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`LEVOROTA‘I‘ORY 150MB! 0?
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`compound is particularly valuable in the treatment of
`'
`The rte-eat invention fem ‘0 the mum 5
`According to the invention, anovel industrial prod~
`.
`hypersotnnis and Alzheimer's disease.
`det'gvmve ofbeuzhydryhulfinyheetamide. the method
`not is recommended which is useful in therapy Ind
`forgtaprevennonmdiumein them: .eepeeitllymn
`belongs to the family ofthe benzylhydrylsulfinyl deriv-
`antidepressant and stimulant for the cenu'al nervous my“.
`the said product being (—)-benzhydrylsu1-
`mtem(CNS).thesaidderivativebeingusefulinpartie-
`finylacetamide.‘
`ularinthetreannentot'hypersomniaonacconntoflts to
`’I‘hislevorotatorycotnpoundcannotbepreparedby
`- trams a“
`isohtionfmmthecorrespondingncemicamide. How-
`tion No. Fr-B-z 385 693) describes the racetnate
`'
`~
`(immmyw‘ WM h" the code
`per 86. by the application of conventional reaction
`.
`.
`precunoroftheamideawordmgtoamethodlcnown
`number CRL 40 476 and the following Itmctnnl for- 15 mm
`mula.
`The method ofpreparation recommended according
`toqtheinventionccnsistsin: ,.
`(l piloting (tybenzhydrylsulfinylaoetic acid with
`(-)-a~ntethyibeozylamine to give the (~)—benzhy~
`drylsulfinyhcetate of (—)-a-ntethylbenzylamine (the
`reaction advantageously being carried out in the pres-
`ence of a small excess of amine relative to the stoi-
`chiometrie conditions. and more particularly with a
`25 molarratioamine/acid ofbetween 1.02/1 and 1/15/1
`and preferably oi between 1.05/1 and 1.10/1),
`(2') converting the resulting (—)-benzhydrylsulfiny-
`laeetste salt of (-)-a-methylbenzylamine to (—)-
`benzhydrylnilfinyheenc and [the conversion adv _ -
`“segmly being (tamed out by hydrolysis in an nerd
`medxmumt.13313313:3” warm we: (especially
`W“
`.h .
`_
`_
`(3') {ubieeuns the retultms (-)-benzhydrylsulfinyln~
`cene acid to an amidst: n reaction with gaseous am-
`Theamidationofstage(3')isadvantageouslycarried
`monia.
`'
`
`as a product (see Example 1 of the said French patent)
`and as stimulant for the central nervous system (CNS). 30
`It is also known that, in Patent Document EP-A-No.
`O 097 071. the neuro ychopharmacological properties
`of the racemate werewcompared with those ofthe m.
`105; cf the formula:
`
`35
`
`x.
`
`z
`/ '
`CH-SO-Cflr-oo-N
`\21
`
`‘
`40
`
`45
`
`‘
`
`out in 2 steps, namely:
`(3a) esten'ficntion of the (—)-benzhydrylsulfinylacetic
`acid to a lower alkyl (~)obenzyldrylsulfinylacetate
`[the lower alkyl being C1—Cs, especially isopropyl.
`ethyl or methyl (preferably ethyl and particularly
`preferably methyD]. followed by
`(3b) transainidation of the resulting lower alkyl (-)-
`benzhydrylsulfinlaeetate with NH; ( the transamida-
`tion reaction preferably being carried out in a lower
`x,
`alcohol and particularly preferably in the alcohol
`corresponding to the alkyl group ofthe ester obtained
`in which:
`in stage 3n). 5 mean of NH: being Passed into the
`x. and x;. which can he identical or different. each
`reaction medium).
`.
`'.
`.
`represent. H. Cl or F.
`(thBeqzyhydx-yhuifinyhewe acid I: I known sub-
`zt represents CH3. CHzChs. CH(CH3)3. it also being so
`stance which ts described as synthesis intermediate in
`possible for zl to “3pm; . hydrogen atom when
`Petent Document FR-ENO. 2 326 181 (uncut-#:16-
`at lent one of the symbols x. and x; is. different
`4'-165' Cl).
`from H. and
`According to the invention. I thenpeutic eompoei-
`22 represents H. it being possible for rum. consid-
`cred together. to represent a piper'idino or morpho- 55 tion I! rwomnsended WhiCh contains (-)-benzhydryl-
`lino group.
`sulfmylacetamide as the active ingredient. in association
`which act on the CNS as sedatives in some cases and as
`Will! I physiologically acceptable excipient- 01' course,
`stimulants in others (see especially Table l on page 3
`in I composition Own! type. the said (-)'h¢n2hydt71‘
`and Table IV on page 4 of the said European patent
`sulfinylacetamide is presentin aphnrmaceutically effec-
`document).
`60 ttve amount.
`It has now been found am the levorotatory eom-
`It is also twommended to use this levorotatory com
`pound (—)-benzhydrylsulftnylaeetamide (Code no.:
