administrative and correspondence documents · 9072n following administration to the deltoid or...

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

209830Orig1s000

ADMINISTRATIVE and CORRESPONDENCE

DOCUMENTS

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration Silver Spring MD 20993

IND 121179 MEETING PRELIMINARY COMMENTS

Alkermes, Inc. Attention: Mark W. Machado, M.S. Manager, Regulatory Affairs 852 Winter Street Waltham, MA 02451

Dear Mr. Machado:

Please refer to your Investigational New Drug Application (IND) submitted under section 505(i) of the Federal Food, Drug, and Cosmetic Act for aripiprazole lauroxil nanoNanoCrystal Dispersion (NCD).

We also refer to your February 24, 2017, correspondence, received February 24, 2017, requesting a meeting to discuss the acceptability of your upcoming 505(b)(2)NDA for the development of Aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD), the injectable extended-release formulation of aripiprazole lauroxil (AL).

Our preliminary responses to your meeting questions are enclosed.

You should provide, to the Regulatory Project Manager, a hardcopy or electronic version of any materials (i.e., slides or handouts) to be presented and/or discussed at the meeting.

In accordance with 21 CFR 10.65(e) and FDA policy, you may not electronically record the discussion at this meeting. The official record of this meeting will be the FDA-generated minutes.

If you have any questions, contact me at (301) 796-3971, or email [email protected].

Sincerely,

{See appended electronic signature page} LCDR Shin-Ye Sandy Chang, PharmD Regulatory Project Manager Division of Psychiatry Products Office of Drug Evaluation I Center for Drug Evaluation and Research

ENCLOSURE: Preliminary Meeting Comments

Reference ID: 4091852

mailto:[email protected]

FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

PRELIMINARY MEETING COMMENTS

Meeting Type: B Meeting Category: Pre-NDA

Meeting Date and Time: May 4, 2017, 11:00 AM – 12:00PM Meeting Location: 10903 New Hampshire Avenue

White Oak Building 22, Conference Room: 1311 Silver Spring, Maryland 20903

Application Number: 121179 Product Name: Aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD). Indication: Schizophrenia Sponsor/Applicant Name: Alkermes, Inc.

FDA ATTENDEES (tentative) Mitchell Mathis, MD Director, Division of Psychiatry Products (DPP) Tiffany Farchione, MD Deputy Director, DPP Javier Muniz, MD Clinical Team Leader, DPP Daniel Lee, MD Clinical Reviewer, DPP Aisar Atrakchi, PhD Nonclinical Supervisor, DPP Amy Avila, PhD Nonclinical Reviewer, DPP Hao Zhu, PhD Office of Clinical Pharmacology (OCP) Team Leader Praveen Balimane, PhD OCP Reviewer David Claffey, PhD CMC Lead, Office of Pharmaceutical Quality (OPQ) Peiling Yang, PhD Biometrics Team Leader, Division of Biometrics I (DBI) Jinglin Zhong, PhD Biometrics Reviewer, DBI Banu Zolnik, PhD Biopharmaceutics Reviewer, OPQ/ONDP/Division of

Biopharmaceutics

Ta-Chen Wu, PhD Biopharmaceutics Team Lead, OPQ/ONDP/Division of

Biopharmaceutics Kevin Krudys, PhD Pharmacometrics Team Leader, OCP/Division of

Pharmacometrics (DPM) Michael Bewernitz, PhD Pharmacometrics Reviewer, OCP/DPM Loretta Holmes, BSN, PharmD Safety Evaluator, Division of Medication Error Prevention

and Analysis (DMEPA)

SPONSOR ATTENDEES Elliot Ehrich, MD Exec VP, Research and Development and Chief Medical

Officer Georgianna Harris, PhD VP, Regulatory Affairs


Alexa Vasios

Tarek Zeidan, PhD

IND 121179 Page 2

Lisa von Moltke, MD, FCP VP, Clinical Research, Clinical Pharmacology & Translational Medicine

John Lally Senior Director, Regulatory CMC Magali Hickey, PhD Director, Formulation Development and CMC Team Lead Jennifer Vandiver, PhD Associate Director, Process Development Mark Machado, MS Associate Director, Regulatory Affairs

Regulatory Affairs Associate II (b) (4) Clinical Pharmacology Consultant

Principal Scientist, Pharmaceutical Chemistry & Formulation Development

Introduction:

This material consists of our preliminary responses to your questions and any additional comments in preparation for the discussion at the meeting scheduled for May 4, 2017, 11:00 AM to 12:00PM, FDA White Oak between Alkermes and the Division of Psychiatry Products. We are sharing this material to promote a collaborative and successful discussion at the meeting. The meeting minutes will reflect agreements, important issues, and any action items discussed during the meeting and may not be identical to these preliminary comments following substantive discussion at the meeting. However, if these answers and comments are clear to you and you determine that further discussion is not required, you have the option of cancelling the meeting (contact the regulatory project manager (RPM)). If you choose to cancel the meeting, this document will represent the official record of the meeting. If you determine that discussion is needed for only some of the original questions, you have the option of reducing the agenda and/or changing the format of the meeting (e.g., from face to face to teleconference). It is important to remember that some meetings, particularly milestone meetings, can be valuable even if the pre-meeting communications are considered sufficient to answer the questions. Contact the RPM if there are any major changes to your development plan, the purpose of the meeting, or the questions based on our preliminary responses, as we may not be prepared to discuss or reach agreement on such changes at the meeting.

1.0 BACKGROUND

ALKS 9072N [aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD)] is novel formulation of the previously approved long-acting injectable antipsychotic, aripiprazole lauroxil (Aristada). Aristada was approved in 2015 for the treatment of schizophrenia (NDA 207533). Adverse events associated with aripiprazole lauroxil are similar to those found with oral (NDA 021436) and depot aripiprazole (NDA 202971), and other atypical antipsychotics.

The approved extended-release aripiprazole lauroxil formulation requires a 21-day overlap with oral medication prior to achieving therapeutic steady state. Given that depot formulations are typically utilized in individuals struggling with medication compliance, expecting these individuals to remain compliant with oral medication for 21 days is often unrealistic. Alkermes developed ALKS 9072N as an injectable extended-release formulation of aripiprazole lauroxil to replace the 21-day oral lead-in. Individual ALKS 9072N molecules are


IND 121179 Page 3

approximately 1,000 times smaller than those contained within the original extended-release aripiprazole lauroxil. The Sponsor expects for rapid induction to improve patient compliance, simplify clinical monitoring during the transition, and maintain uniform therapeutic blood levels throughout the transition from oral to long-acting injectable treatment.

When ALKS 9072N is co-administered with a single dose of the original extended-release aripiprazole lauroxil, therapeutic blood levels of aripiprazole are reportedly achieved within 24 hours, eliminating need for co-administration of oral drug until therapeutic blood levels are achieved. Based upon this mechanism of action, it appears that ALKS 9072N saturates mechanisms of drug clearance, maintaining the aripiprazole plasma concentration at levels normally present at steady state until the original extended-release aripiprazole lauroxil achieves therapeutic blood levels 21 days after administration.

Alkermes originally submitted a pre-IND meeting request in August, 2014, to discuss their planned NDA filing under section 505(b)(2), as well as the adequacy of their control strategy for drug product, nonclinical development programs, and clinical development plans. The meeting was granted as a Written Responses Only (WRO) on July 10, 2014; however, Alkermes withdrew their meeting request prior to FDA issuing the WRO. Alkermes next requested an end of Phase 2 meeting on July 2, 2015. A Type B End of Phase 2 meeting took place on September 9, 2015, wherein the need for a unique NDA application, the agreement to add a study arm to ALK9072-B102 for purposes of pharmacokinetic (PK) bridging to the original extended-release aripiprazole lauroxil, acceptability of deltoid versus gluteal administration, and the need to collect blood whenever an SAE occurred due to concerns of dose dumping were discussed. A teleconference also took place on March 22, 2016, regarding the proposed product control strategy and registration stability.

