`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Application Number: 11522, 8010
`
`APPROVAL LETTER
`
`*7
`
`Page 1 of 66
`
`KVK-TECH EXHIBIT 1008
`
`Page 1 of 66
`
`KVK-TECH EXHIBIT 1008
`
`

`

`NDA ll~522 I S-OIO
`
`Richwood PharmaceuttcolCompananc.
`Attention: William A Nuerue2'
`Chief Operating OlTlcer
`'
`7900 Tanner”a (late Dnse. Suite 200
`Florence. KY “042
`
`Deer Mt. Nucrge:
`
`FEP ‘ 3 ‘9%
`
`Please refer to your supplemental new drug application of September 2i. W95 (S-OlO).
`submitted under section 505th) of the Federal Food. Drug. and Cosmetic Act {or Adderall
`(dextrosmphetamine saccharstc. dextroamphetamine sulfate. amphetamine aspartate. and
`amphetamine sulfate) l0 mu and 20 mg tablets
`
`Supplemental application SW» consists of the resubmission
`and provides critical analyses for the quantitation of d- and l-amphetamlne. and updated
`manufacturing. controls and test procedures. The supplemental application also provides draft
`labeling revised in response to theW notice of August 8.1970 (DESI 5378).
`classifying this drug effective i‘n‘r use in the treatment of narcolepsy. attention deficit disorder
`with hyperactivity. and exogenous obesity.
`
`We have completed the review of this supplemental application including the submitted draft
`labeling and have concluded that adequate information has been presented to demonstrate that
`the drug product is safe and effective for use as recommended with the labeling changes listed
`below. Accordingly. the application. with these labeling revisions. is approved effective as of
`the date of this letter. This action also approves this application on the basis of effectiveness
`of the drug as well as safety andsupersedes the Federal Register notice of September 25.
`1973. thus re-establishing the approval of NDA “-522.
`
`Tits labeling revisions. as agreed to by Rob Falconer of your firm during his telephone
`conversation with Steven D. Hardeman. R. Pin. of this agency on January 26 1996. are r '
`follows:
`
`i.
`
`2.
`
`growth
`The statement currently placed in Warnings. “Clinical experience sunsets
`should be monitored during treatment." should not he repeated under Precautionn
`Pediatric Use.
`
`lhc statement under Precautions that l DM.‘ Yellow iii» causing allergic reactions ts
`unnecessary and should he deleted. as this statement applies to FDBC Yellow its rather
`than so.
`i.
`l
`
`M“
`
`Page 2 of 66
`
`Page 2 of 66
`
`

`

`. NDA ii-SZZ/S-OIO
`
`3.
`
`Under Adverse Reactions-~Curdiovasculsr. the statement. "There have been isolated
`reports of cardiomyopathy associated with chronic amphetamine use." should be added
`
`2
`
`4.
`
`”lite treatment of overdosage section should be updated. as follows:
`(additions are in redlme iunt. deletions arc in strikeout font)
`
`OVERDOSAOE:
`
`TREATMENT—Consult with a Certified Poison Control Center lbi'Wto‘dale guidance
`and advice: Management of acute amphetamine intoxication is largely symptomatic and
`includes gastric lavage. administration oi'activsted charcoal. administration of a cathartic
`and sedation
`Experience with hemodialysls or peritoneal dialysis is
`inadequate to perrrm recommendation in this regard. Acidification oi the urine increases
`amphetamine excretion. but is believed to increase risk or acute renal failure it‘
`myogiobinutia is present.
`it‘ acute. severe hypertension complicates amphetamine
`overdosagc. administration of intravenous phentolamine (Regitinc'. CIBA) has been
`suggested. However. a gradual drop in blood pressure will usually result when sumeient
`sedation has been achie'vcd. Chlorpromazinc antagonizes the central stimulant effects or
`amphetamines and can he used to treat amphetamine intoxication.
`
`We also have the following request and acknowledgment regarding chemistry and manufacturing
`controls:
`
`l.
`
`We request that you place all (i validation batches on long-term stability at ambient lie.
`either JO'IambRH or 25‘Inmtskli] conditions. Please provide your stability protocol and
`commitment tie. storage conditions. sampling times. and tests to be perfumed).
`
`2.
`
`As requested. a 24~month espirstion dating period at ambient conditions is acceptable.
`
`These revisions are terms or lhelsupplement approval. Marketing the product bei‘ore matting.
`exactly as agreed to. the Milton] in tire products's labeling may render the product misbranded
`and an unapproved new drug
`
`Page 3 of 66
`
`Page 3 of 66
`
`

