Medical Device Link.

Originally Published MDDI May 2002

FIRST PERSON

Proposals currently before Congress for changing the regulation of combination products fall short of the needed reform.

Kshitij Mohan, PhD

A famous professor of economics is said to have used the same questions in tests that he gave year after year. When challenged by a student to update the questions, he replied, "In economics, young lady, we don't change the questions—we just change the answers."

So it is with regulatory issues such as how to deal with combination products, and it is now time that the answers to this issue be re-examined and reinvented.

The medical device law came into existence in 1976 because medical devices, given their unique interdisciplinary origins, were a kind of combination product of those days. Neither FDA nor industry possessed the intellectual and organizational frameworks to deal with them adequately. The core technical disciplines of engineering, material sciences, and computer sciences drawn on by the device industry were not the forte of drug developers or the drug reviewers in FDA. Innovation in devices came from small companies that required different economic incentives than those of the giant stalwarts of the pharmaceutical world. For example, small companies building expensive devices could not afford to give away their products even in the investigational stage, unlike the drug industry.

The appropriate science for the validation of devices was different from that for drugs or foods. The engineers and scientists behind innovation in the device arena shared little fraternity with the researchers and chemists of the pharmaceutical world. In many cases, the "valid scientific evidence" represented by the placebo-controlled, double-blind clinical trials of the drug world, or the contamination- and toxicity-driven safety concerns of the food world, simply did not apply to devices.

There were early attempts to deal with devices by increments. Sutures, contact lenses, and other so-called transitional devices were regulated as drugs. Pharmaceutical giants started up device subsidiaries as an extension of their drug business. Most of these incremental efforts were inadequate. Instead, in the classical tradition of innovation-driven change, new regulatory and business paradigms evolved.

There is an obvious parallel between the medical device world of the 1970s and the state of combination products today. Tissue engineering, gene therapy, therapeutic proteins, microelectromechanical systems, robotics, and bioinformatics are creating a myriad of disruptive technologies. These technologies will in turn provide elegant new answers to the same old questions. The drivers of this innovation—academic institutions and technology entrepreneurs—are either unencumbered by or shedding the old organizational and process barriers to the development of new technologies.

Laws and regulations have been slow to shed incrementalism in this area, as they always are, sometimes rightly. Over a decade ago, the Safe Medical Devices Act of 1990 represented the first legislative recognition of the issue. The remedy legislated was predictable: if combination products are permutations or combinations of drugs, devices, and biologics, then let us name a referee—the FDA ombudsman—to ensure that the appropriate FDA center takes the lead for each product and consults with the other appropriate centers.

The process has worked well for some straightforward drug-device combination products, but for more-complex products, particularly those involving biologics, it has faltered. Even at its best, the process increases FDA review time. Simply appointing an FDA center to be the lead on a specific product can take 60 days. At its worst, the process can kill a promising technology because the time, expense, and uncertainty make development economically unacceptable.

Now that the FDA Modernization Act (FDAMA) is a few years old, there has been growing discussion of a "FDAMA Junior." Regulation of combination products is a key part of a new legislative proposal, HR 3580, introduced in the House by James Greenwood (R-PA), Anna Eshoo (D-CA), and others.

Current regulations assume that the scientific and regulatory expertise regarding drugs, devices, and biologics resides exclusively in the centers for drugs, devices, and biologics, respectively. Formally defined relationships between these centers are required to access that expertise for any product that touches on more than one of those areas. On the face of it nothing sounds more logical—until you look at the practical aspects of implementing such a program.

First, you start off with three mutually exclusive organizations. Then you add three disparate sets of legal and regulatory requirements. For added spice, since the government, like industry, is populated by humans, add multiple institutional memories, some legitimate organizational pride, and competitiveness in an era of tight resources. Further, there is the diversity of imaginative combinations that these products entail. As a mathematical problem, the solution would merit a Field's medal. In real life, it should not be surprising that a multitude of problems result.

The law requires that a lead center be chosen based on the primary mode of action of the product. In many instances, however, the primary mode of action is debatable. CDRH has the lead on unmedicated wound dressings. Does the addition of medication change the primary mode of action? If the dressing is a biological membrane that gets absorbed, does the mode of action change? What about a wound dressing of biological origin that is impregnated with a drug? Your answer to these questions may well depend on where you sit—in which center, or where in industry.

Regulators, industry, consultants, and trade associations are trying to tease out the logic of designations and how FDA should meet its commitments. Much of this effort is like measuring length to the fourth decimal place with a crooked ruler. The danger is that the traditional way of dealing with such complexity will make the process even more complex. A new maze of regulations, guidelines, and guidance memos could be the result. The process would end up delaying or denying benefits to patients without providing offsetting benefits of enhanced safety and effectiveness.

