August 7, 2024

FDA promotes user fee waiver options for combination products

Jason Conaty, Ashley Grey, Randy Prebula, Eva Schifini

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The U.S. Food and Drug Administration (FDA) published a revision of its final guidance on “Application User Fees for Combination Products,” replacing guidance of the same name from 2005. The revision modernizes the guidance to align it with current user fee program expectations. While acknowledging that two applications submitted for a cross-labeled combination product each require their own user fee, FDA spotlights in its revised guidance the various waivers, reductions, and exceptions available for application user fees, for both drug-led and device-led combination products. We have summarized those exemptions below, emphasizing FDA’s “barrier to innovation” waiver.

Background

“Combination products” are comprised of two or more different types of products (i.e., a combination of a drug, device, and/or biological product). The drugs, devices, and biological products included in a combination product are referred to as its “constituent parts.” For review purposes, a combination product is assigned to a lead agency center (i.e., the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), or Center for Devices and Radiological Health (CDRH)) based on a determination of the “primary mode of action” (PMOA) of the combination product.

The Prescription Drug User Fee Act of 1992 (PDUFA) added sections 735 and 736 to the Federal Food, Drug, and Cosmetic Act (FDCA), and authorized FDA to collect user fees from persons that submit applications for certain human drug and biological products. Medical device user fees were established by the Medical Device User Fee and Modernization Act (MDUFA). Application fees submitted under the Generic Drug User Fee Amendments (GDUFA) and Biosimilar User Fee Amendments (BsUFA) are not addressed by this guidance.

Multiple Applications & Multiple User Fees?

As in the 2005 version of the guidance that it replaces, the 2024 guidance addresses how FDA applies user fees for combination products when separate applications are submitted for the constituent parts (such as may be the case when the constituent parts may be commercialized and used individually and not as part of a combination product). The revised guidance states that if an applicant submits two applications for a cross-labeled combination product, “each would be assessed the applicable user fee for each application.” But, FDA clarifies that “[f]or most combination products, one application is appropriate.”

In cases where FDA determines that a single application is not appropriate for the combination product and separate applications are needed, the agency says it will consider both applications in assessing user fee factors, spotlighting in this revised the guidance the various exceptions and reductions available to application user fees.

User Fee Exemptions

The guidance contains these helpful summaries depicting waivers, reductions, and exceptions available for PDUFA and MDUFA application fees:

PDUFA Application Fee Selected Waivers, Reductions, and Exceptions
Category	Eligibility
Public Health Waiver	FDA finds that the waiver or reduction is necessary to protect the public health.
Barrier to Innovation Waiver	FDA finds that the assessment of fees presents a significant barrier to innovation because of limited resources available to the applicant or other circumstances.
Small Business Waiver	FDA finds that the applicant is a small business submitting its first human drug application to the agency.
Exception for Orphan Designated Products	A human drug application for a product designated by FDA as a drug for a rare disease or condition pursuant to section 526 is not subject to an application fee unless the application includes an indication other than for a rare disease or condition (in addition or beyond the scope of the designation).
State or Federal Government Entity Exemption	An application submitted by a State or Federal government entity for a product that is not distributed commercially, is not considered a human drug application, and therefore, an application fee is not assessed.
MDUFA Fee Exceptions and Waivers
Category	Eligibility
Humanitarian Device Exemption (HDE)	An application under section 520(m) of the FDCA is not subject to any fee.
Further Manufacturing Use	No fee shall be required for a biologics license application for a product licensed for further manufacturing use only.
State or Federal Government Sponsors	No fee shall be required for a premarket application, premarket report, supplement, or premarket notification submitted by a State or Federal government entity unless the device involved is to be distributed commercially.
Premarket Notification Reviewed by Third Parties	No fee shall be required for a premarket notification submission reviewed by an accredited person pursuant to section 523 of the FDCA.
Pediatric Conditions of Use	No fee shall be required if the proposed conditions of use are solely for a pediatric population. Any supplement that proposes conditions of use for any adult population is subject to the fee then in effect for a premarket application.
First Premarket Application or Premarket Report from a Small Business	The Secretary shall grant a waiver of the fee for one premarket application, or one premarket report, where the Secretary finds that the applicant involved is a small business submitting its first premarket application, or its first premarket report.

The revised guidance also spells out the updated procedures for petitioning FDA for these waivers/reductions in application user fees.

Barrier to Innovation Waiver

FDA’s revised guidance devotes particular attention to explaining PDUFA’s “barrier to innovation” waiver (row two in the first table above), under which FDA says it will reduce application user fees “if the combination product is innovative and the applicant has limited resources or other circumstances.” If the combination product is innovative and the applicant does not have limited resources, “other circumstances” may be present if two applications are required, in which case FDA will reduce the user fees as follows:

Products requiring a MDUFA application and a PDUFA application: An applicant would be assessed the MDUFA application fee associated with the type of MDUFA application, and a PDUFA application fee reduced by the assessed MDUFA application fee [MDUFA + (PDUFA-MDUFA)]. The total amount assessed would be equivalent to one PDUFA application fee.
Products requiring two PDUFA applications: In the case where two full PDUFA fees would otherwise be assessed, the total amount assessed would be equivalent to one PDUFA application fee.

The guidance provides examples for when FDA would deem a medical product “innovative” under the PDUFA “barrier to innovation” provision, including when:

The combination product demonstrates new, progressive methods and forward-thinking in the treatment or diagnosis of disease or is at the forefront of new medical technology.”
There are no comparable alternatives for treatment, prevention, or diagnosis available in the U.S. market.
The combination product introduces a unique or superior method for diagnosing, curing, mitigating, treating, or preventing disease.
The combination product includes a new molecular entity or biological product, receives priority review designation, breakthrough therapy designation (as a drug/biological product), fast track designation, regenerative medicine advanced therapy (RMAT) designation, or breakthrough device designation. We have previously analyzed these expedited review pathways online here and here.

If you have any questions on how FDA may regulate a certain product, or on approval standards for drugs and medical devices more generally, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.

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