Auspar Efmoroctocog Alfa Rhu 150317

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     Australian Public Assessment Report

    for efmoroctocog alfa1

     (rhu)

    Proprietary Product Name: Eloctate

    January 2015

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     Therapeutic Goods Administration

    Sponsor: Biogen dec Australia Pty !td

    1 The non-proprietary name has changed post registration from efraloctocogalfa to efmoroctocog aa to harmonise with the International Non-proprietary Name.

    AusPAR loctate efmoroctocog alfa !rhu" #iogen Idec Australia Pty $td P%-&'1(-'11)*-1-+,ate of inalisation 1* %arch &'1)

    Page & of )1

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     Therapeutic Goods Administration

    About the Therapeutic Goods Administration (TGA)

    •  The Therapeutic Goods Administration !TGA" is part of the Australian

    Goernment ,epartment of /ealth and is responsi0le for regulatingmedicines and medical deices.

    •  The TGA administers the Therapeutic Goods Act 1989 !the Act" applying

    a ris2 management approach designed to ensure therapeutic goodssupplied in Australia meet accepta0le standards of 3uality safety ande4cacy !performance" when necessary.

    •  The wor2 of the TGA is 0ased on applying scienti5c and clinical e6pertise

    to decision-ma2ing to ensure that the 0ene5ts to consumers outweighany ris2s associated with the use of medicines and medical deices.

    •  The TGA relies on the pu0lic healthcare professionals and industry to

    report pro0lems with medicines or medical deices. TGA inestigatesreports receied 0y it to determine any necessary regulatory action.

    •  To report a pro0lem with a medicine or medical deice please see the

    information on the TGA we0site 7http899www.tga.go.au:.

    About AusPARs

    • An Australian Pu0lic Assessment Record !AusPAR" proides information

    a0out the ealuation of a prescription medicine and the considerationsthat led the TGA to approe or not approe a prescription medicine

    su0mission.

    • AusPARs are prepared and pu0lished 0y the TGA.

    • An AusPAR is prepared for su0missions that relate to new chemical

    entities generic medicines ma;or ariations and e6tensions ofindications.

    • An AusPAR is a static document in that it will proide information that

    relates to a su0mission at a particular point in time.

    • A new AusPAR will 0e deeloped to reect changes to indications and9or

    ma;or ariations to a prescription medicine su0;ect to ealuation 0y the TGA.

    Copyright

    AusPAR loctate efmoroctocog alfa !rhu" #iogen Idec Australia Pty $td P%-&'1(-'11)*-1-+,ate of inalisation 1* %arch &'1)

    Page ( of )1

    http://www.tga.gov.au/http://www.tga.gov.au/

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     Therapeutic Goods Administration

    < =ommonwealth of Australia &'1) This wor2 is copyright. >ou may reproduce the whole or part of this wor2 in unaltered form for yourown personal use or if you are part of an organisation for internal use within your organisation0ut only if you or your organisation do not use the reproduction for any commercial purpose andretain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rightsto use as permitted 0y the Copyright Act 1968 or allowed 0y this copyright notice all other rightsare resered and you are not allowed to reproduce the whole or any part of this wor2 in any way!electronic or otherwise" without 5rst 0eing gien speci5c written permission from the

    =ommonwealth to do so. Re3uests and in3uiries concerning reproduction and rights are to 0e sentto the TGA =opyright ?4cer Therapeutic Goods Administration P? #o6 1'' @oden A=T &' oremailed to 7tga.copyrightBtga.go.au:.

    AusPAR loctate efmoroctocog alfa !rhu" #iogen Idec Australia Pty $td P%-&'1(-'11)*-1-+,ate of inalisation 1* %arch &'1)

    Page + of )1

    mailto:[email protected]:[email protected]

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     Therapeutic Goods Administration

    ContentsList of the most common abbreviations used in thisAusPAR5

    I. Introduction to product submission____________________8Cu0mission detailsDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDE

    Product 0ac2groundDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDF

    Regulatory statusDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDF

    Product InformationDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDF

    II. Quaity !ndings_________________________________________"

    IntroductionDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDF

    ,rug su0stance !actie ingredient"DDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD1'

    ,rug productDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD11

    uality summary and conclusionsDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD1&

    III. #oncinica !ndings___________________________________$%

    IntroductionDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD1&

    PharmacologyDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD1(

    Pharmaco2ineticsDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD1+

     To6icologyDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD1)

    Nonclinical summary and conclusionsDDDDDDDDDDDDDDDDDDDDDDDDDDDD1E

    I&. Cinica !ndings_______________________________________$"

    IntroductionDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD1F

    Pharmaco2ineticsDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&1

    PharmacodynamicsDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&1

    ,osage selection for the piotal studyDDDDDDDDDDDDDDDDDDDDDDDDDDDD&&

    4cacyDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&&

    CafetyDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&(

    irst round 0ene5t-ris2 assessmentDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&)

    irst round recommendation regarding authorisationDDDDDDDDDDDDD&

    =linical 3uestionsDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&

    Cecond round ealuation of clinical data su0mitted in response to3uestionsDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&*

    &. Pharmacovigiance !ndings___________________________%'

    Ris2 management planDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD&*

    &I. (vera concusion and ris)*bene!t assessment____+5

    #ac2groundDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD()

    ualityDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD()

    http://var/www/apps/conversion/tmp/scratch_5/HYPERLINK%23_Toc412817703http://var/www/apps/conversion/tmp/scratch_5/HYPERLINK%23_Toc412817703http://var/www/apps/conversion/tmp/scratch_5/HYPERLINK%23_Toc412817703http://var/www/apps/conversion/tmp/scratch_5/HYPERLINK%23_Toc412817703

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     Therapeutic Goods Administration

    NonclinicalDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD(

    =linicalDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD(

    Ris2 management planDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD(E

    Ris2-0ene5t analysisDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD(E

    ?utcomeDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD+&

    Attachment $. DDDDDDDDDDDDDDDDDDDDDDDDDDDD Product Information,+

    Attachment %. DDDDDDDD -tract from the Cinica -vauationReport ,+

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     Therapeutic Goods Administration

    List o the most common abbre!iations used in this

    AusPAR

    Abbreviation

    /eaning

    aPTT actiated partial throm0oplastin time

    A#R annualised 0leeding rate

    A=P% Adisory =ommittee for Prescription %edicinesA=C?% Adisory =ommittee on the Cafety of %edicines

    A aderse eentA/=,? Australian /aemophilia =entre ,irectorsH ?rganisation

    AP= actiated protein =

    ARTG Australian Register of Therapeutic GoodsA= area under the concentration-time cure

    # #ethesda unit=R =linical ealuation report

    =/? =hinese hamster oary

    =I con5dence interal=ma6 ma6imum plasma actiity

    =%I consumer medicine information=CR clinical study report

    , directions for use

    =)' )'J eKectie concentration=G electro cardio gram

    , e6posure day

    %A uropean medicines agencycRn neonatal c receptor

    LIII coagulation factor LIIIG=P Good clinical practice

    G$P Good la0oratory practiceh hour!s"

    /= /#L hepatitis # irus

    /=L hepatitis = irus/em A mice actor LIII de5cient mice

    /IL human immunode5ciency irus/R heart rate

    I=/ International =onference on /armonisation of TechnicalRe3uirements for Registration of Pharmaceuticals for/uman se

    IgG immunoglo0ulin GIgG1 immunoglo0ulin G1

    ICT/ the International Cociety on Throm0osis and/aemostasis

    ITI immune tolerance induction

    I international unitIL intraenous

    M? 2noc2 out

    $= light chain%RT mean residence time

    N#A National #lood Authority

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     Therapeutic Goods Administration

    "# "ntroduction to product submission

    $ubmission detai%s

    Type of submission: New 0iological entity

    Decision8 Approed

    Date of decision: 1E une &'1+

     Active ingredient: fmoroctocog alfa !rhu&"(

    Product name: loctate

    ponsor!s name and

    address:

    #iogen Idec Australia Pty $tdCuite 1 $eel ) 1&( pping Rd

    North Ryde NC@ &11(

    Dose form: Powder for in;ection and diluent

    trengths: &)' international units !I" )'' I *)' I 1''' I1)'' I &''' I and (''' I

    Containers: Type I glass ial !powder" and pre-5lled syringe !diluent"

    Pac" si#e: Cingle

     Approved therapeuticuse:

    $%octate is a %ong&acting antihaemophi%ic factor'recombinant( indicated in adu%ts and chi%dren ' ) 1*

     years( +ith haemophi%ia A 'congenita% factor ,---

    de.ciency( for:

    •  contro% and prevention of b%eeding episodes

    •  routine prophy%a/is to prevent or reduce the

    fre0uency of b%eeding episodes

    •   perioperative management 'surgica% prophy%a/is(

    $%octate does not contain von i%%ebrand factor2 andtherefore is not indicated in patients +ith voni%%ebrand!s disease3

    & recom0inant human

    ( The ingredient name at the time of su0mission and registration wasfraloctocog alfa The name was su0se3uently changed on &' e0ruary

    &'1) to harmonise to the International Non-proprietary Name !INN"fmoroctocog alfa. The AusPAR document has 0een amended 0y replacingthe preious name efraloctocog alfa with approed INN efmoroctocog alfa.

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     Therapeutic Goods Administration

    4oute ofadministration:

    Intraenous !IL" infusion

    Dosage: Refer to the Product Information !PIO Attachment 1"

     A4TG numbers: &1')&1 !&)' I" &1')1F !)'' I" &1')&( !*)' I"

    &1')&) !1''' I" &1')&& !1)'' I" &1')&+ !&''' I"&1')&' !(''' I".

    Product bac&'round/aemophilia is an inherited chromosome-lin2ed 0leeding disorder. InAustralia there are appro6imately &'' people with haemophilia and nearlyall are male. /aemophilia A is the most common form and is due to thede5ciency of factor LIII. Reduced 0lood coagulation results in 0leeding whichis most commonly internal usually into the ;oints or muscles. ?er timerecurrent 0leeds can cause permanent damage such as arthritis chronic

    pain and ;oint damage re3uiring surgery.

    fmoroctocog alfa !rhu" is a recom0inant factor LIII !rLIII" product thatincreases plasma factor LIII leels as a temporary correction of the 0leedingtendency in haemophilia A.

