NDA 21-023
`
`Cyclosporine Ophthalmic Emulsion, 0.05%
`
`Original NDA Filing
`
`February 24, 1999
`
`Volume 1 of 171
`
`"
`
`y»|‘‘’-'.
`
`ii.
`
`1
`
`ALL 2001
`APOTEX V. ALLERGAN
`IPR2015-01282
`
`

`
`ALLERC-AN
`r
`-
`.1
`
`2525 Dupont Drive. PO. Box 19534. Irvine. California. USA 92623-9534 Telephone: (714) 246-4500 Website: www.a|Iergan.com
`
`(Pile
`-3-
`it-—
`
`March 3, 1999
`
`Lori Gorski
`
`Project Manager
`Division of Anti-Inflammatory, Analgesic,
`& Ophthalmologic Drug Products
`HFD-550
`
`Food & Drug Administration
`9201 Corporate Blvd.
`Building 2
`Rockville, MD 20850
`
`Subject:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`NDA 21-023
`
`Dear Ms. Gorski,
`
`In reference to a telephone conversation today with Dr. Su Tso, Chemistry Reviewer,
`please find the following information pertaining to NDA 21-023:
`
`1.
`
`Allergan is requesting market approval for one concentration of cyclosporine
`ophthalmic emulsion, 0.05%.
`
`Allergan confirms that the commercial pack consists of the unit dose vials in a
`polypropylene tray.
`
`Allergan confirms that the 12-month stability data for the product in the
`commercial package will be available by mid to late April 1999.
`
`Allergan confirms that all manufacturing and research facilities listed in
`NDA 21-023 are ready for the pre-approval inspection.
`
`Thank you for your assistance with this project. Please contact me if you need any
`additional infonnation at telephone (714) 246-4391 or fax (714) 246-4272.
`
`Sincerely,
`
`Elizabeth Bancrofi
`
`Director, Regulatory Affairs
`
`cc:
`
`S. Tso, Chemistry Reviewer
`
`2
`
`

`
`ALLERGAN
`
`2525 Dupont Drive, P.O. Box 19534, Irvine. California. USA 92623-9534 Telephone: (714) 246-4500 Website: www.al|ergan.eom
`
`151 /CM
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`
`March 2, 1999
`
`Lori Gorski
`
`.
`Project Manager
`Division of Anti-Inflammatory, Analgesic
`and Ophthalmic Drug Products
`Document Control Center HFD~550
`
`Food and Drug Administration
`9201 Corporate Blvd.
`Rockville, MD 20850
`
`RE:
`
`NDA 21-023
`
`Cyclosporine Ophthalmic Emulsion. 0.05%
`
`Dear Ms. Gorski —
`
`Enclosed is one copy of the microbiological information from Section 4A, Chemistry,
`Manufacturing and Control (CMC) of NDA 21-023. These volumes are:
`
`1)
`
`2)
`
`Volume 1 and 3 from the December 9, 1998 pre-submission of the CMC section
`containing information on the manufacturing process and test for sterility.
`
`Volumes 2 through 11 from the February 24, 1999 original NDA submission
`containing information on the validation of the aseptic process.
`
`The original pagination is retained. These data are contained in the white Microbiology
`review binders as requested.
`
`If you have any questions concerning this or any other section of the NDA, please contact
`me at (714) 246-4391.
`
`Sincerely,
`
`Elizableth Bancrofi
`Director
`
`Regulatory Affairs
`
`EB/mkb
`
`3
`
`

`
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`I
`
`2525 Dupont Drive, PO. Box 19534. Irvine, California, USA 92623-9534 Telephone: (714) 246-4500 Website: www.a||ergan.com
`
`March 1, 1999
`
`Lori Gorski
`
`Project Manager
`Division of Anti-Inflammatory, Analgesic,
`& Ophthalmologic Drug Products
`HFD-550
`
`Food & Drug Administration
`9201 Corporate Blvd.
`Building 2
`Rockville, MD 20850
`
`Subject:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`NDA 21-023 — FIELD COPIES
`
`Dear Ms. Gorski,
`
`Enclosed please find copies of the cover letters Allergan sent to the 2 Field
`Offices involved with the cyclosporine emulsion NDA. We sent an official Field
`Copy of the NDA to the LA District, to represent the corporate R&D offices in
`Irvine, CA, and a copy to the Dallas District to represent the manufacturing site in
`Waco, Texas.
`
`If you have any questions, please let me know. Thank you for your assistance
`with this project. Please contact me if you need any additional information at
`telephone (714) 246-4391 or fax (714) 246-4272.
`
`Sincerely,
`
`Elizabeth Bancroft
`Director
`
`Regulatory Affairs
`
`4
`
`

