Industry Looks To FDA’s New Combo Products Chief For Answers
FDA's Office of Combination Products says it is getting back on track with new leadership in place after months of flux. Industry meanwhile is pushing the office to accelerate the release of rules and guidelines to help companies navigate the relatively new area of regulation.
Thinh Nguyen, who took over as director of the office Jan. 6, says his 14 years of experience at CDRH, where he was a key player in the premarket review office, will serve him well at OCP. "Most of the combination products have a device component," he said in a Feb. 13 interview with "The Gray Sheet."
Nguyen says he will work to "bridge the gaps" between different parts of the industry developing combination products. He will largely pick up where former director Mark Kramer left off on several key issues, he says. Kramer headed the office since it was formed by the 2002 device user fee legislation and departed for the private sector in April 2007.
GMP, Adverse Event Draft Rules Awaited
Industry representatives anticipate that the latest guard change will bring stability after months without permanent leadership.
"It's hard to get out new policy when you've had basically three directors in the span of 12 months, because each new director wants to naturally reexamine what's being developed in the way of policy," said Brad Thompson of the Combination Products Coalition, a trade group representing device and drug companies.
Joanne Less, who now heads FDA's Good Clinical Practice Program, served as acting director in the interim after Kramer's departure.
Thompson says his group is "disappointed" that proposed rules on combination product good manufacturing practices and adverse event reporting have yet to be released, though they were listed in FDA's semiannual agenda in 2006.
"What makes it worse is that FDA takes the view that once they announce their intention to propose a rule, they basically stop talking to industry about it," Thompson said. "There's been no rule and we haven't been able to ask questions."
"The office is going through a lot of transitions right now," Nguyen acknowledged.
In addition to the leadership changes, other senior staffers have left OCP recently, including the office's regulatory counsel Suzanne O'Shea. Nguyen says he has nine people on his staff and will seek a few more if the budget allows.
Despite the challenges, the OCP director says he plans to issue the proposed rules on GMPs and on adverse event reporting "as soon as possible." The official agency goal is to release the draft regulations by May.
The proposed rule on combination product GMPs will "allow manufacturers the flexibility to select either the [drug] cGMP or [device] quality system regulation" and "avoid the necessity to fully implement both sets of cGMP regulations when manufacturing combination products," the 2006 FDA agenda document says.
Thompson says firms have detailed technical questions on exactly how this will play out on a case-by-case basis.
"Perhaps from an industry standpoint, the GMP rule is more acutely needed because the combination product industry is really maturing," he said. "Companies are investing quite a bit in new facilities and they're not entirely sure how to design those facilities from a GMPs perspective, what kinds of systems to put in place and so forth."
Guidance on adverse event reporting is not as high a priority for firms, which currently adopt a "fairly conservative position" of leaning towards over-reporting of adverse events, Thompson says.
"I think FDA wants to improve its reporting rules frankly to better help it clarify to the industry what truly needs to be reported, and what can just be included in records maintained by the manufacturer," he said.
Nguyen's office oversees and develops policy for products that combine drug, device and/or biologic components, such as drug-eluting stents or orthopedic implants with active protein coating.
OCP does not directly regulate products, but passes jurisdiction to the appropriate FDA centers and facilitates review consults (1"The Gray Sheet" Aug. 6, 2007, p. 15).
In fiscal year 2007, the office received 77 original request for designation (RFD) submissions and issued 52 decisions, compared to 63 original RFD submissions and 43 decisions issued by OCP in 2006.
CDRH was selected as the center of jurisdiction for 27 of the 2007 RFDs, including 20 applications for drug/device combination products and seven for products that were ultimately deemed to be traditional medical devices.
OCP also plans in 2008 to release a concept paper on the thorny issue of cross-labeling, where two separately packaged products, possibly with different manufacturers, would each contain labeling explicitly indicating a combined use of the products (2"The Gray Sheet" May 16, 2005, p. 15). O'Shea had been taking the lead on this concept paper.
"We got some input from the public," Nguyen said. "We're in the process of looking at all those comments and seeing what we're going to do with the cross-labeling issues."
In addition, Nguyen plans to provide firms with a clearer definition of the term "chemical action," which OCP uses to distinguish a drug from a device component when determining a combo product's primary mode of action (3"The Gray Sheet" Aug. 29, 2005, p. 7).
The office is also required by CDRH's user fee reauthorization commitments to issue new guidance on contrast agents. Specifically, FDA agreed to develop draft guidance this year on premarket and postmarket review and labeling recommendations for diagnostic imaging devices that are used with imaging contrast agents or radiopharmaceuticals.
Combo-Product Clinical Trials Top Industry Worries
Firms agree that policies on issues such as GMPs, cross-labeling and adverse event reporting are critical, but a recent industry survey of more than 30 combo product makers found that firms were actually most interested in seeing FDA guidance on the rules for conducting combo product-specific clinical trials.
"Most of the results were not too surprising, but the top issue absolutely flabbergasted me," Thompson said.
Further guidance could explain, for example, how to determine a baseline of expected events for adverse event reporting, Thompson says.
"But I get the sense that it's deeper than that, that there are more issues around the [trial] design," he added. "If you have an approved device and an unapproved drug, exactly how do you design the protocol, or vice versa?"
The coalition sent the responses to FDA. Nguyen notes that stakeholders have already begun scheduling meetings with him to share information about such issues.
"I plan to do the same with the internal staff and ask them what's working and not working," he explains.
Thompson cautions that OCP still has a ways to go in providing the needed regulatory clarity for burgeoning technologies, such as nanotechnology that delivers targeted drug therapies, biologic-device products that improve healing after surgery or insulin-delivery systems for diabetes.
"There are some really exciting, very important breakthroughs in a number of different areas, and it sort of breaks my heart to see them retarded because companies are groping around trying to figure out what the rules are for the development and submission to the agency," he said.
- Jessica Bylander