     This AusPAR descri0es the application 0y #iogen Idec Australia Pty $td !thesponsor" to register loctate !efmoroctocog alfa !rhu"" powder for in;ection&)' I )'' I *)' I 1''' I 1)'' I &''' I and (''' I for thefollowing indication8

    $%octate is a %ong&acting antihaemophi%ic factor 'recombinant( indicated inadu%ts and chi%dren ' ) 1* years( +ith haemophi%ia A 'congenita% factor ,---de.ciency( for:

    •  Contro% and prevention of b%eeding episodes3

    •  4outine prophy%a/is to prevent or reduce the fre0uency of b%eeding

    episodes3

    •  Perioperative management 'surgica% prophy%a/is(3

    $%octate does not contain von i%%ebrand factor2 and therefore is not

    indicated in patients +ith von i%%ebrand5s disease3

     The TGA ,elegate of the Cecretary designated recom0inant humancoagulation factor LIII c fusion protein as an orphan drug for the contro%and prevention 'inc%uding routine prophy%a/is( of b%eeding episodes in

    adu%ts and chi%dren +ith haemophi%ia A on &( e0ruary &'1(.

    Re'u%atory status The product receied initial registration on the Australian Register of Therapeutic Goods !ARTG" on &* une &'1+.

    At the time this application was considered 0y the TGA similar applicationswere under consideration in CA !%arch &'1(" =anada !uly &'1(" CouthAfrica !?cto0er &'1(" and apan !anuary &'1+". Cu0missions were

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     Therapeutic Goods Administration

    proposed for New Qealand !&'1+" and uropean nion !" uropean%edicines Agency !%A" !&'1+".

    Product "normation The approed Product Information !PI" current at the time this AusPAR was

    prepared can 0e found as Attachment 1. or the most recent ProductInformation please refer to the TGA we0site at7https899www.tga.go.au9product-information-pi:.

    ""# ua%ity indin's

    "ntroduction=urrently registered rLIII products in Australia includeO

    Mogenate C !octocog alfa" !full-length LIIIO 0a0y hamster 2idney !#/M"cellsO &nd-generationS"

    • Adate !octocog alfa" !full-length LIIIO =hinese hamster oary !=/?"

    cellsO (rd-generationS i.e. no added human or animal proteins inmanufacture"

    • yntha !moroctocog alfa" !# domain deletedO =/? cellsO (rd-generationS"

    • Nooight !turoctocog alfa" !truncated # domainO =/? cellsO ( rd-

    generationS"

    loctate is a new generation of rLIII productO a # domain deleted LIIIlin2ed to the c portion of Immunoglo0ulin G !IgG" and is produced in ahuman cell line.

    ru' substance (acti!e in'redient)

    0tructureRecom0inant coagulation factor LIII c fusion protein !rLIIIc" is a fullyrecom0inant fusion protein consisting of a single molecule of # domaindeleted human coagulation factor LIII !LIII" coalently lin2ed to the dimeric

    c domain of human immunoglo0ulin G1 !IgG1" with no intereningse3uence. rLIIIc is produced in human em0ryonic 2idney !/M" cells.rLIIIc is a heterodimer comprised of LIIIc single chain and c singlechain associated through disulphide 0onds at the hinge regions of the cfragments as well as e6tensie non coalent interactions 0etween the cfragments. rLIIIc confers the pro-coagulation function of clotting factor LIIIfor eKectie haemostasis. The presence of the c domain ena0les rLIIIc to0ind to the neonatal c receptor !cRn" which protects c containingmolecules from cata0olism and e6tending their plasma half-life.

    https://www.tga.gov.au/product-information-pihttps://www.tga.gov.au/product-information-pi

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     Therapeutic Goods Administration

    1igure $. 0chematic diagram of r1&III1c structure.

    ,uring culture the ma;ority of the LIII moiety is processed intracellularly togenerate an appro6imately F' 2,a LIII heay chain and an appro6imately1(' 2,a LIII light chain c fusion !$=-c". The LIII heay chain remainsassociated to the $=-c through metal ion dependent non coalentinteractions.

    /anufacture?ne cell 0an2 ial is used to produce one discrete 0atch of rLIIIc drugsu0stance. It is prepared at the 0ioreactor scale using media that are free ofanimal deried components. =ell 0an2ing processes are satisfactory. All iraland prion safety issues hae 0een addressed for the fermentation andpuri5cation processes.

    Physica and chemica properties The ma;ority of rLIIIc is cleaed intracellularly. The non-cleaed singlechain form referred to as single chain rLIIIc !C=rLIIIc" The C=rLIIIcwas isolated and e6tensiely characterised and is actie and generally

    compara0le to the processed form and is considered a product relatedsu0stance.

    rLIIIc actiity was assessed using the LIII coagulation assay 0ased onactiated partial throm0oplastin time !aPTT" the LIII chromogenic assayand an cRn 0inding assay. In addition a num0er of functionalcharacterisation assays were conducted on rLIIIc drug su0stance. Theprimary structure agreed with the predicted amino acid se3uence. Cites ofglycosylation were con5rmed 0y peptide mapping. rLIIIc post translationalmodi5cations include N lin2ed glycosylation sites sulphated tyrosineresidues and remoal of the lysine residues at the = termini of 0oth peptide

    chains.

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     Therapeutic Goods Administration

    0peci!cationsAppropriate alidation data hae 0een su0mitted in support of the testprocedures for the proposed speci5cations which control identity content0iological actiity !potency" purity and other 0iological and physicalproperties of the drug su0stance releant to the dose form and its intendedclinical use.

    0tabiityReal time data support the shelf life for the drug su0stance of 1 year at-*'=.

    ru' product The rLIIIc drug product is a sterile non pyrogenic single use preseratiefree white to oK white lyophiliUed powder for in;ection for IL infusion in asingle use ial. ach ial contains nominally &)' I )'' I *)' I 1''' I1)'' I &''' I or (''' I of rLIIIc and is presented in a 2it containing a

    ial adapter and a pre5lled diluent syringe with ( m$ of sterile water forin;ection !@I".

     The rLIIIc drug product is lyophilised in a Type I glass ial closed with ateon coated chloro0utyl stopper and sealed with a &' mm aluminium ipoK crimp seal with diKerent colours used for diKerent dose strengths.

     The product is reconstituted for use 0y connecting the pre5lled diluentsyringe and the product ial using the ial adaptor. The diluent is thenadded to the powder and the product allowed to dissole !clear instructionsare proided regarding not to sha2e". ?nce dissoled the product is returned

    to the syringe and used as soon as possi0le. In use data supports thestorage of resuspended product as descri0ed in the PI.

    /anufactureInformation was ealuated on the manufacturing process includingsterilisation lyophilisation and 5ltration steps.

    0peci!cations The proposed speci5cations which control identity potency purity dosedeliery and other physical chemical and micro0iological propertiesreleant to the clinical use of the product hae 0een ealuated.

     The same speci5cations are applied for all the drug product strengthse6cept for protein concentration 3uantity of rLIIIc per ial !as measured0y chromogenic coagulation actiity assay" and endoto6in.

    0tabiityCta0ility data hae 0een generated under stressed and real time conditionsto characterise the sta0ility pro5le of the product. The product is notphotosta0le and should 0e protected from light. The lyophilised product issta0le when froUen. The diluent syringe must not 0e froUen and as they aresupplied in the same pac2age the storage conditions are stipulated on the

    pac2aging.

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     Therapeutic Goods Administration

     The recommended shelf life is 1& months when stored at &= to E= which isless than that proposed 0y the sponsor. There was insu4cient data tosupport the storage of the product for months at room temperature. Noariations in storage temperature during shipping hae 0een approed.

    In use sta0ility data support the in use conditions descri0ed in the PI.

    Labeing2 pac)aging and documentationpdated la0elling pac2aging and PI documents were proided in responseto re3uests from TGA for reisions to 3uality aspects and are consideredaccepta0le.

    ua%ity summary and conc%usions The administratie product usage chemical pharmaceutical andmicro0iological data su0mitted in support of this application hae 0eenealuated in accordance with the Australian legislation pharmacopoeial

    standards and releant technical guidelines adopted 0y the TGA.

     The use of Cchott ials has not 0een supported 0y su4cient data and at thisstage is not recommended for approal !the approed ials aremanufactured 0y Nipro".

     The module ( !3uality" ealuators recommended that loctate!efmoroctocog alfa !rhu"" &)' I )'' I *)' I 1''' I 1)'' I &''' Iand (''' I powder for in;ection ial plus diluent syringe should 0eapproed with the inclusion of speci5c registration conditions relating to0atch release testing and certi5ed product details. ,etails of these

    conditions are 0eyond the scope of the AusPAR.

    """# *onc%inica% indin's

    "ntroduction

    3enera comments The 3uality of the nonclinical studies was generally satisfactory with moststudies performed according to good la0oratory practice !G$P" principles

    and protocols were consistent with the International =onference on/armonisation of Technical Re3uirements for Registration ofPharmaceuticals for /uman se !I=/" guideline for 0iotechnology-deriedtherapeutic products !I=/ C+". All animal studies used the clinical route !ILadministration". The nonclinical testing strategy focussed on the e6tendedelimination half-life of rLIIIc relatie to e6isting registered recom0inantLIII products !for e6ample Adate and yntha9Reacto" with a num0er ofprimary pharmacology and pharmaco2inetic !PM" studies that comparedclotting times and actiity. These studies demonstrated pharmacologicalresponsieness to rLIIIc in all tested species including the rat andcynomolgus mon2ey which were used in the G$P repeat dose to6icity

    + %A9=/%P9I=/9*(1&E91FFE I=/ guideline C !R1" - preclinical safetyealuation of 0iotechnology-deried pharmaceuticals.

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     Therapeutic Goods Administration

    studies. ,etermination of safety pharmacology parameters wereincorporated into the repeat dose to6icity studies. All repeat dose to6icitystudies also monitored anti0ody deelopment. $ocal tolerance was assessedin the repeat dose to6icity studies.

    Comparability of manufactured batches

    Information on the commonality of the manufactured 0atches used in thenonclinical studies to those used in clinical studies was proided. These0atches demonstrated compara0le clotting actiities9e4cacies PM pro5lesand tolerance potentials. Ctudies used either the froUen li3uid formulation of rLIIIc or the lyophilised forms. ?f the two lyophilised formulations theformer was used in Phase III clinical studies as well as the second G$Pmon2ey study and the latter proposed as the commercial use product wase6amined in an immunogenicity study in LIII de5cient !/em A" mice.

