`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-660
`
`CORRESPONDENCE
`
`

`

`Fax
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, RFD-150
`Parklawn Building
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`To:
`
`Mitchell Clark—American BioScience. Inc.
`
`From: Sheiia Ryan, PharmD.
`
`Fax:
`
`310-998-8553
`
`Fax:
`
`(301) 827—4590
`
`
`Phone: 310-883-3141
`Phone: (301) 594-5779
`
`Pages (including cover): 1
`
`Date:
`
`January 4, 2005
`
`Re:
`
`NBA 21-660 Abraxane: Request for commitment to Phase 4 commitments
`
`lUrgent
`
`Ci For Review
`
`E] Please Comment
`
`lPlease Reply
`
`[:1 Please Recycle
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND
`MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM
`DISCLOSURE UNDER APPLICABLE LAW. If you are not the addressee, or a person authorized to deliver the
`document to the addressee, you are hereby notified that any review, disclosure, dissemination or other action based on the
`content of the communication is not authorized. If you have received this document in error, please immediately notify us
`by telephone and retum it to us at the above address by mail. Thank you.
`
`Mitch,
`
`The Division requests American BioScience, Inc. to commit to the following Phase 4 commitment
`requests. Please provide an estimated timeline for completion of commitment #1 and review the
`suggested protocol submission, study start, and final report submission dates for commitment #2.
`
`1- Survival data and analysis results should be submitted from randomized study
`CA012-0 when 80% of the patients have died.
`
`2. You should evaluate Abraxane safety and pharmacokinetics in subjects with hepatic
`impairment, to allow the determination of dosing adjustment for this population.
`
`Protocol Submission: April 2005
`Study Start: November/December 2005
`Final Report Submission: December 2006
`
`Please provide your commitment in writing via facsimile as soon as possible.
`
`Please call should you have any questions.
`
`

`

`American BioSeic?iicc., Inc.
`
`January 4, 2005
`
`Attention: Dr. Sheila Ryan
`Central Document Room
`
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5901 Ammendalc Road, Unit B
`Beltsville, MD 20705
`Tel: (301) 210 2885
`Fax: (301) 594 0498
`
`Via facsimile and
`
`Federal Express
`
`New Drug Application
`
`NDA# 21-660
`
`AbraxaneTM for Injectable Suspension
`
`(paclitaxel protein-bound particles for injectable suspension) (albumin-bound)
`
`Amendment to a Pending Application:
`
`Respgnse to FDA Request for Information
`
`Dear Dr. Ryan,
`
`Reference is made to our pending New Drug Application for Abraxanem, (NDA 21-660).
`Reference is also made to a facsimile from Dr. Ryan dated January 4, 2005 requesting American
`BioScience to commit to two Phase 4 commitment requests. The Agency requested an estimated
`timeline for completion of commitment #1 and to review and wmmit to the protocol submission,
`study start, and final report submission dates for comnfitment #2. The Agency’s Phase 4
`commitment requests are detailed below in bold text and American BioScience’s response
`follows.
`
`1. Survival data and analysis results should be submitted from randomized study
`CA012-0 when 80% of the patients have died.
`
`American BioScience commits to provide survival data and analysis results from
`randomized study CA012—0 when 80% of the patients have died. We estimate that these
`data will be available for submission on or before June 1, 2005.
`
`2730 Wilshire Boulevard, Suite Ill], Santa Monica, California 90403 Tel. (310) 883-1300 Fax: (310) 998-8553
`
`
`
`

`

`JfiN-m-EBBS
`
`15:39
`
`RMERICQN BlDSCIENCE. iNC.
`
`312] 998 8555
`
`FREE/Mb
`
`2. You should evaluate Abraxane safety and pharmacokinetics in subjects with hepatic
`impairment, to allow the determination of dosing adjustment for this population.
`
`Protocol Submission: April 2005
`Study Start: November/December 2005
`Final Report Submission: December 2006
`
`We hereby commit to evaluate the safety and phannacokinetics of ABRAXANE in
`subjects with hepatic impairment, to allow the determination of dose adjustment for this
`population. We commit to conduct the study in accordance with the timeframes
`described above.
`
`The archival copy of the submission is provided on a compact disc (CD) with a file size of
`approximately 334.0 kb along with a paper copy bearing original signatures. The CD has the
`following specifications:
`
`1. CD media: Office Depot single side CDFR; 700MB.
`
`2. CD drive used to create the CD: Dell PC Burner Single Drive 48X CD-RW ROM
`
`Combo Drive
`
`3. Backup software used to create the CD: EZ CD Creator V5.0
`
`This submission is certified as virus free based on a scan of the electronic media using Symantec
`Norton Anti-Virus Corporate Edition-Version 9.0.0.338.
`
`The following is a list of the information provided in this submission:
`
`0 Cover letter
`
`a
`
`Form FDA 356k
`
`Please do not hesitate to contact me on 310 883 3141 if you have any questions concerning this
`submission.
`
`Yours sincerely,
`
`Mitchell G. Clark, B. Phaim, MRPharmS.
`Vice President, Regulatory Affairs
`American BioScience, inc.
`
`2730 Wilshire Boulevard, Suite 110. Santa Monica, California 90403 Tel. (310) 883-1300 Fax: (310) 998-8553
`
`

