`These records are from CDER’s historical file of information
`previously disclosed under the Freedom of Information Act (FOIA)
`for this drug approval and are being posted as is. They have not
`been previously posted on Drugs@FDA because of the quality
`(e.g., readability) of some of the records. The documents were
`redacted before amendments to FOIA required that the volume of
`redacted information be identified and/or the FOIA exemption be
`cited. These are the best available copies.
`
`

`

`28613
`20613
`
`1 OF 3
`1 OF 3
`
`Eye Therapies Exhibit 2015, Page 2 of 286
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`906 /2
`
`Eye Therapies Exhibit 2015, Page 3 of 286
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`- - - - - - - -
`
`NDA 20-613
`
`Alphagan™
`
`(brimonidine tartrate ophthalmic solution) 0.2% Sterile
`
`Allergan
`
`Volume 1 of 1
`
`Joanne Holmes
`phone 7-2527
`e-mail HolmesJ
`
`

`

`NOA 20-613
`
`Allergan, Inc.
`Attention: Adelbert L. Stagg, Ph.D.
`Director, Regulatory Affairs
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92713-9534
`
`Dear Dr. Stagg:
`
`Please refer to your August 31, 1995, new drug application submitted under section 505(b) of
`the Federal Food, Drug, and Cosmetic Act for Alphagan"' (brimonidine tartrate ophthalmic
`soluti:m) 0.2 % .
`
`We acknowledge receipt of your amendments dated October 12 and 23, 1995, and
`February 26, March 1, 18, 22, and 26, April 5, 11, and 25, May 8, 10 (two), 14, 16, June 4,
`12 (two), July 16, and August 28, 1996.
`
`This new drug application provides for the indication of lowering intraocular pressure in
`patients with open-angle glaucoma or ocular hypertension.
`
`We have completed the review of this application, including the submitted draft labeling, and
`have concluded that adequate information has been presented to demonstrate that the drug
`produ~t is safe and effective for use as recommended in the draft labeling in the submission
`dated August 28, 1996 with the following revision: the first sentence of the Clinical
`Pharmacology se:::tion should be revised into the following two sentences, "ALPHA GAN"' is
`an alpha adrenergic receptor agonis1. It has a peak ocular hypotensive effect occurring at two
`hours post-dosing." Accordingly, the application is approved effective on the date of this
`letter.
`
`The final printed labeling (f-PL) must be identical to the draft labeling submitted on August 28,
`I 996, as revised above. Marketing the product witl, FPL that is not identical to this revised
`draft labeling may render the product misbranded and an unapproved new drug.
`
`Please submit sixteen copies of the FPL as soon as it is available, in no case more than 30 days
`after it is printed. Please individually mount ten of the copies on heavy weight paper or
`similar material. For administrative purposes this submission should be designated "FINAL
`PRINTED LABELING" for approved NOA 20-613. Approval of this submission by FDA is
`not required before the labeling is used.
`
`Should additional infonnation relating to the safety and effectiveness of the drug become
`available, additional revisions of that labeling may be required.
`
`

`

`NDA 20-613
`Page 2
`
`In addition, please submit three copies of the introductory promotional material that you
`propose to use for this product. All proposed materials should be submitted in draft or mock(cid:173)
`up form, not final print. Please submit one copy to the Division of Anti-Inflammatory,
`Analgesic and Ophthalmic Drug Prodncts and two copies of both the promotional material and
`the package insert directly to:
`
`Division of Drug Marketing, Advertising and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Validation of the regulatory methods has not been completed. At the present time, it is the
`policy of the Center not to withhold approval because the methods are being validated.
`Nevertheless, we expect your continued cooperation to resolve any problems that may be
`identified.
`
`In addition, we acknowledge the commitment made during the September 6, 1996, telephone
`conversation between Peter Kresel (Allergan, Inc.) and Wiley Chambers (FDA). Allergan,
`Inc .. agreed to conduct a Phase 4 study to further evaluate the potential (in at least two
`
`Pl~ase submit one market package of the drug when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`
`If you have any questions, please contact:
`
`Joanne Holmes, M.B.A.
`Project Manager
`(3UJ / 827-2090
`
`Sincerely yours,
`
`Michael Weintraut, M.D.
`Directtir
`Offi • e :)f Drug Evaluation V
`Cen,er for Drug Evaluation and Research
`
`

`

`FINAL PRINTED LABELING HAS NOT BEEN SUBMITTED TO THE FDA.
`FINAL PRINTED LABELING HAS NOT BEEN SUBMITTED TO THE FDA.
`
`DRAFT LABELING IS NO LONGER BEING SUPPLIED SO AS TO ENSURE
`DRAFT LABELING IS NO LONGER BEING SUPPLIED SO AS TO ENSURE
`
`ONLY CORRECT AND CURRENT INFORMATION IS DISSEMINATED TO THE
`ONLY CORRECT AND CURRENT INFORMATION IS DISSEMINATED TO THE
`
`PUBLIC.
`PUBLIC.
`
`Eye Therapies Exhibit 2015, Page 7 of 286
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Confider111al
`
`Allergan. lnc
`Brunorudine Tartnte C.5'1- Opht.biLlauc Soluuon
`OnginaJ hling For NOA W-613
`Secuon 14
`
`14.
`
`PA TENT CERTIFICATION
`Because the only patent related to brimonidine for use in ophthalmic products has expired, no
`patent certifications will be made at this time. A copy of U.S. Patent No. 3.890,319. which
`covered the active compound brimonidine in Brimonidine Ophthalmic products and expired on
`17 June 1992, is provided in this NOA under Section 13. Patent Information.
`
`

