701 Pennsylvania Avenue, NW Suite 800 Washington, D.C. 20004 2654 Tel: 202 783 8700 Fax: 202 783 8750 www.advamed.org March 20, 2017 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD 20852 Re: Docket No. FDA-2016-D-4412; Draft Guidance for Industry: Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA The Advanced Medical Technology Association ( AdvaMed ) appreciates the opportunity to provide comment on the Food and Drug Administration s ( FDA or Agency ) Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA. AdvaMed represents manufacturers of medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures, and more effective treatment. Our members range from the smallest to the largest medical technology innovators and companies, including manufacturers of combination products that include a drug and a delivery device intended to administer a drug product. We are concerned that this draft guidance proposes an approach that is inconsistent with the Center for Devices and Radiological Health ( CDRH ) Guidance for Industry and Food and Drug Administration Staff: Applying Human Factors ( HF ) and Usability Engineering to Medical Devices (February 3, 2016) (hereinafter 2016 CDRH HF guidance ) and does not appropriately factor in risk-based approaches. The ultimate goal of usability engineering is to ensure the usability and use-safety of the product as assessed through critical tasks analysis, formative/summative usability studies and use-related risk analysis. This draft guidance frequently discusses methods that are similar, but meaningfully different (e.g., comparing "critical external design attributes" and non-inferiority HF studies). Modest changes to the language and suggested study designs in this draft guidance could enable the methodology to be aligned with other FDA HF guidances and recognized standards, while also ensuring the generic product is interchangeable with the reference from a usability perspective and safe for users. The February 2016 CDRH HF guidance describes the use of critical task assessment, and formative and summative HF studies in conjunction with appropriate risk analyses, as the route to determine usability and use-safety. The root cause for use errors with the CDRH guidancesuggested sample size along with subjective feedback are analyzed in the context of use-related risk to determine if the observed errors (or pattern of errors) results in unacceptable risk. This same approach should be used to evaluate a proposed generic product relative to its reference product. The same type of summative study can be executed to evaluate differences in a UI to evaluate for both products whether any use errors, considering their root cause and associated Bringing innovation to patient care worldwide
Docket No. FDA-2016-D-4412 March 20, 2017 Page 2 of 2 risks, result in unacceptable harm (noting the assumption that the residual risk for the reference product is acceptable). A non-inferiority study, as proposed in the Draft Guidance, reduces use errors to solely a statistical assessment, which is contradictory to other guidances and standards. Moreover, many differences in the UI may not be "external design attributes," but internal product design choices that impact product functionality (e.g., spring force of an Auto-injector impacting injection time). Recrafting the language to be more consistent with other HF guidances in terms of the impact of the user interface on critical tasks and the associated risks will improve clarity. Attachment A provides specific comments on the Draft Guidance. The comments suggest wording changes that would provide clarification and request clarification when the intent of the text is unclear. We have provided a line-numbered copy of the language of the Draft Guidance. We appreciate the efforts taken by FDA personnel in preparing this Draft Guidance and support the goals of developing a Guidance that serves the mission of FDA, the needs of industry and the common goal of benefiting public health. AdvaMed would like to thank the FDA for its consideration of these comments. Please do not hesitate to contact me at 202-434-7243 or jelder@advamed.org if you have any questions. Respectfully submitted, /s/ Jordan Elder Associate Vice President Technology and Regulatory Affairs
AdvaMed Comments Draft Guidance for Industry: Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA Docket No. FDA-2016-D-4412 Line Number General General General 30, 34, 157, etc. 86 96 Guidance Text Proposed Change Comment/Rationale The February 2016 CDRH HF guidance describes the use of critical task assessment, and formative and summative HF studies in conjunction with appropriate risk analyses as the route for determine usability and use-safety. The root cause for use errors with the CDRH guidance-suggested sample size along with subjective feedback are analyzed in the context of use-related risk to determine if the observed errors (or pattern of errors) results in unacceptable risk. This same approach can be used to evaluate a proposed generic product relative to its reference product. The same type of summative study can be executed to evaluate differences in a UI to evaluate for both products whether any use errors, considering their root cause and associated risks, results in unacceptable harm (noting the assumption that the residual risk for the reference product is acceptable). A non-inferiority study, as proposed in the guidance, reduces use errors to solely a statistical assessment, which is contradictory to other guidances and standards. We are concerned that this draft guidance proposes an approach that is