. Kacuba, Alice
`
`From:
`Sent:
`To:
`Cc:
`Subject:
`
`Kacuba, Alice
`Thursday, January 29, 2009 3:53 PM
`'sibylle.jennings(gnovartis.com i
`Cottrell, Christy L.
`NDA 22334: Information request
`
`Importance:
`
`High
`
`Hi,
`
`Then Stats revÎewer has the following Information Request. Please submit an amendment ASAP.
`
`Thank you.
`
`Alice
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Division of Drug Oncology Products
`Offce of Oncology Drug Products
`OND/CDER/FDA
`301-796-1381
`(f)301-796-9845
`alice. kacuba(gfda. hhs.gov
`
`Please explain the reasons for discrepancy between the following two tables. The first table is constructed based on
`a_anp dataset in the analysis folder and the second one from anp dataset in the listing folder. Both datasets used are
`from September 30,2008 submission (SN 011).
`
`Table 1: Antineoplastic Therapies for Cut off
`
`Date 28 Feb 2008 (Based on Analysis Data)
`
`.
`
`Therapy type
`
`Missing
`Chemotherapy
`. Hormone therapy
`Immunotherapy
`Anticonvulsant
`Hepatic chemoembolization
`Targeted therapy
`Other
`All
`
`Number of
`
`RA001
`18
`12
`0
`8
`11
`14
`54
`5
`96
`
`patients with AN
`Placebo
`15
`0
`
`1
`2
`
`1
`7
`12
`4
`35
`
`.
`
`. Table 2: Antineoplastic Therapies for Cut off
`
`Date 28 Feb 2008 (Based on Listing Data)
`
`Therapy type
`
`Missing
`Chemotherapy
`
`Number of
`
`RA001
`18
`13
`
`patients with AN
`Placebo
`15
`
`1
`
`1
`
`

`

`Hormone therapy
`Immunotherapy
`Anticonvulsant
`Hepatic chemoembolization
`Targeted therapy
`Other
`All
`
`0
`10
`15
`1
`60
`5
`103
`
`1
`2
`8
`0
`15
`6
`41
`
`Tracking:
`
`RecIpient
`'sibylle.jennings§novartis.com'
`Cottrell, Christy L.
`Chattopadhyay, Somesh
`
`Read
`
`Read: 1/29/20093:54 PM
`
`APPEARS THIS WAY ON ORIGINAl
`
`2
`
`

`

`1i_1i_________"'______._______.______IiIiIi_Ii________~_______________________________........__._____......___________.._
`This is a representation of an electronic record that was signed electronically and
`manifestation of the electronic signature.
`
`this page is the
`
`/s/
`Alice Kacuba
`1/29/2009 03: 58: 46 PM
`
`

`

`DEPARTMENT OF HEA1H AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRTION
`
`TO (Offce/Division): OSE, Sandy Griffith
`
`REQUEST FOR CONSULTATION
`
`FROM (Name, Offce/Division, and Phone Number of Requestor): Alice
`Kacuba, DDOP
`
`DATE
`12-30-2008
`
`NAME
`
`OF DRUG
`
`Afinitor
`
`NAME OF FIR: Novartis
`
`INDNO.
`
`NDANO.
`22-334
`
`TYPE OF DOCUMENT .
`labeling for NDA
`
`DATE OF DOCUMENT
`12-22-08
`
`PRIORlTY CONSIDERATION
`P
`
`CLASSIFICATION OF DRUG
`Oncology
`
`DESIRD COMPæTION DATE
`March 1,2009
`
`REASON FOR REQUEST
`
`I. GENERAL
`
`o NEW PROTOCOL
`o PROGRESS REPORT
`o NEW CORRPONDENCE
`o DRUG ADVERTISING
`o ADVERSE REACTION REPORT
`I ADDITON
`CHANGE
`o MANUFACTURIG
`o MEETING PLANNED BY
`
`o PRE-NDA MEETING
`o END-OF.PHASE 2a MEETING
`o END.OF.PHASE 2 MEETING
`o RESUBMISSION
`o SAFETY I EFFICACY
`o PAPERNDA
`o CONTROL SUPPLEMENT
`
`o RESPONSE TO DEFICIENCY LEER
`o FIAL PRITED LABELING
`o LABELING REVISION
`o ORlGINAL NEW CORRSPONDENCE
`o FORMUATIV REVIEW
`o OTHER (SPECIFY BELOW):
`
`o PRIORITY P NDA REVIEW
`o END.OF-PHASE 2 MEETING
`o CONTROLLED STUDms
`o PROTOCOL REVIEW
`o OTHER (SPECIFY BELOW):
`
`.. DISSOLUTION
`o BIOAVAILABILTY STUDIES
`o PHASE 4 STUDIES
`
`II. BIOMETRICS
`
`o CHEMISTRY REVIEW.
`o PHARMCOLOGY
`o BIOPHARMACEUTICS
`o OTHER (SPECIFY BELOW):
`
`II. BIOPHARMACEUTICS
`
`o DEFICIENCY LETTER RESPONSE
`o PROTOCOL - BIOPHARMACEUTICS
`o IN-VIO WAIVR REQUEST
`
`IV. DRUG SAFETY
`
`o PHASE 4 SURVEILLANCEÆPIDEMIOLOGY PROTOCOL
`o DRUG USE, e.g., POPULATION EXPOSURE, ASSOCIATED DIAGNOSES
`o CASE REPORTS OF SPECIFC REACTIONS (List below)
`o COMPARA TIVRISK ASSESSMENT ON GENERlC DRUG GROUP
`
`o REVIEW OF MARKETING EXPERIENCE, DRUG USE AND SAFETY
`o SUMMARY OF ADVERSE EXPERINCE
`o POISON RlSK ANALYSIS
`
`o CLINICAL
`
`o NONCLINICAL
`
`V. SCIENTIFIC INVESTIGATIONS
`
`COMMENTS I SPECIAL INSTRUCTIONS: The purpose of this consult is request review of the PPI that sponsor revised based
`on our letter based on your review. The revised PPI is in the edr under the Dec 22, 2008 submission.
`
`Thank
`
`you.
`
`Alice Kacuba
`
`SIGNATURE OF REQUESTOR
`Alice Kacuba
`
`METHOD OF DELIVRY (Check one)
`o EMAIL
`18 DFS
`
`o MAIL
`
`o HAND
`
`PRITED NAME AND SIGNATU OF RECEIVR
`
`PRINTED NAME AND SIGNATURE OF DELIVRER
`
`

