Justice CommitteeWritten evidence submitted by Dr Peter Wilmshurst

I am a consultant cardiologist and my work has required me to implant medical device, including coronary artery stents, permanent pacemakers and implants to correct structural cardiac defects, such as atrial septal defects and patent foramen ovale (commonly known as “holes in the heart”). Once implanted, if one of those cardiac implants fails to function properly or if it causes complications, it is usually very difficult to remove the implant from a patient unless major and high-risk cardiac surgery is performed. Since 2004 I have been a Specialist Advisor to the Interventional Procedures Advisory Committee of the National Institute for Clinical Excellence (NICE) and a Clinical External Assessor for the Medicines and Healthcare products Regulatory Authority (MHRA). Both roles have involved me providing advice about appropriate use of medical implants.

I understand that a balance must be struck between making available for patients effective implants as soon as efficacy is proven and doing sufficient checks to ensure that unsafe implants are not marketed. I am concerned that the correct balance has not been struck. I am also concerned that there is inadequate post-marketing vigilance to ensure that late complications are detected.

I find it difficult to understand why the evidence used to support licensing a drug in Europe or the USA is made public when the evidence for licensing a medical implant is kept secret from doctors and patients in Europe, but is published in the USA. When deciding on which implant to use in a particular clinical setting for an individual patient, doctors should be guided by knowledge of the full information about the available implants. This information should be available from the licensing body and from objective scientific reports published in medical journals and presented at scientific conferences. In practice device selection is biased by the secrecy surrounding licensing applications, and by conflicts of interest leading to bias in publication of incomplete and false information about efficacy and safety. My concerns about this have been reinforced by my involvement in clinical trials of medical implants, in one case as the trial principal cardiologist, which made me realise that licensing and use of medical implants is more to do with marketing than science and that the existing regulations for licensing medical implants in Europe is seriously flaws.

I would add that because of my experiences I was asked to write the lead editorial with the title “the regulation of medical devices” for a special issue of the British Medical Journal about medical devices. I concluded that the regulation of medical devices is “unsatisfactory, unscientific and in need of a major overhaul”.1 I have been asked to speak about my concerns about the regulation of medical devices in the UK (for example at the Royal College of Surgeons) and internationally (eg European Society of Cardiology and Irish Cardiac Society).

I wish to provide examples based on an area of my expertise, namely closure of a particular type of hole in the heart, known as a patent foramen ovale (or PFO). I had a significant input into the current NICE guidelines on PFO closure, partly because of my role as a Specialist Advisor to NICE and partly because I was one of two doctors asked to provide advice on the subject to NICE on behalf of the British Cardiovascular Intervention Society.

Currently there are about 10 devices with CE Marks available for PFO closure. Many of the early reports of use of these implants came from the cardiologists who invented the implants, who unsurprisingly reported ease of use, efficacy and safety. In some cases the reports came from hospitals that owned the patents of the implants. Some published reports failed to disclose the financial conflicts of interest. To date there has been no “gold standard” randomised clinical trial showing benefit to patient groups from PFO closure. There have been only two randomised controlled trials of PFO closure with implants and each showed that outcomes in patients who had PFO closure was no different from those who were in the control groups. Therefore we should consider how it is that many thousands of patients in the UK have had PFO closure with these devices when efficacy is unproven.2

I was an investigator in two multicentre clinical trials in the UK that tested two PFO closure devices made by a US medical device corporation, NMT Medical. NMT has subsequently gone into liquidation and I believe that the events I describe were the result of NMT’s reliance on the results of the clinical research and eventually NMT’s need to present negative results in a favourable way.

I was the principal cardiologist in the Migraine Intervention with STARFlex© Technology (MIST) Trial, which randomised patients with migraine with aura and a large PFO to either PFO closure with NMT’s STARFlex© implant or a sham procedure. The STARFlex© implant consists of two joined discs, rather like a cuff link, with each disc being like an umbrella with radiating metal spokes supporting polyester fabric. The implant is positioned so that the discs sandwich the defect with the aim of sealing it. At the time of the MIST Trial, the STARFlex© implant already had a CE Mark for marketing in Europe “for closing atrial-level shunts” despite a relative lack of evidence of clinical benefit in patients. We hoped to demonstrate that a STARFlex© implant would seal a PFO and relieve migraine with aura. It had been anticipated that, based on previous observational reports, PFO closure would improve migraine.

