BBI Washington Editor

WASHINGTON – "We should be using our knowledge to partner with industry to the extent possible to help products get to market so they can help benefit patients," Daniel Schultz, MD, director of the FDA's Center for Devices and Radiological Health, said during a Medical Device Manufacturers Assocation (MDMA; Washington)-sponsored conference last month. He spoke during a seminar on the 510(k) process sponsored by the MDMA and designed to help companies learn the ins and outs of the 510(k) applications, and how to best work with the FDA to streamline the process to best ensure product clearance.

Schultz's comments wrapped up the two-day event, during which other FDA officers provided the FDA perspective to conference participants. He delivered an overview of current CDRH activities and a high-level overview of his projections and plans for the future of the center. An FDA veteran, Schultz was appointed head of CDRH in July, after serving as acting director for several months following the departure of David Feigal, MD, from the post last spring. Prior to the promotion, Schultz was director of the Office of Device Evaluation at CDRH.

Schultz said that CDRH most definitely plays a role in the FDA's Critical Path initiative, which is an agency-wide program intended to streamline and improve the development and review time of new and innovative medical products. Critical Path is "innovative and reflects a new way of thinking," he said. "The idea of critical path was to leverage basic science knowledge, leverage cumulative research experiences both within the agency and outside the agency, to answer very basic scientific questions that can help new products get to market more quickly," he explained. "There is a role for devices in the Clinical Path, and we think there are important questions in the device world that can help new products get to market."

Schultz argued that what makes the device sector so dynamic, and an integral part of the process, is that the device sector is not easily defined and includes a wide spectrum of products. "We don't look like drugs. We don't look like anything, quite frankly, when you look at the device world," he said. "We're everything from Band-Aids to pacemakers and drug-eluting stents."

One idea that Schultz continuously stressed during his talk was that there is no lack of innovation in the device world. "We don't think this is an industry that is stagnating, either," he added. According to the financial firm Dun & Bradstreet, the medical device industry grew from 13,579 to 14,937 companies in fiscal 2004. Sales for the sector totaled roughly $320 billion.

Unfortunately, Schultz said, there also is a 20% annual turnover in individual device firms. "That makes it imperative to communicate with industry on an ongoing basis," he said. "We must get out there and interact, working as hard as we can to get the process right, keeping our guidance help coming, and keeping our meeting opportunities coming."

To meet new performance goals – many of which were mandated by the recent Medical Device Use Fee and Modernization Act (MDUFMA) – Schultz described a "changing workload" at CDRH. He reported a record number of expedited premarket approvals (PMAs), an increased number of 510(k)s with clinical data and more combination products. He did report, however, that for FY04, which ended Sept. 30, the total number of product submissions to CDRH had dropped slightly from 9,872 to 9,178.

Schultz said the drop in applications is not to be confused with there being less work for the center. He described new initiatives, such as expedited PMAs and combination product evaluation and approvals, as being "extremely resource-intensive." He said the center also is actively working with international regulatory bodies to work on streamlining the product application process to find away to make the process more transferable from country to country, possibly cutting down on some of the lag time between when a product is approval abroad and then in the U.S.

For FY05, Schultz said the projected budget is $215,102,889 in both appropriated and user-fee dollars. Just shy of $32.5 million of that was generated by user fees. "We can argue about the exact ratio, but there is a good reason for taxpayers to pay most of the bill, and there is also good reason for industry to fund part of the program in order to get that increment that improves performance, which I think is something that helps us all," he said.

Much of that budget will go toward new hires, Schultz said. During the past two years, CDRH has hired a total of 105 new employees, many of whom are shared among the center's different divisions. Most of the new positions have been scientists and engineers, as well as statisticians, project managers and medical officers. These are the jobs, Schultz said, that "really affect changes in the process that would lead to greater efficiency."

A chunk of the budget also has gone and will continue to be used to fund purchases of new equipment and updated technology for the center. Schultz argued that you cannot hire the best people if you ask them to sit at a desk "behind 20-year-old, antiquated technology. If we're going to do science, people who work in this area need the best equipment." To keep up with the pace of change and technology in the industry, CDRH must be at the same level, Schultz said. "I don't care what pot it comes out of, quite frankly, as long as it happens."

He said the agency is moving toward the day where we soon will see total electronic submissions, cutting down on the paper flow that the center currently manages.

In addition to hiring, training and information technology goals, the CDRH budget will be used to meet MDUFMA-mandated submission time objectives. For PMAs, the center is supposed to have 90% of submissions returned with a decision within 320 days. The 2002 baseline comparison was 69% within the same amount of time. The number improves to a 300-day goal for an expedited PMA. For 510(k), CDRH expects to be able to deliver a decision in 80% of cases within 90 days. The 2002 baseline was 71%. "Our goal is to do faster reviews – bottom line," Schultz said. "No matter what the resource load is. This is something we've got to do. This process should not be a barrier for companies."

But, Schultz said, it also is critical for companies to know the process and active parts of the flow of communication. "I encourage meetings like this, because it is helpful for people to know what we expect, and what industry is thinking."