`

`............._------------------_._------------.~----------.-..._---~-----_..._---------_.._-------_..-....-...._----
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`--------------...----------.............__._--_._-----------------_.._...._-------_.-.............._---_..__._-_..........
`/s/
`Alice Kacuba
`12/30/2008 08: 10: 51 PM
`
`

`

`DEPARTMENT OF HEALTI AND HUMAN SERVICES
`PUBLIC HEALTI SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`TO (Ofjce/Division): OSE, Sandy Griffith
`
`INDNO.
`
`NDANO.
`22-334
`
`DATE
`12-30-2008
`
`NAME
`
`OF DRUG
`
`Afinitor
`
`NAME OF FIR: Novartis
`
`REQUEST FOR CONSULTATION
`
`FROM (Name, Ofjcè/Division, and Phone Number of Requestor): Alice
`
`Kacuba, DDOP
`
`TYPE OF DOCUMENT
`
`Risk
`
`Mapp
`
`DATE OF DOCUMENT
`12-22-08
`
`PRIORIY CQNSIDERATION
`p
`
`CLASSIFICATION OF DRUG
`Oncology
`
`DESIRD COMPLETION DATE
`March 1, 2009
`
`REASON FOR REQUEST
`
`I. GENERAL
`
`o NEW PROTOCOL
`o PROGRESS REPORT
`o NEW CORRESPONDENCE
`o DRUG ADVERTISING
`o ADVERSE REACTION REPORT
`o MANUFACTURING CHANGE I ADDITON
`o MEETING PLANNED BY
`
`o PRE-NDA MEETING
`o END-OF-PHASE 2a MEETING
`o END-OF-PHASE 2 MEETING
`o RESUBMISSION
`o SAFETY I EFFICACY
`o PAPERNDA
`o CONTROL SUPPLEMENT
`
`o RESPONSE TO DEFICIENCY LETTER
`o FINAL PRITED LABELING
`o LABELING REVISION
`o ORIGINAL NEW CORRSPONDENCE
`o FORMLATIV REVIEW
`o OTHR (SPECIFY BELOW):
`
`o PRIORITY P NDA REVIEW
`o END-OF-PHASE 2 MEETING
`o CONTROLLED STUIES
`o PROTOCOL REVIEW
`o OTHER (SPECIFY BEWWI:
`
`-I DISSOLUTION
`o BIOAVAILABILTY STUDIES
`o PHASE 4 STUDIES
`
`II. BIOMETRICS
`
`o CHEMISTRY REVIEW
`o PHACOWGY
`o BIOPHARMACEUTICS
`o OTHR (SPECIFY BEWW):
`
`HI. BIOPHARMACEUTICS
`
`o DEFICIENCY LETTER RESPONSE
`o PROTOCOL - BIOPHARMACEUTICS
`o IN-VNO WAIVR REQUEST
`
`IV. DRUG SAFETY
`
`o PHASE 4 SURVEILANCEÆPIDEMIOWGY PROTOCOL
`o DRUG USE, e.g., POPULATION EXPOSURE, ASSOCIATED DIAGNOSES
`o CASE REPORTS OF SPECIFIC REACTIONS (List below)
`o COMPARATIV RISK ASSESSMENT ON GENERIC DRUG GROUP
`
`o REVIEW OF MARTING EXPERIENCE, DRUG USE AND SAFETY
`o SUMMARY OF ADVERSE EXPERIENCE
`o POISON RISK ANALYSIS
`
`o CLINICAL
`
`V. SCIENTIFIC INVESTIGATIONS
`
`o NONCLINICAL
`
`COMMENTS I SPECIAL INSTRUCTIONS: The purpose of this consult is request review of the "no risk mapp" (Novartis says
`they think can be managed by labt\ng and routine pharmacovigilance actiivties). The submisionis totally electronic
`and is ithe edr. Extended user fee date=3-30-2009.
`
`Thank
`
`you.
`
`Alice Kacuba
`
`SIGNATURE OF REQUESTOR
`Alice Kacuba
`
`METHOD OF DELIVRY (Check one)
`o EMAIL
`l' DFS
`
`o MAIL
`
`o HAND
`
`NTED NAME AND SIGNATURE OF RECENER
`
`PRINTED NAME AND SIGNATURE OF DELIVRER
`
`II
`
`

