Roundtable: Medtech’s Outlook in Regulatory Affairs 4377

GOVERNMENTAL & LEGAL AFFAIRS

This year, there is a lot of FDA-related legislation moving through the House and the Senate. In addition, Congress is in the midst of evaluating other areas of significant concern to medtech manufacturers, such as U.S. patent system reform and the adoption of health information technology. Also on the docket are a wide range of regulatory issues with far-reaching implications for the medical device industry, including FDA initiatives for clinical trials management, adverse-event reporting and recalls, unique device identifiers, and the advertising and promotion of medical devices. The final shape of these and other policy areas promises to have significant implications for firms operating in the heavily regulated field of medical devices.

To find out more about medtech's outlook in regulatory affairs, MX recently spoke to two experts in the field (see sidebar). In this excerpted roundtable discussion, moderated by MX editor-in-chief Steve Halasey, participants discuss the progress and expected outcomes of FDA-related legislation now being considered by Congress, as well as other regulatory developments. The full text of the discussion can be accessed via the MX Web site here.

MX: This year, there is a lot of FDA-related legislation moving through Congress, including reauthorization of the Medical Device User Fee and Modernization Act (MDUFMA II). However, many in industry have expressed disappointment that Congress left so much on its plate over the summer recess, to be addressed in September. What is your sense of the progress and expected outcomes of this legislation, starting with what remains to be ironed out between the House and Senate versions of MDUFMA?

Susan Alpert: I don't think there's a lot that's problematic between the House and the Senate on the user fee component itself. We know that we're going to have user fees, and both the agency and industry have already made commitments about the amounts of the fees and how this five-year period of authorization will work.

Some questions have come up regarding FDA's commitment. But, in fact, the changes in FDA's commitment are not extreme, and I expect them to be ironed out in a fairly straightforward way.

However, there are a number of issues related to other proposals that are being included in the same legislation. In those areas, there are differences in the House and Senate approaches that will need to be ironed out. For instance, the proposals related to clinical trials registries affect industry because they impose requirements related to the timing of registration, the kind of information to be recorded, and follow-up and reporting. The shape of these requirements is murky and still needs to be clarified.

How would you judge the cooperation of industry organizations when working with FDA to create a revised version of MDUFMA that could be sent to Congress?

Bradley Merrill Thompson: From my own observations outside the conference room, it seemed as though folks were getting along much better than in the past.

Alpert: The industry associations—represented by AdvaMed, the Medical Device Manufacturers Association (MDMA), and the National Electrical Manufacturers Association (NEMA)—made a concerted effort to work together as an industry prior to holding conversations with FDA, and the process worked extremely well. There were areas that were more or less important to each of the associations, but everybody's issues got raised and spoken to. We met many times, for many hours, to go over lots of issues. And the result really was an industry position.

Some elements of the proposed legislation are intended to address concerns about the safety of drugs, but could eventually also have an effect on medical device regulations. What other elements of the legislation might prove problematic for the device industry?

Alpert: The device industry gets swept in no matter what's going on. On several of these issues, we obviously knew that the concerns were around. With regard to clinical trial registries, for instance, that issue had been a point of industry discussion for many months. So we knew a proposal was coming, and it was not a surprise.

The pediatric legislation was a slightly different story. We have been working with several groups, including the American Academy of Pediatrics and the Elizabeth Glaser Foundation, on some approaches that FDA might take to dealing with the increasing public emphasis and concern about pediatric devices. So it was not a great surprise that this issue appeared in the legislation.

Having spent a fair amount of time working with a number of organizations, however, we were a bit disappointed that what was proposed in the legislation was pretty much where those organizations started several years ago. It didn't at all take into account our efforts to define what a good pediatric program would look like. So we were a bit disappointed that we had to go back and work through a lot of those same issues yet again.

The legislation still has some issues that will need to be dealt with. But, so far, we haven't been shocked or surprised at any of the proposals. And even the remaining issues that have already taken a fair amount of work were not unexpected in some part.

With regard to the regulation of combination products, are there provisions in the proposed legislation that would make matters more difficult—or perhaps simply leave unresolved known issues that should be addressed?