`

`. NDA ll-S22/S~0|0
`
`Please surmit sixteen copies of the PM. as soon as it is available. in no case more than 30
`days after it is printed or 6 months from the date of this letter. Please individually mount ten
`of the copies on heavy weight paper or similar material. For administrative purposes this
`submission should be designated “FINAL PRINTED LABELINO‘ for approved supplemental
`NBA “-522 / S-Oio, Approval of this labeling by FDA is non required before it is used.
`Should additional information relating to the safety and effectiveness of the dmg become
`available. further revision of that labeling may be required.
`
`3
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 3143!.
`'t
`
`Should you have any questions. picoaeIeontacl Steven D Hardeman. R.Ph.. Regulatory
`Management Officer. at (JOi )594-2777.
`
`.
`
`Sincerely yours.
`
`am 1,0411;
`
`t
`
`I
`
`Robert Temple. MD.
`Director
`
`Office of Drug Evaluation I
`
`Center for Drug Evaluation and munch
`
`
`
`Page 4 of 66
`
`Page 4 of 66
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 11522, $010
`
`MEDICAL REVIEW§S[
`
`”‘-
`
`Page 5 of 66
`
`Page 5 of 66
`
`

`

`nevrav‘ignuo EVALUATION or CLINICAL mm
`1'}
`
`NBA 11.622 (ObatrolIAddaraii)
`sponsor: Richwoed Pharmaceutical
`Drug: Dextroemphotarnlne saccharatalampheiamine aspartaie/dextroamphetamine
`senate/amphetamine sulfate
`ii
`.
`‘
`Material Reviewed: Prepubtication dralt at a Madman; article regarding Addarali and
`other drugs tor attention delicitihyperactlvlly disorder
`Date Received: October 17. WW
`'
`l. Material Reviewed
`
`'
`
`The Ollice oi Health Attila has asked our Division to comment upon this Medical
`Letter draft article. "Adderail and other drugs for attention daticit hyperactivity disorder.”
`Addernii is a combination amphetamine product (see above) which was lormerly called
`Obetrol. (i understand that this‘vproduct may be subject to a compliance action; apparently it
`is being marketed without an approved NDA. This lnlormatien. however. is still confidential.)
`The draft article begins With a reference to the “vigorous" promotion at Adderati, and
`concludes by stating that no litdrature studies are available to support the solely and efficacy
`oi the medication. or the claim that its eilect lasts throughout the school day alter one dose.
`The body oi the article reviews the pharmacotharapy tor attention deiiclt hyperactivity
`disorder (ADHD). and presents a balanced although brlel summary oi important clinical
`considerations. The informationz'on dosing. pharmacotrlnetlcs and adverse eiiects tor the
`most part agrees with what is commonly cited in the titanium or described in the labeling tor
`the psychostimuiants. Some items which might deserve mention as adverse eliects are toxic
`psychosis and cardiovascular eliects; also. there is no relarence to the tact that
`psychoslimuiants are associated with many drug-drug interactions (e.g.. with monoamine
`oxidese inhibitors. pressors. old: as noted in their respective labels). The article does not
`mention lowering ol the selrure‘thrashoid as an adverse ailect: however. this is a somewhat
`controversial topic and the literature on this purported effect at the stimulants is mixed.
`'
`Regarding eliicecy. the article states that no controlled studies have been published to
`support the eiiicacy ol Desoaynior Adderail in ADHD. Nonetheless. Desoiryn is approved for
`this indication. As Desoayn was approved in rate. however, the particular clinical trial data
`which led to approval may not be readily accessible. A law compounds which have been
`used "or! label'
`in none: are also mentioned (ctenldlna. desipramlne. buproprien). but the
`article is not inordinately promotional regarding these drugs.
`
`li. Conclusions and Recommendations
`
`On balance. the dull article is an obleotive and rational summary oi pharmacotherapy
`for ADHD.
`.
`
`
`
`We have reviewed your drall article on 'Adderali and other drugs tor attendee detlclt
`hyperactivity disorder and we believe that it presents a balanced and lair summary oi
`pharmacotherapy tor this disorder. We have no corrections to suggest. but some minor
`
`
`
`Page 6 of 66
`
`Page 6 of 66
`
`

`

`I
`
`I
`
`toxic paychoela and cardiovascular ellecta
`additions might be in order, Space permitting.
`probably deserve mention in the paragraph on adverse etlecta; likewise, 'relerence could be
`made to the tact that many drugdrug lnteractlona, aorne potentially aerleua. occur with the
`psychoalimulanta (e.g.. with meneamlne oxidaae inhibitora. preuera. entlconvulunte ale: aee
`their respective package lneena). Additionally. with respect to the use at non-etlmulant drugs.
`it could be noted that clinical experience with ouch druga la limited compared to the extensive
`experience with paychoaumulanta. end that nen-etlmuiante are not considered first line drugs;
`no non-stimulant druga have been approved by FDA tar this indication.
`.
`We greatly appreciate the opportunity to comment upon thla manuacrlpt. and it we
`may help by providing commentary on other drelle in the future. please do not imitate to
`ask.
`
`flvL"W “Wt/9y
`
`Andrew Moeholder. MD.
`Medical Olllcer. HFD-tzo
`
`.
`orig NDA "-522 Div File
`cc: PLeber/TLaughren/SHardamanMMeahelder
`
`
`
`Page 7 of 66
`
`Page 7 of 66
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 11522, $010
`
`ADMINISTRATIVE/CORRESPONDENCE DOCUMENTS
`
`Page 8 of 66
`
`Page 8 of 66
`
`