`

`This is a representation of an electronic record that was signed electronically
`
`-----------------------------------------------------------....__.._-.._-_._-----------_._------_..-.._-----------._-
`and
`
`this page is the manifestation of the electronic signature.
`___________________.MM__________________._.__________________..___.____________.____________...__..________._________
`/s/
`Alice Kacuba
`12/30/2008 08: 38: 49 PM
`
`

`

`Kacuba, Alice
`
`~rom:
`jent:
`To:
`Subject:
`
`Kacuba, Alice
`Thursday, December 11, 2008 4:49 PM
`'sibylle.jennings~novartis.com'
`FDA revised carton and container labels
`
`Importance:
`
`High
`
`Hi,
`
`The purpose of this email is to provide FDA revisions to the carton and container labels.
`
`COMMENTS To THE APPLICANT
`
`I
`
`Things get finalized at different times. Just got review from OSE on carton and container labels.
`
`Thank you.
`
`Alice
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Division of Drug Oncology Products
`Offce of Oncology Drug Products
`OND/CDER/FDA
`301-796-1381
`(f)301-796-9845
`alice.kacuba~fda.hhs.gov
`
`1
`
`\\\"
`
`-i
`
`

`

`-----_.......__..-------..........-_._.__..----_._._-----------_..--_....._......__.._------_._-----_._..._-_......_-
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature. .
`._--_........._................_-_....._..........._----_....------_...--....__......_-_._...---------_..................-
`/s/
`Alice Kacuba
`12/11/2008 04: 52: 39 PM
`
`

`

`Kacuba, Alice
`
`From:
`lent:
`(0:
`Subject:
`
`Kacuba, Alice
`Sunday, December 07,20085:59 PM
`'sibyiie.jennings~novartis.com'
`IR from Clin Pharm
`
`Importance:
`
`High
`
`Hi,
`
`The purpose of this email is to request an Information Request on behalf of Clin Pharm:
`
`It is stated in the summary of Biopharmaceutics that "All assay methods used to assess systemic exposure in
`human pharmacokinetic studies exhibited sufficient specificity, accuracy, precision, and sensitivity for the
`methods for each clinical pharmacology studies in
`Section 6, Table 6-1 and within-study validation data are provided in each clinical study report." I have not
`been able to locate the bioanalytical reports for multiple studies. .
`
`the individual studies. A list of
`
`purposes and conclusions of
`
`If they are included in the original submission please provide instructions to locate them. Specifically I need
`the reports for the following studies: C2106, C2104, C2108, C2118, C2222, C2235.
`
`Please provide an estimated tum around time for this IR.
`
`Please note that I wil be off site for a mandatory 2 meeting (Mon and Tues) as wil most team leaders and
`you call me on BB, I wil most likely "ignore" until I can get
`
`upervisors in OND. I wil be monitoring BB. If
`
`.0 a place where I can call you back.
`
`Thank you.
`
`Alice
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Division of Drug Oncology Products
`Offce of Oncology Drug Products
`OND/CDER/FDA
`301-796-1381
`(f)301-796-9845
`alice.kacuba~fda. hhs.gov
`
`1
`
`

`

`....._-_...__..---------_...._..-----_......-----_..---_..-_._._.._-_.-_._.---_.__..._.........._...-.__.---._----_.-
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`----..._-------_.._-------------_.._--_._-----_..._-_..__...........__....-.....................-......-_._---------
`/s/
`Alice Kacuba
`12/7/2008 06: 02: 1S PM
`
`

