe this is a serious problem.

In 1986 I went to the Guardian Newspaper with the story after the medical and

pharmaceutical regulators refused to take any action.[1] I supplied the

Guardian's lawyers with over 200 pages of documents and statements, which

convinced them that they could successfully defend any legal action if sued. We

were not.

My research was on heart failure. This is a common condition and it has a worse

5-year survival than many forms of cancer. Twenty years ago there were few

treatment options to improve symptoms and none was proven to improve survival. I

was offered the opportunity to do research on a promising new drug, named

amrinone. It was patented by Sterling-Winthrop. Preliminary research looked

promising. Research, mainly from the company, showed that the drug increased the

strength of contraction of the heart in animals. But the most influential

article and the one that persuaded me that the drug was worthy of research was

on patients and was published in the New England Journal of Medicine in 1978.[2]

The New England Journal is the most influential medical journal in the world.

The article came from the Cardiology Department at Harvard and one of its five

authors was the most well known cardiologist in the world and head of medicine

at Harvard, Professor Eugene Braunwald. The paper was given extra prominence by

being the first article in that issue of the Journal and it was accompanied by

an editorial.

In a large series of experiments we showed that, although amrinone increased the

strength of contraction of normal heart muscle, it did not affect contractility

in patients with heart failure. We also found that amrinone frequently caused

life threatening side effects.

With hindsight there were two things that should have raised my concerns when we

started our research. The first were anomalies in the study from Braunwald's

group. It was a small study, which made claims that were not substantiated by

the observations reported.

Later I discovered that though the article stated that the 5 authors were

employed in the Cardiology Department at Harvard Medical School, 2 were

full-time employees of Sterling-Winthrop and had never worked at Harvard.[3] Two

of the three that worked at Harvard were paid consultants to the company.[3]

These conflicts of interest were not declared.[3] In fact the New England

Journal of Medicine had no policy on declaration of conflicts of interest at the

time. The first statement on conflicts of interest was published in the New

England Journal one month after I wrote to the Massachusetts Medical Society,

which owns the Journal, complaining about the undeclared conflicts of interest

in this case.[3,4]

The second thing that should have alerted me was a letter published in the New

England Journal of Medicine from cardiologists in Los Angeles.[5] The letter

reported fatal side effects from amrinone. The first author, Dr Stanley Rubin,

had a patient with severe heart failure. The patient's wife was a stock-broker.

She saw the dramatic increase in the price of Sterling-Winthrop shares after the

paper from Braunwald's group was published. She reasoned that this proved that

amrinone was an important advance. She asked Dr Rubin to get amrinone for her

husband. Rubin was able to persuade the company to let him have amrinone on a

named-patient basis and the amrinone swiftly killed his patient. Rubin and

colleagues sent the New England Journal the first report of side effects with

amrinone. They did not tell Sterling-Winthrop that they had submitted the

report. Within 48 hours Rubin was under pressure by the company to retract the

report. The Journal admitted that it had sent Sterling-Winthrop a copy of

Rubin's report. The Journal initially refused to publish the report but was

forced to do so when Rubin said that if they did not he would go to the

press.[3,6,7]

However the conflicts of interest involving the New England Journal, the

Cardiologists at Harvard and Sterling-Winthrop did not end there. The company

later produced a congener of amrinone, named milrinone. The initial human

research on milrinone was also performed in Braunwald's department.[8] Unusually

it was agreed before the research had been completed that it would be published

in the New England Journal. When the first 2 referees chosen by the journal to

review the paper recommended rejection, the editor, Dr Arnold Relman sent the

article to 2 more referees. They also recommended rejection, but the Journal

published the paper on milrinone as previously agreed.[3,6,7] This says much

about peer review in the World's most prestigious medical journal.

I discovered this much later. In the early days of our research my colleagues

and I were more concerned that we could not confirm in our large number of

experiments claims made in the small study from Braunwald's department.

We reported to Sterling-Winthrop that we were unable to find evidence that

amrinone injections increased contractility in patients with heart failure and

we reported our experience of serious adverse effects with the oral preparation

of the drug. Company employees asked us to exclude some patients from the

analysis. These were ones where there was a downward trend in contractility. The

effect of excluding them would have been to produce an apparent but spurious

increase in contractility in the remainder. We refused. My supervisor and I were

then threatened with litigation.[1] We published.

Our on-going research studies on amrinone ended when company employees removed

the drug stocks from the pharmacy in the hospital and research institute.[1] As

a result, 2 of our publications contain statements pointing out that the studies

were smaller than planned because Sterling-Winthrop had prematurely discontinued

our trials without our agreement.[9,10]

A number of tactics were used to try to prevent my colleagues and I presenting

our findings at meetings and to discredit us when we did present.[1] One strange

incident involved one of my colleagues, Crowther, who was due to present

some of our work on amrinone on the second day of a meeting in Luxembourg. He

just managed to get on the last flight of the day that would permit him to

attend the first session of the meeting. When he arrived he discovered that his

talk had been rescheduled for the previous day. The organisers had received a

forged letter that appeared to be from him asking for his talk to be brought

forward a day. Those responsible were never identified.

When I presented our findings on side effects a company employee stood up and

said that I had made up the findings.[1] I had to point out that I was an

independent investigator, but that my accuser was a company employee. I had

nothing to gain by claiming that the drug was unsafe. I asked the chairman to

appoint people to review our data. A few days after the meeting I received an

apology from the company, but the hundreds who heard the allegations at the

meeting would not be aware of the company's retraction.[1]

At a number of other meetings at which I presented our findings, three eminent

professors of cardiology, each of who was a paid consultant to

Sterling-Winthrop, made public statements that they had tried to replicate our

findings and failed. None of them acknowledged their affiliation to the company.

