GeNO LLCGENOsyl™ (nitric oxide for inhalation)

NDA 202860 COMPLETE RESPONSE

GeNO LLC

Attention: David Fine, Ph.D. President

2941 Oxbow Circle

Cocoa, FL 32926

Dear Dr. Fine:

Please refer to your New Drug Application (NDA), originally submitted March 20, 2012, our refuse to file letter dated May 18, 2012. and your resubmission dated August 31, 2012. under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for GENOsyl™ ©® (nitric oxide for inhalation).

We acknowledge receipt of your amendments dated May 7, June 14, October 5, 12, 31, November 13, 2012, and January 29, 2013.

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.

PRODUCT QUALITY

1. Provide data on the quantitative determination o hy from at least three different batches. Use this data to propose a specification to be used for release and stability determination. Provide data to show the

cartridge we

2. The Agency does not accept the quality control method used to determine batch release and used to set cartridge expiration dating based on the current method using) nitrogen dioxide at a flow rate of, © We recommend providing data on the cartridges (randomly selected from at least three different batches) using the conversion of 800 ppm nitrogen dioxide tested at the flow rates of

output levels. Present these data in the application and use it to propose a specification for release and stability determination for cartridges. We recommend demonstrating that the specification limits be correlated to performance that ensures that the cartridges meeting release and stability specifications when used under conditions representing projected use at minimum convert the contents of one cylinder of 800 ppm nitrogen dioxide © to acceptable levels of output for nitric oxide and nitrogen dioxide.

3. Provide data from stability studies at long term and accelerated storage conditions to support the proposed cartridge expiration dating period. These data should be from at least three representative commercial scale batches and the cartridges are to be selected randomly. The stability data are to be based on the stability indicating criteria described above. Provide a proposed post approval commitment to a stability protocol to continue to monitor stability of new batches of cartridges on at least one new batch on an annual basis.

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10.

We find your proposed studies to demonstrate cartridge capacity (time to cartridge failure) under simulated real conditions (tandem cartridges on the MVG-2000 delivery system) adequate. Provide these data on cartridges representing at least three batches from production. In addition provide data showing this performance for at least one cartridge which is close to the minimum standards for an acceptable cartridge.

Provide adequate data demonstrating the effectiveness of the ©) Filters with the MVG-

2000 to prevent microbiological contamination of the breathing air, and to prevent particulates from the cartridges and MVG-2000 system from entering the patient.

Include an Identity Parameter in the release specification for 800 ppm nitrogen dioxide may for the acceptance specification ( ii).

Remove all references to ® as the "drug substance" from the application. If necessary to refer to it by another designation, ©® can be referred to in general as a drug substance intermediate.

DMF # referenced in this application was found to be deficient; a list of deficiencies was communicated to the holder of DMF#. These deficiencies impact the approvability of this application and must be corrected by the DMF holder in the form of an amendment to the DMF.

In addition to the data requested in items 1 and 2 above, the following ar are required. The release specification for the ® cartridge is not adequate. The ® nitrogen dioxide conversion used as the standard method with bridging studies oo method is not acceptable. Release testing should provide a means for assuring the following quality parameters with adequate representative data:

A. Amount of © in cartridge; with assay for © indicated by a stability indicating method

B. Assurance that no significant amount of is lost from the cartridge during the assembly, - in other words, demonstrate that the matrix of cartridge is stable throughout variations in the assembly, © processes of the cartridge

iC) © of the cartridge

D. Functional effectiveness of the cartridge in converting 800 ppm nitrogen dioxide exe

with a stability indicating method

In addition to the data requested in item 3 above, the following are required. Provide a stability protocol and criteria for registration stability of the cartridges and postapproval stability commitments. Provide specifications that use the same method of functional effectiveness of the cartridge in converting 800 ppm nitrogen dioxide ©® to nitric oxide. Cartridges should be tested at long term storage and accelerated conditions using storage in commercial packaging. Data from at least three commercial scale batches should be provided to ustily: the proposed expiration period for the cartridges. Specifications should also include how sealing is evaluated at stability timepoints.

