CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`202107Orig1s000
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`1
`
`TEVA1066
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`
`

`

`RPM FILING REVIEW
`
`(Including Memo of Filing Meeting)
`To be completed for all new NDAs, BLAs, and Efficacy Supplements [except SE8 (labeling
`change with clinical data) and SE9 (manufacturing change with clinical data]
`
`A lication Information
`
`Proprietary Name: Korlym
`Established/Proper Name: mifepristone
`Dosage Form: Tablets
`Stren ths: 300 my
`
`Applicant: CORCEPT Therapeutics
`A ~ cut for A licant: N/A
`
`Date of Application: 4/15/1 1
`Date of Receipt: 4/ 18/1 1
`Date clock started after UN: N/A
`
`PDUFA Goal Date: 2/18/12
`
`Action Goal Date (if different):
`2/17/12
`
`
`
`Date of Filin { Meetin 7: 6/14/11
`Filin { Date: 6/17/11
`Chemical Classification: 123 etc. ori ' Ial NDAs on]
`5
`
`Proposed indication: This new drug application provides for the use of Korlym (mifepristone) for the control of
`hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have
`diabetes mellitus type 2 or glucose intolerance and have failed surgery or are not candidates for surgery.
`
`Type of Original NDA:
`AND (if applicable)
`Type of NDA Supplement:
`
`505(b)(2)
`
`If505(b)(2).° Drafl the “505(b)(2) Assessment”form found at:
`h
`://inside. do. ov:9003/CDER/0 ceo 'ewDru s/InlmediateO ce/UCM027499
`and re er to -
`I endixA or urther in ormation.
`
`Review Classification:
`
`Standard
`
`Ifthe application includes a complete response to pediatric W71, review
`classification is Priority.
`
`Ifa tropical diseasepriority review voucher was submitted, review
`classification is Priority.
`
`Resubmission after withdrawal? No
`
`Resubmission after refuse to file? No
`
`Pan 3 Combination Product? No
`
`[:1 Convenience kit/Co—package
`E] Pie-filled drug delivery device/system
`D Pre-filled biologic delivery device/system
`lfyes, can!!!“ the Office 01'Combination
`Products (OCP) and copy them on all Inter— [:1 Device coated/impregnated/combined with drug
`cam" ”WWI“
`El Device coated/impregnated/combined with biologic
`E] Drug/Biologic
`E] Separate products requiring cross-labeling
`E] Possible combination based on cross-labeling of separate
`roducts
`
`Other (drug/device/biological product)
`
`Version: 1/24/12
`
`Reference ID: 3090221
`
`1
`
`2
`
`

`

`
`
`El Fast Track
`E] Rolling Review
`X Orphan Designation
`
`E] Rx-to-OTC switch, Full
`I: Rx—to-OTC switch, Partial
`E] Direct-to—OTC
`
`Other:
`
`El PMC response
`[I PMR response:
`El FDAAA [505(0)]
`El PREA deferred pediatric studies [21 CFR
`314.55(b)/21 CFR 601.27(b)]
`El Accelerated approval confirmatory studies (21 CFR
`314.510/21 CFR 601.41)
`I] Animal rule postrnarketing studies to verify clinical
`benefit and safe
`21 CFR 314.610/21 CFR 601.42
`
`Collaborative Review Division (if OTC product): N/A
`
`List referenced IND Numbers:
`
`"N" and 076480
`
`Goal Dates/Product Names/Classification Pro - rties
`
`PDUFA and Action Goal dates correct in tracking system?
`
`Ifno, ask the document room std/fto correct them immediately.
`These are the dates used or calculating ins
`
`Are the proprietary. established/proper. and applicant names
`correct in tracking system?
`
`Ifno, ask the document room stafl'to make the corrections. Also,
`ask the document room staffto add the established/proper name
`to the supporting IND(s) ifnot already entered into tracking
`5 stem.
`
`Is the review priority (S or P) and all appropriate
`classifications/properties entered into tracking system (e. g.,
`chemical classification. combination product classification,
`505(b)(2). orphan drug)? For MAWDA supplements, check
`the Application and Supplement Notification Checklistsfor a list
`ofall classifications/properties at:
`h
`://inside. da. ov:9003/CDER/0 ceo usinessProcessSu ort/ucm163970Jlt
`E
`
`Ifno, ask the document room stafl'to make the appropriate
`entries.
`
`A lication Inte_ri Polic
`
`Is the application afi‘ected by the Application Integrity Policy
`(AIP)? Check theAIP list at:
`h min/Anvil do. ov/ICECI/En orcemenMcrions/A Iicalionlme
`i‘“""‘"a‘“'“°“‘me“‘°°“““"
`
`'
`
`'PoIi
`
`
`
`/lle ault
`
`II.—
`
`If affected by AIP. has OC/DMPQ been notified of the
`submission? If yes, date notified:
`—EE-—IIE]
`Is Form 3397 (User Fee Cover Sheet) included with
`‘/
`authorized signature?
`
`Version: l/24/12
`
`2
`
`Reference ID: 3090221
`
`3
`
`3
`
`

