Mastering FDA Guidelines: Bridging Human Factors Data for Combination Products

Introduction

In the world of combination products, device constituent parts are sometimes substituted to better meet the needs of intended user populations (e.g., a wider flange to accommodate arthritis patients) and engineering requirements (e.g., a smaller syringe barrel cross-sectional area to accommodate greater viscosity). If this occurs during the later stages of the development cycle or post-market, the former device constituent part might have already undergone human factors engineering activities, including formative usability studies and/or summative usability validation studies. In order to expedite the approval of these updated products, the FDA released draft guidance in December 2019 on this practice, referred to by the agency as “bridging.”

The FDA emphasizes their focus on safety and efficacy throughout the draft guidance and makes note of cases where it might be impossible to bridge data. For example, in the case of a change in the route of administration from intramuscular to subcutaneous, the myriad different complications that may arise would raise such safety and efficacy concerns that bridging of human factors data may not be possible. Similarly, in the case that a device constituent part introduces new tasks to the workflow of the product, a new iteration of the use-related risk analysis might reveal unforeseen critical tasks that have not yet been validated, making a justification for bridging the prior human factors data more difficult.

In this blog, we will cover how to determine if bridging human factors data is practicable for your product and how you can get started on your human factors comparative analysis.

What information should I review for my comparative analysis?

It is important to consider all aspects of both your drug or biologic constituent and device constituent. These include changes to the:

• Local injection adverse reaction profile

• Dose accuracy

• Manufacturing processes that may affect drug constituent quality

• Bioavailability and/or metabolic profile of the drug constituent

• Drug formulation

• User interface of the device constituent [1]

First, you should identify or locate any existing information for your updated product; for the purpose of this example let’s call it “Product B.” This data might have been generated through studies and assessments of the device constituent part of Product B and may already satisfy requirements for your regulatory submission. For instance, your team may have validated safe and effective use of the device constituent of Product B for use on a different product (let’s call this “Product Z”). The unique differences in the risk profile of the drug or biologic constituents can have exponentiated consequences on the overall risk profile of the combination product. This is where the comparative analysis will help you ascertain key differences between your original product that you completed human factors validation testing on (“Product A”) and your updated product (“Product B”).

All aspects and documentation of the user interface should be gathered and thereby considered for your analysis. In this process, it is important to remember that labels, information for safety, packaging, and the device constituent part and its associated controls and displays are all considered parts of the user interface. When performing the comparative analysis, it is recommended to use a table format to show a clear comparison between each component of Product A and Product B.

How do I analyze human factors data to identify differences?

Your team should focus on four key aspects of device use to identify differences in safety and efficacy:

• Physical characteristics

• Use specification

• Workflow

• Labeling

Here, we will examine the criteria and considerations that are key to the comparative analysis of these user interface aspects.

Physical Comparison

Through visual and tactile examination of Product A, think of its key physical attributes. Keep in mind the effect of these on use-safety and relative to the user profile. In particular, consider:

• Dimensions

• Shape (especially its effect on handling)

• Visual cues and labeling

• Tactile feedback

In the example below, there are significant physical differences between Product A and Product B. The reaction of the autoinjector (Product B, right) will produce different tactile feeling and might require more initial force than the prefilled syringe (Product A, left). Product B is also bulkier, changing users’ handling and grip of the product.

Product A (prefilled syringe)

Product B (autoinjector)

Use Specification Comparison

Directly compare the use specifications for Product A and Product B. In many cases, these might be nearly identical; the indications for use and user populations are likely the same. There are some cases, like an emergency use scenario, where the device constituent for Product B is more immediately useful than the device constituent in Product A. Consider the effects of these potential new use scenarios in the context of physical differences of the product. This will help you in your analysis of each device constituent’s workflow.

Comparative Task Analysis

You now have determined the physical and conditional differences between Product A and Product B. With this in mind, review the workflow task analysis for Product A and note which tasks are affected by changes to the physics and handling of Product B, as well as those affected by mismatches between user and use characteristics.

If the changes to the risk profile of critical tasks is limited, you may be able to prepare a use-related risk analysis which focuses narrowly on these impacts. In the case that several or most of your workflow tasks are affected, and that there are significant changes to physical characteristics and the use specification, you should prepare a new use-related risk analysis.

Labeling Comparison

Review every piece of information for safety and other labeling from both Product A and Product B. Note the key differences between each piece of material. Think about why changes, if any, were made to labeling. If it is due to newly identified risks, then it will be difficult to bridge labeling verification and validation to the labeling of Product B.

I found no significant differences that impact usability between Product A and Product B! What do I do now?

ClariMed recommends submitting your well-detailed documentation of findings to the FDA to obtain buy-in and feedback on your work prior to your final Human Factors Submission. Even if you did not identify significant differences, the FDA may have a different assessment or may identify gaps in your assessment requiring additional information. With respect to usability data, the agency will incisively review your risk assessment to make sure that you have examined every possible critical use error.

What should I do if I find significant differences between Product A and Product B?

You might have a case for bridging data to Product B if the differences do not significantly impact critical tasks [2]. Prepare documentation showing your bridging and comparison process and set up a meeting with the FDA to make the case for bridging your human factors data.

Other Helpful Tips

ClariMed also recommends considering the following tips when preparing your comparative analysis:

• If there are multiple indicated user populations for Product B, you might be able to leverage data for certain populations, given that there is usability data for the device constituent part for Product B for each population.

• You may leverage data from a product that is under review by the FDA (if a bridge can be established).

• If you are considering the same combination product for two different user populations, you may be able to bridge data given similar user profile characteristics.

As with any regulatory submission, we recommend developing a plan in advance of your comparative analysis and meeting with the agency for further guidance or recommendations.

Next Steps

ClariMed also recommends considering the following tips when preparing your comparative analysis:

• Preparing a human factors comparative analysis for your product.

• Recommending if a bridging study is warranted based on the comparative analysis.

• Writing a bridging study protocol.

• Participating in discussion with FDA around human factors testing strategy.

• Executing the bridging study.

Contact us today to set up a free 1 hour consult for your project and learn more about our usability engineering services and expertise.

References:

Bridging for Drug-Device and Biologic-Device Combination Products Draft Guidance for Industry, FDA, December 2019

HFES Regulatory Town Hall, CDER/CDRH/Canada, May 20, 2020

Notes:

[1] While all of these aspects may have significant influence on the safety and efficacy of your updated product (Product B), here we will focus on effects on safe and effective use of the device due to user interface changes.

[2] Defined by the FDA as “a user task which, if performed incorrectly or not performed at all, would or could cause serious harm to the patient or user, where harm is defined to include compromised medical care.”