Page 1 of 50
`
` Insys Exhibit 2017
`CFAD v. Insys
`IPR2015-01799
`
`

`
`Declaration of Larry Diilaha
`Serial No. ‘i1iE98,739
`
`4.
`
`Feritanyl is a potent, short acting narcotic analgesic used, inter alia, for the
`
`treatment of breakthrough pain in late-stage cancer patients. Such patients are typicaliy
`
`treated for pain with a baseline dosage of a long acting pain medication. However, for
`
`episodes of breakthrough pain, a fast-acting, highiy potent pain reliever (e.g., fentanyl) is
`
`desirable. Accordingly, effective treatment for pain in 5 minutes compared to 10 or 15
`
`minutes or ionger is significant.
`
`5.
`
`SUBSYS® is-the registered trademark for the Insys brand of sublingual
`
`fentanyt spray.
`
`SUBSYS® is exemplified and claimed in the above-noted patent
`
`application. The specific SUBSYS® formulations are as described in Exhibit A.
`
`6.
`
`These SUBSYS® formulations were evaluated in Phase III,
`
`randomized,
`
`double-blind, placebo-controlled, multicenter studies to evaluate the safety and efficacy.
`
`7.
`
`Patients having breakthrough cancer pain began to experience statistically
`
`significant pain relief as early as 5 minutes after dosing. This is consistent with notion that
`
`the claimed dose needs to have a meaningful blood concentration at about 5 minutes. See
`
`SUB8YS® package insert (Figure 1 in Section 12.3) (Exhibit 1) and the Final Study Report
`
`(See efficiency results and conclusion) (Exhibit 2).
`
`8.
`
`No marketed, competitive fentanyl product has been able to show statistically
`
`significant pain relief any earlier than 10 minutes. See Exhibit B and Exhibits 3-7’.
`
`9.
`
`These publications, Exhibits 1-? described above, demonstrate that
`
`the
`
`presently claimed unit dose provides effective pain reiief at significantly faster times than
`
`placebo or competitive fentanyl products.
`
`10.
`
`Accordingly, the presently claimed unit dose provides efficacious pain relief at
`
`significantly faster times relative to other
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`transmucosai
`
`immediate release fentanyi
`
`formulations, which is both unexpected and, more importantly, a distinct clinical benefit.
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`Page 2 of 3
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`Page 2 of 50
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`

`
`Declaration of Larry Dlltaha
`Serial No. 111593339
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`I hereby declare that all statements made herein of my own knowledge are true and
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`that all ‘statements made on information and belief are believed to be true; and that these
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`statements were made with the knowledge that willful false statements and the like so made
`are punishable by fine or imprisonment. or both, under Section 1001 of Title 18 of the
`
`United States Code. and that such wltlfut false statements may ieopardtze the validity of the
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`application or any patent issuing thereon.
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`Page 3 of 50
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`H.
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`_....___
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`EXHIBIT 2
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`Page 6 of 50
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`

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`Sponsor: INSYS Therapeulics, inc.
`Protocol Number:
`lNS—€}5~0D1
`
`1. TITLE PAGE
`
`FINAL ST U1} 3:’ REP()'RT
`
`A Randomized, Double-Blincl, Placebc—(I0ntrc~l!ed,
`Multi~Center Study to Evaluate the Safety and Efficacy
`elf-"entanyl Sublingual Spray (Fentanyi SL Spray} for
`the Treatment of Breakthrough Cancer Pain.
`
`STUDY DESIGN {PHASE}
`
`'PR()TOCOL NUMBER
`
`Ill
`
`l‘l~lS-05 -001
`
`DRUG PRODUCT
`
`Fentanyl suhlirzgual spray {Fenianyl 8?. Spray)
`Active ingredient: Fentanyl base
`Unit strengti1s: I00, 200, 400, 600, and 300 pg fentanyl
`per acluatieri {unit dose spray device)
`Adrriinistercd dose strengths: 100, 200, 40G, (:00, 300,
`I200 (2;><60{)_), and 1600 (2x80{}) gig fcntariyl
`
`DRUG SUBSTANCE
`
`Fentanyl base
`
`.!NI}ICA'l‘ION
`
`Breakthrough cancer pain
`
`S1-‘ON S01-'1
`
`lrisys Therapeutics, Inc.
`10220
`51st Street, Suite 2
`Phoenix AZ 85044
`
`PRINCIPAL
`IN VEST IGATQ R
`
`A list ofthe investigators involved in this study, along
`with clinical site inforinaticn, is included in A ppemlix
`16. I .4.
`
`MEDICAL MONITEBR
`
`Mauricio Calerc, MD
`Clinimctrics Research Inc.
`
`STUDY DATES
`
`Initiation (Firs: subject enrolled)
`
`l 8 October 200’?