`

`IC....,i.te for al origNI applicalians nl d effoacy ~ I
`
`PEDIATRIC PAGE
`Supplement # ~N~;; .... 14-.... __ Circle one: SE1 SE2 SE3 SE4 SES SE6
`NDA/PLA # d 21) ft .-9Q - 4' I 3
`Hf'.b ::,;'2 ""D Trade (generic) name/dosage form: t/1p ~ r, f {l<(.f¼oa,<i,,,: + ~.a0
`Ar.tion:
`J ci~il'IH,'-- Sc.;/v~)O.~ ;l
`~k-r,k- AP@NA
`,4//4.,,,,r,,v<,
`Therapeutic C l a s s - - - - ' -~ - - - - - - - - - -
`lndication(sl previously approved --W~~==------,----------------(cid:173)
`Pediatric labeling of approved indication(sl is adequate ~madequate __
`
`Applicant
`
`1.
`
`2.
`
`PEDIATRIC LABELING IS ADEQUATE. Appropriate information has been submitted in this or previous
`appUcations and has been adequately summarized in the labeling to pennit satisfactory labeling for an pediatric
`subgroups. Further informatwn is not rtquired.
`
`PEDIATRIC STUDIES ARE NEEDED. Th~re is potential for use in chadren. and further informati~n is required to
`permit adequate labefing for this use.
`
`a.
`
`b.
`
`A new dosing formation is needed, and appficant has agreed to provide the appropriate formulation.
`
`The applicant has evmmitted to doing such studies as wm be required.
`(1) Studies are ongoing,
`(2) Protocols werA submitted and approved.
`(3) Protocols were submitted and are under review.
`(4) 11 M protocol has been submitted, explain the status of cftscussions on the back of this form.
`
`c.
`
`If the sponsor is not willing to do pediatric studies, attach copies ol FDA's written request that such
`studies be done and of the sponsor's written response to that request
`~ PEDIATRIC STUDIES ARE NOT NEEDED. The drug/biolugili product has ittle potential for use in chndren.
`Explain. _on the back of this form. why pediatric studies are not needed. ~ s. , .,d, ad? o•• -~ r<-<'~
`. I' f' d', ,..1-,,, '-
`"P CLY, ,·,,.)'.s
`p tY >' .. _,.- ,~--r
`If none of the above apply, explain, as necessary, on the back of this form.
`EX?LAIN.
`4.
`
`I ,,
`
`EXPLAIN, AS NECESSARY. ANY OF THE FOREGOING ITEMS OM TRE BACK Of THIS FORM.
`
`d Title (PM, CSO, MO, other)
`
`Date /
`
`I
`
`cc: Ori(§J~JPLA /I dQ -v 1 1
`Hfu.: ;;,-:',:IJ
`/Div File
`NDA/PLA Action Package
`HFD-510/GTroendle (plus, for CDER APs and AEs, copy of action letter and labeling)
`
`NOTE: A new Pediatric Page must be completed at the time of eath action even though one was
`prepared at the time of the last action.
`5195
`
`

`

`J.\LLERGAN
`
`DEBARRMENT CERJIEJCATIQN
`
`REF: Bnmonidine Tanrare 0.2% Ophthalmic Solution - NOA 20-613.
`
`U oder the provisions of Section 306(1t) of the Federal Food, Drug and Cosmetic Act. Allergan.
`Inc. bas made a diligent effon to insure that no individual. corporation. pannersbip or
`association debarred under Section 306(a) or 306(b) of the Act. as referenced above. bas
`provided any services in connection with this application. This effon included identifying all
`employees of Allergan. Inc. connected with this application and requiring each of them to
`certify that be or she bas not been debarred. This effect also included a requirement that all
`persons not employed by Allergan. Inc. who provided services in connection with this
`application certify to us that neither they nor any person employed by them bas been disbarred.
`Relying. in part. on these certifications to us. Allergan, Inc. certifies that it did not and will not
`use. in any capacity. the services of any individual, corporation. partnership or association
`debarred under Section 306(a) or 306(b) of the Federal Food. Drug and Cosmetic Act in
`connection with this New Drug Application.
`
`Vice President. Global Regulatory Affairs
`Allergan. Inc.
`
`

`

`-
`
`-
`
`- - - - - - - - -
`
`1
`
`NOA 20-613
`Original
`
`Sponsor:
`
`Medical Officer's Review NOA 20-613
`Original
`
`Submission date:
`Received date:
`Review date:
`
`9{7/95, 4/5/96, 6/12/96
`9/13/95, 4/8/96, 6/14/96
`7/3/96
`
`Allergan Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, California S:2713-9534
`
`Drug name:
`
`Alphagan
`
`Pharmacologic Category:
`
`Alpha adrenergic receptor agonist
`
`Proposea Indication:
`
`For the reduction of elevated intraocular pressure in
`patients with open angle glaucomd and ocular
`hypertension.
`
`Dosage Forrr and
`Route of Administration:
`
`Topical ophthalmic solution.
`
`Submitted:
`
`This application consists of 209 volumes divided into
`15 sections. The clinical section consisted of
`volumes 1. 136-1.142. The sporJsor has identified 2
`Pi1ase Ill studies as pivotal trials: #A:342-103-7831
`and #A342-104-7831
`
`Manufacturing Controls:
`
`See Chemist's Review.
`
`Pharmacology:
`
`See Pharmacology and Toxicology Review.
`
`Related Submissions:
`
`IND#
`
`NOA#
`
`

