More news of NMT Medical MIST Trial - false declarations

More news on the scientific jiggery pokery that took place in the MIST trial paid for by NMT Medical, and some emerging news on the usual attempts at cover-up in this case. Authors denied data, colluding journals, and collusion of the UK regulator (the MHRA) with scientific misconduct. More of the same old story and Déjà vu all over again.

The only chink of light - that there are still great journalists (like Shelley Wood) doing the job that the mainstream medical journals, regulators and leadership of medicine are manifestly failing to do. Well done Shelley.

The Heartwire article of yesterday is reproduced intact below. For my collated postings on this scandal click here

MIST correction published; no new information on disputed echo review for PFO/migraine trial
Sep 9, 2009
Shelley Wood
Heartwire

Dallas, TX - Authors of the controversial Migraine Intervention with STARflex Technology (MIST) trial paper [1] in Circulation have now published a lengthy correction [2] to the manuscript that originally appeared online in March 2008. As previously reported by heartwire, journal editors requested a correction from the authors after questions were raised—most notably by one of the original investigators for MIST—about details purportedly missing from the publication.

The correction by Dr Andrew Dowson (Kings College Hospital, London, UK) and colleagues appeared online Monday August 31, 2009, and the online version of the article has been updated to reflect the changes.

MIST was the first randomized, sham-controlled trial to investigate patent foramen ovale (PFO) closure as a treatment for migraine; the study failed to show a benefit of PFO closure. Garnering even more attention than the study results, however, have been questions from physicians both within and outside of the study about the design and conduct of the study and the airing of its results. The study sponsor, NMT Medical, is currently suing one of the original co-PIs for MIST, Dr Peter Wilmshurst (Royal Shrewsbury Hospital, UK), for concerns he raised to heartwire about how MIST data were being managed.

The disputed echo reviews

Wilmshurst, along with his Shrewsbury Hospital colleague Dr Simon Nightingale, refused to sign off on the manuscript before it was submitted for publication and are not included as authors. Following the publication of MIST in Circulation, Wilmshurst contacted the journal about his concerns.

Conspicuously absent from the correction is information about an "off-protocol" review of the echocardiographic information that suggested a higher residual shunting rate following PFO closure than that reported by Dowson at the TCT 2007 meeting. Dowson reported a 94% closure rate—derived, as per trial protocol, from the follow-up conducted by the implanting cardiologist. Wilmshurst, however, says he conducted an after-the-fact review of echocardiograms, at NMT's behest, which suggested residual shunting in approximately one-third of patients. A residual shunt can point to either incomplete device closure of the PFO or to the presence of pulmonary shunts not properly identified at baseline.

Both Dowson and NMT originally denied to heartwire that this echo review had ever taken place (repeatedly insisting that it was not part of the trial protocol) and rejected Wilmshurst's suggestion that NMT had asked investigators to send their echos to him to review. Another trial investigator, however, Dr Michael Mullen (Royal Brompton Hospital, London, UK), subsequently confirmed to heartwire that a review had indeed been undertaken but insisted the information did not belong in the MIST paper.

Asked by heartwire why information about the disputed echo review is not mentioned in the correction, Circulation issued a statement saying, "The Circulation editors were unaware of this controversy during the review of the paper; however, they investigated the matter at the same time that they investigated Dr Wilmshurst's other claims, and they decided that this information did not belong in the paper."

Also contacted by heartwire, Wilmshurst responded with a written statement:

"The correction of the MIST paper states that I did not sign the Copyright Transfer Agreement because of an internal disagreement about the conduct of study. In an email to Dr Dowson in October 2007, I gave two reasons for refusing to sign the Copyright Transfer Agreement. First, that the paper contained errors, which are confirmed by this correction. Second, that I could not in conscience sign the declaration, [which reads] 'The authors had full access to the data and take responsibility for its integrity.' To sign a declaration knowing it to be false would make me guilty of a criminal offence in the United Kingdom. In November 2007, NMT's lawyer wrote to me: 'No investigator is given a full detailed set of all the data.' For 18 months I pressed Circulation for a correction. I sent the editor hundreds of pages of documents, including a copy of my email to Dr Dowson. All of the errors and omissions in the correction are ones that I reported to Circulation, but not all errors and omissions that I reported have been corrected. In addition, the contributions of some who did little in the study, including an 'author' who died in May 2004, before the trial started, are credited, but the contributions of Dr Nightingale and I, who helped design the trial, were members of the steering committee, wrote the early draft of the paper, and did over 600 of the 2000 patient visits in the trial, are not acknowledged."