`pound to obtain. on the one hand, an arousing drug to
`CRL 40 982) has valuable therapeutic properties com-
`be used in human therapy for hypersomnia. and. on the
`pared with the racemate (iybenzhydrylsulftnylaceta-
`other hand, a stimulating drug. and in particular a drug
`mid: (Code no.: CRL 40 476) and with the dextrorota- 65 for inhibiting aphasia and ideomotor apmia. to be used
`tory
`compound
`(+)-benzhydrylsulftnylacetantide
`in therapy for Alzheimer‘s disease.
`(Code110.: cm.so933). Surprisingly. it has been found
`Further tavtnuget and characteristics ofthe inven~
`that the metabolism of the Ievorotatory compound in
`tion will be understood more clearly from the following
`
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`dmcription of(i) preparation examples and (ii) resuln of
`(b) (+)-bcnzhydrylsulfinylacetic acid;
`M.
`. (inst.)- l90‘-l9l‘ C..
`comparative
`neurophyschopharmacological '
`tests.
`(105’. 6.4.4? (in a 1% solution in CHJOH);
`These data. which in no way imply a limitation. are
`given by way ofilllnmtion
`(c) methyl (+)-benzylhydrylsulfinylaeetate;
`»
`PREPARATION I
`5 M" 6“" 1°9°""°' C”-
`apm‘ Cunt-221' (in a 4% solution in CI-bOH);
`Preparation of (-)-benzhydrylsulfinylacetamide
`and then
`(Example 1; Code no.: cm. 40 982)
`(‘0 fiflfiinm- c”
`M.
`(a) (—)-Benzhydrylsulfinylacetate or (-yenethyl- m
`'
`benzylamine
`51:11:
`(la-+223 (in a 2%;glgtion in (38:08).
`comparative teats w
`were undertaken with
`.
`the levorotatoiy derivative according to the invention
`13 s ((1108 mo!) of (-ha-methylhmzyhmmc Ire
`(Ex. 1; Code no; CR1. 40 982), the dexunrotstory de-
`added toasuspenstonofz1.4g(0.l mol) of(:t)-benzhy-
`drylsulfinylacenc seldom}:- (mam-460469 9.; Code
`rivative (CPI; Code no.: CRL so 983) and the cone
`nos CRL 40 467) in 500 ml ofwater: the mixture is Is spondingracemste(CP2;Codeno.:CRL40476)have
`filteredhouthefiltrateiscooledandthepmducth
`beenmmmarizedbelow.Unleuindicatedotherwise.
`filteredofl‘andtecryatallizedtwicefi'omwOmlo!
`the3productsstudiedintheaeteatswereadtninistered
`water to give 17 3 (yield: 42%) of the (~)-benzhydryl-
`intraperitoneally as a suspension in an aqueous solution
`sulfinylacetate of
`(—ya-methylbenzylamine. Mp.
`ofgumanbieinavolume onOmI/kgtomalemiceand
`(inst.)=l48'-150' C.
`so in a volume of 5 ml/kg to male rats.
`~(b) (—)-Benzhydrylsulfinylacetic acid
`A-TOIGCI‘I'Y
`the (—)-benzhy
`In male mice. the mo(maximum non-lethal dose) by
`Ltulfinylacetate of (-)-a-methyl-
`benzylsmine (17 g) obtainedm this way is dissolved in
`intrapentoneal
`'
`'
`‘on '3 found to be greater
`with 7 ml ol‘concentrated hydrochloric acid (lZN HCl. 25 pound and the racemate, whereas the mac ofthe levo-
`dal.l9 g/cm’). The mixture is filtered cold and the
`rotatory compoundisofthe order ofabout 512 lug/kg.
`precipitateiswashedwithwateranddriedtogivethe
`Insummary.CRL40982'umoretoxicthanCRL40
`expected (—)-benzhydrylsulfinylacetic acid with a
`983 (CPI) and C111. 40 476 (CP2). The fact that the
`yield of about 100%.
`toxicity of CRL 40 982 is greater than that of the other
`M.p. (inst): tar—188' C.
`30 two products does not present a problem since the levo-
`up”. C: -35' (in a 1% solution in CH30H),
`rotatory compound still has a sufficiently wide useful
`(c) Methyl («Mydrylsulfinylacemte
`range of non-lethal concentrations. Here, the fact that
`A suspension of 16.45 g (0.06 mol) of (-ybenzhy.
`CRL 40 982 is more toxic than the other two products
`drylsulfinylacetic acid in 300 ml of water is treated at
`indicates that it is more active.
`20' C. with 16.8 g (0.2 mol) of sodium bicarbonate and 35
`B—BEHAVIOR IN RATS
`18.8 ml (0.21 mol) of methyl: sulfate, with stirring, the
`In male mice. CRL 40 982, CRL 40 983 and CRL 40
`mixtureisstirred for l6 to is hoursat20' c. and filtered
`476 have stimulant effects in male rats. on the Other
`dried to give methyl (—Mydrylsulfinyhcemtg
`not have stimulant effects while the rscemnte (CR1. 40
`with . yield of 35%
`40 476) (i) is a stimulant and (ii) has a mydriatic action at all
`Mp. (use): 1092.110“ c,
`the doses med. the levomtstory and dextromtatory
`aDZO' cg-2z,5' (in . 4% ”hub“ in (33,03),
`isomers betng devoid of this mydriatic action when
