Forging New Regulatory Pathways at FDA
Mark Kramer heads an office in FDA that is very small but could have tremendous influence on the future of device regulation. The Office of Combination Products (OCP) was created in 2002 as a result of the Medical Device User Fee and Modernization Act. Its main duties include assigning combination product reviews to a center and coordinating timely premarket reviews involving more than one center. It also must ensure the consistency and appropriateness of combination-product postmarket regulation.
The seven-person staff is also responsible for developing rules and guidance documents specific to the assignment of combination products. Perhaps its most significant policy initiative to date came in May 2004. It proposed a rule that outlined how such assignments will be made and defined key terms in the process. The full text of the proposal can be found on-line at www.fda.gov/ohrms/dockets/98fr/oc03366.pdf.
Of particular interest is the policy’s scheme, called the assignment algorithm. This algorithm establishes a framework for selecting the lead review center for products for which a primary action cannot be determined. OCP is currently reviewing feedback from industry and other stakeholders. After considering the issues cited, it will publish a final rule.
Kramer, OCP’s director, spoke with MD&DI’s East Coast editor Erik Swain about the reasoning behind the proposal, the duties that the office performs now, and the role the office may play in the future.
Q: How has the role of OCP evolved since it was created?
A: Our statutory roles are the same. However, because of an increasing awareness within the agency and within industry about what the office does, we get a fair amount of requests coming in for help in forging regulatory pathways for products. That’s not one of our statutory roles, but it’s an area where I think we provide the most added value. We help work through difficult regulatory issues involving some challenging products. Some seek resolution of problems, others ask for specific advice, and some may just want help thinking strategies through.
Q: Are combination products the wave of the future, as some are claiming?
A: By all accounts, it seems they are the wave of the future. Not to the extent that everything will become a combination product, however. Device and drug companies are looking toward improvement of existing technologies, such as developing a drug coating for a device to make it safer or more effective, or developing a delivery device for a drug to make it easier to use.
Q: Do you see an expanded role for your office in the future? For example, do you see a day when it performs reviews of combination products?
A: As these products continue to proliferate, there will be more work for us to do. But reviewing products would be a fairly fundamental change. We are a small group right now. It’s not even conceivable that we could perform that function. Besides, the law provides for that authority to remain in the centers.
My own personal take is that to do such a thing, we’d have to have the diversity of expertise that the three centers have now––maybe even more. I don’t know how realistic that is since resources are tight. Also, if another group of reviewers were created, it could add to the complexity [of the process]. There is logic in having drug-eluting stents reviewed by the same people who review other types of stents. What if a drug-eluting stent were approved, but it used a stent that did not meet the standards of the bare-metal stent reviewers? Having the office review products might seem attractive, but it could create new problems. So, for now, we have no intention to do that. I have seen improvements in the way the centers work together. I believe that we can work within the current paradigm to make combination product reviews as consistent and effective as possible.
Q: There is a perception that CDRH has a less rigorous review process than the Center for Drug Evaluation and Research [CDER] or the Center for Biologics Evaluation and Research [CBER], and therefore firms should do what they can to have CDRH be the lead review center for their combination products. Is this a fair perception, and to what extent does OCP take into account a firm’s wishes when assigning a center to a review?
A: The review standards are more similar than they are different. That being said, sponsors do tend to have preferences. During the process used to assign a combination product to a center, a sponsor is required to make its recommendation for a lead center based on the product’s primary mode of action. Most sponsors of combination products historically have been device companies, and they tend to prefer CDRH. [These sponsors are] familiar with the process involved in reviewing [a device] application. They are also familiar with the device guidances, regulatory pathways, and statutes. However, when we have combination products developed by a drug company, they are more apt to request CDER or CBER to review [their products]. That’s because the whole device process is often foreign to them. They are more familiar with the drug process. We are required to assign the lead center based on the primary mode of action of the product.
Q: What kind of feedback have you received from industry regarding the OCP initiative?
A: It looks favorable so far. Many of the comments have been along the lines of “it needs some refinement, but not a major overhaul.” I’ve not yet heard that we are totally off base.
Q: How did you come up with the definition of mode of action?
A: The biologic, drug, and device mode of action definitions are closely tied to the definitions of biologic, drug, and device in the law. There’s nothing magical there. The definitions are designed to be mutually exclusive.
Q: How did you come up with the definition of primary mode of action?
A: Primary mode of action is defined as the most important effect of a combination product. We want to consider what the product does, what is most important about it, and how it works.
Q: How did you come up with the assignment algorithm? Does it address the concerns of those who may be unsure what OCP would do with products that don’t have a single primary mode of action?
A: How we would handle products without a clearly identified primary mode of action was an area of concern. The products that are not usually difficult to assign are the ones where one component is a helper. With a drug-eluting stent, the primary mode of action is the stent. The drug helps the stent do its job better. But there are products without an obvious helper, where the primary mode of action is unclear. The assignment algorithm would allow us to handle them.
Q: The algorithm stipulates that products without a primary mode of action be reviewed by the center that has “the most expertise to evaluate the most significant safety and effectiveness questions” presented by the product. How do you define expertise and how do you decide which safety and effectiveness questions are most significant?
A: If we’re not sure of the most important therapeutic action, then the product will be assigned to the center with direct expertise in that type of combination product area. If no center has direct expertise, then it will be assigned to the center with the most related expertise. We would consider the safety and effectiveness questions raised by that product. From there, we can determine which center has the most expertise related to those questions. As far as which safety and effectiveness questions are most significant, it’s hard to answer that hypothetically. It has to be evaluated in conjunction with the product as a whole, and not just with what is novel about the product.
Q: What is the next major challenge for the office after the proposed rule outlining the assignment process gets implemented? Are there any other statutory voids that need filling?
A: We are continuing to work on a number of issues. We’ve identified areas that need to be clarified, and we are working on them. These include adverse-event reporting and selecting GMP requirements. Should the manufacturer of a drug-device combination follow the QSR, the drug GMPs, or some combination of the two? Also, when are two applications required as opposed to one? There are also cross-labeling issues—when do two different products need to be labeled for use together? We just issued a guidance on dispute resolution. Handling of post-approval changes is also an issue. We have made a lot of progress on many of these issues. It’s just a matter of having the time to write regulations and guidances, and get them out for comment.
Q: What kinds of combination product technologies might we see in 10 years that don’t exist right now?
A: I’m not the best person to answer that, but nanotechnology and drug-delivery technology seem to be waves of the future. Also, in contrast to products that combine two different things, such as a drug and a device, there might be products that perform two functions; for example, a single entity’s acting as both a device and a drug.