Research And Denial At St Jude Medical 2

Research and development is the cornerstone of medical progress, but sometimes R&D turns into its evil twin brother, research and denial.

Yesterday I reported on the the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial presented at the TCT meeting in Miami. The trial missed its primary endpoint, and although there were definite hints of possible benefit in the trial, most outside observers seemed to agree that the trial did not establish a firm basis for the routine clinical use of PFO closure devices in stroke. FDA approval of the device based on RESPECT seems unlikely.

This wasn’t the first we’d heard of RESPECT. Last summer, as I reported here, during an earnings call, St. Jude CEO Dan Starks gave a preview of the RESPECT results: “we are optimistic that these will be favorable results,” he said. Then, yesterday, the company doubled down on its position and issued a press release stating that the trial “provides clinical evidence of risk reduction” and offers “compelling evidence” for use of the St. Jude device “over conventional medical management alone.” A St Jude spokesman told me that the company “absolutely intends to move forward with our regulatory process and will file our PMA submission” in the fourth quarter of 2012.

Deepak Bhatt, an influential interventional cardiologist at Harvard’s Brigham and Women’s hospital, offered a very reasonable assessment of the trial in an interview with Bloomberg News: “We need a definitive trial of this approach if it’s going to be broadly used for PFO closure. Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

The stock market provided further evidence that St. Jude’s view of the trial was not the prevailing view. Despite what the company called “compelling evidence,” St. Jude’s stock price dropped 3.6% when the news of RESPECT was released.

In contrast to St. Jude, Gore, which is conducting REDUCE, a separate study of its own device for PFO closure, said that the RESPECT data “suggest [my emphasis] closure therapy for PFO may be beneficial, but further research is required.” Gore reaffirmed its intent to complete the REDUCE trial and pursue the indication for PFO closure. Of course, by the time REDUCE is completed there’s no guarantee that Gore won’t enter its own reality distortion field. Commercial pressures can be a heavy burden on the objective assessment of reality. But for now Gore’s perspective is sensible.

Closing the Hole in Medical Progress

The mutation of research and development into research and denial has worse consequences than a drop in stock price. It can paralyze medical progress. For more than a decade the value of PFO closure in stroke has been an unanswered question. Trial enrollment has been notoriously slow and difficult. The main reason is that many interventional cardiologists don’t want to randomize their patients because they strongly believe, despite the lack of evidence, in the value of PFO closure. So expensive procedures continue to be performed, despite a lack of evidence, and despite the likelihood that good evidence will ever emerge. It’s a frustrating siutation.

Earlier this year, in an editorial in the New England Journal of Medicine, S. Claiborne Johnston wrote about the harmful effect that off-label use of PFO closure devices has on research. He recommended that reimbursement for PFO closure be limited to patients participating in a clinical trial. Seems like a good idea to me.

During the 9 years it took for the results of this trial [CLOSURE 1] 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.

 

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TCT: Two PFO Closure Trials Miss Primary Endpoints 1

Two trials presented today at the TCT meeting in Miami testing the benefits of PFO closure in patients with cryptogenic stroke have failed to convincingly demonstrate any significant  benefit for the controversial procedure.

The RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial randomized 980 patients  to PFO closure with the Amplatzer PFO Occluder device or medical therapy. According to the lead investigator John Carroll, the rate of recurrent stroke was low in both arms of the trial: 1.6% in the closure group and 3% in the medical group.

This difference vetween the groups did not achieve significance in the intention-to-treat (ITT) analyses:

  • ITT raw count: 46% risk reduction (p=0.157)
  • ITT Kaplan Meier: 50.8% risk reduction, (p= 0.083

However, statistical significance was achieved in the per protocol and as treated analyses:

  • Per protocol Kaplan Meier: 63.4 risk reduction (p=0.032)
  • As treated Kaplan Meier: 72.7% (p=0.007)

The investigators reported that there were very few device- or procedure-related complications. There were a similar amount of serious adverse events in the two groups (23% in the device group and 21.6% in the control group).

The investigators concluded that “for carefully selected patients with history of cryptogenic stroke and PFO, the RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with the AMPLATZER PFO Occluder over medical management alone.”

“The optimal secondary prevention strategy following a cryptogenic ischemic stroke in patients who are found to have a PFO has been unknown,” said Carroll, in a TCT press release. “This need to know is particularly intense for young stroke patients who have no or minimal traditional risk factors for ischemic stroke, yet face a risk of recurrent stroke for many decades. RESPECT makes progress in both removing the ‘unknown’ or cryptogenic cause of some strokes and providing high quality data from a large, long-term randomized trial.”

A similar pattern occurred in the smaller PC (Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism) Trial, in which 414 patients were randomized to PFO closure or medical therapy. The primary endpoint, the composite of death, non-fatal stroke, TIA, and peripheral embolism, occurred in 3.4% of the treatment group compared to 5.2% of the control group (relative risk reduction: 37%, p=0.34). The incidence of stroke was 0.5% versus 2.4% (relative risk reduction 80%, p=0.14).

Study investigator Stephan Windecker said that because of a lower than expected rate of events after a mean followup of 4 years the trial ended up being underpowered to detect meaningful differences. He concluded that “the observed difference in stroke… may be clinically relevant if confirmed in further studies.”

We need a definitive trial of this approach if it’s going to be broadly used for PFO closure,” said Deepak Bhatt, in an interview with Bloomberg News. “Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

Earning Respect?

As reported here over the summer, during an earnings call St. Jude CEO Dan Starks told investors that the results of RESPECT were “favorable.” As I wrote then, the danger of this sort of statement  is that the company’s initial evaluation of the results may clash with the eventual judgement of the medical community. Companies are simply in no position to be objective about their own products or trials. Caution in this case was particularly warranted because of the sorry history of negative trials in this area, as highlighted by the failed MIST trial of the STARFlex Septal Closure System. The results of the RESPECT and PC Trials demonstrate that the communication of medical information should not be left in the hands of industry. (St. Jude stock dropped 3.5% on the announcement of the trial results.)
Click to read the TCT press releases on RESPECT and PC…

St Jude CEO Spills The Beans On PFO Closure Trial 1

(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. This 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. 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 US of “other STJ closure technologies,” since many US 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 which 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 of the trial. 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, and 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 my 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.

Achieving CLOSURE: Final Act of PFO Closure Device Reply

You can choose from a myriad of metaphors– closing the book, sealing the deal, fixing a hole– but the story is simple: the publication of CLOSURE 1 in the New England Journal of Medicine is the final act of the long and sad melodrama of the CLOSURE 1 trial. As initially reported at the American Heart Association in 2010, Anthony Furlan and the CLOSURE I investigators randomized 909 patients with crytpogenic stroke to either medical therapy or PFO closure with the STARFlex Septal Closure System. There were no significant difference in the composite endpoint or its components(stroke or TIA in the first two years, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years):

Composite end point: 5.5% in the closure group versus 6.8% in the medical-therapy group (HR 0.78, CI 0.45 to 1.35, p=0.37)

  • Stroke: 2.9% vs 3.1% (p=0.79)
  • TIA: 3.1% vs 4.1% (p=0.44).
  • Deaths at 30 days and deaths from neurological events at 2 years: zero in both groups
As expected there were more major vascular complications related to the procedure in the treatment group, as well as a higher incidence of atrial fibrillation:
  • Major vascular procedural complicaton : 3.2% vs 0% (p<0.001)
  • Atrial fibrillation: 5.7% vs 0.7% (p<0.001)

In an accompanying editorial, S. Claiborne Johnston discusses 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 of the trial. He continues:

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.