`
`Completion {Database leek}
`
`22 February 2010
`
`REPORT DATE
`
`E33 Decerniver 20 [0 (Version 3.0}
`
`This study was conducted under Good Clinical Hractice accoi-ding to die Declaration of
`Helsinki (2004).
`
`CONFBENTIAL
`
`Version Date: C-3 December 2019
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`Page 7 of 50
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`

`
`Sponsor: INSYS Therapeutm, Inc.
`Protoco! Number:
`INS-05-D01
`
`2. SYNOPSIS
`‘ ................._
`
`..........-.-..........w.................-...................-u-..._........._"wmwm.m ...............................‘......................................,_
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`{ghlfizé .t1'f.$;>(sn:s'0r
`% ?~Esm:e 1:? Product
`Name of
`Ingredient
`
`‘
`
`{nsys "E"i2cra;n-.':utic;~:, inc.
`§ Fcitianyl suhiisagtaai spray (fentanyl S-L Spray}
`‘gikctive iaigrctiieni: Fentznnyi base
`Unit strengtlas: I00, 2G0, 400, 609, and 800 pg fcntanyi per :«:::tiJa£i<:-n (uni1.£ios:-. spray
`devicc)
`. Administered dos-3 strengths: 106, 290, 401), 690, 800, £200 {2:<6{)O}, and Ifzfifi
`(_2xS=f}(f) gxg fenianyi
`
`§
`
`E
`
`5
`
`Titie t3!"St:Itfy
`
`w\n ------------------- I1nk\\ -----------------------------------------------------W-—-I-I-vi
`J1 Ramimnized, {)(aubIe~§3!ind._ Placebo-C0rm'0lied__ Meiiti-Center Study 3'0 Evaluaiic me
`i
`Saftttgu and iifflcacy -C:-f Fentanyl Subiinguai Spray (Fesntzinyl SL Sprsiy} for the Treatnlcm 5
`Uffircakthttsugh (Ear:-::cr Pain.
`E
`
`x_';
`
`'
`
`'
`
`.....
`
`§
`
`E
`
`IIIIIQ
`
`Primary Objective
`
`afissess the eificacy ofFentan}r] SI. Spray fat’ Eh: izrcatmiint Elf isreaktllrougfil CRTECE‘-1' pair:
`in opioid-tolerant subjects.
`
`$esu‘m(iar_v ()i}jee_tit-“cs
`
`Evaluate fhc safely :3!’ {"c::tang;I SL Spray
`
`these opi(:ic¥-tolerant subjects.
`
`An azlaiiiinnaai objccziive was to assess 91$:-.tmeni Sat§5f2icti(>ri with :ne£ii:::estia)£1_
`................................................................lA'V"’|"V|-"'|ll"":
`
`........,......»...............m _............_..—.... ..._
`
`....... _........_................................................ . .... ..... . .... .... . ....
`
`?t=]'i§TI:‘!0I}{¥{;(}{"§ Y
`
`E Study Design
`;
`
`This was 2: .[’husa: iii randoniizcd, double-blind, piawlmu-ccmtroiled rm.-E1i—cen£-r:r stzaaiy of
`the clinical rc.=£g::.“.-113:‘: ta Fimatiyi Sill. Spray as a i.rr:‘.atn1en£ £331‘ breakihrough Ca1T.cEl'}}iiii'1.
`5 Subjects; were to be ttvaiuazed at ScDee11i::g Visit for the usc and re.-sponsm in opioids in
`the previous 24 hours. The Screening Vi:-:i$. was if) occur 23 -6-? days p1"1or to: the €}pcn~
`label 'I'i!:'za£'Em': Visit.
`
`Approximately 136 subj cats who cx}:1eri<:nced<)r:e to four brecakthroiigh camcer pair:
`:
`episodes each day and when were receiving 3 stabic dcasc efschceduled 24-hour -opioids tn
`manage baseiine pain were to ‘mt: s-mtszrc-:d Ema) as titraticm pserimi Fear 5: tnaxitnllna of 22] {+5} ‘
`days is estabiisii the i.‘r;)tii’¥EEi} sicasa of ¥"'e,ntanyl SL Spray required to ef‘f::ctivt:ly' treat Eheir
`brtezakthmligh cancer pain. Subjects who established an npiimai dose of Fesztanyi SI.
`Spray were to be entered into the r:md<ami2x<i, :}oa:bie-blind, piar.:ebc>—comroikci peried of
`the studi‘ {tic-ubEe~b!iI1:E ficriod) for a m-':1ximum_“nf2'|
`-‘r 5 flags :0 determine the c§‘fica::}-‘
`
`versiE3}?3f5
`
`"""""""""""""""WcE"c3Nr=:DENTIAL
`
`Version Date: 03 December 2010
`
`§§§%§§§
`
`it
`3....................................__.......
