Clarification of primary mode of action (PMOA) is a priority for the soon-to-be established Office of Combination Products, according to Mark Kramer, director of the agency's current combination product program within the FDA Office of the Ombudsman.

"We do think...it is time to provide much more clarity: whether it turns out to be a regulation on what PMOA means, or [a] guidance that is developed through the GGP [good guidance practices] process, it is something that is very high on our list," Kramer said Nov. 21 at an AdvaMed educational seminar on the Medical Device User Fee & Modernization Act.

Although the PMOA of a combination product is the basis by which FDA assigns primary jurisdiction of the product's review to a particular center, the term has yet to be defined legislatively or by regulation, Kramer observed.

FDA is currently seeking input from stakeholders within the agency and beyond on how PMOA should be interpreted and used to make jurisdictional decisions.

In October, the agency released results of 25 interviews with FDA staff who are involved with combination products. The report, ¹ 'Regulation of Combination Products: FDA Employee Perspectives,' also presents recommendations and plans for guidance development by FDA's high-level steering committee on combination products.

According to the report, "participants [have] expressed the view that better guidance" addressing definition and interpretation of PMOA "would improve consistency and transparency and reduce 'turf battles' between the centers as new jurisdictional decisions are needed."

The agency is also reviewing remarks made by stakeholders at meetings and comments submitted to FDA's dockets. Interested parties may submit comments until Jan. 24 on PMOA and other combination product-related issues such as intercenter agreements, selection of premarket regulatory authorities, dual applications, combo product GMPs, adverse event reporting and cross-labeling.

The debate over PMOA surfaced earlier this year when FDA announced it was considering changing jurisdiction of wound-healing products. Discussion ensued on whether FDA should consider the whole device or component parts when it considers PMOA and other factors in assigning product jurisdiction (² Also see "Primary Mode of Action Is A Primary Focus Of Combo Products Hearing" - Medtech Insight, 1 July, 2002., p. 8).

More recently, at a Nov. 25 FDA public meeting on combination products, a number of stakeholders suggested that risk-based models should form the basis for jurisdictional assignment.

"The criteria that should be followed in selecting the premarket authority should be based on assuring the safety of the patients, not one purely based on primary mode of action," Guy Chamberland, PhD, Angiogene, maintained. "The division with the most experience with the primary safety issue would have the primary review responsibility."

"In cases where primary mode of action cannot be assigned with certainty, additional criteria should be considered," Owen Fields, PhD, Wyeth, told attendees. FDA should first "consider which component presents the greatest safety risk and the center that has the greatest experience in managing the risk" in those cases.

Additional factors include the centers' experience with clinical, preclinical and manufacturing aspects of the product, precedent, and practical concerns such as agency resources, review time lines, procedural simplicity, flexibility, and sponsor familiarity with center procedures, Fields added.

FDA should be especially cognizant of the role that clinical trial design plays in evaluating a technology, Stuart Portnoy, MD, PharmaNet, emphasized. "I would think that it is critical to...examine which FDA center has the best clinical skills and experience to evaluate the sponsor regarding clinical trial plan issues and then to adequately evaluate the clinical results that were used to support market approval of the combination product," he said.

Portnoy, a former CDRH Division of Cardiovascular Devices branch chief, noted that "clinical trial design determinations ultimately dictate how much and what types of safety and effectiveness data will be collected and analyzed to support market approval."

Other speakers sought to quantify the process of assigning jurisdiction. For example, Zorina Pitkin, PhD, Nephros, presented a proposed risk-based model for classification of combination products that incorporate biologic and device components.

Under that model, products receive a combination product class based on the sum of risk scores for biologic and device components. Risk is largely based on the level of exposure posed by the product both in terms of direct contact with the patient and duration of exposure.

"The purpose is to identify the component of the combination product that potentially presents the highest risk, create one quality system which will encompass the most appropriate regulation that can be applicable to all components of a combination product and to establish a common approach to similar issues," Pitkin explained.

In another attempt to provide a more quantifiable and consistent regulatory process, Mark Hamblin, Carnegie Mellon University, presented a rule-based model for assigning jurisdiction of combination products. Under that model, there are three "pools of points" that correspond to the three centers at FDA - the device center, the drug center and biologics center.

A list of 88 weighted yes/no questions pertaining to general product characteristics and based on jurisdictional rules from the intercenter agreements is answered for each device. Based on answers to the questions, points are assigned to the different pools. FDA would then assign the product to the center whose pool garnered the most points.

Hamblin emphasized the model's applicability to future technologies and suggested that a web-based decision support tool would "offer greater transparency and predictability in the jurisdictional determination process," while allowing for "easy adaptability and variability to accommodate current FDA regulatory requirements."

David Fox, Hogan & Hartson, however, suggested that such an approach does not get at the crux of the jurisdictional assignment issue. "I don't think [the issue] is susceptible to algorithm or to flow chart," the former FDA counsel for the center for drugs maintained.

"This is inherently a management issue for the agency, inherently a human issue," Fox asserted.

Even with the decision support tool, "human decision-making would still be necessary, along with multi-disciplinary review of combination products," Hamblin acknowledged.

Fox downplayed using safety risk itself as the primary criterion in deciding which center should have product jurisdiction. "I am of the view that virtually any of the three centers, any of the application processes can obtain the data you need to ensure safety and effectiveness," the lawyer opined.

Instead, Fox advised FDA to consider how it had ruled previously in similar cases. "I think your best bet is to start with the hundred-plus precedents or so that you already have," he said. "Go back and look at those, try to mine the data and articulate the principles and go from there."

Fox also noted that before FDA can assign jurisdiction, it must first define what constitutes a combination product. "It is very important [to] do a retrospective analysis and look at those decisions" and "tease out the factors the agency relied upon," he counseled.

Under MDUFMA, the Office of Combination Products is required to track designation and review of combination products and report to Congress on those metrics.

FDA is working to develop IT capabilities to identify combination products, Kramer remarked during the AdvaMed meeting.

"Except for CDRH, which actually just implemented this on Nov. 15...there haven't been any flags to identify whether something is a combination product or not," the combination products program director explained.

Also at the center level, "we have a big effort in terms of training people that need to be identifying whether something is a combination [product] or not...and that is a really big logistical issue for us, and we have to handle it right away," Kramer noted. FDA is still finalizing staff for the office. No director has been officially named.

Recruitment of staffers for the office should be conducted in a way that will not disrupt the current review structure at the agency's center level, Portnoy advised during the FDA combination products meeting.

"It is essential for the reviewers of combination products to continue to work from their respective centers and not be pulled out to populate this new office," he said.

FDA Will Accept Primary Mode Of Action Definition Comments Until Jan. 24

More from Archive

More from Medtech Insight