There are no plans to conduct further ALKS 9072N studies. To date, the Sponsor has completed the following studies:

• A Phase 1, placebo-controlled, single ascending-dose study to evaluate the safety,

tolerability, and pharmacokinetics of ALKS 9072N in adults with schizophrenia

• A Phase 1 study of an ALKS 9072N initiation regimen in adults with schizophrenia • A Phase 1 study of ALKS 9072N and oral aripiprazole coadministered with aripiprazole

lauroxil in adults with schizophrenia • A Phase 1, placebo-controlled, single ascending-dose study to evaluate the safety,

tolerability, and pharmacokinetics of ALKS 9072N in adults with schizophrenia • A Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of ALKS

9072N following administration to the deltoid or gluteal muscle in adults with schizophrenia or schizoaffective disorder

The Sponsor’s objective for this meeting is to reach agreement with the Agency on the following: • Acceptability of the format and presentation of data in the application • Suitability of filing ALKS 9072N as a supplement to the Aristada NDA (207533) • The acceptability of Alkermes’ approach to Human Factors validation for ALKS 9072N


IND 121179 Page 4

• Appropriateness of the measures taken to differentiate the ALKS 9072N from the

original aripiprazole lauroxil product to reduce the chance of medication errors.

2.0 DISCUSSION

2.1. Regulatory

Question 1: A proposed Table of Contents (TOC) illustrating the location of the information supporting the AL-NCD application is included.

a) Does the Agency agree with the proposed TOC of the application for AL-NCD?

FDA Response to Question 1a: The TOC must be compliant with the Agency’s latest Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specification. Your proposed TOC appears, on face, to align with the Comprehensive Table of Contents Headings and Hierarchy referenced in that Guidance. We note that you have added some subsections not listed in the hierarchy; the placement of these sections appears reasonable. You have also left some sections out; provided that there is no information in your application that belongs in these sections, this is acceptable.

b) Does the Agency agree with the location of the Human Factors study within Module 3, Section 3.2.R of the eCTD structure in order to remain consistent with the presentation of the Human Factors study in the Aristada NDA (NDA 207,533)?

FDA Response to Question 1b: Please see response to Question 1a. We request that you place new Human Factors study documents in Module 5, Section 5.3.5.4 and hyperlink when referencing documents previously submitted in Module 3, Section 3.2.R.

Question 2: Module 2 summaries of the application will be limited to AL-NCD. Clinical data from studies ALK9072-B101, -B102, and -B103 will be summarized in Module 2.5. Nonclinical data for AL-NCD will be summarized in Module 2.4. Relevant safety and efficacy data from the NDA (207,533) for AL will also be cross-referenced.

Does the Agency agree with the proposal to present only data specific to AL-NCD in the application?

FDA Response to Question 2: We agree.

Question 3: The clinical and nonclinical studies supporting the application for AL-NCD are complete and the final study reports will be included within the application’s eCTD submission. There are no other ongoing studies for AL-NCD.


IND 121179 Page 5

As there are no additional data, does the Agency agree that the 120-day Safety Update is not required?

FDA Response to Question 3: In the absence of additional data, we agree.

Additional Nonclinical Comment It does not appear that Study AT-3317-27, referenced in Table 3 on page 47 of the briefing document, has been submitted to the IND. Please include Study AT-3317-27 in the NDA submission.

Question 4: A literature search was performed as part of the annual Development Safety Update Report (DSUR) for the AL-NCD IND (121,179) submitted 23 January 2017 (Sequence 0031). The cutoff date was 24 November 2016. A new literature search for AL-NCD would require a cutoff date less than 6 months after that of the most recent DSUR. Therefore, within the AL-NCD application Alkermes proposes to cross reference to the literature search performed as part of the IND 121,179 DSUR.

Does the Agency agree with Alkermes’ proposal to cross reference to the literature search performed as part of the IND 121,179 DSUR in place of conducting a new literature search for the AL-NCD application?


Question 5: While FDA previously advised Alkermes that a NDA would be required for AL-NCD, Alkermes proposes that the application for AL-NCD could be filed as a supplement to NDA 207,533 since AL-NCD is the same dosage form, is comprised of the same drug substance as Aristada (AL), is based on a PK bridging strategy, and no new clinical efficacy study will be needed to qualify the minor change in formulation.

Would the Agency reconsider Alkermes’ proposal to file AL-NCD as a supplement to NDA 207,533 (sNDA)?

FDA Response to Question 5: We do not agree. There seem to be significantly different release characteristics as well as a different safety profile with this product. In addition, a separate package insert may be required to avoid safety concerns, medication errors, and practitioner confusion. Therefore, this submission should be submitted as a new original application rather than a supplement.

2.2. Chemistry, Manufacturing and Control (CMC)


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Question 6: Alkermes plans to cross reference the Human Factors summative report from Aristada. In addition, a formative evaluation and risk assessment will be included in the AL-NCD application to confirm suitability of the Aristada presentation and IFU for AL-NCD.

Does the Agency agree with Alkermes’ approach to Human Factors?

FDA Response to Question 6: It is premature for us to determine whether your approach is acceptable. We will need to review your use-related risk analysis and justification for why additional HF validation studies are not necessary.

Please note that a comprehensive use-related risk analysis should include a comprehensive and systematic evaluation of all the steps involved in using your product (e.g., based on a task analysis), the errors that users might commit or the tasks they might fail to perform (consider known problems for similar products), and the potential negative clinical consequences of use errors and task failures. Your risk analysis should also discuss risk-mitigation strategies you employed to reduce risks you have identified and the methods you intend to use for validating the risk-mitigation strategies. This information is needed to ensure that all potential risks involved in using your product have been considered and adequately mitigated and the residual risks are acceptable. In your risk assessment, consider known use problems with your currently marketed Aristada product line.

Based on this risk analysis, you will need to determine whether you need to perform a human factors (HF) validation study under simulated use conditions with representative users performing necessary tasks to demonstrate safe and effective use of the product. The risk analysis can be used to inform the design of a human factors validation study protocol for your product. If you determine that an HF validation study is not needed for your product, submit your risk analysis and justification for not conducting the HF validation study to the Agency for review under the IND. The Agency will notify you if we concur with your determination.

If you determine that a HF validation study is needed, please note that the following items will facilitate an efficient review of your HF study protocol: • A summary of preliminary analyses and evaluations, including formative studies;

• Include in your summary a discussion of key findings and any changes made to your product or labeling, including how the findings were used to update the user interface and risk analysis

• An updated risk analysis for your product; • Detailed HF validation study protocol to include the following elements:

• Description of intended product users, uses, use environments, and training (if applicable) for commercial product

• Graphical depiction and written description of product user interface • Summary of known use problems with previous models or similar products • User task selection, categorization (e.g., critical) and prioritization • Validation testing details

� Objective(s)


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� Type of testing (simulated or actual use) � Test environment and conditions of use � Training provided to participants and rationale for how it corresponds to

real-world training (if applicable) � Distinct user groups broken out by number and type of test participants

and rationale for how they represent the intended user populations � User tasks and use scenarios that will be studied � Description of data to be collected and methods for documenting

observations and interview responses � Methods for root cause analysis of all use errors, difficulties, close calls � Definition of performance success and performance failure � Moderator transcript

• Intend-to-market labels and labeling (including an editable word version of the IFU if an IFU is proposed) that will be tested in the HF validation study

• Five intend-to-market samples of product that will be tested in the HF validation study

The requested information should be placed in eCTD section 5.3.5.4 – Other Study reports

and related information.

We recommend you submit your study protocol for feedback from the Agency before

commencing your study. Please note we will need 90 days to review and provide comments

on the HF validation study protocol. Plan your development program timeline accordingly.

Guidance on human factors procedures to follow can be found in:

Applying Human Factors and Usability Engineering to Medical Devices, available online at:

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo cuments/ucm259760.pdf

Guidance on Safety Considerations for Product Design to Minimize Medication Errors and can be found online at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance s/UCM331810.pdf

Note 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 and can be 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 and can be found online at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u cm349009.pdf


http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uhttp://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM484345.pdfhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidancehttp://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDo

IND 121179 Page 8

Question 7: Alkermes will utilize distinctive artwork, detailed drug product description and prominently displayed text alerting the user to the intended use of the product in conjunction with the first dose of Aristada.

a) Does the Agency agree with the steps taken to differentiate the two products (AL and AL-NCD) to reduce the risk of medication errors?

FDA Response to Question 7a: The proposed overlaps with the currently marketed Aristada which increases the possibility for product selection errors to occur. The

(b) (4)

acceptability of the proposed name, labels, and labeling to differentiate AL-NCD from the currently marketed Aristada to reduce the risk of medication errors will be a review issue. However, your overall approach seems reasonable.