`

`
`
`User Fee Status
`
`Ifa userfee is required and it has not been paid (and it
`is not exempted or waived), the application is
`unacceptableforfilingfollowing a 5-day graceperiod.
`Review stops. Send Unacceptablefor Filing (07V) letter
`and contact userfee stafl.‘
`
`Exempt (orphan)
`
`Ifthefirm is in arrearsfor otherfees (regardless of
`whether a userfee has been paidfor this application),
`the application is unacceptableforfiling (5-day grace
`period does not apply). Review stops. Send UN letter
`and contact the userfee stafl.‘
`
`Not in arrears
`
`505(b)(2)
`(NDAs/NDA Effica Sn lements o
`
`difi‘erence is that the extent to which the active ingredient(s)
`is absorbed or otherwise made available to the site of action
`
`is less than that of the reference listed drug (RLD)? [see 21
`CFR 314.54(b)(1)].
`Is the application for a duplicate of a listed drug whose only
`difference is that the rate at which the proposed product’s
`active ingredient(s) is absorbed or made available to the site
`of action is unintentionally less than that of the listed drug
`[sec 21 CFR 314.54(b)(2)]?
`
`Ifyou answered yes to any ofthe above questions, the application
`may be refusedforfiling under 21 CFR 314.101(d)(9). Contact
`the (b 2 review staj in the Immediate 0] ice 0 New
`_'
`
`Is there unexpired exclusivity on the active moiety (e.g.. 5-
`year. 3-year. orphan or pediatric exclusivity)?
`Check the Electronic Orange Book at:
`hwy/uwmaccessdata.(do.gov/scrigts/cder/ob/detault.cg
`
`If cs. lease list below:
`
`
`
`Ifthere is unexpired, 5—year evclusivitv remaining on the active moietyfor the proposed drugproduct, a 505(b)(2)
`application cannot be submitted until the period ofexclusivity expires (unless the applicantprovides paragraph IV
`patent certification; then an application can be submittedfour years after the date ofapproval.) Pediatric
`exclusivitv will extend both ofthe timefi‘ames in this provision by 6 months. 21 CFR 108(b)(2). Unmpired, 3-_vear
`
`Does another product (same active moiety) have orphan
`exclusivity for the same indication? Check the Orphan Drug
`Designations and Approvals list at:
`
`Version: 1/2411 2
`
`Reference ID: 3090221
`
`3
`
`4
`
`

