CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210563Orig1s000
`210563Orig2s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`IND 102688
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`
`Pharmacyclics LLC
`Attention: Usha Ramesh
`Executive Director, Regulatory Affairs
`995 E. Arques Avenue
`Sunnyvale, CA 94085- 4521
`
`
`Dear Ms. Ramesh:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for ibrutinib.
`
`We also refer to the teleconference between representatives of your firm and the FDA on March
`10, 2017. The purpose of the meeting was to update the Agency on results from the
`bioequivalence studies, and to discuss and reach agreement on the New Drug Application (NDA)
`submission for the registration of the four strengths of the tablet dosage form.
`
` 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 Suria Yesmin, Regulatory Project Manager, at (301) 348-1725.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Bahru Habtemariam, PharmD
`Clinical Pharmacology Team Leader
`Division of Clinical Pharmacology V
`Office of Clinical Pharmacology
`Center for Drug Evaluation and Research
`
`
`
`Enclosure:
`Meeting Minutes
`
`Reference ID: 4068966
`
`
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Type B
`Pre-NDA
`
`Friday, March 10, 2017, 11am – 12pm EST
`Teleconference
`
`Meeting Type:
`Meeting Category:
`
`Meeting Date and Time:
`Meeting Location:
`
`Application Number:
`Product Name:
`Indications:
`
`Bahru Habtemariam, PharmD
`Suria Yesmin, BS, CCRP
`
`IND 102688
`Ibrutinib
`Current approved for (1) mantle cell lymphoma (MCL) who have
`received at least one prior therapy; (2) chronic lymphocytic
`leukemia (CLL)/small lymphocytic leukemia (SLL); (3) CLL/SLL
`with 17p deletion; (4) Waldenström’s macroglobulinemia (WM);
`and (5) marginal zone lymphoma (MZL) who require systemic
`therapy and have received at least one prior anti-CD20-based
`therapy
`Sponsor/Applicant Name: Pharmacyclics LLC
`
`Meeting Chair:
`Meeting Recorder:
`
`FDA ATTENDEES
`Office of Hematology and Oncology Products (OHOP), Division of Hematology Products
`R. Angelo de Claro, MD, Clinical Team Leader
`Tanya Wroblewski, MD, Clinical Reviewer
`Margret Merino, MD, Clinical Reviewer
`Suria Yesmin, BS, CCRP, Regulatory Project Manager
`Esther Park, PharmD, Regulatory Project Manager
`Wanda Nguyen, PharmD, Regulatory Project Manager
`Tran Quyen, PharmD, Regulatory Project Manager
`
`OHOP/Division of Hematology, Oncology, Toxicology
`Christopher Sheth, PhD, Team Leader
`Shwu-Luan Lee, PhD, Reviewer
`
`Office of Clinical Pharmacology (OCP), Division of Clinical Pharmacology V
`Bahru Habtemariam, PharmD, Team Leader
`Vicky Hsu, PhD, Reviewer
`
`
`
`
`
`Reference ID: 4068966
`
`

