Boston Scientific (Natick, Massachusetts) earlier this year completed the purchase of Guidant (Indianapolis). And while it has renamed the company as its Cardiac Rhythm Management (CRM) unit as a way of distancing itself from Guidant’s bad press – and technology problems – it now must deal with what appears to be a continuing round of those problems.

In late June Boston Scientific issued “safety information” concerning another large number of implantable cardiac devices made by its Cardiac Rhythm Management business, formerly Guidant, the result of finding electrical problems in two of its pacemakers, the Insignia and the Nexus; in one of its resynchronization pacemakers, the Contak Renewal TR/TR2; and three of its implantable cardioverter defibrillators (ICDs), the Ventak Prizm 2, Vitality and Vitality 2 ICDs. While not recommending the explant of the devices already implanted, it recalled 23,000 devices in inventory – that number bringing to about 110,000 the number of devices recalled by Guidant over the past year, in addition to warnings concerning thousands of other devices.

Overall, the warnings reportedly appear to impact more than 27,000 patients implanted with the devices, with the company noting that the failures have not resulted in any deaths. It said that patients with the affected pacemakers might experience “intermittent or permanent loss of output or telemetry or premature battery depletion.” Patients with affected defibrillators may experience “inappropriate sensing or premature battery depletion.” Altogether, it reported five confirmed events out of about 27,200 implanted devices.

It said there have been two reports of pacemaker patients experiencing syncope associated with loss of pacing output. One event was “a device malfunction discovered at the time of implant,” it said. The other four events involved devices that were implanted and then had to be replaced.

According to Boston Scientific CRM, the problem involved a supplier’s low-voltage capacitor – a component for electrical charge storage – not performing to expectations. Some capacitors from specific lots may perform in a manner that leads to device malfunction, including intermittent or permanent loss of therapy or premature battery depletion. The company is not recommending any explants of the devices identified in the safety notice.

Some analysts indicated that, given the pinpointing of a supplier as the source of the problem, other similar problems in this area might be uncovered further out. This possibility also was suggested by Boston Scientific CEO Jim Tobin, who in a conference call said that the company is reviewing all of the systems provided by suppliers and acknowledged the presence of “deeper issues.”

While not specifying the dates that the devices were manufactured, he said that the problems had occurred in “batch after batch and now we’re paying the price.” He added that it could take up to two years to resolve all of the engineering problems identified or yet to be uncovered.

Getting a positive public relations spin on what essentially was bad news, the company subsequently garnered statements from both the FDA and the Heart Rhythm Society (HRS; Washington) supporting the handling of the recall.

The FDA placed on its web site a statement saying that it “fully supports” the company’s recommendation that physicians perform follow-up exams of patients with devices that may be susceptible to this malfunction. The statement also appeared to serve the purposes of the agency, which has come under recent fire for lacking the grit to pursue necessary enforcement actions, and a decline in those actions.

Thus, Daniel Schultz, MD, director of the agency’s Center for Devices and Radiological Health, said that the FDA “is committed to keeping the public informed. We support Guidant’s decision to notify physicians and hospitals early in the investigation, and we believe that retrieval of non-implanted devices is a prudent first step.”

Anne Curtis, MD, immediate past president of HRS, said that the society “applauds this proactive, collaborative effort to inform patients and physicians about the most recent device notifications. This is a monumental step in providing optimal patient care ...”

Curtis also put in a plug for the society, saying that Boston Scientific’s action was “based on the society’s draft recommendations released in April. We believe the most important step is for patients to contact their heart rhythm specialist to determine the best course of action.”

FDA lifts its hold on GENASIS angina trial

Corautus Genetics (Atlanta) reported in mid-July that the FDA had lifted the clinical hold imposed March 29 on the company’s GENASIS (Genetic Angiogenic Stimulation Investigational Study) Phase IIb clinical trial for the treatment of cardiovascular (severe angina) disease. Corautus reported in April that it would stop enrollment in the trial after the FDA imposed the hold. Additionally, Corautus reported plans for locking the GENASIS database and conducting analyses of the data for efficacy endpoints and safety information.

Corautus said the FDA notified it that it had addressed the majority of the issues raised in the clinical hold letter and that the clinical hold was lifted. The investigational new drug application (IND) will remain on a “partial hold,” – as Corautus said it had expected – until the remaining issues in the letter, all associated with results of certain tests related to the delivery catheter system and injection procedure, are completed. It said it would submit the results of those tests and the efficacy and safety analyses from the GENASIS trial to the FDA for review later this year.

