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An MD&DI July 1997 Column

WASHINGTON WRAP-UP

To speed product approvals, FDA is reviving an inactive statute that gets the agency involved early during product development.

James G. Dickinson

Reviving a statutory provision that had lain dormant for 20 years, FDA is inviting device innovators to submit early-stage product development protocols (PDPs) instead of premarket approval (PMA) applications for a promised final marketing clearance within 120 days.

The elements of a PDP became law in the 1976 Medical Device Amendments, but were not touched by FDA until this April when Center for Devices and Radiological Health (CDRH) director Bruce Burlington dusted them off and gave them to veteran reviewer Lillian L. Yin, director of the Division of Reproductive, Abdominal, Ear, Nose and Throat, and Radiological Devices, and to colleagues Ed Mueller of the Office of Science and Technology and James Norman of the Office of Management Services.

They in turn placed a PDP proposal on the Internet the same month. It included the statutory language and the accompanying congressional committee report from 1976. "The PDP process will be designed to include multiple methods of achieving its requirement," Yin, Mueller, and Norman wrote. "Provision will be made for 'real-time' reviews, on-site reviews, and other novel review mechanisms."

The PDP proposal is intended to:

"1. Provide a process that will allow FDA to effectively regulate Class III products from initial development to marketing to eventual replacement by more advanced products.

"2. Reduce the FDA resources required to review and approve new Class III devices.

"3. Reduce the total time to get a new Class III device to market.

"4. [Maintain] the overall assurance of safety and effectiveness as compared with the PMA process.

"The process will be designed to facilitate use of expertise outside FDA and will provide a clear development path 'road map' for products to the market."

The 1976 statute requires proposed PDPs to include descriptions of the device and any changes that may be made; any preclinical or clinical trials; manufacturing methods, facilities, and controls; and any applicable performance standards. It must also include proposed labeling; any other information "relevant to the subject matter of the protocol" that may be thought necessary by FDA (the appropriate advisory panel must concur on the need for this additional information); a requirement for progress reports to FDA; and, when completed, records of the trials conducted under the protocol.

FDA has 120 days to approve or reject a PDP. Marketing may not begin until, after approval, the sponsor submits a notice of completion explaining how the protocol has been fulfilled and setting forth the results of any required trials. FDA then has 90 days to accept or reject the notice.

In an interview, Yin said she is excited by this bold step, and looks forward to seeing the first company step forward to take advantage of it, perhaps in a pilot process that will serve as a guide for others.

The PDP process would replace the cumbersome and lengthy PMA process with a simpler, two-step process in which FDA will be involved at an earlier, pre­ investigational device exemption stage and remain involved through subsequent product modifications--an involvement that Yin hopes will expedite review of postmarketing supplements and perhaps eliminate the need for some supplements altogether.

She sees PDPs as eliminating "blind alleys" and unnecessary studies that can plague PMA reviews. Under the protocol, sponsors and FDA can agree in advance on what data are required, what end points are expected, and how future changes will be introduced. "Currently, a lot of companies come in missing this and missing that," Yin said. "This will save a lot of time."

Congress knows how to get FDA's attention: Pull on its purse strings. While there have been other attempts to change the way FDA operates (e.g., Vice President Al Gore's "Reinventing Government" initiative), congressional budget tightening has done more than anything else to radically alter the way the agency does business.

The most dramatic example of this to date came at the end of April when Bruce Burlington and Office of Compliance director Lillian Gill announced to their external advisory committee on medical device good manufacturing practices plans for a new risk-based program that would likely eliminate routine GMP inspections for most companies.

Historically, the Federal Food, Drug, and Cosmetic Act mandated that such inspections take place every two years, but Burlington and Gill were unabashed in acknowledging that lately the agency simply hasn't been able to come close to meeting that goal. Last year, it did better than most years, inspecting 53% of the device facilities scheduled for inspection. But FDA has been focusing most of its energies on preapproval, for-cause, and follow-up inspections regarding previous problems, and has tended to push routine GMP inspections onto the back burner.

Gill also discovered that of the 9000-odd device facilities registered in the United States for at least two years, 515 had never been inspected.

If the best that FDA can do is inspect half of what it's scheduled to, Burlington asked, "How should we set out to do the right half?"

Gill's answer was a risk-based compliance program, which would direct CDRH's 57 field device inspectors to visit the manufacturers of the riskiest devices and leave almost uninspected those who produce the least risky (unless unforeseen problems were to arise).