`

`
`
`If another product has orphan exclusivity, is the product
`considered to be the same product according to the orphan
`drug definition of sameness [see 21 CFR 316.3(b)(13)]?
`
`I
`
`Ifyes, consult the Director, Division ofRegulatory Policy II,
`0] Ice 0 Re nlato Poli
`v
`Has the applicant requested 5-year or 3-year Waxman-Hatch
`exclusivity? (NDAsAVDA eflicaqi supplements only)
`
`\/
`
`7 years requested exclusivity
`
`Note: An applicant can receive exclasivitv without requesting it;
`there are, re nestin exclusivitv is not re aired.
`
`Is the proposed product a single enantiomer of a racemic drug
`previously approved for a different therapeutic use (NDAs
`onl )?
`If yes, did the applicant: (a) elect to have the single
`enantiomer (contained as an active ingredient) not be
`considered the same active ingredient as that contained in an
`already approved racemic drug, and/or (b): request
`exclusivity pursuant to section 505(u) of the Act (per
`FDAAA Section 1 1 13)?
`
`Ifyes, contact Mary Ann Holovac, Director ofDrug Information,
`OGD/DLPS/LRB.
`
`‘/
`
`'/
`
`Format and Content
`
`All paper (except for COL) Do not check mixed submission ifthe only electronic component
`
`is the content 0 labelin COL).
`
`If mixed (paper/electronic) submission, which parts of the
`a lication are submitted in electronic format?
`
`Overall Format/Content
`
`If electronic submission, does it follow the eCTD
`-
`'dance?1
`Index: Does the submission contain an accurate
`com DIChCDSiVC index?
`
`Is the submission complete as required under 21 CFR 314.50
`(NDAs/NDA eflicacy supplements) or under 21 CFR 601.2
`(BLAs/BLA eflicaqv supplements) including:
`
`E] legible
`E] English (or translated into English)
`C] pagination
`E] navi able h perlinks (electronic submissions onl )
`
`
`
`://www fda. ov/downloads/Dru s/GuidanceCon lianceReh lato Information/Guidances/ucn1072349.
`
`
`
`Version: l/24/12
`
`Reference ID: 3090221
`
`4
`
`5
`
`

`

`
`
`Ifno, exlain.
`BLAsonly:Companionapplicationreceivedifasharedor
`
`divided manufacturing arrangement?
`
`If es. BLA #
`Forms and Certifications
`
`-
`I
`
`5
`
`Electronicforms and certifications with electronic signatures (scanned, digital, or electronic — similar to DARRTS,
`e.g., /s/) are acceptable. 0tl1envise,_paperfonns and certifications with hand—written signatures must be included.
`Forms include: userfee cover sheet (3397), application form (356h), patent information (3542a), financial
`disclosure (3454/3455), and clinical trials (3674); Certifications include: debarment certification, patent
`certi cation(s), eld co icerti cation, and ediatric cer ‘ cation.
`A lication Form
`
`Is form FDA 356h included with authorized signature per 21
`CFR 314.50(a)?
`
`Ifforeign applicant, a (1.8. agent must sign theform [see 21 CFR
`314. 50(a (5 .
`
`Are all establishments and their registration numbers listed
`on the form/attached to the form?
`
`'/
`
`Patent Information
`
`(NDAs/NDA effica
`
`su lements o )
`
`Is patent information submitted on form FDA 3542a per 21
`CFR 314.53(c)?
`
`Financial Disclosure
`Are financial disclosure forms FDA 3454 and/or 3455
`
`mm- Comment
`/
`
`included with authorized signature per 21 CFR 54.4(a)(1) and
`(3)?
`
`Forms must be signed by the APPLICANT, not an Agent [see 21
`CFR 54.2(g)].
`
`Note: Financial disclosure is requiredfor bioequivalence studies
`that are the basis or a I roral.
`
`Clinical Trials Database
`Is form FDA 3674 included with authorized signature?
`
`m“ Comment
`1
`
`Ifyes, ensure that the application is also coded with the
`supporting document category, “Form 36 74. ”
`
`Ifno, ensure that language requesting submission oftheform is
`included in the acknowled ement letter sent to the a licant
`—EEIIEI- Comment
`Is a correctly worded Debarment Certification included with
`/
`authorized signature?
`
`Certification is not requiredfor supplements ifsubmitted in the
`original application; Ifforeign applicant, bo_th the applicant and
`the US. Agent must sign the certification filer Guidancefor
`Industry: Submitting Debarment Certifications].
`
`Version: l/24/12
`
`Reference ID: 3090221
`
`6
`
`6
`
`