    Pharmaco%o'y

    Primary pharmacoogyCtudies using surface plasmon resonance techni3ues demonstrated 0indingof rLIIIc to mouse rat cynomolgus mon2ey and human c receptor !cRn"!a4nities calculated as )'J eKectie concentration !=)'"8 mouse 11.* n%rat 1'.* n% mon2ey )&.1 n% human )1.* n%". The association 0etweenthe c moiety and cRn is the pro0a0le mechanism for the prolongedcirculating half-life of rLIIIc). A4nity of rLIIIc for on @ille0rand actor!@" was compara0le to that of the registered recom0inant LIII productyntha. Cimilarly throm0in mediated dissociation of rLIIIc from @ was

    similar to that of yntha and cleaage9actiation of rLIIIc 0y throm0ingenerated similar 0y products as the recom0inant LIII comparator !rLIII"Reacto. The a0ility of rLIIIc to form the tenase comple6 with actiatedactor I was similar to Reacto and similarly actiated protein = !AP="inactiated rLIIIc to a similar degree as Reacto.

    In io acute and prophylactic e4cacy of rLIIIc was demonstrated in !/emA" mice. =lotting actiity of rLIIIc measured 0y a LIII speci5cchromogenic assay was detected at up to *& hours post dose whereasactiities of e3ual doses of either rLIII products Reacto or Adate were0elow the leel of 3uanti5cation 0y +E hours post dose consistent with thelonger elimination half-life !tV" of rLIIIc than Reacto or Adate. Acutee4cacy assessed 0y measuring 0lood loss sustained following in;ury in /emA mice treated with rLIIIc or rLIII !Adate" was similar 0etween the twoLIII products. ,iKerent manufactured 0atches of rLIIIc demonstrateddose dependent reduction of 0lood loss following in;ury. Prophylacticprotection in /em A mice was more eKectie with rLIIIc than rLIII!Adate" where0y all mice that receied rLIIIc suried in;ury !tail eintransection" and rates of re 0leeding were signi5cantly lower in this groupthan in mice that receied Adate which also had lower surial rates!appro6imately )'J".

    ) The a00reiation rLIII-c was used 0y the non-clinical ealuator and has0een replaced in the te6t with rLIIIc for consistency.

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     Therapeutic Goods Administration

     The actiities of rLIIIc drug su0stance puri5ed processed r=LIIIc andC=rLIIIc were compared 0y the chromogenic and the aPTT assays.C=rLIIIc actiity was lower than puri5ed processed rLIIIc and rLIIIcdrug su0stance when actiity was assessed 0y the aPTT assay or 0ymonitoring throm0in generation whereas the chromogenic assay 5ndingsdid not reeal diKerences in actiities among the diKerent forms. urther

    rLIIIc speci5c actiity !assessed 0y aPTT" was appro6imately 1'J lowerthan puri5ed processed rLIIIc suggesting a minor inuence of C=rLIIIcin the total actiity of rLIIIc drug product. In /em A mice prophylactice4cacy was compara0le 0etween C=rLIIIc and rLIIIc drug su0stance inwhich surial rates and re-0leeding eents were similar 0etween the twoforms of rLIIIc.

    0econdary pharmacodynamics and safety pharmacoogyCince rLIIIc is intended as a replacement therapy to restore de5ciencies inendogenous LIII to normal leels secondary pharmacology studies werenot essential. @ith regard to safety pharmacology studies cardioascularsystems !heart rate !/R" and electro-cardio gram !=G"" were part of theprotocols for the two piotal + wee2 rat and mon2ey studies. /oweer =G5ndings were con5ned to narratie assurances 0y a eterinary pathologistwho inspected the waeform readings. No other organ systems wereinestigated. Neertheless there were no oert aderse 5ndings to indicatespeci5c eKects on organ systems and its use as a replacement for anendogenous su0stance would suggest a low ris2 of targeted to6icity.

     Therefore in iew of the product type the a0sence of safety pharmacologystudies is not considered to 0e a de5ciency.

    Pharmaco&ineticsPM parameters were determined from single dose studies in mice rats dogsand mon2eys and repeat dose to6icity studies in rats and mon2eys.

    Relatie to non c su0unit containing rLIII comparators rLIIIc displayedprolonged elimination tV and higher area under the concentration-timecure !A=" in mice rats and dogs. The tV for rLIIIc and rLIII !yntha"were indistinguisha0le in mice lac2ing the cRn receptor whilstoere6pression of the cRn receptor resulted in higher tV and A= forrLIIIc con5rming that its prolonged actiity is dependent on its interactionwith the cRn receptor. or reasons that were not clear the tV and A= of

    rLIIIc and yntha were compara0le in mon2eys. In itro cRn 0indingassays showed compara0le 0inding of rLIIIc to human and mon2ey cRn!=)' appro6imately )' n%" and greater 0inding to mouse and rat cRn !=)'appro6imately 1' n%". Relatiely long tV was o0sered in patients !clinicaloeriew".

    In a tissue distri0ution study iodinated !1&)I" rLIIIc was administered to/em A mice and dou0le 2noc2 out !M?" mice !LIII9@ M?" and distri0utionwas monitored 0y 3uantitatie whole 0ody radiographic analysis. /igh leelswere detected in highly perfused organs such as lier lungs 2idneys andspleen. Tissue radioactiity leels were signi5cantly lower in the /em A mice

    The te6t of this paragraph has 0een slightly amended from the original forclarity.

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    than in dou0le M? mice. The elimination tV was appro6imately & hours indou0le M? mice compared to. E hours in /em A mice. In particular highleels of radioactiity !relatie to 0lood" were noted in lier and 0ile ofdou0le M? mice compared to /em A mice.

    ?erall as with clinical 5ndings prolonged tV and slower clearance relatie

    to non c su0unit containing comparators were nota0le features of the PMpro5le of rLIIIc in all tested animals e6cept mon2eys. As well thedeelopment of neutralising anti rLIIIc anti0odies resulted in lowere6posures after repeat dosing limiting the utility of repeat dose to6icitystudies in animal species.

    To+ico%o'y

    Acute toicityA single dose to6icity study to determine dose tolerance was conducted in

    cynomolgus mon2eys. %a6imum tested dose rLIIIc was &'''' I92g ILwith a seen day o0seration period in which no signi5cant clinical signs orgross pathological 5ndings were noted. /aematological parameters at up to1 hours post dose were also monitored in which shortened aPTT !0ut notprothrom0in time !PT"" was o0sered while platelet and 50rinogen leelswere not altered. ?erall rLIIIc was well tolerated in the mon2ey anddisplayed a low order of acute to6icity 0y the IL route.

    Repeat dose toicityour repeat dose to6icity studies were performed and assessed the chroniceKects of rLIIIc in rats and mon2eys. @ith the e6ception of one non G$P

    pilot study in mon2eys all other studies using the IL route were for +wee2s and included protocols for measuring anti0odies that deeloped oerthe course of the treatment period. Ctudies were generally consistent withI=/ guideline re3uirementsO howeer due to the deelopment of anti0odiesduration of the studies was short for a chronic use product. In fact in one ofthe mon2ey studies there were profound impairments of haemostaticfunction as a result of anti0ody deelopment which neutralised endogenousLIII !ac3uired haemophilia" and aKected surial of test animals. ,osingregimen used in the animal studies was eery second day !compared toclinical use of eery ( to ) days for routine prophyla6is and eery 1& to +Ehours for the control and preention of 0leeding episodes". It was noted also

    that the formulation of rLIIIc used in these studies included a diKerentdrug su0stance 0atch from the 0atch used in clinical trials and intended forregistration. /oweer the 0atch in the other mon2ey study was also thedrug product formulation used in a Phase III and an e6tension clinical study.

    Relative exposure

    Plasma e6posures !as ma6imum plasma actiity !=ma6" and A=" ascertainedfrom the repeat dose to6icity studies are compared with human e6posures in

     Ta0le 1 0elow. ,ay 1 PM parameter alues were used since 0lood LIII leelsdropped considera0ly with repeated dosing 0ecause of the deelopment of

    neutralising anti0odies. Relatiely high e6posures were achieed in rat andmon2ey studies8 =ma6 !e6posure ratios up to E in rats and & in mon2eys"Oand A= !e6posure ratios up to appro6imately &' in rats and 1+' in

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    mon2eys". /oweer since neutralising anti0odies to rLIIIc aKected leelsof e6posure to the test article potential to6icities were li2ely to 0eminimised in the repeat dose studies. Indeed the reported aderse eKectsin these studies were secondary to changes associated with the eKect ofneutralising anti0odies on endogenous LIII. or this reason the relatielyhigh e6posure ratios that were deried !as either =ma6 or A= comparisons"

    may not ade3uately reect the true safety margin of rLIIIc relatie toclinical dosing.

    4abe $ -posures in , 6ee) repeat7dose toicity studies.

    0pecies0tudy #o.4estbatc

    hpotency9

    0tudyduration

    :osingregimen

    :ose;I<*)g=

    Cma;>g*mL=asI

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    Major toxicities

    Repeated doses of rLIIIc were generally well tolerated 0y 0oth animalspecies used with no oert and targeted to6icities noted. =linical signs wereminimal with incidences of swelling and discolouration noted in hindlim0sand forelim0s of treated mon2eys. These eKects were li2ely to 0e a

    conse3uence of impaired haemostasis due to neutralising anti0odies andtrauma from 0lood collections !for e6ample for to6ico2inetics or clinicalpathology analyses".

    @hile the clinical releance of anti0ody deelopment is uncertainantigenicity was neertheless a confounding factor in assessing to6icities inthe animal studies. Anti rLIIIc anti0odies were detected in 0oth rat andmon2ey repeat dose studies with onset of deelopment earliest in high dosegroup animals. Anti0odies were against the LIII moiety of rLIIIc and werefound to hae a neutralising eKect on endogenous LIII. In mon2eys thisaKected haematological parameters shown as decreased red 0lood cells

    !R#=" haemoglo0in and haematocrit leels associated with impairments tohaemostasis and haemorrhaging. Antigenicity also caused prolonged aPTTin which aPTT on days 1F and &* of treatment was progressiely longer inhigh dose group animals and persisted !al0eit to a slightly lesser degree" inthe recoery cohort animals. @ith regard to other to6icologicalinestigations there were no untoward changes noted in 0ody weight organweights serum chemistry measurements and gross pathology.

