Vero Biotech, LLCGENOsyl® Delivery System (Nitric Oxide)

NDA 202860 COMPLETE RESPONSE

Vero Biotech, LLC

Attention: Alfred W. Schweikert, PhD, RAC Vice President of Regulatory Affairs

387 Technology Circle NW

Suite 125

Atlanta, GA 30313

Dear Dr. Schweikert:

Please refer to your New Drug Application (NDA) dated and received July 23, 2018, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for GENOsyl® © Delivery System © (Nitric Oxide).

We also acknowledge receipt of your amendment dated December 18, 2018, which was not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this letter.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

FACILITY INSPECTIONS

During a recent inspection of the Vero Biotech manufacturing facility (FEI: 3014617112) for this NDA, our field investigators conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this NDA may be considered for approval.

CDRH (DEVICE

1. In prior communication, we noted your device incorporates sensory feedback for adjustment of Nitric Oxide delivery and flow rate. These sensors and the controlled outputs © However, due to the closed-loop technology utilized in the design of the proposed device, FDA believes conformance to certain clauses of this standard will provide evidence of safety and adequate performance. This standard may be particularly relevant to |

Reference ID: 4938686

NDA 202860

Page 2

Reference ID: 4938686

closed-loop systems whose failure may introduce the same risk to the patient as

(b) (4)

devices (e.g., over- and under-delivery of medication).

In order for FDA to be assured of the safety of your device, we previously requested that

the following be provided in your submission.

a. evidence of conformity to the following clauses/sub-clauses:

b. performance testing to demonstrate that u the device meets the following:

(b) (4)

nder various disturbances or variabilities

i. The transient specifications will continue to be met. Please quantify the relevant transients such as overshoot, undershoot to show that the device

meets its specifications as per

(b) (4)

ii. The control system continues to be stable. You may provide this evidence

either analytically or experimental

ly.

1. Analytic stability: In case you have developed a mathematical model and designed the control system based on pole/zero

analysis, relative and abso!

lute stability of the system may be

conducted analytically. This would provide powerful evidence of

stability.

2. Experimental stability: If the control system design was not

through a model-based tec!

nique, stability will need to be

demonstrated experimental

ly. This will need to be demonstrated

for an extended and sufficiently long period of time which will require the waveforms to be reproduced for long enough duration to provide reasonable evidence of output stability. The duration of this testing should be clinically relevant.

In the Performance Testing Summary provided in Section 2.3.R, you state that

analysis

© is not applicable to

the device. This information is not sufficient or complete. As stated above, we

acknowledge that the controlled outputs are not

0) (4) ® standard.

However, we believe that conformance to certain clauses of the standard will provide

NDA 202860

Page 3

2.

Reference ID: 4338686

evidence of safety and adequate performance of the device. Please provide the information requested above or provide itemized responses with rationale as to why the requested information is not applicable.

The device appears to be tested by software only to demonstrate delivery shutdown at NO, levels exceeding 3 ppm. Please provide testing of the physical device to demonstrate delivery shutdown.

The GeNOsyl) Ds was able to pass electrostatic discharge (ESD) immunity testing wa)

This information is needed so that we can assess the safety of the GeNOsyl oe

in the electromagnetic environments of intended use.

The use of passive radio-frequency identification (RFID) tags that are interrogated by active readers (interrogators) for tracking material and personnel in hospitals is increasing. Because the GeNOsyl ©® is a critical medical device, in addition to the EMC testing that was performed, we recommend that you test the GENOsyl ® 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 equivalent. (AIM = Association for Automatic Identification and Mobility, www.aimglobal.org.) Please include information in the Operator’s Manual specific to the risks and test results.

An acceptable alternative to AIM 7351731 testing is ad hoc testing using RFID emitters at all the following frequencies emitting at the maximum RF output power, based on the environment of use.

(4)

This information is needed so that we can assess the safety of the GeNOsyl sak}

in the healthcare electromagnetic environment.

Your device relies on an internal © battery for backup if main power is lost. We could not locate any information in your submission related to this battery other than it complies with ©® as supplied by the manufacturer. Additional information is needed to demonstrate the combination of the battery and system are safe. Please provide

NDA 202860

Page 4 the following information (or point to where it is in the submission) to demonstrate your battery safety when it is integrated with your device:

a. Device’s surface temperature in the event of a battery short circuit,

Note: The surface temperature test should be conducted when the battery supplies the maximum current possible. The maximum current is the current amount that is just below the thermal or current protective circuit threshold at which these protective circuits disconnect the battery from the system.

b. Information to demonstrate that the battery manufacturer safety requirements such as environment, electrical, load, venting, air flow, charging speed, etc. are met after the battery is integrated in the system.

HUMAN FACTORS

The human factors (HF) validation study, submitted on July 23, 2018, does not provide sufficient evidence to demonstrate that your proposed product can be used safely and effectively by the intended users for its intended uses and use environments. We acknowledge your written responses, dated November 20, 2018 and November 30, 2018, submitted in response to the General Advice Letter dated November 16, 2018, however, the information provided does not

adequately address our concerns.

1.

