FDA's recent announcement that it is reconsidering jurisdiction for wound products indicates a problematic shift in the agency's interpretation of "primary mode of action," AdvaMed maintained at a June 24 public hearing to discuss the regulation of combination products containing live cellular components.

While FDA historically has determined the primary mode of action of a combination product based on its function, the agency now appears to be basing its decision on the individual components within the product, AdvaMed rep Carolyn Jones observed at the meeting. She questioned whether this approach would be appropriate for wound-healing products.

"FDA's proposed interpretation appears to require the evaluation of the constituent parts of these products, which is largely unworkable for this class of products."

Wound-healing products are "not like drug-eluting stents or laser-activated pharmaceuticals," Jones said. "All of the components of these wound products...work together to serve the same essential function of facilitating wound healing."

"It would be virtually impossible, and financially impractical, to tease out the level and type of contribution of synthetic and extra-cellular versus cellular components, using current methodologies," Jones asserted.

FDA first announced that it was considering whether to shift wound-healing tissue products from CDRH jurisdiction to the Center for Biologics Evaluation & Research in a May 15 Federal Register notice. The decision would depend on the products' primary mode of action, which is determined by "how the product acts on the body and...the relative contribution of each of its component parts," the notice stated.

AdvaMed's comments were echoed by a number of other presenters at the hearing, including Advanced Tissue Sciences, manufacturer of Dermagraft . Consistent with its planned remarks, Organogenesis also maintained that it is impossible to elucidate a dominant mode of action for its Apligraf product (¹ Also see "Potential Jurisdictional Change Draws Protest From Wound Product Firms" - Medtech Insight, 24 June, 2002., p. 8).

FDA Science Board member Robert Nerem, PhD, Georgia Institute of Technology, also suggested that reliance on components to determine primary mode of action was at odds with FDA's historical approach. His presentation urged FDA "to shelve the proposal" and "enter into a constructive dialogue with the tissue engineering community."

"If in an emerging area like tissue engineering all FDA can do is shoe-horn these products into the existing structure, then congressional action may well be necessary," Nerem suggested. He also expressed concern about how an uncertain regulatory path could affect product development. "The proposed transfer may serve as an impediment to the further introduction of tissue-engineered products, in particular those based on existing platform technologies."

Stakeholders also questioned the need for FDA action, given the strong safety record of wound-healing products in the past. Interactive wound dressings have not had major safety problems or unanticipated adverse events, and demonstrate a safety profile comparable to traditional wound dressings, firms reported.

A change in jurisdiction in the absence of safety concerns would set a poor precedent and could spook investors in a market that relies heavily on private funding, Tissue Informatics, Inc. General Counsel David Smith, JD, cautioned.

Both Smith and Nerem characterized the tissue industry as being at a critical and vulnerable stage of development and maintained that a predictable path to market is crucial. "There were, at one point, 16 publicly traded companies with $2.5 bil. net capital value," Smith noted. "If you look at what has happened to those companies, and what may be anticipated for those companies going forward, it is not necessarily the rosiest of pictures."

"The best approach is...true intercenter collaboration," he proposed. "What I mean by that is collaboration that...really transcends assumptions that medical products are a combination of invisible parts susceptible to serial regulation."

While the hearing's focus was on wound-healing products, speakers made clear that FDA's decision would have potential jurisdictional ramifications for other areas regulated by CDRH as well. Interpretation of primary mode of action, for example, could affect the demarcations of intercenter agreements when they are revised. The agreements have not been updated since 1991, and industry has been pushing to see them clarified to ease the path to market for combination products.

"One important theme in the CDRH-CDER Intercenter Agreement is that combination products that have primarily a structural, physical, or reconstruction purpose are regulated as devices," Jones pointed out. "Not just wound-healing products, but also a wide variety of other extra-cellular products have been granted device status based primarily on their structural, replacement and repair functions."

Among future products that could be impacted by FDA's decision are encapsulated pancreatic islet cells, hepatocyte-based liver-assist devices, and mensenchymal cell-based structural grafts, the International Society for Cellular Therapy suggested.

While the majority of speakers urged FDA to preserve the current regulatory path for wound-healing products that have already gained approval as devices, proposals varied as to how the agency should treat similar products in the future. Some stakeholders suggested that looking at components within combination products and evaluating which component poses the greatest public heath risk should form the basis for designating primary jurisdiction for future products.

Recently, CDRH Director David Feigal commented that "the principle that is starting to be discussed worldwide is whether or not the component with the most complex public health issues and regulatory issues shouldn't be the one that drives the regulatory scheme" (² Also see "MDA Merger Qualms Fuel Device Industry Critique Of EU Drug Directive" - Medtech Insight, 24 June, 2002., p. 12).

At the June 24 meeting, ISCT suggested that the regulatory structure should be determined based on the "element most in need of control."

Complexity, criticality, variability, contribution to long-term outcome, and how the element interacts with its environment should form the basis for assessing which component should dictate primary jurisdiction, according to ISCT. In most cases, the biological component would be the element with the most concerns and should be handled by CBER's planned Office of Cells, Tissues and Gene Therapy, which should include representatives from CDRH, ISCT suggested.

The pharmaceutical trade association, PhRMA, urged FDA to settle on a mechanism for product jurisdiction that would create a level playing field. "When non-wound-healing applications for these [wound] products are proposed, we think that review should be based on mode of action, not historical approval mechanisms or claims or lack of claims, so that parity of regulations can exist," PhRMA rep Sara Radcliffe proposed.

With the exceptions of the approved wound-healing products, the drug trade association testified that "products containing living cells should be regulated within CBER's office of cell and gene therapy," including "cells in biomaterials or synthetic matrix." Under the PhRMA proposal, CDRH would review the matrix component as a consult to CBER. PhRMA also advocated that "jurisdictional issues should be handled through the Office of the Commissioner with representation from relevant centers."

The association also set forth a timetable, suggesting that as an initial step FDA should issue a "draft guidance six months after the close of dockets, outlining the classification of the jurisdiction for such products, processes for communication between CBER and CDRH, performance targets and a timeline for publication of the revised intercenter agreements."

At the same time, FDA must be cognizant of international regulatory developments as it formulates its policy, Genzyme Corp. maintained. Company rep Alison Lawton stated that it is "absolutely critical that FDA continue to have discussions with other regulatory authorities, such as the Europeans and the Japanese...so that anybody...developing such products is able to have one approach worldwide."

"We know that in Europe at the moment, the European Commission is currently drafting two new directives with regard to cell therapy and it looks as though they are moving toward the approach that if it contains a cell, that will define how it becomes regulated," she added. UK's Medical Devices Association recently published a code of practice on the topic.

Patient safety groups urged FDA to disregard historical precedent and assign jurisdiction to the center best equipped to regulate the devices. The Patient and Consumer Coalition testified that "the Center assigned jurisdiction should have adequate in-house expertise to evaluate a product based on its primary mode of action" and noted that it opposes use of any outside consultants chosen or paid for by industry. The National Center for Policy Research for Women & Families added that it has a "strong concern that any centers that are having difficulty in meeting the staffing requirements for inspections and adverse event monitoring should not be given the additional burden of regulating...complex combination products."

Primary Mode of Action Is A Primary Focus Of Combo Products Hearing

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