`
`REPORT PARTICULARS
`..........___________............._,.,,._._.._......_...._......,...__...__......_...________.........................................~.._.........................,._,:
`
`_
`
`}“t:!3Ii¢atim:s
`kiwi..................
`__________________________.._.___.______..........__,..__,__....................................................
`Re.p¢_art. time
`i 03 Daccrnber 201:: (Version. 3.0)
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`{S October 206? (first subject euroiiccl} I0 22 'f<‘e=‘t>ruary 38 E {.3 {database iock}
`...._....,..._...__............._.............
`........................__...._,.......
`Principal
`A iist ofthe i5}‘v't:st'igEl!L‘1E'5 inw:-Ives} in this study, along with clinical site i£3‘fi)rTfi‘:ifii){i, is
`Investigator
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`Page 8 of 50
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`“ I-‘ I III
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`

`
`Sponsor: INSYS Therapeutics, Inc.
`Protocol Number:
`INS-O5“-_0D1
`....,............ .%MM ..............
`
`.——....................
`
`° oxycotione, E1},*droco<:ic:m-3, or codeine with acetamimphett). The subjtect was to have 21
`stats]: tiaiiy pattern averaging t)f':~3 to 4 breakthrough pain episodes during the -1- day
`5 Screening Pt-.‘.1'io:i.
`
`Maj“. Exclusion
`Criteria
`
`;
`
`‘
`
`Current use ofco11n:11e:rc-i:aiI},r avai.l:t1::Ee era! short-acting fentany] for breakthrough
`pain. Subj cots; previously on Actiqfi‘ or Fentorarg can be erirollasi if they have had a
`asew-zn day washout.
`
`Rapiély inoteasingr’uI:c:o:str<)Eied pain.
`
`Painful erythemzt, oedema or uiccrs under the iOt1_t§',l!t:.
`
`5
`
`l<1fficn<'.y
`
`:
`
`___
`Safety
`
`E EvaluationofStudyMedicationwastobematteat30and60minutesaftereachdoseof
`
`sttidy medication. The primary efficacy endpoint ofthe study was the Surarmcti Pain
`Into-stsity [}ift"erent:w {SPID) at 30 anintatos srfter tiosistg (f*3PU')3¢}. ‘Flu: secondary‘ eificacy
`errdpoénts were Tom} Pain Relict" {TO'l‘PAR} at 30 minutes (_'i"OTf’.*‘sR_-g-.1} after dosing arts}
`~ Suiajccfs Global Evaluation of Study Medication, recordtzd at 3% mimtt-as after dosing.
`§1
`;
`The measurements of 'E‘()TPAR and SPID were catcuim-:ti over the 6%) minutes tresittnent
`i
`. gmriod for each of the 10 doses of study medication used to treat bmaktlrough pain in the ‘
`douh-le~blirrd periori.
`A Troatmcnt Satisféctiota Quttstittnttairc for Medication (TSQM; was completed by
`\
`to__r_§corti th.'.:i1' satisfaction with the Era-zatmesnt n1edi::ation_
`Aclvcrse events {AB} w::rt: recorded and reported for safety assessirieni. The effects of
`treatarsert on vital signs and oiinicai laboratory meastrrenaexnis were assessed throughout
`the study. Safety was asse.-;se<i on the-. foiiowing criteria:
`
`_
`
`A.F;s:'Seri-mas «‘\<i\«'-;:rse: Events {SEARS} occurring tl:to:1_gE1(rtit the study
`l_.zab::rztiory evaiuatiorss (serurn chemistry, hetnata)E;)gy, urinalysis}
`Vital signs asses-sntcstts {blood prcsstsre, heat’: rate, respiration rate and
`temperature}
`Pfaysical ezxziminal ions
`
`ST.ATIS'I'ICAL METHODS AND ANJXLYSIS
`5...........»"m_ww~ ..m...
`..w.................w.-um.
`Efficacy
`.'\naiys£:s; 0Fet"f:car:;,e were based on the in1ont—t0-treat popuiation defined as alt
`raiadoniized subjects who prcvici-ed infcsrsned ¢:ot3s;er1t', took Eifliti)’ rurtdicatirén and head at
`
`tit
`
`tttI
`
`t
`
`:
`
`‘ leastonepair: nzeétssrraerraeotfollowing€LdtfliE1§S£l'aIi0t] of:-:t..tc1ymedication.
`
`The '.m::}y:~:is of the primary eraripoint. SPIDN, was preceded by 3 data redasctiosr
`algoritlam. Within each subject, SE’.II),., was summarized mrer brcakthrougit pain
`cpistuié-.5 treated with Fr::r1ta.::yi SL Spray and over episodes treated with placebo. Tht:
`9 diff3.:rcnoe Wi5.':'EiIt subject. 0f’thc two SPl£}-;.;;.s\1nm1aries was then caicuitsted. Atiditionttliy.