`

`_ J
`
`RN-B4—2EIZS
`
`15:48
`
`RMERICFIN BIUSCIENCE. INC.
`
`.5121 ':l‘:ll:£ beci
`
`H.U_S/ldb
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FunnAppruved.‘ OMB No. 0910-0338
`
`
`FOOD AND DRUG ADMINISTRATION
`Expratrbn Date: August 31. 2005
`
`
`SEE OMB Statement on page 2
`
`
`
`APPLICATION TO MARKET A NEW DRUG, BIOLOGIC,
`APPUCATION NUMBER
`0R AN ANTIBIOTIC DRUG FOR HUMAN USE
`
`(Title 21, Code of Federal Regulafions, Parts 314 & 601)
`
` APPLICANT INFORMATION
`
`
`NAME OF APPLICANT
`
`DATE OF SUBMISSION
`
`TELEPHONE NO. memes Area Code)
`
`FACSIMILE {FAX} Number (Include Area Code)
`
`
`APPLICANT ADDRESS (Number, Street, CII): State. Country. ZIP Code or Mail
`COW- EW U-S- License "umber WNW issued):
`2730 Wilshire Boulevard, Suite 1 10
`Santa Monica, CA 90403
`
`AUTHORIZED U.S. AGENT NAME & ADDRESS (Number: Street. city. State.
`ZIP Code, telephone It FAX number) IF APPLICABLE
`Not Applicable
`
`
`
`PRODUCT DESCRIPTION
`
`. To nosed
`
`-——
`
`CHEMICAL/BIOCHEMICAUBLOOD PRODUCT NAME (If any)
`
`NEw DRUG OR ANTIBIOTIC APPLICATION NUMBER. OR BIOLOGICS LICENSE APPLICATION NUMBER (rprevrausiy issued) 2| -660
`PROPRIETARY NAME (trade name) IF ANY
`ESTABLISHED NAME (9.9.. Pmper name, USP/USAN name)
`
`
`
`Abraxancm (paclitaxe! albumin nanoparticle for injectable
`
`
`
`CODE NAME (Harry)
`
`
`ARI-007
`
`5B,—20—epcxy«l,2a,4,7B,I33,—hcxahydroxytax-l I-en-9-one 4,] 0-diacetate 2-benzoate l3-
`
`ester with (2R,SS)-n-benzc 1-3- hen Iisosetine
`
`ROUTE OF ADMINISTRATION.
`DOSAGE PORM-
`STRENGTHS:
`
`
`
`100 mg/Vial
`
`
`
`
`
`Lyophilized Cake For Injectable Suspension
`IOROPOSED) INDICATIONIS) FOR USE:
`......
`
`Intravenous Infusion
`
`HLICATION DESCRIPTION
`APPLICATION TYPE
`(check one)
`
`
`
`El ABBREVIATED New ORUC APPLICATION (ANOA. 21 CFR 314.94;
`lg NEW DRUG APPLICATION (CDA. 21 CPR 314.50)
`[I BIOLOGICS LICENSE APPLICATION (BLA, 21 CFR Part 501)
`
`B 505 (b)(2)
`D505 (mm
`IF AN NOA. IDENTIFY THE APPROPRIATE TYPE
`IF AN ANOA. 0R 505mm}. IDENTIFY THE REFERENCE LISTED DRUG PRODUCT THAT IS THE BASIS FOR THE SUBMISSION
`
`Bristol Mxers Sguibb Comganx
`HcIderoIApproved Applicallon
`Taxo! ggaclitaxel} Injection
`Name of Drug
`3 AMENDMENT TO APENDING APPLICATION
`CI RESUEMISSION
`TYPE OF SUBMISSION (check one)
`D ORIGINAL APPLICATION
`U ESTABLISHMENT DESCRIPTION SUPPLEMENT
`D EFFICACY SUPPLEMENT
`CI PRESUBMISSION
`D ANNUAL REPORT
`U LABELING SUPPLEMENT
`CI CHEMISTRY MANUFACTURING AND CONTROLS SUPPLEMENT
`
`CI OTHER
`
`IF A SUBMISSION OF PARTIAL APPLICATION. PROVIDE LETTER DATE OF AGREEMENT TO PARTIAL SUBMISSION
`
`IF A SUPPLEMENT, IDENTIFY THE APPROPRIATE CATEGORY
`REASON FOR SUBMISSION
`
`Amendment to an NBA. Submission in Res-onse to FDA Rea uest for Information-Phase 4 commitment.
`
`U CBEJD
`
`El Prior Approval (PA)
`
`PROPOSED MARKETING STATUS {check one)
`
`B PRESCRIPTION PRODUCT (Rx)
`
`El OVER THE COUNTER PRODUCT (OTC)
`
`NUMBER OF VOLUMES SUBMITTED
`
`1
`
`THIS APPLICATION IS U PAPER
`
`E PAPER AND ELECTRONIC
`
`I] ELECTRONIC
`
`ESTABLISHMENT INFORMATION (Full estahtlshment information should be provided In the body of the Application.)
`Provide locations OI all manufacturing. packaging and central sites fur drug Substance and drug product (ccnIinuaIlon sheets may be used if necessary). Include name,
`address, contact. telephone number, registration number (CFN). DMF number, and manufacturing stage analortype OI Iesilnq (e.g. Final dosage form. StablIlIy Iesilng)
`conducted at the site. Please indicate whether the site is ready Ior inspection or. if not. when it will be ready.
`Drum Substance Manufacturer (Paclimxeh:
`——-"
`
`I
`
`Aibumin Human. USP manufacture and testing :
`I
`.__,
`--"
`Drug Product Manufacture and testing :
`—“
`.
`Icrican Pharmaceuticai Partners, Inc. 2020 Rubv Street. Meirose Park. Illinois. 60l60 and 2045 N. COrncII Avenue, Melrose Park,
`.0160. Contact Tina Perkins 708 486 2078;
`“—-"
`I.
`~—-"’
`Sites are read for ins ection.
`
`I Cross References (list related License Applications, INDE, NDAC, PMAS, 510005, IDEC, BMFS. and UHF: referenced In the current application)
`
`FORM FDA 356R {4103)
`
`PAGE 17°F 5
`
`