`

`
`
`Note: Debannent Certification should use wording in FDCA
`Section 306(k)(1) i.e., "[Name ofapplicant] hereby certifies that it
`did not and will not use in any capacity the sen'ices ofany person
`debarred under section 306 ofthe Federal Food, Drug, and
`Cosmetic Act in connection with this application. " Applicant may
`not use wordin « such as, “To the best 0 mv knowled e_,_ "
`
`Field Copy Certification
`DAs/NDA effica
`sn. lements on]
`
`NA Comment
`
`For paper submissions only: Is a Field Copy Certification
`(that it is a true copy of the CMC technical section) included?
`
`Field Copy Certification is not needed ifthere is no CMC
`technical section or ifthis is an electronic submission (the Field
`Oflice has access to the EDR)
`
`Ifmaroon field copyjacketsfrom foreign applicants are received,
`to the a ro riate teld 0] ice.
`
`Controlled Substance/Product with Abuse Potential mm-—
`I
`
`Is an Abuse Liability Assessment. including a proposal for
`scheduling. submitted per 21 CFR 314.50(d)(5)(vii)?
`
`Ifyes, date consult sent to the Controlled Substance Stafi’:
`
`For non—NMEs:
`
`Date ofconsult sent to Controlled Substance Stafl :
`
`
`
`—EE-—IIE]
`PREA
`/
`
`Does the application trigger PREA?
`
`Ifyes, notify PeRC RPM (PeRC meeting is requiredf
`
`Note: NDAs/BLAs/eflicacv supplementsfor new active ingredients,
`new indications, new dosageforms, new dosing regimens, or new
`routes ofadministration trigger PREL All waiver & deferral
`requests, pediatric plans, andpediatric assessment studies nmst be
`reviewed bv PeRC rior to a; moral o the a Ilication/su I lement.
`
`If the application triggers PREA. are the required pediatric
`assessment studies or a full waiver of pediatric studies
`included?
`
`If studies or full waiver not included, is a request for full
`waiver of pediatric studies OR a request for partial waiver
`and/or deferral with a pediatric plan included?
`
`If a request for full waiver/partial waiver/deferral is
`included, does the a lication contain the certification(s)
`
`://inside fda. ovz9003/CDER/OfficeofNewDru s/PediatricandMatemalHealthStaff/ucmOZ7829.htm
`2h
`
`
`Version: 1/2411 2
`
`6
`
`Reference ID: 3090221
`
`7
`
`7
`
`

`

`
`
`required by FDCA Section SOSB(a)(3) and (4)?
`
`I no, reuest in 74-d¢ * letter
`
`BPCA (NDAs/NDA efficacy supplements only):
`
`Is this submission a complete response to a pediatric Written
`Request?
`
`Ifyes, notifly Pediatric Exclusivity Board RPM (pediatric
`exclusivi determination is re uired)’
`mm
`Is a proposed proprietary name submitted?
`/
`
`Ifyes, ensure that the application is also coded with the
`supporting document category, “Proprietary Name/Requestfor
`Review. ”
`
`_mmfl-—
`Is a REMS submitted?
`/
`REMS plan
`submitted
`
`Ifyes, send consult to OSE/DRISK and noti/jr 0C/
`OSI/DSC/PMSB via the DCRMSRMP mailbox
`
`_rescri.tion Labelin;_I Not applicable
`
`Check all types of labeling submitted.
`Package Insert (PI) Medication Guide
`Container Labels.
`
`—EEIII§l-—
`
`IsElectronicContentofLabeling(COL)submittedinSPL III-
`
`M III—
`
`If PI not submitted'in PLR format. was a waiver or
`
`deferral requested before the application was received or in
`the submission? If requested before application was
`submitted, what is the status of the request?
`
`Ifno waiver or deferral, request applicant to submit labeling in
`PLR ormat be are the (lin date.
`
`4 h
`
`_Ill—container labels consulted to OPDP?
`
`MedGuide, PPI. IFU (plus PI) consulted to OSE/DRISK?
`(send WORD version Ifavailable)
`
`Container labels. PI. PPI sent to OSE/DMEPA and
`
`appropriate CMC review office (OBP or ONDQA)?
`
`/
`
`J
`
`3h
`
`://inside fda. ov:9003/CDER/OfficeofNewDru s/PediatiicandMatemalHealthStaff/ucmOZ7837.htm
`
`://inside fda. ovz9003/CDER/OfficeofNeme s/Stud End
`25576.htm
`
`intsandLabelin
`
`evelo mentTeam/ucmO
`
`Version: 1/24/12
`
`7
`
`Reference ID: 3090221
`
`8
`
`8
`
`