(b) (4)

FDA Response to Question 7b: Nonproprietary names consist of the drug name and dosage form. (b) (4)

(b) (4)

(b) (4) While we recognize the need for distinguishing this product from the currently marketed product, we do not have a mechanism to allow the nonproprietary name to do so.

2.3. Clinical

Question 8: A description of the format of the population PK datasets and control streams is included and a Clinical Pharmacology Summary Highlights document will be a part of the application. Does the Agency agree that the information to be included in the submission will be adequate to support the OCP review?


Question 9: The three studies supporting this application, i.e., ALK9072-B101, -B102 and -B103 are complete. Given the differences in study designs, summaries of safety data from the three Phase 1 studies will be presented individually. Tables comparing relevant data from all 3 clinical studies will be provided for review. The text portion of the Integrated Summary of Safety (ISS) that provides exposure and safety data from the completed studies will reside in Module 2.7.4 Summary of Clinical Safety (SCS) and the tables, appendices and datasets will be provided in Module 5.

Does the Agency agree with the proposed presentation of the ISS?


IND 121179 Page 9


3.0 OTHER

PREA REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.

Please be advised that under the Food and Drug Administration Safety and Innovation Act (FDASIA), you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End of Phase 2 (EOP2) meeting. In the absence of an EOP2 meeting, refer to the draft guidance below. The iPSP must contain an outline of the pediatric study or studies that you plan to conduct (including, to the extent practicable study objectives and design, age groups, relevant endpoints, and statistical approach); any request for a deferral, partial waiver, or waiver, if applicable, along with any supporting documentation, and any previously negotiated pediatric plans with other regulatory authorities. The iPSP should be submitted in PDF and Word format. Failure to include an Agreed iPSP with a marketing application could result in a refuse to file action.

For additional guidance on the timing, content, and submission of the iPSP, including an iPSP Template, please refer to the draft guidance for industry, Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM360507.pdf. In addition, you may contact the Division of Pediatric and Maternal Health at 301-796-2200 or email [email protected]. For further guidance on pediatric product development, please refer to: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.ht m.

PRESCRIBING INFORMATION

In your application, you must submit proposed prescribing information (PI) that conforms to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57 including the Pregnancy and Lactation Labeling Rule (PLLR) (for applications submitted on or after June 30, 2015). As you develop your proposed PI, we encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, which include:

• The Final Rule (Physician Labeling Rule) on the content and format of the PI for human drug and biological products.


http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htmailto:[email protected]://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

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• The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of information related to pregnancy, lactation, and females and males of reproductive potential.

• Regulations and related guidance documents. • A sample tool illustrating the format for Highlights and Contents, and • The Selected Requirements for Prescribing Information (SRPI) − a checklist of important

format items from labeling regulations and guidances. • FDA’s established pharmacologic class (EPC) text phrases for inclusion in the Highlights

Indications and Usage heading.

The application should include a review and summary of the available published literature regarding drug use in pregnant and lactating women, a review and summary of reports from your pharmacovigilance database, and an interim or final report of an ongoing or closed pregnancy registry (if applicable), which should be located in Module 1. Refer to the draft guidance for industry – Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products – Content and Format (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM425398.pdf).

Prior to submission of your proposed PI, use the SRPI checklist to ensure conformance with the format items in regulations and guidances.

MANUFACTURING FACILITIES

To facilitate our inspectional process, we request that you clearly identify in a single location, either on the Form FDA 356h, or an attachment to the form, all manufacturing facilities associated with your application. Include the full corporate name of the facility and address where the manufacturing function is performed, with the FEI number, and specific manufacturing responsibilities for each facility.

Also provide the name and title of an onsite contact person, including their phone number, fax number, and email address. Provide a brief description of the manufacturing operation conducted at each facility, including the type of testing and DMF number (if applicable). Each facility should be ready for GMP inspection at the time of submission.

Consider using a table similar to the one below as an attachment to Form FDA 356h. Indicate under Establishment Information on page 1 of Form FDA 356h that the information is provided in the attachment titled, “Product name, NDA/BLA 012345, Establishment Information for Form 356h.”


http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances

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Site Name Site Address

Federal Establishment

Indicator (FEI) or

Registration Number (CFN)

Drug Master

File Number

(if applicable)

Manufacturing Step(s) or Type of Testing

[Establishment function]

1. 2.

Corresponding names and titles of onsite contact:

Site Name Site Address Onsite Contact (Person, Title)

Phone and Fax

number Email address

1. 2.

505(b)(2) REGULATORY PATHWAY

The Division recommends that sponsors considering the submission of an application through the 505(b)(2) pathway consult the Agency’s regulations at 21 CFR 314.54, and the draft guidance for industry, Applications Covered by Section 505(b)(2) (October 1999), available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. In addition, FDA has explained the background and applicability of section 505(b)(2) in its October 14, 2003, response to a number of citizen petitions that had challenged the Agency’s interpretation of this statutory provision (see Docket FDA-2003-P-0274-0015, available at http://www.regulations.gov).

If you intend to submit a 505(b)(2) application that relies for approval on FDA’s finding of safety and/or effectiveness for one or more listed drugs, you must establish that such reliance is scientifically appropriate, and must submit data necessary to support any aspects of the proposed drug product that represent modifications to the listed drug(s). You should establish a “bridge” (e.g., via comparative bioavailability data) between your proposed drug product and each listed drug upon which you propose to rely to demonstrate that such reliance is scientifically justified.

If you intend to rely on literature or other studies for which you have no right of reference but that are necessary for approval, you also must establish that reliance on the studies described in the literature or on the other studies is scientifically appropriate. You should include a copy of such published literature in the 505(b)(2) application and identify any listed drug(s) described in the published literature (e.g. by trade name(s)).


http:http://www.regulations.govhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

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If you intend to rely on the Agency’s finding of safety and/or effectiveness for a listed drug(s) or published literature describing a listed drug(s) (which is considered to be reliance on FDA’s finding of safety and/or effectiveness for the listed drug(s)), you should identify the listed drug(s) in accordance with the Agency’s regulations at 21 CFR 314.54. It should be noted that 21 CFR 314.54 requires identification of the “listed drug for which FDA has made a finding of safety and effectiveness,” and thus an applicant may only rely upon a listed drug that was approved in an NDA under section 505(c) of the FD&C Act. The regulatory requirements for a 505(b)(2) application (including, but not limited to, an appropriate patent certification or statement) apply to each listed drug upon which a sponsor relies.

If FDA has approved one or more pharmaceutically equivalent products in one or more NDA(s) before the date of submission of the original 505(b)(2) application, you must identify one such pharmaceutically equivalent product as a listed drug (or an additional listed drug) relied upon (see 21 CFR 314.50(i)(1)(i)(C), 314.54, and 314.125(b)(19); see also 21 CFR 314.101(d)(9)). If you identify a listed drug solely to comply with this regulatory requirement, you must provide an appropriate patent certification or statement for any patents that are listed in the Orange Book for the pharmaceutically equivalent product, but you are not required to establish a “bridge” to justify the scientific appropriateness of reliance on the pharmaceutically equivalent product if it is scientifically unnecessary to support approval.

If you propose to rely on FDA’s finding of safety and/or effectiveness for a listed drug that has been discontinued from marketing, the acceptability of this approach will be contingent on FDA’s consideration of whether the drug was discontinued for reasons of safety or effectiveness.

We encourage you to identify each section of your proposed 505(b)(2) application that is supported by reliance on FDA’s finding of safety and/or effectiveness for a listed drug(s) or on published literature (see table below). In your 505(b)(2) application, we encourage you to clearly identify (for each section of the application, including the labeling): (1) the information for the proposed drug product that is provided by reliance on FDA’s finding of safety and/or effectiveness for the listed drug or by reliance on published literature; (2) the “bridge” that supports the scientific appropriateness of such reliance; and (3) the specific name (e.g., proprietary name) of each listed drug named in any published literature on which your marketing application relies for approval. If you are proposing to rely on published literature, include copies of the article(s) in your submission.

In addition to identifying the source of supporting information in your annotated labeling, we encourage you to include in your marketing application a summary of the information that supports the application in a table similar to the one below.

List the information essential to the approval of the proposed drug that is provided by reliance on the FDA’s previous finding of safety and effectiveness for

a listed drug or by reliance on published literature


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Source of information (e.g., published literature, name of

listed drug)

Information Provided (e.g., specific sections of the 505(b)(2)

application or labeling)

1. Example: Published literature Nonclinical toxicology

2. Example: NDA XXXXXX “TRADENAME”

Previous finding of effectiveness for indication A

3. Example: NDA YYYYYY “TRADENAME”

Previous finding of safety for Carcinogenicity, labeling section B

4.