`

`Clinical Studies Conducted In Support of Brimonidine
`for the Reduction of Elevated IOP
`
`2
`
`A342-106-7831
`A342- I 19-7831
`A342-120-8042
`
`y
`
`y
`
`y
`
`y
`
`Phase
`
`tudy
`Description
`
`Clinical
`Pharmacokinetics
`
`0
`Volunteers
`
`Safety and
`Comfort/
`Dose-titration
`
`s
`Cotm
`Dose
`
`Efficacy and
`Safety Dose
`Response
`
`n-ang e g auco
`ocular hypertension
`
`A342-104-7831
`
`

`

`Significantly greater incidences of
`0.35"• is safe and comfortable.
`i,runon111me, 11 1 concentrabOn or
`
`conjunctiva! blanchin1 was
`
`lowering intraocular pressure than
`brimonidine is more cff',cacious in
`0. '" than vehicle. In addition,
`rersrted with u~ of brimonidine
`
`is vehicle in normal subjects.
`
`Si1nificanlly 1reater incidences of
`O.'"· is safe and comfortable.
`u.runomame, at a concentrataon 01
`
`conjunctiva! blanchin& and
`
`lowerin, intnocular rressure than
`brimonidine is more efficacious in
`0.5" lhan vehicle. In addition,
`reported wi use of brimonidine
`subjective rr.t°ru of dry eye were
`
`is veh1ele in norma subjects.
`
`0.0 ll, and 0.2" differ from each
`srui to conclude that brimonidine
`
`lowering intraocular pressure than
`brimonidinc is more efficacious in
`
`J::tr1monHltne, at conccntrauons of
`
`0.08ll, and 0.2,i,, is safe •nd
`
`comfortable. In 1ddi1ion,
`
`There is no evidence from this
`is vchide in normal subjccls.
`
`other in etrJCacy .
`
`comfonablt.
`0.02ll, and 0.08ll,, is safe and
`Brimonidine, at concentrations of
`
`.,,,,.
`
`:,:,111
`
`(18-60)
`ov.O
`
`••
`
`4 aays
`
`Snidy Conclusion
`
`(B/W;Q)
`
`Race•
`
`(MIF)
`Sex
`
`3
`
`, ...... ,. , "!>"' UI
`
`__
`
`Subjects I Year,
`
`(Min-Mu)
`
`Duration
`
`Dose
`
`Treatment
`
`Study
`
`Design
`
`Investigator
`
`Stu~:, No.
`
`v,.,., •
`
`.,,. '
`
`(19-67)
`o,.u
`
`'
`
`40
`
`4 ... y,
`
`bid
`vuc eye
`
`Paralled vehicle
`MISl:CU u.,o,.
`
`77
`n...,-...,-J 11-u• Ker.ss
`
`v,..v,o
`
`jj/lj
`
`(19-66)
`o•.I
`
`•o
`
`4 oays
`
`bid
`lJIJC eye
`
`Paralled vehicle
`MISu:o v.)ll,
`
`42
`)>4<·1VO·OV 1'-ep&SS
`
`.
`
`v,. '/ j
`
`oodl
`
`(18-72)
`.H.j
`
`OU
`
`4 days
`
`bid
`une eye
`
`0.<l8ll, bid
`0 'J8ll, qd
`0 02,i, bid
`0 02ll, qd
`Titrated
`!Jne eye
`
`vehicle
`
`Paralled 02,i,
`MISl:eQ U.vo,.
`
`31
`::,_, .. "-1Ul-,c Kepass
`
`vehicle
`Titration 0.08ll,
`Masted U.v,ll>
`
`29
`JJ'"ft1.·1u1•/8 LAIOOVltZ
`
`EHiy Dose-Tolerance Studies
`
`