`within each subjoct the mean basetino pain intensity was caicuiaiod over alt i>rcakt!trcug}:
`; pain episodes treated with stzsdy mt-:éii(::itEoI1 {regartliess 0E'tre:s!m¢111.'). Wi1?1§r1—sub_ir:ct
`difihrenoes in SPZDN were then analyzed using anzilysis of co-variatscr: {ANCOVA}
`ttsi:1gt?=.e wi£hi:1—:suiJ}L*::t meal: bztstfline pair; intensity as a zwvariate.
`
`3 t
`
`. The se:¢;or;dary emipoints ofTO'!"PAR3u and Subject Globai .Ev3.h.aation oi"-Study
`: Medicaticssi, rcr.'0rde-zi at 3-0 rnitmttis post-dose, were analyzeti in at similar manner. The
`uvenzil tyoe. 1 error rate fo'rtE1e primary and secomiary arzalyses was sot at 8.95. The p-
`.‘:ia.*.=.J.sé§..*.’.=.<.>.*.r.'.z..i.t3.t:__§§§s2o!§r:e'.2332%weinrt.:£2té;§.¢J;~§.Es!.§;>;a2z£tE.95.s.9;<2.s3J.2:5r.i§9.t1§.9s.§ir3.t..t.t!$:_.._
`
`‘
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`Version 3.0
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`CONFHDENTIAL.
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`Page 10 of 50
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`

`
`Sponsor: INSYS Therapeutics. inc.
`Protocoi Number:
`INS-05-001
`
`E-ioeitberg tiiglii-(:3; iuii,-.1”-é";-?».“i§“;~1;é':“t:~=er endpoint was to
`f)l'iE!12ti'}" endpoint was deterinirieai to
`signi Eicant.
`
`As 2-: serisitivity analysis. the WithiI1—subject sumrraaries of‘ trecatrractit ef€‘e::r were ans.I'y2sti
`using the Wiicexeii signed rank test. As zidciitioii-at sensitivity anaiyses, the
`meastirements ot'1’i_. Pain Intensity Difference {FED}, and Si-‘I121 were analyzed using a
`singie mixed model in which P1" was the dependent variable. Inference on P} E) and SW!)
`at ail time {.'30il1i.E!.iilCiu(iiIig iht-3 3i} minute pritnaijr
`pciint, was performed witisiri this
`model, as those measmes are iincar t;-zytzfrsinaiions ofPI at \"3'i'iGt.1S time points. The fixed
`efiecis of the mode} were iteatrnent_ time, and E1'cai.}‘.'1t‘.1‘\l-Eit'3‘!C iriteractitan. The }’£in(ii)E‘i3
`effects were subject and hreakthrtsuglt pain episode within subject, and the random error
`associated with time period within episode.
`.............e.,..........\;....
`E Safety analyses {adverse events, tabs, and vital signs) were performed tart the safety
`popuizatioti, defined as all randomized suinj acts who took at {east one dose otstutiy drug.
`Descriptive: statistics were presenteti for titzmograpitic-s, baseline c:}:a1'actei'istics,
`sutsirtiary of iab-oratory patstncters, vitzsi sigias and physiczei examinations.
`l
`STUDY POPULATION RESULTS
`..._...._....... . . ... . ......__._..W.
`.W.._....._........_..._.._..._...
`......._,.._. . .. . ,._
`'I‘itr:3't'ior: ptsgauiatiozr, mean age was 55.6 is 12.13. }"E:)iil'5 (range: from 24 to 35 years), with
`I
`i ?7‘i'/{J ofrsuitt-j acts <65 years of age and 95% of subjects <?5 years of age. 53% ofsiliajects
`were female and 9 i ‘ii. of subjects were White.
`
`:
`
`,.............._,.___...W.
`i Demographics
`
`fin.......................................
`
`I if? years {range from 24 to 35 years, with 83% _
`1'1"? population: itllfiiit“. age was 54.1
`of subjects <65 years efage and 9794: of subjects <":'S _‘.‘t-.‘tir€E of age. Sci-*2-ta efsuizjeets were
`feinaie and 9 1% of suiijeets. were White.