`

`IND 102688
`Page 2
`
`Office of New Drug Products (ONDP)/Division of New Drug Products I
`Anamitro Banerjee, PhD, Branch Chief, Branch II
`
`ONDP/Division of Biopharmaceutics/Branch I
`Om Anand, PhD, Reviewer
`
`
`SPONSOR ATTENDEES
`Usha Ramesh, PhD, Executive Director, Regulatory Affairs CMC
`Urte Gayko, PhD, Global Head of Regulatory
`Heow Tan, MS, MBA, Chief, Quality and Technical Operations
`Marcel Beulen, PhD, Executive Director, Analytical Chemistry
`Juthamas Sukbuntherng, PhD, Head of Clinical Pharmacology and DMPK
`Robert Kuehl, Executive Director, Drug Product Development
`Parag Shah, PharmD, MS, Senior Manager, Regulatory Affairs CMC
`Daniel Schaufelberger, PhD, Senior Scientific Director, CMC Leader
`Jan de Jong, PhD, Scientific Director, Clinical Pharmacology
`
`
`1.0
`
`Pharmacyclics LLC requested a pre-NDA meeting with FDA on December 20, 2016, to update
`the Agency on results from the bioequivalence studies, and to discuss and reach agreement on
`the New Drug Application (NDA) filing for the registration of the four strengths of the tablet
`dosage form. The Applicant also made reference to the Type C meeting package submitted on
`March 18, 2016, and the Type C Meeting held on April 27, 2016, to discuss the development
`plan for a new immediate-release tablet dosage form in four strengths (140 mg, 280 mg, 420 mg
`and 560 mg). Pharmacyclics had also discussed the dissolution method with the Agency through
`communications on August 19 and September 28, 2016, and gained acceptance by email for the
`proposed QC dissolution method on October 21, 2016.
`
`FDA sent Preliminary Comments to Pharmacyclics LLC on Friday, March 3.
`
`
`2.0
`
`BACKGROUND
`
`DISCUSSION
`
`2.1
`
`
`Clinical Pharmacology
`
`Question 1: In accordance with the agreements reached at the Type C Meeting with the
`FDA held on 27 April 2016, two bioequivalence (BE) studies were conducted to
`demonstrate BE of the tablet dosage form to the capsule dosage form. In one study
`(Study No. 1) 1x 560 mg tablet was compared to 4x140 mg capsule and the second study
`(Study No. 2) compared 1x140 mg tablet to 1x140 mg capsule. The results from the two
`studies indicate that the areas under the curve (AUC∞ and AUClast) for the plasma
`concentrations of the tablet formulation and the capsule formulation meet bioequivalence
`criteria. The Cmax of the 140 mg tablet and the reference capsule formulation also met
`bioequivalence criteria with a GMR of 90% and 90% confidence interval of 84-96%,
`whereas for the 560 mg tablet both the GMR and the 90% CI for Cmax fall below the 80%
`
`
`
`Reference ID: 4068966
`
`

`

`IND 102688
`Page 3
`
`
`
`
`
`
`
`2.2
`
`
`lower limit. However, based on ibrutinib exposure-response relationships and
`mechanism of action as a covalent BTK inhibitor, Pharmacyclics considers the lower
`Cmax not clinically relevant and the 560 mg tablet may be considered bioequivalent to
`four 140 mg capsules despite not meeting the BE criterion for Cmax. Does the Agency
`agree?
`
`FDA Response to Question 1:
`Yes, your justification appears acceptable. When submitting the NDA, please also
`include adequate justification indicating that the lack of Cmax bioequivalence does
`not have clinically relevant consequences.
`
`Discussion: There was no discussion.
`
`Question 2: At the Type C Meeting held on 27 April 2016, Pharmacyclics discussed the
`tablet development program and obtained agreement on the biowaiver strategy for the
`280 mg and 420 mg tablet strengths. The Agency agreed that biowaiver for intermediate
`strengths was acceptable based on comparability of dissolution profiles of the 280 mg
`and 420 mg tablets to one of the two BE strengths using the 0.1N HCl medium and the
`QC medium. Pharmacyclics would like to reconfirm this agreement with the FDA.
`
`FDA Response to Question 2:
`Yes, the FDA reconfirms that the proposed approach for requesting a biowaiver for
`the intermediate (280 and 420 mg) tablet strengths of your product appears
`appropriate. However, FDA’s final decision on the approvability of the biowaiver
`request for the intermediate strengths is a review issue and will be based on the
`totality of the information provided in the NDA.
`
`In addition, note that in the briefing package, dissolution profile of the 560 mg
`strength in 0.1N HCl (Figure 14) was not provided; in the NDA, submit the
`dissolution profiles in 0.1 HCl and the proposed dissolution method for all the
`strengths.
`
`Discussion: There was no discussion.
`
`Chemistry, Manufacturing and Controls
`
`Question 3: Pharmacyclics plans to submit the NDA for the new tablet dosage form in
`August 2017. At the time of filing 6 month of stability data will be available on the
`registration stability batches and will be included in the submission. Pharmacyclics
`proposes to submit stability data obtained at the month time point for the registration
`batches during the review of the tablet NDA. Does the Agency agree that this plan is
`acceptable?
`
`FDA Response to Question 3:
`We recommend that you provide at least twelve (12) months of long-term stability
`data and at least six (6) months of accelerated stability data for three batches of the
`drug product manufactured using multiple batches of drug substance at the time of
`
`
`
`Reference ID: 4068966
`
`(b)
`(4)
`
`