`

`OTC Labelin_
`Check all types of labeling submitted.
`
`Not Applicable
`I Outer carton label
`D Immediate container label
`D Blister card
`I] Blister backing label
`E] Consumer Information Leaflet (CIL)
`E] Physician sample
`
`Is electronic content of labeling (COL) submitted?
`
`I no, reIuest in 74-(1 I
`
`I letter.
`
`Are annotated specifications submitted for all stock keeping
`units (SKUs)?
`
`I no, reIuest in 74-4 I
`
`I letter.
`
`If representative labeling is submitted, are all represented
`SKUs defined?
`
`I no mates! in 74-41:
`
`letter.
`
`_-II_
`switch sent to OSE/DMEPA?
`—EE-—IIEI
`Are additional consults needed?
`\/
`
`-—EE-—IIEI
`End-of Phase 2 meeting(s)?
`‘/
`
`I es,sIeei; consult(s)anddate(s)sent:
`.-
`Date(s):
`
`
` —--
`
`
`
`Date: 9/14/10
`
`—-II
`
`Date(s):
`
`Version: 1/2411 2
`
`8
`
`Reference ID: 3090221
`
`9
`
`9
`
`

`

`
`
`
`
`NDA 202107 for mifepristone
`Filing Meeting – Tuesday June 14, 2011
`
`
`
`
`
`
`
`
`Sponsor: CORCEPT
`Drug: mifepristone 300mg Tablets
`
`
`
`Indication: For the treatment of hypercortisolism associated with Cushing’s Syndrome
`505(b)(2)
`
`
`
`
`
`Orphan Drug designation
`Paper submission
`
`Review Team:
`
`Division Director: Mary Parks, M.D.
`OND DMEP PM: Jena Weber, BS/Julie Marchick, MS
`CDTL: Dragos Roman, M.D.
`Clinical: Marina Zemskova, M.D.
`Chemistry: Xavier Ysern, Ph.D. (Su Tran, Ph.D., Ali Al-Hakim, Ph.D.)
`ONDQA PM: Kushboo Sharma
`Biopharm: Minerva Hughes, Ph.D. (Angelica Dorantes, Ph.D.)
`Pharm/Tox: Pat Brundage, Ph.D. (Todd Bourcier, Ph.D.)
`Pharm/Tox/Stats: Steve Thomson, Ph.D. (Karl Lin, Ph.D.)
`Clin Pharm Jee Eun Lee, Ph.D (Jaya Vaidyanathan, Ph.D.)
`Biometrics: Japo Choudhury, Ph.D. (Todd Sahlroot, Ph.D.)
`DMEP Safety: Amy Egan, M.D., John Bishai, Ph.D.
`DSI: Susan Leibenhaut, M.D. (Tejashri Purohit-Sheth, M.D.)
`DRISK: Suzanne Robottom, PharmD
`DDMAC: Sam Skariah, PharmD., Olga Salis, PharmD.
`DMEPA: Lena Maslov, PharmD., Zach Oleszczuk
`OSE: Rita Tossa, Claudia Karwoski, (Gerald Dal Pan, M.D.)
`OCC: Carla Cartwright, JD
`OC: Suzanne Barone
`ORP: Kristen Miller, Kristen Everett, Liz Dickinson, JD
`DCRP/QT: Devi Kozeli, RAC
`
`Receipt Date: April 18, 2011
`60-day Filing Date: June 17, 2011
`74-day letter: July 1, 2011
`Standard Review – 10 month Goal Date: February 17, 2012 (the 18th is a Sat).
`
`Filing Meeting: June 14, 2011
`Team Meeting#1: ~ August 2011
`Team Meeting #2: ~ November 2011
`Mid-Cycle Meeting: September 12, 2011
`AC Meeting: NN
`PeRC Meeting: N/A
`
`Version: 1/24/12
`
`Reference ID: 3090221
`
`9
`
`10
`
`