`
`V Aitencflm
`
`T
`-1‘
`T1-
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`T‘
`2525 Dupont Dnve, PO. Box 19534. Irvine. camomsa. USA 92623-9534 Telephone: (714) 2464500 Website: www.aIIergan.c0m
`
`March 1, 1999
`
`Tyler Thomburg
`Director, US Activities Branch
`Dallas District Office
`
`Food and Drug Administration
`3310 Live Oak
`
`Dallas, TX 75204
`
`RE: NDA 21-023
`
`Original NDA - Field Copy of Chernig, Manufacturing and Control Section
`
`Dear Mr. Thornburg:
`
`Enclosed are copies of the Chemistry, Manufacturing and Control (CMC) section for
`NDA 21-023. An archival and review copy of the enclosed binders were submitted to the
`FDA Maryland Office on the following dates:
`
`December 9, 1998
`
`February 24, 1999
`
`Pre-submission of CMC
`
`Original NDA submission
`
`A certification that the enclosed volumes are an identical copy of the sections as they
`appear in the archival and review copy of the application is contained in Volume 1, page
`1 147 of the February 24, 1999 submission.
`
`Sincerely,
`
`ElizabethBanclgfi
`
`Director
`
`Regulatory Affairs
`
`Enclosure (2 boxes)
`
`BB1mkb
`
`5
`
`

`
`“
`
`‘
`ALLERGAN
`:_:_-i__
`
`2525 Duponl Drive, P 0, Box 19534, Irvine. California. USA 926239534 Telephone: (714) 246-4500 Website: www.aI|ergan.com
`
`1
`__,_--'-
`:-T-'#
`Ts
`
`March 1, 1999
`
`Elaine Mesa
`District Director
`Irvine Office
`19900 Mac Arthur Blvd.
`Suite 300
`
`Irvine, CA 92612-2445
`
`RE: NDA 21-023
`
`Original NDA — Field Copy of Chemig, Manufacturing and Control Section
`
`Dear Ms. Mesa:
`
`Enclosed are copies of the Chemistry, Manufacturing and Control (CMC) section for
`NDA 21-023. An archival and review copy of the enclosed binders were submitted to the
`FDA Maryland Office on the following dates:
`
`December 9, 1998
`
`February 24, 1999
`
`Pre-submission of CMC
`
`Original NDA submission
`
`A certification that the enclosed volumes are an identical copy of the sections as they
`appear in the archival and review copy of the application is contained in Volume 1, page
`1 147 of the February 24, 1999 submission.
`
`Sincerely,
`
`Elizazg Bancroft
`
`Director
`
`Regulatory Affairs
`
`Enclosure (2 boxes)
`
`EB/mkb
`
`6
`
`

`
`-# F:
`1T
`
`--—
`:-
`
`ALLERGAN
`
`2525 Duponl Drive. PO. Box 19534, Irvine. California, USA 92623-9534 Telephone: (714) 246-4500 Website: www.a|lergan.com
`
`March 1, 1999
`
`Tyler Thomburg
`Director, US Activities Branch
`Dallas District Office
`
`Food and Drug Administration
`3310 Live Oak
`
`Dallas, TX 75204
`
`RE: NDA 21-023
`
`Original NDA — Field Copy of Chemistry, Manufacturing and Control Section
`
`Dear Mr. Thomburg:
`
`Enclosed are copies of the Chemistry, Manufacturing and Control (CMC) section for
`NDA 21-023. An archival and review copy of the enclosed binders were submitted to the
`FDA Maryland Office on the following dates:
`
`December 9, 1998
`
`February 24, 1999
`
`Pre-submission of CMC
`
`Original NDA submission
`
`A certification that the enclosed volumes are an identical copy of the sections as they
`appear in the archival and review copy of the application is contained in Volume 1, page
`1 147 of the February 24, 1999 submission.
`
`Sincerely,
`
`Elizabeth Bane ofi
`Director
`
`Regulatory Affairs
`
`Enclosure (2 boxes)
`
`EB/mkb
`
`7
`
`