`

`submission. Review of any data submitted more than thirty days after the
`submission of the original application will depend on available resources. Note that
`the expiration period granted to the drug product will be based on the quantity and
`quality of the stability data provided in the submission.
`
`The Quality amendment to this IND dated December 21, 2016, proposes higher
`levels of impurities in the drug product specifications compared to what is currently
`approved for the capsules. In your submission, you should justify the proposed
`specifications. If toxicology studies are used to qualify each individual impurity at
`the proposed specification, submit pertinent data for review and comment.
`
`Discussion: The Agency strongly recommends that you provide 12 months data for the
`stability batches. The 12-month timepoint may be provided within 30 days of initial
`submission. If you provide less than 12 months, i.e., months data, the expiry dating
`period would depend on the data provided in the submission. The proposed stability
`data to be submitted for the alternate site, i.e., 3 months long term intermediate and
`accelerated stability data from 3 registration batches each of 560 mg and 140 mg
`strength manufactured at the alternate site is acceptable.
`
`The toxicology data to support impurity specifications for the new formulation appear
`adequate. A final decision will be made during the review of the application.
`
`Question 4: Ibrutinib is a first-in-class, orally administered, potent BTK inhibitor.
`Ibrutinib was granted four breakthrough therapy designations (BTD) for the following
`indications:
` Relapsed or refractory mantle cell lymphoma (MCL) with at least one prior
`therapy
` Chronic lymphocytic leukemia (CLL) with 17p deletion
` Waldenström’s macroglobulinemia (WM)
` Chronic graft-versus-host disease (cGVHD)
`
`
`Ibrutinib capsules 140 mg were approved by the FDA on 13 November 2013. In order to
`lower the patient pill burden and improve patient compliance with therapy,
`Pharmacyclics has developed a new tablet dosage form in four different strengths
`(140 mg, 280 mg, 420 mg, and 560 mg). Pharmacyclics plans to submit a NDA for the
`tablet dosage form based on results from BE studies comparing the tablet dosage form
`with the capsule dosage form. Considering the Breakthrough Therapy status of ibrutinib
`and given that the planned NDA filing for the tablet dosage form does not include any
`new efficacy or safety data, does the Agency agree that the review period for this NDA
`be the same as that of a Prior Approval Supplement (i.e., 4 months)?
`
`FDA Response to Question 4:
`Given the composition of the approved capsule and the proposed tablet are not
`identical, the change in dosage form requires the submission of a New Drug
`Application (NDA). Therefore, we do not agree the review period for this new NDA
`will be the same as that of a prior approval supplement. A non-new molecular
`
`IND 102688
`Page 4
`
`
`
`
`
`
`Reference ID: 4068966
`
`(b)
`(4)
`
`

`

`IND 102688
`Page 5
`
`
`entity NDA will either receive a priority review of 6 months or a standard review of
`10 months. Once the NDA is submitted, the Division will determine the review
`timeline.
`
`
`
`Discussion: The review timeline will be determined once the NDA is submitted. Also,
`the Agency recommended that the Sponsor avoid any potential for a drug shortage
`situation with the proposed transition from a capsule to tablet formulation.
`
`
`
`3.0 OTHER MEETING INFORMATION
`
`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.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from these requirements. Please include a statement that confirms this finding, along with a
`reference to this communication, as part of the pediatric section (1.9 for eCTD submissions) of
`your application. If there are any changes to your development plans that would cause your
`application to trigger PREA, your exempt status would change.
`
`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.
` 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.
`
`
`
`Reference ID: 4068966
`
`

`

`IND 102688
`Page 6
`
`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.
`
`
`SUBMISSION FORMAT REQUIREMENTS
`
`The Electronic Common Technical Document (eCTD) is CDER and CBER’s standard format for
`electronic regulatory submissions. Beginning May 5, 2017, the following submission types:
`NDA, ANDA, BLA and Master Files must be submitted in eCTD format. Commercial IND
`submissions must be submitted in eCTD format beginning May 5, 2018. Submissions that do
`not adhere to the requirements stated in the eCTD Guidance will be subject to rejection. For
`more information please visit: http://www.fda.gov/ectd.
`
`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.”
`
`
`
`
`
`
`
`Reference ID: 4068966
`
`