`
`‘
`
`Subject Disposition
`
`:
`
`A iota} of 13% suiajeots were treated during the titration period ofthe stttdy, and
`comprised the safety population. Of these, 93 subjects (75%) were F£l}'ttiO!l'ti'1.(‘.Ei it) the
`doubie--iziinti perioti <;-f'1i1e study. A tetai tat"35 suhfieets (2 7%} in the safety pepuistiori
`withdrew from the study‘ eariy, with the rttost (:0l"m‘fi£)£‘: reasons for termination being
`5 voiurstary withdrawal (16 subjects or 12°/u) and AE.-; {'1 siihgjccis or .*':%_‘z. Ct:-nsitieriraig only
`those subj-eats rand-;)mi:=.e(i to the double-blind period -Jfthe study, 3 subjects (33;-is}
`tenrririated the study eariy (one sirhjcci withdrew (Eu: to each of 13:: ;‘'\}P'., tioti«a:ompiiain::te
`and voiumary witi*:(ir'.swal}. Tiicsrtz were 95 subjects {_'}'3% of the safh-E)’ popuiaiion} who
`%
`‘ cmrtpieted the double-blind 3>erie>¢i, and Qt!subjects{fiE§%}roiieti<:vterioti1e: safety
`_
`portion of the sitasiy. Tiretea were '39 subj eats {{ii%} who completed if) doses ofstudy
`.......... ..§L~!s.ss.sss<j32s.is:.§.i3s.2 ,....._.._._....._...................~._......i
`EFFICACY RESULTS
`
`E
`g
`’
`: ww
`
`eificae;-itii-n<i;>“o‘ii1t that this study was the evaltiatitsn of $i"Ii'.'F_;;. I-iigitfl SPID
`i values indicate itatgsrowx-sm-:rt£.'s in pain intensity. SP2L'3;st: was significisrtily imprnwed
`{p<I{I.0{3f}‘-.} when bresiithmugh pain episodes were treated with Feiitanyi SL Spray
`compared to gilacebta. Mean {.1 81)} 8231133., scores were 640.3 i 458,3 Ear i-'-‘es-itzmyi SI,
`‘ Spray and 399.6 4*. 39} .2 for piaceiao, with a afiiffererice of 240.7 :1: 363.9 between the two
`treatments. -.‘:5}“!I} vziitres at ail time points were sigiiificantiy improved wit-;:n pair: was
`treated with Fcntaziyi SL Splay colnpared with piactrim. The prop-zyrtiori 0t":=:!.:t:j€:ci.s with
`imprmred SP1 E) values when treated with I-‘erriarsyi ESL Spray rsmgeti From 68% at S}‘i.{)_t;
`ti) 1'9’?/O Bi.
`
`0:12-oftwts sccoruiary effi-may enzipoints for this study was the evesitssttiuiz of 'i”()'i'P./isR3,-;_ :
`_ }'1ig1'Lr:t‘ TO'i‘P.r-‘LR vaiues indicate an imptovcnieitt in totai pain reiief. For TGTPAR;.;-,,
`TOTPAR was sigtsific-anti}; imp:-ovcci (p<:0.i}(ti}l) when iareakiirrougti pair: cpisoaies were [
`treated with l<‘eniar;3'i S}. Spray compared to placebo. Mean (% SD} 'i“()’i‘F'AR_»_.;, scores
`were 78.3 at 2:14 for Fetatairyi Si, Spray and 61.0 cf: 2&8 for piaceé-:0, with a difference of
`'
`11323 .-i- 19.5 between the two tt'€‘.E1i.rr)¢tE1.'$. The p-vaiue '
`‘
`’
`'
`‘ using 1-Eociaber
`‘s method. The adiusted ,-vaiee rezrsairictt .sig§_1i_i_f_§g_a;_r3_t____________;
`
`“Version 3.0
`
`CONF1DENTiAL
`
`Version Date: 03 December 2010
`
`5*?"
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`ti
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`iE i\ s
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`Sponsor: INSYS Therapeutics. Inc.
`Protocoi Number:
`lNS—05-D01
`
`gwzompaatd to iiase beginning ofthe period, izadicatingan imgzrovcmenlwin satisfaciimiviviih the, pain reli€:fIne:di;'.ati0a:._«‘
`At the and ofthc §}:2£'in(§, 8.9% e;{'sui3_§e<;ts were at icast saiisfieii wish Fentzangvi 5-.‘ei.. :‘3przay_. compa.rc:<€ with /ii“/E: of
`suiijcc-"L3 whc were satisfied with their cumin: pain medicsiticii at baseiine. Similatiy, 9i3‘3~‘§: of suiijectsa at the and of
`the period were at teas! .-satisfied with the amczusst eftime: ii
`le)0i~L Fentsenyi S1. Spray to start werking, compawd
`with ?.E% i3:i.’s1ahje<'.E.=s at baseline. Co:np:3r:abie increzases in szttisfactiot; were also seen far the other questions,
`including symptosn relief, c<:I:E'1:Een£:':.‘ in the nxcdicatimi, and ccsiwenienc-:2 <af'us£:.
