In medical devices and drug–device combination products, threshold analysis is one of the most misunderstood yet critically scrutinized regulatory requirement. It is often perceived as a preliminary comparison exercise; in reality, it is a foundational regulatory justification that can determine whether a submission progresses smoothly or fails early with significant cost and delay.
Threshold Analysis as a risk-based, evidence-driven assessment that must be performed by experienced professionals. Any attempt to oversimplify or treat it as a template-driven activity exposes companies to regulatory rejection, additional study requirements, and lost time to market.
1. What Is Threshold Analysis?
Threshold Analysis is a structured comparison and risk evaluation conducted to identify, assess, and minimize differences in design particularly differences in the user interface—between a proposed product and its reference product.
For generic combination products, threshold analysis is used to compare the proposed product against the Reference Product to determine whether any differences could impact:
- Substitutability
- Safe and effective use
- Clinical performance or safety profile
Regulators expect threshold analysis to be conducted after the user interface design is finalized and representative of the intended commercial product. This is not a theoretical exercise—it is a decision-making document grounded in real product design.
2. Why Threshold Analysis Is Critically Important
Threshold Analysis is not just informative, it is determinative:
a. It Identifies Use-Related Risks Early
Regulatory guidance emphasizes that differences in user interface can increase the risk of use-related errors, particularly for patients and caregivers, who may not have the training or adaptability of healthcare professionals.
Even small differences in external design attributes can impact:
- Administration technique
- User confidence and behavior
These risks are magnified when a generic product is substituted for the RLD in real-world Use.
b. It Determines the Need for Additional Studies
The outcome of threshold Analysis directly influences whether:
- No further human factors data is required, or
- Additional studies, such as comparative use human factors studies become mandatory
An incorrect or weak threshold Analysis often results in regulatory requests for additional
data, which are costly and time-consuming.
c. It Is Subject to High Regulatory Scrutiny
Regulators do not accept unsupported conclusions. They expect:
- Clear identification of differences
- Risk-based categorization of those differences
- Justified conclusions aligned with current guidance
Threshold Analysis is reviewed as a defensible regulatory argument, not an internal assessment.
3. Types of Threshold Analyses Expected by Regulators
There are three types of analyses that together form a robust threshold analysis. Each serves a distinct purpose and must be executed rigorously.
a. Labeling Comparison
A detailed, side-by-side, line-by-line comparison of:
- Full prescribing information
- Instructions for Use (IFU)
- Descriptions of delivery device constituent parts
This analysis evaluates whether differences in labeling or instructions could alter user behavior or understanding.
b. Comparative Task Analysis
This analysis compares how users perform critical tasks when using the proposed product versus the reference product. The focus is on identifying whether design differences could affect the user’s ability to safely and effectively complete those tasks.
This step requires deep understanding of user behavior, use environments, and task dependencies—far beyond a superficial workflow comparison.
c. Physical Comparison of the Device
A direct physical evaluation of the delivery device constituent part, including:
- Visual examination
- Tactile assessment
- Evaluation of size, shape, force, and interaction points
This comparison is essential to identify differences in external critical design attributes that may not be obvious from documentation alone.
4. Outcomes of Threshold Analysis—and Their Regulatory Consequences
Once threshold analysis is completed, regulators classify the outcomes in three categories, each with very different implications.
a. No Design Differences Identified
If no differences are identified between the user interfaces of the proposed product and the reference product, regulators may determine that:
- Certain data (including comparative use human factors studies) may not be necessary
However, this conclusion is accepted only when supported by rigorous analysis and clear documentation.
b. Minor Design Differences
A difference may be considered minor only if it:
- Does not affect an external critical design attribute
- Does not impact substitution or administration
Even minor differences must be supported by data demonstrating that the risk is negligible.
For products intended solely for healthcare professionals, risks associated with substitution may sometimes be addressed through threshold analysis alone—but this determination must be justified.
c. Differences That May Not Be Minor
If any aspect of the analysis suggests that a difference could impact an external critical design attribute related to administration, regulators may:
- Expect design modifications to minimize differences, or
- Require additional data to demonstrate that the difference does not impact safety or effectiveness.
In such cases, threshold analysis becomes the trigger point for further regulatory action.
5. When Threshold Analysis Is Not Enough
If threshold analysis indicates that a design difference may not be minor, regulators expect sponsors to first attempt to redesign the user interface to more closely align with the reference product.
If differences remain in the final design, regulators may request comparative use human
factors studies to assess whether:
- User performance of critical tasks is affected
- The observed use error rate could impact approval
These studies may be limited to specific user groups—patients, caregivers, or healthcare providers—depending on who is most likely to be impacted by the design differences.
6. Why Threshold Analysis Is Not a DIY Exercise
Threshold Analysis sits at the intersection of:
- Regulatory law
- Human factors engineering
- Risk management
- Clinical use understanding
Attempting to prepare this document based on internet summaries or partial guidance often leads to:
- Misclassification of design differences
- Incorrect assumptions about “minor” changes
- Regulatory objections and data requests
Regulators do not evaluate intent; they evaluate evidence and justification.
7. 3i Concept’s Professional Approach to Threshold Analysis
We prepare threshold analysis reports that are:
- Fully aligned with FDA and global regulatory guidance
- Risk-based and evidence-driven
- Designed to withstand regulatory scrutiny
3iconcept Medical Device Solutions work focuses on defensible decision-making, not superficial compliance. We understand how regulators interpret differences, where they focus their questions, and how to build a threshold analysis that supports approval rather than delays it. If your product involves a complex user interface or potential design differences, threshold analysis is not optional. It is critical. Have questions or need support? Reach out at [email protected] and get a clear response fast.