DEPARTMENT OF HEALTH & HUMAN SERVICES'
`
`Public Health Service
`and Drug Administration '
`Food
`Rbckvile,MD 2Q857
`
`
`Our STNs: BL 103792/5187 and 103792/5189
`
`MAY 22 2008
`
`Genentecli, Incorporated
`Áttention:Todd W.Rich, M.D.
`
`Vice President
`Clinical and Commercial RegulatorY,Àffairs
`1 DNA Way, MS #242
`San Francisco, CA' 94080-4990
`
`South
`
`Dear Dr. Rich: ..' .
`
`
`Your request to supplement yôti biologics license application for trastuzumab (Herceptin) to
`approved:
`
`expa.dthe breast
`
`c,ancerindication
`
`as follows has been
`
`."
`
`.
`
`( "
`
`
`Herceptin, as Pai of a treatment regimen
`
`
`containing doxorubicin, cyclophosphamide, and
`docetaxel,Jor the 'adjuvant treatment ofHER2 over~expressing, node-positive or high-
`risknode:'negative, breast cancer (BL 103792/5187). '
`
`Herceptin, as par of a treatment regimen containing docetaxel.and'carboplatin, for the
`ådjùvanttreatment ofHER2 over'-expressing, noae-positive or high~risk node~negative,
`breast cancer (BL 103792/5189).
`
`REQUIRED
`
`PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA)
`
`active ingredients, new indications, new
`
`a~minisiration are required to contain
`
`) product forthe claimed iiidication(s) in
`
`(21 U.S.C. 355c), all
`
`applications for new
`dosage forms, new dosing regimens, or new,'routes of
`the sáfetÝ andeffectivenessoftlie
`this requirementis waived,
`
`an assessment of
`
`pediatric patients
`
`unless
`
`deferred, or inapplicable. . (
`
`
`We are
` waiving thepediatrlc study re4uirement for these supplements b~causenecessary studies
`are i11possibleor highly impracticable. HER2 over-expressing, node-positive,orhigh-risk node-
`does not occur in.pediatric.patients. !
`
`negative, breast
`
`canCer
`
`PQSTMARKTING REQUlREMENTS'UNDER5~5(o)
`
`Title ix, Subtite,A, Section 901 of
`
`areiidsthe Federal Food, Drug" and
`
`
`trials for certain purposes, if FDA makes
`
`
`the FoodåndDrugAdixiinistration Act of2007 (FDAAA)
`Cosmetic Act (FDCA) to a~thorize FDA to require holders
`of approved drug and biologic product applications to conduct postmarketingstudies and clinical
`certain findings required by. the statute (section
`25, 2008.
`
`
`505(0)(3)(A), 21 U.S.C. 355(b)(3)(A)). This provision took effect
`,
`
`on March
`
`IMMUNOGEN 2195, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Page 2 - BL 103792/5187.and 103792/5189
`
`Herceptin was first approved
`
`
`breast cancer, in patients who
`
`
`have
`
`received one or
`
`in 1998 asa single agent for HER2 over-expressing metastatic
`more chemotherapy regimens for metastatic
`disease. It was also approved incombination with paclitaxel for the first-line treatment of HER2
`over-expressing metastatic breast cancer. The label for Herceptinhas a black box warning
`
`coiicerning cardiomyopathy., Now,
`
`however, Herceptinis being approved as a component
`
`of
`
`two
`
`novel
`
`high-risk
`
`node-negative, breast
`
`Herceptin in th((se new treatment situations. Our new analysis of available
`
`
`toxicity associate? withBerceptin may be different with
`
`
`the use of this
`
`
`with
`
`with the fact that Herceptin wil
`
`
`now
`
`be indicated for use with Carboplatin,Y'e are
`
`~k )
`
`
`adjuvant treatment regimens for patients with HER2 over-expressing, node-positive or
`cancer following surgical resection, and our recenütnalysis of tHe
`ßata inyour supplements indicate the nood to assess the long-term cardiovascular risks of
`scientific data /
`
`indicates that the long-term incidence and severity of the known serious risk of cardiovascular
`
`drug in new combination
`these adjuvant chemotherapy regimens. In addition, based on new information associated
`concerned
`Herceptin with CarbJplatin may cause adrug-dnig interaction (DDI) that coul4
`creating an unèxpected serious
`
`that the
`
`use of
`
`
`,affeètthe pharacokinetics of one
`
`or theother.oftlie two drugs,
`
`
`W ehave. determined that
`
`an analysis of spontaneous post~årkèting adverse
`
`
`under subsection 505
`
`
`(k)(1 ) of the FDCA wil not be suffcient to assess the
`
`
`events reported .