    %ortalities due to seere haemorrhage occurred at the high dose !1'''I92g" in one mon2ey study 0ut not in the second mon2ey study at thesame doses. Reasons for the diKerence 0etween the two studies are notclear 0ut might 0e related to the test formulation. A froUen li3uidformulation was used in the study with mortalities while a lyophilisedformulation was used in the second study. /oweer in 0oth studies similaranti0ody titre leels were noted oer a similar onset period. =hanges tohaematological parameters were also similar and signs of haemorrhagingand prolonged aPTT were apparent in 0oth inestigations. The lyophilisedformulation is to 0e mar2eted for clinical use and was used in a Phase IIIclinical trial.

    Anti0ody deelopment against rLIIIc was also studied in mice. #othrLIIIc and recom0inant coagulation factor LIII !rLIII" !Reacto" showedcompara0le incidence and e6tent of immunogenicity particularly at higher

    doses !&)' and 1''' I92g" suggesting that the c su0unit does not conferany greater immunogenicity to rLIIIc than would 0e anticipated. Indeedcharacterisation of the anti0odies showed that they were predominantlyagainst the LIII moiety rather than the c su0unit. A second mouse studycompared two diKerent lyophilised drug product 0atchesO howeer neither0atch induced an antigenic response 0earing in mind that a dose of only )'I92g was used compared to )' &)' and 1''' I92g tested in the othermouse study.

    ?erall the repeat dose to6icity studies highlighted aderse eKects thatwere secondary to antigenic reactions against rLIIIc in the test animals.

     The deelopment of neutralising anti0odies against rLIIIc led toimpairments to haemostasis discolouration of lim0s and e6tremities anda0errant haematological parameters.

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    3enotoicity and carcinogenicityNo genoto6icity studies were conducted using rLIIIc which is accepta0leaccording to guideline recommendations !I=/ CWR1X" for a recom0inanthuman protein su0stance not containing an organic chemical lin2er. Thesponsor proided two genoto6icity studies !0acterial reerse mutation andan in itro chromosomal a0erration" on an unrelated su0stance !alefacept"

    that contains the same c lin2er which were preiously ealuated 0y the TGA. #oth studies gae negatie results.

     The a0sence of carcinogenicity studies is also accepta0le on the groundsthat standard studies of carcinogenicity in animals are not feasi0le due tothe deelopment of anti0odies with repeat administration of 0iologicalsu0stances.

    Reproductive toicity The sponsor did not conduct any reproductie to6icity studies on rLIIIc. This is accepta0le in iew of the fact that rLIIIc is for the replacement of

    normal physiological LIII actiity in haemophilia A which is a se6 lin2eddisease that occurs predominantly in males. emales are rarely aKectedtherefore e6posure to rLIIIc during pregnancy and em0ryofetaldeelopment is considered remote. Animal studies on fertility reproductieand deelopmental to6icity hae not 0een conducted on other registeredrecom0inant clotting factor products !for e6ample Adate and Mogenate".rLIII has 0een used in haemophilia A patients for years and there is noeidence of aderse eKects on fertility or em0ryofetal deelopment.

    Pregnancy classication

     The sponsor did not nominate a pregnancy category for rLIIIc. @hilst thepatient population aKected 0y haemophilia A and intended to use rLIII ismales with a se6 lin2ed disease there are some rare instances wherefemales are a[icted and thus an appropriate category should 0e assignedto coney to prescri0ers potential ris2s on fetal health arising from maternale6posure.. Recom0inant LIII and most other coagulant factors are classi5edas category #&* drugs 0ased on the lac2 of animal reproductie to6icitystudies. Pregnancy category #& is considered appropriate for rLIIIcE.

    * =ategory #&8 Drugs +hich have been ta"en by on%y a %imited number of pregnant +omen and +omen of chi%dbearing age2 +ithout an increase in the

    fre0uency of ma%formation or other direct or indirect harmfu% eects on thehuman fetus having been observed3 tudies in anima%s are inade0uate or

    may be %ac"ing2 but avai%ab%e data sho+ no evidence of an increasedoccurrence of feta% damage3

    E The ,elegate su0se3uently assigned efmoroctocog alfa!rhu" to use in pregnancy =ategory= !Drugs +hich2 o+ing to their pharmaco%ogica% eects2 have caused or may be suspected ofcausing2 harmfu% eects on the human fetus or neonate without causing malformations.

     These eKects may 0e reersi0le. Accompanying te6ts should 0e consulted for further details"on the 0asis that placental transfer is a signi5cant consideration and the eKects on thedeeloping fetus are un2nown.

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    Loca toeranceAssessment of local tolerance to rLIIIc was incorporated into the scheduleof macroscopic and microscopic o0serations of the + wee2 repeat doseto6icity studies in rats and mon2eys. In;ection site reactions !periascular50rosis swelling and discolouration of hindlim0s9forelim0s" were noted inmedium dose females and high dose males and females from one of the

    four wee2 mon2ey studies.. In the second four wee2 mon2ey studytreatment related changes associated with local reactions were con5ned todiscolouration of e6tremities where 0lood collection or dose administrationwas performed. The 5ndings were secondary to LIII neutralising anti0odies.No other signs of irritation or inammation !for e6ample oedemalymphocyte in5ltration" were reported in any of the studies.

    Paediatric userLIIIc is indicated for use in adults and adolescents !\ 1& years old". No

     ;uenile to6icity studies were conducted.

    *onc%inica% summary and conc%usions

    •  The nonclinical dossier was satisfactory for a 0iotechnology deried

    therapeutic product. The clinical route !IL administration" was used in allanimal studies and the animal models used were responsie to thetested article.

    • Primary pharmacology studies demonstrated compara0le characteristics

    of rLIIIc to registered recom0inant LIII replacement products.Association of rLIIIc with the neonatal c receptor was demonstrated ina num0er of speciesO as well rLIIIc was shown to a0ly form the tenase

    comple6 with actiated actor I to 0ring a0out coagulation. rLIIIc wasinactiated 0y AP= to a similar e6tent as a rLIII comparator product. Inanimal models of haemophilia A !/em A mice and /em A dogs"sustained clotting actiity !as 0oth acute and prophylactic protection"was demonstrated and correlated with sustained plasma LIII leels.

    • Cafety pharmacology assessments were incorporated in the G$P repeat

    dose to6icity studies. There were no oert aderse 5ndings to indicatespeci5c eKects on the function of critical organ systems.

    •  The elimination tV and plasma LIII leels were higher for rLIIIc than

    for comparator rLIII products in all tested species e6cept mon2eys.Ctudies in cRn M? mice and hcRn transgenic mice con5rmed thatprolonged elimination tVof rLIIIc is dependent on its interaction withthe cRn receptor. Repeat dosing resulted in shorter tV and lower A=s inmon2eys or 0ecame undetecta0le in rats 0y the last sampling time0ecause of anti0ody deelopment. A tissue distri0ution study in /em Amice and LIII9@ dou0le M? mice showed high upta2e of rLIII in lierand @ appeared to reduce lier upta2e and clearance of rLIIIc.

    • In a single dose to6icity study in mon2eys doses of up to &'''' I92g IL

    were well tolerated causing no mortalities or nota0le acute to6icities.

    • Repeat dosing of rLIIIc was generally well tolerated 0y 0oth rats and

    mon2eys with no speci5c targeted to6icities seen in either species. The

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    deelopment of neutralising anti rLIII anti0odies accounted for most ofthe aderse 5ndings !impaired haemostasis su0cutaneoushaemorrhaging and associated decreases in R#= haemoglo0in andhaematocrit".

    • Genoto6icity and carcinogenicity studies were not conducted which is

    accepta0le and consistent with I=/ guidelines for 0iotechnology deriedtherapeutic products. No reproductie to6icity studies were conductedwith rLIIIc. Gien that haemophilia A is a se6 lin2ed disease that occursin males rLIIIc is a recom0inant human protein and no test articlerelated 5ndings were noted in the reproductie organs in the repeat doseto6icity studies the a0sence of reproductie to6icity studies is notconsidered a de5ciency of the nonclinical data.

    • Repeat dose to6icity studies showed no signi5cant local reactions e6cept

    for LIII neutralising anti0ody related haemorrhage at the in;ection and0lood sampling sites.

    • Although the animal models used to assess potential repeat dose

    to6icities of rLIIIc were not ideal due to the deelopment of anti LIIIanti0odies in iew of the class of product !replacement human clottingfactor" short term administration of rLIIIc was well tolerated.

    •  There are no nonclinical o0;ections to registration.

    Recommended reisions to nonclinical statements in the draft PI are 0eyondthe scope of the AusPAR.

    ",# C%inica% indin's

    A summary of the clinical 5ndings is presented in this section. urtherdetails of these clinical 5ndings can 0e found in Attachment &.

    "ntroductionloctate is a long acting antihaemophilic factor !recom0inant" indicated inadults and children !\ 1& years" with haemophilia A !congenital factor LIIIde5ciency" for control of 0leeding episodes routine prophyla6is to preentor reduce the fre3uency of 0leeding episodes and perioperatie

    management !surgical prophyla6is".

    Cinica rationae/aemophilia is an inherited lin2ed 0leeding disorder. In Australia there areappro6imately &'' people with haemophilia and nearly all are male./aemophilia A is the most common form and is due to the de5ciency offactor LIII. Reduced 0lood coagulation results in 0leeding which is mostcommonly internal usually into the ;oints or muscles. ?er time recurrent0leeds can cause permanent damage such as arthritis chronic pain and

     ;oint damage re3uiring surgery. Plasma deried coagulation factorconcentrates were eKectie 0ut were associated with a high rate of 0lood

    0orne iruses such as hepatitis # irus !/#L" hepatitis = irus !/=L" andhuman immunode5ciency irus !/IL". Kectie rLIII products hae 0eendeeloped su0se3uently although their use is limited 0y the deelopment of

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    inhi0itor !anti rLIII 0inding anti0ody" in up to ('J of patients. Inhi0itorsdeelop most commonly within 1'' e6posure days in preiously untreatedpatients !PPs" 0ut may also deelop in preiously treated patients !PTPs".

