BB&T Washington Editorand Staff Reports

In a development that hardly catches medical societies and imaging providers flat-footed, the Centers for Medicare & Medicaid Services decided to use the coverage with evidence (CED) development rubric to reimburse for the use of a radioisotope of sodium fluoride for metastatic bone cancer. While a number of factors may have converged to prompt CMS to move in this direction, one of the prime drivers may have been the ongoing shortage of technetium-99 (Tc-99).

CMS said that CED coverage will be used to pay for the use of NaF-18 with PET scanning for both initial staging of the cancer and for ongoing staging after completion of initial treatments. The agency had tackled this topic last year and issued a proposed decision memo dated Nov. 30, 2009, stating at the time that the rate of false positives was an issue. CMS acknowledged the ongoing shortage of Tc-99 in the proposed decision memo, although the Tc-99 predicament was not specifically cited as a reason for the NaF-18 coverage analysis.

Robert Atcher, MD, past president of the Society for Nuclear Medicine (SNM; Reston, Virginia), is on record as saying that SNM had approached CMS on the issue, and that reimbursement for this application in the U.S. has lagged behind payment policy in Europe. Atcher also stated that SNM is interested in helping to bankroll a registry for NaF-18 when used with PET scanners.

Quick turn-around on FDA warnings in place

The Dec. 3, 2009, warning letter to Z-Medica (Wallingford, Connecticut), maker of hemostatic devices, including the QuikClot combat gauze, was another instance in which FDA quickly hammered out a warning letter in what would have been record time in years gone by. The inspection ended Nov. 3, but a Nov. 20 response from the company to the inspectional findings was not enough to stave off the warning letter, which FDA issued exactly one month after the inspection ended.

The 30-day turn-around on this warning beats by five days the elapsed time between the agency's inspection of Guidewire Technologies (Salem, New Hampshire), which was the recipient of a Feb. 26 warning letter addressing findings during an inspection that was completed by Jan. 22. The foreshortened time between inspections and warning letters suggests that the agency's emphasis on safety, especially as relates to sterility, is one of the prime drivers of the agency's regulatory activity. Sterility was an issue in the Guidewire warning letter as well, and was cited by FDA in it's action against Steris (Mentor, Ohio), which had to recall all of its SS1 sterilizers over changes made to the system since its inception, even those units that bore the original cleared configuration.

In the case of Z-Medica, the agency managed to rapidly turn around a re-inspection as well. Denny Lo, senior VP of Z-Medica, told BB&T that FDA sent an investigator back out to review the proposed corrections between Jan. 27 and Feb. 2, the results of which earned the company a close-out letter.

Boston Sci halts shipments, recalls inventory

In what may be one of the biggest medical device recalls ever, Boston Scientific (Natick, Massachusetts) reported in March that it had stopped shipment and is retrieving field inventory of all its implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds). The move caused a spike in trading and the company's stock dove 16.45% on the day of the announcement. Wall Street's reaction was brutal: the company was promptly labeled the Toyota of the medical industry in a Wall Street Journal blog.

“FDA didn't ask for a recall. But FDA will review the root cause for the ICDs recall as part of recall classification process,“ Dick Thompson, an FDA spokesman, told BB&T. “We were notified just last night.“

Thompson said the reason for the recall will be reviewed as part of a 30-day notice submission. In the mean time, apparently there are no reports of adverse events for any patients who have received the devices. And there was no indication that the manufacturing process changes would prompt explantation of the devices already in patients.

“Preliminary information indicates that there are no product failures or adverse events related to this issue,“ Thompson said. The company pledged to work closely with FDA to resolve the situation quickly.

Device firms are required to report any manufacturing changes affecting the safety or effectiveness of a device. The news comes just over two weeks after Boston

Scientific negotiated a plea deal on behalf of Guidant, a subsidiary plagued with product liability problems when it was acquired for $27.2 billion in 2006. Guidant was criminally charged with concealing information from the FDA regarding catastrophic failures in some of its ICDs, including charges of submission of false and misleading reports to FDA and failure and refusal to report medical device corrections.

