US FDA Finalizes 2016 HFE Draft Guidance for Combination Products

By Allison Strochlic

In September 2023, the US Food and Drug Administration’s (FDA) Office of Combination Products released new guidance, Application of Human Factors Engineering Principles for Combination Products: Questions and Answers Guidance for Industry and FDA Staff. This guidance expands upon nuanced considerations when applying human factors engineering (HFE) during the development of combination products, and per the document’s introduction, “finalizes the February 2016 draft version entitled Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development.”  

Clarifications on FDA HFE expectations for combination product development 

The questions (and responses) cover topics such as risk analysis, critical tasks, training, actual-use studies, formative studies, HF validation timing and communications with FDA. We expect that these topics reflect those that come up frequently in Agency-Sponsor correspondence and/or via HFE industry conferences attended by the FDA. The Q&A document, which is intended for use in conjunction with other relevant guidance documents, doesn’t drastically change – but rather, clarifies – FDA’s current expectations for applying HFE during combination product development. 

Key takeaways from FDA HFE Q&A document 

Below, we outline some key takeaways of the Q&A document based on our initial reviews: 

• Introduces new “combination product critical task” term. The Question 5 response introduces a new term: “combination product critical task.” This term reflects and further clarifies an important concept: that the definitions of a critical task for a medical device (regulated by the Center for Devices and Radiological Health [CDRH]) and a combination product (regulated by the Center for Drug Evaluation and Research [CDER]) differ with respect to the level of harm that might occur should a task be performed incorrectly or not performed at all. In particular, the CDRH definition refers to the potential for “serious harm,” whereas the CDER definition refers to “harm.” As such, the CDER definition reflects a broader set of harms, rather than only focusing on those considered “serious.” While both the CDRH and CDER critical task definitions indicate that “harm is defined to include compromised medical care,” this guidance further clarifies that “For a combination product critical task, compromised medical care includes consideration of medication errors,” referencing a definition from yet another FDA guidance document that defines “medication error” to include “any preventable event that may cause or lead to inappropriate medication use.” (Notably, CDRH does not include this additional clarification when discussing “compromised medical care.”) This clarification helps explain why the FDA has expressed concern regarding some combination product dosing errors, even though some such errors (e.g., an underdose of a growth hormone or fertility medication) would not result in harm per se. 

• Reinforces training as part of the combination product user interface. The Question 8 response reinforces that training is considered part of the product user interface. The training format, approach, and materials should be submitted to the FDA for review and included in a representative manner in the HF validation test. If end-user training is optional or not ensured, an HF validation test could include trained and untrained participants or might only include untrained users to reflect the higher-risk use scenario. 

• Clarifies the difference between an HF actual-use validation study and an actual-use/clinical trial study. Based on the Question 9 response, it seems that the use of the phrasing “actual use” in the context of HF validation studies has led to some Sponsor confusion, and this Q&A document clarifies the difference between these terms. It reinforces the human factors focus of an HF actual-use study, with HF personnel (“evaluator”) involved to observe user interface interactions, as compared to other “actual use” studies, such as clinical trials. The FDA reminds any Sponsor considering integrating HF actual-use validation activities into a clinical trial to seek the Agency’s explicit feedback before doing so, noting that usability tests and clinical trials have different objectives and endpoints. 

• Explains HF data that might be needed to support a clinical investigation. The Question 11 response sets the expectation that Sponsors conduct a use-related risk analysis (URRA) specific to a planned clinical investigation prior to conducting such an investigation to ensure that potential harm is sufficiently mitigated. In addition to serving this primary URRA objective (ensuring potential harms are sufficiently mitigated), the FDA calls out that a URRA conducted before a clinical investigation can also serve to identify any use errors that could jeopardize the evaluability of the clinical investigation’s results. If the URRA suggests unacceptable use-related risks to clinical investigation subjects, the FDA clarifies that Sponsors might need to conduct an HF validation test – and submit the results to the FDA for review – before conducting the investigation. 

The good news for our customers is that our team’s approaches to advising our clients and applying HFE during combination product development is well-aligned with the Q&A document. 

Navigate the FDA’s HFE expectations with Emergo by UL 

Please reach out if we can help you consider how this new guidance, and/or other existing HFE guidance documents, impacts the HFE work needed for your particular combination product. We remain eager to help our customers plan HFE in a compliant and efficient (read: cost- and time-effective!) manner, as well as to help our customers respond to Additional Information and other regulator requests for HFE-related information.