Laboratorios Farmaceuticos Rovi, S.A.risperidone extended-release injectable suspension

NDA 214835 COMPLETE RESPONSE

Laboratorios Farmaceuticos Rovi, S.A.

c/o PharmaLex

Attention: Nick Palmer

Senior Manager, Consulting and Scientific Affairs 1700 District Avenue, Suite 100

Burlington, MA 01803

Dear Mr. Palmer:

Please refer to your new drug application (NDA) dated and received January 8, 2021, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for risperidone extended-release injectable suspension.

We also acknowledge receipt of your amendments dated September 10, 2021, and September 23, 2021, which were 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.

OPHTHALMOLOGY

On August 21, 2021, we sent an information request with several questions about your ophthalmologic examination data. On September 1, 2021, we received your response to our questions (eCTD #0032). In your response, you committed to perform a full data re- check and re-analyses of ophthalmologic findings and submit a response no earlier than October 15, 2021. Of the six ophthalmologic questions in our August 21, 2021, information request, you must fully address questions 1, 2, 4, 5, and 6 in (or prior to) your NDA resubmission.

HUMAN FACTORS The results of your human factors (HF) validation study indicated the need for further revisions to your user interface in order to mitigate residual risk.

In particular, we are concerned that your intended users may have difficulty injecting the full dose of medication due to the viscosity of the product, as evidenced by use difficulties and use errors in your human factors validation study.

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We sent an information request on August 20, 2021, for you to provide data or information (for example, anthropometry or other data) to support that the intended users will be able to reliably deliver the full dose of medication, and that the injection rate used in the glide force testing is representative of actual use. We have received a response to this information request; however, the additional information will not be reviewed at this time. Therefore, we cannot conclude that the proposed product user interface supports safe and effective use by the intended users, for the intended use, and in the intended use environment.

We recommend you provide data or information to support that the intended users will be able to reliably and effectively deliver the full dose of medication. If you are unable to provide such data or information, we recommend you redesign the product to ensure that it supports use by the intended users, for the intended uses, and in the intended use environments. Any product redesign will require an additional human factors validation study to demonstrate that the design mitigations were effective.

Additionally, we recommend you take additional measures to ensure that the finger flange remains in place during injection and does not interfere with the operation of the syringe.

PRODUCT QUALITY

Drug Product ow 1. Due to intra- and inter-batch dissolution result variability, attributed to we

recommend developing a test to directly monitor molecular weight and a Propose a limit and provide a justification for the proposed limit.

2. In aresponse to an information request dated July 30, 2021, you provided additional information supporting the omission of 08 and © testing on the drug product. However, no data for the drug product was included, specifically during long-term storage controlled room temperature). Provide data demonstrating that © remains unchanged on stability of the drug product (e.g., result from drug product registration stability batches stored for 12 months under long-term conditions).

4)

3. In aresponse to an information request dated August 6, 2021, you provided additional dissolution profiles predictions using drug product with inherent viscosity of . The model predicts that drug product with this viscosity ©® Would likely meet the proposed specifications

probability). Therefore, the model cannot be used to support the currently proposed limits as it does not discriminate between failing and passing product. As such, tighten the inherent viscosity specifications (both raw material and sterilized material).

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

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4. We remind you of the following outstanding information requests:

a. You previously committed to establishing direct PLGA testing on non- reconstituted drug-product in your response to information request dated May 21, 2021.

b. Perform a thermal cycling study to determine acceptable temperature/humidity excursions of the powder syringe (risperidone and PLGA) to ensure short term freeze/thaw conditions do not adversely impact the drug product.

Biopharmaceutics 1. The provided in vitro drug release testing (IVRT) data from the clinical and

registration batches show high inter-batch and intra-batch variabilities. The observed high variabilities could come from inconsistent drug product quality, dissolution method, analytical method/assay, or other sources. You have not provided adequate information/data to confirm and address the source(s) of this variability. We recommend that you investigate and identify the source(s) of the observed variability and provide data supporting the findings.

2. The proposed wide dissolution acceptance criteria ranges are permissive and unacceptable. Please note that, in general, the selection of the dissolution acceptance criteria ranges is based on mean target value + #% and >"% for the last specification time-point. Wider specification ranges may be acceptable if they are supported by an established “safe space” based on an approved IVIVC model, PBBM, etc. For an established safe space, the acceptable dissolution specifications should ensure bioequivalence/clinical relevance of future batches with dissolution profiles falling between the identified extreme ranges within the limits.