Boston Scientific said in a statement that it had identified two instances of changes to production that, while successfully validated, were not submitted to the FDA. The devices in question, which treat heart failure and manage heart rhythm, made up about 15% of the company's total sales of $8.19 billion in 2009.

“A planned process review revealed that two manufacturing process changes were not submitted for FDA approval,“ Ray Elliott, President/CEO of Boston Scientific, said in a prepared statement. “We are acting voluntarily and expeditiously to resolve this situation, and we have seen no evidence of any risk to patient safety. We apologize for the inconvenience these actions will cause patients and physicians.“

Boston Sci wins at panel on indication for CRT-Ds

Boston Scientific (Natick, Massachusetts) managed to rebound after its recall of cardiac electrophysiology equipment in a meeting of the circulatory systems advisory committee in March, but the development bodes well for all firms in the business of making CRT-D units. The company successfully sought the panel's approval of its attempt to expand the indication for CRT-Ds beyond those in class III or IV heart failure, and the firm's success suggests it will have a larger market for its hardware than any competitor. The only question is how long the company will have the expanded pool of patients to itself.

The current indications for CRT-D (at press time, FDA had yet to formally announce it will go along with the panel's recommendation) are for patients with left ventricular ejection fraction of 35% or less and a QRS interval equaling or exceeding 120 milliseconds (ms) who have been diagnosed with New York Heart Association class III or IV heart failure. The panel's recommendation was based on data from the well-known Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), which enrolled more than 1,800 patients to establish whether CRT-D would reduce the risk of mortality and heart failure events by 25% in NYHA class I and II heart failure patients who exhibit a left ventricular ejection fractions of 30% or less and a QRS interval persisting for at least 130 ms.

Arthur Moss, MD, the principal investigator in MADIT-CRT, said double blinding was deemed “impractical if not impossible“ because patients with implanted electrophysiology devices have to present a card to providers regarding the device. However, he said, “there was total and complete blinding“ of the committee charged with adjudicating adverse events.

The patients in the control arm, who received only ICD units, numbered 731 and the remaining 1,089 were randomized to CRT-D. Moss noted that the data indicated a 34% reduction in heart failure events at 48 months, well in excess of the 25% target, as well as a superior outcome for the combined endpoint of all-cause mortality and heart failure events. However, all-cause mortality was by itself statistically indistinguishable between the two groups at roughly 7%.

MADIT-CRT produced a rate of freedom from system-related complications (SRCs) at three months of 85%, substantially better than the target of 70%. Dislodgement of the lead attached to the left ventricle in the CRT-D unit was the source of a number of the SRCs in this arm, accounting for 51 events (in 46 patients) of the 214 reported. This 4.3% rate of problems with the ventricular lead is apparently seen as falling well within the historical range.

Presenting on behalf of FDA, Kimberly Selzman, MD, of the Office of Device Evaluation and the chief of cardiology at the Salt Lake City Veterans Administration Hospital (Salt Lake City, Utah) informed the panel that beta blockers were used by 90% of the enrollees in MADIT-CRT, but that 30% or less of the patients in each arm were at the appropriate dose of 150 milligrams a day of carvedilol (Coreg). She also cited “a fairly small representation of [NYHA] class I subjects,“ which she said “may have affected the combined results,“ including mortality.

All-cause mortality was about 7% in both groups, and Selzman said no treatment effect was observed in class I patients, perhaps “due to a small sample size.“ A total of 13 patients in class I NYHA heart failure made it to 48 months, suggesting “a need for more data“ for this population.

