When Investigators Bite the Hand That Feeds Them

... it can get ugly:

A scientific dispute has become a slander suit, in a legal case involving NMT Medical and its device for closing congenital holes in the heart.

The lawsuit, pending in London, was filed in 2007 by NMT Medical after a clinical trial failed to show that its device could eliminate migraine headaches in people with the congenital heart opening, known as a patent foramen ovale, or P.F.O.

NMT Medical contends that one of the British researchers in the study slandered and libeled it when he was quoted in an online publication as saying the trial may have failed because the product did not work well. The researcher, Dr. Peter Wilmshurst, was also quoted as saying the company had withheld trial data because it feared that it might undercut sales of the device for other uses, like stroke treatment.

“I’m not as concerned about the companies as I am about the fact that the patients who are in the studies will suffer,” Dr. Wilmshurst was quoted by the publication, theheart.org, which covers cardiology.

The controversy surrounding this trial has been ongoing since 2007 when Dr. Wilmshurst stated:

In an interview with heartwire (registration required), Wilmshurst, a cardiologist, alleges that NMT has attempted to marginalize his role in the trial--including claiming that he was never a co-PI for MIST I--and to bar his hospital from participating in MIST III. He also asserts that NMT has repeatedly blocked his attempts to view the complete MIST I data set, lied about whether echocardiograms from the MIST patients have been independently reviewed, and massaged the data to portray its PFO device in the best possible light.

But we must continue to ask where are the regulators in this case? Why has this contentious argument between corporation and investigator been permitted to come to one of litigation?

What a mess.

While this trial has exposed the underbelly of the scientific process when egos, patient interests and business interests collide head-on, the new legal actions also make a mockery of England's regulatory process to resolve these differences before they reach this level of contentiousness.

-Wes

PFO Closure and Migraines

There has been a remarkable amount of excitement about closing patent foramen ovales (PFO's) or larger atrial septal defects (ASDs) to cure intractable migrane headaches based on observational studies, and many, many companies have rushed to develop devices for this indication.

This week's Circulation (on-line version) released the much anticipated MIST trial (Migraine Intervention With STARFlex Technology) results which randomized 147 patients with a moderate to large PFOs between implantation of a STARFlex PFO closure device and a sham (or placebo) procedure.

The study's primary efficacy end point was migraine headache cessation during the analysis phase. It was derived from diary data.

Secondary efficacy comparisons were incidence of migraine during the healing phase; change in the severity of migraine attacks based on MIDAS (over a 3-month retrospective period) and headache impact test (HIT-6) (over a 1-month retrospective period) scores; change in the frequency of migraine attacks other than elimination of attacks; change in the characteristics of migraine (with or without aura and change thereof); change in the severity, frequency, and character of migraine relative to effective closure rate or presence of residual leak; and change in quality of life based on the SF-36v2 questionnaire (over a 1-month retrospective period).

The bottom line? The authors concluded that "no significant effect was found for primary or secondary end points."

Ouch.

To be fair, this was a tough group to fix: all had lots and lots of migraine headaches that were refractory to multiple medical therapies. The authors also note that the study was "underpowered" to show such a difference (do I sense backpedaling??) and the there was a trend toward fewer hours of headache experienced in the treatment group. The investigators want us to wait for the longer-term MIST-III trial results.

But the scuttlebutt doesn't stop there with this trial. Oh, no.

It is interesting that the study's prior "co-principle investigator's" name does not appear on the author list for this manuscript. Wow.

Last year at TCT 2007, Peter Wilmshurst,MD claimed there was data mismanagement over this trial and that perhaps the reason the study was negative was because of the poor performance of the device:

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, which then had the echocardiograms reviewed again, by the data monitor, Dr Luke Missault (St Jan Hospital, Brugges, Belgium). That second review, says Wilmshurst, who also sits on the steering committee for MIST, was statistically consistent with his own review. Wilmshurst states that all communications with NMT ground to a halt after he told the company the results of his review of the residual shunts. Ironically, while 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.

The author's and manufacturer's decision not to report the effectiveness of residual interatrial shunt data following ASD closure is troubling, given the controversy.

Clearly, the definitive jury about migraines and PFO closure is still out, but there are still many other trials (including MIST-III, PREMIUM and ESCAPE) pending with other companies devices, so hopefully more data will be forthcoming soon.

One thing's for sure, though, the MIST-I results will be a headache for gaining FDA approval of future devices without a clear headache improvement and more comprehensive residual interatrial shunt data to back up the observations.

-Wes

Image reference.

12 Mar 08 Addendum: More analysis on the MIST trial is available from theHeart.org (registration required).