Microbiology ow Your application referenced the Drug Master File (DMF) This DMF was found inadequate to support your submission. Deficiencies were sent to the DMF holder on May 11, 2021. These deficiencies must be adequately addressed before this application can be approved. As part of your response to this letter, include the date the DMF holder amended their DMF to address the deficiencies.

Powder prefilled _syringe (Risperidone+PLGA)

1. We acknowledge the provided container closure integrity validation reports for the drug product and the diluent DMSO (UDMI-IVP-21-013/00 and UDMI-IVP-21- 014/00) by microbial immersion method in 1.11.1 (Seq-0023). It is noted that the syringes were exposed to the vacuum condition but not a pressure condition. Note that the additional vacuum process is not considered the pressure condition. The microbial immersion container closure integrity test should be conducted using pressure and vacuum conditions. These conditions may be necessary to ensure that debris, dried product, and/or particulate matter are completely removed from potential leak paths. Commit to

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

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using both vacuum and pressure conditions for future container closure integrity testing by microbial immersion.

. We acknowledge the provided i i i 2015 qualification summary

and 2019 reaqualification runs f process of | OPM and in pages 5-30 of 132 (1.11.1 Response, Seq-0013) and the validation reports UDMI-IC-16-023/01, UDMI-IVP-19-

017/00 (1.11.1, Seq-0013), and ICO-ROV-SM-7710.1505 (1.11.1, Seq-0014).

Address the following issues:

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

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FACILITY INSPECTIONS

During a recent inspection of the

manufacturing facility for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

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

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In addition to responding to the deficiencies presented above, please note and acknowledge the following comment in your response. Inspections of the following facilities:

e Rovi Pharma Industrial Services SA (FEI: 3007512884; Spain)

e Rovi Pharma Industrial Services SA (FEI: 3002989591; Spain)

are required before this application can be approved. FDA must assess the ability of these facilities to conduct the listed manufacturing operations in compliance with CGMP. Due to restrictions on travel, we were unable to complete inspections during the current review cycle for your application. You may respond to deficiencies in this Complete Response Letter while the travel restrictions remain in effect. However, even if these deficiencies are addressed, the application cannot be approved until the required FDA inspections are completed and any findings are assessed with regard to our application. We will continue to monitor the public health situation as well as travel restrictions. We are actively working to define an approach for scheduling outstanding inspections once safe travel may resume and based on public health need and other factors.

Because approval of your application requires inspections that cannot be completed in a timely manner due to COVID-19 travel restrictions, the FDA has made aan initial determination that the amendment to your application in response to this complete response letter will be received as an amendment as described in the 2020 Guidance for Industry Review Timelines for Applicant Reponses to Complete Response Letters When a Facility Assessment Is Needed During the COVID-19 Public Health Emergency.

For more information, please see the FDA guidances related to COVID 19. These guidances can be found at: https://www.fda.gov/emergency-preparedness-and- response/coronavirus-disease- 2019-covid-19/covid-19-related-guidance-documents- industry-fda-staff-and-otherstakeholders.

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 Prescription Drug Labeling Resources’ 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.

"https :/Avww.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

? httos:/Awww.fda.gov/drugs/labeling-information-drug-products/preqnancy-and-lactation-labeling-drugs- final-rule

U.S. Food and Drug Administration

Silver Spring, MD 20993

www.fda.gov

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CARTON AND CONTAINER LABELING

Submit draft carton and container labeling based on our proposed revisions dated September 17, 2021.

PROPRIETARY NAME

Please refer to correspondence dated, August 29, 2021 which addresses the proposed proprietary name, Risvan. 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.

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 in the original submission.

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application 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.

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

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(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 application 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 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.

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

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If you have any questions, call Latrice Wilson, Senior Regulatory Project Manager, at (240) 402-5317. Sincerely,

{See appended electronic signature page}

Tiffany R. Farchione, MD

Director

Division of Psychiatry

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.

TIFFANY R FARCHIONE 09/24/2021 01:21:11 PM

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