Corautus is developing a gene therapy product candidate using the VEGF-2 gene to promote therapeutic angiogenesis in ischemic muscle and has an alliance with Boston Scientific to develop, commercialize and distribute the VEGF-2 gene therapy products. In early June it responded to the FDA’s halt of the GENASIS Phase IIb clinical trial for vascular endothelial growth factor-2 (VEGF-2), a chest-pain drug, after some patients suffered adverse events. And it has been working with Boston Scientific, which makes the Stilleto catheter used to deliver the drug, over the past several weeks to evaluate the adverse events.

Corautus said that three incidents of pericardial effusion, a condition where excess fluid builds in the sac surrounding the heart, were not related to the drug. The company said it hopes to advance the drug into late-stage clinical trials. Corautus stopped enrolling patients in the trial on March 14, but it has continued to gather follow-up data on treated patients. The company said it will lock the database on Aug.14 for the 295 patients treated in the trial.

The efficacy and safety analyses to be performed on the database will include 295 patients at three months, 241 patients at six months and 103 patients at 12 months. Corautus said it expects to present the results from the trial this fall.

Richard Otto, company president and CEO, said, “A major clinical and regulatory focus for the past few months has been to successfully respond to the issues raised by the FDA in the clinical hold letter of March 29 ... [W]e will work with personnel from Boston Scientific [Natick, Massachusetts] to complete the additional testing requested by the FDA. We continue to have active dialogue with the FDA regarding our development plans.” He added, “More recently our clinical focus has been on obtaining follow-up data on all of the 295 patients treated in the trial. Our decision to lock the GENASIS clinical database will allow comprehensive analyses and review of patient data for efficacy endpoints and safety information.”

Otto said the company believes it has appropriately investigated the events that led to the trial suspension and has “developed a plan for dealing with these issues in potential subsequent clinical trials.”

FDA cancels meeting focused on Biopure trial

Under fire from an advocacy group criticizing the closed-door meeting of an advisory panel, to discuss a trial for Hemopure, a blood substitute/oxygen therapeutic being developed Biopure (Cambridge, Massachusetts), the FDA, on the eve of that meeting, abruptly cancelled it. Biopure was on tap July 17, along with the U.S. Navy, to discuss human testing of Hemopure in trauma subjects, a trial the FDA had put on hold over concerns about its safety, with a backstory of criticism concerning the ethics of the study.

The study is designed to treat patients in ambulances, a situation in which the patient is often unable to provide consent, or in a condition in which understanding of consent would be difficult. But the lack of informed consent is an ethical hurdle that has served as a magnet for criticism of Biopure and other companies relying on such a protocol.

Cancellation of the meeting appeared to be a response to a lawsuit filed by the advocacy group Public Citizen (Washington), which argued that the meeting should be open to the public. Public Citizen said the agency had violated federal rules requiring that every meeting of an advisory committee shall be open to the public unless the head of the agency determines that a portion of the meeting may be closed – in writing, with the reasons for closure explained. The group pointed to a Federal Register notice of the meeting that gave no description of the topics to be discussed.

Sidney Wolfe, director of Public Citizen’s Health Research Group – which monitors the safety of medical devices, blood products and drugs – said: “The public has a right to know what happens at this meeting, and I should have a right to attend and to participate in the discussion concerning the testing of this product.”

Biopure, the FDA and the Navy said the meeting was closed in order to protect trade secrets related to the product. Biopure said it had not signed a waiver enabling the meeting to be open, since that would have required additional time to prepare.

In its statement canceling the advisory meeting, the agency said that it had done so because of “significant public interest in the proposed study and the benefit of public discussion.” It said the rescheduled meeting would include “information [that] can be shared with the public.” The statement further said: “The complexities involved in the development and evaluation of the safety and effectiveness of such products can raise many unique scientific issues.”

“Given the level of public interest in this matter, the parties will work toward greater public involvement at this early stage,” the agency said. “The development of safe and effective treatments that could substitute for blood holds significant public health promise and could potentially save many lives.”

Public Citizen reacted to the cancellation by calling it “de facto admission that the meeting, had it been held in its closed format, would have violated the Federal Advisory Committee Act.”

The proposed trial is seen as an attempt, by the Navy, to find a blood substitute that is easier to store on ships than blood itself. It has proposed testing Hemopure in more than 900 patients – non-Navy personnel – around the country.

Biopure reported last month a submission to regulatory authorities in the UK seeking approval for the use of Hemopure to treat anemia. The product already has been approved for sale in South Africa.

Another blood substitute developer that has run up against the lack-of-informed-consent barrier is Northfield Laboratories (Evanston, Illinois). That company has been the target of stories by the Wall Street Journal focusing on the waiver of consent using its Polyheme product in a trauma study and deaths in an earlier trial, and drawing critical comments by Sen. Charles Grassley (R-Iowa) regarding what he termed “urgent ethical concerns.”