Reference ID: 4938686

Your study did not adequately evaluate participants’ ability to detect, comprehend, and implement the appropriate actions in response to critical alarms. We acknowledge your written response including the trace matrix matching the critical high priority alarms to applicable use scenarios and user comprehension knowledge tasks. We also acknowledge that the HF study did evaluate participant performance of some tasks that would be applicable in an alarm scenario. However, none of the scenarios in the HF study evaluated critical audible and visual alarms within the context of an alarm status. Therefore, the participants in the study had no opportunity to detect the alarm during simulated use, then troubleshoot the alarm to determine and perform the appropriate response to address the alarm in the timeframe necessary to prevent patient harm. While we do not expect that all critical alarms are evaluated in a simulated use scenario, we remain concerned that the study methodology employed remains deficient to demonstrate that users will be able to identify an alarm and know how to respond to the alarm in a manner and timeframe necessary to avoid patient harm. Given the critical alarms are system features intended to alert the user to dose deviations and system failures, we believe that the HF study methodology was inadequate to provide sufficient evidence to demonstrate the effectiveness of these aspects of the user interface.

Confounding variables (incorrect system set-up for the testing scenarios, moderator error, and mi levice components) occurred during the study, interrupting participant simulation of several critical tasks, which may have confounded the interpretation of your study results. It is not possible to discern whether these study interruptions may have impacted the participant performance of the critical tasks.

NDA 202860 Page 5

3. Numerous use errors and use difficulties with critical tasks occurred in the study that could result in delay of therapy, interruption of therapy, and overdose. We acknowledge the clinical evidence provided in your response that supports the safety of brief interruption © of nitric oxide doses and short-term variation of nitric oxide doses over a range of © However, the data provided in the HF study is inadequate to demonstrate that intended users can detect critical alarms and implement the appropriate response within the brief timeframe necessary to avoid patient harm (see number | above).

4. We acknowledge your revised Usability FMEA and modifications to the user interface (i.e., revisions to the Quick References Guide (QRG), Operator’s Manual (OM), and Training Program) to address use errors and use difficulties observed in the study; however, none of these modifications were validated in a subsequent human factors study. You state that none of the changes made as part of the mitigation strategy altered the user interface or modes of use and thus no additional human factors testing is required. We disagree. Per the Applying Human Factors and Usability Engineering to Medical Devices guidance (2016), all sources of information transmitted by the device (including packaging, labeling), training and all physical controls and display elements (including alarms and the logic of operation of each device component and of the user interface system as a whole) comprise the user interface. Thus, the modifications and revisions to the, QRG, OM, and Training Program are considered alterations of the user interface. We expect user performance to be evaluated using all components of the final intend-to-market user interface, including the QRG, OM, and training program, for the final intend-to-market device to provide the data to demonstrate that the mitigation strategies are effective and do not introduce new use-related risks.

To address these concerns, we recommend you evaluate the use-related errors observed in the HF study, employ additional mitigation strategies as appropriate, update your use-related risk analysis, and conduct another HF validation study using appropriate study methodology, and the finalized intend-to-market user interface. We provide additional recommendations in the enclosed table for your consideration and recommend they are implemented prior to conducting your HF study. Ensure that your device, Training Program, QRG, and OM used in the new HF study are representative of the intend-to-market commercial product.

We strongly encourage to you to submit your HF study protocol for the Agency’s review and feedback prior to commencing your HF validation study, although such review is not a requirement.

Place the requested information in eCTD Section 5.3.5.4 — Other Study reports and related information.

Please refer to our draft guidance titled “Contents of a Complete Submission for Threshold

Analyses and Human Factors Submissions to Drug and Biologic Applications” for the content of a human factors validation study protocol submission. The guidance is available online at

Reference ID: 4338686

NDA 202860 Page 6

ittps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM621902.pdf

Guidance on human factors procedures to follow can be found in “Applying Human Factors and Usability Engineering to Medical Devices,” available online at: ttp://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu ments/ucm259760.pdf

See also the Guidance titled “Safety Considerations for Product Design to Minimize Medication Errors” available online at: ttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM331810.pdf

ote that we recently published two draft guidance documents that, while not yet finalized, might also be useful in understanding our current thinking and our approach to human factors for combination products, product design, and labeling:

“Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development,” found online at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM484345.pdf

“Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors,” found online at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc m349009.pdf

REGULATORY

We refer to the Paragraph IV certifications under 21 CFR 314.50(i)(1)(i)(A)(4) that you submitted in your July 23, 2018, resubmission and remind you of the requirement to amend your application to include documentation of timely sending and receipt of notice of Paragraph IV certification as described under 21 CFR 314.52(e), by each person required to receive notice.

PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) — a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the prescribing information conforms with format items in regulations and guidances. Your response must include updated content of

Reference ID: 4938686

NDA 202860 Page 2

labeling [21 CFR 314.50(1)(1)()] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataS tandards/StructuredProductLabeling/default.htm

PROPRIETARY NAME

The review of your proposed proprietary name has been suspended pending response to the deficiencies with the application as described in this letter. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

DETERMINATION OF PRODUCT EXPIRATION DATE

Regarding the stability studies, we note that a hold-time for the antioxidant cartridges used in the manufacture of the cassettes has not been adequately established. Based on your submitted stability data, the proposed expiration dating of 12 months for the GENOsyl_ ™® drug product cassette is acceptable. However, the date of expiration needs to be marked based on the date of manufacture of the oldest cartridge used in the cassette assembly, as opposed to the manufacturing date of the cassette.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” December 2017 at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM59054 1.

Reference ID: 4938686

NDA 202860 Page 3

If you have any questions, please call Brian Proctor, Regulatory Project Manager, at (240) 402-

3596.

ENCLOSURE: Labeling Comments

Sincerely,

{See appended electronic signature page}

Norman Stockbridge, M.D., Ph.D. Director

Division of Cardiovascular and Renal Products Office of Drug Evaluation I

Center for Drug Evaluation and Research

5 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

Reference ID: 4938686

Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

NORMAN L STOCKBRIDGE 01/23/2019 11:20:55 AM

Reference ID: 4938686