`

`1 3a..
`I
`
`In».
`
`H I M o R A N u u H
`
`‘
`
`onus-smu- O" "mm AND HUMAN IIRVICII
`PUBLIC "mm BIRVICI
`TOOD AND DRUG ADKINIO‘I’MTION
`
`_W_JW
`
`DME:
`FROM:
`
`THRU:
`
`SUBJECT:
`
`TO:
`
`November 1, 1994
`Steven D. Hardcman, RJ’h.
`Consumer SaleryOllicer
`l
`Division of Neuropharmacologlcal Drug Products, l-lFD-l20
`
`”/I/fl
`
`9"
`
`Thomas Laughton, MD.
`Psychiatric Group Leader
`Division of Neuropitarmacolostlcal Drug Products, HFDoi20
`
`NDA 11-522 Obeiroi‘l ADDERALL' tdextroamphetamine sulfate,
`dextroamphetamine saccharate, amphetamine sulfate, amphetamine aspartatei
`l0 mg and 20 mg Tablets Administrative History
`
`Paul Leber, MD.
`Director
`Division of Neuropharmacologicai Drug Products, HFD-tZO
`
`During my conversation oi May‘ t3, W”, with Peggy Spade (NY District . FDA) and Brad
`Williams (Ollice of Compliance). the approval status of NBA ii-522 lObetrolW came into
`question.
`I attempted to conduct a detailed administrative review of the NDA, however, no
`record of the original file could be located. The Division Document Room Personnel insist that
`the ND/\ is withdrawn and the tile has been retired by the Central Document Room.
`Sultsettuent ellorts to retrieve the application were unsttccesslui.
`i located a personal file and the
`following issues emerged:
`I,
`
`in theW notice at February 1!. i973. the Commissioner announced an
`opportunity lor hearing on his proposal to withdraw approval at new drug applications
`for combination amphetamines.
`
`The Commissioner, based on the review at the medical documentation altered to support
`the claims 0! saletv and ellicaw (or Obetrol tablets. lound that Reaar Pharmacal Corp.
`tailed to present substantial evidence of eliectlveness. Approval oi NBA "-522 was
`withdrawn by the Commissioner’s order etlective on October 5, i973. Notice ot the
`ruling was published in theW at September 25, 1973,
`'Final Order on
`Certain Combination Anorectic Drugs'.
`(attachment ii
`
`t.
`
`J.
`
`Page 9 of 66
`
`Page 9 of 66
`
`

`

`4.
`
`5‘
`
`(s.
`
`7.
`
`t).
`
`9.
`
`vol
`
`
`
`..
`
`.
`
`to [aim Geigerlcompllancel, Dave Barash, C50,
`in his telecon oi February 26, I962,
`explained that the product was being marketed. without an approved NDA, and asked
`what action would be taken. An inspection took place on lanuary 28. 1982, and no
`validation data was available.
`(attachment 3)
`
`The sp nsor (Thad Demos . thhwood Pharmaceuticals) contacted me via phone in early
`1997 0 request the status of the review of their reformulation supplement.
`I informed
`hum of the following:
`
`a.
`
`l).
`
`c.
`
`rl.
`
`e.
`
`it appears that the NDA was withdrawn by the commissioner in a Federal Register
`Notice in September I973.
`
`Aside lrom references lh COMiS and a personal llleflhe Division has 'no records
`on the NDA.
`i informed him that COMlS ls merely a document tracking
`database.
`
`I advised that he should request a complete lunpurgedl copy oi all documents
`including supplements, amendments and annual repons under the Freedom oi
`lnlormation Act.
`I reminded him that he must also provide prool of ownership of
`Rexar's NDA. He informed me that Richwood had purchased Rexar.
`I lnlormed him that Rexar (Richwoodl is in a precarious situation in that they are
`unable to provide documentation ol their NDA’s approval status and appear to be
`marketing without an approved NBA.
`
`in the letter of October 2t, 1994, the sponsor requested copies at material contained in
`my personal file.
`in my letter at October 26, 1994,
`l forwarded a copy oi the September
`25, t97J, Federal Register notice and a copy at the Division's letter at September 9.
`t980. (attachment 4)
`
`Following the sponsor‘s lnlllal inquiry. l contacted Doug Ellsworth and Lee Draplttn
`lcompllancel to ask the status of compliance actions tor this product.
`in his phone call of
`September 23. 1994, tarry Daurro 0! FDA NY District Compliance iniormed me that a
`”Warning Letter' for the Obetrol products was to be issued to the sponsor on October 24,
`t994. (attachment 5)
`‘
`
`—_——-——-—-——-——'—-——'——_——-——'
`
`Page 10 of 66
`
`Page 10 of 66
`
`