`

`¡ E'"
`~..~,~"~
`
`""'':''lf',,''',"'~1.'~:'
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`Food and Drug Administration
`Rockvile, MD 20857
`
`DISCIPLIN REVIW LETTER
`
`NDA22-334
`
`Novaris Pharmaceutical Corporation
`Attention: Sibylle R. Jennings, Ph.D.
`One Health Plaza
`East Hanover, New Jersey 07936-1080
`
`Dear Dr. Jenning:
`
`Please refer to your New Drug Application (NA) submitted under section 505(b) of
`
`Food, Drug, and Cosmetic Act for Afinitor (everolimus) Tablets.
`
`the Federal
`
`Our review ofthe proposed tradename in your submission is complete, and we have the
`following comments:
`
`1. We do not object to the proposed tradename of Afinitor
`
`2. This proposed tradename wil need to re-reviewed within 90 days of approvaL.
`
`We are providing these comments to you before we complete our review ofthe entire application
`to give you preliminary notice of issues that we have identified. In conformance with the
`prescription drug user fee reauthorization agreements, these comments do not reflect a final
`decision on the information reviewed and should not be construed to do so. These comments are
`preliminary and subject to change as we finalize our review of your application. In addition, we
`may identify other information that must be provided before we can approve this application. If
`your response,
`and in conformance with the user fee reauthorization agreements, we may not be able to consider
`your response before we take an action on your application during this review cycle.
`
`you respond to these issues during this review cycle, depending on the timing of
`
`If you have any questions, call me at (301) 796-1381.
`
`Sincerely,
`
`¡See appf-:Jlded eteCí/'O/!Ù:: signa/urt! .lJag,el
`
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Division of Drug Oncology Products
`Offce of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`

`

`.............---.-...-_....---------_...---_._---_.....---......_....---_...----------_...---_..---_._.---.............
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`----_.._._.....-._._--_......_._....._.._--_...........--_._----_........"'.---_._----_.........---_........---_.....
`/s/
`Al ice Kacuba
`12/7/2008 05: 51: 50 PM
`This letter corrects a typo in the 12-4-08 letter.
`"..do object..,n to lido not object..." The 12-4-08
`letter was emailed tot he sponsor.
`
`

`

`'l~4'''''RVIC''.''-r( E,f- DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`Food and Drug Administration
`Rockvile, MD 20857
`
`DISCIPLINE REVIW LETTER
`
`NDA22-334
`
`Novartis Pharmaceutical Corporation
`Attention: Sibylle R. Jennings, Ph.D.
`One Health Plaza
`East Hanover, New Jersey 07936-1080
`
`Dear Dr. Jenning:
`
`Please refer to your New Drug Application (NA) submitted under section 505(b) of
`
`. Food, Drug, and Cosmetic Act for Afinitor (everolimus) Tablets.
`
`the Federal
`
`Our review of the proposed Patient Package Insert in your submission is complete, and we have
`the following comments:
`
`1. Please revise the Patient Package Insert as attched.
`
`We are providing these comments to you before we complete our review of the entire application
`to give you preliminaiy notice of issues that we have identified. In conformance with the
`prescription drug user fee reauthorization agreements, these comments do not reflect a final
`decision on the information reviewed and should not be constred to do so. These comments are
`preliminary and subject to change as we finalize our review of your application. In addition, we
`may identify other information that must be provided before we can approve this application. If
`you respond to these issues during this review cycle, depending on the timing of your response,
`and in conformance with the user fee reauthorization agreements, we may not be able to consider
`your response before we take an action on your application during this review cycle.
`
`If you have any questions, call me at (301) 796-1381.
`
`Sincerely,
`
`(See appended electronic signature page)
`
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Drug Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`Division of
`
`

`

`/4 Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`~ Draft Labeling (b4)
`
`Draft Labeling (b5) .
`
`Deliberative Process (b5)
`
`Withheld Track Number: Administrative- 10
`
`

`

`--------------------_.-------------------------------------------_._--_._----_._-----_..__._-------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature. .
`..--....._.__._-------------------.-._----------_...-...__.._._--------_._---------_..._---_._-----------------------
`/s/
`Alice Kacuba
`12/4/2008 07: 20: 04 PM
`
`

`

`iJSlIlVt('es
`
`( ~ DEPARTMENT OF HEALTH & HUMAN SERVICES
`~~5~~
`
`Public Health ServiCe
`Food and Drug Administration
`Rockvile, MD 20857
`
`DISCIPLINE REVIEW LETTER
`
`NDA22-334
`
`Novartis Pharmaceutical Corporation
`Attention: Sibylle R. Jennings, Ph.D.
`One Health Plaza .
`East Hanover, New Jersey 07936-1080
`
`Dear Dr. Jenning:
`
`Please refer to your New Drug Application (NA) submitted under section 505(b) of
`
`Food, Drug, and Cosmetic Act for Afinitor (everolimus) Tablets.
`
`the Federal
`
`Our review of the proposed tradename in your submission is complete, and we have the
`following comments:
`
`1. We do object to the proposed tradename of .Äfinitor
`
`2. This proposed tradename wiI1 need to re:'reviewed within 90 days of approvaL.
`
`prescription
`
`We are providing these comments to you before we complete our -review of the entire application
`to give you preliminary notice of issues that we have identified. In conformance with the
`drug user fee reauthorization agreements, these comments do not reflect a final
`decision on the information reviewed and should not be construed to do so. These comments are
`preliminary and subject to change as we finalize our review of your application. In addition, we
`may identify other information that must be provided before we can approve this application. If
`you respond to these issues during this review cycle, depending on the timing of your response,
`and in conformance with the user fee reauthorization agreements, we may not be able to consider
`your response before we take an action on your application during this review cycle.
`
`If you have any questions, call me at (301) 796-1381.
`
`Sincerely,
`
`(See appended electronic signature page)
`
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`of Drug Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`Division
`
`