`
`E Tiiere were no new safe I issues iriexeiifieei fer }'-‘entsanyl SL Sgzray. Three deaths were i“.':i3-1>t'I‘.i£')i.i in this study, each
`:
`i"wEii::i1 was eassesseci as unrciated to study drug. in each case, the saiisjrzcfs dcaih was reiatcd to the pmgstssion of
`the undcriyiikg disease cat‘ cancer. The rate of seriaus: aciwrsc t-wants was haw. wiih zappmximately 5‘?/o cit‘-szabjesszts
`experiencing an SAE in each of the titration anti d<>u’ol::—biis:d peiicds. The reiasi frequeniiy reporteci AR was
`nausea. AES as$es&2:cd with an intensity ofsewuzrc and which were 3% Peaks! possibly rseisaieti to study drug were
`experienced by 3 subjects; none <:nf'Ei’:r:st: events was considered serious.
`
`CONFIDENTIAL
`
`Version Date: 03 December 2010
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`EXHIBIT 3
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`304-
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`RX. Pr)ri‘enoy rent’ an‘. 2" Prdn 5'9 (I999) 303-_i}2
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`controlled and tolerated. they are commonly described as
`‘breakthrough pains.’ Breakthrougli pains that are precipi-
`tated by a voluntary action. such as movement, are often
`labeled ‘incident’ pains. In the cancer setting. breakthrough
`or incident pain usually implies a moderate to severe tran-
`sitory pain that punctuates a persistent background pain that
`is generally well controlled by opioid therapy.
`Breakthrough pain is a challenging clinical phenomenon.
`The prevalence of breakthrough pain in a prospective sur-
`vey of inpatients with cancer pain was 64% (Portenoy and
`Hagen. 1990) and surveys indicate that the likelihood of a
`satisfactory response to opioid therapy is lower among those
`who report this type of pain than those who do not (Merca-
`dante et al., 1992; Bruera et al.. 1995). Clinicians conunonly
`observe a strong association between physical and psycho-
`social impairments. and either the frequency or i11te11sity of
`these transient pains.
`The potential for adverse consequences associated with
`breakthrough pain has been the impetus for the development
`of specilic therapeutic strategies. In those populations trea-
`ted with long—term opioid therapy,
`the most common
`approach is the co-administration of a supplemental short-
`acting analgesic ‘as needed,’ along with the scheduled lo11g—
`acting opioid regimen. Guidelines for cancer pai11 manage-
`ment now include instructions for the use of such a supple-
`mental opioid analgcsic fWorld Health ()rganizatio11. 1990;
`American Pain Society, 1992; Jacox et al.. 1994), and the
`term ‘rescue dose’
`is widely applied to describe this
`approach. Based on clinical observations. the selection of
`rescue drugs typically l'ocuses on pure ;,t—opioid agonists
`with relatively short half-lives and lime-action proliles.
`characterized by a rapid onset. early peak effect and a dura-
`tion long enough to treat most breakthrough pains. In the
`cancer population. morphine sulfate, oxycodone and hydro-
`morphonc are commonly used for this purpose.
`Oral transmucosal fentanyl citrate {O'tFC) is currently
`undergoing investigation as a new treatment for break-
`through pain.
`In this formulation.
`the potent synthetic
`opioid. fentanyl.
`is incorporated into a sweetened matrix
`that
`is dissolved in the mouth, allowing rapid absorption
`of part of the dose directly througli the buccal mucosa (Stan-
`ley et al.. I989; Streisand et al.. 1991). Currently approved
`by the United States Food and Drug Administration for
`anesthetic premedication and conscious sedation in moni-
`tored scttings. (_)TF(I has been anccdotally reported to be an
`effective therapy for cancer-related breakthrough pain (Fine
`et al.. 1991}.
`The systematic investigation of a new opioid formu-
`lation for breakthrough pain is unique. In the absence of
`previous controlled clinical
`trials of
`treatments
`for
`breakthrough pain. new tnethoclologies were developed
`to accomplish this goal. A recent study of OTFC demon-
`strated the feasibility of a randomized. placebo-controlled.
`multiple cross-over design (Farrar et al.. 1998). The present
`study applied a novel controlled dose titration method-
`ology to evaluate the safety a11d ellicacy of ascending
`
`doses of OTFC.‘ as specific therapy for breakthrough pain
`i11 cancer patients receiving varied scheduled oral opioid
`regimens for chronic cancer-related pain. This method-
`ology incorporated blinding and randomization procedures
`i11to the evaluation of recurrent pains in the home environ-
`meat.
`
`2. Methods and materials
`
`This Inulticentcr study evaluated the effects 011 break-
`through pain produced by ascending doses of OTFC,
`using random assignment and double-blind drug adminis-
`tration to ensure that the patients and study staff were una-
`ware of the actual dose administered as dose titration
`
`ensued. The study was approved by the Institutional Review
`Boards at each site and all patients gave written consent
`prior to participation.