`
`1
`J--—
`
`F *:
`
`2-
`T
`
`ALLERGAN
`
`2525 Dupont Drive, PO. Box 19534, Irvine, California, USA 92623-9534 Telephone: (714) 2464500 Website: www.aHergan.<:om
`
`March 1, 1999
`
`Elaine Mesa
`
`District Director
`Irvine Office
`19900 Mac Arthur Blvd.
`Suite 300
`
`Irvine, CA 92612-2445
`
`RE: NDA 21-023
`
`Original NDA — Field Copy of Chemisgy, Manufacturing and Control Section
`
`Dear Ms. Mesa:
`
`Enclosed are copies of the Chemistry, Manufacturing and Control (CMC) section for
`NDA 21-023. An archival and review copy of the enclosed binders were submitted to the
`FDA Maryland Office on the following dates:
`
`December 9, 1998
`
`February 24, 1999
`
`Pre-submission of CMC
`
`Original NDA submission
`
`A certification that the enclosed volumes are an identical copy of the sections as they
`appear in the archival and review copy of the application is contained in Volume 1, page
`1 147 of the February 24, 1999 submission.
`
`Sincerely,
`
`Elizagth Bancroft
`
`Director
`
`Regulatory Affairs
`
`Enclosure (2 boxes)
`
`EB/mkb
`
`8
`
`

`
`F} I «-
`2
`T-
`#1
`T-—
`j:
`T‘
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`
`ALLERC/yam,
`
`‘I
`
`2525 Dupont Drive, PO. Box 19534, Irvine, California, USA 92623-9534 Telephone: (714) 246-4500 Website: www.al|ergan.com
`
`"'
`
`DESK COPY
`
`Lori Gorski
`
`Project Manager
`Division of Anti-Inflammatory, Analgesic,
`& Ophthalmologic Drug Products
`HFD-550
`
`Food & Drug Administration
`9201 Corporate Blvd.
`Building 2
`Rockville, MD 20850
`
`Subject:
`
`Cyclosporine ophthalmic emulsion, 0.05%
`NDA 21-023
`
`Dear Ms. Gorski,
`
`As discussed, enclosed please find 20 copies of the first volume of NDA 21-023,
`Cyclosporine ophthalmic emulsion. The Archival and Review copies of the entire NDA
`were shipped to the Central Document Room on Wednesday, February 24, 1999.
`
`Also enclosed please find one copy of the electronic version (.pdf files) of the NDA on 4
`CD Rom disks. Please note that the disks should be copied onto a network or a hard
`drive so that all files can be accessed. The files cannot be accessed on multiple CDs by
`pointing from one to another. If you require additional copies of the CD Rom disks or
`additional instructions on how to navigate through the files, please let me know. The
`Word versions of the files will be sent under separate cover as soon as they are compiled.
`
`Thank you for your assistance with this project. Please contact me if you need any
`additional information at telephone (714) 246-4391 or fax (714) 246-4272.
`
`Sincerely,
`
`Elizabeth Bancroft
`Director
`
`Regulatory Affairs
`
`9
`
`

`
`'~»..~ALtE|gcAI;s
`
`2525 Dupont Drive. PO. Box 19534. Irvine. California, USA 92623-9534 Telephone: (714) 246-4500 Website: www.aI|ergan.com
`
`February 17, 1999
`
`U. S. Food and Drug Administration
`C/O Mellon Bank
`‘
`Three Mellon Bank Center
`
`27"‘ Floor (FDA 360909)
`Pittsburgh, PA 15259-0001
`
`NDA 21-023
`
`Cyclosporine ophthalmic emulsion
`User Fee Number 3632 Application Fee Payment
`
`Dear Sir or Madam:
`
`In accordance with your Establishment of Prescription Drug User Fee Rates for Fiscal
`Year 1999, enclosed please find A11ergan’s check number 103765, dated February 1,
`1999, in the amount of $272,282. This represents full payment for our Cyclosporine
`ophthalmic emulsion application, which requires clinical data.
`
`If you have any questions or concerns, please contact me at (714) 246-4391.
`
`Sincerely,
`
`Q&);w,éAb4flaaxt1(,4,fi/
`
`Elizabeth Bancroft
`
`Director, Regulatory Affairs
`
`EB/dmo
`
`Enclosure: Check Number 103765
`
`10
`
`