Please be advised that circumstances could change that would render a 505(b)(2) application for this product no longer appropriate. For example, if a pharmaceutically equivalent product were approved before your application is submitted, such that your proposed product would be a “duplicate” of a listed drug and eligible for approval under section 505(j) of the FD&C Act, then it is FDA’s policy to refuse to file your application as a 505(b)(2) application (21 CFR 314.101(d)(9)). In such a case, the appropriate submission would be an Abbreviated New Drug Application (ANDA) that cites the duplicate product as the reference listed drug.

Office of Scientific Investigations (OSI) Requests

The Office of Scientific Investigations (OSI) requests that the following items be provided to facilitate development of clinical investigator and sponsor/monitor/CRO inspection assignments, and the background packages that are sent with those assignments to the FDA field investigators who conduct those inspections (Item I and II). This information is requested for all major trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials). Please note that if the requested items are provided elsewhere in submission in the format described, the Applicant can describe location or provide a link to the requested information.

The dataset that is requested in Item III below is for use in a clinical site selection model that is being piloted in CDER. Electronic submission of the site level dataset is voluntary and is intended to facilitate the timely selection of appropriate clinical sites for FDA inspection as part of the application and/or supplement review process. This request also provides instructions for where OSI requested items should be placed within an eCTD submission (Attachment 1, Technical Instructions: Submitting Bioresearch Monitoring (BIMO) Clinical Data in eCTD Format).

I. Request for general study related information and comprehensive clinical investigator information (if items are provided elsewhere in submission, describe location or provide link to requested information).


IND 121179 Page 14

1. Please include the following information in a tabular format in the original NDA for each of the completed pivotal clinical trials: a. Site number b. Principal investigator c. Site Location: Address (e.g., Street, City, State, Country) and contact information

(i.e., phone, fax, email) d. Location of Principal Investigator: Address (e.g., Street, City, State, and Country) and

contact information (i.e., phone, fax, email). If the Applicant is aware of changes to a clinical investigator’s site address or contact information since the time of the clinical investigator’s participation in the study, we request that this updated information also be provided.

2. Please include the following information in a tabular format, by site, in the original NDA for each of the completed pivotal clinical trials: a. Number of subjects screened at each site b. Number of subjects randomized at each site c. Number of subjects treated who prematurely discontinued for each site by site

3. Please include the following information in a tabular format in the NDA for each of the completed pivotal clinical trials: a. Location at which sponsor trial documentation is maintained (e.g., , monitoring plans

and reports, training records, data management plans, drug accountability records, IND safety reports, or other sponsor records as described ICH E6, Section 8). This is the actual physical site(s) where documents are maintained and would be available for inspection

b. Name, address and contact information of all Contract Research Organization (CROs) used in the conduct of the clinical trials and brief statement of trial related functions transferred to them. If this information has been submitted in eCTD format previously (e.g., as an addendum to a Form FDA 1571, you may identify the location(s) and/or provide link(s) to information previously provided.

c. The location at which trial documentation and records generated by the CROs with respect to their roles and responsibilities in conduct of respective studies is maintained. As above, this is the actual physical site where documents would be available for inspection.

4. For each pivotal trial, provide a sample annotated Case Report Form (or identify the location and/or provide a link if provided elsewhere in the submission).

5. For each pivotal trial provide original protocol and all amendments ((or identify the location and/or provide a link if provided elsewhere in the submission).

II. Request for Subject Level Data Listings by Site

1. For each pivotal trial: Site-specific individual subject data listings (hereafter referred to as “line listings”). For each site, provide line listings for:


IND 121179 Page 15

a. Listing for each subject consented/enrolled; for subjects who were not randomized to treatment and/or treated with study therapy, include reason not randomized and/or treated

b. Subject listing for treatment assignment (randomization) c. Listing of subjects that discontinued from study treatment and subjects that

discontinued from the study completely (i.e., withdrew consent) with date and reason discontinued

d. Listing of per protocol subjects/ non-per protocol subjects and reason not per protocol e. By subject listing of eligibility determination (i.e., inclusion and exclusion criteria) f. By subject listing, of AEs, SAEs, deaths and dates g. By subject listing of protocol violations and/or deviations reported in the NDA,

including a description of the deviation/violation h. By subject listing of the primary and secondary endpoint efficacy parameters or

events. For derived or calculated endpoints, provide the raw data listings used to generate the derived/calculated endpoint.

i. By subject listing of concomitant medications (as appropriate to the pivotal clinical trials)

j. By subject listing, of testing (e.g., laboratory, ECG) performed for safety monitoring

2. We request that one PDF file be created for each pivotal Phase 2 and Phase 3 study using the following format:

III. Request for Site Level Dataset:

OSI is piloting a risk based model for site selection. Voluntary electronic submission of site level datasets is intended to facilitate the timely selection of appropriate clinical sites for FDA


IND 121179 Page 16

inspection as part of the application and/or supplement review process. If you wish to voluntarily provide a dataset, please refer to the draft Guidance for Industry Providing Submissions in Electronic Format – Summary Level Clinical Site Data for CDER’s Inspection Planning” (available at the following link http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire ments/UCM332468.pdf ) for the structure and format of this data set.


http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire

IND 121179 Page 17

Attachment 1 Technical Instructions:

Submitting Bioresearch Monitoring (BIMO) Clinical Data in eCTD Format

A. Data submitted for OSI review belongs in Module 5 of the eCTD. For items I and II in the chart below, the files should be linked into the Study Tagging File (STF) for each study. Leaf titles for this data should be named “BIMO [list study ID, followed by brief description of file being submitted].” In addition, a BIMO STF should be constructed and placed in Module 5.3.5.4, Other Study reports and related information. The study ID for this STF should be “bimo.” Files for items I, II and III below should be linked into this BIMO STF, using file tags indicated below. The item III site-level dataset filename should be “clinsite.xpt.”

DSI Pre-NDA

Request Item1

STF File Tag Used For Allowable File

Formats

I data-listing-dataset Data listings, by study .pdf I annotated-crf Sample annotated case

report form, by study .pdf

II data-listing-dataset Data listings, by study (Line listings, by site)

.pdf

III data-listing-dataset Site-level datasets, across studies

.xpt

III data-listing-data-definition Define file .pdf

B. In addition, within the directory structure, the item III site-level dataset should be placed in the M5 folder as follows:

C. It is recommended, but not required, that a Reviewer’s Guide in PDF format be included. If this Guide is included, it should be included in the BIMO STF. The leaf title should be “BIMO Reviewer Guide.” The guide should contain a description of the BIMO elements being submitted with hyperlinks to those elements in Module 5.

1 Please see the OSI Pre-NDA/BLA Request document for a full description of requested data files


IND 121179 Page 18

References:

eCTD Backbone Specification for Study Tagging Files v. 2.6.1 (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire ments/ElectronicSubmissions/UCM163560.pdf)

FDA eCTD web page (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elect ronicSubmissions/ucm153574.htm)

For general help with eCTD submissions: [email protected]


mailto:[email protected]://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electhttp://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire

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This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.

/s/

SHIN-YE CHANG 05/02/2017




IND121179 MEETING MINUTES

Alkermes, Inc. Attention: Mark W. Machado Manager, Regulatory Affairs 852 Winter Street Waltham, Massachusetts 02451-1420

Dear Mr. Machado:

Please refer to your Investigational New Drug Application (IND) submitted under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Aripiprazole Lauroxil Nano (ALKS 9072N).

We also refer to the teleconference between representatives of your firm and the FDA on March 22, 2016. The purpose of the meeting was to receive feedback regarding the proposed drug product control strategy and registration stability plan.

A copy of the official minutes of the teleconference is enclosed for your information. Please notify us of any significant differences in understanding regarding the meeting outcomes.

If you have any questions, call me/Grafton Adams, Regulatory Project Manager at (240) 4027765.

Sincerely,

{See appended electronic signature page}

Wendy I. Wilson-Lee, PhD. Branch Chief, Branch I (Acting) Division of New Drug Products I Office of New Drug Products Office of Pharmaceutical Quality Center for Drug Evaluation and Research

Enclosure: Meeting Minutes



MEMORANDUM OF MEETING MINUTES

Meeting Type: Type B Meeting Category: End-of-Phase 2

Meeting Date and Time: March 22, 2016 Meeting Location: Teleconference

Application Number: 121179 Product Name: Aripiprazole Lauroxil Nano Indication: Treatment of Schizophrenia Sponsor/Applicant Name: Alkermes, Inc.

