Threshold Analysis and Comparative Use Human Factors Studies

The Abbreviated New Drug Application (ANDA) pathway allows for the approval of generic drugs without the need for full clinical trials, provided the generic meets stringent criteria. Two important aspects of this approval process are threshold analysis, and comparative use studies which help demonstrate that the generic product is equivalent in safety, usability, and performance to the brand-name reference listed drug. In addition, the applicant must show that their proposed drug product is the same as the reference listed drug in terms of bioequivalence (i.e. active ingredients, dosage form, route of administration, strength), manufacturing standards and labeling. Bioequivalence studies confirm that the drug itself is absorbed and acts in the body in the same way as the reference product demonstrating that the generic drug delivers the same active ingredient at the same rate and extent as the reference listed drug.

In contrast, the threshold analysis ensures the delivery system (e.g., autoinjector) functions reliably and does not interfere with safe and effective drug administration. It is essential to assess the user interface of the generic drug-device combination product in comparison to the reference listed drug’s interface. This evaluation helps determine whether additional Human Factors studies may be needed due to introduction of differences in product design which may introduce additional use issues or safety risks. A threshold analysis should be conducted to see if extra data, such as from comparative Human Factors studies, is required to evaluate any identified differences in the user interface of the generic product versus the reference listed drug.

The FDA provides a guidance document on conducting threshold analysis and the need for comparative use Human Factors studies for a drug-device combination product submitted in an ANDA.

A threshold analysis helps pinpoint differences between the user interface of a generic drug-device product and that of the original, reference listed drug. According to FDA guidelines, there are three types of threshold analyses that can be used during development to identify, assess, and reduce these differences. The FDA advises that companies carefully examine any differences in the user interface that could impact how well patients, caregivers, or other users can safely and effectively use the product.

The following are the three types of threshold analyses recommended by the FDA:

Labeling comparison:

This involves a detailed, side-by-side comparison of the entire prescribing information, instructions for use, and descriptions of the device constituent parts between the generic combination product and the original reference listed drug.

Comparative task analysis:

Compare task analyses between the reference listed drug and the proposed generic combination product.

Physical comparison of the delivery device constituent part:

This means acquiring the reference listed drug to closely examine its physical characteristics and comparing these to the device constituent parts of the proposed generic combination product.

Threshold analysis can have the following outcomes:

No design differences:
If there are no design differences between the user interface of the proposed generic combination product and the user interface of the reference listed drug, certain information such as data from comparative use Human Factors studies may not be required to support approval of the Abbreviated New Drug Application.
Differences in design:
When performing a threshold analysis, the sponsor should clearly define what constitutes a design difference. According to FDA guidance, if differences are identified between the user interface design of a proposed generic combination product and that of its reference listed drug, the sponsor should focus on whether these differences involve external critical design attributes that may impact the product’s substitutability compared to the reference listed drug. The sponsor should establish and categorize these differences as follows:
- Minor design differences: The FDA considers a user interface design difference between a generic combination product and the reference listed drug to be minor if it doesn’t affect any critical features that impact how users interact with it. Minor design differences are usually acceptable if data shows they don’t interfere with safe and effective use. For products typically used only by healthcare providers, the FDA may allow threshold analysis alone (without extensive Human Factors studies), as providers are better able to handle small design changes compared to patients or caregivers.
- Other design differences: The FDA may not consider a design difference as minor if it appears to impact any critical feature related to product use, such as how the product is administered. In these cases, applicants should try to adjust the design to make it more similar to the original product. If differences remain, the FDA may require extra data, like a comparative use Human Factors study, to assess if the design changes could affect the product’s safety or effectiveness. Ultimately, the FDA will decide if these differences are acceptable based on study results.

Comparative Use Human Factors Studies

When the sponsor identifies differences between the generic and the reference listed drug products that may not be minor, as observed in threshold analyses, the FDA may request additional data through a comparative use Human Factors study to assess whether these differences impact the safety or effectiveness of the product. This data can be collected through a comparative use Human Factors study, which evaluates how users perform critical tasks with the proposed generic product compared to the reference listed drug.

The study focuses on tasks affected by differences in the external critical design attributes of the delivery device. It aims to determine if these differences lead to a higher error rate for critical tasks. The goal is to show that the use error rate for the generic product is no worse than that of the reference listed drug when used by patients and caregivers in realistic scenarios and environments consistent with the product’s labeled conditions of use.

By demonstrating comparable performance between the generic product and the reference listed drug, the study provides evidence to support that the user interface differences do not compromise the product’s safe and effective use.

Why Choose Improvita for Threshold Analysis and Comparative Use Human Factors Studies?

Improvita has extensive experience and knowledge of conducting Human Factors & Usability Testing activities which also includes evaluating the user interface of products and determining the need for Human Factors Testing. We support combination drug/device and medical device development with the user needs front and center. We have a proven history of supporting complex Human Factors & Usability Testing programs.

To learn more about Improvita’s Threshold Analysis and Comparative Use Human Factors Studies consulting services, contact us to discuss your specific needs.

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