     The ne6t generation of recom0inant products will 0e long acting with theaim of reducing the fre3uency of the IL in;ections re3uired for long termprophyla6is in patients with seere disease.

    loctate is a replacement therapy to increase plasma factor LIII leels as atemporary correction of the 0leeding tendency in haemophilia A. The LIIIportion of loctate is a glycoprotein WfunctionallyX similar to endogenousLIII found in human plasma. @hen in;ected it 0inds to on @ille0randfactor in the circulation and acts as a replacement for the LIII de5ciency.

     The other portion of loctate is the c fragment of human IgG1 which 0indsto the neonatal c receptor which is e6pressed throughout adult life. Thisreceptor protects immunoglo0ulins from lysosomal degradation and acts toprolong their plasma tV. The design of loctate ena0les replacement of allthe functions of LIII with an e6tended half-life compared with the naturally

    occurring factor.

    3uidanceA pre su0mission meeting with the TGA was held. The sponsors werere3uested to ;ustify the use of a single piotal study and to ;ustify the lac2of randomisation in the clinical trial program in the proposed su0mission./oweer the TGA proisionally accepted the sponsorsH ;usti5cation for thelac2 of an actie comparator control in the piotal study. Cuch a noninferiority study would not 0e feasi0le 0ecause of the large patient num0ersre3uired in the orphan haemophilia population.

     The TGA has adopted the %A guideline on rLIII products !1FFFF" 0ut thelatest guideline !&''F1'" had not yet 0een adopted at the time the clinicalealuation was prepared. The TGA has encouraged the sponsor to complywith the earlier guideline 0ut has sought the opinion of the clinical ealuator0efore considering potential discrepancies further.

    Contents of the cinica dossier The su0mission contained the following clinical information8

    • ?ne Phase I9IIa clinical pharmacology study !FFE/A1'1" a completed PM

    study in PTPs.

    • ?ne population PM analysis !=PP-1&-'&-#II#'(1 deried from clinical

    studies FFE/A1'1 and FF*/A('1.

    • ?ne piotal Phase III e4cacy9safety study A-$?NG !FF*/A('1" an open

    la0el uncontrolled ( arm study in adult PTPs.

    F =P%P9#P@G91)19FF. Note for guidance on the clinical inestigation ofrecom0inant factor LIII and I products.

    1' %A9=/%P9#P@P91++)((9&''F. Guideline on the clinical inestigation of recom0inant andhuman plasma-deried factor LII products. Wthis has since 0een adopted 0y the TGAX.

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    • ?ne interim progress report of the supportie e4cacy9safety study

    !E/A'1T" an ongoing study in adult PTPs who hae completedFF*/A('1 and paediatric patients who hae completed E/A'&P,.

    • =linical ?eriew Cummary of =linical 4cacy Cummary of =linical

    Cafety Cummary of =linical Pharmacology Cummary of #iopharmaceutic

    studies and Analytical %ethods and literature references.

    Paediatric data The su0mission included one progress report from an ongoinge4cacy9safety study !E/A'&P," in paediatric PTPs 7 1& years withcompleted patients continuing into E/A'1T.

    ,ata from this and the Phase III piotal study that included preiouslytreated patients aged 1& years and oer will form the 0asis of a futuresu0mission for use in children 7 1& years of age.

    3ood cinica practiceAll studies were conducted in compliance with the principles of the I=/guidelines on Good =linical Practice !G=P" and the ethical principles outlinedin the ,eclaration of /elsin2i.

    Pharmaco&inetics

    0tudies providing pharmaco)inetic dataPM Ctudies FFE/A1'1and the population pharmaco2inetic report !=PP1&-

    '&-#II#'(1" were proided in the dossier. None of the PM studies hadde5ciencies that e6cluded their results from consideration.

    -vauators summary and concusions on pharmaco)inetics The actiity time pro5les of rLIIIc hae 0een ealuated and compared withrLIII !Adate" in a Phase I9IIa PM study in 1 patients with haemophilia A.

     The study used LIII actiity as a surrogate endpoint as recommended 0ythe %A and the International Cociety on Throm0osis and /aemostasis!ICT/" to estimate A= tV mean residence time !%RT" and clearance.rLIIIc had a superior PM pro5le compared with Adate with appro6imateincreases in half-life and %RT of )(J for the &) I92g dose and *J for the

    ) I92g dose. The prolongation of actiity was due to a (J reduction inthe clearance of rLIIIc compared to Adate The primary PM pro5le was0ased on the one stage clotting assay and con5rmed 0y similar results usingthe chromogenic assay. The compartmental and non compartmentalanalyses were complemented 0y the population PM analysis whichcon5rmed the long term sta0ility of the PM parameters. The population PMmodels ade3uately descri0ed the actiity data in the PM and Phase IIIstudies. The ma;or coariate for rLIIIc actiity was clearance and therewas no clinically meaningful inuence related to 0ody weight haematocritor age.

     The PM and the piotal studies were well conducted and complied with TGAand %A guidelines. The population PM models deried from the com0ined

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    data hae 0een used to deelop useful dosing recommendations forclinicians.

    Pharmacodynamics

    0tudies providing pharmacodynamic dataNone su0mitted.

    osa'e se%ection or the pi!ota% study,oses of &) I92g and ) I92g were well tolerated in the Phase I9IIa CtudyFFE/A1'1. #ased on the PM data it was estimated that EEJ of patientswould sustain LIII trough leels : 1J ( days after a &) I92g dose and thatE(J of patients would sustain trough leels : 1J + days after a )' I92gdose. #ased on these assumptions the starting dose for Arm 1 of the piotalstudy was a twice wee2ly regimen with &) I92g on the 5rst day followed 0y

    )' I92g on the fourth day. ,ata from FFE/A1'1 were also used to generatedose ad;ustment algorithms for indiidualised prophyla6is regimens.

    -icacy

    0tudies providing eDcacy data?nly one e4cacy study has 0een performed.

    Pivotal ecacy study 

    Ctudy FF*/A('1 !A-$?NG" was an open la0el multicentre ealuation of thesafety e4cacy and PM of rLIIIc in the preention and treatment of0leeding in PTPs with seere haemophilia A. The primary o0;ecties of thestudy were to compare the e4cacy and safety of rLIIIc gien in arioustreatment regimens as prophyla6is and on demand during surgicaltreatment.

    -vauators concusions on eDcacyor the assessment of clinical e4cacy for control of 0leeding episodesroutine prophyla6is to preent or reduce the fre3uency of 0leeding episodesand perioperatie management !surgical prophyla6is" 0ecause of the

    limited aaila0ility of haemophilia A patients the latest Guideline11

     !notadopted 0y the TGA at the time the clinical ealuation was prepared"recommends the enrolment of at least 1'' patients using LIII actiity as asurrogate endpoint and without the need for a control group. The initialstudy should 0e conducted in PTPs aged \ 1& years with a study in PPsconducted post mar2eting. In the piotal study a total of 1) patients aged: 1& years were randomised and all were PTPs. Patient num0ers wereade3uate and 1( adolescent patients were included.

    ,espite the lac2 of a control group the study clearly demonstrated thatrLIIIc is eKectie in adults and adolescents with haemophilia A. In the

    11 %A9=/%P9#P@P91++)((9&''F. Guideline on the clinical inestigation ofrecom0inant and human plasma-deried factor LII products.

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    piotal Phase III study there were *)* 0leeding episodes !in 1' patients" of which F*.EJ were controlled with ] & rLIIIc in;ections !E*.(J with onein;ection" with a total median dose per in;ection of &E I92g. A total of *E.1Jof patients ealuated the response to the 5rst in;ection as e6cellent or good.

     The inestigatorsH glo0al assessment of response was rated as e6cellent oreKectie for FF.(J of the patient isits. Prophylactic treatment was more

    eKectie than episodic treatment. In Arm 1 of the piotal study !prophyla6istailored to LIII trough leels" +).(J of patients had no 0leeding episodesduring the e4cacy period with a F&J reduction !p 7 '.''1" in annualised0leeding rate compared with Arm ( !the episodic treatment group". Cingledose wee2ly prophyla6is was less eKectie than tailored prophyla6is 0ut1+.)J of patients in Arm & had no 0leeding episodes during the study. Ninema;or surgeries were performed in nine patients during the study. Theresponse to rLIIIc was e6cellent in eight cases and good in one case aftera single preoperatie dose to maintain haemostasis !median dose )1.+I92g".

     The study conduct was satisfactory and the e4cacy results support the useof rLIIIc for control of 0leeding episodes routine prophyla6is andperioperatie management.

    $aety

    0tudies providing evauabe safety dataCtudy FF*/A('1 proided ealua0le safety data. There were few aderseeents !As" in the PM study FFE/A1'1 with no serious aderse eents!CAs" or deaths. The study contri0uted less than '.&J of the total rLIIIc

    e6posure and these safety data are not assessed further.

    Pivotal ecacy studies

    In the piotal e4cacy study the following safety data were collected8

    • As CAs and deaths.

    • As of special interest including inhi0itor deelopment anaphyla6is

    hypersensitiity eents serious throm0otic eents or suspectedinfectious agent transmission were reported to the Cponsor as CAsirrespectie of whether they met the criteria for CAs.

    • $a0oratory tests were performed at a central la0oratory.

    Other studies evaluable for safety only 

    tudy 87A*P$D

    Ctudy E/A'&P, is an open la0el multicentre ealuation of the e4cacysafety and PM of rLIIIc for routine prophyla6is in paediatric PTPs withhaemophilia A. The 5rst patient was enrolled in August &'1& and the studyis still ongoing. The cut-oK point for this interim analysis was anuary &'1(.

     The data hae 0een used for ealuation of CAs and As of special interestand no e4cacy data hae 0een analysed.

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     Therapeutic Goods Administration

     The primary o0;ectie of the study is to ealuate the safety of rLIIIc inpaediatric PTPs with haemophilia A. The primary endpoint of the study is thefre3uency of inhi0itor deelopment.

    At the cut-oK point (( patients hae 0een enrolled into the study and &(hae receied at least one dose of rLIIIc. Patient demographics were

    proided. ?f the (( patients ((J were 7 years old and the remainderwere aged in the range to 1& years. The ma;ority of patients were @hite!)EJ" and &1J were #lac2.