`
`é ALLERGAN
`Irvine, Calilornia 92623
`
`Account with Vendor
`Account at Vendor
`
`1000003970
`
`Check Number 1 O 3 7 génm
`Document Number
`02/01/1999
`Date
`
`FOOD AND DRUG ADMINISTRATION
`C/O MELLON BANK
`PO box 360909
`PITTSBURGH PA 15251-6909
`
`Invoice
`Date
`
`Gross
`Amount
`
`scoun
`
`I
`
`D.
`1
`
`Net
`Amount
`
`Invoice
`Number
`
`CKRQOIZI99
`
`USER FEE NUIBER
`3632
`
`Total
`
`272,232.00
`
`o.oo
`
`272,282.00
`
`DO NOT CASH THIS CHEC
`HOLD AT AN ANGLE TOWARD
`WACHOVIA BANK OF NORTH CAROLINA, N,A.
`WINSTON-SALEM. NORTH CAROLINA
`
`YOU CAN SEE THE WORD "SAFE" IN THE BACKGROUND
`WAY FROM A LIGHT TO vemrv SAFETY FEATURES mom‘ 3. BACK
`Check Number
`
`E ALLERGAN
`
`Irvine. California 92623
`
`103785
`THIS NUMBER BLEEDS THHU TO BACK
`
`USER FEE NUMBER 3632
`
`PAY
`
`Date
`
`02/01/1999
`
`$
`
`##!t272,282_00#
`
`-~- TWO HUNDRED SEVEN'I'Y-TWO THOUSAND TWO HUNDRED EIGHTY-TWO USD""
`
`FOOD AND DRUG ADMINISTRATION
`CIO MELLON BANK
`PO box 360909
`PITTSBURGH PA 15251-6909
`
`aim-555%
`
`II‘ L0 3 ?E. Sn‘
`
`I105} LOTESSIZD L373‘? DOB‘? I?I!'I
`
`11
`
`

`
`%ALLERGAI\I
`A
`
`CHECK REQUEST
`
`CHECK APPROPRIATE BOX:
`
`I SURGICAL - 0110
`
`. AGN, INC - 0010
`I: VPLP-0040
`D WACO - 0050
`MAKE CHECK PAYABLE T0:
`U. 5. Food and Drug Administration
`
`D HATO REY, PUERTO RICO
`D AGN SALES .0120 D AGN AMERICA
`D OMS -0150
`D AMO (PUERTO RICO) D oTI-IER
`E AGN SERVICES - 0170 D CANADA
`VENDOR #: (IF KNOWN)
`
`DATE:
`
`1I21I99
`
`ADDRESS:
`
`Mellon Bank (FDA 360909)
`
`socIAL SECURITY #: REQUIRED FOR NEW vENDoRs
`
`-
`
`-
`
`Three Mellon Bank Center, 27th Floor
`CITY/STATE/PROVINCE/COUNTRY: ZIPCODE:
`
`OR
`Tax I.D. #
`
`Pittsburgh, PA 15259-0001
`
`INTERNAL ORDER #:
`
`A
`EXPLANATION:
`User Fee for Cyclosporine NDA submission, User Fee Number 3632
`
`SHOULD THIS BE ON THE PURCHASING CARD?
`THE SHADED FIELDS ARE THE MINIMUM FIELDS REQUIRED.
`
`CHECK TOTAL
`
`PREPARED BY (PLEASE PRINT):
`
`Elizabeth Bancroft
`APPROVED SIG ATURE MU ‘Q PPEAR ON "AUTHORIZED SIGNATURE L|ST"
`APPROVED BY (PLEASEPRINT):
`-
`I I!
`“W” voua s LIMIT;
`Peter Kresel, Sr. VP
`.
`$1 million
`I”: sTR c oNs OP PRER
`1. FILL OUT THE CHECK REQUEST FORM COMPLETELY. INCOMPLETE FORMS WILL BE RETURNED.
`2. ATTAcI-I SUPPORTING DOCUMENTATION. WITHOUT DOCUMENTATION, THIS FORM WILL BE RETURNED.
`3. PLEASE Do NOT USE THIS FORM FOR THE FOLLOWING:
`- EMPLOYEE REIMBURSEMENT OF ANY KIND
`- IN LIEU OF A VENDOR INVOICE
`' IN LIEU OF AN INVOICE PAID AGAINST A P.O.
`" IT IS NOT NECESSARY TO ATTACH A CHECK REQUEST TO AN APPROVED INVOICE
`CHECK NEEDED BY:
`
`’
`
`4-Feb-99
`SPECIAL MAILING INSTRUCTIONS:
`
`PLEASE CALL DONNA ODDY FOR PICK-UP X 6824. DO NOT MAIL
`
`MAIL CODE:
`LS-1 F
`
`12
`
`

