{"id":30647,"date":"2012-07-24T12:44:13","date_gmt":"2012-07-24T16:44:13","guid":{"rendered":"http:\/\/blogs.nejm.org\/cardioexchange\/?post_type=voices&p=30647"},"modified":"2012-07-24T12:44:13","modified_gmt":"2012-07-24T16:44:13","slug":"st-jude-spills-the-beans-on-pfo-closure-trial","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/cardioexchange\/2012\/07\/24\/st-jude-spills-the-beans-on-pfo-closure-trial\/","title":{"rendered":"St. Jude Spills the Beans on PFO Closure Trial"},"content":{"rendered":"

(Updated at bottom with statement from St. Jude Medical)<\/em><\/strong><\/p>\n

Dan Starks, the CEO of\u00a0St. Jude Medical, stated during a quarterly earnings call last week that results of\u00a0the RESPECT trial of PFO closure for crytpogenic stroke<\/a>\u00a0were \u201cfavorable\u201d and that the full trial results will be presented in October at\u00a0the TCT meeting in Miami<\/a>. But his statement raises more questions than it answers.<\/p>\n

It should be noted that it is impossible to ascertain the actual results of the trial from his remarks. He did not even state whether the trial had met its primary endpoint, and there are always potential dangers when the full data from a large trial are analyzed. Further, when asked to confirm whether RESPECT was indeed scheduled for presentation at TCT, TCT\u2019s Gregg Stone told CardioBrief that \u201cthe submission deadline [for late-breaking clinical trials] has not even been reached yet.\u201d<\/p>\n

Jonathan Tobis, an expert in PFO closure at UCLA, told CardioBrief that any evaluation of the trial should await the full presentation of the data: \u201cThis is anybody\u2019s guess until the data is presented,\u201d he said.<\/p>\n

Here is the transcript of the relevant portions of the conference call:<\/p>\n

Dan Starks (CEO):<\/strong>\u00a0Earlier this year, we announced that we completed enrollment in our landmark RESPECT clinical trial, evaluating the benefit of PFO closure in patients who suffer from cryptogenic stroke. As a reminder, the RESPECT trial enrolled 980 patients and generated more than 2,700 patient years of experience. We expect the results of this trial to be presented at a late-breaking clinical trial session during the TCT meeting later this year.<\/p>\n

In stark contrast to prior randomized trials of competitive PFO devices for mitigation of risk in cryptogenic stoke patients, we are confident our trial will demonstrate greater benefit and less risk in the device arm of the trial.<\/p>\n

Michael Weinstein (JP Morgan analyst):<\/strong>\u00a0\u2026 Dan, you mentioned that the PFO closure for stroke RESPECT trial, can you just update us on the filing of that data and that PMA with the FDA? \u2026<\/p>\n

Dan Starks:<\/strong>\u00a0On the PFO closure, the submission to FDA is being prepared as we speak and there is a lot of data to analyze and prepare and organize. And so, I would be confident that the PMA submission will be in during the fourth quarter and I suspect that we would be unlikely to get that submission in before the end of the third quarter. So timing wise that\u2019s our update.<\/p>\n

Within that, though, one can see that we have a number \u2013 since our organization is strongly focused on preparing that submission, obviously we\u2019re no longer blinded to the data and that was the basis for the level of confidence we\u2019ve expressed that when the full trial results are reported at the TCT, we are optimistic that these will be favorable results.<\/p><\/blockquote>\n

Comment:<\/em><\/strong>\u00a0The statement that the \u201ctrial\u00a0will demonstrate greater benefit and less risk\u201d for St. Jude\u2019s PFO closure device is highly unusual. One danger is that the company\u2019s initial evaluation of the results may clash with the eventual evaluation of the academic investigators, peer reviewers, other experts, and, ultimately, FDA reviewers and consultants. Companies are in no position to be objective about their own products or trials. That is why academic investigators, peer reviewers, editors, FDA reviewers and consultants, and other interested experts play important roles in discussing and ultimately judging the value of new therapies. Taking the word of a company is simply not acceptable any more.<\/p>\n