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The following comments are not requirements for the complete response to this application, but they are recommendations to assist in more efficient review of the application:

11. We encountered difficulty in re-locating pieces of information in your version of organization using the electronic common technical document format. On resubmission, we recommend a re-formatting. Since the drug substance, nitric oxide, altsy

we recommend presenting the information in the eS

The MVG-2000 Delivery system can be described in the 3; 2.1 P

section, normally reserved for the drug product. This MVG-2000 Delivery System

delivered to the patient.

sections as separate components.

12. It is important that detailed manufacturing descriptions be provided in each unit. In the 3.2.S sections, the manufacturing description belongs in section 3.2.S.2.2. In the 3.2.P sections, the manufacturing description belongs in section 3.2.P.3.3.

LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate. If you revise labeling, your response must include updated content of labeling [21 CFR 314.50(1)(1)()] in structured product labeling (SPL) format as described at

http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

FACILITY INSPECTIONS

The Agency expects all facilities involved in the manufacture, processing, packing or holding, which includes packaging and labeling operations, testing and quality control, of the drug product to be ready for inspection at the time of application submission.

1. Inspections of the following manufacturing facilities included in this application were attempted. However, inspections could not be completed as these sites were not ready for inspection.

. OO) . . e GeNO LLC: FEI 3010143995 2. Because of deficiencies related to the manufacture and stability of the © cartridges noted

in our letter to you dated February 21, 2013, we have deferred the inspection of manufacturing facility during this review cycle.

Note that all new facilities and those that were inspected before and are relisted for the manufacture, processing. packing or holding of the product must be ready for inspection with your re-submission. Satisfactory inspections are required before this application may be approved.

PATENT CERTIFCATIONS

Under 21 CFR 314.54(a)(1)(vi), a 505(b)(2) application must contain a patent certification or statement with respect to any relevant patents that claim the listed drug and that claim any other drugs on which the investigations relied on for approval of the application were conducted, or that claim a use for the listed or other drug. Your 505(b)(2) application relies upon the Agency’s finding of safety and effectiveness for NDA 20845 for INOmax (nitric oxide) for inhalation, 100 and 800 ppm, but does not contain a patent

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certification or statement with respect to each patent listed in FDA’s “Approved Drug Products with Therapeutic Equivalence Evaluations” (the Orange Book) for the listed drug upon which you rely (see 21 CFR 314.54(a)(1)(vi)). After you submitted your 505(b)(2) application, the NDA holder for INOmax (nitric oxide) for inhalation, 100 and 800 ppm, timely filed information on U.S. Patent No. 8,431,163 (‘163 patent) for listing in the Orange Book. In accordance with section 505(b)(2) of the FDCA and 21 CFR 314.50(i), you must submit an appropriate patent certification or statement with respect to the ‘163 patent.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

1. Describe in detail any significant changes or findings in the safety profile.

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as the original NDA submission.

¢ Present tabulations of the new safety data combined with the original NDA data.

e Include tables that compare frequencies of adverse events in the original NDA with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop- outs from the newly completed trials. Describe any new trends or patterns identified.

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

5. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original NDA data.

6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

7. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

8. Provide English translations of current approved foreign labeling not previously submitted.

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. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

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Under 21 CFR 314.102(d), you may request a meeting or telephone conference 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 FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1532

22.pdf.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, please call Russell Fortney, Regulatory Project Manager, at (301) 796-1068.

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

ce: GeNO LLC Attention: Ruth E. Stevens, Ph.D., MBA 9825 Kenwood Road, Suite 203 Cincinnati, OH 45242

Reference ID: 3333534 Reference ID: 4538636

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

NORMAN L STOCKBRIDGE 06/28/2013

Reference ID: 3333534 Reference ID: 4538636