Selzman pointed out that the presence of blockage of the left bundle branch – the cluster of nerves based in the left ventricle that delivers the electrical pulse responsible for ventricular contraction – was associated with an improvement in the study arm, but that the effect did not seem to hold for the patients in class I heart failure. She also acknowledged the greater benefit of CRT-D seen in women, but shrugged, “the cause of this is not readily apparent.“ Women were twice as likely to be non-ischemic as men and substantially more likely to suffer from blockage of the left bundle branch, but the source of the greater benefit in women was not discernible. “There were no differences in complications“ between the two sexes, Selzman reported. She also remarked, “the benefit to CRT-D patients without left bundle branch blockage is not clear.“

Panelist Bill Maisel, MD, an electrophysiologist at Beth Israel Deaconess Hospital (Boston), said he did not agree with the observation that no benefit was seen in class I NYHA patients because while enrollment in the study arm was greater than in the control arm and outcomes numerically similar, the hazard ratio for class I patients seemed to favor CRT-D. Maisel also posed the possibility that the trial would have had to enroll “about three or four times the number“ it did enroll in order to determine how many patients would have to have received a CRT-D unit to ward off a heart failure event in one patient.

Regarding the appropriate real-world population for CRT-D, Maisel said he could think of “several reasons I think it would be wrong to carve out class I patients from this trial,“ reminding panelists that a third of the class I patients in the trial had experienced more severe heart failure within a year of enrollment. Leaving class I patients with ejection fractions of 30% or thereabouts with no option but an ICD would force some of them back into the hospital for a CRT-D within 12 months or so, he said. Another panelist was heard to observe that he saw “a pretty fine line between class I and II“ heart failure, a sentiment that drew support from several others. Panel chairman Hirshfeld summarized that the comments were “focused on the fact that patients with ejection fractions of less than 30% are by definition a sick population, and attempts to carve out a subset . . . are relatively weak.“

As for the effects associated with left bundle branch block and QRS intervals, the remarks ranged from support for limiting use of the device in class I patients to those with blockage of the left bundle branch on one hand, to avoiding an overly prescriptive label that might tie an electrophysiologist's hands on the other. The panel concluded that the data on these issues might appear in the label, but the panel seemed disinclined to recommend any limitation on indications during discussions.

All the same, the voting procedure resulted in a recommendation that the use of CRT-D be limited in class I patients to those with left bundle branch blockage and sinus rhythm, and whose QRS intervals are 130 millisecond or longer. This proposal passed unanimously with the exception of one abstention. The panel then unanimously recommended that the post-approval study include a comparator group, and the final vote for approvability was likewise unanimous.

AGA Medical gets IDE for cardiac plug

The abnormal heart rhythm known as atrial fibrillation (AF) carries a high risk of stroke, which is why many patients are put on a lifelong regimen of warfarin (Coumadin). But the side effects of this blood-thinning drug, mainly bleeding, can be dangerous. AGA Medical Holdings (Minneapolis) has for some time been working on a new technology, the Amplatzer Cardiac Plug (ACP), that would fix the underlying problem and eliminate the need for warfarin.

AGA won an investigational device exemption (IDE) in April for the ACP, which is intended to prevent thrombus embolization from the left atrial appendage (LAA) in patients who have nonvalvular atrial fibrillation. The ACP is designed to close the left atrial appendage.

“The reason you potentially want the left atrial appendage closed is, if you're a patient with atrial fibrillation, the left atrial appendage remodels and gets thicker. There are lots of nooks and crannies - hiding places where clots have been shown to form. Those clots are associated with 90% of strokes. If you close it off and seal it, then you no longer have a place for clots to form and hide,“ Rachel Ellingson, senior director of AGA's business development, told BB&T.

The IDE trial is designed to demonstrate efficacy and device safety and will randomize patients in a 2:1 ratio of patients on the device to controls, who will receive warfarin only, the current standard of care.