Meeting Chair: Wendy I. Wilson-Lee, Ph.D. Meeting Recorder: Dahlia Woody/Grafton Adams

FDA ATTENDEES Wendy I. Wilson-Lee, PhD., Branch Chief (Acting) David J. Claffey, Ph.D., CMC Lead Psychiatry Products Okpo Eradiri, Ph.D., Biopharmaceutics Lead (Acting) Banu Zolnik, Ph.D., Biopharmaceutics Reviewer Andrei Ponta, Ph.D., Drug Product Reviewer Johnathan Swoboda, Ph.D., Microbiology Reviewer Dahlia A. Woody, M.S., PMP, FAC-P/PM, Regulatory Business Process Manager CDR Grafton G. Adams, RN, M.S., Regulatory Business Process Manager

SPONSOR ATTENDEES John Lally, Senior Director, Regulatory CMC Magali Hickey, Ph.D., Director, Formulation Development and CMC Team Lead Michael Palmieri Jr, Ph.D., Senior Director, Analytical Development Mark Machado, M.S., Manager, Regulatory Affairs Tarek Zeidan, Ph.D., Senior Scientist, II Jennifer Vandiver, Ph.D., Senior Process Engineer, II Chad Hasson, M.S., Associate Director, Quality Tracy Burns, Associate Director, Project Management Greg Smith, Scientist III


IND 121179

Page 2

1.0 BACKGROUND Aripiprazole lauroxil (ARISTADA™) is an injectable extended-release formulation of an atypical antipsychotic manufactured by Alkermes for the treatment of schizophrenia. A New Drug Application (NDA) for ARISTADA was approved on October 5, 2015.

Alkermes has developed a nano-crystal dispersion formulation of aripiprazole lauroxil referred to as “aripiprazole lauroxil nano”. Aripiprazole lauroxil nano is a single dose product to be used as part of an initiation regimen upon starting ARISTADA in lieu of 21 days of oral aripiprazole.

Alkermes is requesting a Type B [End of Phase 2 (EoP2)] meeting with the Division of Psychiatry Products (DPP) to discuss the Chemistry, Manufacturing, and Controls (CMC) plan intended to support the approval of aripiprazole lauroxil nano for initiation of treatment with ARISTADA for treatment of schizophrenia.

FDA sent Preliminary Comments to Alkermes on Friday, March 18, 2016.

2. DISCUSSION

2.1. Chemistry, Manufacturing, and Controls

Question 1: Does the Agency agree with the proposed control strategy for aripiprazole lauroxil nano?

FDA Preliminary Response: The proposed drug substance and drug product specifications are a review matter; however, the Agency has the following additional recommendations:

• We note that the proposed drug product formulation contains sodium citrate. Justify its inclusion, as the already approved Arpiprazole Lauroxil suspension does not contain this excipient.

• The drug product control strategy will need to control both the aripiprazole content as well as the delivered volume. It is currently unclear whether the proposed tests meet this criterion. Include assay testing as part of release and stability testing. The associated analytical method should be a specific, stability-indicating assay test capable of determining drug product strength (content).

• The meeting package indicates that that no polymorphism or loss of crystallinity was observed following drug product manufacturing and storage (6 months accelerated and 9 months long-term conditions) and that polymorphic form will be monitored under long term conditions through the end of shelf life. In order to determine the need for polymorph testing, include a description of the analytical method used to determine polymorphic form along with the release and stability results in the submission.

• Provide data demonstrating that the drug product is not adversely impacted, in terms of agglomeration, by pH at the lower and higher specification limits (pH 6.0 and 7.4).

• Regarding particle size:


IND 121179

Page 3

o Include in the submission justification of the proposed particle size acceptance (b) (4)criteria. The proposed particle size d50 limit is nm. As part of the

formulation selection, three formulations were tested in the clinic (A, B, and C) which differed only in particle size distribution as well as total Polysorbate 20

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)content for formulation C % w/w instead of % w/w). The d50 of the three formulations were nm, nm, and nm, respectively. The current proposed specification would accommodate two of the developmental formulations (Formulation A and B) but the third formulation (Formulation C) would be just outside of the higher limit of (b) (4) nm.

o Provide a detailed description of the dynamic light scattering (DLS) method used as there are several risk factors to consider when evaluating whether a methodology is appropriate for characterization of nanomaterials. For example, sample preparation may significantly impact the nanomaterial attribute being measured during analysis (e.g. dilution, sonication).

o We recommend reporting detailed DLS results in your submission (e.g. intensity, volume, or number weighted distributions).

o As particle size is a critical quality attribute, we recommend implementing a secondary method of monitoring particle size (e.g. TEM) as part of commercialization. Similarly, we also recommend monitoring particle morphology as it could impact the drug product quality.

• We note that particulate matter is being monitored as part of the development plan. As the drug product is a suspension for injection, we recommend continuing to monitor particulate matter on release as part of the commercial control strategy.

Meeting Discussion: See slides 1 through 7. Alkermes confirmed that release testing does not include a separate criterion for volume and assay as the dose delivery assay release test accounts for both measurements. Noting this, Alkermes indicated they will include a justification for using the proposed dose delivery assay method in the NDA submission. FDA acknowledged that the method and its justification will be assessed during the review.

FDA acknowledged that laser diffraction with static light scattering is used for particle size measurement. Alkermes indicated that an additional method of measuring particle size (SEM) is included as part of the pharmaceutical development. Alkermes will provide full characterization in the NDA submission and monitor particle size for changes through drug product development and during manufacturing process changes (e.g. scale-up). FDA indicated that though the particle size control strategy is a review matter, Alkermes’ overall approach is reasonable.

Alkermes will also provide justification for the testing strategy in the NDA submission.

Question 2: Does the Agency agree that the proposed dissolution test conditions are acceptable?

Alkermes will specify and provide justification for the proposed bulk hold time in the NDA. (b) (4)


IND 121179

Page 4

(b) (4)

(b) (4)

FDA Preliminary Response: No, we do not agree

Provide a dissolution method development report in the NDA including, but not limited to, the

following:

Dissolution Method: 1. Detailed description of the dissolution test being proposed for the evaluation of your

product and the developmental parameters (i.e., selection of the equipment/apparatus, in vitro dissolution/release media, agitation/rotation speed, pH, assay, sink conditions, etc.) used to select the proposed dissolution method as the optimal test for your product. Include the data supporting the selection of the type and amount of surfactant. The testing conditions used for each test should be clearly specified.

(b) (4)

The dissolution profile should be complete and cover at least % of drug release of the label amount or whenever a plateau (i.e., no increase over 3 consecutive time-points) is reached. We recommend use of at least twelve samples per testing variable;

2. Provide the complete dissolution profile data (individual, mean, SD, profiles) in SAS transport file format for your product. The dissolution data should be reported as the cumulative percentage of drug dissolved with time (the percentage is based on the product’s label claim);

3. A list of critical material attributes (CMA) and critical process parameters (CPP)

affecting dissolution;

4. Data to support the discriminating ability of the selected dissolution method. In general, the testing conducted to demonstrate the discriminating ability of the selected dissolution method should compare the dissolution profiles of the target formulation and the variant formulations that are intentionally manufactured with meaningful variations for the most relevant critical manufacturing variables (i.e., ± 10-20% change to the specification-ranges of these variables); In addition, if available, submit data showing the capability of the selected dissolution method to reject batches that are not bioequivalent.

5. Supportive validation data for the dissolution method (i.e., method robustness, etc.) and analytical method (precision, accuracy, linearity, stability, etc.).

Dissolution Acceptance Criterion: For the selection of the dissolution acceptance criterion of your product, the following points should be considered:

a. The dissolution profile data from the pivotal clinical batches and primary (registration) stability batches should be used for the setting of the dissolution acceptance criterion of your product (i.e., specification-sampling time point and specification value).

b. The in vitro dissolution profile should encompass the timeframe over which at least % (b) (4)of the drug is dissolved or where the plateau of drug dissolved is reached, if incomplete dissolution is occurring.

c. The selection of the specification time point should be where Q= % dissolution occurs. (b) (4)

d. The dissolution acceptance criterion should be established based on average in vitro dissolution data for each lot under study, equivalent to USP Stage 2 testing (n=12).