NMT chief financial officer Richard Davis, also commenting on the correction for heartwire, emphasized that the "clarifications were made on request of the editors of the journal.

"The correction that appears in the journal Circulation includes a single error in the reference to a histogram contained in the original manuscript. No changes to the results, analysis, or conclusions of the study are made. The remainder of the published correction contains clarifications, many of which were not included in the original manuscript due to the word-count limitations.

"To comply with these word-count requirements, the manuscript focused specifically on the critical elements of the trial design and results. All serious adverse events were listed; other information was excluded that was deemed irrelevant to the findings regarding the effect of PFO closure on migraine. One procedural embolization in a cohort of 74 patients is not uncommon for these types of devices, and retrieval of a device due to poor positioning followed by replacement with a second device, as happened in two cases, is also not unusual. It is important to note that these procedural difficulties were not considered serious by the investigator or the safety committee of the study."

Clearing the MIST

The correction runs over 700 words long, with a four-page data supplement, and addresses what Dowson and colleagues term "a number of errors and omissions," including:

• An explanation of why Wilmshurst and Nightingale were not listed as authors.
• An expanded description of how intracardiac shunts were assessed.
• Clarification on specific adverse events related to failure to find or cross a PFO, two cases of device embolization, and one nondeployment.
• New information on patients who withdrew from the study and why.
• A correction to the units used for number of migraine days per month for Figure 3.
• Reiteration of the reasons for excluding two patients from an analysis looking at median total migraine days and the calculations used.
• Clarification that the authors' conflicts of interest information provided in the article was accurate.

To this last point, the correction states: "The authors confirm that they disclosed all relevant relationships and potential conflicts of interest that were present during the two years leading up to manuscript submission, as required by the American Heart Association." The Circulation manuscript itself notes that two study authors—Mullen and Dr David Hildick-Smith (Brighton and Sussex University Hospitals NHS Trust, UK) have ownership interests in NMT Medical and that Mullen has received teaching honoraria and has acted as a consultant to NMT, but that the remaining authors report no disclosures.

Of note, at the time of Dowson's October 2007 TCT presentation, he disclosed that he had received grant/research support from NMT, and Davis estimated in an interview with heartwire shortly after Dowson's presentation that up to 10 study investigators and/or steering committee members had received consulting fees from the company. Wilmshurst once told heartwire that he and Nightingale had turned down offers for "large" consultancy payments from NMT.

1. Dowson A, Mullen MJ, 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.
2. Correction for Dowson et al. Circulation 2009; DOI: DOI: 10.1161/CIRCULATIONAHA.109.192626. Available at: http://circ.ahajournals.org.

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NMT Medical - the MIST trial starts to unwind

I have posted previously (here and here) about this ethical and scientific scandal. The saga involves a medical device, and the conduct and conclusions of the Migraine Intervention with STARflex Technology (MIST) I trial. Peter Wilmshurst and another "author" of this study alleged scientific misconduct, hiding of data from authors and legal bullying by the sponsor, NMT Medical. They refused to sign the manuscript, made their views public, and were sued.

Now the remaining authors have been forced to submit an extensive manuscript "correction" which addresses a few of the many problems raised. Amongst other things there is an admission that "side effects" of the device were misrepresented. Devices embolized inside the heart and to the left pulmonary artery. A device that embolised into the pulmonary artery was reported to be in "an unsatisfactory position" and was not mentioned at all in the paper (or apparently to the Ethics Committee). The stated "authors" declare that they "regret" the "errors".

The Journal (Circulation) did not question the changing authorship on the four versions of the paper that they received. The Editor in Chief of Circulation (Dr Loscalzo) earlier wrote to say that "We now consider the matter closed". The UK regulator, the Medicines and Healthcare Regulatory Authority (MHRA) previously stated that it had "reviewed the "available evidence" and has found nothing to suggest that there is a problem". Since the ejected authors and presumably the regulators had no relevant evidence at all, the MHRA response and their definition of "a problem" appears predictably odd to say the least.

The text of the statement of "correction" is here.

I don't think that this is going to be last word on this sorry matter.

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NMT Medical closes migraine trial in U.S. - a case to watch

This news-snippet rings a few alarm bells. I have posted about some apparently dodgy dealings in a clinical trial involving Boston-based NMT Medical, the MIST I trial, and UK clinical investigators.

