Shortcomings in heart failure drug trial open “can of worms”BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2218 (Published 08 May 2017) Cite this as: BMJ 2017;357:j2218
All rapid responses
Large multicentre trials are considered to be the gold standard for determining the relative benefits of treatments, but I believe that the sums of money for each patient entered into trials call their value into question.
The finding of considerable national variations in the numbers of trial subjects who had no drug metabolite in their blood in the TOPCAT Trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) raised questions about the integrity of the conduct of the trial in Russia. The trial’s principal investigator has questioned whether some patients randomised in Russia and Georgia actually had the disease under investigation.
This is not the first time that large international trials have shown potential evidence of research fraud, even at national levels. In the POISE Trial, 947 patients from Iran and Columbia, 10.2% of all patients in the trial, were excluded from the analysis “because fraudulent activity had taken place”.
The contract research organisation, New England Research Institutes (NERI), employed to organise the TOPCAT Trial was criticised in the article by Hawkes, although it responded that it was appropriately neutral, and the trial was rigorously conducted according to best practices. I have experienced some of the problems that can arise when contract research organisations are involved in clinical trials.
I was the principal cardiologist in the MIST Trial (Migraine Intervention with STARFlex Technology). Dr Andrew Dowson was the Chief Investigator. He was appointed to that role though the trial sponsor, NMT Medical, knew that three months earlier Dowson had been removed from a similar role in an unrelated trial and he had been reported to the General Medical Council (GMC) for falsifying research. He entered false clinical examination findings on clinical record forms for patients that had not attended and signed to confirm that the findings were true. Two years later, while the MIST Trial was in progress, the GMC found Dowson guilty of misconduct, but even then Dowson and NMT did not inform me.
NMT was a Boston company set up to manufacture and market the STARFlex device under licence from the patent owner - the Harvard University affiliated Boston Children’s Hospital.
Another member of the MIST Trial steering committee, Dr Simon Nightingale, and I expressed concerns to the West Midlands Multicentre Research Ethics Committee (WMMREC), which had approved the trial, that NMT Medical was attempting to influence the reporting of the trial data. The WMMREC suspended ethics approval and hence prevented submission of the paper to a journal, until they had seen and approved a version to be submitted. On 7th September 2007, Mr Nigel Trim, the Chief Executive of Matrix Contract Research, sent WMMREC a version of the paper with a covering letter. On the basis of that WMMREC restored ethics approval and permitted submission of the paper.
Dr Nightingale and I refused to be authors, because the paper contained false and incomplete data. The paper was submitted to Circulation and published without our names. I spent much effort in persuading the editor of Circulation, Dr Loscalzo (a Harvard cardiology professor whose department was receiving funding from NMT at the time) that the MIST paper was false and incomplete. In 2015 another Fitness to Practise Panel found Dowson guilty of misconduct in the MIST Trial including two counts of dishonesty. The findings of dishonesty were upheld in the High Court when Dowson appealed and he was suspended from the Medical Register.
Fitness to Practise Panels avoid commenting on the actions of non-doctors, but in the determination in Dowson’s case they commented on Mr Trim’s letter to WMMREC. They said:
“The panel considered that WMMREC’s decisions (to restore ethics approval and permit publication) will have been coloured by the arguments contained in Mr Trimm’s (sic) letter to them of 7th September 2007. In the panel’s view that letter contained a number of distortions, errors and omissions including the suggestion (i) that Dr Wilmshurst’s review (of the contrast echocardiograms) was done at his own request rather than as a result of a request from NMT and (ii) that the live assessments of the echocardiograms were ‘gold standard’. The letter did not report that the assessments were done by interventional cardiologists reviewing their own work and after minimal training in the required assessments; that the results had been inconsistent between sites; and that the reviews had been requested precisely because of concerns about the reliability of the per protocol measures. It is not clear that WMMREC would have taken the same view if these matters had been presented accurately and fairly.”
NMT sued me for libel, but the actions ended after four years when the corporation went into liquidation. NMT also instructed their lawyers to sue Dr Nightingale, but they did not serve that claim. In another multicentre trial NMT employed a co-principal investigator who had been warned by the US Food and Drug Administration that he might face criminal prosecution for misconduct in research.
It is difficult to know what reported findings one can trust when much medical research is performed by people and organisations that appear to care more about generating income than obtaining accurate results.
1. Hawkes N. International heart drug trial opens “can of worms”. BMJ 2017;357:j2218.
2. POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE Trial): a randomised controlled trial. Lancet 2008;371:1839-47.
3. Dowson A, Mullen M J, Peatfield R, et al. Migraine intervention with STARFlex Technology (MIST) Trial: A prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008;117:1397-1404.
4. Determination of the Fitness to Practise Panel of GMC in case of Dr Andrew Dowson, March 2006.
5. Determination of the Fitness to Practise Panel of GMC in case of Dr Andrew Dowson, February 2015.
6.  EWHC 3379 (Admin): Mr Justice Edis between Andrew John Dowson and the General Medical Council.
Competing interests: My conflicts are disclosed in my response.