Presentation
Design and Labeling Differences Between FDA-Approved Generic and RLD Inhalers: Human Factors Comparative Use Considerations
DescriptionBackground:
Generic drugs are intended to provide a more affordable and accessible alternative to Reference Listed Drugs (RLDs), providing patients with treatments that are equivalent in safety, efficacy, and intended use. Drugs are often used in conjunction with a device component, such as an injection system or inhaler, forming a drug–device combination product that introduces additional complexity to development and patient use. In respiratory care, inhalers are among the most widely used drug–device combination products for managing conditions like asthma and chronic obstructive pulmonary disease (COPD). However, design differences between a generic inhaler and its RLD counterpart can affect device–patient interaction, including changes in grip, dose counter visibility, mouthpiece comfort, and device feedback. While the Food and Drug Administration (FDA) provides guidelines to ensure therapeutic equivalence for drug–device combination products, only 3% of inhalers submitted through the Abbreviated New Drug Application (ANDA) process include comparative use of Human Factors (HF) data, raising concerns about equivalence between RLD and generic inhalers. Currently, there is a lack of research highlighting to what extent inhaler designs can differ without compromising equivalency, and/or risk the increase of use error. Therefore, more research is needed to explore the ergonomic and cognitive impact of design differences on patient adherence and usability.
This study aims to systematically compare generic inhalers with their RLD counterparts, focusing specifically on device design and labeling aspects that may influence use error rates. By developing a comprehensive framework for analyzing physical attributes, handling requirements, and instructional resources, we seek to identify meaningful differences between RLD and generic inhalers that could potentially impact correct usage, inform future HF research by emphasizing areas where usability improvements are needed within inhalers, and highlight where current FDA HF comparative analysis may benefit from future studies.
Research Design and Methods:
The study sample was drawn from inhalers approved in the FDA’s Orange Book, focusing specifically on current inhalers on the market (n = 226). Generics were then matched to their RLDs through cross-referencing with manufacturer resources and medical databases, producing five RLDs (Advair Diskus, Spiriva Handihaler, Proair HFA, Proventil HFA, and Symbicort) paired with eight generics for comparison.
In alignment with the FDA’s recommended comparative framework, a comparative analysis was performed based on two of the three types of comparative methods: 1) physical comparison and 2) labeling comparison. Data used for the comparative analysis were obtained by reviewing manufacturer-provided materials, including details on the device design, stock images of the device, and any instructional resources (IFU, instructional videos, advertisements, leaflets). A comparative task analysis was not included due to the scope of the study and the availability of devices in physical form (solely digital), which limited evaluation or observation of task execution.
Within the physical design category, inhalation type, overall shape, mouthpiece geometry, handling requirements, cover mechanisms, and the presence and positioning of dose counters were examined. These dimensions were selected based on prior evidence showing their relevance to inhaler and/or device use error. The labeling domain involved a detailed review of on-device markings, warnings, and supplemental resources (i.e., quick start guides, websites, videos, and brochures). A line-by-line comparison of the Instructions for Use (IFUs) was also conducted, evaluating textual details and use of instructional sensory cues.
Results:
The comparative analysis revealed differences across nearly every category of physical design and labeling. Device shape showed major variation: for example, the Advair Diskus (RLD) used a circular disk, whereas its generics ranged from asymmetrical to triangular disk forms. Differences extended into device handling as well, including the type of grip required (e.g., five-finger pinch vs. power grip), and the orientation of the forearm and wrist. Mouthpiece designs were generally within the same category but still displayed notable variation (e.g., large oval vs. oval rectangle), which can affect seal formation and deposition. Cover types and handling methods diverged as well, with some RLDs using rotator covers while generics used hinged or pull-off covers, requiring distinct grip strategies. Labeling comparisons revealed that some generics omitted safety warnings or instruction reminders present on RLDs, while others added or expanded supplementary resources such as quick-start guides, videos, or brochures. The line-by-line IFU comparison highlighted the Advair Diskus group as the most divergent, with differences spanning visual, tactile, auditory, and spatial cues, as well as textual changes driven by design.
Discussion:
According to the FDA, it is expected that “end-users can use the generic combination product when it can be substituted for the RLD without the intervention of the health care provider and/or without additional training prior to use of the generic combination product.” Yet, the findings of this study indicate that this expectation may not always hold true. Physical and labeling comparisons uncovered several meaningful differences between RLD and generic inhalers. Although these discrepancies may seem “minor,” prior research suggests that they can influence patient satisfaction, adherence, and device performance, often in conjunction with patient characteristics (e.g., health literacy, digital literacy, and age) that standardized evaluations fail to capture. To aid comparative analysis of generic inhalers, future research should focus on variations in mouthpiece shape, device handling, and instructional design.