`
`known serious risk of
`patient population and when the drug is used in combination
`potential for an unexpected serious riskàssociated with an
`effect on pliaracokinetics from the use of Herceptin in cømbination with Carboplatin.
`
`
`c,årdiovascular toxicity in the new
`
`
`with other therapies, or assess the
`
`
`Furhermore, the new pharacoyigilance sy~tem that FDA is required to
`
`
`establish
`
`under
`
`section
`been est~blished and is not sufficient to assess either this
`known serious fisk or the potential for this unexpected serious risk.
`
`505(k)(3) oftheFDCA has not yet
`
`Finally, we have determined that only a clinical trial (rathèr than a nondinical or obserVational
`
`potential for this unexpected
`
`
`to assess thÍs known serious risk or the
`
`study) wil be sufficient
`
`serious risk.
`
`Therefore, based on appropriate scientific data, FDA has determined thàt you are required,
`pursuant to section 505(0)(3) oftheFDCA,.to conduct th~ following postmarketing clinical trials
`of Herceptin:
`
`1. To provide an update 'of cardiac' safety from all 3 treatment arms
`
`
`in Study BCIRG006 at
`the timewheitthe last patient enrolled reaches 5 years o'f follow-up. Theupdatewil
`include analysis ofpèr-protocoldefined ~ardiac events,changesin LVEFmeasurements,
`patients who developed anew per~protocol defined symptomatic
`
`and riartatìves for any
`
`
`cardiac event. ' .
`
`
`The timetable you submitted on April
`
`
`according to thefollowing schedule:
`
`24, 2008, states that you will conduct this trial
`
`J
`
`Completion
`
`of S-year follow-up:
`Final Report Submission:
`
`June
`
`30, 2009
`
`March 31,2010
`
`
`IMMUNOGEN 2195, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Page 3 - BL 103792/5I87 and 103792/5189
`
`2. To perform aUDI trial in
`
`metastatic cancer patients to evaluate the impact of
`
`
`Herceptin
`onCarboplatin pharacokinetics and to evaluate the inipact of Carboplatinon Herceptin
`pharmacokinetics. Herceptinconcentrations in the DDI trial wil be compared to clinical
`trials B016348, B015935, and W016229.
`
`pharmacokinetic data from clinical
`
`
`The timetable you submitted on
`
`
`May 13, 2Q08, states that you will conducUhistrial
`aCQording to the following schedllle:' (,
`
`
`Protocol submission:
`Study Initiation:
`Final report submission:
`
`ì
`
`March 31, 2009
`30, 2009
`January 31, 2013
`
`September
`
`We acknowledge your written connitmentto complete a drug:drug interaction (DDI) trial as
`correspondence (email).
`
`described in your May 13, 2008, electronic
`
`
`Submitthe protocol fnrcontinued assessment of cardiac safety and your DDI trial
`
`
`protocol to
`with a cross-reference letter to yot1r BLA, STN 103792. Submitall final
`report(s) to your BLA, 8TN 103792.
`
`your IND 451 7
`
`
`Use the
`
`following designators to prominently label all submiSsions; inCluding supplements,
`relating to this postmarketing clinical trial as appropfiate: .
`
`. Required Postmarketing Protocol
`
`under 505(0)
`
`
`. Reqùired PostmRrketing Final Report under 505(0)
`
`. RequiredPostmarketing CorreSpondence under 505(0)
`
`
`to report
`
`
`You are required
`
`periodically to FDA 011 the status ofthese postmarketing clinical trials
`pursuant to sections505(0)(3)(E)(ii) and 506B qftheFDCA, as well as 21 CFR 601.70. Uiider'
`section 505( 0)(3)(E)(ii),you are also requìred toperlodica1lY report to FDA on the status of any
`~tudy or clinical trialotherwise undertaken to investigate a safety issue associated with
`Herceptin.
`
`POSTMARKEtING STUDY COMMITMENTS SUBJECT TO REPORTING
`REQUIREMENTS-ÖF 21 CFR601.70.