`

`Primary Reviews completed: January 13, 2012
`Wrap-Up meeting: ~ January 13, 2012
`Secondary reviews completed: January 20, 2012
`D81 inspections complete: To be determined
`Send labeling and PMR/PMC to sponsor: ~ January 27, 2012
`CDTL review complete: January 27, 2012
`Action Package to Division Director: January 28, 2012
`Action letter sign-off: NLT February 17, 2012
`
`Consults requested or to be requested prn:
`
`DDMAC: labeling
`TQT team
`OSE: Trade Name
`
`DRISK: Labeling, Med Guide
`DSI: Clinical sites
`
`DRUP: Possibility of pregnancy in Cushing’s patients; what precautions or additional
`precautions should be taken?
`
`Discussion Points:
`
`Should an AC be scheduled? No.
`
`REMS — specific to indication under this NDA
`Inspections: DSI/clinical and CMC/EER
`Exempt from PREA (Orphan)
`
`Notes:
`
`Additional info requested for TQT team to review
`Review of PLR labeling underway
`Employee list not to be included in NDA AP
`
`REVIEW TEAM:
`
`Discipline/Organization
`
`Reviewer: MZemskova
`
`Regulatory Project Management
`
`JWeber
`
`Cross-Discipline Team Leader (CDTL) DRoman
`
`CPMS/TL:
`
`JMarchick
`
`Version: 1/24/12
`
`10
`
`Reference ID: 3090221
`
`11
`
`11
`
`

`

`
`
`
`
`Social Scientist Review (for OTC
`products)
`
`
`OTC Labeling Review (for OTC
`products)
`
`
`Clinical Microbiology (for antimicrobial
`products)
`
`
`Clinical Pharmacology
`
`
`Biostatistics
`
`
`Nonclinical
`(Pharmacology/Toxicology)
`
`Statistics (carcinogenicity)
`
`
`Immunogenicity (assay/assay
`validation) (for BLAs/BLA efficacy
`supplements)
`
`Product Quality (CMC)
`
`
`Quality Microbiology (for sterile
`products)
`
`CMC Labeling Review
`
`Facility Review/Inspection
`
`
`TL:
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`Reviewer:
`
`TL:
`
`
`DRoman
`NN
`
`
`
`NN
`
`
`
`NN
`
`
`
`JELee
`
`JVaidyanathan
`
`JChoudhury
`
`TSahlroot
`
`PBrundage
`
`TBourcier
`
`SThomson
`
`KLin
`
`NN
`
`NN
`
`XYsern
`
`STran
`
`NN
`
`
`
`XYsern
`
`STran
`
`SLeibenhaut
`
`TPurohit-Sheth
`
`Y
`NN
`
`
`
`NN
`
`
`
`NN
`
`
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`N
`
`N
`
`
`
`
`
`Y
`
`Y
`
`
`
`
`
`Y
`
`Y
`
`Y
`
`Y
`
`Version: 1/24/12
`
`Reference ID: 3090221
`
`11
`
`12
`
`

`

`
`
`OSE/DMEPA (proprietary name)
`
`“Ems“ ”M9
`
`--—
`mm“ (“M9 -—-
`-—-
`Bioresearch Monitoring (OSI) -—-
`-—-
`Controlled Substance Staff(CSS) -—-
`
`TL'
`
`NN
`
`Other reviewers
`
`DRUP TQT MHT
`
`——-
`
`
`
`
`FILING NIEETING DISCUSSION:
`
`GENERAL
`
`505(b)(2) filing issues?
`
`Per reviewers. are all parts in English or English
`translation?
`
`YES
`
`0
`
`0 0
`
`0 Electronic Submission comments
`
`Not Applicable
`
`CLINICAL
`
`FILE, review issues for 74-day letter
`
`Clinicalstudysite(s)inspections(s)needed? NOS—
`
`0 Advisory Committee Meeting needed?
`Ifno, for an originalM‘lE or BLA application, include the
`reason. For example:
`this drug/biologic is not the first in its class
`the ch'nical study design was acceptable
`the application did not raise significant satin?
`or etficacy issues
`the application did not raise significantpublic
`health questions on the role ofthe
`drug/biolog'c in the diagnosis, cure,
`miti ation treatment or ; revention ofa
`
`Version: 1/24/12
`
`12
`
`Reference ID: 3090221
`
`13
`
`13
`
`