One prominent difference pertained to the shape of the mouthpiece. Four generics differed from their RLD counterparts, with changes such as oblong versus oblong terraced or oval large versus oval rectangle shapes. These differences can influence how easily users achieve a tight lip seal, potentially affecting drug deposition. While prior research suggested that patients, particularly children, preferred oblong shapes, the evidence was not statistically significant. Future research should investigate how mouthpiece geometry affects oral anatomy, patient comfort, and drug delivery efficiency across diverse populations.
Device handling also showed important differences. In some cases, changes in device shape altered how the inhaler was held and operated. The RLD required hand-specific handling, while the generic’s upright, symmetrical design enabled ambidextrous use and supported a power grip. This suggests that small design changes can shift handling strategies, with implications for ease of use and adherence. Future investigations should focus on how patients naturally adapt their handling over time, beyond manufacturer instructions, using both human-subject studies and simulation tools like digital human models.
Generic inhalers offered more instructional resource materials than RLDs, but exclusively in digital formats. While this seems beneficial, reliance on digital-only resources risks excluding populations with limited digital or health literacy, particularly older adults and young children. Research is needed to compare the effectiveness of print, digital, and hybrid instruction formats to ensure accessibility for all user groups.
While most inhaler groups had nearly identical IFUs, the Advair Diskus and its generic counterparts varied in all sensory language. Some generic IFUs removed auditory and spatial cues that provided critical feedback, while others added helpful visual elements like magnifiers or color-coded images. From a broader perspective, the differences highlight a potential gap in current regulatory evaluations: equivalence in wording does not necessarily translate to equivalence in comprehension or usability. There is potential value in examining the standardization of multimodal cueing within IFUs, guided by FDA standards.
Conclusions:
Therapeutic equivalence does not guarantee functional equivalence. Device design and labeling are integral to the effectiveness of medication, and their influence on adherence and patient safety should not be overlooked. By demonstrating the range of differences between RLDs and generics, this analysis calls for the requirement of clear, empirically grounded definitions of inhaler design differences to be characterized and methodically evaluated in relation to their impact on usability. Without requiring comparative usability data, regulators risk approving generics that meet pharmacological standards but inadvertently create usability burdens that undermine their therapeutic potential.
Generic drugs are intended to provide a more affordable and accessible alternative to Reference Listed Drugs (RLDs), providing patients with treatments that are equivalent in safety, efficacy, and intended use. Drugs are often used in conjunction with a device component, such as an injection system or inhaler, forming a drug–device combination product that introduces additional complexity to development and patient use. In respiratory care, inhalers are among the most widely used drug–device combination products for managing conditions like asthma and chronic obstructive pulmonary disease (COPD). However, design differences between a generic inhaler and its RLD counterpart can affect device–patient interaction, including changes in grip, dose counter visibility, mouthpiece comfort, and device feedback. While the Food and Drug Administration (FDA) provides guidelines to ensure therapeutic equivalence for drug–device combination products, only 3% of inhalers submitted through the Abbreviated New Drug Application (ANDA) process include comparative use of Human Factors (HF) data, raising concerns about equivalence between RLD and generic inhalers. Currently, there is a lack of research highlighting to what extent inhaler designs can differ without compromising equivalency, and/or risk the increase of use error. Therefore, more research is needed to explore the ergonomic and cognitive impact of design differences on patient adherence and usability.
This study aims to systematically compare generic inhalers with their RLD counterparts, focusing specifically on device design and labeling aspects that may influence use error rates. By developing a comprehensive framework for analyzing physical attributes, handling requirements, and instructional resources, we seek to identify meaningful differences between RLD and generic inhalers that could potentially impact correct usage, inform future HF research by emphasizing areas where usability improvements are needed within inhalers, and highlight where current FDA HF comparative analysis may benefit from future studies.
Research Design and Methods:
The study sample was drawn from inhalers approved in the FDA’s Orange Book, focusing specifically on current inhalers on the market (n = 226). Generics were then matched to their RLDs through cross-referencing with manufacturer resources and medical databases, producing five RLDs (Advair Diskus, Spiriva Handihaler, Proair HFA, Proventil HFA, and Symbicort) paired with eight generics for comparison.
In alignment with the FDA’s recommended comparative framework, a comparative analysis was performed based on two of the three types of comparative methods: 1) physical comparison and 2) labeling comparison. Data used for the comparative analysis were obtained by reviewing manufacturer-provided materials, including details on the device design, stock images of the device, and any instructional resources (IFU, instructional videos, advertisements, leaflets). A comparative task analysis was not included due to the scope of the study and the availability of devices in physical form (solely digital), which limited evaluation or observation of task execution.