`

`
`JFlNHIZlél-ZBIS
`15:48
`FIMERICFIN BIDSCIENCE. INC.
`51H BBB 85:35
`Edda/KID
`
`1ND 55.974;
`
`lndena DMF #12876; Institute Grifols. PLAIELA #1l81 for Albumin Human USP; Stelmi BM? #5 4258 and I2343
`
`for vial stoppers; Kimble Glass DMF#14106, for glass vials; The Glass Group, DMF 9645 for glass vials.
`
`This application contains the following items: (Check all that apply)
`
`
` 2. Labeling (check one)
`El Draft Labeling
`[:1 Final Printed Labeling
`3. Summary (21 CFR 314.50 ((1))
`
`
`
`A
`
`Chemistry. manufacturing. and controls information (6.9.. 21 CFR 314.50(d)(1); 21 CFR 601.2)
`
`
`
`
`
`8
`Samples (21 CFR 314.50 (8K1): 21 CFR 501.2 (3)) (Submit only upon FDA's request)
`
`c. Methods validation package (e.g.. 21 CFR 314.50te)(2)(l): 21 CFR 601.2)
`.5.
`E- 5. Nonclinical pharmacology and toxicology section (13.9.. 21 CPR 314.50(d)(2); 21 cm 601.2)
`
`
`
`6. Human phannacoklnetlcs and bioavailabilily section (e.g.. 21 CFR 314.50(d){3): 21 CFR 601.2)
`
`
`7. Clinical Microbiology (e.g.. 21 CFR 314.50rdll4ll
`E- 5 Clinical data section (9.9.. 21 CFR 314.50(o)(5): 21 CFR 601.2)
`
`
`E 9. Safety update report (e.g., 21 cm 314.50roxslrvixb); 21 CPR 601.2)
`
`10. Statistical 86611011 (6.9.. 21 CFR 314508285); 21 CFR 601.2)
`
`11. Case report tabulations (3.9., 21 CFR 314.50(1)(1); 21 CFR 501.2)
`
`I:- 12. Case report forms (e.g., 21 CFR 314.50 (0(2); 21 CFR 601.2)
`
`E 13. Patent information on any patent which claims the drug (21 U.S.C. 355(b) or (c))
`
`. A patent certification with respect to any patent which claims the drug (21 U.S.C. 355 (b)(2) or (j)(2)(A))
`Iil w
`
`
`
`. Establishment description (21 CFR Part 600. “ll applicable)
`
`
`. Debarment certification (FD&C Act 306 00(1))
`
`. Field copy certification (21 CFR 314.50 (0(3))
`
`
`E . User Fee Cover Sheet (Form FDA 3397)
`
`
`Ii. 19. Financial Information (21 CFR Part 54)
`
`IE. 20 OTHER (Specify) American BioScicnce. inc. submission in response to FDA request received Jan 04, 2005
`CERTIFICATION
`
`
`
`
`
`
`
`
`
`I agree to update this application with new safety information about the product that may reasonably aflecl the statement of contraindications.
`warnings. precautions. or adverse reactions in the draft labeling. I agree to submit safety update reports as provided for by regulation or as
`requested by FDA. If this application is approved. 1 agree to comply with all applicable laws and regulations that apply to approved applications.
`including. but not limited to the following:
`Good manufacturing practice regulations in 21 CFR Pans 210. 211 or applicable regulations, Parts 606. andlor B20.
`Biological establishment standards in 21 CFR Part 600.
`Labeling regulations in 21 CFR Parts 201.606.6112). 660, andlor 809.
`in the case of a prescription drug or biological product. prescription drug advertising regulations in 21 CFR Part 202.
`Regulations on melting changes in application in FDdrC Act section 506A, 21 CFR 314.71. 314.72, 314.97, 314.99. and 601.12.
`Regulations on Reports in 21 CFR 314.30. 314.81. 600.80, and 600.81.
`. Local. state and Federal environmental impact laws.
`"this application applic- to a drug product that FDA has proposed for scheduling under the Controlled Substances Act. I agree not to market the