The previous saga involved a medical device, and the conduct and conclusions of the Migraine Intervention with STARflex Technology (MIST) I trial. MIST I had two co-principal investigators:

1. Dr Peter Wilmshurst, a respected cardiologist and
2. So-called headache specialist Dr Andrew Dowson. Although Dowson described himself as a neurologist, he is not. More importantly, Dowson has restrictions on his medical practice following previous research misconduct.

Wilmshurst states that NMT has repeatedly "blocked his attempts (as principal investigator) to view the complete MIST I data set, has lied about whether echocardiograms from the MIST patients have been independently reviewed, and has massaged the data to portray its PFO device in the best possible light". He was sidelined from the study, his concerns were ignored, and Dowson presented the findings which have now been questioned. For details see here.

Several ethical, procedural and scientific issues arose in MIST I which went beyond the issue of migraine to other aspects of the device. One can only hope that NMT are not going be so foolish as to attempt to threaten Dr Wilmshurst for quite properly discussing scientific procedures involving patients. The of MIST I is ongoing, and it seems that NMT may have resorted to legal threats - always a credible scientific tactic. This case is worth keeping on the radar.

Now we read that NMT is shutting down the MIST II trial. This may be appropriate as MIST I showed no efficacy for migraine. However questions have to be asked when trials are shut down. If the continuation of MIST II was in any way dependent on the outcome of MIST I, then the ethics of starting MIST II have to be questioned. If the termination was truly related to difficulty with recruitment then this raises other issues.

NMT Medical closes migraine trial in U.S. Mass High Tech, 23 Jan 2008

NMT Medical Inc. reports plans to shut down its migraine technology trial, MIST II, to instead focus on using its technology to prevent the onset of stroke.

According to officials at Boston-based NMT, the move should save the company approximately $14 million over the next two to three years, as it redistributes funds originally budgeted for MIST II (Migraine Intervention with STARFlex Technology). NMT has stopped enrolling patients in MIST II, which was being conducted at 20 centers in the United States.

NMT president and CEO John E. Ahern said that strict enrollment requirements from the U.S. Food and Drug Administration has made MIST II an expensive endeavor "with little likelihood of being completed in a reasonable time frame."

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NMT Medical and a new UK research scandal

An important new scandal involving inappropriate research procedure, misconduct in procedure, and possible misconduct in data analysis has blown up in the UK this week.