`(d) CRL so 982
`administered on their own:
`Adrystrcam ofNI-igyasispassedatroomtempera-
`atadoseoleBmg/h5CRL40476causeaexcitation
`ture into I solution of 100 ml ofmethanol containing 8.6 45 with an inmate is! the fur mien for 2 1:. «Ophthalmos
`g (0.03 mol) of methyl (—)-benzhydrylsulfinylacetate.
`for l 11 Inc! mm for l for 2 h:
`.
`.
`NH: introduced in this way is reacted with the solution
`1‘ fl9°59 0‘_32 “IS/k8. C131: 40 4.75 causes excitation
`for 5 h, with stirring. The methanol is evaporated 00‘,
`(Wt. lawns ‘15 h) With an increase in the fee:
`the evaporation residue '3 taken up in ether and the
`Faction for l h. exophthnlmos for 0.5-1 h and mydrissis
`product ‘3 filtered off and recrystallized from ethanol to 50 for 14 h;
`*
`‘
`give CRL so 932 with in overall yield of 32%. this
`It a dose of 8 Ins/ks. C81, 40 476 came: exophthah
`product is in the term orwhite crystals which are solu-
`mos for 0-5-1 h Ind mm for M h;
`ble in alcohols and acetone and insoluble in water and
`a! a dose of 2 gas/ks. CRL 40 476 induces transient
`cm“.
`‘
`mydnasls appearing l h after administration. wherein
`M.p. (inst.)ul$3':~l$4' c.
`u a dose- of 64 Ins/ks. 16 nus/ks. 4 Ins/ks and 1
`agar c- .10- (in . 2% solution in c3303),
`lug/kg, CR]. 40 982 and CR1. 40 983 cause behavior.
`reactivities and vsriations in the rectal temperature and
`PREPARATION II
`pupil diameter which are substnntially comparable to
`those of the conwl troup-
`Preparation of (+)-benzhydrylsulfinylacetnmide
`.
`C—MOTOR A
`(Companson product CPI; Code no.: CRL 40 983)
`The mice (6 mm1:333? .
`l )
`'ve
`The following are obtained successively using the
`CRL 40 476. C111. 40 982 or CRL ‘0 983 four hours
`procedure indicated in Preparation I above but replae-
`before being placed in an actilneter, where their motil-
`ing the (-ya-methylbenzylamine with (+)—a-methyl-
`-ity is recorded for 30 minutes. It is found that. at doses
`benzylartu‘ne.
`.
`65 of l28 mg/kg and to a lesser extent 64 Ins/kg. the three
`(a)
`the (+)—benzhydrylsulfinylacetate of
`(+)-a~
`substances used cause an increase in the motor activity
`methylbenzylamine.
`four hours after their administration. However.
`the
`M.p. (insL)==l48'—150 C.;
`hyper ctivity induced by CRL 40 982 and GM. 40083
`.
`_
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`
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`dtfi’crent. whefeu, the: Idlmnmnnon ofCRL 40 982.
`theAUC.+’*ofCRL40476is
`xmmelyhmce the
`20 AUC..+” of CRL 40 476 whack each result from the
`
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`me]recuved thefollowsIttheat:ofoneoralIdmm-
`roduoeo in the or
`‘
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`istntion per week: 2mm"' nations ofCRL40476(for ‘°
`nbbxumdmeelmnnmnnosummntefi'eczwudso
`tofthe
`‘tionswil‘
`'I'vid ”.1“.
`observedinvitmforCRLw982.
`..
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`E—CLINICAL TRIALS
`mum: of cm... 40 982 Ind l Idmtnfsfrguoh of
`the kinetics ofthe cxuousmdcnuompm: ‘5 .mhmfnmm“w“f°'.m ‘h‘t‘h‘d‘m"
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`cm. 40 467
`(I)
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`35.11 a: 6.93
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`m: a: 21.66
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`
`Code no.
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`(I)
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`46.16 a: 6.95
`cm. 40 m
`mum ”12:12.58
`0
`cu. 40 m
`50.94 a: 1.71
`
`an
`an:
`cm
`Net-
`cm
`m '- nudnw an
`(p
`~ my ‘
`«an e
`..
`-
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`“W’m Hanna-1' can. (p <
`
`um
`
`)
`
`Whnt ‘n chimed h:
`1. (—yBenzhydx-ylsulfinyhcetnmide.
`
`-
`
`4. A therapeutic compoution oompmmg In unount
`—)benzhydryhulfmyheetnmde m combxnnuon With 1
`
`5. A therapeutic composition comprising nn Amount
`trentment. an effecuve mount of e pharmneeutienl
`effective I: I central nervous system stimuhnt of (-)-
`composmon commas elsentinlly of (—)—benzhydryl~
`beuzhydtylsulfinyhoetnmide in combination with n
`sulfinylneetnmide n: In moms ngent.
`3 A method for the treatment ofAlzhetmex-‘s disease, 25 physioloyenlly acceptable empxent.
`
`
`
`35
`
`55
`
`65
`
`