I was also asked to be the core echocardiography laboratory in another NMT trial, the BEST Trial, that tested the efficacy of PFO closure with a modified implant called the BioSTAR©. The BioSTAR© had no CE Mark. It differed from the STARFlex© implant in that the polyester fabric was replaced with a porcine collagen membrane. Short duration experiments in sheep had demonstrated that once implanted the collagen membranes of the BioSTAR©, but obviously not the metal spokes, were replaced by the animals’ own cell to seal the defect. The purpose of the BEST Trial was to obtain evidence that the device would successfully seal a PFO in patients. The core echocardiography laboratory was essential because it would determine whether each PFO had been sealed successfully. There was no attempt to demonstrate clinical benefit from the BioSTAR© implant, although obviously it was hoped that patients would benefit. NMT hoped that the BioSTAR© would be granted a CE Mark.

In the MIST Trial we found that implantation of a STARFlex© implant did not lead to cessation of migraine more frequently than a sham procedure. In the implant arm three out of 74 patients were free of migraine during the analysis period compared with three out of 73 patients in the sham procedure (control) group.3 One possible explanation for the lack of clinical efficacy might be inadequate sealing of the cardiac defect by the STARFlex© implant as some of our observations suggested. I was keen for full disclosure of all the findings, but NMT objected to full reporting of those findings. As a result the final version of the paper omitted disputed findings about efficacy of PFO closure with NMT’s STARFlex© implant and also omitted mention of some potentially life-threatening complications experienced, such as the fact that in some patients the implants fell out of the PFO to lie free in the heart or to be carried by blood flow to a pulmonary artery. Those patients need additional procedures to remove the dislodged devices in order to prevent life-threatening complications. So the original version of the paper published in the most prestigious cardiology journal, Circulation did not provide readers with full information about efficacy or safety.

One other doctor on the trial steering committee and I refused to be authors of the paper because it contained statements which were false and misleading. In addition there was inadequate declaration of financial conflicts of interest, including the fact that a vice-president of NMT wrote part of the paper and that the first author of the paper, the principal headache specialist, owned NMT shares during the trial. At the start of the trial that doctor had declared to the West Midlands Multicentre Research Ethics Committee, which approved the trial, that no investigator owned NMT shares. After considerable efforts and 18 months delay after the original publication I managed to get Circulation to publish a new version of the paper with a correction of 700 words and a data supplement of 4 pages.4 , 5 , 6

In the meantime, NMT started three defamation claims against me in the UK; each time for both libel and slander. Two claims were because I expressed concerns about inaccuracies in data presentation at a cardiology meeting in the USA and my comments were published by an American on-line cardiology website. The other claim was after I spoke about the defamation claims on the Today Programme on BBC Radio 4. The US website, the website’s reporter and the BBC were not sued. The claims against me went on for nearly four years. NMT also asked their lawyers to bring claims against the other doctor on the steering committee who had refused to be an author of the paper and against my hospital. Those claims were not served. Other threats were made to try to prevent clinicians discussing any version of the trial results that NMT did not want disseminated.

While NMT was trying to silence me and other doctors, NMT’s website and annual reports contained misleading testimonials from the three patients who had a STARFlex© implant and who were migraine free during the analysis period.7 Their testimonials and the website suggested that the procedure had cured their migraine, but an equal small number of patients in the control group were also migraine free. NMT, as the sponsor, should not have been able to identify or contact the patients. Also of concern was the fact that the NHS website of the Royal Brompton Hospital in London carried similar information and a testimonial from one of the three patients suggesting that a STARFlex© implant could cure migraine. The web page was put up sometime in 2006 (presumably after the results of the trial were first presented in March 2006) and remained on the Royal Brompton Hospital’s website until 28 November 2010. The Royal Brompton Hospital removed it only after Dr Ben Goldacre asked the hospital to comment before he wrote about it in his “Bad Science” column in the Guardian newspaper.8

The Royal Brompton Hospital’s website were headed: “Heart trial offers relief for migraine suffers.” This is surprising because the MIST Trial showed that a STARFlex© implant did not help migraine. The web page included the following statements about the MIST Trial:

“Our researchers investigated the relationship between migraine headaches and holes in the heart. Their study indicates that as many as 40 percent of patients could have their migraine symptoms significantly relieved through intervention to close the holes in their hearts.”