“Warfarin is a tough drug to tolerate,“ Ellingson said. “Many patients just can't tolerate it and it has a very narrow therapeutic window. If you take too much, you risk bleeding. If you take too little, there's not enough benefit.“

President/CEO John Barr said, “Stroke can be a debilitating condition, and is a significant concern to the approximately 4.5 million people in the U.S. and Europe suffering from atrial fibrillation. Approval of this study will allow us to further evaluate our approach to reducing strokes in patients with atrial fibrillation by using our ACP to permanently seal the appendage, hopefully sparing patients from spending the rest of their lives on anticoagulants.“

Ellingson said the company expects to enroll the first 400 patients sometime during the second half of 2010. Interim analyses will be performed after the first 400 patients are enrolled and at predetermined periodic intervals thereafter, until a possible maximum of 2,000 patients are enrolled. These analyses will determine when the trial has achieved its endpoints and whether AGA is able to conclude the trial prior to enrolling all 2,000 patients. The only other cardiac plug in development in the U.S. is the experimental Watchman, developed by Atritech (Plymouth, Minnesota). An FDA panel narrowly backed the device last spring, but the agency has since asked for a confirmatory trial to substantiate effectiveness.

AGA is accustomed to being a pioneer. In fact, last year, the company competed an initial public offering, raising $199.4 million, one of the few to succeed in the dismal market. “We were the only medical device company to do an IPO last year,“ Ellingson said. “I think we truly view it as a significant testament to our company to go public when no other company could.“

The ACP received European CE mark approval in December 2008, and is currently sold in Europe, South America and parts of the Pacific Rim.

Medical device tax costly for some companies

A medical device excise tax that aims to raise $20 billion throughout a 10-year-period is causing deep concerns and frustration for some parts of the med-tech industry. The tax is part of the newly adopted healthcare law, which is set to bring sweeping reform throughout the country. Members of industry argue that the tax could cause an undue financial burden for medical device companies-especially those smaller companies who have revenue in the $60 million range.

“The tax is an absolute disaster,“ Albert “Ace“ Edwards, president of the Southeastern Medical Device Association (SEMDA; Norcross, Georgia), told BB&T. “You've got to explain the logic of taking money from a healthy industry not receiving any funding from the government and giving it to an industry [dependent upon federal funding]. I don't see the logic in that.“

Members of SEMDA include a number of smaller companies who can't weather the tax storm as easily as say Medtronic (Minneapolis) could. “Some of our companies are at $50 million in revenue, but they aren't to the point where they turn a profit yet,“ Edwards said. He added that this tax has the potential to harm innovation; by taking away additional dollars that these companies would have to initiate clinical work or navigate through the PMA and 510(k) approval process.

In an unattributed statement, the Medical Device Manufacturers Association (MDMA; Washington) echoed similar statements and said it is “very concerned about the impact a $20 billion device tax will have on patient care, innovation and small businesses,“ making the case that under the tax, “many companies will owe more in taxes than they generate in profits.“ MDMA says that such a scenario will force firms to lay off employees and cut budgets for research and development.

The statement also notes that absent an elimination of the tax, “structuring it to provide relief for smaller companies is critical,“ urging that Congress address the issue “before the tax takes effect in 2013.“

“Minnesota is going to bear about 25% of the [medical device excise] tax,“ said Don Gerhardt, the chief executive of LifeScience Alley (Minnesota), a trade group that represents med-tech companies. “With it being a tax on revenue instead of profit – well that's going to be a bit difficult. This is an enormous issue for Minnesota, with the potential to effect 300,000 jobs at minimum.“ Gerhardt said he has been in conversations with companies and they have said they're considering layoffs. Other options include halting proposed expansions all together.

Legislators that support the tax contend that other industries – from pharmaceutical companies to hospitals – have agreed to commit billions to help pay for expanding health insurance coverage to most Americans, and they argue that it's only fair that device companies contribute their fair share. In the meantime, companies are either adopting a “wait and see attitude“ to see if the tax is scaled back a bit or approaching lawmakers and asking for the tax to be scrapped.