Industry groups call for changes to FDA’s guidance on use-related risk analyses

Stakeholders want the US Food and Drug Administration (FDA) to provide more clarity on its expectations for use-related risk analyses (URRA) for “stand-alone” non-combination medical products. They also called for more alignment with the agency’s human factors guidance and ISO standards.

In July, FDA requested comment on it URRAs for drug and biologics-led combination products and nonprescription drug products that are part of an investigational new drug application (IND), a new drug application (NDA), a biologics license application (BLA) or a supplement to these applications. While the guidance is geared toward combination products, it states that it may also apply to certain “stand-alone” prescription or non-prescription drugs. (RELATED: FDA releases draft guidance on use-related risk analysis for combo products, Regulatory Focus 9 July 2024).

The guidance specified that “a URRA is important to help identify use-related hazards associated with the user interface design of the combination product, as well as to characterize risks so they can be mitigated (such as through risk controls) or eliminated through improved product user interface design.”

The deadline for commenting was 9 September.

Questions about scope

Three groups called for more clarity on the extent to which the guidance covers non-combination stand alone products.

FDA specifies that the guidance may apply to some “stand-alone drug and biological products (i.e., those that are not part of a combination product) including human prescription drug products, biological products, that are the subject of an IND, NDA, or BLA and supplements to these applications, human nonprescription drug products that are the subject of an IND or NDA, and supplements to these applications.”

In its comments, the Biosimilars Forum stated that “stand-alone” provision is confusing and is “effectively opening the door to apply the draft guidance to virtually all stand-alone drugs and biological products.”

The group wants FDA to provide additional explanation and examples of how the guidance will be applied to non-combination products. This information, it said, “Is critical for sponsors to understand when and for which non-combination medical products FDA would expect a URRA and to plan their development accordingly.”

The International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) also requested clarity on what is meant by stand-alone products.

IPAC-RS noted that “we acknowledge that drug products with complicated dosing may need additional assessments to mitigate medication errors. However, for stand-alone drug and biologic products that do not have complicated dosing (e.g., titration, multiple vials) or an increased risk profile (e.g., emergency use) we do not believe a URRA comparative assessment is necessary to justify the omission of an HF validation study.”

Groups want more alignment with other guidelines and standards

Groups also requested that FDA align this document with its other human factors (HF) guidances covering medical devices, combination products and biologics.

IIPAC-RS requested that the guidance align with FDA’s draft guidance on the “Content of Human Factors Information in Medical Device Marketing Submissions Draft Guidance for Industry and Food and Drug Administration Staff” issued in December 2022.

The International Society for Pharmaceutical Engineering (ISPE) called for FDA to align this document with the September 2023 final guidance titled on human factors engineering principles for combination products.
Design Science, a human factors consulting firm, requested the guidance be aligned with FDA’s 2018 draft guidance on threshold analyses and human factors submissions for drugs and biologics.

Groups call for ISO alignment

IPAC-RS also suggested the guidance align with the terminology used in the International Organization for Standardization (ISO) standard 14971:2019 regarding such terms as use-error, risk, and hazard. The group said these terms are used interchangeably within the draft guidance “but are distinct within ISO 14971:2019.”

ISPE also recommended harmonizing terminology with ISO 14971. The group said, “There are several examples in this guidance where the terms and definitions do not align with this international standard.”

IPAC-RS question guidance’s applicability to orally inhaled products

IPAC-RS also wanted clarity – as well as examples – on how the guidance would apply to orally inhaled and nasal products.

“Most of the examples contained within the draft guidance seem to have been written with injectable products in mind,” said IPAC-RS. “While we appreciate that the list of examples is not intended to be exhaustive, certain common products such as orally inhaled and nasal drug products (OINDPs) may raise distinct considerations that would benefit from a specific example, particularly in the context of an existing product that would be subject to the amendment process.”

IPAC-RS also suggested the guidance list examples for the integration of connected “smart” devices and applications which can prevent certain types of users’ mistakes. These include devices to support personalized use of inhalers.

Abide by user fee goals

In the meantime, the Biosimilars Forum urged FDA to abide by the user fee goals set in the Biosimilar User Fee Amendment (BsUFA) commitment letter for reviewing human factors protocols.

“While data is not yet available for FDA’s URRA review goals, we urge FDA to also apply those timelines to submitted threshold analyses, particularly given FDA’s express recognition in the URRA Draft Guidance of the combined role of the URRA and threshold analysis in determining whether a HF study may be needed.”

Under the BsUFA III Commitment Letter, FDA committed to reviewing URRAs and notifying sponsors of agreement or non-agreement with comments for 50% of submissions within 60 days of receipt beginning in FY 2023 and to reviewing HF protocol submissions and providing written comments for 90% of submissions within 60 days of receipt beginning in FY 2023.

Yet according to the Forum, FDA did not meets its Preliminary Procedural and Processing Goal Performance Results for reviewing human factors protocols for FY 2023, and cited FDA’s FY 2023 BSUFA report to Congress.

The group stated that, “In the face of delays, biosimilar developers are left with few options—continue to wait and further delay the program or conduct the HF study without first receiving feedback and risk the agency raising objections during review of the application. This can result in delayed access for patients and burdening biosimilar manufacturers, already operating on challenging margins, with unnecessary costs.”

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Industry groups call for changes to FDA’s guidance on use-related risk analyses

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