`

`BEST POSSIBLE COPY
`BEST POSSIBLE COPY
`
`Public Health Service
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`W...
`Office of Orphan Products Development(HF—35)
`Food and Drug Administration
`5600 Fishers Lane
`Rockville. MD 20857
`
`_
`
`(
`
`January 4, 1999
`
`Cephalon, Inc.
`145 Brandywine Parkway
`West Chester, PA 19380-4245
`
`Attention:
`
`Paul M. Kirsch
`
`Director, Regulatory Affairs
`
`Dear Mr. Kirsch:
`
`Reference is made to your orphan product Provigil (modafinal), which was designated an orphan
`product pursuant to section 526 of the Federal Food, Drug, and Cosmetic Act (FFDCA) (21
`U.S-C- § 360bb) on March 15. 1993— for the treatment of excessive daytime
` .
`sleepiness in narcolepsy.
`
`p
`
`z,
`(it
`
`This letter is to inform you that as the first sponsor of Provigil to obtain marketing approval for
`this indication, you are entitled to seven years of exclusive marketing approval pursuant to Section
`527 of the FFDCA (21 U.S.C. § 360cc) for the use of Provigil to improve wakefulness in patients
`with excessive daytime sleepiness associated with narcolepsy. The exclusive seven year approval
`period began on December 24, 1998, the date of approval of your new drug application (NDA 20-
`7 17).
`
`Please note that holders of exclusivity for approved orphan products are required to assure the
`availability of sufficient quantities of an orphan drug to meet the needs of patients. Failure to do
`so could result in the withdrawal of the product’s exclusive approval [21 CFR 316.36(b)].
`
`Thank you for your efforts in developing Provigil for the treatment of narcolepsy. The whole
`premise of the Orphan Drug Act and program is based on the realization that the resources and
`commitment devoted to the development of products for "orphan" populations may not provide
`financial returns to their sponsors. It is with genuine gratitude that we recognize your efforts.
`
`,
`(
`
` ., /S/
`
`Sincerely yours, Marlene E. Haffner, MD, MPH
`
`Rear Admiral, United States Public Health Service
`Director, Office of Orphan Products Development
`
`..
`
`
`
`

