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FDA’s Office of Combination Products is expected to publish two proposed rules by the end of the year, its director said at the Regulatory Affairs Professionals Society annual conference this week. Thinh Nguyen said the topics are good manufacturing practices for combination products and adverse event reporting for combination products.

The former has been anticipated by industry for a long time. Device manufacturing is governed by the Quality System Regulation, while pharmaceutical manufacturing is governed by the Good Manufacturing Practices Regulation. The office put out a draft guidance in 2004 about how these should be integrated for combination products, but has not issued any further official word.

Nguyen implied that the proposed rule on GMPs won’t be too different from the 2004 draft guidance. “When it comes out, you won’t be too surprised,” he said. “In the meantime, work with us and have patience.”

The draft guidance states that before the constitutent parts are combined, they should follow the manufacturing rules that already govern them. Once they are combined, they should follow one set of rules, and incorporate select provisions from the other set of rules. Manufacturers should have a plan in place that determines which of those provisions are and are not needed. But the guidance is unclear on which set should be primarily followed for which products, when exactly “combination” occurs, and what to do about products that are used and/or marketed together but not manufactured together.

The office is also about ready to publish a guidance on imaging devices for use with radiopharmaceuticals, Nguyen said. Also forthcoming are two guidances on autoinjectors, he added. One will cover the regulatory pathway for them, and the other will cover testing and other technical information.

– From DeviceTalk.

The Government Accountability Office is preparing a report on whether the 510(k) process is adequate enough to assess the safety and effectiveness of medical devices, and the buzz at the Regulatory Affairs Professionals Society annual conference this week is that it may have some unfavorable conclusions. Some consumer groups and members of Congress have complained that the process is not rigorous enough.

“Industry and FDA are unified on the 510(k) process. We believe it works well, is flexible, and is not undemanding,” said Patricia Shrader, senior vice president of corporate regulatory and external affairs for Becton Dickinson, who spoke at a session on the FDA Amendments Act of 2007. “But the GAO report may not be entirely positive. And if the GAO says the bar must be raised, then the impact on IVDs may be rather disproportionate.”

Similarly strong words were uttered by industry and CDRH personnel during the conference’s CDRH executive staff briefing. “The majority of products which have turned out to have severe problems are not 510(k)s,” said Susan Alpert, senior vice president and chief quality and regulatory officer at Medtronic. “This program has not created a significant risk for the American public.”

Pamela Adams, senior vice president and COO at Etex Corp., said the attacks on the 510(k) program arise from misconceptions, particularly that 510(k) products can get on the market without clinical data. In fact, 10-15% of 510(k) applications include clinical data. She said AdvaMed is working to educate policymakers and the media about these misconceptions.

CDRH Director Daniel Schultz said the 510(k) program has matured over the years into something that “allows us the flexibility to apply appropriate criteria and thresholds.”

But, he said, industry should not view the program as an easy way to market, and should not balk if the center asks for more data. “If we want the 510(k) program to survive, and to be based on risk, it has to work both ways,” he said. “We will ask for less information about simpler devices, but we will ask more and harder questions as the technology advances. `It’s just a 510(k)’ is a phrase that should be taken out of our lexicon.”

– From DeviceTalk.

CDRH has appointed Jonathan Sackner-Bernstein, MD as associate CDRH director for postmarket operations, CDRH Director Daniel Schultz told those at the Regulatory Affairs Professionals Society annual conference this week. He will oversee the center’s Postmarket Transformation Initiative and head the “CDRH Matrix.” The latter is a group of 13 cross-cultural teams, made up of people from different parts of the center who specialize in the same product areas. It was created to better enable dialogue about adverse events and other postmarket issues among center employees who oversee different regulatory stages of the same products. And that could mean that safety problems get identified and addressed more quickly.

Sackner-Bernstein is a cardiologist who had served on the faculty at Columbia University and as chief medical officer of a contract research organization, Clinilabs. For CDRH, he had served on the Medical Device Dispute Resolution Panel.

In June 2008, Congress gave FDA an additional $150 million in an emergency supplemental appropriation. For Fiscal Year 2009, the Bush Administration has asked for an additional $325 million in funding for the agency. The question is, in addition to what? The FY08 budget figure after the $150 million was added, or before it was added? Some in Congress, particularly the Senate, want the former, but the Bush Administration, and perhaps the House as well, wants the latter.

The Alliance for a Stronger FDA, a coalition that supports increased funding for FDA, endorses the Senate position. “The Alliance advocates a level of funding that is consistent with the Senate position , i.e. an appropriation level of $2.04 billion, creating $325 million in new funds in addition to the $150 million in supplemental monies,” it said in a release to the media. “We hold this position regardless of whether the FDA is funded by an individual bill, an omnibus or a [continuing resolution]. Also, we have consulted our sources and are satisfied that the agency can absorb this amount of money and spend it appropriately. There is a need for this level of funding now and for further increases in subsequent fiscal years.”

UPDATE: The Alliance issued a release stating that the increased funding may not kick in until winter, and urging Congress to enact it sooner. Given everything else that is going on in Congress right now, FDA’s budget for the first few months of FY ‘09, which begins Oct. 1, is likely to be enacted by Continuing Resolution. And funding via Continuing Resolution is often enacted at the previous year’s level. So the budget increase that everyone agrees should happen might not until toward the end of the calendar year.

CDRH’s Office of Device Evaluation (ODE) received 9415 major submissions in FY 2006, up 8.3% from 8690 in the previous fiscal year. The ODE 2006–2007 annual report says the increase is primarily due to a jump in the number of premarket approval (PMA) supplements received. In FY 2007, the number received went down to 9276.