Rather than trying to suit innovation to the needs of an outmoded regulatory system, let us examine how the system can and should be changed.

First, let us agree on a few assumptions:

• Combination products need to meet the general norms of safety and effectiveness in the context of risks versus benefits as enforced by FDA.
• Even though these products are complex, the basic tools of regulatory science—including disciplined design practices, bench testing, animal trials, clinical trials, good manufacturing practices, and postmarket monitoring—can be applied to almost all of them.
• There is nothing sacred about the sharp lines between drugs, devices, and biologics. The future of medical technologies should not be held hostage to history.
• Small groups of bright people in academia and industry, working in a conducive framework, create these combination products. There are many equally bright people within FDA. The agency, through its advisory committees, has or can have access to some of the best minds in any new area of science and technology. It is possible to create mechanisms that will provide FDA with adequate scientific expertise to address these new products.
• Whether it is FDA or industry, resources are needed to make any program a success. The fact that managers in FDA cannot reallocate resources or fire underperformers with the same facility as their colleagues in industry is not their fault. Congress needs to fulfill its responsibilities through appropriate funding.

Given these assumptions, what could be a solution to this problem? In a trade association meeting a year or two ago, when new legislative initiatives were being discussed, I casually recommended the creation of an office of combination products at FDA. Others have made the same recommendation. The suggestion has picked up enough support that it is now included in the proposed legislation.

The creation of such an office will not, by itself, be a panacea. Where it is located, what authorities it has, and what resources it is given will determine whether it speeds or further slows innovation in combination products.

However, the current proposals include the creation of an office of combination products in the office of the commissioner, to play an advocacy and coordinating role among the centers. This model, based on the success of FDA's Office for Orphan Products Development, is ill suited to this case. Unlike combination products, orphan products used to suffer neglect by FDA and industry. This was not because they challenged the review process, but because their markets were limited and they did not have strong support within or outside the agency.

So how should an organization for review of combination products be established? I believe it should be influenced by the structure of the organizations that innovate these technologies and products.

The best starting point would be to create a new office of combination products within CDRH. Eventually it could become an independent center. Until that happens, CDRH is an appropriate home for the following reasons:

• It is one of the most interdisciplinary of all the FDA centers. Even today it has competencies ranging from molecular biology to software engineering. Its Office of Science and Technology is a laboratory-based research and validation methodology development group with some competency in most of the technologies behind combination products.
• The most complex combination products are invariably devices involving drugs or biologics, or both.
• CDRH has a flexible regulatory culture, because of the unique nature of medical devices and the medical device regulatory structure.
• CDRH has successfully integrated diverse programs. For example, the old Bureau of Radiological Health was successfully merged into the device center.

It is important that this new office be created through separate authorizing legislation. It should have the principal responsibility for regulating combination products, not just an advisory or advocacy role. The authorizing and follow-up legislation should ensure that the new organization is appropriately funded. An admonishment to go forth and do good will not be enough.

The permanent staff of the new office should be recruited after identifying the technical core competencies needed. It should consist of some key current members of other FDA offices and centers, particularly CDER, CBER, and the ODE and OST offices in CDRH. In addition to a permanent staff, some scientists and reviewers from FDA and NIH and even academia should have joint appointments to this office. Most of the interdisciplinary groups and consortia in academia (e.g., the MIT Media Lab or the Johns Hopkins center for computer-assisted surgery technology) are organized in this way.

The regulatory scope of the new office should be defined clearly and simply. Products that involve totally new chemical entities or biologics that could become stand-alone products, or in which the device component is clearly ancillary to the product, should continue to be regulated in the centers for drugs or biologics. All other combination products and devices used with blood products or biologics, or devices of biological origin, should be directly regulated by the office of combination products. Where there are doubts, or compelling but contradictory arguments about jurisdiction, the product should be assigned to the office of combination products. There is no reason why the office could not recruit or access adequate expertise to adequately review such products.

The creation of such a regulatory structure would have two major benefits. First, it would improve healthcare through a more efficient partnership among FDA, academia, and industry to speed the introduction of beneficial new technologies. Second, and just as important, it could become a model for how all of FDA will evolve to meet the changing needs of the 21st century.

Kshitij Mohan is a former head of FDA's Office of Device Evaluation and was the top science and technology officer at Baxter International and Boston Scientific Corp. He is currently chief regulatory and technology strategist for King & Spalding in Washington, DC.

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