`

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`Page 1 of 5
`
`Exclusivity Summary Form
`
`(
`
`Exclusivity Summary Form
`(Modified: October 14. 1993)
`
`SUPPL #
`I
`l
`EXCLUSIVITY SUMMARY FOR NDA # 3Q: !
`
`
`Trade Name:
`(ov'
`i
`Generic Name: mngfi [3} I
`Applicant Name:
`562 g EEC» HFD #
`‘942
`
`Approval Date If Known:
`
`
`PART I: IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original applications, but only for certain
`supplements. Complete PARTS II and III of this Exclusivity Summary only ifyou answer "yes" to one or
`more of the following question about the submission.
`
`a) Is it an original NDA?
`YES/35m I____/
`
`b) is it an effectiveness supplement?
`YES I__I NO [:4
`If yes, what type? (SE1, SE2, etc.) 2
`
`c) Did it require the review of clinical data other than to support a safety claim or change in
`labeling related to safety? (If it required review only of bioavailability or bioequivalence data,
`answer "no.")
`YES 1.6! NO I____I
`
`If your answer is "no" because you believe the study is a bioavailability study and,
`therefore, not eligible for exclusivity, EXPLAIN why it is a bioavailability study, including
`your reasons for disagreeing with any arguments made by the applicant that the study was
`not simply a bioavailability study.
`
` W I
`
`f it is a supplement requiring the review of clinical data but it is not an effectiveness
`supplement, describe the change or claim that is supported by the clinical data:
`
`I F
`
`orm OGD-011347 Revised 8/2719?
`cc: Original NDA Division File HFD-93 Mary Ann Holovac
`
`d) Did the applicant request exclusivity?
`YES I ‘/INOI
`I
`_.*__.
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`5 K,
`r.
`e) Has pediatric7¢lusivity been granted forthis Active Moiety?
`
`——
`YES]
`I NC I
`I
`
`(
`
`12/1 1/98
`http://oitweb/oit/OIT_Org/ddms/exclusum.htm
`
`
`

`

`Exclusivity Summary Form
`
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`Page 2 of 5
`
`L.
`
`I'FHYEOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
`SIGNATURE BLOCKS ON PAGE 8.
`2. Has aproduct with the same active ingredient(s), dosage form, strength, route ofadministration, and
`dosmg schedule, previously been approved by FDA for the same use? (Rx to OTC switches should be
`answered NO - plea
`indicate as such)
`
`YES I
`
`I NO I M I
`
`If yes, NDA #
`
`. Drug Name
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`3. Is this drug product or indication a DESI upgrade?
`YES I
`I NO I
`I
`
`IF THE ANSWER TO QUESTION 3 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS ON
`PAGE 8 (even if a study was required for the upgrade).
`
`PART II: FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES.
`
`(Answer either #1 or #2 as appropriate)
`
`1. Single active ingredient product.
`
`Has FDA prevrous y approved under section 505 of the Act any drug product containing the same
`active moiety as the drug under consideration? Answer "yes“ if the active moiety (including other
`esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this
`particular form of the active moiety, (2.9., this particular ester or salt (including salts with hydrogen or
`coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate) has
`not been approved. Answer "no" if the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug) to produce an already approved active moiety.
`YES I__I no /_4
`
`(I ‘
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
`
`NDA#
`
`NDA#
`
`
`
`
`
`NDA#
`
`
`
`2. Combination product.
`
`If the product contains more than one active moiety(as defined in Part II, #1), has FDA previously
`approved an application under section 505 containing any one of the active moieties in the drug
`product? If, for example, the combination contains one never-before-approved active moiety and one
`previously approved active moiety, answer "yes." (An active moiety that is marketed under an OTC
`monograph, but that was never approved under an NDA, is considered not previously approved.)
`YES!
`[NO]
`I
`
`If "yes," identify the approved drug product(s) containing the active moiety,
`and, if known, the NDA #(s).
`
`NDA#
`
`NDA#
`
`NDA#
`
`
`
`
`
`
`
`-
`
`m»
`
`"
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON PAGE 8. IF "YES" GO TO PART III.
`
`.
`
`-
`
`12/ 1 1/98
`http://oitweb/oit/OIT_Org/ddms/excIusum.htm
`
`
`