`
`We acknowledge ýourwritterrcommitmentto provide additionalinformation on the ongoing
`as outlinpdbelow:
`
`BCIRG006study as describeci in your April 24;c2008, letter
`
`3, To provide
`
`an update of
`
`efficacy
`
`from all 3 treatment arms in Study BCIRG006 at the
`time when the last patientenrolled reaches 10years of~ollow-up, withaninterim update
`follow-up.
`
`of efficacy at 5-years of
`
`
`The timetable you submitted On April 24, 2008, states that you
`
`
`according to the following schedule:
`
`wil conduct this trial
`
`IMMUNOGEN 2195, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Pàge 4 - BL 103792/5187
`
`
`and 103792/5189
`
`(
`
`Complètion of 5~year follow-up:
`5-year DFS and OS update
`Completion of 10-yearfollow-up
`Final report submission (lO-year DFS alld OS update)
`
`Juiie 30, 2009
`March 31,2010
`30, 2014
`31, 2015.
`
`March
`
`June
`
`Submit
`
`Submit the protocol to your IND, 451 7, with a cross-reference letter to your BLA, STN 103792.
`all final report(s) to yourBLA, 8m 103792. Use the following designators to,
`prominently label all submissions, including supplements, relating to this postmarketing clinical
`trial as appropriate:
`
`\ .
`
`. Postmarketing Commitment Protocol
`
`. Postmarketing Commitment - Final Report
`
`. Postmarketing Correspondence
`
`. Anual Status Report ofPostmarketing Commitments
`
`
`For each postmarketing study subjectto the reporting requirementsof21 CFR601 .70, you must
`describe the status in an anual report on postmarketing studies for this product. Thê status
`report for each study should include:
`
`. information to identify and descri(be the postmarketing commitment,
`
`
`. the original schedule for the commitment,
`
`
`. the. status öf the .commitment (i.e. pending,. ongoing, delayed, terminated, or
`
`
`. , an explanation ofthe status including, for clinical stlldies, the
`
`patient
`
`accrual rate
`
`(i.e. number enrolled to date and the total planed enrollment), and
`. a revisedscheduleifthe study schedule has changed and an explanationQfthe
`
`
`,basis for the revision. .
`
`submitted), .
`~ , ..... . . "
`
`As described in 21 CFR 601 .70( e), 'we may publicly disclose information regarding these
`postmarketing studies on our Web site (http://ww.fda.gov/cder/pmc/default.htm). Please refer
`Post marketing Study
`Administration
`
`Moderiizatis:n Act of 1997 (see http://wwwJda.gov/cder/guidance/5569fnl.htm) for further '.
`
`inforiàtion. .
`
`
`to the February 2006 Guidance for Industry: Reports on the Status
`
`of
`
`Commitments - Implementation of Section i.0 of the Food and Drug
`
`
`;
`
`CONTENT OF LABELING
`
`Within 21 days ofthe date ofthis letter, submit1content oflabeling (21 CFR 601. 14(b)l in
`as described at
`
`. structrired product Ia1Jeling (SPL) format,
`
`http://ww.fda.gov/oc/datåcouncilísp1.html, that is identical in content to
`
`the enclosed labeling ­
`text. Upon receipt, we wil transmit that version to the National Library of Medicine' for public
`dissemination. For admitlistrative purposes, please designate these submissions "Product
`103792/5189." In
`
`letter, 'amend any pendingsupplement(s).'for this'BLA
`the changes approved in this supplement.
`
`Correspondence - Final SPLfor approved STN BL 103792/5187 and
`
`addition, within 21
`
`âays'ofthe
`
`date of
`
`this
`
`with content oflabeling in SPL format to include
`
`
`IMMUNOGEN 2195, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Page 5 - BL 103792/5187 and 103792/5189
`
`You may submit draft copies ofthe proposed introductory advertising and promotional labeling
`with a cover letter requesting advisory comments to the Food and Drug Administration, Center
`for Drug Evaluation and Research, Division of Drug Marketing, Advertising and
`Communication, 5901-B Ammendale Road, Beltsvile, MD 20705-1266. Final printed
`advertising and promotional labeling should be submitted at the time of initial dissemination,
`accompanied by a FDA Form 2253.
`
`All
`
`promotional claims must be consistent with and not
`
`contrary to approved labeling. You
`should not make a comparative proinotional claim or claim of superiority over other products
`unless you have ,substantial evidence to support that claim.