`
`2.}. Sl'ta‘d_\' popnlnttort
`
`Adult patients with cancer-related pain were eligible for
`the study if they (I) were receiving a scheduled oral opioid
`regimen equivalent to 60-1000 mg oral morphine per day
`(2) had experienced at least one episode per day of break-
`through pai11 between 0700 and 1600 h oil the 3 days imme-
`diately preceding screening, and (3) had achieved at least
`partial relief of this breaktlirougli pain by the use of an oral
`opioid rescue dose. Breakthrough pain was defined as a
`t1'aI1sitory flare of pain to moderate. severe or excruciating
`intensity that occurred on a backgrotlnd of chronic pain that
`was maintained at moderate intensity or less by the fixed
`schedule opioid regiment. if patients had more than one type
`of breakthrough pain or had breakthrough pain in more than
`one location.
`they were asked to identify one pain as a
`‘target’ breakthrough pain for the study. A standard relative
`potency table (Jacox et al.. "199-4) was used to determine the
`morphine equivalent dose for patients who were receiving
`an opioid other than morphine.
`Patients were excluded from the study if they had a recent
`history of substance abuse. neurologic or psychiatric
`impainnenl sufficient to compromise data collection. any
`major organ impairinent that could increase the risk of stip-
`pletnental opioids for treating breakthrough pain. or any
`recent therapy that could potentially alter pain or response
`to analgesics during the study. Specific exclusion criteria
`included renal or hepatic function tests greater than three
`times the upper limit of normal, trcatlnent with strontiun1—89
`within 60 days. a11d treatment with radiotherapy to a painful
`site within 30 days prior to the study. Patients who had
`moderate to severe oral l‘t‘tl1Ct.‘JSlIiS were also excluded.
`
`2.2. Procedures
`
`Patients who remained eligible following screening
`proceeded to the two phases of the study: (I) opioid dose
`
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`R.K. Porremay 9:‘ cu’. /Prim 79 {I990} 303-JI3
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`3'35
`
`stabilization and baseline data, and (2) O'l‘l~‘C dose ti-
`tration.
`
`2.2.}. Opioid dose s-tabilizntion and baseline data
`Baseline data concerning the performance of the patient’s
`usual rescue dntg were collected on 2 consecutive days
`during a period of stable dosing. ‘Stable’ dosing was defined
`as at least 3 consecutive days during which the scheduled
`opioid regimen yielded an average daily pain of moderate
`severity or less, tolerable. opioid side effects. and the. need
`for four or fewer rescue doses. If patients had a history of
`stable dosing for at least 3 consecutive days prior to screen-
`ing. baseline data collection about the performance of the
`usual rescue drug was allowed to proceed immediately after
`screening. Patients who did not meet the criteria for a stable
`opioid regimen at tl1e time of screening underwent adjust-
`ment of the regimen using a standardized procedure based
`on widely accepted guidelines for the management of call-
`cer pain (American Pain Society. 1992; Jacox et al., 1994;
`Levy. 1996). This stabilization period, which could continue
`for as long as 1 month. was stopped when the criteria for
`stable dosing were achieved for 3 consecutive days. After
`stable dosing was achieved. the patients collected baseline
`data for 2 consecutive days. Patients were allowed 5 work-
`ing days to identify 2 consecutive baseline days with break-
`through pain that could be assessed between 0000 and 1600
`h.
`
`2.2.2. O't"l’C' dose titrurtori
`
`The ()Tl"'(_‘ dose titration phase followed the baseline data
`collection. Patients were given multiple O'l‘l~‘C units at a
`specific dose; only one unit dose was administered at
`:1
`time. They were instructed to consume up to four separate
`0'I‘l~‘C units at 15 min intervals to treat a breakthrough pain.
`The goal of this phase was to gradually increase the size of
`the O’l‘FC unit dose until the target breakthrough pain could
`be adequately treated using only a single ()TF(..‘ unit.
`Each day. up to two episodes of breakthrough pain
`between l)7"()0 and 1600 h could be selected for ()TF(.‘ treat-
`
`ment. The usual rescue drug was used to treat all other
`breakthrougli pains on these study days. If two breakthrough
`pains were treated with the O'l‘FC during a single day. a
`minimum of 2 h was 1'cquired between the end of treatment
`for the first and the start of the second.
`
`Once a pain was selected for OTFC treatment. the patient
`recorded pain data, then consumed an entire OTFC unit. if
`possible during a period of l5—2O min. To ensure that the
`dung was tolerated and that the decision to consume another
`unit was consistent with the protocol, patients were initially
`required to call the study nurse prior to taking the second or
`third ()Tf’('.‘ unit.