Thompson: The current proposals are really more in the latter category than the former. There are proposals that may be problematic for devices, or for drugs, but I don't see any proposals that are any more problematic for combination products in particular.

One combination product issue that has been a bit neglected is how to develop an integrated approach to adverse-event reporting. In the unfortunate circumstance that someone is hurt through the use of a combination product—and the product involves multiple manufacturers, or one manufacturer with multiple components that variously qualify as a drug, device, or biologic—it can be very difficult to figure out which reporting obligations apply to the situation. FDA has been working on a proposed rule for quite some time, but in this area it's very difficult to develop a truly unified approach by using the existing statutes as a framework for rule making.

There are other areas that could probably benefit from statutory clarification, but it might be a bit premature for Congress to take them on. For example, FDA has been working for quite some time to come up with an approach to good manufacturing practices (GMP) requirements for combination products. In this area, the existing statute is probably not so much of a problem. The statute gives FDA a fair amount of latitude about how to implement its broad directives, so the agency can probably use rule making to clarify whatever it needs to. But that issue does need to be sorted out one way or another.

A third area that has been neglected, and where some attention would be helpful, is that of international harmonization. All around the world, regulators are now coming to grips with what combination products are and the best approach to regulating them. But there's very little dialogue going on internationally about what the best practices are from a regulatory standpoint.

I don't know whether harmonization is a particularly appropriate subject for legislation. But harmonization is much easier to accomplish when you're building the system than later, after it's already constructed. So I'm worried that the lack of dialogue as we're developing our combination product regulatory systems will come back to haunt us later, when we end up with the inevitable conflicts among the approaches taken by different jurisdictions.

FDA Initiatives

FDA already has a number of active initiatives in a wide variety of areas. Will the agency be able to do anything more in these areas as a result of forthcoming legislation?

Thompson: There are at least five or six other areas where you probably will see a fair amount of activity.

One issue that is still very open is the regulation of genetic testing. The proposed legislation speaks in terms of having the Institute of Medicine conduct a study to determine the best regulatory approach to the genetic testing category.

But this entire issue is more complex because of its relation to the broader issue of how to regulate lab-developed tests. And independent of the legislation, there's a whole lot of pressure from all sorts of quarters to reconcile the tremendous differences between the regulations that apply to tests that are developed by traditional IVD manufacturers and those applicable to tests developed by laboratories.

FDA recently released a revised draft of its guidance on in vitro diagnostic multivariate index assays (MIAs), which deals with a narrow subset of lab-developed tests. Although narrow in its scope, this guidance is still profound in its approach, because it is among FDA's earliest explicit forays into regulating tests developed by laboratories.

A second area would involve further adjustments in the advisory committee process. This is an area covered in the proposed legislation, but there are differences between the House and Senate versions. So this will be a topic of discussion in conference.

FDA is also still grappling with this issue. But fundamentally, the agency is going to have to come to grips with wanting to have its cake and eat it, too. On one hand, FDA wants advisory committees that, if optimally composed, will include people who get their hands dirty working with drugs and devices—practitioners who actually use products in clinical trials or have some familiarity with them. But on the other hand, the agency seems to expect that the people it recruits will have no ties to the various parties who have an interest in producing or selling the drug or device.

The agency is going to have to sort this issue out. It has already released new guidance about advisory panels, but Congress apparently wants it to do more. So FDA is going to have to resolve this issue.

Alpert: Congress focused on the dollar. But it did so without recognizing that there are physicians who are working or have worked with medical device companies in the past, who may have been inventors of products that are now owned by different companies, and they are still receiving royalties. According to the proposed legislation, those dollar amounts would now become a means for identifying potential conflicts of interest—and thereby disqualifying those panel members.

The proposed legislation has not fully determined how FDA should define conflicts of interest. Not only is it unclear how those conflicts are supposed to be defined, it also isn't clear whether an advisory committee would be prohibited from having any conflicted people, or would be permitted to have one or even more than one conflicted person.

These are things that will get worked out. And along the way, hopefully, they will get worked out in such a way that preserves FDA's freedom to use its best judgment about who it selects and how it constitutes panels, so that it gets the best possible advice. That advice is very important for the decision making that FDA has to do.

Brad, were there more issues on your list of regulatory areas to watch?