`

`G°:st-inslillanoo. Brimonidine
`intraocular eressurc 12 hours
`vehicle in lowering elevated
`r1moru ane
`cfficacmus
`and cli~al~trcani:;; more
`0.5" brimonidine arc atalistically
`administered 0.08" • 0.2", and
`demonstrate that twice-daily
`1 nc rUIUIS 01 ouS SIUu7
`
`bnmonidine 0.08" or vehicle.
`hYJ>OICnsivc effect than
`significantly greater peak ocular
`2" and 0.5" demonstrated a
`
`0
`
`onclusions can be drawn from this
`
`comfortable. In addition, the
`0.02" and 0.08". is sate and
`Hn!?l0n1U1ne, at concentntJOm"'oT"
`
`brimonidine 0.08
`is e 1C1cious
`result, nf this SIU~ sugf,s'-' that
`
`for the treatment of elevated
`
`Sllltt,lica) power of this ~ WU
`kept in mind, however, that the
`intraocular prusure. h must be
`
`very low, therefore, no u:n
`
`study.
`
`.,,.,. . .... ~,,.,
`
`,, .L-<>V.U
`
`.
`
`. ,..
`
`.LO uayS
`
`OKI
`
`vehicle
`~.08"
`Paralled 0.2"
`Masked u.,,.
`
`Van Buskirk
`Zimmerman
`
`:r
`
`Lewis
`Epstein
`Chorlin
`
`31
`IU4.L-) Ill-1'
`
`v,.,,v
`
`o,,
`
`(34-79)
`UL.j
`
`u
`
`J aays
`
`bid
`
`vehicle
`J.08\li
`J.v. )I,
`
`Paralled
`MISllCO
`
`29
`>'4.L·IV>•/0 t\Cpass
`
`Shoa-Ie!l!l ~tudiU o( I:!!!:ra~utic ResJ!Qnse
`
`Study Conclusions
`
`(BIW/0)
`
`Race•
`
`(MIF)
`Sex
`
`4
`
`--I -----------...
`
`Subject,
`
`-
`
`(Min-Max)
`
`Yens
`
`I
`
`Duration
`
`Dose
`
`Treatment
`
`Study
`
`Design
`
`Investigator
`
`Study No.
`
`

`

`per day dosing.
`signifiunt advantage over twice
`rimes per day offers no clinically
`Oosina of brimonidine 0.2 ~ rhme
`
`ocular hypertensron.
`,.,jth open-angle Jlaucoma •nd/or
`wu we -tolerated in subjects
`lowerinft of elevated !OP and
`!Mee-daily wu effective in the
`nnmoruurne v .• ~ _ aosca
`two drop sizes.
`,.,jth regard to safety berween the
`re were no differences
`I P.
`ec:J'Fall~flicacious in reducing
`a regular-tip or mic,o-bp is
`administered r...ice-<lai'r in either
`that brimonidine O. 5"
`JDC resurts or ullS stu_uy suggest
`
`the recovery period.
`the systolic blood presrure during
`limited to a shght suppression of
`brimonidine UJ>'?D exercise were
`The cardiovascular effects of
`exercise and recovery bean rate.
`significant suppre!<ion of both
`ll50Ciated .;th a statistically
`tachycardia wbereas timolol was
`ha no effect on exercise-induced
`su~nsion 0.25 'i,; ind vehicle
`Brimonidine 0.2" • betaxo,ol
`0.25", timolol 0.5. or vehicle.
`0. 2" , llctaxolol su~nsion
`were observed with brjmonidinc
`effects on ;,ulmonary function
`normal healll>y vo unlCers, no
`n u1IS acutC-<JOSmfi stuay m
`
`I
`
`I 1'011>
`
`,u,n
`
`(26-73)
`n.U
`
`,u,
`
`11. wee1:s
`
`uru vs. ua
`
`,v:.asr:ea u.,,.
`
`Paralled
`
`31
`/\..,..~-11:,,-10 1 wal&en
`
`Bera
`
`,,,,,,
`
`,u,,,
`
`.. ,._., ·J.1..0
`
`IV>
`
`e aays
`
`UN
`
`-
`
`Paralled vehicle
`MIS&c:u 0.JJe
`
`Saraenr
`Walten
`42
`l'U"l~-J 10-0V ,u,pus
`
`'"""
`
`.-,u
`
`(21--60)
`
`, .. ,
`
`,o
`
`5 weeks
`
`tweet
`
`vehicle
`~ 2-t
`~25,i;
`v.J JO
`
`Crossover
`
`Mask.ea
`
`Ordman
`Rudikoff
`Pu<juale
`Nordlund
`
`31
`11'..J .. '"•l l)·to I\.Oblll
`
`Stwn-Itrm ~9iedg Q( ibe[l~utic Bes~n~ (~onlinued}
`
`Study Conclusions
`
`(BIW/0)
`Race•
`
`(M/F)
`Sex
`
`.>
`
`l'l'Um~r OJ Mean "Kem
`
`(Min-Mu)
`
`Years
`
`Subjects
`
`Duration
`
`Dose
`
`Treatment
`
`Study
`
`-Design
`
`lnvcsti1ator
`
`Study No
`
`