`

`11.
`
`12.
`
`13.
`
`In the September 1994 edition of the journal of the American Academy of Child and
`Adolescent Psychiatry, Richwood Pharmaceuticals (new owners 0! Rexar Pharmacall is
`promoting Obetrol (renamed ADDERALL) as a unique once a day alternative in the
`treatment of ADHD. (attachment 6i
`
`In a consult request irom HFY-l/Oillce of Health Affairs, the Division was asked to
`comment on the Medical Letter dralt article 'Adderail 'and Other Drugs {or Attention
`Deficit Hyperactivity Disorder". (attachment 7)
`
`A copy of the ADDERALL advertising and a copy of the 'Warning Letter“ was forwarded
`to Sherry Danese (DDMAC) on October 31',
`i994.
`
`cc:
`HFD-120
`HFDJL’O/Leber
`
`ILaughren
`IPurvis
`lHardeman
`
`November I, 1994
`
`C:\DOCS\NDA\OBETROL\OBETROL.MEM I
`
`MEMORANDUM FOR RECORD
`
`”——
`
`Page 1 1 of 66
`
`Page 11 of 66
`
`

`

`
`
`Page 12 of 66
`
`Page 12 of 66
`
`

`

`i
`
`e
`
`0'1“
`fix?
`.
`/-.5‘2.z
`on; o!
`anarnod ( run, or lor similar,
`lumuf" no related drum. Ull nouco
`would .. .acinded at to ouch dnm.
`tn romonat to the Mtlu in the Poa-
`eaat l‘icounl oi February la. in), re-
`ouetta tor n hoorlno were tweets-ed from
`(our mraont tor m'c nrun. The persons
`and the drool woro nnniod lr. iho Frncru.
`l'tzolnn nolioo oi March :0. lit?! m In
`mm. The auhiect llnal order conccma
`only two oi
`thou venom mounting
`homo“.
`-
`l'trilar Phannacot Co.. m Minoan
`Mm, Valley Bit-corn. NY mu. roouoated
`a hearing for the dnlin
`hetroi-lo and '
`Obotroi-til Tobieta (RDA i412i.'t‘hese '
`drug: are the euhicct c! an NDA which
`was mode conditionolly eitccttn on
`July at. me. and fully eilocilve on hob-
`runry 23. am. The Obetrol drun had
`been ret'ietrod hy- the tilts-NRC and
`iound to tie ponihir emotive ea, an ad-
`lunot in the monument oi torne tonne ‘
`ot ohoaitr in which an apnoiite depres-
`oent ta indicated. The NAB-tine naming
`tl-iu incorporated into the August I. mo
`Pcocut thll‘fll notice ditcuued thou
`(35 PR INTI).
`'i McQuctiin
`Delco Chomioot 69..
`Parkway North. Mount. Vernon. NY
`iosso. reouutod a hearing for the druz:
`Deicooota outtnincd nelcote mioia and
`Consul" and Doitobue Tabieta and
`Coneulet. Punuont to tho Aunt" I. "to
`hunt. l'tutrmt order. the Commiu
`elonor roooivrd trout names Pharmatat
`iuo. too Prospect 5i. tnwood. NY lion.
`tour new out: applications on tho lol-
`loainc date:
`tor the ioiIoa-illt' drum
`North to. li‘n‘l. "DA ”-1“. Dcicoboto
`home. I out. to on. it met and on
`that: North )3.
`in". RDA i'l-ldl.
`Dolcohore comma. I met to mod to the.
`and to mm: March so. it‘ll. NBA i'i-loo,
`Daleooote sultaioed Mom Cannon.
`5 mo. to the. ll tom. and :0 nut: and
`June at. )071. "DA l'l-tiD. Dolcobeee
`fltuiairied iteleue Double-Layer Tahieta.
`0 mm. to me. it one. and to me. All {m
`or the druae consist oi a combination of
`amphetamines and methamphetamine;
`No dnta eras eutnnitted in support oi the
`eitloocy oi time combination «on: the
`mower iomty pmohrawd the conclu-
`elont etated in the Ami 3. mo Recast.
`Mote?" notice in concert oi the aatetr
`ahdemuiotthedrunioruaeaa
`anomtloa and to Incline narcoleou
`it
`ran.
`amid minltut brain «attention to
`Due to the lam niouher oi on drug
`animations reoeiino moment
`to the
`Mount I. "to recent lteamea order.
`a "mo and evaluation oi the m dm
`aooltoattone muted or lemon waa
`deleted. Item no notified oi
`thin
`Mine in a letter from the Food and
`time mutilation on Home: n.
`ma. On January to. ion. a letter no
`not to Damn trout i. Richard Grout.
`MD. Milnl Director. Ollce oi Beientltlo
`Initiation. homo oi Mn. atatina
`the,eohcluoioo oi the Peed and One
`humiliation.» that tho iota it" amt
`Imitation. Mimi!“ by Barron millet
`not to am heal. the emit-Item
`
`”‘1‘:-
`CKIIUHVC will not huvo :. minimum. on-
`‘ virnnmrntni Immct. Conic: at the on.
`I-Ironmontnl Impact onnli'aie report no
`nrzilohlc in ihr Oii.:o at tho Mntstnnt
`Coinmminnor
`ior Public Alloira.
`llm.
`toil-t2 or the 0mm 0! the llcorimz Clerk.
`Pool mud llrm: Mministrntion. Rm. 6-
`lut. 5680 Fulton Lone,
`itocicvillc. MD
`2035:.
`noted St .icmbor it. lii'iJ.
`Viaott. O. Wooten.
`Dlrocior, Bureau 9/ Poodt.
`Int Damn-2029! Filed O-II-TIHHI In]
`
`
`[DESI ”7|; Docket No. moo-m; NBA
`“-3211
`CER‘MIN COMBINATION MtOREC‘flC
`'
`DRUGS
`‘
`final Ordor on Obioctione and Mount tor
`n iii-avian RenardInrt Withdrawal at lip-
`provoi oi Now bruit Applications
`in tho “it'll“. mourn of August 8.
`low (35 m ”652) the Commissioner 0!
`Fowl and Drum publuhod a “Moment
`0: ruiir)‘ m cm. ”0.46) coucernina am-
`phezammu tor human use. The etote-
`nmit contained tho midllicl oi tilet‘ood
`one Dru: Administration baled uuon ro-
`llom resolved irom the Notional hoode-
`my oi Bolencrt-aniouol floeoorch Coun-
`cil
`inns—Knot Drill: Bmoocr Stud:
`Oroun. Also published in tho l‘totaat
`nmsrna oi Autnut I. mo in m lcfili