     To date no deaths hae 0een reported. ?ne treatment emergent CA has0een reported8 a deice-related infection considered unrelated to treatment.

    tudy 87A1$T 

     This is an e6tension study to the Phase III study FF*/A('1 and thepaediatric study E/A'&P,. It is an open la0el multicentre ealuation of thelong term safety and e4cacy of rLIIIc for prophyla6is and episodic !ondemand" treatment of 0leeding episodes in PTPs with haemophilia A. Thestudy is still ongoing. The primary o0;ectie of the study is to ealuate thelong-term safety of rLIIIc. The secondary o0;ectie is to ealuate thee4cacy of rLIIIc in the preention and treatment of 0leeding episodes.

    As of * anuary &'1( 1)' patients from FF*/A('1 were enrolled andreceied at least one dose of rLIIIc F) of whom completed the 5rst month safety isit.

    No A data hae 0een analysed at the anuary &'1( cut oK. There were nodeaths. There were 1' CAs reported 0y E patients all of which were

    considered unrelated to study treatment. There were no As of specialinterest !inhi0itors anaphyla6is serious hypersensitiity or throm0oticeents". No uni3ue safety features were identi5ed in the adolescent group.

    Patient eposurePatient e6posure data are limited to the piotal Phase III Ctudy FF*/A('1.

     The e6tension Ctudies E/A'1T and E/A'&P, are still ongoing and thePMCtudy =PP-1&-'&-#II#'(1 contri0uted less than '.&J of the oeralle6posure data. 6posure in the piotal study is shown in Ta0le & and Ta0le (.A total of 1+ patients receied at least one dose of rLIIIc for a medianduration of ('.) wee2s !range 7 1 to )+ wee2s". ?erall F*.'J EF.'J

    1+.'J and (.*J of patients receied treatment for at least 1( & (F and)& wee2s respectiely. or all dosed patients the median total e6posuredays !,s" was )* !range 1 to 1&(" with 111 patients haing \ )' ,s. Themean total num0er of in;ections gien was )* !range 1 to 1(".

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    4abe % 0tudy ""'EA+@$. :uration of dosing 6ith r1&III1c safetyanaysis set.

    4abe + 0tudy ""'EA+@$. -posure data. 0ummary of inFections

    and days of eposure to r1&III1c. 0afety anaysis set.

    0afety issues 6ith the potentia for maFor reguatory impactLiver toxicity 

    No issues identi5ed.

    aematological toxicity 

    No issues identi5ed.

    !erious s"in reactions

    No issues identi5ed.

    Cardiovascular safety 

    No issues identi5ed.

    #n$anted immunological events

    No issues identi5ed.

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    -vauators concusions on safetyIn general rLIIIc was well tolerated. In the single piotal Phase III study1+ preiously treated adult and adolescent patients with haemophilia Areceied at least one dose of rLIIIc. The study was su4cient in siUe toade3uately assess the ris2 of inhi0itor formation and ery common orcommon As. A total of 1+ patients hae 0een treated for at least &

    wee2s and a long term e6tension study is ongoing. There was no place0ocontrol group 0ut the types and incidence of As were consistent with thosee6pected in the haemophilia population. @ith the e6ception of arthralgiarecorded in *.FJ of patients the most common As Wnasopharyngitis!1&.&J" headache !*.FJ" and upper respiratory tract infection !RTI"!).)J"X are commonly reported in the general population. No deaths or CAswere considered related to rLIIIc treatment 0y Inestigators. The patternof infections was unremar2a0le and there was no eidence of immunecompromise or increased ris2 of infection. The A pro5le in patients withunderlying /IL9/=L was similar to the rest of the patient population. Cafetyin adolescents appeared similar to that of the adults and there appeared to

    0e no eKects related to race #%I or geographic region. There were nomeaningful patterns or trends in clinical chemistry haematology or italsigns. No patient deeloped an inhi0itor or other As of special interest.

     Target organ to6icity is not a feature of 0iologics 0ut there were no cases ofanaphyla6is or hypersensitiity reactions. In 2eeping with the orphanpopulation limited patient num0ers hae 0een treated 0ut no safety signalshae 0een detected to date.

    .irst round beneit/ris& assessment

    1irst round assessment of bene!ts The 0ene5ts of loctate in the proposed usage are8

    • Kectie control of 0leeding with E*.(J of acute 0leeds controlled with a

    single in;ection.

    • Kectie as routine indiidualised prophyla6is with F&J reduction in

    annualised 0leeding rates compared with episodic !on demand"treatment.

    • Kectie as once wee2ly prophyla6is with *J reduction in annualised

    0leeding rates compared with episodic !on demand" treatment.

    • Kectie for perioperatie management with 1''J e6cellent or good

    haemostasis.

    • A long half-life !1E.F* h1&" 1.)( fold longer than Adate !rLIII".

    • Reduced dosing fre3uency. Almost F'J of patients had a history of

    re3uiring three or more prophyla6is in;ections9wee2 of LIII 0efore thestudy compared with an aerage dosing interal of ( days or longer onrLIIIc.

    1& #ased on data from Ctudy FF*/A('1.

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     Therapeutic Goods Administration

    • =lear dosing recommendations 0ased on population PM data.

    • No cases of inhi0itor formation in 11' patients with at least )' ,s

    !upper 0ound of F)J con5dence interal !=I" was (.(J".

    • ully recom0inant with no human or animal addities.

    • @ell tolerated with no anaphyla6is or hypersensitiity reactions to date.

    1irst round assessment of ris)s The ris2s of loctate in the proposed usage are8

    •  The safety data0ase includes only 1E' patients aged \ 1& years.

    ncommon As such as hypersensitiity reactions may not hae 0eendetected.

    • $ong-term safety has not 0een esta0lished.

    • No safety data in children aged 7 1& years.

    • No safety data in PPs !at higher ris2 of inhi0itor deelopment".

    • Ris2 of seere hypersensitiity reactions not yet 2nown.

    1irst round assessment of bene!t ris) baance The 0ene5t ris2 0alance of loctate gien the proposed usage isfaoura0le.

    .irst round recommendation re'ardin' authorisationAuthorisation is recommended for the use of loctate in adults and children!\ 1& years" with haemophilia A for control and preention of 0leedingepisodesO routine prophyla6is to preent or reduce the fre3uency of 0leedingepisodesO and perioperatie management !surgical prophyla6is". Approal issu0;ect to satisfactory response to 3uestions raised.

     The TGA ,elegate has e6pressed concern a0out whether the data supportan indication that encompasses adult and9or adolescent patients. The %AGuidelines on recom0inant coagulation factor LIII !rLIII" products !&''' and

    &''F ersions" are silent on adolescents and recommend patient studies inan inclusie population aged \ 1& years. Although there is no speci5cre3uirement the safety and e4cacy study included 1( adolescent patientswhose response was similar to that of the adult population.

    C%inica% uestions

    Pharmaco)inetics@ould the sponsors suggest why all the reported 0leeding eents in the PMstudy FFE/A1'1 occurred in the rLIIIc group and none in the Adate

    group^

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     Therapeutic Goods Administration

    -DcacyIn the piotal study &.EJ of patients had ma;or informed consent _issuesH.Please clarify and proide assurance that the study was performed to fullG=P and was ade3uately monitored.

    $econd round e!a%uation o c%inica% data submitted in response to uestions The sponsor responses to clinical 3uestions !a0oe" were ta2en into accountin the ,elegateHs oeriew. Cee vera%% conc%usion and ris";bene.tassessment3

    @ith regard to the 3uestion on pharmaco2inetics the ,elegate noted thatthe disparity in reported 0leeding 0etween Adate and rLIIIc groups wasdue to the study design and the limited follow up period for Adate !+ days".

    @ith regard to the 3uestion on e4cacy the issue was resoled to thesatisfaction of the ,elegate.

     Therefore a second round ealuation report was not prepared.

    ,# Pharmaco!i'i%ance indin's

    Ris& mana'ement p%an The sponsor su0mitted Australian ris2 management plan !R%P" ersion 1data loc2 point 1+ Ceptem0er &'1& which was reiewed 0y the TGAHs ?4ceof Product Reiew !?PR".

    0afety speci!cation The sponsor proided a summary of ongoing safety concerns which areshown at Ta0le +.

    4abe , 0ummary of ongoing safety concerns.

    (ngoing safety concernsImportant identi5ed ris2s None

    Important potential ris2s Inhi0itor deelopmentAn inhi0itor is de5ned as a neutralisinganti0ody alue \ '. #ethesda units

    W#X9m$ identi5ed and con5rmed 0yretesting of a second sample within & to +wee2s.Allergic reaction or anaphyla6isA serious allergic reaction associated withadministration of rLIIIc is de5ned as aneent that is \ Grade & on theRecommendations for Grading of Acuteand Cu0acute To6ic Kects on the @orld/ealth ?rganisation scale.

    Important missing

    information

    Cafety pro5le in patients \ ) years old

    Cafety pro5le in children 7 1& years old

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     Therapeutic Goods Administration

    Pharmacovigiance panRoutine pharmacoigilance actiities are proposed to address all ongoingsafety concerns. Additional pharmacoigilance actiities are proposed toaddress the two potential ris2s of inhi0itor deelopment andanaphylactic9hypersensitiity.

     The additional actiities descri0ed 0y the sponsor are8 1." $/peditedreporting to regu%ators of inhibitors and *3( Targeted fo%%o+&up by0uestionnaire of inhibitors from spontaneous reports2 other programs +here

    data are being hand%ed as so%icited2 and a%% c%inica% tria% serious adverse

    events 'A$s(.

    %oreoer to address the two potential ris2s of Inhi0itor deelopmentS and/ypersensitiity9Anaphylactic reactionS and the missing information ofCafety pro5le in children 7 1& years oldS two clinical trials are ongoing atthe time of ealuation.

    Ris) minimisation activities@ith regard to the need for ris2 minimisation actiities the sponsor hasconcluded8 Prophy%actic treatment +ith %ong&acting r

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     Therapeutic Goods Administration

    4abe 5 Reconciiation of issues outined in the R/P report.

    Recommendation inR/P evauationreport

    -tract of the0ponsors s+$R/P response

    (PRevauatorscomment

    It is 0rought to the

    ,elegateHs attentionthat the proposedindication in Australiaincludes Perioperatiemanagement !surgicalprophyla6is"S althoughit appears that this wasnot the indicationgranted orphan drugstatus.