The average total elapsed time for original PMAs and panel-track PMA supplements has decreased overall from FY 2003 to FY 2006. The report says an increase in elapsed time in FY 2005 was likely due to a staffing shortage from that year because there was uncertainty over the continuation of the medical device user fee program.

The average ODE review time from receipt to final decision for 180-day PMA supplements has continued to improve, the report says. For the FY 2007 receipt cohort, the average ODE review time was 95 days, down from 109 days in FY 2006 and 111 days in FY 2005. The report also sees a “significant improvement” in the average total elapsed time for 180-day PMA supplements since FY 2005. For the FY 2007 receipt cohort the total time was 126 days, down from 169 days in the FY 2006 receipt cohort and from 238 days in FY 2005.

– James G. Dickinson

Permitting medical device makers to modify an existing device based on bench testing is allowed by regulations and is not an unsafe approach, wrote CDRH director Daniel Schultz in a recent letter to the New England Journal of Medicine.

Schultz took issue with the March 6 article written by William Maisel that criticized FDA’s handling of adverse events related to the recall of Medtronic’s Sprint Fidelis implantable cardioverter-defibrillator leads. Maisel is the director of the Medical Device Safety Institute at the Beth Israel Deaconess Medical Center (Boston).

“In evaluating an application involving a modified device, we analyze the proposed modification, determine the potential types of failure, and tailor testing requirements accordingly,” Schultz wrote. “In many cases, our questions are best answered by performing appropriate engineering analyses, but in other cases, we also require clinical data…To require that these modified devices undergo clinical trials across the board as a condition of FDA approval would limit the availability of improved products. Also, most of these trials would have insufficient power to detect small but clinically meaningful differences in performance.”

Maisel’s article criticized FDA and Medtronic over the Fidelis recall. After concerns arose about Fidelis’s performance, he said, Medtronic notified doctors of a “limited number” of devices that had a higher-than-expected lead fracture rate. The company said Fidelis’s performance was “in line with other Medtronic leads” and cited a small prospective postmarketing study that found a 1.1% lead failure rate within two years of implantation.

Maisel said the company didn’t report that the study was “grossly underpowered to detect even a moderate increase in fracture rate in the Fidelis as compared with its predecessors. In short, despite implantation of the device in hundreds of thousands of patients during several years on the market, the available postmarketing data were insufficient to provide a definitive conclusion about whether there was a performance problem.”

Even as Medtronic maintained that the lead functioned within acceptable parameters, Maisel said, the company submitted an application to FDA in May 2007 for design and manufacturing changes and received approval two months later.

But already-manufactured leads remained available and continued to be used. By the following October, Medtronic had confirmed 665 fractures in returned leads, five deaths, and a 2.3% fracture rate within 30 months of implantation, and recalled the product.

Schultz’s letter answered that there is “nothing inherently wrong” with allowing a device maker to continue to market existing models while modified (and presumably improved) models await FDA approval, unless the older models pose an undue health risk.

“The continued marketing of Fidelis leads occurred when available data indicated that the fracture rate was similar to that of other leads,” he said. “When continued monitoring of the situation showed otherwise, the lead was recalled and existing stocks were promptly called back.”

Schultz complained that Maisel’s article “diverts attention from deeper problems. For example, how can bench testing be better designed to be predictive of clinical performance? How can postmarketing clinical registries be used more effectively as early warning systems, alerting us to low-frequency, unexpected problems with devices?” he asked.

Also, Schultz said, “Given that we cannot detect low-rate events without a steady flow of accurate information, how can physicians be persuaded to report adverse events to us promptly? We welcome thoughtful input on these issues from clinicians, patients, and the medical device industry.”

– James G. Dickinson

How much did FDA spend in litigating its cases against Utah Medical Products (Midvale, UT), which it lost in 2005, and TMJ Implants (Golden, CO), which is currently under appeal? Judging by FDA responses to two Freedom of Information Act requests I filed seeking revelatory documents, the agency does not know.

“This is to advise you that we have no responsive records from the Office of Chief Counsel,” wrote deputy chief counsel for program review Ann Wion in identical responses dated June 26.

In each case, my requests sought “legal expense summary documents showing accumulative dollar amounts and full-time equivalent (FTE) employee resources expended in all regulatory enforcement activities and [civil money penalties] litigation against [company]…”

FDA’s response suggests that when it comes to initiating litigation, cost is not a consideration, a comment that provoked some lively reactions on my Web site, www.fdaweb.com.

One FDA employee indignantly said cost should never be a concern—public health and safety should be the only concern when FDA considers litigation. This, however, overlooks the fact that in the two cases for which I sought cost information, FDA did not allege that there were any public health and safety problems. Moreover, the question begs the issue of public accountability, of which keeping track of costs is surely a part.

Others suggested that since it is the Department of Justice that brings FDA cases to court, my cost inquiries should be directed there, instead.

So that is what I have done, as well as filing with CDRH for its investigational (as opposed to litigation) costs in bringing these two cases forward.

I’ll keep you posted.

– James G. Dickinson

FDA Commissioner Andrew von Eschenbach said in a column on the agency’s Web site that it has hired about 1300 new experts in the past six months. These include physicians, scientists, investigators, and inspectors. He also says efforts are underway to establish agency offices overseas, including in China, India, Latin America, and Europe. Eventually, he says, FDA will even have at least one office in the Middle East. The office in China is almost ready.

These are the fruits of the additional funds the government gave FDA, after it had been obvious for years that it did not have enough money to successfully perform its mission. More fruits are coming: The agency’s IT systems are being revamped, and it is getting new data management tools.