Using medical device reporting (MDR) data and device recall statistics from the last five years, CDRH's Office of Science and Technology assigned scores of 0 to 100 to each device type, with 100 representing a top inspection priority.

The 49-page list, known as the Compliance Policy Model, started with the highest-priority devices ranked in the high 90s. These included intravascular administration sets and diagnostic catheters, low-energy dc defibrillators and infusion pumps, continuous ventilators, apnea detectors, and implantable pacemaker pulse-generators. It worked down to such products as sterilizer baths, skin-graft guards, and periodontal test kits.

The advisory panel quickly picked the list apart, citing numerous inappropriate items. Committee chairman Ronald Zabransky, chief of microbiology at the Department of Veterans Affairs in Cleveland, fought to control the eruption of objections from his colleagues. Noting that although he himself had "found one which [he] thought was ridiculous," he would not allow the proceedings to erupt into unproductive arguments over specific examples.

Burlington and Gill quickly summoned the list's author, research biologist Stephen Sykes, who explained the numerical methods used and readily acknowledged instances of "imperfect" numerical sources. However, he insisted, if used only to establish compliance "bins" for determining priorities, his list was a useful tool and, indeed, the only available one.

Gill proposed to construct three bins of prioritized devices: those ranked 70 or higher, those ranked 40 to 69, and those ranked 0 to 39.

To spend FDA's dwindling enforcement resources on areas that best protect public health, Gill proposed to focus her office's activities on those in the 70-plus bin with scores higher than 90, and to prioritize remaining resources on the others in descending order.

The 20 devices with scores higher than 90 would be evaluated by a multidisciplinary CDRH team, who would review MDR and recall profiles, examine individual reports, and use team members' expert knowledge of the products and new technologies in the devices to develop strategies for problem evaluation and resolution.

For the remainder of the prioritized devices, Gill proposed scheduling half of the 70-plus Class III and Class II/Tier 3 devices for comprehensive inspections (i.e., examination of manufacturing specifications and procedures, reprocessing of devices or components, finished-device inspection procedures, device master records and device history records, complaint files, organization, environmental controls, cleaning and sanitation, equipment, labeling, distribution, and personnel). A complete inspection usually takes about 70 hours, and will take about 90 hours when FDA's new design controls take effect.

For Class II and Class I devices ranked above 70, she proposed "limited" inspections (i.e., examination of complaint-handling systems, MDR and device tracking, failure investigations, audits, in-process and finished-device rejects, procedures for change control, validation, and components) for 35% of registered facilities. Limited inspections were also proposed for half of the 40-plus Class III and Class II/Tier 3 devices, 35% of the 40-plus other Class II devices, and 15% of the 40-plus Class I devices. Gill proposed no routine GMP inspections for any devices ranked 0 to 39.

In discussing these ideas, the advisory committee agreed that CDRH was on the right track and had made a good start. But, after listening to industry critics, the committee questioned the accuracy of the MDR database and the reliability of the recall database--the entire foundation for Sykes's list.

Members balked at the idea that, using CDRH's proposed strategy, one firm's problems with a device could taint an entire category of similar devices and place it unfairly in a high-priority inspection zone, possibly subjecting innocent firms to unnecessary comprehensive inspections. FDA should develop a way of assessing an individual firm's compliance history, rather than depending on potentially faulty statistics about device categories.

The advisory committee members were also uncomfortable with the distinction between limited and comprehensive inspections.

And lest anyone think that the proposal was anything new, Medtronic's legal counsel, Robert Klepinski, asserted that his pacemaker firm was already experiencing multiple comprehensive inspections because it had five pending PMAs at CDRH. The proposal merely solidifies what FDA is already doing, he alleged. Despite protestations by FDA officials who work inside the Washington Beltway that the infamous "gotcha" syndrome is a thing of the past, it actually is alive and well in the field, Klepinski complained.

Gill denied that her proposals are not new, and suggested that Klepinski may have confused multiple PMA­related inspections with routine GMP inspections.

Clearly, it's back to the drawing board for Gill; the advisory committee gave her a lot to work with.

One thing is certain, however. Something closely resembling her concept is coming soon to an FDA office near you--fiscal reality mandates it.

James G. Dickinson is a veteran reporter on regulatory affairs in the medical device industry.

Copyright ©1997 Medical Device & Diagnostic Industry