IND 121179

Page 5

e. A detailed discussion of the justification of the proposed dissolution acceptance criterion should be included in the appropriate section of the CTD.

Data Presentation: In the dissolution method development report, present detailed experimental data as follows:

a. Include individual vessel data as much as possible in the narrative portion of the report, particularly regarding investigation of selection of equipment, media, agitation speed, etc.

b. In addition to the mean dissolution data presented in graphical and tabular formats in the dissolution development report, submit all individual vessel dissolution data for the clinical and registration/stability batches in “.xpt” format.

c. Batch release and stability dissolution data should be presented graphically; the plot(s) of individual vessel data for the clinical and stability batches should include data at release, time zero stability time point, and over the duration of stability testing under long-term storage conditions.

Meeting Discussion: See slide 8. The Agency acknowledged Alkermes’s experience in development of the dissolution method for Aristada and stated that a separate meeting is not needed. Alkermes will provide a comprehensive dissolution method development report at the time of NDA submission.

Question 3: Does the Agency agree with the proposed registration stability plan?

FDA Preliminary Response: We remind you that stability studies should include samples stored in the inverted or horizontal position as well as the upright position to determine the effects of the primary container closure

(b) (4)on product quality. We also recommended testing of the three strength supportive stability batches under accelerated conditions as part of the stability protocol.

Meeting Discussion: See slides 9 and 10. Alkermes agreed to conduct and broaden the stability studies to include drug product in the tipdown orientation held under accelerated, intermediate, and long-term conditions. Alkermes will include six months of data at the time of submission and will provide additional data as it becomes available. Alkermes indicated that stability testing for samples in the tipdown orientation will include the same tests as other stability studies (description, impurities, dissolution, sterility, etc.).

(b) (4)Alkermes confirmed the intent to conduct stability testing

for all three strength batches at the same storage conditions.

Additional Post-Meeting Comments Comments from the Center for Device and Radiological Health (CDRH) are still pending. FDA commits to provide any additional feedback or guidance via a General Advice letter if comments are received from CDRH.

6.0 ATTACHMENTS AND HANDOUTS

Alkermes Meeting Discussion Topics Presentation


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/s/

WENDY I WILSON-LEE 04/11/2016




IND 121179 MEETING MINUTES

Alkermes, Inc. Mark W. Machado, M.S. Manager, Regulatory Affairs 852 Winter Street Waltham, MA 02451

Dear Mr. Machado:

Please refer to your Investigational New Drug Application (IND) submitted under section 505(i) of the Federal Food, Drug, and Cosmetic Act for aripiprazole lauroxil nano

We also refer to the meeting between representatives of your firm and the FDA on September 9, 2015. The purpose of the meeting was to discuss the nonclinical and clinical development plan intended to support the approval of aripiprazole lauroxil nano for initiation of treatment with ARISTADA for treatment of schizophrenia.

A copy of the official minutes of the meeting is enclosed for your information. Please notify us of any significant differences in understanding regarding the meeting outcomes.

If you have any questions, call Shin-Ye Sandy Chang, Regulatory Project Manager at (301) 7963971 or email [email protected].

Sincerely,

{See appended electronic signature page}

Mitchell V. Mathis, M.D Director Division of Psychiatry Products Office of Drug Evaluation I Center for Drug Evaluation and Research

Enclosure: Meeting Minutes


mailto:[email protected]


MEMORANDUM OF MEETING MINUTES

Meeting Type: Meeting Category:

Meeting Date and Time: Meeting Location:

Application Number: Product Name: Indication: Sponsor/Applicant Name:

Meeting Chair: Meeting Recorder:

FDA ATTENDEES

B End of Phase 2

September 9, 2015 1:00 – 2:00 PM (EST) 10903 New Hampshire Avenue White Oak Building 22, Conference Room: 1315 Silver Spring, Maryland 20903

121179 aripiprazole lauroxil nano schizophrenia Alkermes, Inc.

Mitchell Mathis, M.D. Shin-Ye Sandy Chang, Pharm.D.

Tiffany Farchione, M.D., Deputy Director, DPP Jing Zhang, M.D., Clinical Team Leader, DPP Gregory Dubitsky, M.D., Clinical Reviewer, DPP Aisar Atrakchi, Ph.D., Nonclinical Supervisor, DPP Amy Avila, Ph.D., Nonclinical Reviewer, DPP Hao Zhu, Ph.D., Office of Clinical Pharmacology (OCP) Team Leader Huixia Zhang, Ph.D., OCP Reviewer

SPONSOR ATTENDEES

Elliot Ehrich, M.D., Sr. VP, Research and Development and Chief Medical Officer Georgianna Harris, Ph.D., VP, Regulatory Affairs Srdjan Stankovic, M.D., Sr. VP, Clinical Development and Medical Affairs Lisa von Moltke, M.D., VP, Clinical Pharmacology and Translational Medicine Marjie Hard, Ph.D., Associate Director, Translational Medicine Daniel Deaver, Ph.D.,VP, Nonclinical Development Mark Machado, M.S., Manager, Regulatory Affairs


IND 121179 Page 2

1.0 BACKGROUND

Aripiprazole lauroxil is an injectable extended-release formulation of a prodrug of the atypical antipsychotic aripiprazole that is being developed by Alkermes for the treatment of schizophrenia. Because of a delay in achieving therapeutic levels of aripiprazole following aripiprazole lauroxil injection, oral aripiprazole must be administered for 21 days after the first injection. A New Drug Application (NDA 207533) for aripiprazole lauroxil (Aristada) is currently under review.

Alkermes has developed a nano-crystal dispersion formulation of aripiprazole lauroxil referred to as Aripiprazole Lauroxil Nano (or ALKS 9072N). Aripiprazole Lauroxil Nano and aripiprazole lauroxil differ mainly in the particle size distribution of the drug substance, the former in the nanometer range and the latter in the micron range. The smaller particle size of the nano formulation accelerates the rate of dissolution of aripiprazole lauroxil to provide earlier appearance of circulating aripiprazole compared to the micron formulation. A single ALKS 9072N injection co-administered with a single 30mg oral dose of aripiprazole is expected to provide adequate therapeutic coverage during the initial 21 day period, thus obviating the need for daily oral aripiprazole when initiating aripiprazole lauroxil.

Alkermes intends to submit an NDA for Aripiprazole Lauroxil Nano to initiate treatment with aripiprazole lauroxil in the treatment of schizophrenia under section 505(b)(2), referencing oral aripiprazole tablets (NDA 021436) and aripiprazole lauroxil (NDA 207533). Alkermes will provide a pharmacokinetic bridging package using data from ongoing clinical studies and prior data obtained during the development of aripiprazole lauroxil.

Three studies are intended to support an NDA for Aripiprazole Lauroxil Nano:

Study ALK9072-B101: A Phase 1, Placebo-controlled, Single Ascending-dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ALKS 9072N in Adults with Schizophrenia. This completed study evaluated three different formulations of ALKS9072N in the dose range of 221mg to 882mg in 112 subjects (74 exposed to ALKS 9072N). The sponsor reports that more rapid release of aripiprazole was demonstrated compared to aripiprazole lauroxil and total exposure did not exceed exposures previously seen with repeated doses of aripiprazole lauroxil. A formulation and dose ( (b) (4)mg) were chosen for development.

The sponsor further notes that pharmacokinetic simulations showed that a 30mg oral dose of aripiprazole co-administered with ALKS 9072N was an appropriate loading regimen for rapid achievement of therapeutic aripiprazole concentrations and maintenance of therapeutic levels without exceeding the upper bound of the therapeutic window. The time to achieve a target concentration was consistent with prior observations with 21 days of oral aripiprazole when starting aripiprazole lauroxil treatment. Also, this regimen may have an advantage in minimizing fluctuations in aripiprazole concentrations. The adequacy of this regimen will be further evaluated in study ALK9072-B102, described below.


IND 121179 Page 3

Study ALK9072-B102: A Phase 1 Study of ALKS 9072N and Oral Aripiprazole Co-administered with Aripiprazole Lauroxil in Adults with Schizophrenia. This is a double-blind, placebo-controlled study to assess the pharmacokinetics, safety, and tolerability of IM ALKS 9072N 662mg co-administered with a single oral dose of aripiprazole 30mg and IM aripiprazole lauroxil 441mg or 882mg. The two IM injections will be given at separate sites. The observed results and simulation data will be used to compare this initiation regimen to historical data from the administration of 21 days of oral aripiprazole after aripiprazole lauroxil in terms of aripiprazole plasma concentrations and the time to reach therapeutic concentrations. These results, along with the therapeutic window for aripiprazole (94 to 534 ng/ml), are intended to establish a bridge between the two initiation regimens.