`product until the Drug Enforcement Administration makes a final scheduling decision.
`The data and information in this submission have been reviewed and. to the best of my knowledge are certified to be true and accurate.
`Warning: A willfully false statement is a criminal ofiense. US. Code. title 18, section 1001.
`
`“@Sfifif-P‘Pr‘
`
`
`
`
`
`
`
`
`
`TYPED NAME AND TITLE
`Mitchall Cr. Clark Vice President, Regulatory Affairs
`
`
`
`Telephone Number
`(
`310
`
`
`) 883 314i
`
`including the lime (or reviewsng
`r‘ublic reporting burden for this collection or information is estimated to average 24 hours per response,
`‘ructions, searching existing data sources. gathering and maintaining the data needed. and completing and reviewing the collection or information.
`
`1d comments regarding this burden estirnate or any other aspect of this collection of information. including suggestions for reducing this burden to:
`
`
`
`R rF RE usuwt OR - 2-.
`
`
`-\
`_.
`-
`‘
`-
`ADDRESS (Sinner. City. State, and ZIP Code}
`
`2730 Wilshire Boulevard, Suite 1 [0. Santa Monica, CA 90403
`
`
`
`DATE;
`1/4/05
`
`FORM FDA 356i! (4103)
`
`PAGE 2 OF 5
`
`
`
`

`

`JRN-EI4—2BBS
`
`1 5 1 48
`
`RNERICRN BIDSCIENCEIINC-
`
`313 998 3553
`
`P.85/85
`
`Department of Hearth and Human Services
`Food and Drug Administration
`An agency may not condud or sponsor, and a person is
`EgcédRuang'rgdg}Adminlsmon
`CDER, HFD—99
`‘ "‘1 ficckifille PIKE
`not required to respond to. a collection at information
`1229m1kina Avenue
`
`
`lille. MD 20852-1448
`Rodwifie, MD 20352
` unless it displays a currently valid OMB cantrol number.
`
`
`
`
`
`
`APPEARS THIS WAY
`0“ ORIGINAL
`
`APPEARS THIS WAY
`0“ ORIGINAL
`
`FORM FDA 358?! {4103]
`
`PAGE 3 OF 5
`
`TDTQL F’ . I215
`
`

`

`
`
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD—ISO
`Parldawn Building
`5600 Fishers Lane, Rockville, MD 20857
`
`
`To:
`MitchaIICIark—flAmencan BioScience, Inc From: Sheila Ryan, PharmD
`
`
`Fax:
`(310) 998-8553
`Fax:
`(301) 59443498
`
`
`Phone: (310)883-3141
`Phone: (301)594—5771
`
`
`
`Pages (including cover): 1 January 7, 2005 Date:
`
`
`
`
`
`Re: NBA 21—660 for Abraxane
`
`l Urgent I For Review
`
`Cl Please Comment
`
`[I Please Reply
`
`Cl Please Recycle
`
`
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND
`MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM
`
`DISCLOSURE UNDER APPLICABLE LAW. If you are not the addressee, or a person authorized to deliver the
`document to the addressee, you are hereby notified that any review, disclosure, dissemination or other action based on the
`content of the communication is not authorized. If you have received this document in error, please immediately notify us
`by telephone and return it to us at the above address by mail. Thank you.
`
`Mitch,
`
`Please refer to your new drug application for Abraxane (NDA 21—660). Please note that the following
`reference should be included in the final printed labeling for this application:
`
`ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations
`for Practice Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.‘
`
`Please contact me should you have any questions.
`
`Sincerely,
`
`Sheila Ryan
`
`Project Manager
`Division ofOncology Drug Products
`
`a;
`Ii (
`
`l- 7“C‘:§
`
`
`
`