Within the physical design category, inhalation type, overall shape, mouthpiece geometry, handling requirements, cover mechanisms, and the presence and positioning of dose counters were examined. These dimensions were selected based on prior evidence showing their relevance to inhaler and/or device use error. The labeling domain involved a detailed review of on-device markings, warnings, and supplemental resources (i.e., quick start guides, websites, videos, and brochures). A line-by-line comparison of the Instructions for Use (IFUs) was also conducted, evaluating textual details and use of instructional sensory cues.
Results:
The comparative analysis revealed differences across nearly every category of physical design and labeling. Device shape showed major variation: for example, the Advair Diskus (RLD) used a circular disk, whereas its generics ranged from asymmetrical to triangular disk forms. Differences extended into device handling as well, including the type of grip required (e.g., five-finger pinch vs. power grip), and the orientation of the forearm and wrist. Mouthpiece designs were generally within the same category but still displayed notable variation (e.g., large oval vs. oval rectangle), which can affect seal formation and deposition. Cover types and handling methods diverged as well, with some RLDs using rotator covers while generics used hinged or pull-off covers, requiring distinct grip strategies. Labeling comparisons revealed that some generics omitted safety warnings or instruction reminders present on RLDs, while others added or expanded supplementary resources such as quick-start guides, videos, or brochures. The line-by-line IFU comparison highlighted the Advair Diskus group as the most divergent, with differences spanning visual, tactile, auditory, and spatial cues, as well as textual changes driven by design.
Discussion:
According to the FDA, it is expected that “end-users can use the generic combination product when it can be substituted for the RLD without the intervention of the health care provider and/or without additional training prior to use of the generic combination product.” Yet, the findings of this study indicate that this expectation may not always hold true. Physical and labeling comparisons uncovered several meaningful differences between RLD and generic inhalers. Although these discrepancies may seem “minor,” prior research suggests that they can influence patient satisfaction, adherence, and device performance, often in conjunction with patient characteristics (e.g., health literacy, digital literacy, and age) that standardized evaluations fail to capture. To aid comparative analysis of generic inhalers, future research should focus on variations in mouthpiece shape, device handling, and instructional design.
One prominent difference pertained to the shape of the mouthpiece. Four generics differed from their RLD counterparts, with changes such as oblong versus oblong terraced or oval large versus oval rectangle shapes. These differences can influence how easily users achieve a tight lip seal, potentially affecting drug deposition. While prior research suggested that patients, particularly children, preferred oblong shapes, the evidence was not statistically significant. Future research should investigate how mouthpiece geometry affects oral anatomy, patient comfort, and drug delivery efficiency across diverse populations.
Device handling also showed important differences. In some cases, changes in device shape altered how the inhaler was held and operated. The RLD required hand-specific handling, while the generic’s upright, symmetrical design enabled ambidextrous use and supported a power grip. This suggests that small design changes can shift handling strategies, with implications for ease of use and adherence. Future investigations should focus on how patients naturally adapt their handling over time, beyond manufacturer instructions, using both human-subject studies and simulation tools like digital human models.
Generic inhalers offered more instructional resource materials than RLDs, but exclusively in digital formats. While this seems beneficial, reliance on digital-only resources risks excluding populations with limited digital or health literacy, particularly older adults and young children. Research is needed to compare the effectiveness of print, digital, and hybrid instruction formats to ensure accessibility for all user groups.
While most inhaler groups had nearly identical IFUs, the Advair Diskus and its generic counterparts varied in all sensory language. Some generic IFUs removed auditory and spatial cues that provided critical feedback, while others added helpful visual elements like magnifiers or color-coded images. From a broader perspective, the differences highlight a potential gap in current regulatory evaluations: equivalence in wording does not necessarily translate to equivalence in comprehension or usability. There is potential value in examining the standardization of multimodal cueing within IFUs, guided by FDA standards.
Conclusions:
Therapeutic equivalence does not guarantee functional equivalence. Device design and labeling are integral to the effectiveness of medication, and their influence on adherence and patient safety should not be overlooked. By demonstrating the range of differences between RLDs and generics, this analysis calls for the requirement of clear, empirically grounded definitions of inhaler design differences to be characterized and methodically evaluated in relation to their impact on usability. Without requiring comparative usability data, regulators risk approving generics that meet pharmacological standards but inadvertently create usability burdens that undermine their therapeutic potential.
Event Type
Oral Presentations
TimeMonday, March 231:30pm - 1:52pm EDT
LocationGramercy
Medical and Drug Delivery Devices