`
`63 FR 70777 Tuesday, December 22,‘1998
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Food and Drug Adinistration
`Establishment of Prescription Drug User Fee Rates for Fiscal Year 1999
`AGENCY:
`Food and Drug Administration, HHS.
`ACTION: Notice.
`
`is announcing the rates for
`The Food and Drug Administration (FDA)
`SUMARY:
`prescription drug user fees for fiscal year (FY) 1999.
`The Prescription Drug User
`Fee Act of 1992 (the PDUFA), as amended by the Food and Drug Administration
`Modernization Act of 1997 (the FDAMA), authorizes FDA to collect user fees for
`certain applications for approval of drug and biological products, on
`establishments where the products are made, and on such products.
`Fees for
`applications for FY 1999 were set by the FDAMA, subject to adjustment for
`inflation. Total application fee revenues fluctuate with the number of fee-paying
`applications FDA receives.
`Fees for establishments and products are calculated so
`that total revenues from each category will approximate FDA‘s estimate of the
`revenues to be derived from applications.
`FOR FURTHER INFORMATION CONTACT: Michael E; Roosevelt, Office of Financial
`Management
`(HFA-120), Food and Drug Administration, 5600 Fishers Lane, Rockville,
`MD 20857, 301-827-5088.
`
`SUPPLEMENTARY INFORMATION:
`
`I. Background
`
`L. 105- 115),
`L. 102-571), as amended by the FDAMA (Pub.
`The PDUFA (Pub.
`establishes three different kinds of user fees.
`Fees are assessed on:
`(1) Certain
`types of applications and supplements for approval of drug and biological products,
`(2) certain establishments where such products are made, and (3) certain products
`(21 U.S.C. 379h(a)). When certain conditions are met,
`FDA may waive or reduce fees
`(21 U.S.C. 379h(d)).
`the application
`For 1998 through 2002, under the amendments enacted in the FDAMA,
`feefrates are set in the statute, but are to be adjusted annually for cumulative
`inflation since 1997. Total application fee revenues are structured to increase or
`decrease each year as the number of fee-paying applications submitted to FDA
`increases or decreases (workload adjustment).
`For 1998 through 2002, FDA is required to set fee rates for establishment and
`product categories each year, so that the total fee revenue from each of these two
`categories are projected to be equal to the total revenue FDA expects to collect
`from application fees that year. This procedure continues the arrangement under
`which one-third of the total user fee revenue is projected to come from each of the
`three types of fees--application fees, establishment fees, and product fees.
`This notice establishes fee rates for FY 1999 for application, establishment, and
`product fees. These fees are retroactive to October 1, 1998, and will remain in
`effect through September 30, 1999.
`For fees already paid on applications and
`supplements submitted on or after October 1, 1998, FDA will bill applicants for the
`difference between fees paid and fees due under the new fee schedule.
`For
`applications and supplements submitted after December 31, 1998,
`the new fee
`schedule must be used.
`Invoices for establishment and product fees for FY 1999
`will be issued in December 1999, using the new fee schedules.
`.
`
`II.
`
`Inflation and Workload Adjustment Process
`
`The PDUFA, as amended by the FDAMA, provides that fee rates for each FY shall be
`adjusted by notice in the Federal Register.
`The adjustment must reflect the
`greater of:
`(1) The total percentage change that occurred during the preceding FY
`in the Consumer Price Index (CPI), or (2)
`the total percentage pay change for that
`FY for Federal employees stationed in the Washington, DC metropolitan area.
`The
`FDAMA provides for this annual adjustment to be cumulative and compounded annually
`after 1997 (see 21 U.S.C. 379h(c)(l)).
`
`13
`
`