`

`
`
`From:
`Sent:
`To:
`Subject:
`Mitch,
`
`Ryan, Sheila
`Wednesday, January 05, 2005 9:33 AM
`'Mitchall Clark'; 'Monica Batra'
`NDA 21 —660 Response to fax dated 12-29-04
`
`Please refer to your facsimile dated December 29, 2004 for ABRAXANE. Regarding
`your proposed changes to the Clinical Pharmacology section of the labeling, we have the
`following response:
`
`Our concern with both proposals described in your recent fax transmission is that they do
`not appear to add to insight on how one might use this drug/formulation in a practical
`setting.
`“‘ ' 9"
`i”
`
`—-
`
`For these reasons our recommendation is to avoid such language.
`
`Please contact me should you have any questions.
`
`Thank you,
`Sheila
`
`Sheila Ryan, Pharml)
`Regulatory Project Manager
`Division ofOnrology Drug Products
`Phone: 301—594—5771
`Fax: 301694-0498
`
`Email: ryans@cder.fda.gov
`
`

`

`
`
`Fax
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, RFD-150
`Parklawn Building
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`To:
`
`Mitchell Clark
`
`Fax:
`
`310-998—8553
`
`Phone: 310-883-3141
`
`From: Amy Baird, 080
`
`Fax:
`
`301-827—4590
`
`Phone: 301-594-5779
`
`Pages {including cover): 1
`
`Date: December 30, 2004
`
`Re:
`
`NBA 21-660 Abraxane.
`
`- Urgent
`
`- -For Review
`
`D Please Comment
`
`'
`
`'Please Reply
`
`C] Please Recycle
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND
`
`MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM
`DISCLOSURE UNDER APPLICABLE LAW. If you are not the addressee, or a person authorized to deliver the
`document to the addressee, you are hereby notified that any review, disclosure, dissemination or other action based on the
`content of the communication is not authorized. If you have received this document in error, please immediately notify us
`by telephone and return it to us at the above address by mail. Thank you.
`
`0 Comments:
`
`Per the request of the clinical review team:
`
`You have provided us with summary data and narratives for patients who died while on study. Please provide
`us with this information for any additional patients who died within 28 days of study drug for each treatment
`arm of Study CAO12-0.
`
`Please call should you have any questions.
`
`Thank you,
`
`Amy Baird
`
`

`

`a-----_--_--_____--—---—-nu...-nun-nu..----_-----—--—----—---------.-------un----—----------—q---------—------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`.q—q-pgqnuununuu------u--__-—--u—------nun-un-----——---nun-II-guuuu-uu-u_—------------—--q----------------------_—-
`
`/S/
`
`Amy Baird
`12/30/04 11:49:38 AM
`CSO
`
`

`

`
`
`toe—B flew
`
`Fax
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-lSlI
`Parklawn Building
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`To: MitchaIIClark—American BioScience, lnc From: Sheila Ryan, PharmD
`
`
`Fax:
`(310) 998-8553
`Fax:
`(301) 594—0498
`
`
`Phone: (310) 883—3141
`Phone: (301) 594-5771
`
`
`
`Pages (including cover): 1 Date: December 16, 2004
`
`
`
`Re: NBA 21660 for Abraxane—infonnation requests
`
`I Urgent I For Review I Please Comment
`
`[:1 Please Reply
`
`D Please Recycle
`
`
`
`THIS DOCUIWENT IS INTENDED ONLY FOR THE USE OF THE PARTY T0 WHOM IT IS ADDRESSED AND
`MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM
`
`DISCLOSURE UNDER APPLICABLE LAW. If you are not the addressee, or a person authorized to deliver the
`document to the addressee, you are hereby notified that any review, disclosure, dissemination or other action based on the
`content ofthe communication is not authorized. If you have received this document in error, please immediately notify us
`by telephone and return it to us at the above address by mail. Thank you.
`
`Please refer to your new drug application for Abraxane (NDA 21-660). Please provide the following
`information as soon as possible to facilitate our review of this application:
`
`1. Please provide your analysis for both treatment arms of the incidence of motor
`neuropathy, grade 1-2 and 3-4.
`2. Please comment on Item 10 in the study protocol which states "After study treatment
`administration, grade 1 and grade 2 laboratory abnormalities will not be recorded as
`adverse events unless considered clinically significant by the investigator. All grade 3
`and 4 laboratory abnormalities will be recorded as adverse events." Does this mean that
`we have significant under-reporting of gr l~2 laboratory abnormalities?
`3. Please clarify/j ustify why the proposed label
`——-
`-
`-
`certain toxicities for which the clinical trial specified decrease to 220 mg/m2, and
`subsequently to ISO mg/m2.
`In the Pl (label) you have provided data for asthenia for patients in all of the trials. What
`was the incidence in the arms of the randomized trials? Please provide your analysis for
`"asthenia" and Alis that constitute asthenia for the 2 treatment arms in the randomized
`
`4.
`
`trial, grade 1-2 and 3—4.
`
`Please contact me should you have any questions.
`
`
`
`