`

`two to five hours.
`elimination half-life ranging from
`plasma declined with an appuent
`concentration of brimonidine in
`ours to 3_2 hours). The
`!::;st-dosing (range from I. 7
`at approximately two hours
`human plasma (fmax) occurred
`brimonidine were found in
`muimuin concentrations of
`, uc mean tJme at w111cn
`
`following multiple dosing_
`minimal systcmk accumulation
`parameters, and there was
`changes in brimomdine PK
`di Mt result ii, siinificant
`Rdnated r,~•1lar administration
`to that of young adult,_
`elderly subjects was comparable
`c imination of rimonidinc in
`Srtemic a SO'i'tion and
`after 10 dabs of repeated osing.
`raean Cmax wu 0.0 85 nJ.'mL
`muhiplc ocular dosi~. The
`but detectable afler single and
`The systemic absorption was low
`subject, were well tolerate .
`wtrate to elderly and you':f
`doses of 0_2" brimonidine
`, ue resu,_ts s,.,wea mat ocu11r
`
`pg/mL).
`pl,sma to the lower limit of 2.00
`sensitivity to erect brimonidine in
`method emploJ.ed has the
`pos1-instillllion. (The assay
`plasma al 24 hours
`brimonHline was detectable in
`3.59 pg/mL to 265.ClO pg/mL. No
`levels of brimonidtnc ranged from
`brimonidine 0.5". D<1ecuble
`ours post-instillation of
`~lasma were dctecled within four
`rcaa; 1cve1s DI onmomamc m
`
`6
`
`u•••••
`
`""'"
`
`(21-35)
`
`., .•
`
`analysis)
`(27 safe,y
`
`..
`
`I ~Y
`
`qa
`
`Masted 0.2" 0.5"
`
`vehicle
`
`U.ud~
`
`Crossover
`
`42
`A34Z-IZU-ov r,.cn
`
`0/9/0
`
`v,u,I
`
`3/6
`
`J,.
`
`(65-73)
`
`70
`
`(2/19)
`
`.
`
`9
`
`I
`
`I days
`
`1v oay
`
`qd (elderly)
`o,a (YOUDI)
`
`0.2"
`u.,,.
`
`Open
`
`31
`l'LI .. -'·IVO-la notml
`
`v-,,1
`
`.,v
`
`(22-24)
`
`...•
`
`•
`
`1 aay
`
`stet
`
`u ,,.
`
`Probe
`vpen
`
`42
`M•.:-1u,-ou r,ach
`
`Srudaci of Pharmf!cQityn1mic f!:o~nte~
`
`

`

`cuntralatcral e ect.
`baseline day su,1cgests a miiu
`eye on day 8 compared 10
`flow in the contralatcral control
`decrease in !OP and aqueous
`uvcoscleraJ outflow. The
`aqueous flow and an increase in
`associated with I decreast-in
`reduction in IOP in humans is
`I ne DrllhODldlllC·lnuucea
`
`7 .
`
`lv,,,v
`
`U/o
`
`(26-78)
`.J,. I
`
`•
`
`• aays
`
`DIO
`
`J.Ao/11
`
`Masked
`
`Uni1atera1
`
`831
`'JNU-*v•-1 & 101onst1
`
`

`

`Non-
`..... uh ... ,
`
`(M/F) White)
`Sex
`
`a
`
`.J'1' 11:,v
`
`,<27.9 -83.9) 226
`~-"
`~I /I
`·-
`
`Subjects (Min. Max)
`of
`in Years
`,umocr m~dU n.i;~
`
`-~
`
`olu
`
`1 urup
`
`Duration
`
`Dose
`
`0.5% Timolol
`
`Parallel
`Masked
`
`Atlas
`
`A
`
`Zimmerman
`Wilensky
`Tortora
`Terry
`Sturm
`Sloan
`Silverstone
`Siegel
`Schuman
`Rotberg
`Perell
`Levy
`Lamping
`Labarta
`Katz
`'ones
`Horwitz
`Hersh
`Gross
`David/Klemperer
`Craven
`Choplin
`7831 Barnebey
`103-
`00-~ ~ .. , "'
`No.
`Stt1dy
`•
`
`Treatment
`
`Design
`Study
`
`Investigator
`
`Controlled Clinical Studies:
`
`

`

`"
`
`404/79
`
`(32. 8-83. 0)
`61.4 Tim
`(28.5-86.4) 237
`246/
`62.7 Brim
`
`483
`
`bid
`
`I drop
`
`0.5% Timolol
`0.2%
`
`Non-
`(White/
`
`(M/F1 White)
`Sex
`
`Duration Subjects (Min. Max)
`of
`in Years
`Number Mean Age
`
`Dose
`
`Treatment
`
`Parallel
`Masked
`Double
`
`Design
`Study
`
`Balazsi/K...sner
`
`W tcrs
`Tr~
`Tingey
`Ticho
`Stamper
`Spim
`Murphy
`Mundorf
`Morrison
`Mikelberg
`Mel
`M~
`Lewis
`LcB anc
`Has~
`Goldberg
`Gaasterland
`Foerster
`Fichman
`Dirks
`Crichton
`Cooke
`Cantor
`Brooks
`Blaydes
`7831 Beehler
`04-
`A342-1 Abelson
`
`Investigator
`
`No.
`Study
`
`9
`
`Controlled Cllnlcal Studies (continued)
`
`