`

`Exclusivity Summary Form
`
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`Page 3 of 5
`
`( *
`
`PART III THREE-YEAR EXCLUSIVITY FOR NDA'S AND SUPPLEMENTS.
`To qualify for three years of exclusivity, an application or supplement must contain "reports of new
`clinical investigations (other than bioavailability studies) essential to the approval of the application
`and conducted or sponsored by the applicant." This section should be completed only if the answer to
`PART ll, Question 1 or 2 was "yes."
`
`1. Does the application contain reports of clinical investigations?
`(The Agency interprets "clinical investigations" to mean investigations conducted on humans other
`than bioavailability studies.) if the application contains clinical investigations only by virtue of a right
`of reference to clinical investigations in another application, answer "yes," then skip to question 3(a). If
`the answer to 3(a) is "yes" for any investigation referred to in another application, do not complete
`remainder of summary for that
`investigation.
`u—m—
`YES I
`I NO I
`I
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. A clinical investigation is "essential to the approval" if the Agency could not have approved the
`application or supplement without relying on that investigation. Thus, the investigation is not essential
`to the approval if 1) no clinical investigation is necessary to support the supplement or application in
`light of previously approved applications (i.e., information other than clinical trials, such as
`bioavailability data, would be sufficient to provide a basis for approval as an ANDA or 505(b)(2)
`application because of what is already known about a previously approved product), or 2) there are
`published reports of studies (other than those conducted or sponsored by the applicant) or other
`publicly available data that independently would have been sufficient to support approval of the
`application, without reference to the clinical investigation submitted in the application.
`(a) In light of previously approved applications, is a clinical investigation (either conducted
`by the applicant or available from some other source, including the published literature)
`necessary to support approval of the application or supplement?
`u————-—
`YES]
`[NO]
`l
`
`( 1
`:
`
`If "no," state the basis for your conclusion that a clinical trial is
`not necessary for approval AND GO DIRECTLY TO SIGNATURE BLOCK 0N PAGE 8:
`
`Wm...—
`
`(b) Did the applicant submit a list of published studies relevant to the safety and
`effectiveness of this drug product and a statement that the publicly available data would not
`independently support approval of the application?
`....__._
`YES]
`[NO]
`I
`
`-
`
`are
`
`(1) If the answer to 2(b) is "yes," do you personally know
`of any reason to disagree with the applicant's conclusion? it not applicable, answer NO.
`”a...—
`YES]
`[NO]
`I
`
`If yes, explain:
`
`(2) If the answer to 2(b) is "no," are you aware of published studies not conducted or sponsored by the
`applicant or other publicly available data that could independently demonstrate the safety and
`effectiveness of this drug product?
`.—_~_—
`YESI
`INOI
`I
`
`If yes, explain:
`
`(
`
`(c) If the answers to (b)(1) and (b)(2) were both "no," identify the clinical investigations
`submitted in the application that are essential to the approval:
`Studies comparing two products with the same ingredient(s) are considered to be bioavailability
`
`-
`
`http://oitweb/oit/OITgOrg/ddms/exclusum.htm
`
`12/1 1/98
`
`———-———I
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`

`

`>~
`
`.
`
`.
`
`~
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`~
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`.
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`Exclusivity Summary Form
`
`studies for the purpose of this section.
`
`Page 4 of 5
`
`(
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`ii. In addition to being essential, investigations must be "new" to support exclusivity. The agency
`interprets "new clinical investigation" to mean an investigation that 1) has not been relied on by the
`agency to demonstrate the effectiveness of a previously approved drug for any indication and 2) does
`not duplicate the results of another investigation that was relied on by the agency to demonstrate the
`effectiveness of a previously approved drug product, i.e., does not redemonstrate something the
`agency considers to have been demonstrated in an already approved application.
`
`a) For each investigation identified as "essential to the approval," has the investigation been
`relied on by the agency to demonstrate the effectiveness of a previously approved drug
`product? (If the investigation was relied on only to support the safety of a previously
`approved drug, answer "no.")
`
`Investigation #1 YES!
`
`IMO!
`
`Investigation #2 YES!
`
`INOI
`
`I
`
`I
`
`If you have answered "yes" for one or more investigations, identify
`each such investigation and the NBA in which each was relied upon:
`
`
`
`
`b) For each investigation identified as "essential to the approval", does the investigation
`duplicate the results of another investigation that was relied on by the agency to support
`the effectiveness of a previously approved drug product?
`—~_____
`lnvestigation#1YESl
`IMO!
`I
`__._.__
`Investigation #2 YES]
`[NO]
`I
`
`( '
`
`~
`
`If you have answered "yes" for one or more investigation, identify
`the NBA in which a similar investigation was relied on:
`
`
`
`
`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application
`or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less
`any that are not "new"):
`
`
`
`
`4. To be eligible for exclusivity, a new investigation that is essential to approval must also have been
`conducted or sponsored by the applicant. An investigation was "conducted or sponsored by" the
`applicant if, before or during the conduct of the investigation, 1) the applicant was the sponsor of the
`ND named in the form FDA 1571 filed with the Agency, or 2) the applicant (or its predecessor in
`interest) provided substantial support for the study. Ordinarily, substantial support will mean
`providing 50 percent or more of the cost of the study.
`
`a) For each investigation identified in response to question 3(c): if the investigation was
`carried out under an lND, was the applicant identified on the FDA 1571 as the sponsor?
`
`Investigation #1
`
`IND#
`
`*—
`YES]
`[NO]
`IExplain:
`
`lnvestigation #2
`
`IND#
`
`YESI
`
`INOI
`
`IExplain:
`
`(b) For each investigation not carried out under an IND or for which the applicant was not
`identified as the sponsor, did the applicant certify that it or the applicant's predecessor in
`
`‘
`
`“
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`12/ 1 1/98
`http://oitweb/oit/OIT_Org/ddms/exclusum.htm
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`Exclusivity Summary Form
`interest provided substantial support for the study?
`Investigation #1
`
`YES I___I Explain
`
`NO l__l Explain
`
`(
`
`__..._____._._________W
`
`_____..__.__________WW
`
`Investigation #2
`
`YES I___I Explain
`
`NO I_I Explain
`
`MW
`
`“MM
`
`(c) Notwithstanding an answer of "yes" to (a) or (b), are there other reasons to believe that
`the applicant should not be credited with having "conducted or sponsored" the study?
`(Purchased studies may not be used as the basis for exclusivity. However, if all rights to the
`drug are purchased (notjust studies on the drug), the applicant may be considered to have
`sponsored or conducted the studies sponsored or conducted by its predecessor in interest.)
`YES I__l NO]
`I
`
`If yes, explain:
`
`
`
`
`/S/
`
`
`
`te:
`
`/'o?//'/98
`
`Signature of Office/Division Director
`
`Signature:
`
`Date:
`
`cc: Original NDA Division File HFD-93 Mary Ann Holovac
`
`Previous Page
`
`APPEARS THIS WAY 0N ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`12/1 1/98
`http://oitweb/oit/OIT_Org/ddms/exclusum.htm
`
`
`