1. The saga involves a medical device, and the conduct and conclusions of the Migraine Intervention with STARflex Technology (MIST) I trial. A brief summary is below (a detailed press report is here)
2. MIST I was the first large trial to test whether the use of a new device to close a patent foramen ovale would reduce the incidence of migraine headaches. As it turns out, the results of the trial may have implications for the company which extend far beyond the issue of headache.
3. The study was sponsored by NMT Medical (of Boston, MA) and had two co-principal investigators who are as different as chalk and cheese a) Dr Peter Wilmshurst, a cardiologist and b) a so-called headache specialist Dr Andrew Dowson.
4. Dowson: Although Dowson described himself as a neurologist, he is not. More importantly, Dowson has restrictions on his medical practice following previous research misconduct (interesting fiddling of research records here, GMC restrictions here). Dowson states that NMT was fully aware of the research misconduct "undertakings" when he was chosen to be co-principal investigator.
5. Wilmshurst: By contrast, Wilmshurst is a highly respected cardiologist, and has worked in the field of PFO closure for 20 years. Wilmshurst was on the international planning committee that designed the MIST trial, and was originally selected to head up the trial before Dowson was put forward by the company as coinvestigator. NMT's website has multiple press releases naming Wilmshurst and Dowson as co-principal investigators. The protocol as submitted to the MREC (Multicentre IRB) in the UK states that "the study principal investigator will be shared by two physicians due to the nature of the trial".
6. According to Wilmshurst, his troubles with the sponsor began after he and Dowson presented the MIST I trial results at the ACC 2006 meeting. To the disappointment of many, MIST I was negative: PFO closure was no better at curing migraine than a sham procedure among people with PFOs and migraine with aura. One hypothesis explaining failure was that there may have been a high rate of residual shunts among patients. "Although a higher rate of residual shunts would help explain the negative outcome in MIST, it has much larger implications for a device already marketed in Europe for the treatment of cryptogenic stroke".
7. According to Wilmshurst (who has the emails to prove it) NMT officials instructed MIST investigators to send all patient echocardiograms to Wilmshurst for independent review immediately following the ACC. According to Wilmshurst, he ultimately reviewed the contrast echoes for all but one of the patients who underwent the scan at follow-up. At the TCT 2007 meeting last week, Dowson reported that the closure success rate was 94%, according to the implanting physician--in other words, a residual shunt rate of just 6% for the trial. Wilmshurst's review of the echocardiograms, however, suggested that the residual shunt rate was far higher--approximately one-third of the echocardiograms--a number he says was rejected by NMT. A second review of the echocardiograms (by Dr Luke Missault in Belgium) apparently yielded similar findings. NMT then ceased all communication with Wilmshurst and apparently refused further review of the echocardiograms stating that "to have echocardiograms reviewed at a single center would be a violation of study protocol, since it was not something that was specified in the patient consent process". !!!
8. Wilmshurst states that NMT has repeatedly "blocked his attempts to view the complete MIST I data set, has lied about whether echocardiograms from the MIST patients have been independently reviewed, and has massaged the data to portray its PFO device in the best possible light". Dr Andrew Dowson presented the "findings" at the TCT 2007 meeting (TCT 2007: Transcatheter Cardiovascular Therapeutics October 20 - 25, 2007, Washington, DC). It is not clear whether Dowson has the Echo data either, or whether and has the expertise to interpret it. "In fact, the first Wilmshurst learned that these data were going to be presented at TCT was when he arrived in Washington for the meeting and saw the trial listed in the TCT program."
9. Wilmshurst aired concerns about irregularities in the MIST trial and the activities of its sponsor, NMT Medical, during a presentation at this week's TCT 2007 meeting. NMT retaliated by claiming Wilshurst is not a principal investigator, cannot see the study data and has dropped Wilmshurst from the trial for so called "protocol violations" and so called "violations of the investigator's agreement". Asked for examples of these violations, the company declined to provide any "at this stage". NMT's lawyers also accused him of "breaching confidentiality agreements". Wilmshurst states that it is his duty to speak out "I cannot permit a confidentiality agreement to be used to allow NMT to make statements that are untrue in the belief that I or others who know that they are lying will remain silent". Wilmshurst also notes that he and other investigators at his center have "declined large consultancy payments from the sponsor".
10. Several other trial investigators are asking questions. One stated "There should be complete transparency of the MIST echo data with an independent core lab review of the studies that have already been done". The company provided a different excuse to this investigator implying that his proposal of transparency is somehow inappropriate because he "receives consultancy fees from [another] company, AGA". (? logic)
11. Wilmshurst and another colleagues (including Dr Simon Nightingale, who is also on the MIST steering committee) have repeatedly asked for the complete data collected in the MIST trial. According to Wilmshurst, the partial data they have seen, is "simply inconsistent". Wilmshurst also states that he and Nightingale have repeatedly asked for a full explanation as to why two patients, described as outliers, were excluded from secondary analyses of MIST I.
12. "For the past year, Wilmshurst says the company has responded to his emails only by threatening him with legal action and telling him that he is forbidden to speak publicly about the trial. Attempts were made by NMT to drop his center as a trial site (despite the fact that it had been the second-largest enroller). This was vetoed by the ethics board. Later however the center withdraw from after learning that the CRO running the trial (Matrix) had been ordered by the company not to provide clinical record forms to the center.
13. THE MREC (IRB) ordered NMT to meet with the steering committee and with the data safety and monitoring board. However, according to Wilmshurst, the company has more than once announced that it would hold this meeting, only to cancel at the last minute.
14. Dowson, the other investigator with headache expertise has now submitted the study publication to Circulation who have apparently accepted it. It is apparently going to be published "in a matter of weeks".
15. The company states that "outside independent auditors" have reviewed the data in the paper. "They seem to be comfortable at least with what's been presented to them . . . . Ethically it's important to get the data out there so we can do further studies."
16. So it seems OK for unknown "outside independent auditors" to (supposedly) see some data ("at least with what's been presented to them"), but not the clinical investigators or study authors.

The procedure in this trial may constitute research misconduct irrespective of any manipulation of the data. In fact it seems hard to know whether this is science or black magic. The corrupted (and unreformed) UK regulator the MHRA is now apparently also on the case, so perhaps yet another amusing obfuscation is heading our way. As assessors of black magic for the homeopathy industry, the MHRA are probably well placed to comment on this stuff. After a few years of silence and poor leadership the bleeding starts.

See NMT medical's code of ethics. There isn't much there about patients or research integrity, or the hiring of shonky investigators to bypass those who care.

The integrity of UK science isn't looking too good either. It's deja vu again and again for this type of problem.

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