`

`_....__......_..__...__............---_..--_..._--_.._---_.._-_...-.....__.__....-.....--_..._----_._._-_.._-----_..-
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---_._._.._--_.--------------_._..__._------_._---_..--------......---_.._---_._------_.__._.__.__...-.__...------_..-
`/5/
`Alice Kacuba
`12/4/2008 07: 18: 47 PM
`
`

`

`Kacuba, Alice
`
`From: Kacuba, Alice.
`Sent: Friday, November 28, 2008 10:48 AM
`
`To: 'sibylle.jennings~novartis.com"
`Cc: Bullock, Julie; Mehrotra, Nitin
`Subject: RE: NDA 220334 Follow-up on TC this morning
`
`Importance: High
`
`Sibylle,
`
`Please be sure that all emails
`
`are
`
`eventually
`
`sent
`
`in
`
`by
`
`Gateway.
`
`Withan.allelectronic
`
`Page 1 of2
`
`NDA, I
`
`can not archive incoming emails from sponsors so it is your responsibilty to
`
`be sure all
`information sent in emails to FDA are sent in my Gateway to make a complete application.
`
`Thank you.
`
`Alice
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Division of Drug Oncology Products
`Offce of Oncology Drug Products
`OND/CDER/FDA
`301-796-1381
`(f)301-796-9845
`alice.kacuba~fda.h hs.gov
`
`From: sibyl
`
`Ie. jenningstQnovartis.com (mailto :sibylle.jenningstQnovarts.com)
`Sent: Wednesday, November 26, 2008 6:37 PM
`To: Bullock, Julie; Mehrotra, Nitin
`Cc: Kacuba, Alice
`Subject: NDA 220334 Follow-up on TC this morning
`
`Dear Julie, dear Nitin,
`
`Thank you very much for the helpful and constructive TC this morning.
`Please find attached Table 6.2 from our response document submitted last week showing all changes and
`additions which we discussed this morning in track change mode. I wil be in touch with you next week to update
`in the attachment.
`
`you on the actual submission date of the documentation described
`Please let me know if you have any questions.
`Thanks again and best regards,
`Sibylle
`
`Sibylle Jennings
`
`1112812008
`
`

`

`Page 2 of2
`
`Novartis Pharmaceuticals Corporation
`PH; Dev - Oncology ORA II
`USEH, Building 104 Room 3K25
`Novartis Pharmaceuticals Corporation
`One Health Plaza
`East Hanover, NJ 07936-1080
`USA
`Phone: +18627781196
`Email: sibylle.jenningsß!novartis.com
`
`11128/2008
`
`

`

`------~---_..._--_..-..__._--_....-...-_..._..._.._.--...------_..._..-._._.-_..__.__....-----------------------_._--
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`_...._--_..-----_._--_..----_..----------_.._-------_.-_._..__.._.._---_..._-_._----.-----------------------_._------
`/s/
`Alice Kacuba
`11/28/2008 10: 51: 19 AM
`
`

`

`Kacuba, Alice
`
`Cram:
`ent:
`''a:
`Subject:
`
`Importnce:
`
`Follow Up Flag:
`Due By:
`Flag Status:
`
`Hi,
`
`Kacuba, Alice
`Tuesday, November 04, 20084:21 PM
`'sibylle.jennings~novartis.com'
`FW: Everolimus data to sponsor please.
`
`High
`
`Follow up
`Monday, November 03, 2008 12:30 AM
`Flagged
`
`There are discrepancies with your concentration data set compared to the patient listings for the clinical pharmacology
`study report for c2101/02. Below are few examples of errors I found. Please resubmit a corrected data set. In addition,
`verify that other clinical pharmacology oncology datasets submitted are free of data errors.
`
`study re
`listings
`
`SCHTIME CONC treatment ann Cone
`6 38.28 RAD001 70 mg/week
`8 58.57 RAD001 70 mg/week
`2 -199 RAD001 30 mg/week
`1 -199 RAD001 30 mg/week
`24 56.32 RAD001 10 mg/day
`24 43.29 RAD001 5 mg/day
`
`Dataset c21 02cnc.xpt information
`
`Study Center # Sub #
`2101 1001 10029 C2101_xx-10029, WK-4 6.0 hr
`0029, WK-4'8.0 hr
`01_xx-1
`2101 1001 10029 C21
`2101 1001 10009 C2101_1001-10009-1 WK4, D1, 2h
`0007 -1 WK4, D1 ,1
`001-1
`, WK-4 24 hr
`002-1 0016 . WK-4 24 hr
`
`2101 1001 10007 C2101_1
`
`2101 1002 10024C2101_1002-10024
`
`2101 1002 10016 C21
`
`01_1
`
`Please provide an estimated turn around time on this request.
`
`Thank you.
`
`Alice
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Division of Drug Oncology Products
`Offce of Oncology Drug Products
`OND/CDER/FDA
`301-796-1381
`(f)301-796-9845
`alice. kacuba(§fda. h hs.gov
`
`1
`
`