“Dr Mullen said ‘This is significant news for migraine sufferers. For the first time this study has shown that closing a PFO can have a substantial effect in reducing the symptoms for patients with severe migraine’.”

“Zoe Willows, a patient involved in the trial, suffered migraines with acute aura for over 22 years. ‘My doctors just kept on prescribing different pills and medications but nothing ever worked’, she said. I’ve now been completely cured and can live my life as a normal person.”…. “I encourage other migraine sufferers like me to go to their GPs and insist they refer them to a specialist to test whether they too have a hole in their heart.”

Dr Mullen, who worked at the Royal Brompton Hospital as an NHS consultant, was a member of the MIST Trial steering committee. While on the steering committee and during the clinical trial he owned NMT shares and received payments from NMT for consultancy work and teaching. The Royal Brompton Hospital’s website also had a photograph of Zoe Willows. Beneath her testimonial on the Royal Brompton Hospital’s website was a statement saying “Read more about the study on the MIST website” with a link to NMT’s website.

So at a time when NMT were misrepresenting the results of the MIST Trial in the scientific literature and on the corporation’s website, they were also able to use an NHS website to misrepresent the results of this clinical trial and were using the English defamation laws and threats of libel action to silence those researchers who were concerned about the accuracy of their reports.

As stated above, my role in the BEST Trial was to be as the core laboratory for the echocardiography studies in the Trial to determine whether implanting a BioSTAR© implant successfully sealed a PFO in each patient. Once I started to question the efficacy of PFO closure with the STARFlex© implant in the MIST Trial I was dropped from my role in the BEST Trial. The BEST paper was also published in Circulation.9 Circulation sold reprints of the paper to NMT for distribution to cardiologists. Such reprint sales to industry by major journals may bring the largest journals as much as $500,000 for a single article. There is a suggestion that the income from reprint sales influences the conduct of those journals in allowing trials to be presented in the most “positive” manner, because sponsors will not buy reprints for distribution if the article says that their product is ineffective or unsafe.

In the BEST Trial only 57 patients had a BioSTAR implant. The trial reported high rates of successful PFO closure with the BioSTAR© implant, but the decision by NMT to drop me from acting as the core echocardiography laboratory and my experience in the MIST Trial raise questions in my mind about the accuracy of the reported rate. In the patients the follow-up was for only six months. On the basis of this slim evidence, the BioSTAR© implant was granted a CE Mark.

The award of a CE Mark in June 2007 was rapidly followed by comments by investigators on BBC television and in the press about the BioSTAR© implant. A public relations company employed by NMT arranged the interviews. The media were not informed that the two investigators put up to speak to them were conflicted because they also owned NMT shares. The published reports contained the quotation from one of them that “PFO appears to allow blod(sic) clots and other debris to clog up arteries in patients, which not only causes strokes but other problems. Using the bioabsorbable device is a radical rethink of a treatment option for migraine but it seems to have shown some very positive results. For a proportion of sufferers, this could end up as a cure for them.” This claim was unjustified because the BEST Trial had not investigated the effect of the BioSTAR© implant on migraine and in the MIST Trial PFO closure with the STARFlex© implant had not helped migraine.