`

`
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`Center for Drug Evaluation and Research, RFD—150
`Parklawn Building
`5600 Fishers Lane, Reckville, MD 20857
`
`
`
`To:
`Mitchell Clam-American BioScience, inc From: Sheila Ryan, PharmD
`
`
`Fax:
`(310) 998-8553
`Fax:
`(301) 594-0498
`
`
`Phone: (310) 883-3141
`Phone: (301) 594—5771
`
`
`
`
`Pages (including cover}: 2 Date: December 13, 2004
`
`
`
`Re: NBA 21-660 for Abraxane—information request
`
`I Urgent I For Review I Please Comment
`
`El Please Reply
`
`[I Please Recycle
`
`
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM [T [S ADDRESSED AND
`MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM
`DISCLOSURE UNDER APPLICABLE LAW. Ifyou are not the addressee, or a person authorized to deliver the
`document to the addressee, you are hereby notified that any review, disclosure, dissemination or other action based on the
`content ofthe communication is not authorized. Ifyou have received this document in error, please immediately notify us
`by telephone and return it to us at the above address by mail. Thank you.
`
`
`Mitch,
`
`Please refer to your new drug application for Abraxane (NDA 21-660). Included in this facsimile are
`information requests regarding this application from the clinical review team. Please provide the
`requested information as soon as possible to facilitate our review of this application.
`
`Please contact me as soon as possible should you have any questions.
`
`S" cerely,
`
`Sheila Ryan
`
`
`
`
`
`
`
`

`

` W N
`
`December 13, 2004
`DA 21-660
`
`RE: information requests . Page 2W
`
`REQUESTS:
`
`1. We request your analysis for the incidence of neutropenic fever by grade and by treatment arm
`for study CAO 1 2-0.
`
`The ADEX dataset indicates the following incidence of grade 3/4 febrile neutropenia when we
`searched for events which contain the NCI—CTC preferred term febrile neutropenia.
`
`
`
`
`
`Incidence of febrile neutro nenia by treatment arm CAOIZ—O)
`ABI—OO? (n=229
`1 1 4.8%)
`
`Grade 3-4
`
`
`
`
`
`
`s (3.6%)
`
`
`We also conducted a search for all grade events which contain (as an NCIpreferred term) the
`term febrile neutropenia with the following results:
`
`
`All grades
`
`ARI-007 n:229)
`55 grow
`
`Taxol 112225)
`42 (18.7%)
`
`We note that CTC version 3 includes definitions only for grade 3 or higher febrile neutropenia.
`Please provide an explanation for these inconsistencies. Did the term “febrile neutropenia”
`capture additional events such as neutropenia in the absence of fever, etc?
`
`2.
`
`In the Adverse Event table (5) in the PI, please clarify what is contained in the definition of
`“infection.” Is this any infection, regardless of ANC? Please provide the incidence of
`“infection” for each treatment arm in study CA012—0 according to “all” vs. “grade 3-4.”
`
`3. For the AE “Fluid Retention,” we found 24 patients in the ABl-OO7 arm with grade lor 2,
`compared with your report of 22 patients. Can you explain this discrepancy?
`
`4. Regarding incidence of AES in the proposed labeling, please clarify if any of the numbers are
`derived from a treatment-emergent approach. If so, what rules were employed if patients had
`worsening ofpre—existing baseline findings?
`
`5. Regarding in—text table 65 (treatment exposure by cycle and dose) from the study report of
`CA012—0, the protocol provides for step dose—reductions either to 220 or 180 mg/m2 for
`toxicity. Please clarify why the first column specifies an ABI—007 dose of 208 mg/m2 (instead
`oflSO)
`
`