`

`Not Applicable
`
`NO
`
`Not Applicable
`
`FILE, review issues for 74-day letter
`
`NO
`
`FILE, review issues for 74-day letter
`
`FILE, review issues for 74-day letter
`
`Not Applicable
`
`
`FILE, review issues for 74-day letter
`
`Not Applicable
`
`YES
`
`
` YES
` NO
`
`
`
` YES
` NO
`
`
` Not Applicable
`
`
`
`
`
`
` •
`
`
`•
`
`disease
`
` Abuse Liability/Potential
`
`If the application is affected by the AIP, has the
`division made a recommendation regarding whether
`or not an exception to the AIP should be granted to
`permit review based on medical necessity or public
`health significance?
`
`
`CLINICAL MICROBIOLOGY
`
`CLINICAL PHARMACOLOGY
`
`• Clinical pharmacology study site(s) inspections(s)
`needed?
`
`
`BIOSTATISTICS
`
`NONCLINICAL
`(PHARMACOLOGY/TOXICOLOGY)
`
`IMMUNOGENICITY (BLAs/BLA efficacy
`supplements only)
`
`PRODUCT QUALITY (CMC)
`
`Environmental Assessment
`
` •
`
`
`
` Categorical exclusion for environmental assessment
`(EA) requested?
`
`If no, was a complete EA submitted?
`
`
`If EA submitted, consulted to EA officer (OPS)?
`
`
`Quality Microbiology (for sterile products)
`
` •
`
`
`
` Was the Microbiology Team consulted for validation
`of sterilization? (NDAs/NDA supplements only)
`
`Version: 1/24/12
`
`Reference ID: 3090221
`
`13
`
`14
`
`

`

`
`
`Facilig' Inspection
`
`0 Establishment(s) ready for inspection?
`
`.
`
`Establishment Evaluation Request (EER/TBP—EER)
`submitted to OMPQ?
`
`Facing/Microbiology Review (BLAs only)
`
`Not Applicable
`
`CMC Labefin Refiew
`
`REGULATORY PROJECT MANAGEMENT
`
`Signatory Authority: Mary Parks, M.D., Division Director
`
`REGULATORY CONCLUSIONS/DEFICIENCIES
`
`a The application is unsuitable for filing. Explain why:
`
`X
`
`The application. on its face. appears to be suitable for filing.
`
`Review Issues: review issues have been identified for the 74-day letter.
`
`
`
`R—eviewClassification. Standard Review
`
`ACTIONS ITEMS
`
`a BLA/BLA supplements. Iffiled send 60-day filing letter If priority review:
`
`Ensure that any updates to the review priority (S or P) and classifications/properties are
`entered into tracking system (e.g. chemical classification combination product
`classification, 505(b)(2)_ o han dru-V).
`If RTF. notify everybody who already received a consult request. OSE PM. and Product
`Quali PM (to cancel EER/TBP-EER).
`If filed. and the application is under AIP. prepare a letter either granting (for signature by
`Center Director) or denying (for signature by ODE Director) an exception for review.
`
`I
`
`I
`
`0
`
`notify sponsor in writing by day 60 (For BLAs/BLA supplements: include1n 60-day
`filin letter: For NDAs/NDA sun lements: see CST for choices)
`
`Version: l/24/12
`
`14
`
`Reference ID: 3090221
`
`15
`
`15
`
`