`I'M o notice (DB3: me» on druu ton-
`tninlno amphetamine: and their outta.
`etnthm thot
`the own were recorded
`no pauiuiv cliccthe tor their rinimod
`onnrecuc cliect tnd incited euttiuiiuot
`evidence of cilccliveneaa {or their other
`Inhaled lildll’MlOltie The “element of
`honor him contained the nndinea ot the
`Commiulnnrr that become oi tho eit-
`tcmit-o me at tho drugs In the treatment
`oi ohecity. and their stimulant meet on
`the narrow whom. they have a poten-
`lial
`lor minute ond actual atntu. and
`production date indicated that ampheta-
`minca are produced and prucribod In
`quantum Bl‘t‘flll’ In cunt oi demon-
`atmied medical merit. In a condition tor
`continued mot-action oi omiiliolhminea.
`the atotemont oi volley required relohoi-
`inn ae enoeilt-rd and tho eubmtuion til I
`new drug application iNDM Itthlii one
`year ior oh ouch drun not then the lub-
`im of NBA approval.
`lloldere oi ao-
`nrm-od Nmta I‘M. renuircd to eublnit
`tithlttiliiml evidence oi total! and alib-
`alnntlol wideooe oi edtcaoy in the torn
`oi adequate and eretl-oootrotiod citnloel
`int'utlltationa.
`Oil
`l'ohnlory it, I"). the Continu-
`alolior puiitlahed in the lie-tut Monroe
`in Flt “til it nnol ordet nation that
`tlmn wee - tacit oi elihttnhtlot "1de
`oi ellectirmoae tor. and It recotmaod
`otrntiht tor the abuse oi.
`lined eo'rn-
`lnoiion druae tor anomtte on which
`contolnod.
`among other
`tnereMeute.
`omnhotoniino. Methamphetamine. or
`dexteoamphetamine.
`in addition.
`the
`Conunlnionrr
`iound that alternative
`therapeutic meaaum which are an and
`oilective are available too tile. The Corn-
`
`'
`
`'--ioncr niao ateiod in the limit ordcl’
`a mixture at doxtroomuhctomlno
`.
`u... ainnhcinmino it ordlnnriiy rrgnrrlcd
`o: n ainoir druit entity. A aimlior conclu-
`aion at to It mixture of dextronmphoto-
`mine and methamphetamine. end/or
`amphetamine and mothumnhclomine,
`mu‘not mndn. in til." (2| Cl’lt 3.“)
`the Food and Dmtt Administration ut
`forth in policy on tilted-combination
`druoa tor prucriotion tuo reouiriuothot
`eoch‘ druo In a fixed-combination drul
`contribuio to tho claimed elleot oi the
`drug: acctloa XV. tnirn. 'X'heroiore, druaa
`conlotnlng combination: oi ampheta-
`mine and nicthomplloiomlno and/or
`dextrootnphotomiuo and methampheta-
`mine; are mud combination drum. The
`Duel Eortler niao atated that a propotai
`to withdraw lPDl’OVM oi auch combina-
`tion'druzs ior aiioroctio the was pub.
`Iiahcd clot-where In the llnll tattle at the
`Front“. ltuunm.
`111.1 notice in tho “DIME “tonne
`oi Februon' it. it?! til m tam. tho
`Commiuiohor announced an opportunity
`tor marina on hie nronotoi to withdraw
`approval of new drill onnlicoliona ior
`tho combination amphetamine or “Mr
`anorectic drun. This notice woe based
`on evolution oi doto aubrnltted hur-
`auant to the noon". itconml notice oi
`Auoult I. mo m m ”Gill. Tillt dliit
`who tound. alter review. not to provide
`aulielontlol
`endonco tlint
`the druu
`named in the Funnel. nootrrla notloo oi
`rconiorv it. it'll. were eilective ot hired
`combination {or their claimed nnorootlo
`um. noted on thin loci: oi auhttnntial
`evidence at eilectivcnote oi the dnm to
`fixed combinations. tho rocoonltod lio-
`tentlol tor aotm oi time combination
`mas. and thearollohlllty oi oilcmntlve
`thcreheutic measure! which ore oitie and
`elective.
`the named dniu were mo
`found to be lockino in moot oi allot}.
`Tho Commietioner further lound thot
`the data submitted in reenonee to the
`noun. ltcoiarra notice or August I.
`trio. did not auohort a contention that
`the combination in-oduota decreoao the
`Incidence or atveritr oi aide elleoia ae-
`aoelated with the abuse potential oi the
`atnele entity anorectic onto. Notice trite
`therelore given to holder: of the named
`new dru
`application: and all other
`lntereete pet-lone. includinl thoae our.
`wine einiilar. Manual or retitled anion
`it mu m cm limitil
`that
`the
`Oommleeimer monotod to withdraw ap-
`moval oi time new drwi annilcotione
`led on a lack oi euottantiet evidence
`oi edeoth'enoae and a tool: or nroot oi
`uietr. Mi hoidera oi the NDA‘I and nor-
`aona marltctlild aimttu. identical or re-
`tated own. and other intereated per-
`aona Iere invited to teoueet a Marine
`on the urn-WM v'ilhnrnaale mi in nth.
`nut nth ouch howl. a well omontnd
`and iuiioiaotual anemia a u" olinioat
`and other theeflientloilal data they were
`mm to more in aumiort ol their on-
`goeition to tile oitltdrawoi oi the named
`DA'I and an! alien ainttlar. identical
`or related cruel. 'nle notice outed that
`it auhltanttat evidence oi elleetieoneee
`and evidence oi eaietr oaa received ior
`
`"0th Rain“. VOL II. "C. IH—WHOAV. "INN." II. ten
`
`Page 13 of 66
`
`c
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`Page 13 of 66
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`