`
`The FDAMA also structures the total application fee revenue to increase or
`decrease each year as the number of fee-paying applications submitted to FDA
`increases or decreases. This provision allows revenues to rise or fall as this
`portion of FDA's workload rises or falls.
`To implement this provision each year:
`FDA will estimate the number of fee-paying applications it anticipates receiving.
`The number of applications estimated will then be multiplied by the inflation—
`adjusted statutory application fee. This calculation will produce the FDA estimate
`of total application fee revenues to be received.
`The PDUFA also provides that FDA shall adjust the rates for establishment and
`product fees so that the total revenues from each of these categories is projected
`to equal the revenues FDA expects to collect from application fees that year.
`The
`FDAMA provides that the new fee rates based on these calculations be adjusted
`within 60 days after the end of each FY (21 U.S.C. 379h(c)(2)).
`
`III.
`
`Inflation Adjustment and Estimate of Total Application Fee Revenue
`
`The FDAMA provides that the application fee rates set out in the statute be
`adjusted each year for cumulative inflation since 1997.
`It also provides for total
`' application fee revenues to increase or decrease based on increases or decreases in
`the number of fee-paying applications submitted.
`
`A. Inflation Adjustment to Application Fees
`
`Application fees are assessed at different rates for qualifying applications
`depending on whether the applications require clinical data on safety or
`effectiveness (other than bioavailability or bioequivalence studies)
`(21 U.S.C.
`379h(a)(1)(A) and (b)). Applications that require clinical data are subject to the
`full application fee. Applications that do not require clinical data and
`supplements that require clinical data are assessed one-half the fee of
`applications that require clinical data.
`If FDA refuses to file an application or
`supplement, 75 percent of the application fee is refunded to the applicant
`(21
`U.S.C. 379h(a)(1)(D)).
`The application fees described previously are set out in the FDAMA for 1999.
`($256,338 for applications requiring clinical data, and $128,169 for applications
`not requiring clinical data or supplements requiring clinical data)
`(21 U.S.C.
`379h(b)(1)), but must be adjusted for cumulative inflation since 1997. That
`adjustment each year is to be the greater of:
`(1) The total percentage change that
`occurred during the preceding FY in the CPI (all items; U.S. city average); or (2)
`the total percentage pay change for that FY for Federal employees, as adjusted for
`any locality-based payment applicable to employees stationed in the District of
`Columbia.
`The FDAMA provides for this annual adjustment to be cumulative and
`compounded annually after 1997 (see 21 U.S.C. 379h(c)).
`The adjustment for FY 1998 was 2.45 percent
`(62 FR 64849, December 9, 1997). This
`was the greater of the CPI increase for FY 1997 (2.15 percent) and the increase in
`applicable Federal salaries (2.45 percent).
`The adjustment for FY 1999 is 3.68 percent. This is the greater of the CPI
`increase for FY 1998 (1.49 percent) and the increase in applicable Federal salaries
`(3.68 percent).
`_
`Compounding these amounts (l.0245 times 1.0368) yields a total compounded
`inflation of 6.22 percent for FY 1999.
`The adjusted application fee rates are
`computed by applying the inflation percentage for FY 1999 (106.22 percent) to the
`FY 1999 statutory application fee rates stated previously.
`For FY 1999 the
`adjusted application fee rates are $272,282 for applications requiring clinical
`data, and $136,141 for applications not requiring clinical data or supplements
`requiring clinical data. These amounts must be submitted with all applications
`during FY 1999.
`
`14
`
`

`
`B. Estimate of Total Application Fee Revenue
`
`Total application fee revenues for 1999 will be determined by the number of fee-
`paying applications FDA receives in FY 1999 (from October 1, 1998,
`through
`September 30, 1999) multiplied by the fee rates calculated in the preceding
`paragraph. Before fees can be set for establishment and product fee categories:
`each of which are projected to be equal to total revenues FDA collects from
`application fees, FDA must first estimate its total 1999 application fee revenues.
`To do this FDA has traditionally calculated the number of full application fees FDA
`received in the preceding fiscal year, made an allowance for waivers and
`exemptions, and used that figure as a basis for estimating the next year's
`application volume.
`For FY 1998, FDA received and filed 101 human drug applications that require
`clinical data for approval, 23 that did not require clinical data for approval, and
`93 supplements to human drug applications that require clinical data for approval.
`Because applications that do not require clinical data and supplements that require
`clinical data are assessed only one-half the full fee,
`the equivalent number of
`these applications subject to the full fee is determined by summing these
`categories and dividing by 2. This amount is then added to the number of
`applications that require clinical data to arrive at the equivalent number of
`applications that may be subject to full application fees.
`In addition, as of September 30, 1998, FDA assessed fees for three applications
`that required clinical data, one application that did not require clinical data,
`and one supplement, all of which were refused filing or withdrawn before filing.
`After refunds,
`the full application paid one-fourth the full application fee and is
`counted as one-fourth of an application, and the application that did not require
`clinical data and the supplement each paid one-eighth of the full application fee
`and are each counted as one-eighth of an application.
`Using this methodology,
`the approximate equivalent number of applications that
`required clinical data and were subject to fees in FY 1998 was 160, before any
`exemptions, waivers or reductions. Under the FDAMA, FDA may waive fees for certain
`small businesses submitting their first application and certain orphan products are
`exempted from application fees.
`In addition,
`the FDAMA excludes from fees bulk
`biological products that are further manufactured, and provides exceptions for
`certain supplements for pediatric indications.
`In FY 1998 waivers or exemptions
`applied to 41.5 equivalents of full applications. Therefore, based solely on 1998
`data,
`FDA estimates that approximately 118.5 (160 minus 41.5) equivalent
`applications that require clinical data will qualify for fees in FY 1999, after
`allowing for exemptions. waivers, or reductions.
`This estimate based on the data from 1998 alone predicts a substantial drop in
`applications, and represents a substantial departure from FDA experience over the
`past 5 years. Over that period the estimated number of fee-paying applications
`increased fairly consistently at a rate of about 7 percent each year, as set out in
`Table 1 of this document.
`
`Table 1.
`
`Estimated Number of Fee-Paying Full Application Equivalents
`Year
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`. .
`. . . . . . .
`. . . . . . . . . . . . . .
`. .
`. . . 116
`.
`. . . . .
`. .
`1993 . . .
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`. . . . . .
`. . . . . . . . . . . . . 124
`. .
`1994 . . .
`1995 . . . .
`. .
`. . . .
`.
`. ...... . . . . . . . .
`. . . ....
`131
`
`Since the volume of fee-paying applications FDA received in 1998 represents such a
`substantial departure from the trend experienced over the previous 5 years, and
`since sharp changes produce disruptive volatility in both fees and revenues,
`FDA
`reexamined the process to be used in estimating the next year's application volume.
`FDA considered several different approaches (continuation of current method, using
`
`15
`
`