`

`.........__.......__..._______._.___..._______________----------_._-----_.----_...-----------------------_.-____a_MM.
`This isa representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---_.._-------_....--_.__..-_._------------_._-----_.--------._------_..----_._-------------_..._---------------_...
`lsi
`~-- --- --- ------ ------
`Alice Kacuba
`ii/~/2008 04: 23: 28 PM
`
`

`

`.."stIlYI('t.r. .
`
`~'~ ~(~ DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Serviæ
`
`Food and Drug Administration
`Rockvile, MD 20857
`
`NDA22-334
`
`Novartis Pharaceutical Corporation
`Attention: Sibylle Jennings, Ph.D.
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Dear Dr. Jennings:
`
`Please refer to your June 27, 2008 new drug application (NA) submitted under section 505(b)
`of the Federal Food, Drug, and Cosmetic Act for Affinitor334 (everolimus) Tablets, 5mg and
`10 mg.
`
`On October 14,2008, we received your October 14, 2008 major amendment to this application.
`The receipt date is within 3 months of the user fee goal date. . Therefore, we are extending the
`goal date by three months to provide time for a full review of the submission. The extended user
`fee goal date is March 30, 2009.
`
`If you have any questions, call me at 301-796-1381.
`
`Sincerely,
`
`(See appended electronic signature page)
`
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Drug Oncology :Products
`Offce of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`Division of
`
`

`

`-----------------------------------------------------------~.~--~-------~------~------_._.._--~--------.----_._------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`-----_..-_._--------_._-----_._-_......---_..---------.__....._-_..._-_.~-----------------_..__..------------_._---_.
`/s/
`Alice Kacuba
`10/3 0/2008 06: 55 : 43 PM
`
`

`

`.."'~~z. ~
`
`C"SiiiVlC~
`
`g -Ø~"1~"';::::if DEPARTMENT OF HEAL TH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockvile, MD 20857
`
`NDA22-334
`
`INFORMTION REQUEST LETTER
`
`Novartis Pharmaceuticals Corporation
`Attention: Sibylle R. Jennings, Ph.D.
`Associate Director, Drug Regulatory Affairs
`One Health Plaza
`East Hanover, New Jersey 07936-1080
`
`Dear Dr. Jennings:
`
`Please refer to your new drg application (NA) received on June 30, 2008, under section
`the Federal Food, Drug, and Cosmetic Act for AfinitortI (everolimus) Tablets.
`
`505(b) of
`
`We also refer to your submission dated September 5, 2008.
`
`We are reviewing
`
`the Chemistr, Manufacturing and Controls section of
`
`your submission and
`have the following comments and information requests. We request a prompt written response
`your NDA.
`
`in order to continue our evaluation of
`
`r
`
`-.~---.1 -- - .., ....
`
`b\A)
`
`-l
`
`

`

`NDA22-334
`
`i
`
`\\\6,'
`
`-l
`
`7. Provide statistical evaluation of
`
`the updated stabilty data submitted in your September 5,
`2008 submission. Provide analyses for all attributes (e.g., assay, water, impurities,
`dissolution, etc.) that have noticeable change over time.
`
`8. Be advised that any post approval change in the drug substance CMC that has been
`referenced to other NDA(s) and DMF(s) must be implemented in accordance witl 21 CFR
`314.70.
`
`If you have any questions, call Deborah Mesmer, Regulatory Health Project Manager, at 301-
`796-4023.
`
`

`

`NDA22-334
`
`Sincerely,
`
`(See appended electronic signature page)
`
`Sarah C. Pope, Ph.D.
`Branch Chief (Acting)
`Pre-Marketing Assessment II
`Office of New Drug Quality Assessment
`Center for Drug Evaluation and Research
`
`Division of
`
`

`

`._._--_._--_.............................------_............_-_......_-_...............................--........._--
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`............................._................_-_...........-------------.-.---_._......._........................--.
`/s/
`Sarah Pope
`10/17/2008 04: 40: 33 PM
`
`