`

`I.
`
`/
`lofted io neniomtroie that eneh ”Im,ol'\e§tebliehlnd "'M . ”m” “ “NM“ ”a
`Well-controlled. eet ioitli It “30.1mm
`nent of the time mourn n contribution i.
`the rintmed effect and that the donut!
`it). lint-e not been met.
`oi eat-h contnonrnt it ouch that the coin-
`f'nte etudy ie. on he ioco. insufficient
`to support any claim oi cuntli’ehm ior
`L-luntlen it tale end elicctlve tor it etc»
`the onetrol Products. The Cetrtmlnionei
`tvlncenl patient population requiring
`limit that this article it not inpatentlei
`ouch centurion: therapy ee defined In
`c‘riduite ol the eiiieecr oi Ottetrel Tell-
`the lebellne [or the dru: tat cm 3.80).
`lele.
`in roiiioiiee to this letter. Dclco Chemi-
`til Oberlin in
`‘b. The Treelmrni
`eel Co..
`ine..
`'l
`ltteoucelen Pei-knee
`North. Mount \Prhon. NY limo. notified
`neiienie Willi Cardiovoreuier Direeee.
`r'renkiin Blmon. MD. end Arthur nem-
`the Food and Dru: Adniliitilretion thet
`etoln. ".13.. A rieioloee. Vol. l! No.1. Jen-
`it wee reiormnieline the product: outi-
`ner-y. lDdl. 32-31. Title to e revert oi the
`Ject to the submitted new dnie onpllce-
`olmity problem in the United Stolen
`tlone into "tinnle enttt! emphetomine
`end o ttudr conducted with Obetrol.
`preperettont." No tut-thee oommunlce-
`ldd
`.‘i‘iie etudy reported oomieled oi
`lion hoe token piece.
`peurnu who were teen or the inventi-
`The other drug: named In the norm.
`Rtoieree notice at March :0. it‘ll. will
`yelore ier "ve nine“ periodi oi time. The
`he the eubieet oi ordere rullne on the
`mixture etoted the mt en conducted
`ior two montne. on “opprepriete” period
`reouette tor tteorltiee to be pubttelted in
`the Frozen. neeisree u. o iuturo due.
`o.
`time. Why the two monthe em "ep-
`I. The time: n. Obetrol lo dud Ohetrol
`p priete“ to not etittod. The otellderd
`iol- dotennlnlilc "overweight" wee elven
`:0 Tobie". rctneetiveiy contain at the.
`etch or 5 me. each oi metiinmphetomine
`_et‘— “overweight by In, elontliird need.”
`tneelierete.
`inetnemnitetitrotne
`lll'dro-
`new Obotroi to end obotroi to were ed-
`mlnielered. with dilute end time oi ed-
`chloride. emettetnmine euilete. end deit-
`m nietretlon altered to conierm to indi-
`troemphetemine eulinte per tebiet.
`vl lill reduii'emente.
`ii. The lone Deicoheee own are combi-
`’o otteoipt one mode to me our cell-
`nettone oi deetloeinphetemlne eultnto.
`methamphetamine hydrochloride. moth-
`lrole in the etudy. The lnveetiietore re-
`amphetamine odlvote end emphetiunine
`ported litet e pieeebo eulutttute woe et-
`lttlillte.
`ternnted with twenty-live pettente eiur
`ii. neeemmmird Ueee e. Obetroi l0
`tour meta oi treethient. but tilie type
`entt Oiletrot to 'l'eiitete ere recommended
`oi pieceoo employment to not e
`leoebo
`eo trot contempieted by in“ mm
`in eltoeenout otiuitr no I ehert-torm to
`in week» ediunct
`to o reelmeoni
`ill mm ml. einoe the reeuieuori re-
`oulree thet the loot drue be eompered
`I’dllllt
`reduction
`based
`on
`eelorio
`It
`the reeulte oi I petieni. group to
`reitrietlon.
`.
`h. The Doloohete druee ore reeom-
`e~l on e placebo. in ell reepeetephyeiceily
`Manual to the loot drill. line beoli ell.
`meiided ill euoeenoue oheenr. oe e eliort-
`term in few o-eelttl editinet in n reetmen
`ministered throughout
`the etude. The
`euoieot etudy did not comply with the
`oi erelciit teduetion billed on eolorie re-
`reeuletion.
`,
`etrirtion. end in the treatment oi hereo-
`The peert popuietion wee mode up
`lener end mitiltnel brein dretunotton in
`children.
`clip-timid tome oi whom lied tome eon
`m. The note to .i'iinildri Ctetme oi t!-
`at eerdioeeiouler dleoeee with or without
`(reiiwem it. Olmrot to end Olmroi re
`dil'heiee. tome with dieiietee Ilene. end
`Tnbieie i. I'uiiltrhed Sludiu. lteeer hoe
`ee .
`I'ltli no other dleoeee condition.
`Time II no lnioroletien It to euileblitlr
`eulimltted rive ltterotute rentinto which
`oi the pelionte to be included in it etude
`it eontentle
`luuport
`the eideeer oi
`to determine the eiteetirenete oi en en»
`Obetroi Tobieu. For
`the
`iotioe-lu
`mild. end no eutmnee oi eomplrobililr
`reeeone. time etudiei no not eulietentie
`evident-e oi the eneetireneu oi opetroi
`oi the tool eroup with e oentrol new.
`tinee e control eroup nee not employed
`Tebloto etnee thee ere not edeouete end
`il iamlliol idlililiel “Nil Ind iiiil l.
`e-elloeontroiiett elitiieei lneeetieelione.
`Deanne of the met emotion in the
`e. Modere Monument or chomp-
`tireleet oondiuone oi the petiente end
`The 'loeiei niri'. Milton l'
`“1)..
`other medieetlone they were teeine.
`1
`LAMA. July It, fl”. Vol.