`
`a 2- or 3-year rolling average, and linear regression) and chose the linear
`regression projection method as the best alternative for this estimate.
`
`Linear regression is well suited to situations like this where there are several
`years of historical data,
`the potential exists for shifts from year—to-year, and
`there is no obvious causative rationale to reasonably predict the year-to-year
`fluctuations.
`It also provides a damping effect on year-to-year fee and revenue
`fluctuations and allows for more stability in both fee levels paid by industry and
`in agency resource planning. Under this approach,
`the analysis takes into account
`the number of fee-paying PDUFA submissions each year since PDUFA began in 1993,
`adjusts those numbers conservatively to reflect additional exemptions/waivers that
`would have been granted between 1993 and 1997 if the current law governing
`exemptions and waivers had been in effect then, and fits the best line to those
`data points.
`The extension of that line to the next year estimates the number of
`submissions for that year. Beginning now for FY 1999, FDA will make this annual
`estimate based on a linear regression analysis of data
`on all fee-paying full application equivalent submissions from 1993 through the
`latest year
`(1998 in this case).
`This will mean that our estimated number of applications will be higher in 1998
`than it would have been under our previous estimating method.
`It will also mean
`that in future years, if there is a sudden rise in application volume,
`the
`regression analysis process will dampen the effect of such year-to-year increases
`as well. We believe that this is a fair and reasonable approach, and that it will
`insulate fees and revenues from significant fluctuations that may occur in any
`single year.
`.
`Using this approach, a linear regression line based on the adjusted number of fee-
`paying full application equivalent submissions since 1993 projects the receipt of
`150 fee-paying full application equivalent submissions in 1999, as reflected in
`Table 2 and the graphic of this document.
`
`Table 2.
`
`Year
`
`1993
`
`1994
`
`1995
`
`1996
`
`1997
`
`1998
`
`1999
`
`Adjusted Fee-Paying Full Application
`
`Equivalents
`
`101.0
`
`108.9
`
`112.5
`
`136.3
`
`161.5
`
`118.5
`
`Regression Line
`
`103.9
`
`111.6
`
`119.3
`
`127.0
`
`134.6
`
`142.3
`
`150.0
`
`BILLING CODE 4160-O1-F
`
`[GRAPHIC]
`
`[TIFEVOMITTED] TN22DE‘.98.022
`
`BILLING CODE 4160-01-C
`
`The total FY 1999 application fee revenue is estimated by multiplying the adjusted
`application fee rate ($272,282) by the equivalent number of applications projected
`to qualify for fees in FY 1999 (150), for a total estimated application fee revenue
`in 1999 of $40,842,300. This is the amount of revenue that FDA is also expected to
`derive both from establishment fees and from product fees.
`
`IV.
`
`Fee Calculations for Establishment and Product Fees
`
`A. Establishment Fees
`
`At the beginning of FY 1998 the establishment fee was based on an estimate of 275
`establishments subject to fees.
`By the end of FY 1998, 343 establishments
`qualified for and were billed for establishment fees, before all decisions on
`requests for waivers or reductions were made.
`we estimate that a total of 25
`establishment fee waivers will be granted in 1998,
`for a net of 318 fee-paying
`
`16
`
`