`

`
` To:
`
`Re:
`
`NBA 21-660 for Abraxane-estabiished name
`
`M I
`
`Urgent I For Review I Please Comment
`
`El Please Reply
`
`El Please Recycle
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND
`MAY CONTAIN INFORMATION THAT IS PRIVILEGED, CONFIDENTIAL AND PROTECTED FROM
`DISCLOSURE UNDER APPLICABLE LAW. Ifyou are not the addressee, or a person authorized to deliver the
`document to the addressee, you are hereby notified that any review, disclosure, dissemination or other action based on the
`content of the communication is not authorized. Ifyou have received this document in error, please immediately notify us
`by telephone and return it to us at the above address by mail. Thank you.
`
`
`Mitch,
`
`Please refer to your new drug application for Abraxane (NDA 21-660). Attached are comments
`regarding the established name for this application.
`
`Please contact me as soon as possible should you have any questions.
`
`Thank you,
`
`eilaRyan %
`
`Regulatory Project Manager
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`Center for Drug Evaluation and Research, HFD-150
`Parklawn Building
`5600 Fishers Lane, Rockville, MD 20857
`
`Mitchall Clark—American BioScience, Inc From: Sheila Ryan, PharmD
`
`Fax:
`(310) 998—8553
`Fax:
`(301) 594-0498
`
`
`Phone: (310) 883—3141
`Plume: (301) 594-5771
`
`
`
`
`Pages (including cover): 2 Date: December 7. 2004M
`
`

`

`
`
`WW
`
`NDA 21-660
`RE: established name
`
`December 7, 2004
`Page 2
`
`The Division of Oncology Drug Products with the concurrence from Center for Drug Evaluation
`(CDER) Labeling and Nomenclature Committee recommend the following established name for
`the ABI-007 drug product:
`
`“Paclitaxel Protein Bound Particles for Injectable Suspension"
`
`To further differentiateAbraxane from currently marketed paclitaxel drug products, you have the
`option to add a parenthetical statement underneath the name of the drug product, for example:
`(Cremophor ELTM free)” or “(albumin bound)”. Therefore, the ABI-007 drug product name
`would read:
`
`Abraxane for Injectable Suspension
`(Paclitaxel Protein Bound Particles for Injectable Suspension)
`(Cremophor ELTM free)
`
`or
`
`Abraxane for Injectable Suspension
`(Paclitaxel Protein Bound Particles for lnjectable Suspension)
`(albumin bound)
`
`Please make appropriate labeling changes. If you have any questions, please contact me as soon
`as possible.
`
`
`
`

`

` Fax
`
`DIVISION OF ONCOLOGY DRUG PRODUCTS
`
`Center for Drug Evaluation and Research, HFD-150
`Parklawn Building
`5600 Fishers Lane, Rockville, MD 20857
`
`
`
`
`
`To: Mitchell Clark—American BioScience, Inc From: Sheila Ryan, PharmD
`
`
`Fax:
`(310) 998-8553
`Fax:
`(301) 594-0498
`
`
`Phone: (310) 883-3141
`Phone: (301) 594-5771
`
`
`
`Pages (including cover): 1 Date: December 2, 2004
`
`
`
`lRe: NDA 21-660 for Abraxane-information requests
`
`.Urgent I For Review
`
`IPIease Comment
`
`[I Please Reply
`
`[I Please Recycle
`
`
`
`THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PARTY TO WHOM IT IS ADDRESSED AND
`MAY CONTAIN INFORMATION THAT IS PRIVIIEGED, CONFIDENTIAL AND PROTECTED FROM
`
`DISCLOSURE UNDER APPLICABLE LAW. If you are not the addressee, or a person authorized to deliver the
`document to the addressee, you are hereby notified that any review, disclosure, dissemination or other action based on the
`content of the eomniiuiication is not authorized. If you have received this document in error, please immediately notify us
`by telephone and return it to us at the above address by mail. Thank you.
`
`Please refer to your new drug application for Abraxane (NDA 21-660). Please clarify the following
`regarding the safety data from study CAO 1 2—0 which appears in your table 5 (AE5) of the proposed
`label:
`
`I. What terms are included under the AE “hypersensitivity reaction?” Please provide a table with the
`incidence of each component for grade 3 or 4 and for grade 1 and 2.
`
`Ex)
`
`{JJ
`
`Are you able to provide data which shows grade 3 or 4 vs. grade I or 2 elevation of transaminases,
`alkaline phosphatase, and bilirubin’.’
`
`What terms are included under the AE “fluid retention?” What is the incidence for grade 3-4 vs.
`grade 1—2 and overall?
`
`4. The incidence is given for AE Nausea and Vomiting. Does this include both N and V, or either
`one? Can you distinguish grade 1—2 vs. 3-4 for each of the components and overall?
`
`Please contact me should you have any questions.
`
`
`
`

`

`M N
`
`December 2. 2004
`DA 21-660
`RE: information requests
`Page 2
`'-'_l——l—l-—-——I——-—__—~_
`
`APPEARS THIS WAY
`0" ORIGINAL
`
`W’ARSTHWWAT
`
`0" ORIGINAL
`
`

