CDU Contributing Editor

BOSTON, Massachusetts – Can a company attain FDA approval of a device when its pivotal clinical trial does not meet its primary endpoints? That question created a red-hot debate at the 22nd annual scientific sessions of the North American Society of Pacing and Electrophysiology (Natick, Massachusetts) in early May.

The Contak-CD is a combination implantable cardioverter-defibrillator (ICD) and biventricular pacing (BVP) device, developed by cardiac rhythm market (CRM) leader Guidant (Indianapolis, Indiana). The company and a team of electrophysiologists have been investigating whether patients who suffer from later stage congestive heart failure (CHF) and are susceptible to lethal ventricular tachycardias (VTs) can benefit from combination therapy. Numerous earlier landmark clinical studies, such as the Multi-Center Automatic Implantation Defibrillator Trial (MADIT), the Antiarrhythmics Vs. Implantable Defibrillator (AVID) trial and the Multicenter Unsustained Tachycardia Trial (MUSTT) have strongly demonstrated that ICDs are enormously proficient at protecting patients from a sudden cardiac death (SCD) episode. The success of ICD therapy has fueled robust growth, creating a worldwide market that will reach approximately $2 billion worldwide this year.

Meanwhile, a variation on cardiac pacemaker technology, called biventricular pacing, used in the fairly mature $3 billion annual pacemaker industry, has more recently been under investigation here and abroad to determine whether CHF patients could benefit from cardiac resynchronization therapy (CRT) delivered by BVP products. Studies such as the Pacing Therapy for Congestive Heart Failure (PATH-CHF) and the Multisite Stimulation in Cardiomyopathy (MUSTIC) trial, reported in the past couple of years, have shown very promising results for CHF sufferers. This patient group suffers from a degenerative disease that leads to a miserable quality of life (QOL), frequent hospitalizations, and, ultimately, to their demise. CHF patients are in desperate need of alternative therapies, as medical management used in the earlier stages of the disease stages does not significantly alter disease progression, boost QOL and reduce mortality, while the more heroic, later-stage measures (e.g., the implantable ventricular assist device) are highly invasive, enormously expensive and not widely available.

The Contak-CD trial, the most comprehensive CRT study done to date, sought to evaluate whether the combination of a BVP and an ICD device could broaden the benefits to CHF patients in the mid to later stages of their disease. Begun in 1997, more than 500 patients were enrolled in this study, with the primary endpoint to show that Contak-CD could lower a composite measure of CHF and ventricular arrhythmia symptoms by 25% or more. In front of a standing-room-only crowd in a hotel meeting room, a panel of well-known investigators reported that the study failed to attain that goal, showing a lower-than-expected reduction of 21% in the composite score and thus not reaching statistical significance.

But, in a somewhat surprising turn of events, those investigators unanimously expressed their support for the Contak-CD, noting that the device could measurably benefit patients and saying that they were enthusiastic about its use in the community. Dr. James Coman, of the Oklahoma Heart Institute (Oklahoma City, Oklahoma), told the audience at the Guidant-sponsored event that, despite not meeting the specified endpoint, the trial results were "decidedly positive" and the device "deserves rapid approval" by the FDA. Coman said that he sees a "tremendous groundswell of interest and patient need" in the community where he practices. Another of the investigators, Dr. Paul Ludmer, an EP physician who practices at the East Bay Arrythmia and EP Center (Oakland, California), added that he hopes and expects "expedited FDA approval."

This presents the FDA with an interesting dilemma – can it or will it approve a life saving device that did not meet its primary endpoint in a pivotal clinical trial? At a NASPE clinical tutorial session the afternoon after the presentation at the Marriott, FDA representative Russ Pagano was noncommittal when posed that question. "It will depend on numerous factors," he told the audience, and "we certainly are not precluded from approving a device that does not reach its endpoints in a clinical trial." Guidant officials were upbeat after the release of the study, pointing out that the FDA has granted the company's premarket approval application (PMA) expedited review and that the PMA has already been accepted for filing. "We think that this indicates the FDA is positive about our device and the clinical results," Guidant group chairman Jay Graf told CDU's sister publication, Medical Device Daily.

Both the Guidant device and the InSync device from its cardiac rhythm management industry archrival, Medtronic (Minneapolis, Minnesota), will be discussed at FDA Circulatory System Panel meetings this month.

Wall Street analysts who attended both the presentation to physicians and an analyst briefing later that evening were mixed in their reactions. Morgan Stanley Dean Witter device analyst Glenn Reicin reduced his rating on Guidant shares from "outperform" to "neutral," citing "the new uncertainties that have been created by the Contak-CD trial," while J. P. Morgan analyst Michael Weinstein noted that "the fact that the trial failed to meet its primary endpoints leaves the company open to several inherent risks." On the positive side, Kevin Kotler of ABN-Ambro maintained his "add" rating on Guidant, saying that "the jury was still out regarding the interpretation of the data" and pointing out that the device "did slow the progression of CHF, albeit less than its pre-defined goal."

During a presentation at the Deutsche Banc Alex. Brown Health Care 2001 Conference in Baltimore, Maryland, a week after the company's Boston presentation, Guidant President and CEO Ron Dollens most definitely was on the offensive, ticking through the positive results from the Contak-CD trial one after another and expressing something close to bemusement over the focus by many on the fact that the trial did not meet its clinical endpoints.

Dollens saved his best oratory during the usual half-hour allotted each presenting company for a discussion of the Contak-CD trial findings and the outlook for that combination implantable cardioverter defibrillator and biventricular pacing device. While much of the response in the aftermath of the release of the Contak trial results was on not reaching the endpoint of a 25% or greater reduction in composite measurements of heart failure and ventricular arrhythmia symptoms, Dollens' take was that there is precious little difference between 25% and the actual 21% reduction reported in the trial.

He said that those who focused on the shortfall in the composite number seemed to have missed the point on other outcomes. Dollens noted that those included a 23% lower death rate, 13% lower rates of hospitalization, 14% improvement in quality of life and substantial improvements in New York Heart Association classification. "At the start of the trial," he said, "60% of patients were in Class 3 or 4, and at the end, after just 4 1/2 months, 80% were in Class 1 or Class 2." He also emphasized a 9% improvement in oxygen update, which he described as "of real importance to [heart failure] patients and their families."

Controversy or not, Dollens noted that the device, which he described as "absolutely being important to us," is being moved along the regulatory pathway. Presuming positive action by the agency, he predicted commercial launch of the Contak-CD in the U.S. by late in 3Q01 or early 4Q01.