`
`Please refer to http://ww.fda.gov/cder/biologics/default.htm for information regarding
`therapeutic biological products, including the addresses for submissions.
`
`This information wil be included in your biologics license application file.
`
`If you have any questions, call Monica L. Hughes, M.S., RPM, at 301 -796-2320.
`
`Sincerely,
`
`12~4.i44­
`Director '
`
`
`Patricia Keegan, M.D.
`
`Division of Biologic Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`Enclosure: Package Insert Labeling
`
`IMMUNOGEN 2195, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`First-Line
`
`.
`
`Table 8
`
`Stidy 5: . Effcacy Results in
`
`Treatment fór Metastatiç Breast Cancer
`
`'.
`
`Paclitaxel Subgroup
`
`AC Subgroup
`
`Combil1ed Results
`Herc,ptin
`* Aii
`Chemo-
`thenipy
`(n -235)
`
`llerceptin
`All
`+
`Chemo'
`therlpy Paclitaxel Paclilaxel
`(n=234)
`(n= 92)
`(n= 96)
`.
`
`.
`
`Herc,ptin
`+AC'
`(11= 143)
`
`AC
`(n=138)
`
`Primary Endpoint
`
`Medial1
`7.2
`TIp(moN.o
`
`95%CI
`
`p-value~
`
`7,8
`
`4.5
`
`4,5
`
`,
`6.7
`!
`5, 10
`
`2.5
`
`2,4
`
`7.6
`
`7,9
`
`5.7
`
`5,7
`
`,
`
`-: 0.0001
`
`-: 0.0001
`
`0.002
`
`Secondary .Endpoints
`Overåll
`45
`Response Rateb
`
`
`29
`
`38
`
`95%CI
`
`39:51
`
`23,35
`
`28,48
`
`15
`
`)\
`8,22
`
`50
`
`38
`
`42,58
`
`30,46
`
`p-valuê e
`
`-:0.001
`
`-: 0.001
`
`0;10
`
`8.3
`
`5.8
`
`8.3
`
`4.3
`
`8.4
`
`6.4
`
`
`Previously Treated Meta:;latic Breast Çanrer (Study 6)
`
`Herceptiiiwasstidiedasa single agenrin amultiçenter, open.label,
`single-an clinical tral (Study6) inpatients with HER20verexpressing
`one or two prior
`metastatic breast cancer who had relapsed following
`chemotherpyregiinens formetastatic disease. Of222 patients enolled,
`66% had re¡eived prior adjuvant çhemotherpYi68% hadreceivedtwoprior
`25% h¡idreceived prior
`chemotherpy regimens for metastatic disease, and
`myeloablat~ve treatment withherntopoietic rescu~. Patients were treat~ .
`
`
`with a loading dose of4 rng/g IV followed by weekly doses of Herceptin at
`
`
`2 lnglgIV. ". .
`
`
`The ORR (complete response+partial response),as detered by an
`
`indepeidentResponseEvaluation Conuittee, was 14%, witha2%çomplete
`ráte and a 12% partialresponser¡ite. Complete respoiiseswere
`response
`The
`with disease limited t~ ski andJymph nodes. .
`obsered .ònlyin patients
`OVerall response r¡ite in patients whosetimots tested as CTA 3+ was 18%
`while in those that tested as CTA 2+,it was 6%.
`16 1I0WSUPPLIEU/S:rORAGEAN HANLING
`
`16.1 How SuppUed
`Herc~tinis supplied ina multi-use vialçontaining 440 mgtrStuzumab as
`contains one vial
`Each
`caron
`a lyophilized sterle piiwder, under vacuum.
`Injection
`Baçterostatic Water for
`Herçeptin~ aldone vial (20 ni)Of
`(BWFl), USP, containing 1.1% benl alcohol as a preseratiVe. NDC
`50242- 134-68.
`
`
`5 ,11
`
`~, 7
`
`4,8 .
`
`Do not use beyond
`
`the
`
`reconstitution
`
`when stored refìgerated
`
`"
`16.2 . Stabilty iifid Storage
`are stable ati-8°C (36-46°F) priortò reconstitition.