`. pit.
`end the oerlettone oi douee end dure-
`ltlI-Itlt. Tint report it euoetentleiii
`tlon oi edminietretion reported or the
`o dleeottrte on the cotton oi obeetty end
`eulhore. on, opooiilo iintlilll lie the in-
`the verloue olelllode- oi ttveoline the eon-
`mtieetere releted to the eileetlt-eneee
`ditien. it merely neoite tnet the outlier
`ei Ghent» le oi eueetioneoio vehie.
`ieele tliet tome limetlootele. Ineludlne
`leetionlto.itieiteltliltelill neutree
`htmeeli. here eeteoitehed o domino
`thet 'o elem-ten oi
`the mthode oi
`therooeutiie ootion with oemtn We in
`enelrote end on evoiuotion oi the dole
`promotine Violent reduction. There to no
`derived iron the etude. ineiudlne one
`nrlnel ellpierl deln i-re-nntrti. no 1'"-
`euuien oi the lnreetieulione ee to em oi
`enumerate etetlelioet metitoee“ be one-
`otit
`Ne eueh dole to mounted in thie
`the etudiee. he eenlroie or etotletieel
`etude. 'i‘heroioro. it ie not pouliile to
`methode. end no reierenee to the coined-
`evoluete lite enelrileel end etotietieel
`ettlon oi the time thee eere employed
`in order to determine
`in tile iileeelieetlone.
`to required
`5, methode entitle
`litmliteliei m ci‘lt lion). 'i'he
`theiroliottr et
`roeuito end the inm-
`tieetor‘e eoneluolohe.
`outlier mentione thot Clairol woe tiled
`The reunite oi the etude um eteted in
`in "title" etudr. but the reierenee to
`erhleh etude in union. The entorto in
`eeneni tonne oi the totel number oi
`
`NO‘HCES
`
`.
`
`1674-;
`
`,
`
`por- I: lost; with itn oversee brine ee-
`tiL
`to tech patient. No eetuol petieltt
`mud were elelcd. The int-citieetare
`ttote that the l‘lil" oi weight leee reeled
`i rein "elntoet nothing" to 25 pounde. The
`euthore admit
`that
`their remit: ere
`“made up oi combining the good with the
`bed.
`the etleetlve eith the inoilchve
`e-eleht reduoer." Thus.
`it ie impoeeble
`to drove on: tneenlneiui eonehuione no
`lo the emcee, oi Obetrol iron the stud:
`become iull reverie oi petlent deto ob-
`‘teined iroro the etudr ere not presented
`It required in litmlzlnitltiilleliil.
`in odditien. tince Ohetrol to e combi-
`iiiillon drill e1lhin the meenine oi nee.
`the inveelieetore must then tiiet both
`the amphetamine end methornnhetemino
`eomnonenu oi the time contribute to the
`drum put-pond eiieet. lie ouch ehovtnl
`no nude in title eludy.
`The commiuiener finds thet thte etudy
`it not euhilentiel evidence at the ode:-
`tiveneu ol Ohetroi Tobieie.
`e. Treeiment or corn Diobeiiee and
`Arierioreleroliee. Arthur liemetein. MD.
`end rrenltitn dimon. MD. Merlot iroln
`Citrtieoi' Medicine. Mop. mi. DD.
`i-e.
`Title to mother report oi the etude die-
`cutted in ii. ehove. it eontelne no more
`petient iniormollon or dole then doee
`the other revert. end no ttetittleoi onelr-
`eie. For the roe-one eteted eeeve.
`the
`Commieeloner ilndit thll Itudr to not rule-
`etenltel evidence oi the elleettnneee oi
`Olietmi Tehiett.
`ti. the ol on Annheiemine~€ombino-
`lion Dru in en Anti-oboe"! Clinic. liter-
`rill nennen. MD. end up Andereoo.
`l‘Dee fi'do "e H“. J; J.nq IN. w. 22-
`:i. Title to e resort oi etude eomueted
`with Oiletroi-l home. The petient
`ventilation numbered it: the only inedi-
`enl problem oi the group no oeeeilyd’he
`drue tree lute-d in 25 peuente end eon-
`‘ end with it pellente to when: no med-
`eetion wee odmtnletered. ‘nie euthoee
`Iteted tiilt "the Met outeom oi title
`etude will eerelt lie ultimote re-orelue-
`tion when the Dottente ere nun-ed one
`"or iron the time their entered the
`eiinte prooretn.“
`The petionte were eeleelnd et readout.
`end nndernlr pieeed on Miter the one
`or he tnltmlilt. Both toot end «litre!
`petionte core Detailed eeeh week. more
`nutritionel «name one pemeleeted
`in the nine
`dieeueetene. no re-
`eulteebteln .ehoerodtheuheeroopte
`whom the one lied been odmtnietered
`Ioit eit ewroee oi re: pomde over e Ion
`mil period. Ihlietheeentrol new tool
`on eveneo oi ul pounde o'er the ten
`not period. The utuel nelehi leee tor
`eeoh petient to taunted. 'me outhero
`eotnludedthet'themonthooro-
`:hetonine Detonation III “to to ice
`who to men. on the omen. oe the
`eouuot m“
`The etude to «Mint in oererel re-
`epeeto. mm. the decree oi overweleht
`oi the petiente it not epeeiiied. iteeond.
`the ntothod oi rondomlelne the emotion
`oi the ntienloie not outed. nor to e toote
`oi rendotn numlere pmntee. it Ildit
`telttll. Dole to not mud on to the
`number oi entrente in the till" end the
`
`W”
`
`—
`
`Page 14 of 66
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`Page 14 of 66
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`