`

`Pediatric Page Pn'ntout for ANNA MARIE HOMONN...
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`Page 1 of 1
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`(A
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`PEDIATRIC PAGE
`(Complete for all original application and all efficacy supplements)
`
`.
`,
`PROVIGIL (MODAFINIL) IOO/ZOOMG
`NDA/BLA Number. 20717 Trade Name.
`TABLETS
`121mg?”
`Generic Name:
`MODAFINIL
`Supplement Type:
`Dosage Form:
`TAB
`.
`Proposed
`.
`Regulatory Action. fl
`Indication:
`NARCOLEPSY
`
`IS THERE PEDIATRIC CONTENT IN THIS SUBMISSION?
`
`NO
`
`What are the INTENDED Pediatric Age Groups for this submission?
`NeoNates (0-30 Days )
`Children (25 Months—l2 years)
`Infants (1-24 Months)
`Adolescents (13-16 Years)
`
`Label Status
`Formulation Status
`Studies Needed
`
`Study Status
`
`Are there any Pediatric Phase 4 Commitments in the Action Letter for the Original Submission?
`COMMENTS:
`
`(:1 0
`
`;
`
`
`This Page was completed based on information from a PROJECT MANAGER/CONSUMER SAFETY OFFICER,
`/S/
`
`
`1 gnature
`
`,
`
`/;L[ / I Z ‘2 fi
`Date
`
`APPEARS THIS WAY ON ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`-
`
`http://cdsm1web1[PediTrack/editdata_finn.cfin?ApN=2071 7&SN=O&ID=342
`12/l l/98
`
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`

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`Debannent Certification Under the Generic Drug Enforcement Act of 1992
`
`Cephalon, Inc, certifies that it did not and will not use, in any capacity, the services of any
`person debarred under subsections (a) or (b) [Section 306 (a) or (b)],
`in connection with
`this new drug application.
`
`APPEARS THIS WAY 0N ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`l«
`
`
`
`
`
`ITEM 1 00010.
`
`