Twenty years later none of those failures to replicate has been published. This

tactic came to an end at a European Congress of Cardiology, in front of several

hundred doctors. I pointed out that a professor who made these claims was a paid

consultant to the company and that he had been making the claims for two years.

I suggested that if he continued to make the claims without publishing his data

people might think that he was lying. My findings were not challenged again.

At one point, my supervisor and I were asked to meet with the company and a

different American professor of cardiology who is an opinion leader in the

treatment of heart failure and who was a consultant to the company. The American

professor told us that we were mistaken about the drug. He said that he was

aware of finding by other investigators and that these entirely refuted ours. He

advised us that we should not publish any more of our findings. He said that we

would be found to be wrong and our reputations would be adversely affected. We

went on to present 14 abstracts, and 15 publications.

One of the presentations was at the American Heart Association meeting in

November 1982. I presented data, which showed that amrinone did not have the

cardiac effects claimed. After my presentation, 3 professors of cardiology at

separate American university hospitals told me that they had also obtained

results similar to ours. They were unaware of each other's research or of our

research. They informed Sterling-Winthrop. The company arranged meetings between

each of them individually and the same professor of cardiology, who had told us

that our findings were aberrant. He also told each of them the same thing. He

persuaded two of them not to publish. The third did publish, after much soul

searching because he was afraid that he would lose research contracts with

Sterling-Winthrop and other pharmaceutical companies. After he published he

received threats, including a threatening phone call at 2am.

The Netherlands Committee for the Evaluation of Medicines spotted our paper on

the side effects of amrinone.[11] There were major discrepancies when compared

with the clinical record cards submitted by the company on our patients. We

showed that the company had sent the Netherlands Committee forged clinical

records for our patients with the information on adverse events deleted.

Because of this I contacted the UK Committee on Safety of Medicines and

discovered that Sterling-Winthrop had also failed to notify the CSM of side

effects in our patients.[1] During discussions 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

CTC for amrinone injection.[1] 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.

When I raised this with the company, the senior vice president bragged that they

were telling the government that if the company was prosecuted it would close

down its large manufacturing plant near Newcastle upon Tyne. The company was not

prosecuted for breaches of the Medicines Act.[1]

I tried unsuccessfully to get sanctions against the company or its employees,

but the Association of the British Pharmaceutical Industry, the Faculty of

Pharmaceutical Medicine of the Royal College of Physicians and the General

Medical Council were not interested.[1] I spoke to editors of medical journals,

including BMJ, Lancet and Nature. None disputed the facts but all were afraid to

take on a multinational pharmaceutical company with unlimited financial and

legal resources. One editor mentioned the loss of advertising revenue from the

company.

The process of being rejected by all the official bodies that I believe should

have dealt with the issues took nearly 5 years. While this was going on, in

1984, the company told a hearing of the Food and Drugs Administration in the USA

that there had been over 1400 serious adverse events in 1200 patients given

amrinone in 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.[1] In

those countries it was being sold as an over the counter treatment for heart

failure. I approached Oxfam, which had workers in the developing countries where

this was happening.[1] They collected evidence, which was presented at a meeting

of the World Health Association in Geneva. Sterling-Winthrop was finally

embarrassed into withdrawing the drug world wide in 1986.[1]

It was my contact at Oxfam who put me in touch with Erlichman, a Guardian

reporter. He and the deputy editor, Preston, were convinced by the

evidence I had and so were the Guardian's lawyers. The paper 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.[1]

I had seen how corporate greed and personal ambition had tended to distort

scientific evidence. Sterling-Winthrop believed that my supervisor and I could

be bribed or threatened into suppressing our data. Others, such a Drummond

Rennie, Deputy Editor of the Journal of the American Medical Association, have

documented this occurrence.[12] Some professors preferred to suppress their

findings rather than run the risk of losing prestige by appearing mistaken or

losing lucrative contracts for future pharmaceutical research. Financial

conflicts of interest caused some opinion leaders to behave dishonestly.

Conflicts of interest, affected publication decisions at the New England Journal

of Medicine. The institutions including government, which one might expect to

help preserve research integrity, were not prepared to take on a multinational

pharmaceutical company.

However these are not the only obstacles to honesty in medical research I have

come across.[13] In one case an eminent clinician, who was the president of his

specialist society, and who had a large private practice doing a particular

interventional procedure wished to publish a series of 400 cases. It was then

the largest series in the United Kingdom. When the data was analysed it was

found that his mortality rate for the procedure was unacceptably high compared

with rates in other countries. If this became known it would have a disastrous

impact on his private practice. So the mortality rate was falsified. However,

they had already published an abstract at an obscure meeting at which amongst

other things they reported the deaths in the first 254 patients. The number of

deaths reported in the abstract was greater than in the 400 reported in the

paper. This discrepancy became common knowledge in the specialty. I was present

during a meal at which a junior doctor that was a co-author of the paper

admitted that the falsification had occurred. He implied that he and other

junior doctors had little option but to go along with their boss. Five other

junior doctors heard the admission. I contacted the editor of the journal. It

was part owned by the specialist society of which the senior author of the paper

was the president. The editor knew of the rumours. He said that if I could get

one of those who heard the incriminating admission to confirm it, he would act.

I went back to those who had heard the admission. Now, years after those events,

some have provided me with written statements confirming that they heard the

admission, but at the time all said that they would not support my efforts to

get the paper retracted. Some said that it would be bad for their careers. Some

said that it would be bad for medicine or the specialty. One said that he

thought that it was the sort of thing that any of us would do. Those 5 junior

doctors went on to get consultant posts and one went on to be a president of the

society himself.

My efforts to get the paper retracted were common knowledge in the specialty...

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