    #iogen IdecHs

    application fororphan drugdesignationspeci5ed thefollowing indicationswhich are consistentwith the indicationspresented in theproposed la0elling8

    • =ontrol and

    preention !including

    routine prophyla6is"of 0leeding episodesin adults andchildren with/aemophilia AO

    • Perioperatie

    management inadults and childrenwith /aemophilia A./oweer the letterfrom the TGA

    informing #iogenIdec that rLIIIc wasdesignated as anorphan drug notedthat the indicationis for the control andpreention !includingroutine prophyla6is"of 0leeding episodesin adults andchildren with

    haemophilia A.S#iogen IdecHsinterpretation of the

     TGAHs orphandesignation letterwas that the use ofrLIIIc forperioperatiemanagement!surgicalprophyla6is" was

    coered under the0roader indicationfor the control and

     The response is

    noted./oweer thisissue is drawnto the attentionof the ,elegateforconsideration.

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     Therapeutic Goods Administration

    preention !includingroutine prophyla6is"of 0leedingepisodes.S

    It is recommended thatthe sponsor proidesfollow up forms tocollect informationregarding aderseeents for the twopotential ris2s ofInhi0itordeelopmentS andAllergic reactions oranaphyla6isS for reiewprior to approal.

    Chould the ,elegatere3uest follow-upforms for thepotential ris2s ofInhi0itordeelopmentS andAllergic reactions oranaphyla6isS asrecommended 0ythe ealuator#iogen Idec agreesto proide them forreiew prior to

    approal.

     This response isconsideredunaccepta0le.

     The R%P is notthe ,elegateHsresponsi0ility0ut that of theR%P ealuatorand the directorof the R%Psection.urthermorethe sponsor has

    speci5ed theuse of follow upforms for thetwo potentialris2s of Inhi0itordeelopmentandAnaphylactic9/ypersensitiity inthe R%Pproided for

    ealuation.Cu0mission ofthesedocuments is a0asicre3uirement forsu0mission of aalid R%P. Inthe TGAguideline Ris2%anagement

    Plan !R%P"uestions ̀AnswersLersion 1.(?cto0er&'1&SZ it isstated8Shat must beinc%uded in the

    4BP Particu%ar attention

    shou%d be paidto ensuring: &

    a%%

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     Therapeutic Goods Administration

    attachments2

    anne/es andappendices

    referred to inthe 4BP are

    inc%uded in fu%%3

    This e/c%udesthe

    $udravigi%ance Anne/ 13 

    =onse3uentlythe R%P in itscurrent ersionis incompleteand thereforeconsideredunaccepta0le.

    It is recommended thatthe sponsor proidesan R%P in the format including thesection Additional re3uirementsSincluding the points8 1."Potential for oerdose&." Potential fortransmission ofinfectious disease (."

    Potential for misuse forillegal purposes +."Potential for oK la0eluse and )." Potential forpaediatric oK-la0el useand other re3uiredinformation speci5ed inthe TGA guideline R%P`As documentersion 1.( dated ,ec-&'1&Z.

    #iogen Idec aims toproide the TGA aR%P in the format including thesection Additional re3uirementsSincluding the points81." Potential foroerdose &."Potential fortransmission of

    infectious disease(." Potential formisuse for illegalpurposes +."Potential for oK la0eluse and )." Potentialfor paediatric oK-la0el use and otherre3uired informationspeci5ed in the TGAguideline Z.

     This response isconsideredinsu4cient. Thesponsor has notproided theR%P in there3uestedformat and didnot specify adate forsu0mission of

    the re3uesteddocument. It isrecommendedthat thesponsorsu0mits there3uested R%Pdocument forreiew prior toapproal.

     The followingrecommendations aremade regardingamendments to theta0le of ongoing safetyconcerns8A." It is recommendedthat patient groupswith hepatic and renalimpairment 0e includedas missing information

    in the ta0le of ongoingsafety concerns.Pharmacoigilance and

    Chould the ,elegatere3uest these R%Pamendments asrecommended 0ythe ealuator#iogen Idec agreesto add the followingpatient groupsincludingpharmacoigilanceand ris2

    minimisationactiities for thesepatients groups as

     The sponsorHs ;usti5cation fornot includingthe followinginformation atpresent isaccepta0le.1. patientgroups with /ILand /=L&. patients

    with mild tomoderatehaemophilia

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     Therapeutic Goods Administration

    ris2 minimisationactiities should 0eassigned asappropriate.#." It is recommendedthat the sponsor

    proides detailedcomments on theaaila0le dataindicating that thesafety for patientgroups with /IL and/=L has 0eenesta0lished. If thesafety for the producthas not 0eensatisfactorily

    esta0lished for thesepatient groups then itis recommended thatthese patient groups 0eincluded in the ongoingta0le of safetyconcerns andpharmacoigilance andris2 minimisationactiities should 0eassigned as

    appropriate.=." It is recommendedthat preiouslyuntreated patientsS 0eincluded in the ta0le ofongoing safety asmissing information.Pharmacoigilance andris2 minimisationactiities should 0eassigned as

    appropriate.,." It is recommendedthat patients with mildto moderatehaemophiliaS 0eincluded in the ta0le ofongoing safety asmissing information.Pharmacoigilance andris2 minimisationactiities should 0e

    assigned asappropriate.." It is recommended

    appropriate asmissing informationin the ta0le ofongoing safetyconcerns8A". patient groups

    with hepatic andrenal impairment#". patient groupswith /IL and /=L=". preiouslyuntreated patients#iogen Idec does notthin2 it would 0einformatie to addthe following itemsto the ta0le of

    ongoing safetyconcerns as missinginformation in theta0le of ongoingsafety concerns0ased on the clinicaleidencesummarised 0elow8,". patients withmild to moderatehaemophilia

    ". throm0oticeents

    (. throm0oticeents.

     Therecommendation remains toinclude the

    following in theta0le of ongoingsafety concernsas missinginformation8 A."patient groupswith hepaticand renalimpairment and=." preiouslyuntreated

    patients.Ris2-%inimisationandpharmacoigilance actiitiesshould 0eassigned asappropriate.

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     Therapeutic Goods Administration

    to the ,elegate to drawthe attention of theclinical ealuator toassess whether it isappropriate not toinclude throm0otic

    eents in the ta0le ofongoing safetyconcerns.It is recommended thatthe R%P 0e reised toinclude adherence ofthe pharmacoigilanceactiities in accordanceto the Australianre3uirements asdescri0ed in the

    document Australianre3uirements andrecommendations forpharmacoigilanceresponsi0ilities ofsponsors of medicinesSersion 1.1 dated ,ec-&'1&.

    Chould the ,elegatere3uest the R%P 0ereised asrecommended 0ythe ealuator#iogen Idec willreise the R%P toinclude adherence of 

    pharmacoigilanceactiities inaccordance to theAustralianre3uirements.

     The R%P is notthe ,elegateHsresponsi0ility0ut that of theR%P ealuatorand the directorof the R%Psection.

     Thisrecommendation remains.

    It is recommended thatthe sponsor reises theR%P to include

    su0mission dates forinterim and 5nal studydata to the TGA.

    Chould the ,elegatere3uest reisions tothe R%P to include

    su0mission dates fordata from ongoingstudies to the TGA asrecommended 0ythe ealuator#iogen Idec agreesto modify the ta0lesof the R%P toindicate Wthere3uestedinformationX

     The R%P is notthe ,elegateHsresponsi0ility

    0ut that of theR%P ealuatorand the directorof the R%Psection.

     Thisrecommendation remains.

    It is recommended thatthe sponsor amendsthe R%P to list the useof follow up forms asroutine ris2minimisation actiity.

    Chould the ,elegatere3uest the R%P 0eamended asrecommended 0ythe ealuator#iogen Idec willamend the R%P tolist the use of followup forms as routineris2 minimisationactiity.

     This response isconsideredunaccepta0le.

     The R%P is notthe ,elegateHsresponsi0ility0ut that of theR%P ealuatorand the directorof the R%Psection.

    urthermore inaccordancewith the

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     Therapeutic Goods Administration

    releant guideline theuse of speci5c3uestionnairesas a follow-upto a reported

    suspectedadersereaction isconsidered to0e routinepharmacoigilance.=onse3uentlythe R%P should0e amendedaccordingly. The

    R%P in itscurrent ersionis unaccepta0le.

     The R%P is lac2ingdiscussion9proision ofinformation a0outcertain clinical aspectshighly releant to theuse of the product inthe targeted patientpopulation. This

    includes the increasedris2 of anti0odydeelopment forpatients with high ris2gene mutations !Gouwet al.1( Gosh et al.1+". Itis recommended thatthe sponsor reised theR%P to includediscussion on thispoint and descri0es

    how it has 0eenconsidered in theclinical deelopment

     The eligi0ility criteriafor the Phase IIIstudy were selectedto ensure arepresentatie studypopulation of PTPswith seerehaemophilia A. No

    inclusion ore6clusion criteria inthe Phase III studyrestricted the studypopulation 0asedupon genemutations. Inaddition genotypedata were collectedfrom studyparticipants and was

    representatie of thee6pected mutationfre3uencies in the

     This response isconsideredinsu4cient.

     The sponsorstates8 Areised R%P willinclude adiscussion on

    the eKect of thee6clusioncriteria acrossthe clinical trialprogram andthe implicationsfor treatment of the targetpopulation./oweer thesponsor has not

    su0mitted theupdated R%Pand it is unclear

    1( Gouw C et al.The %ultifactorial tiology of Inhi0itor ,eelopment in /emophilia8 Geneticsand nironment. Ceminars Throm0osis and /emostasis &''FO()8*&(-*(+.

    1+ Gosh C et al. Immune Response to LIII in /emophilia A8 An ?eriew ofRis2 actors. C%inic 4ev A%%erg -mmuno%. &''F (*8)E.

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     Therapeutic Goods Administration

    program and in thegeneration of the R%P.

    general populationof patients withhaemophilia A. Areised R%P willinclude a discussionon the eKect of the

    e6clusion criteriaacross the clinicaltrial program and theimplications fortreatment of thetarget population.

    when thesponsor is goingto su0mit theupdated R%P.

     Thisrecommendatio

    n remains.