`

`10
`
`APPLICANT'S RATIONALE FOR DOSE AND REGIMEN
`
`A three <lay dose-response study (S342- l 09-7829) was conducted that compared the safety and
`efficacy of brimonidme 0.02%, 0.08%, and vehicle in 13 subjects with glaucoma or ocular
`hypertension (S342-109-7831). Subjects were treated twice-daily in both eyes. Toe results showed a
`significant difference in mean !OP change from baseline only at one timepoint. At this visit, the
`0.08% group had a significantly greater decrease than the vehicle group.
`
`A one-month dose-response study (A342-l10-7831) was conducted comparing the safety and efficacy
`of brimonidine tartratc 0.08 % , 0.2 % , 0.5 % , and vehicle in !94 subjects with open-angle glaucoma or
`ocular hypertension (A342-116-7831; Derick et al., 1993). Subjects were treated twice-daily in both
`eyes. Results f:om this study indicated that all three brimonidiric concentrations lowered !OP
`significantly more than vehicle at all follow-up visits (p<0.05). At days 14, 21, and 28, the 0.5%
`concentration lowered JOP to the same extent as the 0.2% concentration. The 0.5% concentration,
`however, was associated with a greater incidence of blurring of vision and foreign body sensation.
`Incidence of fatigue and/or drowsiness and dry mouth were also higher for this concentration than for
`either the 0.2% or the 0.08% concentrations. Based on the rc,,-ults of the dose-response study,
`brimonidine 0.2 % was selected for funher clinical development in the treaanent of open-angle
`glaucoma and ocular hypertension.
`
`Dosing of brunonidine 0.2% at twice per day (b.i.d.) was compared to three times per day (t.i.d.) in
`a lhree-month study (A342-l 19-7831) to ascertain if more frequent instillation would sigruficantly
`enhance overall clinical effectiveness (A342-119-7831). One-hundred one patients with glaucoma or
`ocular hypertension were randomly assigned to the b.i.d. or t.i.d. groups. The data demonstrated that
`t.i.d. dosmg did not enhance overall clinical effectiveness. At morning trough, !OP was reduced
`approximately 4 mm Hg for both dosing regimens. At the afternoon trough, t.i.d. dosing resulted in
`a significantly greater reduction in IOP at three hours (3 mm Hg greater with t.i.d. than b.i.d. dosing)
`and one hour ( 1.4 mm Hg greater) before the evening dose. The value of this additional decrease is
`minimal, since a) !OP is generally lowest in the afternoon and evening (Henkin<! ct al., 1973; David
`et al, 1992), b) both regimens resulteo in afternoon trough IOPs of under 20 IIIIJl Hg, c) there was not
`an enhanced !OP reduction at the morning trough,,a.,d d) compliance will likely suffer with t.i.d.
`dosing (Kass et al , 1987). Brimonidine was safe whether dosed b.i.d. or t.i.d. The conclusion from
`this study was that while t.i.d. dosing was safe, it did not contribute to a clinically significant
`enhancement of efficacy.
`
`One small, additional study (A342-!16-8042) was conducted to aso:rtain whether a smaller drop size
`(26 uL) of brimonidine would be as effective as the standard drop size (35 uL) while enhancing the
`safety profile (A342-l 10-7831). Sixty-seven patients with glaucoma or ocular hypertension were
`dosed b.i.d. for seven days. The results showed that the smaller drop size did not enhance the safety
`profile and therefore, the 35uL drop size was used iu all future studies.
`
`Reviewer's Comments: The applicants rationale for bid dosing is seriously flawed. The morning
`trough measured was taken in each group 9-12 hours after the evening dose. The equivalence between
`groups is reflective of the equal arrwunts of time since the last dose in each group.
`The difference in the afternoon measurement demonstrates CM need for an additional afternoon dose.
`An occasional missed afternoon dose due to compliance issues is still bmer than a routinely missed
`dose because it was not attempted.
`
`