Study ALK9072-B103: A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ALKS 9072N Following Administration to the Deltoid or Gluteal Muscle in Adults with Schizophrenia or Schizoaffective disorder. This is a multicenter, randomized, open-label, single-dose study to compare the bioavailability of aripiprazole after ALKS 9072N injection into the deltoid versus gluteus muscle in a total of 46 adult patients. Patients must be clinically stable and on a stable regimen of oral antipsychotic medication. After injection of study drug on Day 1, patients will be maintained on an inpatient basis until Day 8, when they will be discharged and followed as outpatients until Day 80. Patients will remain on their existing oral antipsychotic (except aripiprazole) throughout the trial. Blood samples for pharmacokinetic analysis will be obtained from Day 1 up to Day 80 and include assays for aripiprazole lauroxil, Nhydroxymethyl aripiprazole, aripiprazole, and dehydro-aripiprazole. The results are intended to support administration into either the deltoid or the gluteal site depending on patient preference.

The objective of this meeting is to reach agreement with the Division of Psychiatry Products (DPP) on the development plan to support approval of Aripiprazole Lauroxil Nano for initiation of treatment with aripiprazole lauroxil in the treatment of schizophrenia. Specifically, Alkermes seeks agreement on the following issues:

• plan to submit Aripiprazole Lauroxil Nano as a supplement to the aripiprazole lauroxil NDA

• proposed plan to demonstrate comparability in exposure based on a PK bridge using data from two clinical studies, which provides demonstration of safety and efficacy in reference to aripiprazole lauroxil & oral aripiprazole

• adequacy of a single PK & safety study evaluating deltoid administration to support deltoid muscle injection

• size of safety database • non-clinical Program

FDA sent Preliminary Comments to Alkermes on September 2, 2015.


IND 121179 Page 4

2.0 DISCUSSION

2.1. Regulatory

Question 1: Aripiprazole Lauroxil Nano is being used for the same indication as aripiprazole lauroxil and is to be used in conjunction with a single 30 mg dose of aripiprazole as an alternative to the 21 days of oral aripiprazole initiation regimen upon starting aripiprazole lauroxil. Aripiprazole Lauroxil Nano is the same dosage form and is comprised of the same drug substance, aripiprazole lauroxil, as aripiprazole lauroxil with the primary difference being the reduction in the particle size distribution in order to accelerate the rate of dissolution of the active moiety. Minor additional changes to the suspension vehicle composition are listed in Table 5, including the rationale for each change where applicable. Aripiprazole Lauroxil Nano will be supplied in a pre-filled syringe (PFS). The primary packaging components for Aripiprazole Lauroxil Nano are identical to those used in aripiprazole lauroxil.

Does the Agency agree that following approval of NDA 207,533 for aripiprazole lauroxil, Aripiprazole Lauroxil Nano can be filed as a Supplement to NDA 207,533 (sNDA) in accordance with 21 CFR Part 314.70 (b)?

FDA Response to Question 1: No. Aripiprazole Lauroxil Nano is a new formulation of Aripiprazole Lauroxil. Therefore, a separate NDA will need to be filed.

Discussion: No further discussion.

2.2. Clinical

Question 2: The safety and pharmacokinetics of Aripiprazole Lauroxil Nano in adults with schizophrenia is being evaluated in a single-ascending dose study (ALK9072- B101; Section 4.2.1.1), and in a study evaluating the combination of Aripiprazole Lauroxil Nano and a single oral aripiprazole dose as an initiation regimen for aripiprazole lauroxil (ALK9072B102; Section 4.2.2.1). The results of these studies will be used to demonstrate that the proposed initiation regimen results in aripiprazole concentrations that are within the therapeutic window for aripiprazole (94-534 ng/mL) observed for the oral aripiprazole tablet (10-30 mg/day). Historical reliance on prior PK data obtained during the development of aripiprazole lauroxil, where aripiprazole lauroxil was initiated with 21-days oral aripiprazole, will be used to establish a PK bridge by demonstrating achievement of therapeutic concentrations within a comparable timeframe between the two dose initiation regimens. Alkermes believes that the proposed development of this new dosing regimen is sufficient to provide substantial evidence of effectiveness.

To support the review of a sNDA, does the Agency agree that the pharmacokinetic data from Studies ALK9072-B101 and ALK9072-B102 will be sufficient to establish substantial evidence of effectiveness for this new dose initiation regimen?


IND 121179 Page 5

FDA Response to Question 2: No. PK bridging needs to be established between the proposed initiation regimen (i.e., ALK9072N, one single 30 mg oral aripiprazole, and aripiprazole lauroxil) and the dose initiation regimen in the Aristada program (i.e., 21-day of oral aripipraozle and aripiprazole lauroxil). Also, the adequacy of these data presumes that Aristada is found to be safe and effective.

Discussion: Sponsor agreed to add an arm in their Study ALK9072-B102 to include 33 subjects receiving 21-day oral aripiprazole supplement with Aripiprazole Lauroxil. Data generated will be compared directly with proposed dosing initiation regimen (i.e., ALK9072N, one single 30 mg oral aripiprazole, and aripiprazole lauroxil). In addition, data from the study will be incorporated into PopPK models for further comparison.

Question 3: The safety, tolerability and relative bioavailability of Aripiprazole Lauroxil Nano in adults with schizophrenia will be evaluated in a single-dose study (ALK9072-B103; Section 4.2.2.2) comparing deltoid and gluteal injections to support the interchangeability of the two injection sites. Alkermes believes that providing an option of either deltoid or gluteal injection sites have the potential to improve flexibility and convenience by providing the option of alternate sites of administration when co-administered with aripiprazole lauroxil.

Does the Agency agree that the clinical development plan with an additional study (ALK9072-B103) could support inclusion of deltoid administration of Aripiprazole Lauroxil Nano in the sNDA?

FDA Response to Question 3: The proposed single dose study to assess the PK of ALKS9072 N after administration at different injection sites is acceptable. However, if the PK difference is large between the two injection sites, additional safety/tolerability studies may be required.


Question 4: Safety and tolerability of aripiprazole lauroxil was studied across three monthly doses in combination with an initial 21 days of 15 mg oral aripiprazole in study ALK9072003 (N=662). Study ALK9072-B101 explored the overall safety and tolerability of Aripiprazole Lauroxil Nano delivered in three different intramuscular formulations (N=74). Study ALK9072-B102 will determine the safety tolerability and PK of 662 mg Aripiprazole Lauroxil Nano administered in conjunction with 30 mg oral aripiprazole and either 441 mg or 882 mg aripiprazole lauroxil. The reason for conducting the study in this manner is to determine the maximum exposure possible when 30 mg aripiprazole, Aripiprazole Lauroxil Nano and aripiprazole lauroxil are given concurrently. Co-administration of Aripiprazole Lauroxil Nano and aripiprazole lauroxil and oral aripiprazole dosing should approximate the maximal exposure possible to aripiprazole lauroxil and metabolites when both products are initiated concurrent with a single oral dose (N=66). Study ALK9072-B103 will describe the safety, tolerability and PK of deltoid or gluteal administration (N=46). It is anticipated that at the time of submission a total of N=186 subjects will have received one dose of Aripiprazole Lauroxil Nano. In addition, the submission under 505(B)(2) regulation will reference human safety experience with aripiprazole lauroxil and oral aripiprazole.


IND 121179 Page 6

Does the Agency agree that studies ALK9072-B101, ALK9072-B102 and ALK9072-B103, together with referenced safety exposure for aripiprazole lauroxil and oral aripiprazole, provide sufficient safety exposure to support a substantive review of the sNDA?

FDA Response to Question 4: Assuming that the NDA for Aristada is approved and that the planned investigations reveal no unexpected safety concerns, we agree.

Additional Comment: Please address the concern of potential dose dumping of ALKS9072N. We recommend that you collect blood samples in your clinical program whenever an SAE occurs to determine if it is concentration related. In addition, we also recommend that you assess the potential for dose dumping in the presence of elevated temperature using in vitro method(s).