Smoothing the 510(k) waters

The MDMA-sponsored conference, co-hosted by the Washington office of law firm Latham & Watkins, brought together FDA officials, industry representatives and attorneys to present details on a wide range of 510(k)-related topics. Those topics included an introduction to the FDA's premarket review of medical devices, the content of a 510(k), FDA regulation of combination products, expedited reviews, practical considerations from the agency's perspective, clinical trial considerations and good clinical practices.

One overriding theme was to explain the FDA's expectations, how the agency has operated in the past and how best to communicate with the agency to ensure timely and hassle-free product clearances. "Changing technology is constantly reminding them [the FDA] what their statutory responsibilities are," said John Manthei, a partner at Latham & Watkins. "In developing a product and looking at the intended market, how you plan is just as important as the regulatory process itself."

Perhaps one of the most informative presentations of the meeting came from Mark Kramer, director of the FDA's Office of Combination Products. That office was established in late 2002 as a resource for industry and FDA reviewers. Combining drugs and devices, devices and biologics, or biologics and drugs can cause confusion concerning proper classification, within both the industry and even individual FDA centers, and which center has product review responsibilities.

In its statutory role, the Office of Combination Products is responsible for the assignment of these products, to ensure timely and effective premarket review, postmarket regulation, dispute resolution and product review guidance, Kramer said. The key to unlocking combination product confusion in many instances, he told participants, is the product's defined primary mode of action (PMOA), the criteria used by the agency to assign primary jurisdiction for premarket review and regulation.

In May, the Office of Combination Products published in the Federal Register a proposed rule on PMOA, defining it as the means by which a product achieves a therapeutic effect. Because combination products have more than one mode of action, the primary mode would be what provides the most therapeutic action of the combination product. Thus, Kramer said the main question FDA and companies must ask themselves is, "Which part is most important of what this product is intended to do?"

For example, a drug-eluting stent's primary mode of action is the opening of an artery, the secondary action being that the drug prevents inflammation and restenosis of the artery. As a result, it is regulated as a device by the Center for Devices and Radiological Health. By contrast, a drug-eluting disk is assigned to drug regulation since its primary mode of action is cancer chemotherapy, while the secondary action is drug delivery via a device.

"Historically, most combination products have had a device-focused PMA," Kramer said. Because of that, most consultations are from CDRH [first, and then] to the Center for Drug Evaluation and Research (CDER). From October 2003 through August 2004, 17 combination devices were assigned to CDRH, six to CDER, and three to the Center for Biologics Evaluation and Research.

"Our role is to make sure sponsors know what will be required and for review staff to understand the importance of coordinating when more than one center is involved," Kramer said. "It is a change in culture among the different centers. But that comes with education, and we have to demystify how each center works to the other. That comes with increased awareness and time."

One important area Kramer addressed was how user fees apply to combination products, a common point of some confusion. For a single marketing application, a company would only pay the fee associated with that type of application, unless a sponsor chooses to submit two marketing applications when only one would suffice. This, Kramer said, would add an extra level of regulatory assurance and, especially with a new product in the drug sector, provide greater marketing security and exclusivity. In a situation where the FDA would require two applications – though under what specific circumstances remains unclear – for a device and a drug, the payment mandated under the Prescription Drug User Fee Act would be reduced by the amount required under the Medical Device User Fee and Modernization Act.

Kramer acknowledged the complexity here and urged manufacturers to contact his office for clarification. "What we want is to make the regulatory landscape as transparent as it can be," he said. "It is important that the fees or the process required with a combination product not act as a barrier."

With the number of combination product application already at 58 for the year as of the time of his appearance at the conference, Kramer said he foresees only good things in the future for his office. He predicted more systematized consultation process and a more predictable processes for assignment, premarket review and postmarket regulation.

Taking an overview look at the FDA's current operations, Manthei said that the agency of today is a far cry from what it was 10 years ago, and he characterized the its recent faster responses to 510(k) submissions as "phenomenal." He said, "If you compare the FDA of the mid-1990s to today, there has been a remarkable improvement. The current [review time] of 90 days is pretty good, though with user fees we should expect even greater improvement."

In FY03 a total of 3,914 510(k) submissions were filed, compared to 53 PMAs. And while the FDA has improved its 510(k) processes and review times, companies must remain vigilant, according to Carolyne Hathaway, also a partner with Latham & Watkins. Though a 510(k) is more common than the more complex PMA route to market clearance, the 510(k) process should not be taken lightly, she said.

Prepare as far ahead as possible to avoid wasted time, she told seminar participants, adding that too many companies too often begin FDA communication on a last-minute basis. The earliest possible communication with the agency "can mitigate the need to prolong the process and get a sense for the FDA's agreement or buy-in," Hathaway advised. "The FDA usually wants more information, but creating a relationship lessens the likelihood of major information being requested after the 510(k) is submitted."

Hathaway also cautioned that selecting the appropriate predicate device – another device already cleared that reviewers will use for comparison – is essential to 510(k) clearance. The best match can be found through a search of FDA databases, a process outlined by Hathaway and other speakers at the two-day conference.