`
`All patients who entered the dose titration phase were
`randomly assigned to begin treatment with either a 200 or a
`400 _u.g O"[‘F(" unit. All units were identical in appearance
`and both the patient and the investigator were blind to
`this starting dose. With the option to consume up to four
`
`units to treat a breakthrough pain episode. the full starting
`dose to treat a breakthrough pain could be as high as 800
`,-.tg for those randomized to receive the 200 _t.I.g unit and
`1600 pg for those randomly assigned to receive the 400
`pg unit.
`The size of the ()Tl"*(_‘ unit dose could be increased or
`
`decreased on successive days. The available O'l‘l~‘C units
`contained 200. 400. 600. 800. 1200. or 1600 pg of fentanyl
`citrate. I-Lach increase or decrease consisted of a change to
`the next step in this sequence of doses. For example, titra-
`tion for a patient who received the 400 pg ()'l‘l"'C unit would
`consist of an increase to the 600 pg O’[‘FC unit or a decrease
`to the 200 pg OTFC unit. When this new unit was used to
`treat a breakthrough pain. as many as four could be con-
`sumed at 15 min intervals, if needed.
`The decision to titrate or maintain the dose for another
`
`day was made following a daily telephone assessment that
`evaluated response to the (')TF(.‘. including the number of
`units consumed and a global evaluation of analgesia and
`side effects. Simple guidelines were developed to encou-
`rage consistency iii the investigators‘ judgments concent-
`ing dose
`titration. For example.
`investigators were
`encouraged to decrease the size of the OTFC u11it
`if the
`patient consumed at single unit and experienced 1Inacccpta-
`ble side effects. Conversely. investigators were encouraged
`to consider a dose increase if no unacceptable side effects
`occurred and two or more units were required to provide
`adequate pain relief for an episode of breakthrough pain.
`All potential dose changes were discussed with the patient
`a11d a request for a change in dose was conmnuiicated to the
`pharmacist only if the patient agreed. New OT}-‘C units
`were provided each time a decision to change the dose
`was made.
`
`111 contrast to the decision to reduce the dose, which was
`promptly implemented by the study pharmacist. the request
`to increase the dose was ignored one-third of the time to
`create additional uncertainty concerning the actual dose of
`OTFC. Wlieti
`the study pharmacist received a request to
`increase the dose, a separate randomization table was con-
`sulted that assigned each request into an ‘increase dose‘ or
`‘ignore request’ category. If the request for a dose increase
`was ignored.
`the following request was always fulfilled.
`Combined with the double—blind. random assignment to a
`starting dose, this second randomization and blinding pro-
`cedure reduced the likelihood that the patient or investigator
`would know either the size of the dose or whether it repre-
`sented a true increase over the prior dose.
`The titration process continued until a dose o1‘0TF('.‘ was
`found that provided adequate relief of the target pain on 2
`consecutive days without the need to take more than one
`unit. On each of these days. one or two breakthrough pains
`could be treated with the OTFC. Patients who could not
`
`attain adequate relief of the breakthrough pain with a single
`1600 pg dose. the highest strength available. and those who
`could not be adequately titrated during a maximum of 20
`days, were removed from the study.
`
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`RX. Pr)i‘i‘ertoy at at‘. 2" Pm'n .79 (I999) 303-_il2
`
`2.3. Ouf(.'r)m.<3 rireasrrras
`
`All patients completed a questionnaire that provided
`detailed information about their persistent pain and break-
`through pains, and both disease-related and detnograpliic
`intorniation. 011 each day of tlie study. patients completed
`a daily diary that recorded global information about the
`persistent and breakthrough pain. pain treatments. and
`changes in medical condition. 'l‘his infortnation was used
`to ensure that the underlying pain syndrome remained stable
`during the study. On the evenings of the 2 baseline days and
`each OTFC treatment day. patients also recorded a global
`performance evaluation of the rescue drugs used during the
`day. These global performance scales ranged from 0 (poor)
`through 4 (excellent).
`The primary outcome data comprised pain scores col-
`lected during treatment of one or two episodes of break-
`through pain during both baseline days and the 2 days
`following successful titration of the OTFC dose. Data col-
`lection was similar for all these episodes of breakthrough
`pain.
`Immediately before drug admiuistratioii, patients
`recorded pain intensity in a study diary using an 11-point
`numerical scale (0. no pain; 10. pain as bad as you can
`imagine). Measurements of pain intensity and pain relief
`were recorded at approximately 15. 30 and 60 min after
`starting treatment. Breakthrough pains that required tnore
`than one 0'I‘FC unit were assessed at only 15 min after
`starting the dose. Pain was again evaluated on the 11-
`point uutnerical scale and pain relief was assessed using a
`four—point categorical scale (0. ‘none’; 4. ‘complete'). A
`global impression of the drug's performance, which used
`a rating from 0 (poor