2.3. Nonclinical

Question 5: Alkermes nonclinical plan to support a single clinical administration of Aripiprazole Lauroxil Nano includes 4-week repeat-dose studies conducted with Aripiprazole Lauroxil Nano to address local tolerability of the formulation; genetic toxicology, single-dose/repeat-dose general toxicology, and developmental and reproductive toxicology studies conducted with aripiprazole lauroxil along with Aripiprazole Lauroxil Nano studies to address the systemic toxicity of aripiprazole lauroxil and its metabolites; and reference to the aripiprazole oral tablet NDA (NDA 21-436) relative to the Agency’s previous findings of safety for aripiprazole and its metabolites.

Does the Agency agree that the nonclinical safety program outlined for Aripiprazole Lauroxil Nano is sufficient to support a substantive review of the sNDA?

FDA Response to Question 5: On face, the nonclinical program for aripiprazole lauroxil nano appears adequate. However, we remind you that additional nonclinical studies may be

(b) (4)necessary if exposures to aripiprazole lauroxil and/or the N-hydroxymethyl aripiprazole

are higher in humans after adminiatration of aripiprazole lauroxil nano, or the coadministraiton of aripiprazole lauroxil nano with aripiprazole lauroxil, compared to exposures reached in nonclinical studies.

Because aripiprazole lauroxil nano is intended to be co-administered with aripiprazole lauroxil and oral aripiprazole, please provide a justification as to why you are not planning to conduct a combination toxicity study. [Reference ICH M3(R2)]

The final determination whether the nonclinical data with aripiprazole lauroxil nano, along with the additional supporting information with aripiprazole lauroxil, will be adequate to support the NDA will be a matter of review.


IND 121179 Page 7

In addition, we have the following comments: • If additional nonclinical studies are conducted, we recommend including longer recovery

periods to assess complete reversibility of local toxicity findings as well as including a negative control group to distinguish toxicities due to excipients from those of aripiprazole lauroxil nano.

• Additional nonclinical studies may be necessary if any impurities are found that would require qualification. Refer to ICHQ3A(R2), ICHQ3B(R2), and ICH M7 guidance documents.


3.0 PREA REQUIREMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.

Please be advised that under the Food and Drug Administration Safety and Innovation Act (FDASIA), you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of an End of Phase (EOP2) meeting. In the absence of an End-of-Phase 2 meeting, refer to the draft guidance below. The PSP must contain an outline of the pediatric study or studies that you plan to conduct (including, to the extent practicable study objectives and design, age groups, relevant endpoints, and statistical approach); any request for a deferral, partial waiver, or waiver, if applicable, along with any supporting documentation, and any previously negotiated pediatric plans with other regulatory authorities. The PSP should be submitted in PDF and Word format. Failure to include an agreed iPSP with a marketing application could result in a refuse to file action.

For additional guidance on the timing, content, and submission of the PSP, including a PSP Template, please refer to the draft guidance for industry, Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM360507.pdf. In addition, you may contact the Division of Pediatric and Maternal Health at 301-796-2200 or email [email protected]. For further guidance on pediatric product development, please refer to: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.ht m.

4.0 DATA STANDARDS FOR STUDIES

Under section 745A(a) of the FD&C Act, electronic submissions “shall be submitted in such electronic format as specified by [FDA].” FDA has determined that study data contained in electronic submissions (i.e., NDAs, BLAs, ANDAs and INDs) must be in a format that the Agency can process, review, and archive. Currently, the Agency can process, review, and


http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htmailto:[email protected]://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

IND 121179 Page 8

archive electronic submissions of clinical and nonclinical study data that use the standards specified in the Data Standards Catalog (Catalog) (See http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm).

On December 17, 2014, FDA issued final guidance, Providing Electronic Submissions in Electronic Format--- Standardized Study Data (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM292334.pdf). This guidance describes the submission types, the standardized study data requirements, and when standardized study data will be required. Further, it describes the availability of implementation support in the form of a technical specifications document, Study Data Technical Conformance Guide (Conformance Guide) (See http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM384744.pd f), as well as email access to the eData Team ([email protected]) for specific questions related to study data standards. Standardized study data will be required in marketing application submissions for clinical and nonclinical studies that start on or after December 17, 2016. Standardized study data will be required in commercial IND application submissions for clinical and nonclinical studies that start on or after December 17, 2017. CDER has produced a Study Data Standards Resources web page that provides specifications for sponsors regarding implementation and submission of clinical and nonclinical study data in a standardized format. This web page will be updated regularly to reflect CDER's growing experience in order to meet the needs of its reviewers.

Although the submission of study data in conformance to the standards listed in the FDA Data Standards Catalog will not be required in studies that start before December 17, 2016, CDER strongly encourages IND sponsors to use the FDA supported data standards for the submission of IND applications and marketing applications. The implementation of data standards should occur as early as possible in the product development lifecycle, so that data standards are accounted for in the design, conduct, and analysis of clinical and nonclinical studies. For clinical and nonclinical studies, IND sponsors should include a plan (e.g., in the IND) describing the submission of standardized study data to FDA. This study data standardization plan (see the Conformance Guide) will assist FDA in identifying potential data standardization issues early in the development program.

Additional information can be found at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electr onicSubmissions/ucm248635.htm

For general toxicology, supporting nonclinical toxicokinetic, and carcinogenicity studies, CDER encourages sponsors to use Standards for the Exchange of Nonclinical Data (SEND) and submit sample or test data sets before implementation becomes required. CDER will provide feedback to sponsors on the suitability of these test data sets. Information about submitting a test submission can be found here: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electr onicSubmissions/ucm174459.htm

5.0 LABORATORY TEST UNITS FOR CLINICAL TRIALS


http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electrhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electrmailto:[email protected]://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM384744.pdhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanceshttp://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm

IND 121179 Page 9

CDER strongly encourages IND sponsors to identify the laboratory test units that will be reported in clinical trials that support applications for investigational new drugs and product registration. Although Système International (SI) units may be the standard reporting mechanism globally, dual reporting of a reasonable subset of laboratory tests in U.S. conventional units and SI units might be necessary to minimize conversion needs during review. Identification of units to be used for laboratory tests in clinical trials and solicitation of input from the review divisions should occur as early as possible in the development process. For more information, please see the FDA website entitled, Study Data Standards Resources and the CDER/CBER Position on Use of SI Units for Lab Tests website found at http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm372553.htm.


http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/ucm372553.htm

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MITCHELL V Mathis 10/09/2015


Structure BookmarksCENTER FOR DRUG EVALUATION AND .RESEARCH. CENTER FOR DRUG EVALUATION AND .RESEARCH. APPLICATION NUMBER:.

209830Orig1s000. 209830Orig1s000. ADMINISTRATIVE and CORRESPONDENCE .DOCUMENTS. ADMINISTRATIVE and CORRESPONDENCE .DOCUMENTS.

DEPARTMENT OF HEALTH AND HUMAN SERVICES DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 IND 121179 MEETING PRELIMINARY COMMENTS Alkermes, Inc. Attention: Mark W. Machado, M.S. Manager, Regulatory Affairs 852 Winter Street Waltham, MA 02451 Dear Mr. Machado: Please refer to your Investigational New Drug Application (IND) submitted under section 505(i) of the Federal Food, Drug, and Cosmetic Act for aripiprazole lauroxil nanoNanoCrystal Dispersion (NCD). We also refer to your February 24, 2017, correspondence, received February 24, 2017, requesting a meeting to discuss the acceptability of your upcoming 505(b)(2)NDA for the development of Aripiprazole lauroxil NanoCrystal Dispersion (AL-NCD), the injectable extended-release formulation of aripiprazole lauroxil (AL). Our preliminary responses to your meeting questions are enclosed. You should provide, to the Regulatory Project Manager, a hardcopy or electronic version of any materials (i.e., slides or handouts) to be presented and/or discussed at the meeting. In accordance with 21 CFR 10.65(e) and FDA policy, you may not electronically record the discussion at this meeting. The official record of this meeting will be the FDA-generated minutes. If you have any questions, contact me at (301) 796-3971, or email . [email protected]@fda.hhs.gov

Sincerely, {See appended electronic signature page} LCDR Shin-Ye Sandy Chang, PharmD Regulatory Project Manager Division of Psychiatry Products Office of Drug Evaluation I Center for Drug Evaluation and Research ENCLOSURE: Preliminary Meeting Comments Fi

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