`

`Page 1 of3
`
`PostX: $subject
`
`Kacuba; Alice
`
`From: Kacuba, Alice
`Sent: Thursday, October 09, 2008 3:58 PM
`
`To: 'sibylle.jennings~novartis.com'
`
`Subject: Clin Pharm Information Requests (IR) X2
`
`Importance: High
`
`Sibylle,
`
`Below are 2 Information Requests form Clin Pharm:
`
`1. Please re-submit the combined data sets (individual data listings and PK parameters) for
`your C2101-02 PK data analysis. The data set submitted in the original submission folder
`rad001c2101-02 does not contain all the data. Specifically I believe it is missing the necessary.
`data from study C2101 and this data was not found in the datasets for study C2101 (only the
`RAD001 + gemcitabine data was in the rad001c2101 folder). .
`
`concentration data for study C2119. In addition, please ensure that all
`
`2. Please resubmit the data set and provide the nominal sampling times (0, 1, 1.5 etc) for your
`of the other PK studies
`include the nominal time as a column for the concentration data sets and resubmit if
`necessary.
`
`3. Please provide an estimated turn around time as the e1in pharm reviewer has identified
`these IRs as Urgent.
`
`Thnak you.
`
`Alice
`
`Alice Kacuba, RN, MSN, RAC
`Chief, Project Management Staff
`Division of Drug Oncology Products
`Offce of Oncology Drug Products
`OND/CDER/FDA
`301-796-1381
`(f)301-796-9845
`alice.kacubatIfda. hhs.gov
`
`From: sibyl
`
`Ie. jennings(§novarts.com (mailto:sibylle.jenni ngs(§novartis.com)
`sent: Thursday, October 09, 20082:36 PM
`To: Kacuba, Alice
`Subject: Fw: Request for data for Everolimus.... follow-up on upcoming dataset submissions
`
`Dear Alice,
`
`This is to briefly update you on the upcoming dataset submissions in response to the
`
`10/9/2008
`
`

`

`PostX: $subject
`
`Page 2 of3
`
`information requests dated Oct 2 and Oct 8, 2008.
`We experienced major problems with our IT systems today, which will unfortunately cause a
`one day delay for the planned submission of the datasets for study C2107 (biomarkers) and
`C2239 (full efficacy and safety datasets), so submission date will be Monday, Oct 13.
`The submission of the adverse event datasets for study C2107 requested yesterday is targeted
`for next Wednesday, Oct 15.
`listings that are under preparation following the TC with Dr Ryan on
`The by patient
`September 24 are targeted to be submitted early next week as well.
`Please let me know if you have any questions.
`Best regards,
`Sibylle
`
`Sibylle Jennings, PhD
`Novartis Pharmaceuticals Corporation
`Sr. Assoc. Director, Drug Regulatory Affairs - Oncology
`USEH, Building 104 / Room 2E27
`Novartis Pharmaceuticals Corporation
`One Health Plaza
`East Hanover, NJ 07936-1080
`USA
`Phone: +1 8627781196
`Fax: +1 9737815217
`Cell: +1 8625964679
`Email: sibylle.jennings~novartis.com
`
`Forwarded by Sibylle Jennings/PH/Novartis on 10/09/2008 02 :27 PM
`
`Sibylle Jennings/PH/Novartis
`10/08/2008 03 :12 PM
`
`To
`alice . kacuba~fda. hhs . gov
`cc
`
`Subject
`Re: FW: Request for data for Everolimus... .
`
`Hi Alice,
`At the moment everything is prepared to submit the previously requested datasets this Friday
`(Oct 10). We.probably need slightly more time for adding the AE datasets. for study 2107. I
`will follow-up with you tomorrow on when you can expect our response (s) to the last
`submission requests.
`
`Kind regards,
`Sibylle
`
`Sibylle Jennings, PhD
`Novartis Pharmaceuticals Corporation
`Sr. Assoc. Director, Drug Regulatory Affairs - Oncology
`USEg, Building 104 / Room 2E27
`Novartis Pharmaceuticals Corporation
`
`10/9/2008
`
`

`

`PostX: $subject
`
`Page 3 of3
`
`One Health Plaza
`East Hanover, NJ 07936-1080
`USA
`Phone: +1 8627781196
`Fax: +1 9737815217
`Cell: +1 8625964679
`Email: sibylle.jennings~novartis.com
`
`II Kacuba, Alice" ",alice.kacuba~fda.hhs.gov"
`10/08/2008 02:46 PM
`
`Please respond to
`alice. kacuba~fda. hhs. gov
`
`To
`sibyl
`
`cc
`
`Ie. j ennings~novartis. com
`
`Subject
`FW: Request for data for Everolimus.. . .
`
`Hi,
`Regarding last Information Request:
`Please submit adverse event data also for C2107 study.
`
`Study C2107:
`10 mg/day was identified as the optimum dose by PK-PD modeling. However, the submission only
`contains the PK data. Kindly provide the other relevant data including biomarkers and
`adverse events.
`
`Thank you.
`Alice
`Alice Kacuba, RN, MSN, RAC
`Chief, Proj ect Management Staff
`Di vision of Drug Oncology Products
`Office of Oncology Drug Products
`OND/CDER/FDA .
`301-796-1381
`(f) 301-796-9845
`alice. kacuba~fda. hhs. gov
`
`10/9/2008
`
`