`Vials. of Her6eptin
`the viaL. A vial of
`eKpiration
`date staped on
`after
`Herceptin reconstitited with BWFI, as supplied" is stable for 28 days
`at 2-8°C (3(j46°F). . Discard any
`days. Avial of Herçeptin
`
`remaÍling multi-ilo~e reçoiistitutei solution after28
`should be used
`re¡onstitiedwithunpr~serêi SWFI(not supplied)
`and an.y unused portion discarded. DoNot Freeze HerceptÍl
`iiediately
`followigreconstitition or dilution. "
`infusion diluted in pòlyvinylchloride or
`The solution ófHerceptin tor
`polyethyleie bags çontaining 0.9% S~diuin Chloride Iije¡tion, USP, should
`use.
`be stored at 2-8°C (36-46°F)fornol1ore than 24 hour prior to
`17 PA l'IENTCÔuNŠELINGlNFORM¡\TI()N
`
`contact ahealtheareprofessionaFi111inediately for an). of
`. Advisepatients to
`thefollowing:new onset or worseiing shortess Ç)fbreath, cough, swelling
`of the. ¡ies/legs, sw~lling ¿fthe face, palpitations, weight gain of more
`than
`5 pounds in 24 hour, diziness or loss of consciousness (see, Boxed
`Warning: Cardiomyopathy).
`. Advise women with reproductivepotentjal to use effe¡tive ()ontrçeptive
`iuethods dur~ treatneitand for a tnjnumof six months following
`
`Herceptin (see Pregrancy (8.1).
`. Ençourge pre~ant women who are using Herceptin to enoll in the
`Cancer
`and Childbir Registr (see Pregrçmry (8.1)).
`
`HKRCEPT~..(trllstuzumabJ
`Manufàdured by:
`Geneiíteçh, Inc.
`¡DNAWay
`SoutlSanFrancisço, CA 94080-4990
`
`4839800.
`
`112006 Genente¡h, Inc.
`
`
`Resp
`Median
`Duration
`(nîoS)b.,
`
`25%,75%
`
`quartile
`Med Surival
`
`(ìnos)
`
`95%CI
`
`6,15
`
`25;1
`
`4,8
`
`20.3
`
`22.1
`
`18.4
`
`6, 15
`
`26~8
`
`21;4
`
`
`22,30
`
`11,24
`
`23,33
`
`18,27
`
`13,24
`17,29
`.0.17
`0.16
`0.05
`p-valué
`'.
`a AC= Artlicycline (doxorubtCll or eprrbicii) and cyclophosphanude.
`b Assessed by
` an inilependentResponse Evaluation Commttee.
`
`'Kaplan'-Meier Estimate.
`
`d log-tank test.
`
`e x2-test.
`
`
`, Data fiom Study 5 suggest that the beneficial treatment effects were
`limited to patients with the highest level of HER2 protein
`largely
`overexpression(3+) (see Tåble 9).
`
`9
`Table
`Treatrent Effects in Stuy 5 as ,a
`
`Function of HER2 Overexpression or Amplification
`
`
`HER2Assay
`Result
`
`CTA
`
`2+ or 3+
`
`FISH (+)"
`
`FISH (-)"
`
`CTA2+
`
`FISH(+)
`
`FISH (-)
`
`CTA3+
`
`Numberof
`Patients
`(N)
`469
`
`Relative Risk for
`Time to Disease
`Progression
`95%C
`0.9(1040,.0.61)
`
`Relative Riskb for
`Mortality
`(95%C
`
`0.80 (0.64, 1;00)
`
`325
`
`126
`
`120
`
`32
`
`83
`
`349
`
`0.4(0.34,0.m
`
`0.70 (0.53, 0.91)
`
`0.62 (0.42, 0.94)
`
`1.06 (0.70,1.63)
`
`0.76 (0.50, 1.5)
`
`1.~6 (0.82, 1.94)
`
`0.54 (0.21,1;35)
`
`1. 1 (0.53,3.27)
`
`0.77 (0.48, 1;25)
`
`1. 11 (0.68, 1.2)
`
`0.42 (0.33, 0.54)
`
`0.70 (0.51, 0.90)
`
`0042 (0.32, 0.55)
`
`0.67(0.51,0.$9)
`FISH(+)
`293
`FISH(-) 43 0043(020,0;94) 0.88 (0.39, 1;98)
`apISH testing results were aya.iiable for
` 4510fthe469 patients eiiolled
`onStldy, ..,',.. .'
`
`
`b The relative
`
`
`or death in the
`
`Herceitin plus chemotherpy arm verus the chemotherapy arm.
`
`
`risk representsth~ risk of progression
`
`IMMUNOGEN 2195, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`