`

`11
`
`Study Design - Phase ill Studies
`
`In the two phase ill studies (A342-103-7831 and A342-104-7831), all patients were diagnosed with
`glaucoma and/or ocular hn,enension. Patients were required to meet the following inclusion and
`exclusion criteria to panic1pate in the study:
`
`Inclusion Criteria: Male or female volunteers, 21 years of age or older, with
`post-washout lOPs of 23 mm Hg or greater (but less than 35 mm Hg) in each eye at the Hour 0
`measurement, and corrected visual acuity of 20/80 (A342-104-7831) or 20/100 (A342-103-7831)
`English units or bc,tter in each eye.
`
`Exclusion Criteria: Existence of any uncontrolled systemic disease.-; pregnancy,
`nursing, or childbearing potential (an adult female was considered of childbearing potential uilless she
`was post-menopausal, bad her uterus and/or both ovaries removed, or bad a bilateral tubal ligation1;
`contraindications 10 alplu:-adrenoceptor agonist therapy sucb as depression, cerebral or coronary
`insufficiency, Raynaud's phenomenon, onhostatic hypotension, or thromboangiitis obliterans;
`contraindications to beta-adrenoceptor antagonist therapy (such as chronic obstructive pulmonary
`disease, bronchial asthma, hean block more severe than first degree or uncontrolled congestive bean
`failure); abnormally lcw or high hean rate or blood pressure for age; known hyperseru.;t1vity to any
`of the ingredients in the study medication, or diagnostic agents used in the study; chronic treatment
`with any other topical or systemic alpha-adrenor.cptor agonist or alpha-adrenoceptor antagonist;
`alteration of exist:ng chronic therapy with agents which could have a substantiw effect on !OP, a
`substantial effect on the ocular activity of alpha-adrenergic agonists, or substantially interact with
`alpha-agonists; and treatment with adrenerg1c-augmenting psychotropic drugs.
`
`Ophthalmic Exclusion Criteria: Corneal abnormalities that would preclude ac.:urate
`readings with an applanation tonometer, use of contact lenses during thf' study, any other actiw
`ocular disease, dry eye (with confirmation of a Schirmer strip test < 5 mm), Sjogren's syndrome or
`kerazoconjunctivitis sicca. required use of other ocular medications during the study, asymme~ of
`IOP > 5 mm Hg between eyes, visual field loss of 50% or greater or any visual field loss which in
`the opinion of the investigator was functionally significant, laser or other intraocular surgery within
`the past six months, and r.apping of the optic disc~ 0.8 in either eye.
`
`Study Design: Before study medications were dispensed, subjects provided written
`informed consent. At the prestudy visit (vISit I), an ophthalrnii, ex•minatinn co11.sisting of assessments
`of intraocular pressure (IOP), visual acuity, biomicroscopy, ophthalmoscoP.y, pupil size, Schirmer
`tear test, and a visual field were performed to determine a subject's eligibility to panicipate in the
`study. Those subjects meeting the initial entry criteria were enrolled into the study and a medical and
`ophthalmic history was taken. For systemic safety evalu.-.tion, heart rate and blood pressure were
`measured. An ECG was optional at this visit. Blood samples were drawn to evaluate the subject's
`complete blood count (CBC) and blood chemistry.
`
`The washout period was four days to four weeks depending on the prestudy glaucoma medication that
`wa;, used. Following washout, all subjects returned for a baseline examination (visit 2, day 0). If no
`washout period was required, visits I and 2 could occur on the same day. At this visit, baseline
`measurements c,f !OP, visual acuity, pupil size, heart rate, and blood pressure were taken.
`Measurements of !OP were taken between 7:30 and 9:30 am (corresponding to trough, 12 hours after
`treatment-hour O ) ~nd again between 9:30 and 11 :30 am (corresponding to peak, two hours after
`treaanent). Biornicrn~copy and a Schirmer tear test were performed. Subject comfon was also
`assessed. Subjects who qualified for entry were randomly assigned to one of the two treaanent
`groups (brimonidine 0.2 \t, or timolol 0.5 % ). Subjects were instructed to instill the study medication
`at twelve hour intervals, between the hours of 7:30 AM and 9:30 AM and between 7:30 PM and 9:30
`PM, for a duration of 12 mooths. Subjects were instructed not to use the morning medication on the
`day of a scheduled visit.
`
`Subjects returned for follow-up examl.nations at weclcs I and 2, and months I, 2, 3, 6, 9, and 12. At
`these eiwrun,uions, efficacy was assessed by evaluating changes from baseline in IOP, visual fields,
`and cup/disc ratio (month 6 and 12). Ocular safety was assessed by evaluating changes from baseline
`in visWII acuity, pupil size, biomicroscopy, a.id ocular discomfon. A Schirmer tear test (month 6 and
`12) and an ophthalmoscopic eumina!lon (month 6 and 12) were also assessed for ocular safety.
`Systemic safety was assessed by evaluating changes from baseline in hean rate and blood pressure,
`systemic discomfon, and CBC and blood chemistry (months 6 and 12). Peale (two hours
`post-instillation) measurements of !OP were taken at week I and 2, and at months 1, 3, 6, and 12.
`Subject comfon was also assessed at all follow-up visits.
`
`

`

`Statistical Analysis: One year data from A342-J03-7831 and six-month data from
`A342-104-7831 were analyz•.:d in each respective final report. In this integrated swnmary,
`meta-analysis was pcrformej for the combined six-month data from both studies. However, in some
`tables/graphs, Months 9 and 12 data from A342-J03-7831 were also included.
`
`lntraocular pressure was the key variable for both pivo!al studies. A p-value less than or equal to
`0.05 was considered statis!iCJ..lly significant for the main effects and 0. JO for the trcannent-by-study
`interaction effects.
`
`The followin
`
`12
`
`10n, ms co or, 1agnos1S,
`
`two-way
`
`ys1s o vanancc
`
`two-way
`significant changes
`
`es or
`
`oscopy, ocu ar an
`10nucroscopy, op
`systemic discomfort, adverse events
`
`1-square test or
`
`;
`two-way
`significant changes
`
`es or
`
`Size
`
`pressure
`
`two-way
`
`two-way
`
`two-way
`
`;
`two-way
`baseline as a covariate
`
`covanancc w1
`
`Two major analyses were performed on the two combined studies:
`
`(I)
`
`(2)
`
`Preferred Analysis. Subjects from the efficacy analyzable population were included in this
`analysis. The preferred analysis was the primary analysis for efficacy.
`
`Responder Analysis. Responders were defined as subjc:,..-is included in the preferred analysis
`with an IOP reduction of at least 3 mm Hg or greater from baseline at two consecutive visits
`within the first month of trcatmem (trough effect, Hour O measurement).
`
`

