US Food and Drug Administration (FDA) draft guidance on combination products’ premarket review principles needs further clarity on a range of issues, according to commenters.
The public comment period on the February draft guidance
—a document tasked with implementing goals set forth under section 3038 of the 21st Century Cures Act of 2016
—closed earlier this week.
Commenters show appreciation for FDA’s efforts to serve such goals of greater “clarity, predictability and consistency” but they call on the agency to further address confusion, with one commenter going as far as requesting a redraft.
Bradley Merrill Thompson, an attorney at law firm Epstein Becker Green, says the Combination Products Coalition (CPC) believes that the draft “has the potential to drive increased efficiency and consistency in the premarket review of combination products, leading to benefits realized both by sponsors and FDA.”
Yet comments cite the need to ensure close alignment to least burdensome principles according to the statute or regulation and avoid more confusion in flagging portions of the draft guidance or lack thereof.
Commenters advise FDA to include more language on cross-labeled products, as well as guidance on the use of prior FDA findings of safety and effectiveness and issues around combination products including previously approved, cleared or licenses constituent parts. They caution against restricting combination products to either the premarket approval application or de novo pathways and favor greater discussions on the 510(k) pathway, including the roles of general and special controls.
Ralph Hall, principal at business management consultant Leavitt Partners and advisor to the Bringing Real-world Insight for Device Governance and Evaluation (BRIDGE) Coalition, argues that the agency “should seriously consider assessing this guidance under least burdensome principles” and reissue it as a draft because the current version “creates confusion and provides no clarity to the regulated community.”
Hall says the draft guidance not only fails to deliver on the promises of the least burdensome provisions of the FD&C Act
but is also contradictory to statutory intent and lacks statutory and regulatory basis. He takes issue with the draft’s use of certain concepts and language. These include the concept of a “combination device,” as well as the phrases “generally coincide” and primary mode of action (PMOA) of a constituent part.
There is consensus across many commenters around the proposed PMOA approach, particularly as it relates to whether a constituent part of a combination product is subject to a non-lead FDA center. This coincides with the growing trend across FDA-regulated sectors of cross-center collaboration.
Hall argues that the draft suggests FDA has “undefined and unfettered discretion to make whatever center assignment it desires without consideration of the PMOA” and this lacks “clarity and certainty.”
AdvaMed echoes the BRIDGE Coalition’s stance on agency center-specific discretion. “We agree that, sometimes, use of a non-combination predicate or the addition of indications and ingredients may affect the paths for premarket review,” says AdvaMed technology and regulatory affairs senior vice president Janet Trunzo. “The draft guidance should qualify its generalizations with the caveat that center staff have authority for premarket review decisions and they make these decisions on a case-by-case basis.”
In addition to suggesting that FDA has wide discretion to make decisions on whether a biologics license application (BLA) or a new drug application (NDA) is required, PhRMA’s concerns around the PMOA approach are focused on when the agency expects a single application to be necessary versus cases in which multiple, separate applications are appropriate for reviews of constituent parts.
“Whether to file a single or multiple applications is a significant issue facing combination product developers and the draft guidance currently provides limited discussion of this important question,” says PhRMA vice president of law and senior counsel for biopharmaceutical regulation Kelly Goldberg and director of science and regulatory advocacy Matthew Raymond.
There is also common ground regarding the question FDA posed to avoid duplicative efforts. Both AdvaMed and the BRIDGE Coalition recommend a single portal and a single point of contact.
“This would enable all the information on the combination product, including the submission packages, interactive responses and additional information to be available to both centers reviewing the applications, thus avoiding requests to both companies resulting in providing duplicative information,” Trunzo argues.