`

`
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`Jena M. Weber
`Regulatory Project Manager
`
`
`
`Julie Marchick
`Chief, Project Management Staff
`
`• notify OMPQ (so facility inspections can be scheduled earlier)
` Send review issues/no review issues by day 74
`
`Conduct a PLR format labeling review and include labeling issues in the 74-day letter
`
`BLA/BLA supplements: Send the Product Information Sheet to the product reviewer and
`the Facility Information Sheet to the facility reviewer for completion. Ensure that the
`completed forms are forwarded to the CDER RMS-BLA Superuser for data entry into
`RMS-BLA one month prior to taking an action [These sheets may be found at:
`http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/UCM027822]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`February 16, 2012
`Date
`
`February 21, 2012
`Date
`
`Version: 1/24/12
`
`Reference ID: 3090221
`
`15
`
`16
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JENA M WEBER
`02/21/2012
`
`JULIE C MARCHICK
`02/21/2012
`
`Reference ID: 3090221
`
`17
`
`

`

`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA #/Product Name:
`
`PMR/PMC Description:
`
`NDA 202107/Korlym (mifepristone)
`To obtain drug use data to better characterize the reporting rates of adverse
`events associated with the long-term use of Korlym (mifepristone).
`
`
` 06/17/2012
` 08/17/2012
` 02/17/2013
` 02/17/2014
` 02/17/2015
` 02/17/2016
` 02/17/2017
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Interim report submissions:
`
`
`
`
`
`
`
`
`
`Final Report Submission:
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Endogenous Cushing’s syndrome is a rare disorder (~20,000 patients with Cushing’s syndrome in
`the U.S.). The indication for Korlym (mifepristone) is for the control of hyperglycemia due to
`hypercortisolism in adult patients with endogenous Cushing’s syndrome who have type 2 diabetes
`or glucose intolerance who have failed surgery or who are not candidates for surgery. The estimated
`number of patients who would be candidates for Korlym (mifepristone) therapy is ~5,000. For these
`patients, there are currently no approved medical therapies. The clinical development program
`consisted of 1 trial enrolling 50 patients, 30 of whom were followed in an extension trial for a
`variable duration of time. The small size and the relatively short duration of the trials precluded an
`assessment of the potential long-term complications of Korlym treatment, including retinopathy,
`endometrial hyperplasia and/or vaginal bleeding, and major adverse cardiovascular events (due to
`reductions in HDL-cholesterol associated with Korlym [mifepristone] use). These adverse events
`will be collected using enhanced pharmacovigilance. The purpose of the drug use PMR is to
`provide a denominator for these adverse events to see if reporting rates in the Korlym-treated
`population exceed the background incidence rates in the Cushing’s population.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`PMR/PMC Development Template
`
`Last Updated 2/13/2012
`
`Page 1 of 3
`
`Reference ID: 3088503
`
`18
`
`

`

`Potential adverse events associated with long-term exposure to Korlym (mifepristone) include
`endometrial hyperplasia and/or vaginal bleeding, retinopathy, and major adverse cardiovascular
`events, due to observed reductions in HDL-cholesterol. Because of the small size and short duration
`of the clinical trials, a determination regarding these risks could not be made. The drug use PMR
`will provide a denominator for the adverse events and will provide information on dose, duration of
`use of the product, patient age, patient gender, indication for treatment, and prescriber specialty.
`
`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`A drug utilization study to provide the following information about users of Korlym (mifepristone):
`age, gender, dose, duration of use, indication for treatment, and prescriber specialty.
`
`PMR/PMC Development Template
`
`Last Updated 2/13/2012
`
`Page 2 of 3
`
`Reference ID: 3088503
`
`19
`
`

`

`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Drug utilization study
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 2/13/2012
`
`Page 3 of 3
`
`Reference ID: 3088503
`
`20
`
`

`

`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA #/Product Name:
`
`PMR/PMC Description:
`
`202107/Korlym (mifepristone)
`A drug-drug interaction clinical trial to determine a quantitative estimate of
`the change in exposure of mifepristone following co-administration with
`ketoconazole (a strong CYP3A4 inhibitor).
`
` 08/18/2012
` 05/18/2013
` 08/18/2013
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Endogenous Cushing’s syndrome is a rare disorder (~20,000 patients with Cushing’s
`syndrome in the U.S.). The indication for Korlym (mifepristone) is