`

`Study # l
`Protocol # A342-103-7831
`
`13
`
`Demograph.ics
`(All S\.lbj ects)
`
`0.2t Brlll
`
`0.5t Tim
`
`All
`
`222
`62.5
`10.3
`34.4
`83.4
`
`Variable
`Age (Years)
`
`Sex
`
`Race
`
`Iris Color
`
`Diagnosis
`
`N
`Mean
`SD
`Min
`Max
`
`<45
`45-65
`>65
`
`Male
`Female
`Caucasian
`Hispanic
`Black
`Asian
`Other [bl
`
`Blue
`Green
`Hazel
`Brown
`
`OAG
`ORT
`OAG/Ol!T [c)
`
`P-value
`
`0. 969
`
`221
`443
`62.6
`62.5
`ll.2
`10.7
`27.9
`27.9
`83.9
`83.9
`17 ( 7. 7')
`16 ( 7.2t)
`33( 7. 4t)
`100 (45.2t) 104 (46.8t) 204 ( 46. Ot)
`104 (47.UJ 102 (45.9t) 206( 46.5\)
`100 (45.2t) 117 (52.7t) 217( 49.0t) 0.134
`121 (54 .St) 105 (47.Jt) 226 ( 51.0\)
`175 (79.2t) 172 (77.5t)
`34 7 { 78.Jtl o.585
`16 ( 7 .2t I
`le ( 8.lt)
`34( 7. 7')
`26 (11.81)
`25 (ll.3t)
`51( ll.5t)
`4
`( l. St)
`s ( 2.3t)
`9( 2. Ot)
`0 ( 0. Ot)
`2 ( 0.9t)
`2 ( 0.5\)
`79 (35.7~)
`79 (3S.6t) 158 ( 35. 7tl 0.710
`12 { 5. 4\)
`5 ( 2.3t)
`17 ( 3. et)
`23 (10.4\)
`27 (12. 2t)
`50( ll.3t)
`107 (48,;41) lll (50.0t) 2l.8( 49.2\)
`137 (62.0t) 138 (62.2t) 275( 62 .lt) 0.933
`81 (36.7\J
`80 (36.0t) 161 ( 36.3\)
`3 ( 1.4\)
`4 ( l.Bt)
`7 I 1. 6\)
`
`[bl Other: two Hawaiians
`[cl One eye with OAG and the fellow eye with OHT.
`
`

`

`14
`
`Demographics
`
`(Preferr"d Analysis)
`
`Variable
`
`Age (Years)
`
`Sex
`
`Race
`
`N
`Mean
`SD
`Min
`Max
`
`<45
`45-65
`>65
`
`Male
`Female
`
`0.2t Brm
`
`0.5t Tim
`
`All
`
`P-value
`
`186
`62.7
`11.4
`27.9
`83.9
`
`0.713
`
`188
`62.2
`10.3
`34.5
`81.4
`
`374
`62.5
`10.9
`27.9
`83.9
`
`( 8.H)
`15
`81 (43.St)
`90 (48.4\-)
`
`28( 7.St)
`13 ( G . 9t)
`171 ( 45.7\-)
`90 (47.9t)
`85 (45 .2t) 175( 46. st)
`
`84 (45. 2t)
`102 (54.St)
`
`187 ( 50.0t) 0.052
`103 (54.St)
`85 (45. 2t) 187( 50.0ti
`
`Caucasian
`Hispanic
`Black
`Asian
`Other [bl
`
`150 (80.6t)
`14
`( 7. St)
`( 9. 7\)
`18
`( 2.2t)
`4
`( O.Ot)
`0
`
`145 (77.H)
`17
`( 9.0t)
`21 (ll.2t)
`( 2.H)
`4
`( O.St)
`l
`
`295 ( 78. 9t)
`31( a .n>
`39( 10.4.t)
`8 ( 2.lt)
`l ( o.n)
`
`0.456
`
`Iris Color
`
`Blue
`Green
`Hazel
`Brown
`
`69 (37.H)
`( 4.3t)
`8
`20 (l.O.St)
`89 (47.St)
`
`68 (36.2t)
`( 2.7\-)
`5
`20 (l.0.6t)
`95 (SO.St)
`
`137 ( 36.6t) 0.648
`l.3 ( 3.St)
`40 ( 10.7\-)
`184 ( 49.2t)
`
`Diagnosis
`
`OAG
`OHT
`OAG/OHT [cl
`
`115 (6l.. St)
`68 (36 .'6t)
`( l..6t)
`3
`
`118 (62.St)
`66 (35. H)
`( 2.H)
`4
`
`233 ( 62 .3t) 0.886
`134 ( 35.St)
`7 (
`l.. 9t)
`
`[bl Other: one Hawaiian
`(c] One eye with OAG and the fellow eye with OHT.
`
`Reviewer'• Comment ■ : There was no significant differences between the two
`treatments groups in age, sex, race, iris color, diagnosis distribution,
`medical or ophthalmic history.
`
`

`

`.nvestigators
`
`~aim; and Addres~
`
`. Diane Albracht, MD
`21675 Redwood Rd
`Cuuo Valley, CA 94540
`
`Walrer Alias, MD
`Nalle Clinic
`1350 South Kings Dr
`Charloae, NC 28207
`
`Howard Barnebey, MD
`90 I Boren St, So ire I 030
`Seallle, WA 98104
`
`Neil Cboplin, MD
`Naval Hospital of San Diego
`Dept. of Ophthalmology, Code 69
`San Diego, CA 92134
`
`E. Randy Cruen, MD
`Glaocoma Associates
`·50 E. Harvard, Suite 205
`Jenver, CO 80210
`
`Roben David, MD
`lllmar Klemperer, MD
`Ben-Gurion Univeniry of the Nege\·
`Sorou Medical Cenrer
`Beer-Sheva 84101 Israel
`
`Ronald Gros.s, MD
`Baylor College of Medicine
`6501 Fannin, C529
`Houston, TX 77030
`
`Stanley Hersh, MD
`1201 W. Main St, Suite 100
`Waterbury, CT 06708
`
`Ba