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`(
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`'
`
`MEMORANDUM
`
`DATE:
`
`December 17, 1998
`
`FROM:
`
`Deputy Director
`Division of Neuropharmacological Drug Products/HFD-IZO
`
`TO:
`
`File, NDA 20-717
`
`Supervisory Review of Sponsor’s Response to Approvable Letter for
`SUBJECT:
`NDA 20-717, for the Use of Modafinil in Patients with Narcolepsy
`
`BACKGROUND
`
`On 12/29/97, the Agency issued an Approvable letter to Cephalon, Inc., sponsor of NDA
`20-717, for the use of modafinil in patients with narcolepsy. That letter included requests
`for the following information:
`
`Clinical
`
`('1‘
`
`‘
`
`1) A complete accounting of the exact number of patients exposed to modafinil, with
`clear dose/duration data.
`
`2) Updated and detailed information about the extent of safety information at single and
`daily doses of 400 mg and greater.
`
`3) Laboratory data for foreign studies
`
`4) Safety update
`
`Pharmacology
`
`’
`
`“E”
`
` .
`
`
`
`Biopharmaceutics
`
`K
`
`Information about the interconversion of enantiomers was requested.
`
`

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`/‘\/
`
`More information about drug interactions with CYP3A and CYP2C19 substrates was
`requested, and a study to evaluate the interaction of modafrnil and clomipramine was
`requested.
`
`Specific dissolution specifications were requested to be adopted.
`
`In addition, of course, attached to the letter was drafi labeling, which provided text in M.
`many areas that we requested the sponsor adopt, as well as questions embedded in
`labeling that the sponsor was to answer.
`
`The sponsor responded to these requests in a submission dated 6/30/98. This submission
`has been reviewed by Dr. Joel Freiman, clinical reviewer (reviews dated 12/15/98 and
`12/16/98), Dr. Aisar Atrakchi and Dr. Glenna Fitzgerald, pharmacology (reviews dated
`6/98 and 11/17/98, respectively), Dr. Rae Yuan, Biopharmaceutics (review dated
`10/27/98), and Dr. Martha Heimann, chemistry (review dated 7/16/98). Dr. Michael
`Klein ofHFD-170, has performed a number of informal reviews of labeling (some
`embodied in e-mails) related to abuse potential issues.
`
`In this memo, I will briefly summarize the responses, and offer my recommendations for
`action on the NDA.
`
`Clinical
`
`As Dr. Freiman notes, based on a detailed examination of Case Report Forms, the
`sponsor has clarified the number of discrete individuals who have been exposed to at
`least 1 dose of modafinil. This number is now 2265 (760 domestic, 1505 foreign). Of
`these, 737 had been exposed for at least 180 days, and 477 for at least 1 year.
`
`We were particularly interested in the experience at daily doses of400 mg or greater,
`given the sponsor’s desire to include statements in labeling about the safety ofthis dose.
`The submission discusses the domestic and foreign data separately.
`In particular, the
`sponsor employed a number of assumptions and maneuvers to derive their figures for the
`foreign data (no such assumptions were needed for the domestic experience).
`
`For example, most of the foreign smdies did not expose patients to these doses. Of the 81
`foreign studies, these doses were reached in only 26 studies. Ofthese 26 studies, only 2
`had direct information about the dose on any given study day. In the remaining 24
`studies, no such direct information was available. Some ofthese studies employed a fixed
`dose schedule, some a variable dose schedule.
`
`For the fixed dose studies, the dose the patient was supposed to have received (from the
`randomization or treatment assignment codes) was determined, and duration of exposure
`information was obtained from the CRF (although it is unclear ifthere was any
`independent way to assess whether or not the patient actually took the dose assigned).
`
`
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`

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`For the variable dose studies, only those patients whose modal dose was at least 400 mg
`were included in the safety analysis.
`
`Some patients were enrolled into several studies. In these cases, the sponsor presented
`their total duration of exposure as the total number of days receiving modafinil (even if
`there had been periods between studies during which they received no drug), and
`presented the dose received as the average (weighted?) dose they_1§ceived, when they had
`been in fixed dose studies.
`
`A total of 680 patients received at least one day of400 mg/day. Of these, 182 were
`exposed for between 6 months and 1 year, with an additional 93 exposed for at least 1
`year. A total of 128 patients were exposed to at least one day of dosing greater than 400
`mg/day, with only 9 of these exposed for greater than 2 weeks. Most of this total dosing
`was given as a single daily dose (681 of the total 808 patients). Nearly all of the
`exposure at daily doses of at least 400 mg for more than 90 days was derived in the
`domestic extensions to controlled trials 301 and 302.
`
`Information on deaths, discontinuations, and serious adverse events are reported from all
`sources of data as of January 31, 1998.
`
`DEATHS
`
`
`
`,
`
`(
`
`'
`
`‘
`
`One death, a 38 year old man who died in a snowmobile accident who had been receiving
`400 mg/day, was reported in a US extension study. A second death, a suicide in a-