Many companies in the past have released highly positive press releases of trials that\u00a0ultimately\u00a0have \u00a0been received in a far harsher light. In some of these cases, there have also been suspicions that the premature release of results could be used to affect a stock price. Indeed, Starks\u2019 statement was first reported by an analyst for\u00a0Merrill Lynch, who wrote that the statement by Starks was \u201ca major disclosure\u201d and concluded that the statement suggests that the trial \u201chit its primary endpoint.\u201d Ultimately, he wrote, the PFO closure market represents a $500 million \u201cannual market opportunity.\u201d Maybe. But that\u2019s an awfully long way to go on the basis of few vague words spoken in the heat of a conference call.<\/p>\n

Caution is warranted especially because of the sorry history of negative trials in this area. It\u2019s possible of course that the St. Jude device is superior to\u00a0the failed\u00a0STARFlex Septal Closure System from the now-defunct NMT Medical<\/a>, but until it can be convincingly demonstrated otherwise, the burden of proof lies with those who advocate the continued use of these devices. But the Merrill analyst believes that positive results from RESPECT could spark greater usage in Europe (where the device is already available, despite the complete absence of evidence supporting its use) and greater usage in the U.S. of \u201cother STJ closure technologies,\u201d since many U.S. physicians \u201cbelieve in the mechanism and the technology as a valid tool to prevent strokes.\u201d<\/p>\n

But let\u2019s remember the\u00a0NEJM<\/em>\u00a0editorial by S. Claiborne Johnston<\/a>\u00a0that accompanied the Closure 1 trial earlier this year. In it he outlined some of the troubling issues raised by the trial. Because of off-label use of closure devices, enrollment in the trial took 5 years and forced a reduction in the sample size. He continued:<\/p>\n

During the 9 years it took for the results of this trial to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.<\/p><\/blockquote>\n

There are more reasons to be skeptical. Although Starks was quick to bring up RESPECT, he was silent about another St. Jude PFO Closure trial, the European-based\u00a0PC-Trial<\/a>, which was finished and had completed its followup\u00a0before<\/em>\u00a0the RESPECT trial. To date, the company has yet to release any information about the results of the trial.
\n\"\"
\nThe entire case, I think, highlights the importance of restoring the system whereby trial investigators, not companies, present the results of clinical trials. It\u2019s not a perfect system by any means. But it\u2019s a lot better than the alternative offered here by St. Jude\u2019s CEO.<\/p>\n

I\u2019ve asked for comments from St. Jude, the RESPECT trial investigators, and other experts. I\u2019ll update this story as necessary.<\/p>\n

Click here for a full transcript of the St. Jude conference call.<\/a><\/p>\n

Update:<\/em><\/strong>\u00a0Shortly after publication of the above story, I received the following statement from St. Jude in response to an earlier request. I will leave it for readers to decide whether this adequately addresses the issues I\u2019ve raised.<\/p>\n

St. Jude Medical has previously expressed confidence in our RESPECT program because of fundamental differences in clinical trial design, patient selection, and device design compared to competitive programs. Mr. Starks was reiterating this confidence and optimism that because of these differences, the outcomes of the RESPECT trial would be different than prior randomized trials.\u00a0We have also publically indicated our intention to file the PFO PMA before the end of this year which, of course, requires the Company to have visibility into the data in order to perform the required analysis.\u00a0 Mr. Starks\u2019 statement that we are now unblinded to the data is intended to be nothing more than a reflection of the fact that we are analyzing the data for the PMA submission. In his comments, there was no specific data or endpoint information disclosed.\u00a0 It would be our intention to issue a press release, including formal statements by the Steering Committee membership, at the same time the RESPECT clinical trial results are presented or published, which, as Mr. Starks indicated, will likely occur during the TCT meeting.<\/p>\n

The PC Trial is an investigator-sponsored trial, funded by St. Jude Medical. You would need to contact the trial sponsors for further information about the presentation of results.<\/p><\/blockquote>\n","protected":false},"excerpt":{"rendered":"

Larry Husten asks readers to assess the ethical dimensions of St. Jude’s recent statements about the RESPECT trial.<\/p>\n","protected":false},"author":196,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[9],"tags":[1175,1372,561,1373,253],"class_list":["post-30647","post","type-post","status-publish","format-standard","hentry","category-interventional-cardiology","tag-cryptogenic-stroke","tag-ethnics","tag-pfo-closure","tag-respect","tag-stroke"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/30647","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/users\/196"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/comments?post=30647"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/30647\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=30647"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=30647"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=30647"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}