`-.
`
`l
`
`me ‘
`
`NOTICES
`'1
`-
`t
`‘
`760’
`dmioi
`do.
`o-
`o
`Dun-rm. an“ to ma... ~sirtetrulne hydrochloride one o
`33': $3533....- to demonotroto thot stored; and .9 to whom Obotrol I’M ed-
`eouot nttmhon oi potienu were placed "intnietered. There to no explonntion elven
`in each emup and to lotion up on these alter the ruletieii in the number at out:-
`pnueitu to ucerultn why they dropped -iceto tn encli lroun. The no trcotment
`out. Finally, the emiyttcot technique tor 'eroun lied on obeelty duration oi to retro
`evaluating the reeulto to not deeorlteod gor
`lonrer In Ill com:
`the other two
`mime it
`lmpooolhlo to oetohtleh the erouoehedoloneobeumlumtlond'hero
`elnnlnohnco oi.tho mamma- oi treet- 'to no reuon elven why the to non tor
`ment at the two groupe (I tsunami ,tho no'treotrnent group to olmtneont or
`(II) to) NH.
`‘ohr the lock oi oveclno ountlon at
`In Idltlon to the Ibovo doilclenotco. the 39W"? 10? "I! 0W! "'0 em" 3 “m“
`etudv t. not Inoqttote end well-controlled
`Tlcont.
`.
`The reeulto o:
`the etudy moved on
`to eetohlieh the emcecy oi count tor the
`Iver-no tone of u pounde In two min.
`ioiloo'lnc reuono. .Ae poin