`

`IND 102688
`Page 7
`
`
`Site Name
`
`Site Address
`
`
`
`
`1.
`2.
`
`Corresponding names and titles of onsite contact:
`
`
`Federal
`Establishment
`Indicator (FEI) or
`Registration
`Number
`(CFN)
`
`
`
`Drug
`Master
`File
`Number
`(if
`applicable)
`
`
`
`Manufacturing
`Step(s)
`or Type of Testing
`[Establishment
`function]
`
`
`
`
`Phone and
`Fax
`number
`
`
`
`Email address
`
`
`
`
`Site Name
`
`Site Address
`
`
`
`
`Onsite Contact
`(Person, Title)
`
`
`
`1.
`2.
`
`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).
`
`
`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)
`
`
`
`Reference ID: 4068966
`
`

`

`IND 102688
`Page 8
`
`
`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.
`
`
`II. Request for Subject Level Data Listings by Site
`
`
`
`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.
`d. 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).
`e. 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).
`
`
`
`
`1. For each pivotal trial: Site-specific individual subject data listings (hereafter referred to as
`“line listings”). For each site, provide line listings for:
`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
`
`
`
`
`
`
`
`
`
`Reference ID: 4068966
`
`

`

`IND 102688
`Page 9
`
`
`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
`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.
`
`
`
`
`
`
`Reference ID: 4068966
`
`

`

`IND 102688
`Page 10
`
`
`
`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.”
`
`
`
`
`
`
`
`
`
`
`STF File Tag
`
`Used For
`
`Allowable
`File Formats
`
`data-listing-dataset
`annotated-crf
`
`data-listing-dataset
`
`Data listings, by study
`Sample annotated case report
`form, by study
`Data listings, by study
`(Line listings, by site)
`Site-level datasets, across
`studies
`data-listing-data-definition Define file
`
`data-listing-dataset
`
`.pdf
`.pdf
`
`.pdf
`
`.xpt
`
`.pdf
`
`DSI Pre-
`NDA
`Request
`Item1
`I
`I
`
`II
`
`III
`
`III
`
`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
`
`
`
`Reference ID: 4068966
`
`

`

`ISSUES REQUIRING FURTHER DISCUSSION
`
`None.
`
`ACTION ITEMS
`
`None.
`
`IND 102688
`Page 11
`
`
`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: ESUB@fda.hhs.gov
`
`
`4.0
`
`
`
`
`5.0
`
`
`
`
`6.0
`
`
`
`ATTACHMENTS AND HANDOUTS
`
`The Sponsor provided the attached response document for the meeting.
`
`
`
`Reference ID: 4068966
`
`54 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BAHRU A HABTEMARIAM
`03/13/2017
`
`Reference ID: 4068966
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`