     The consumermedicine information!=%I" and directions foruse !," areconsidered part of the

    ris2 management andtherefore it isrecommended thatsection CponsorHsconclusion in regard tothe need for ris2minimisation actiitiesSof the R%P 0e reisedto ma2e reference tothe =%I and ,.

    #iogen Idec 0elieesthat the ris2managementdescri0ed in the =%Iand , is 0ased

    upon informationproided in theProduct Information!PI". Therefore#iogen Idec 0elieesthat the =%I and, documents donot warrant aseparate referencewithin the R%P.

     This response isconsideredunaccepta0le.In accordancewith the

    releant guideline thepac2age leaet!e3ual to theAustralian =%I"is considered aseparateroutine ris2-minimisationactiity.=onse3uently it

    is e6pected thatthe =%I9, arereferenced inthe R%P. Thisrecommendation remains.

    It is recommended thatan o[a0el useSsection 0e included in areised R%P. Thisshould include 0ut not

    0e limited to oK la0eluse for Immuno

     Tolerance Induction Therapy !ITI" !Riard etal.1)". The reised R%Pshould include adiscussion on how thispoint has 0eenconsidered during theclinical deelopment

    #iogen Idec willreise the R%P toinclude a section onpost authorisationoK la0el use

    including 0ut notlimited to oK la0eluse for !ITI". Thedocument will alsoinclude a discussionof how oK la0eluseS was consideredduring the clinicaldeelopmentprogram and in the

     This response isconsideredinsu4cient. Thesponsor has notsu0mitted the

    updated R%Pand it is unclearwhen thesponsor is goingto su0mit theupdated R%P.

     Thisrecommendation remains.

    1) Riard G et al. Immune tolerance induction in haemophilia A patientswith inhi0itors 0y treatment with recom0inant factor LIII8 a retrospectienon-interentional study 7aemophi%ia !&'1(" 1F ++F+)).

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     Therapeutic Goods Administration

    program and in thegeneration of the R%P.Pharmacoigilance andris2 minimisationactiities should 0eassigned as

    appropriate.

    generation of theR%P.

    It is recommended thatthe sponsor amendsthe R%P to include adiscussion a0out theuse of the product in ahome treatmentsetting and proidesinformation on how anyris2s associated withthis treatment setting

    will 0e addressed in theR%P.

    #iogen Idecac2nowledges thatappropriatematerials andtraining will 0ere3uired in order tofacilitate appropriatepreparationadministration andstorage of the

    product for thosepatients and carerswho choose to self-administer loctate.

     The PI =%I and ,will 0e included ineach loctate pac2insert. Thereforeeach patient willreceie a copy ofthese materials.

    #iogen Idec 0elieesthat the =%I and, documents donot warrant aseparate referencewithin the R%P.In addition infusiontraining 2its are0eing deelopedwhich will 0eproided free of

    charge tohaemophilia centresand appropriatehealth careproiders.A patient pac2consisting ofeducationalmaterials will also 0eproided to all newloctate patients.

    #iogen Idec 0elieesthat the potentialincreased ris2 of

     The sponsordescri0es theuse of8 1."Infusion training2its and &." apatient pac2.

     These actiitiesrepresentadditional ris2minimisation

    actiities.=onse3uentlythese actiitiesshould 0ereferenced inthe R%P whichis currently notthe case.urthermore adescription ofthe Infusion

    training 2its andpatient pac2pac2s has to 0esu0mitted forreiew prior toapproal. Thesedocumentsshould 0eattached asanne6 to theupdated R%P. In

    addition therecommendation made in theround 1 R%Preport remains.

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     Therapeutic Goods Administration

    inappropriatepreparationadministration andstorage of theproduct has 0eenade3uately

    addressed 0y themeasures detaileda0oe.

     The remaining ?PR recommendations related to reisions to productla0elling and the , document. ,etails of these are 0eyond the scope ofthe AusPAR.

    Advisor committee considerations %dvice from the %dvisory Committee on the !afety of Medicines&%C!OM'

     The application was su0mitted for adice from the A=C?%.

    (utstanding issues(ssues in relation to the RMP

     The sponsor has insu4ciently or unaccepta0ly addressed the ma;ority of therecommendations made in the round 1 R%P report. The ma;ority of therecommendations made in the round 1 R%P report remain !see Ta0le )a0oe".

    Recommendation•  The Australian Ris2 %anagement Plan ersion 1 data loc2 point 1+-Cep-

    &'1& to 0e reised to the satisfaction of the TGA must 0e implemented.

    • Recommendations made in the section outstanding issuesS must 0e

    addressed to the satisfaction of the ?PR prior to approal.

    ,"# !era%% conc%usion and ris&beneit assessment

     The su0mission was summarised in the following ,elegateHs oeriew andrecommendations8

    3ac&'roundAustralian clinical guidelines for treatment of /aemophilia A include8$vidence&based c%inica% practice guide%ines for the use of recombinant and

     p%asma&derived

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     Therapeutic Goods Administration

    LIII in recom0inant products has a half-life of appro6imately 1' to 1) hours!compared with loctate8 appro6imately 1*.* hours1" resulting in similardosing fre3uencies across registered products !in adults". The generalapproach is to modify dosage regimens !dosage interals doses" 0ased onindiidual factors8 0leeding phenotype 0ut also indiidual PM.

    ua%ity There were no %odule ( o0;ections to registration.

    aluated data support a shelf-life of 1 year at -*'= for drug su0stance and1 year at & to E= for drug product. There were insu4cient data to supportstorage of the product for up to months at room temperature.Recommendations were made to modify statements regarding storageconditions that are found on la0els and in the PI.

     The following comment was made a0out speci5cations8

    FThe eva%uator has concern +ith regarding the high speci.cation %imit setfor non processed isoform 'Cr

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     Therapeutic Goods Administration

    Information a0out formulations used across the clinical study programmewas proided. The formulation proposed for commercial use diKers !inmanufacture" from the piotal Phase III study formulationO a compara0ilitye6ercise included physicochemical and in itro characterisation and PMealuation in animal models.

    Pharmaco)ineticsCtudy FFE/A1'1 was a cross oer study comparing rLIIIc and Adate inpreiously treated adults with seere haemophilia A. @ashout was + b days!Adate was gien 5rst for each patient". Two doses were assessed indiKerent patients8 &) I92g !n median age +& years" and ) I92g !n 1' median age (' years". #ased on the one stage clotting assay at the &)I92g dose half-life for rLIIIc was 1*.* hours ersus 11.)* hours forAdate !rLIIIc )(J higher". At ) I92g alues were 1*.&+ hours and F.Fhours respectiely !rLIIIc *J higher". ?ther PM parameters aligned withthese diKerences. There was a disparity in reported 0leeding !all 1( reportswere after rLIIIc" 0ut the study was designed so that there were only +days during which a 0leed could hae occurred _on AdateH.

    Population PM analysis =PP-1&-'&-#II#'(1. This analysis drew on data fromFF*/A('1 A-$?NG !n1+" and FFE/A1'1 !n1". %odels were created forAdate and rLIIIc. or the prophyla6is model a 2ey 5nding was that the )I92g wee2ly dose regimen resulted in &*J of su0;ects remaining a0oe 1Jactiity at trough whereas the )' I92g 3)day regimen resulted in )(.+Jremaining a0oe the 1J threshold. ,etails of the treatment model areproided in the =R !Attachment &"O one conclusion was that only in isolatedcases would : 1 dose 0e needed within 1 to & days for mild moderate0leeds. The target range of E' to 1'' I9d$ for ma;or 0leeds was stated as

    attaina0le with &+ to +E hourly infusions. The ma;or coariate for rLIIIcactiity was clearance.

    -Dcacy %)LO*+ &,,-%./0'

     The study was an open la0el study of rLIIIc in preiously treated adultsand children \ 1& years with seere haemophilia A. In a su0group there wasa single dose cross oer PM comparison with Adate !Ctudy FFE/A1'1. seePM section a0oe"O otherwise the study was uncontrolled. There were (arms8

    • Arm 18 indiidualised prophyla6is !&)-) I92g eery (-)days to maintain

    trough 1 - (J actiity"O the PM su0group was drawn from this arm.

    • Arm &8 wee2ly prophyla6is !) I92g eery * days".

    • Arm (8 episodic !on demand" dosing.

    • Perioperatie management su0group !patients from Arms 1 - ( who

    needed ma;or surgery".

     The rationale for dosage selection in this study is proided in the =R.

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     Therapeutic Goods Administration

     There was randomisation into Arms & or ( for those su0;ects preiouslyusing an on demand approach who did not want to enter Arm 1 directlyOotherwise the study was not randomised.

    1) patients were enrolled and 1)( completed the study. In Arm 1 therewere 11E patientsO in Arm & there were &+ patientsO in Arm ( there were &(

    patients. Informed consent issues were identi5ed in &*J of su0;ects 0ut thesponsor clari5ed that in only ( out of ++ patients were issues consideredsigni5cant and in (out of ( cases the deiations were corrected on study.

    All patients were maleO the median age was (' years !range 1&-)". Therewere 1( patients aged 1& to 1* years. The median num0er of 0leeds in theprior 1& months was .' in Arm 1 patients who had 0een on a prophylacticregimenO across patients who had 0een on an on-demand regimen mediannum0er of 0leeds was &+ to &F.). Two patients withdrew 0ecause of Asand 1 patient died !suicide".

    stimated annualised 0leeding rate oer the e4cacy period was &.F for Arm1 E.F for Arm & and (*.( for Arm (. Annualised no 0leeding was estimatedfor +).(J of su0;ects in Arm 1 1*.+J in Arm & and 'J in Arm (. In the 11adolescents in Arm 1 the median annualised 0leeding rate was 1.F& !similarto the rate for patients 1E to ) years at 1.++".

    Around *EJ of patients considered that responses to rLIIIc in;ections for a0leeding episode were good or e6cellent across arms. ?ther e4cacy resultsare descri0ed in the =R. Nine ma;or surgeries were performedOhaemostasis was e6cellent or good in all cases.

    0afety The clinical ealuator considered that Phase III Ctudy FF*/A('1 proidedthe 0est characterisation of safety for rLIIIc 0ut noted that safety datawere also presented from ongoing Ctudy E/A'&P,. ?nly &( patients hadreceied 1 b dose and only one treatment emergent CA has 0een reported!infection considered unrelated to rLIIIc". There were also safety datafrom those A-$?NG patients wh