IntelGenx Corp.RizaFilm (rizatriptan) oral film 10 mg

NDA 205394 COMPLETE RESPONSE

IntelGenx Corp.

Attention: Ross C. D’Emanuele 50 South Sixth Street, Suite 1500 Minneapolis, MN 55402-1498

Dear Dr. D’Emanuele:

Please refer to your new drug application (NDA) dated March 26, 2013, received March 27, 2013, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for RizaFilm (rizatriptan) oral film 10 mg.

We acknowledge receipt of your amendment dated September 26, 2019, which constituted a complete response to our March 28, 2019, action 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.

PRODUCT QUALITY

1) With respect to the manufacturing process:

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2) With respect to drug product stability:

We acknowledge the out of specification (OOS) investigations submitted in response to the September 26, 2019, action letter. However, due to the manufacturing process deficiencies described in Item 1 above, we have determined that stability data obtained from testing of the existing exhibit batches cannot be used as primary data for establishment of product shelf life. Therefore, we recommend the following: a) Submit 12 months of long-term stability data for exhibit batches manufactured as recommended in Comment 1. Stability testing should be performed using fully validated methods and the suitability of analytical equipment should be verified prior to use. The product shelf life assigned will be based on review of this stability data. b) If you intend to use the 2017 or 2018 batch stability results as supportive data, provide the raw HPLC data for all corrected analytical results. Additionally, regarding INV-2019-017, in order to support disqualification of the OOS stability results obtained using © for analysis of this product, further investigation is needed to identify the root cause.

FACILITY INSPECTIONS

3) During a recent inspection of the a drug substance manufacturing facility for this NDA, our field investigator observed objectionable conditions at the facility and conveyed that information to the representative of the facility at the close of the inspection. Satisfactory resolution of the observations is required before this NDA may be approved. Please list communications submitted to, or held with, the Agency to facilitate resolution of the observed objectionable conditions, or deficiencies, noted at the facility.

4) During the recent inspections of IntelGenx Corp. (FEI 3005721224) for oral film products, our field investigator observed objectionable conditions at the drug product manufacturing facility. In addition, during the review of the submission dated 09/26/2019, we are recommending manufacture of new exhibit batches tested in accordance with cGMPs. Please note that that this information will be reviewed by the Agency during the review of the application and a follow up Pre approval inspection may be needed to verify that the facility has taken necessary corrective actions to ensure oral film product quality.

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

1 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm08415 9.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items rom 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 labeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) ‘ormat as described at FDA.gov.?

CARTON AND CONTAINER LABELING

If you resubmit this application, include draft carton and container labeling revised as ollows:

General Comments (Container labels and Carton Labeling)

e The usual dose statement can be improved to ensure consistency with the Physician Labeling Rule (PLR) formatted prescribing information labeling. We recommend you revise the usual dose statement:

to read “Recommended Dosage: See prescribing

(4)

information.”

e The current temperature statements do not contain the temperature scale designation (i.e., “°C” or “°F”) after each numerical value. We are concerned that this information could be misinterpreted and may pose a risk of drug degradation. Ensure that the degree symbol and temperature scale follow each numeric value denoting temperature ranges to increase clarity. For example, revise “59° - 77°F (15° - 25°C)” to read “59°F to 77°F (15°C to 25°C)”.

Container Labels

e As currently presented, the format for the expiration date is “YYYY MM.” However, it is unclear whether the month (that is, MM) will be displayed using numerical (for example, 06) or alphabetical (for example, JU) characters. Therefore, we were not able to assess the appropriateness of the proposed expiration date format from a medication safety perspective. Please clarify whether you propose to use only numerical characters for the expiration date, or whether you propose to use alphabetical characters for the month. Additionally, to minimize confusion and reduce the risk for deteriorated drug medication errors, FDA recommends that the human-readable expiration date on the drug package label include a year, month, and non-zero day, if space permits. FDA recommends that the expiration date appear in YYYY-MM-DD format if only

2 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 Zhtm 3 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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numerical characters are used or in YYYY-MMNM-DD if alphabetical characters are used to represent the month.

Carton Labeling

e It is unclear what information will be contained within the “Serialization Area.” Therefore, we are unable to assess the acceptability of the information. Please clarify the specific information you intend to display in the “Serialization Area.”

e As currently presented, there is no product identifier on the carton labeling. In September 2018, FDA released draft guidance on product identifiers required under the Drug Supply Chain Security Act. The Act requires manufacturers and repackagers, respectively, to affix or imprint a product identifier to each package and homogenous case of a product intended to be introduced in a transaction in(to) commerce beginning November 27, 2017, and November 27, 2018, respectively. The draft guidance is available from: https:/Awww.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs- gen/documents/document/ucm621044 pdf

e We recommend that you review the draft guidance to determine if the product identifier requirements apply to your product’s labeling.

e We did not identify a placeholder (“LOT” or “EXP”) for the lot number and expiration date on the carton labeling. The lot number and expiration date are required per 21 CFR 201.10(i)(1) and 21 CFR 211.137, respectively. Ensure that the lot number and expiration date are present on the carton labeling in accordance with 21 CFR 10(i)(1) and 21 CFR 211.137.

e We note the statement

(b) (4)

which could lead to confusion. Consider relocating this statement to the back panel, deleting the statement altogether, or address this concern by other means.

PROPRIETARY NAME

Please refer to correspondence dated, January 29, 2020, which addresses the proposed proprietary name, RizaFilm. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

ADDITIONAL COMMENTS We have the following comments/recommendations that are not approvability issues:

You should develop a ®® dosage strength of your product to support dosing and administration in pediatric patients age 6 through 11 years.

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 U.S. Food and Drug Administration

Silver Spring, MD 20993

www.fda.gov

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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

his 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 ‘ake before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

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

If you have any questions, call Alina Salvatore, Regulatory Project Manager, at 240- 402-0379.

Sincerely, {See appended electronic signature page}

Nick Kozauer, MD

Acting Director

Division of Neurology 2

Office of Neuroscience

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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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.

NICHOLAS A KOZAUER 03/24/2020 10:24:20 PM

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