`

`
`
`From: Ryan, Sheila
`Sent: Tuesday, November 30, 2004 3:25 PM
`To: 'Mitchall Clark'
`
`Subject: RE: NDA 21-660 Abraxane
`Mitch,
`
`We have additional requests regarding this response:
`
`1. Please explain how the two variables WClNPD and WCINPDDT in data sets resp and respu
`are defined.
`
`2. Please submit the SAS program that defines these two variables.
`
`Please submit this information as soon as possible to facilitate our review of the application.
`
`Please contact me should you have any questions.
`
`Thank you.
`Sheila
`
`Sheila Ryan. PharmI)
`Regulatory Project Manager
`Division ofOncology Drug Products
`Phone: 30i7594 5771
`Fax: 301 594 0498
`
`Email: ryanstaicder.tritium!
`
`-----Original Message-m-
`
`From: Mitchall Clark [mailto:MClark@ArnericanBioScience.com]
`Sent: Tuesday, November 16, 2004 4:51 PM
`To: Ryan, Sheila
`Subject: FW: NDA 21—660 Abraxane
`
`Dear Sheila
`
`Reference is made to your e—mail from yesterday in which you requested information
`concerning the datasets provided in NBA 21-660 for Abraxane.
`
`Provided below is our response. Your questions are provided in bold font. followed by
`our response:
`
`FDA Question 1
`
`You specify in the study report section 10.2 that there were 3 (2 AB] and l
`Taxol) patients randomized, but did not meet eligibiity criteria, and were not
`treated. In your fax October 20, you indicate that 6 patients were
`
`
`
`

`

`
`
`randomized but not treated. For these patient numbers, please specify the
`patient numbers, treatment arm, and specific eligibility problem or other
`reason for no therapy. In addition, from dataset “elig”, please clarify the
`specific criteria which rendered patient 437 ineligible and whether she was
`actually treated as randomized on the Abraxane arm.
`
`ABI Response:
`
`Provided in the table below is a listing of patients who were randomized but not
`treated, including the reasons for not receiving treatment.
`In addition, the reason
`for patient 437 violating an eligibility criterion is described. This patient did
`receive treatment.
`
`
`
`
`
`Patient
`
`SiteiSubject
`3201314
`
`
`
`
`
`Randomized
`Eligibility Violation
`Reason
`Treated?
`
`
`Eeatment
`{YestNo}
`Not Treats
`
`Patient enrolled under protocol amendment
`ABI-OO?
`No
`Ineligible p
`
`1 which required patient to have failed prior
`chemotherapy in adjuvant or metastatic
`setting (consistent with Taxol indication).
`
`
`This patient did not receive chemotherapy
`in either the adjuvant or metastatic setting
`
`
`and thus was ineligible.
`
`1201109
`Taxol
`Patient enrolled under protocol amendment
`Ineligible F
`1 which required patient to have failed prior
`chemotherapy in adjuvant or metastatic
`setting (consistent with Taxol indication).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`312/290
`
`ABl-OOT
`
`This patient did not receive chemotherapy
`in either the adjuvant or metastatic setting
`
`and thus was ineligible.
`NA
`
`
`Patient witl
`consent in
`
`
`
`
`baseline pi
`
`prior to firs
`
`__
`_
`of study—do
`
`160” 84
`Taxol
`NA
`Patient witl
`consent in
`
`
`113/171
`
`ABI-OO?
`
`
`Patient was a screen failure and was
`randomized in error by the site.
`
`End of study reason noted as “incl/excl not
`met”.
`
`321/504
`ABl-OOT
`Patient was randomized in error; incomplete
`Eligibility on
`baseline evaluations (FACT, EORTC, ECG,
`not be con!
`CBC. and clinical chemistry not done).
`- CBC. CX
`clinical Che
`not done.
`
`
`
`Baseline p.
`prior to firs
`of studm1
`lneligibie F
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`227/437
`
`ABl-OOT
`
`Yes
`
`Patient did not complete two week washout
`of hormonal therapy prior to study drug
`administration.
`
`Patient last took Arimidex on Aug 28. 2002
`and had their first dose of study drug on
`Aug 29, 2002.
`
`Patient we:
`treated
`
`
`
`FDA Question #2
`
`In some of your SAS programs (such as dur_response_rec.sas and
`dur_response_o_rec.sas), the variables “wcinpd” and “wcinpddt” are called
`for logrank test. However, these two variables are not in the referred data
`
`sets. In addition, the program dur_response_rec.sas intends to analyze
`duration of response on responders as defined by reconciled target lesion
`response, whereas dur_response_o_rec.sas is for responders as defined by
`reconciled overall response. Why are the same “progression date” variable
`and “censoring indicator” variable used in both programs? Please provide
`these t