Thompson: Yes. Another one is the area of third-party inspections, which has been an area of great mutual frustration for both FDA and industry.

Everybody thought that mutual recognition of third-party inspections was an idea with important potential for today's resource-constrained world. There was a strong feeling that FDA's need to focus on the highest risk areas could be fully realized only if there were some other system that could at least help out with routine inspections.

But despite such high hopes, when the last Congress finished its legislative work and the authorized program was finally implemented, the program just wasn't what it had promised to be.

Since then, just about everyone has taken a look at the program with an eye toward making improvements. FDA has been working on it. The agency entered into an agreement with its counterparts in Canada last fall. FDA earnestly wants to make this program a go, but its hands are fairly tied based on the existing statute.

Based on the current draft of the proposed legislation, it seems likely that some changes will be made in the statutes relating to third-party inspections. In that case, FDA and industry would have new hope that the program could be developed in a way that makes it more useful to everyone.

Alpert: There was a lot of discussion around the topic of third-party inspections during the negotiations between industry and the agency. At the beginning there were some concerns on the part of the agency, but I think we wound up in a position that the agency was also comfortable with.

Because Congress is unfamiliar with how the process would work, some members are concerned that FDA is somehow giving up its rights, authority, and ability to ensure compliance with regulations. But during the negotiations, we were very clear that that's not the intent at all.

The intent is to have an ongoing audit program that's more manageable for companies but doesn't take away any of FDA's rights or authority.

Congress has also become interested in the issue of unique device identifiers. How do you see this issue playing out?

Thompson: The unique device identifier issue has been very contentious, in part because the technology is being proposed as a solution for a relatively unspecified or undefined risk, but with a fairly high defined cost. So the first step, it would seem, is to figure out whether unique device identifiers solve a real problem.

FDA has been trying to proceed in a deliberative way, holding a public meeting and getting its ideas out to all of the industry stakeholders in anticipation of possible rule making. So the agency has been trying to look at these issues closely.

Congress may step in and take away the threshold question of whether unique device identifiers need to be implemented. In that case, the question will evolve into how to do it in a way that adds real value and doesn't waste precious healthcare resources.

When you are standing on the outside of this issue, it seems really simple: you either put a bar code on a product or you don't. But when you really look at the issues carefully, this is logistically a very complicated area.

Alpert: That's right, and there are a lot of unaddressed issues. The proponents haven't even decided whether the identifiers would have to be placed on the packaging or on the device itself. When you ask people in Congress and at FDA about this, the answer you get depends on who you're talking to. But the difference between these two requirements is like night and day.

On the issue of device safety, over the past year FDA has been especially concerned with questions about how best to conduct postmarket monitoring of approved devices. How do you see this area evolving over the coming year?

Alpert: This issue came up in proposed legislation in the form of a question of whether there ought to be money and resources earmarked for postmarket activities.

CDRH has already changed the way it looks at products in the postmarket environment, both in terms of the visibility of its program and what staff are assigned to it. Clearly, a lot of these changes have been made in reaction to public and Congressional concern over product safety and the objectivity of FDA's assessments of postmarket data.

CDRH took a good step by focusing its work and internal resources to improve communications among various groups within the device center. These changes have brought compliance folks and scientists—staff from the Office of Device Evaluation (ODE), the Office of Compliance, the Office of Science and Engineering Laboratories, and the Office of Surveillance and Biometrics (OSB)—into much closer contact over many more issues. And the center is also creating working groups that are developing expertise in specific product areas. And once this expertise has been developed, it will be a great benefit to both the agency and to industry.

But in the meantime, there is a concern that legislation could have a harmful effect on both the intent and the process.

Unaddressed Challenges

Aside from the issues now being addressed in new legislation or current FDA initiatives, are there other important medical device issues that are not getting the attention they should?

Thompson: One topic that is rapidly becoming the unmentioned elephant in the room is promotional issues. I had an opportunity to moderate the device state-of-the-center session at this year's FDLI meeting, which featured a presentation by CDRH director Daniel Schultz, MD. During the question-and-answer session that followed his speech, the only thing the audience really wanted to talk about was promotional issues.