inconsistent with the CDRH Human Factors guidance and does not appropriately factor in the risk-based approaches. The ultimate goal of usability engineering is to ensure the usability and use-safety of the product as assessed through critical tasks analysis, formative/summative usability studies and use-related risk analysis. This guidance frequently discusses methods that are similar but meaningfully different (e.g., comparing "critical external design attributes" and non-inferiority HF studies). Modest changes to the language and suggested study designs in this guidance could enable the methodology to be aligned with and consistent to, other FDA Human Factors guidances and recognized standards, while also ensuring the generic is interchangeable with the reference from a usability perspective and safe for users. Many differences in the UI may not be "external design attributes", but internal product design choices that impact product functionality (e.g., spring force of an Auto-injector impacting injection time). Recrafting the language to be more consistent with other HF guidances in terms of the impact of the user interface on critical tasks and the associated risks will improve clarity. " conduct threshold analysis " " conduct comparative analysis " Comparative analysis describes the analysis more clearly. " difference in device and labeling " Add sentence to the end of the scope section. "differences in device, packaging and labeling " This guidance is not intended to address the HF work needed to assess sponsorinitiated modifications to a commercial combination product. Human factors activities needed to support this type of product change are discussed in Section 8.2 of the 2016 CDRH HF guidance. Page 1 of 5 Packaging is part of the product UI and should be included. The Agency may also wish to consider addressing training material. This is an important detail needed in the product scope. A sponsor may easily incorrectly interpret this guidance as being relevant for post-approval changes to marketed products.
106-116 121 This section provides more detail than necessary describing what is needed for an Abbreviated New Drug Application in the Chemistry Manufacturing Controls section. "This section discusses support the design of the user interface of the proposed generic." End this section at the end of the sentence in line 105 and provide a reference to appropriate guidances. "This section discusses support assessment of the usability and use safety of the proposed generic..." To clarify the text. 135-136 140 165-168 "the overall design of the user interface and should generally seek approval of a presentation approved for the RLD." "FDA may accept such design differences if they are adequately analyzed, scientifically justified and do not preclude approval in an ANDA..." "To conduct a comparative analysis of the user interface of the proposed generic combination product and its RLD, potential applicants should examine, among other things, the external critical design attributes of the proposed delivery device " "the overall design of the user interface and should generally seek approval of a presentation as similar as possible to the RLD." "FDA may accept such design differences if they are adequately analyzed, scientifically justified and result in acceptable residual risk related to the usability and use safety of the product." "To conduct a comparative analysis of the user interface of the proposed generic combination product and its RLD, potential applicants should examine, among other things, the critical product use tasks and design attributes of the product that could impact the user's ability to perform these tasks safely and effectively " To clarify the text. The acceptability of design differences from an HF perspective should be based on the acceptability of residual risks related to the usability and use safety of the product. Other CMC or clinical aspects of the product are out of scope for this guidance. The term "external critical design attributes" and associated analysis may be unclear to sponsors and redundant to analyses typically performed as part of established risk management (per ISO 14971) and usability engineering processes (ISO 62366, CDRH HF guidance) where the differences between the products are determined and their potential to impact usability and use safety is assessed through a risk analysis (e.g., a use-related failure modes and effects analysis). This risk analysis will be performed as part of product development, and it is suggested that this be leveraged for the purposes of the comparative analysis and assessment of acceptable risk. The need to conduct human factors validation should be based on the risk analysis of the differences in the UI and focus on the hazardrelated use scenarios and critical tasks. Page 2 of 5