`

`------_._--------------------------------_..-..._....-.__..-_......._-------------------_._.------_._-----....---_..---
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---..__...-_._...-......_..._---_............__...__._._-_.-_.._.-_._-----_.__.-._---_.._------------------------_....__.
`/s/
`Alice Kacuba
`10/9/2008 04: 01: 06 PM
`
`

`

`Kacuba, Alice
`
`~rom:
`.ent:
`fa:
`Subject:
`
`Kacuba, Alice
`Wednesday, October 08,20082:46 PM
`sibylle.jennings~novartis.com
`FW: Request for data for Everolimus....
`
`Importance:
`
`High
`
`Hi,
`
`Regarding last Information Request:
`
`Please submit adverse event data also for C21 07 study.
`
`Study C2107:
`
`10 mg/day was identified as the optimum dose by PK-PD modeling. However, the submission only
`contains the PK data. Kindly provide the other relevant data including biomarkers and adverse
`events.
`
`Thank you.
`
`Alice
`\Iice Kacuba, RN, MSN, RAC
`';hief; Project Management Staff
`Division of Drug OncologyProducts
`Offce of Oncology Drug Products
`OND/CDER/FDA
`301-796-1381
`(f)301-796-9845
`alice.kacuba~fda.hhs.gov
`
`Tracking:
`
`Recipient
`sibylle.jennings(§novarls.com
`Mehrotra. Nitin
`
`Read
`
`Read: 10/8/20082:48 PM
`
`

`

`----_.---_..-_..--------_._---_......_-_............-~....------_.__..__......._...-------------_._--_..----..-------
`This is a representation of an electronic record that was signed electronically and .
`this page is the manifestation of the electronic signature.
`------.---------_.-_..__..._-...-_......--..........._.....-_.....__..__._---......__.-.....__.-_............-_._-_..
`/s/
`Alice Kacuba
`10/8/2008 02: 51: 55 PM
`Sent by email 10-8-08.
`
`

`

`MEMORANDUM OF TELECON
`
`DATE: Sepember 24, 200~
`
`APPLICA nON NUMBER: NDA ~
`
`BETWEEN:
`Andrea Kay (clinical)
`Peter Berry (medical writing)
`Tomas Haas (statistics)
`Lila di Scala (Statistics)
`Sibylle Jennings (DRA US).
`Representing: Novartis PharmacentIcal Corporation
`
`AND
`
`Division of Drug Oncology Products, HF-150
`Name: Qin Ryan, M.D., Medical reviewer
`Somesh Cahattopadhyay, Ph.D., Statistical Reviewer
`
`SUBJECT: Discussion of
`
`data sets
`
`that FDA requested.
`
`HISTORY: The Division had sent Information Requests to the Sponsor. The Sponsor requested a
`tcon to clarify the requests prior to submitting the datasets.
`
`TODA Y'S PHONE CALL: IR Discussion with the applicant
`
`FDA Requests:
`
`1. Please identify which dataset contains reasons for PFS events and reason, censor date, censor
`information.
`
`Discussion: The applicant wil submit these datasets from the Feb 28, 2008 cut-off date
`with the safety update submission.
`
`2. Please provide an exploratory analysis on the difference of PFS between the central review
`and investigator assessment.
`
`Discussion: Applicant wil submit all
`
`listings and tables from the Feb 28 2008 cut off date.
`FDA recommends the applicant provide a listing with all PFS disagreements between the
`IRC and investigator assessments. As requested by the applicant, the FDA would suggest
`
`

`

`the following headings for the PFS disagreements:
`
`Subject
`ID
`
`Randomized
`treatment
`
`Example.
`
`1
`
`PFS
`Status
`byIRC
`(event or
`censor
`Censor
`
`PFS
`Status
`by
`IN
`
`Date
`Date of
`PFSby
`ofPFS
`byIRC IN
`
`Difference
`(days)
`
`Reason of
`IRC
`assessment
`
`Reason of
`INV
`assessment
`
`Comments
`
`PD
`
`5/1/10
`
`710/10
`
`80
`
`CTwith 6
`lesions
`
`3
`
`CT with
`lesion
`
`Inadequate
`assessment
`bvIN
`
`3. Please provide an8;lysis of
`
`missing tumor assessments for both central and local assessments.
`
`Discussion: The applicant wo