CardioExchange Archive

(Updated at bottom with statement from St. Jude Medical)

Dan Starks, the CEO of St. Jude Medical, stated during a quarterly earnings call last week that results of the RESPECT trial of PFO closure for crytpogenic stroke were “favorable” and that the full trial results will be presented in October at the TCT meeting in Miami. But his statement raises more questions than it answers.

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’s Gregg Stone told CardioBrief that “the submission deadline [for late-breaking clinical trials] has not even been reached yet.”

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: “This is anybody’s guess until the data is presented,” he said.

Here is the transcript of the relevant portions of the conference call:

Dan Starks (CEO): Earlier 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.

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.

Michael Weinstein (JP Morgan analyst): … 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? …

Dan Starks: On 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’s our update.

Within that, though, one can see that we have a number – since our organization is strongly focused on preparing that submission, obviously we’re no longer blinded to the data and that was the basis for the level of confidence we’ve expressed that when the full trial results are reported at the TCT, we are optimistic that these will be favorable results.

Comment: The statement that the “trial will demonstrate greater benefit and less risk” for St. Jude’s PFO closure device is highly unusual. One danger is that the company’s 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.

Many companies in the past have released highly positive press releases of trials that ultimately have  been 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’ statement was first reported by an analyst for Merrill Lynch, who wrote that the statement by Starks was “a major disclosure” and concluded that the statement suggests that the trial “hit its primary endpoint.” Ultimately, he wrote, the PFO closure market represents a $500 million “annual market opportunity.” Maybe. But that’s an awfully long way to go on the basis of few vague words spoken in the heat of a conference call.

Caution is warranted especially because of the sorry history of negative trials in this area. It’s possible of course that the St. Jude device is superior to the failed STARFlex Septal Closure System from the now-defunct NMT Medical, 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 “other STJ closure technologies,” since many U.S. physicians “believe in the mechanism and the technology as a valid tool to prevent strokes.”

But let’s remember the NEJM editorial by S. Claiborne Johnston that 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:

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.

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 PC-Trial, which was finished and had completed its followup before the RESPECT trial. To date, the company has yet to release any information about the results of the trial.

The entire case, I think, highlights the importance of restoring the system whereby trial investigators, not companies, present the results of clinical trials. It’s not a perfect system by any means. But it’s a lot better than the alternative offered here by St. Jude’s CEO.

I’ve asked for comments from St. Jude, the RESPECT trial investigators, and other experts. I’ll update this story as necessary.

Click here for a full transcript of the St. Jude conference call.

Update: Shortly 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’ve raised.

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. We 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.  Mr. Starks’ 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.  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.

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.