168-180 194 206 226-228 "external critical design attributes are those." "as a result, there is concern that patients or caregivers who encounter different user interfaces, such as differences in external critical design attributes, may be at increased risk" Remove prescribing information from the list or consider rewording to note aspects of the prescribing information that impact usability and use safety. "If differences are identified between the design of the user interface of the proposed generic combination product and the user interface of its RLD, the sponsor should focus on whether the difference involves an external critical design attribute that may potentially impact..." Where differences between the generic and the RLD have the potential to impact the user's ability to perform a critical task, applicants should analyze these differences in the context of a userelated risk analysis (e.g., use-related failure modes and effects analysis) to assess the level of risk. Risks should be reduced where possible by design since users experienced with the generic products are unlikely to be retrained or read the instructional material upon receiving the generic. "as a result, there is concern that patients or caregivers who encounter different user interfaces, especially if they impact their ability to perform critical tasks, may be at increased risk " N/A "If differences are identified between the design of the user interface of the proposed generic combination product and the user interface of its RLD, the sponsor should focus on whether the difference may impact a critical task, hence the usability and use safety of the product. A risk analysis consistent with ISO 14971 and 2016 CDRH HF guidance is suggested as well as an assessment of the product residual risk " As noted in the previous line, a risk analysis is the industry standard tool for assessing design, process and use-related risks. Notably, these tools are used when sponsors make product changes to assess the impact of a change on safe and effective use and can be used similarly here. This approach will ensure analysis consistency with the risk management process applicants follow for other aspects of product development. Revised to recognize that the acceptability of different user interfaces will come back to whether they will affect the ability to perform critical tasks. Most of the PI content is outside the scope of human factors and the usability and use safety of the product. The acceptability of the differences in the product User Interfaces should come back to critical tasks and an analysis of acceptable risk. Page 3 of 5
232-235 250-254 289-292 305-429 FDA views the impact of a design difference to be minor if the differences in the user interface of the proposed generic combination product, in comparison to the user interface of the RLD, does not affect an external critical design attribute. Other design differences: FDA may not view a design difference as minor if any aspect of the threshold analysis suggests that differences in the design of the user interface of a proposed generic combination product as compared to the RLD may impact an external critical design attribute that involves administration of the product "the objective of the comparative use human factors studies described in this guidance is to demonstrate that the use error rate, associated with the change in an external critical design attribute for the proposed user interface, does not preclude approval of the proposed product in an ANDA" We suggest removing the proposed non-inferiority study design. FDA views the impact of a design difference to be minor if the differences in the user interface of the proposed generic combination product, in comparison to the user interface of the RLD, do not affect the ability of the user to perform critical tasks. Other design differences: FDA may not view a design difference as minor if any aspect of the comparative analysis suggests that differences in the design of the user interface of a proposed generic combination product as compared to the RLD, may impact the user's ability to perform critical tasks. "the objective of the comparative use human factors studies described in this guidance is to demonstrate that the residual risk related to use errors associated with the generic do not preclude approval of the proposed product in an ANDA" A comparative use human factors study should be designed to provide sufficient data that the proposed generic product can be used with no increase in risk to usability and use safety as compared to the RLD when analyzed in the context of a risk assessment. The acceptability of the differences should come back to critical tasks and an analysis of acceptable risk. The acceptability of the differences should come back to critical tasks and an analysis of acceptable risk. We would recommend not calculating use error rates, but focusing on the root cause of observed errors and associated risks. Consistency with 2016 CDRH HF guidance. We would propose one of the following two options: Option 1: One study design could be considered where the sponsor evaluates Page 4 of 5
differences in the generic product user interface to demonstrate that no use errors result in unacceptable use-related risks. The sponsor should consider testing both users experienced with the RLD as well as naive users. Option 2: A second study design option can be implemented where the sponsor evaluates the differences between the generic product and RLD user interfaces by testing those differences with users first using the RLD and then the proposed generic product. This approach would demonstrate whether differences between the two products would preclude switching from one product to the other without retraining. For either study design, and per FDA s 2016 CDRH HF guidance, root cause analysis for any user errors, close calls and use difficulties should be performed. Additionally, "the root cause of all use errors and problems should then be considered in relation to the associated risks to ascertain the potential for resulting harm" (8.1.6 CDRH HF guidance) and determine where the residual risk is acceptable or whether additional risk control measures need to be implemented. Study designs and sample sizes should be consistent with the aforementioned guidances and consensus standards (e.g., Appendix B 2016 CDRH HF guidance). Page 5 of 5