Other published quotations, such as “this treatment (BioSTAR) does the repair job and then disappears in a natural way” suggested that the BioSTAR© implant entirely disappears once replaced by the patient’s own tissue. In fact only the collagen disappears, leaving behind a series of metal spokes inside the heart. There is of course nothing “natural” about having animal collagen implanted, as indicated by allergic reactions subsequently reported in patients given the implant. Furthermore, the evidence now suggests that, in distinction to what happens in sheep, in some patients the porcine collagen disappears without being replaced by the patient’s tissue. That results in return of the hole in the heart more than six months after implantation. So the follow up period in the BEST Trial had been too short. In fact, because the hole was then splinted open by the metal framework of the BioSTAR© implant, the amount of blood crossing the defect can be greater after the implant than before. In addition the metal spokes are no longer restrained by the collagen sheets that were present when the BioSTAR© was first implanted or by the polyester fabric in the STARFlex© implant. Relative to the number of implants there has been a high rate of cardiac perforations resulting from the metal spokes of the BioSTAR© implant moving and perforating the cardiac chambers compared with the rates seen with other devices used for PFO closure. These perforations occur later than the 6 months after implantation.

NMT went into liquidation in April 2011. Had they still been trading, NMT would probably have refused to reveal details of their device sales for commercial reasons, but the accountants who dissolved the company informed MHRA that 505 BioSTAR© implants had been sold in the UK. We do not know whether all 505 had been implanted but we do know that there were at least two cases of cardiac perforation requiring emergency cardiac surgery and many recurrent atrial-shunts in the UK. In Europe 1500 BioSTAR© implants were sold and there have been at least three cardiac perforations, one of which was fatal, and two others required emergency cardiac surgery. The true rates may be higher because there has been no vigilance of complications with the device. MHRA do not know all the centres in the UK that used the BioSTAR© implant or how many they used or what complications they experienced.

In the UK we have a registry of interventional cardiac procedures, but at present there is no record of the type, lot number or serial number of devices implanted. There is also very poor late reporting of complications with devices in the UK, because many complications that I have heard about do not seem to have been reported to MHRA. I have expressed my concerns to MHRA about the problems with BioSTAR© implant for two years because it seemed clear to me that the complications with this device are 50–100 times greater than with other PFO implants. I am unclear whether MHRA lacks the power or will to take effective action to investigate concerns or provide guidance to protect patients when there are concerns about medical implants.

I am concerned that my experiences with medical implants in my area of expertise are mirrored in other areas with ineffective and unsafe devices being CE Marked on the basis of inadequate evidence, poor science and misreporting as a result of conflicts of interest.

I believe that we need greater transparency and scrutiny of evidence used for approving medical implants. Commercial interests in confidentiality should not be allowed to take precedent over patient safety. Therefore the evidence used to obtain a CE Mark should be made public and the reasons why approval was granted should be stated. We should have a registry of all devices implanted, so that when problems are encountered the patients with that device or lot number of the device can be contacted if appropriate. We should require stricter vigilance.

June 2012

1 Wilmshurst P. The regulation of medical devices. British Medical Journal 2011;342:1093-4.

2 Wilmshurst P. CLOSURE 1 seen through the MIST. British Medical Journal 2012;344:51.

3 Dowson A, Mullen MJ, Peatfield R, Muir K, Khan AA, Wells C, Lipscombe SL, Rees T, De Giovanni JV, Morrison WL, Hildick-Smith D, Elrington G, Hillis WS, Malik IS, Rickards A. 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 http://circ.ahajournals.org/cgi/content/full/circulationaha;120/9/e71

5 http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.727271/DC1

6 http://circ.ahajournals.org/cgi/content/full/117/11/1397

7 http://www.badscience.net/2010/12/nmt-are-suing-dr-wilmshurst-so-how-trustworthy-are-they/

8 http://www.badscience.net/2010/12/nmt-are-suing-dr-wilmshurst-so-how-trustworthy-are-they/

9 Mullen MJ, Hildick-Smith D, De Giovanni JV, Duke Christopher, Hillis WS, Morrison L. BioSTAR Evaluation Study (BEST). A prospective, multicenter, phase 1 clinical trial to evaluate the feasibility, efficacy, and safety of the BioSTAR Bioabsorbable Septal Repair Implant for the closure of atrial-level shunts. Circulation 2006;114:1962-7.

Prepared 30th October 2012