Issued January 1, 2019
Issued
January 1, 2019
Application
Other • 202860
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This is a Complete Response letter from the FDA to Vero Biotech, LLC, for their New Drug Application (NDA) 202860 for GeNOsyl® Delivery System (Nitric Oxide). The FDA has determined that the application cannot be approved in its present form due to deficiencies identified during facility inspections, issues related to the device's design and testing (CDRH concerns), and inadequacies in the human factors validation study.
The application cannot be approved due to unresolved manufacturing facility deficiencies, significant issues with the device's safety and performance testing (including stability, delivery shutdown, electromagnetic compatibility, and battery safety), and inadequate human factors validation study results, particularly regarding critical alarm detection and response, and unvalidated user interface modifications.
During a recent inspection of the Vero Biotech manufacturing facility (FEI: 3014617112), field investigators conveyed deficiencies that require satisfactory resolution before the NDA can be considered for approval.
Recommended response: Address all deficiencies identified during the facility inspection and provide evidence of satisfactory resolution to the agency.
The device incorporates sensory feedback and closed-loop technology. FDA believes conformance to certain clauses of a standard will provide evidence of safety and adequate performance. Specifically, evidence of conformity to certain clauses/sub-clauses, performance testing to demonstrate transient specifications are met, and control system stability (analytically or experimentally) are required. The current submission's performance testing summary stating analysis is not applicable is insufficient.
Recommended response: Conduct and submit performance testing demonstrating transient specifications and control system stability, providing either analytical or experimental evidence. Justify any non-applicability with robust rationale.
The device appears to be tested by software only to demonstrate delivery shutdown at NO2 levels exceeding 3 ppm. Physical device testing is required to demonstrate delivery shutdown.
Recommended response: Perform and submit physical device testing to demonstrate delivery shutdown capabilities.
Information is needed to assess the safety of the GeNOsyl in electromagnetic environments. The device needs to be tested for immunity to RFID readers according to FDA-recognized AIM standard 'Medical Electrical Equipment and System Electromagnetic Immunity Test for Exposure to Radio Frequency Identification Readers' (AIM catalog number 7351731) or an equivalent ad hoc testing. Operator's Manual should include risks and test results.
Recommended response: Conduct EMC testing for RFID immunity per AIM 7351731 or equivalent ad hoc testing. Update the Operator's Manual with relevant information.
Cited: Medical Electrical Equipment and System Electromagnetic Immunity Test for Exposure to Radio Frequency Identification Readers
The device relies on an internal battery for backup, but insufficient information was provided regarding its safety when integrated with the device. Specific information required includes device's surface temperature in the event of a battery short circuit and demonstration that battery manufacturer safety requirements are met after integration.
Recommended response: Provide comprehensive data on battery safety, including short-circuit temperature and confirmation that manufacturer safety requirements are met post-integration.
The human factors (HF) validation study did not adequately evaluate participants’ ability to detect, comprehend, and implement appropriate actions in response to critical alarms. None of the scenarios evaluated critical audible and visual alarms within the context of an alarm status, preventing participants from detecting, troubleshooting, and responding to alarms in a timeframe necessary to prevent patient harm.
Recommended response: Redesign and conduct HF study scenarios to specifically evaluate user performance in detecting, interpreting, and responding to critical alarms within clinically relevant timeframes.
Confounding variables (incorrect system set-up, moderator error, missing device components) occurred during the study, interrupting participant simulation of several critical tasks, which may have confounded the interpretation of study results.
Recommended response: Ensure rigorous study design and execution in future HF studies to eliminate confounding variables and ensure data integrity.
Numerous use errors and difficulties with critical tasks occurred in the study that could result in delay or interruption of therapy, and overdose. While clinical evidence for brief interruptions was provided, the HF study data is inadequate to demonstrate users can detect and respond to critical alarms within the necessary timeframe to avoid patient harm.
Recommended response: Implement additional mitigation strategies for identified use errors and difficulties, and validate their effectiveness in a new HF study.
Acknowledged revisions to the Usability FMEA, Quick References Guide (QRG), Operator's Manual (OM), and Training Program were made to address observed use errors, but these modifications were not validated in a subsequent human factors study. The agency disagrees with the sponsor's assertion that no additional testing is required, citing that these changes constitute alterations to the user interface.
Recommended response: Update the use-related risk analysis and conduct a new HF validation study using the finalized intend-to-market user interface, including all revised QRG, OM, and training program materials. Submit the HF study protocol for agency review.
The primary themes are manufacturing quality issues, insufficient device performance and safety data, and critical flaws in the human factors validation study, all of which prevent approval.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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