Questions that the audience raised included what uses of peer-reviewed literature are permissible, and what uses are impermissible; off-label promotions; and so forth.

Alpert: Yes, this is an issue of increasing interest since FDA's rule on the dissemination of information on unapproved and new uses for marketed drugs, biologics, and devices

(21 CFR 99) died. The legislation had a sunset provision that was allowed to end the use of this provision.

Thompson: Part 99 really wasn't worth the paper it was written on. But there is currently nothing to replace it, nor any earnest discussion about developing guidance in this area. It's almost unconscionable that FDA has abdicated its regulatory responsibilities to give guidance in this area.

Companies in this business are looking to do the right thing. They're in business now, they plan to be in the business 50 years from now, and their reputation is everything to them.

Companies want to play by the rules, so they go to some poor lawyer and ask what those rules are. But all that the lawyer can do is tell the company to rely on first principles: don't lie, don't cheat, and a few other general platitudes. And when the company asks questions that require more-specific answers, the lawyer can give an educated opinion—but there's no FDA guidance to back it up.

Such an absence of regulatory guidance creates two problems. First, it puts companies in jeopardy, because they can easily and innocently stumble into practices that FDA considers violative.

Second, it encourages disreputable companies to push the envelope and do things that wouldn't be considered by companies that want to take the high road.

In the area of device advertising and promotion, everyone in FDA has an opinion. The problem is you can't find two opinions that are the same.

Alpert: And no one is willing to go on the record and make their opinion official.

Thompson: Right. So this is a constant source of frustration.

It also really impedes the whole medical device delivery process. Companies don't know what they are permitted to say about their products. And they don't know when it's appropriate to share information and when it's not appropriate to share information.

Alpert: And it's not good enough for a company to hear for the first time that it has created false claims when the U.S. attorney walks in and says so.

The absence of FDA guidance invites the frequent involvement of the Department of Justice. What's the solution?

Thompson: I think there are two distinct issues. The first is whether industry needs substantive direction. The second is whether industry needs a process that can be used to get input from the agency. And I imagine that the correct answer is that industry needs a little bit of both.

First and foremost, I would urge FDA to develop guidance that reflects what the FD&C Act requires in the way of using peer-reviewed literature, textbooks, and so forth. I have a long list of questions that come up every day from companies in this industry, so developing guidance to address those questions is at the top of my list.

Second, to handle the inevitable additional questions that aren't answered in the guidance—and have yet to be identified—FDA should create some process or mechanism for obtaining agency input. It doesn't need to be a big apparatus like DDMAC, it just needs to be a point person in the agency who will be able to respond with some authority over permissible promotional practices.

FDA has often invited industry to draft guidance. Is there an opportunity here for some of the industry's marketing associations to pull to­gether that kind of effort?

Thompson: I suppose so. Normally I'm very bullish on that idea because it offers an opportunity for industry to add value by developing thoughtful approaches. The problem here is that if industry attempts to create guidance in isolation from FDA, the chances of coming up with something that FDA will find useful are very low.

I really think such an effort needs to be preceded by more of an in-depth dialogue between industry and the agency. After that, perhaps, industry could come up with a proposal. But there's got to be some dialogue first, because otherwise industry is just shooting in the dark.

Closing Thoughts

In closing, what notions do you consider most important for Congress, FDA, and industry to consider when handling current and future regulatory issues?

Alpert: This is going to be a very challenging time for FDA. Implementation of new legislation is always challenging, but in this case the new legislation will require changes because of modifications that have been made in the user fee program.

Beyond the legislative agenda, FDA must address all the matters that we've been discussing. Many of these areas are becoming more and more important to the regulated industries, and they should not be neglected.

It behooves FDA to take advantage of opportunities to work broadly across all of the participants in the healthcare environment. It is a huge challenge, but the agency should try to find ways to address all of these stakeholders in appropriate ways, and to put in place communications channels that will have a lasting effect.

Thompson: As the agency implements all of the new policies and rules that will follow this legislative cycle, it should remember to follow good guidance practices. More transparency and public participation is greatly preferable to unilaterally releasing guidance from the podium or some of the other practices the agency has followed in the past. The agency should make an effort to work in an open and participatory way that gains input from industry and results in better guidance.

Copyright ©2007 MX