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`Miranda Raggio/3-9-15 Revised to MPC
`
`CDER Breakthrough Therapy Designation Determination Review
`
`IND/NDA/BLA #
`Request Receipt Date
`Product
`Indication
`
`IND 102688
`April 27, 2016
`Ibrutinib
`Sponsor: For the treatment of Chronic Graft Versus Host Disease(cGVHD)
`FDA: Treatment of chronic graft-versus-host-disease(cGVHD) after failure
`of 1 or more lines of systemic therapy.
`Tyrosine kinase inhibitor
`
`Drug Class/Mechanism of
`Action
`Sponsor
`ODE/Division
`Breakthrough Therapy
`Request Goal Date (within 60
`days of receipt)
`Note: This document should be uploaded into CDER’s electronic document archival system as a clinical review
`and will serve as the official Clinical Review for the Breakthrough Therapy Designation Request (BTDR). Note:
`Signatory Authority is the Division Director.
`
`Pharmacyclics LLC
`CDER/OHOP/DHP
`July 1, 2016
`
`Section I: Provide the following information to determine if the BTDR can be denied without Medical
`Policy Council (MPC) review.*Section I to be completed within 14 days of receipt for all BTDRs*
`
`1. Briefly describe the indication for which the product is intended (Describe clearly and concisely since the
`wording will be used in the designation decision letter): Treatment of chronic graft-versus-host-
`disease(cGVHD) after failure of 1 or more lines of systemic therapy.
`
`2. Are the data supporting the BTDR from trials/IND(s) which
` are on Clinical Hold?
` YES
`
` NO
`
`If 2 above is checked “Yes,” the BTDR can be denied without MPC review. Skip to number 5 for clearance and sign-
`off. If checked “No”, proceed with below:
`
`3. Consideration of Breakthrough Therapy Criteria:
`
`a.
`
`Is the condition serious/life-threatening1)?
`
` YES NO
`
`If 3a is checked “No,” the BTDR can be denied without MPC review. Skip to number 5 for clearance and sign-off. If
`checked “Yes”, proceed with below:
`
`b.
`
`Are the clinical data used to support preliminary clinical evidence that the drug may demonstrate substantial
`improvement over existing therapies on 1 or more clinically significant endpoints adequeate and sufficiently
`complete to permit a substantive review?
` YES the BTDR is adequate and sufficiently complete to permit a substantive review
` Undetermined
`
`1 For a definition of serious and life threatening see Guidance for Industry: “Expedited Programs for Serious Conditions––Drugs and
`Biologics” http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf
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`Reference ID: 3949146
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`Miranda Raggio/3-9-15 Revised to MPC
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` NO, the BTDR is inadequate and not sufficiently complete to permit a substantive review; therefore
`the request must be denied because (check one or more below):
`
`i. Only animal/nonclinical data submitted as evidence
`ii.
`Insufficient clinical data provided to evaluate the BTDR
`(e.g. only high-level summary of data provided, insufficient information
` about the protocol[s])
`iii. Uncontrolled clinical trial not interpretable because endpoints
`are not well-defined and the natural history of the disease is not
`relentlessly progressive (e.g. multiple sclerosis, depression)
`iv. Endpoint does not assess or is not plausibly related to a serious
`aspect of the disease (e.g., alopecia in cancer patients, erythema
`chronicum migrans in Lyme disease)
`v. No or minimal clinically meaningful improvement as compared
`to available therapy2/ historical experience (e.g., <5%
`improvement in FEV1 in cystic fibrosis, best available
`therapy changed by recent approval)
`
`4. Provide below a brief description of the deficiencies for each box checked above in Section 3b:
`
`If 3b is checked “No”, BTDR can be denied without MPC review. Skip to number 5 for clearance and sign-off (Note:
`The Division always has the option of taking the request to the MPC for review if the MPC’s input is desired. If this is
`the case, proceed with BTDR review and complete Section II). If 3b is checked “Yes” or “Undetermined”, proceed
`with BTDR review and complete Section II, as MPC review is required.
`
`5. Clearance and Sign-Off (no MPC review)
`
`Deny Breakthrough Therapy Designation
`
`
`
`{See appended electronic signature page}
`Reviewer Signature:
`{See appended electronic signature page}
`Team Leader Signature:
`{See appended electronic signature page}
`Division Director Signature:
`__________________________________________________________________________________________________
`Section II: If the BTDR cannot be denied without MPC review in accordance with numbers 1-3 above,
`or if the Division is recommending that the BTDR be granted, provide the following additional
`information needed by the MPC to evaluate the BTDR.
`
`6. A brief description of the drug, the drug’s mechanism of action (if known), the drug’s relation to existing
`therapy(ies), and any relevant regulatory history. Consider the following in your response.
`
`Brief Description of the Drug
`Ibrutinib is a first-in-class, orally administered covalent-binding inhibitor of Bruton’s Tyrosine Kinase(BTK). Ibrutinib
`inhibits B Cell Receptor(BCR) signaling in human B-cells and helps to drive malignant B-cells into apoptosis. BTK
`expression is limited to cells of hematopoietic origin. A summary of the selective BTK inhibition and mode of
`action of ibrutinib is as follows:
`specific and irreversible bond formed with cysteine-481 in BTK
`
`
`2 For a definition of available therapy refer to Guidance for Industry: “Expedited Programs for Serious Conditions––Drugs and
`Biologics” http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf
`2
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`Miranda Raggio/3-9-15 Revised to MPC
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`highly potent BTK inhibition at IC50 = 0.5 nM
`orally administered with once-daily dosing resulting in 24-hour target inhibition
`no cytotoxic effect on T-cells or natural killer cell
`promotes apoptosis and inhibits migration and adhesion in malignant B cells.
`
`Ibrutinib also covalently inhibits interleukin-2 inducible T-cell kinase(IT