`
`In FY 1999 fees will be based on an estimate of 318 establishments
`establishments.
`paying fees after taking waivers into account.
`The fee per establishment is
`determined by dividing the adjusted total fee revenue to be derived from
`establishments ($40,842,300), by the estimated 318 establishments, for an
`establishment fee rate for FY 1999 of $128,435 (rounded to the nearest dollar).
`
`B. Product Fees
`
`At the beginning of FY 1998 the product fee was based on an estimate that 2,100
`products would be subject to product fees.
`By the end of FY 1998, 2,279 products
`qualified and were billed for product fees before all decisions on requests for
`waivers or reductions were made. Assuming that there will be about 55 waivers
`granted, FDA estimates that 2,224 products will qualify for product fees in FY
`1999, after allowing for waivers and exemptions. Accordingly,
`the FY 1999 product
`fee rate is determined by dividing the adjusted total fee revenue to be derived
`from product fees ($40,842,300) by the estimated 2,224 products for a product fee
`rate of $18,364 (rounded to the nearest dollar).
`
`V. Adjusted Fee Schedules for FY 1999
`
`The fee rates for FY 1999 are set out in Table 3 of this document.
`
`Table 3.
`
`Fee Category Fee Rates For FY 1999
`
`Applications
`
`. . . .
`. . . . . .
`Requiring clinical data . . .
`. . . .
`Not requiring clinical data . . . . .
`Supplements requiring clinical data .
`Establishments .
`. . .
`. .
`. . . .
`.
`. . . . . . .
`. . . .
`Products .
`.
`. . . . .
`.
`. . .
`.
`. .
`. .
`.
`. . . . . . .
`. . . .
`
`. ..
`. . . . . . . . . . . . . . .
`. . . . . . . . . . .
`.
`.
`. . . ... . . . . . . . . . .
`. .
`. . . .
`. . . . . . . . . . . . ..
`. . . . . . . . . . . .
`.
`. . . . . . . . . .
`.
`. . . .
`.
`. .
`. .... . . . . . ........... . . . . .....
`.
`. . . ........... . .
`. .
`. . . . . . . . . . . .
`. . . .
`. . . . . . . . . . .
`. ..
`.
`. . . . . . . . . . . . . . . . . .
`. . . . . . . . . . .
`. . . . . . . .[ . . . . . .
`. . . . . . . .
`.
`. . . . . .
`. . . . .
`. ..
`
`$272,282
`$136,141
`$136,141
`$128,435
`$18,364
`
`VI.
`
`Implementation of Adjusted Fee Schedule
`
`‘A. Application Fees
`
`Any application or supplement subject to fees under the PDUFA that is submitted
`after December 31, 1998, must be accompanied by the appropriate application fee
`established in the new fee schedule.
`Payment must be made in United States
`currency by check, bank draft, or U.S. postal money order payable to the order of
`the U.S.
`Food and Drug Administration. Please include the user fee ID number on
`your check.
`Your check can be mailed to:
`Pittsburgh,
`PA 15251-6909.
`they can be
`If checks are to be sent by a courier that requests a street address,
`sent to: Mellon Bank, Three Mellon Bank Center, 27th Floor
`(FDA 360909),
`Pittsburgh,
`PA 15259-0001.
`(Note: This Mellon Bank Address is for courier
`delivery only.)
`Please make sure that the FDA P.O.
`Box number (P.0.
`Box 360909)
`is on the enclosed check.
`
`Food and Drug Administration, P.O.
`
`Box 360909,
`
`FDA will bill applicants who submitted application fees between October 1, 1998,
`and December 31, 1998, based on the adjusted rate schedule.
`
`B. Establishment and Product Fees
`
`By December 31, 1998, FDA will issue invoices for establishments and product fees
`for FY 1999 under the new fee schedules.
`Payment will be due by January 31, 1999.
`FDA will issue invoices in October 1999 for any products and establishments subject
`to fees for FY 1999 that qualify for fees after the December 1998 billing.
`
`17
`
`

`
`WORLDWIDE REGULATORY AFFAIRS
`APPROVAL SHEET
`
`REVIEWER
`
`SIGNATURE
`
`Elizabeth Bancroft
`RA Director
`ShVP Global Re9Aff
`
`Peter Kresel
`
`Bob Koda
`RA Consultant
`
`1
`/
`
`-
`
`/
`
`N/A
`
`°Z
`
`;
`
`PRODUCT:
`
`Cyclosporine Ophthalmic Emulsion
`
`PROJECT:
`
`NDA Sections 1 through 3
`
`COUNTRY:
`
`USA
`
`ANALYST:
`
`Mari Bradford (X4392)
`
`DATE ROUTED:
`
`DATE MAILED:
`
`18
`
`

`
`Allergan Confidential
`Cyclosporine ophthalmic emulsion
`
`Original NDA 21—023
`Section 1
`
`Volume 1
`
`Table of Contents
`
`Vol.
`
`Page
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`Section 1 INDEX AND CERTIFICATIONS .
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`002
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`005
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`COVER LETTER .
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`1.1 MASTER INDEX .
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`1.2 LIST OF PRIOR RELATED SUBMISSIONS .
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