3936B2 04 Schering-Temodar

8/10/2019 3936B2 04 Schering-Temodar

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BRIEFING BOOK FOR THE MARCH 13, 2003 ODACMEETING REGARDING ACCELERATED APPROVAL

CLINICAL PHASE 4 COMMITMENTSNDA 21-029 TEMODAR ( te !"!#! $%e &

SCHERING-PLO'GH CORPORATION

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION


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BRIEFING BOOK FOR THE MARCH 13, 2003 ODACMEETING REGARDING ACCELERATED APPROVAL

CLINICAL PHASE 4 COMMITMENTSNDA 21-029 TEMODAR ( te !"!#! $%e &

SCHERING-PLO'GH CORPORATION

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

TABLE OF CONTENTS

I GENERAL INFORMATION 1A. Drug Name............................................................................................. 1B. Indication................................................................................................ 1C. Accelerated Approval Date...................................................................... 1D. Outline of the Summary Basis of Approval............................................. 1II DESCRIPTION OF COMMITMENTS INCL'DING TITLES OF

INDIVID'AL ST'DIES 3III INFORMATION CONCERNING THE COMMITMENT ST'D) 4A. Essentials of the Study Design................................................................ 1. Summary of the Study Sites !"eography# Num$er%................................ &. 'atient 'opulation !Eligi$ility(E)clusion Criteria%.................................. *. Endpoints................................................................................................ + . ,reatment Schema................................................................................... + +. Efficacy and Safety -onitoring..............................................................

. Statistical Design..................................................................................... /B. Date of Initiation.................................................................................... 10C. Accrual................................................................................................... 10D. Estimated ,imelines for Study Completion............................................ 10E. Estimated ,imelines for Su$mission of Study esults............................ 11IV OTHER ISS'ES 11A. Difficulties encountered in conduct(accrual(completion of trial..... ........ 11 1. Changes in -edical 'ractice.................................................................. 11 &. Natural 2istory of the Disease................................................................ 11 *. Safety Considerations............................................................................. 1&

. ,imelines................................................................................................ 1&B. Other Applicant Concerns...................................................................... 1*Attachment 1 ........................................................................................................... 1Attachment &................................................................................................. 1Attachment *................................................................................................. 13Attachment ................................................................................................. &0


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BRIEFING BOOK FOR THE MARCH 13, 2003 ODAC MEETING REGARDINGACCELERATED APPROVAL CLINICAL PHASE 4 COMMITMENTS

NDA 21-029 TEMODAR * ( te !"!#! $%e&

SCHERING-PLO'GH CORPORATION AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

I GENERAL INFORMATION+

A D . N/ e 4 ,E-ODA 5 !temo6olomide%

B I %$ /t$! 4 7or the treatment of adult patients 8ith refractory anaplastic astrocytoma

!AA%# i.e.# patients at first relapse 8ho have e)perienced disease progression on a drugregimen containing a nitrosourea and procar$a6ine.

C A e#e /te% A ! /# D/te 4 August 11# 1999

D O t#$ e ! t5e S / 6 B/7$7 ! A ! /#+

,he ,E-ODA 5 clinical development program for malignant gliomas focused on"B- and AA from 199* to 1993. ,he Ne8 Drug Application !NDA% for temo6olomide capsules for the treatment of recurrent malignant "B- !glio$lastomamultiforme% and AA 8as su$mitted to the 7DA on August 1 1993.

During the NDA revie8 process# the 7DA agreed that there 8as no standard of carefor relapsed AA in recurrent disease# and agreed to revie8 the AA indication under the accelerated approval regulations 8ith a 'hase commitment to confirm clinical

$enefit in an AA population in a randomi6ed controlled study to $e approved $y theAgency.

,he clinical section of the AA accelerated approval NDA 8as $ased upon amulticenter *& institution open:la$el 'hase & study of temo6olomide in the treatmentof adult patients 8ith AA at first relapse !Study C(I9 :1&*%. ,he primary efficacyendpoint of this study 8as progression:free survival !'7S% at si) months. Secondary

efficacy endpoints 8ere overall survival# o$;ective response and 2


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OS 8as 1*. months and survival rate at months 8as /+@ !9+@ CI 3:3&@% thesafety profile 8as accepta$le.

In AA patients 8ho 8ere refractory to $oth a nitrosourea and procar$a6ine# the 7DAanalysis indicated that the overall response rate !C ' % 8as &&@ 8ith 9@

complete response and the median duration of all response 8as +0 8ee s !1 :118ee range% 8ith median duration of complete response of 8ee s !range +& to 118ee s% the median '7S 8as . months and median OS 8as 1+.9 months.

,he Oncologic Drugs Advisory Committee !ODAC% in its 1(1&(1999 meetingunanimously agreed !1&: es# 0:No% that4

,he patients 8ith relapsed AA 8ho have received $oth nitorsourea and procar$a6ine could $e considered unresponsive to other therapies.

,he AA 'hase & study 9 :1&* sho8s that temo6olomide capsules are effective for

the treatment of relapsed anaplastic astrocytoma in patients 8ho have had prior treatment 8ith a nitorsourea and procar$a6ine.

,he safety of temo6olomide capsules is accepta$le for this indication.

In early 7e$ruary 1999# the sponsor su$mitted a protocol concept sheet !'CS% for a proposed post:approval study in ne8ly diagnosed AA patients to $e conducted $y thecooperative group adiation ,herapy Oncology "roup ! ,O"%. At that time the

proposal 8as for a t8o:arm study comparing radiation 8ith BCN to radiation 8ithBCN follo8ed $y temo6olomide. ,here 8as no need for a 'hase 1 safety program

prior to this 'hase * study.On 7e$ruary 1 1999# the 7DA issued an approva$le letter for ,E-ODA 5 for theindication Ftreatment of adult patients 8ith refractory anaplastic astrocytoma# i.e.#

patients at first relapse 8ith disease progression on a nitrosourea and procar$a6inedrug regimenG.

,he 'CS of the ,O" study in ne8ly diagnosed AA patients !Study 93:1*% 8asrevie8ed $y the 7DA and initial comments 8ere communicated to ScheringCorporation on -arch +# 1999. ,he protocol 8as revised in colla$oration 8ith ,O"to incorporate the 7DA comments and 8as re:su$mitted to the Agency on >une & #

1999. ,he revised protocol included a third arm to study the dou$let of BCN (temo6olomide. ,his revised protocol reHuired a 'hase 1:safety assessment of the dou$let and the 7DA reHuired su$mission of the safety data prior to initiating thestudy 8ith the BCN (temo6olomide com$ination. Additional 7DA comments 8erereceived on >uly 3# >uly *0 and August *# 1999.

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On August 11# 1999# 7DA approved ,E-ODA 5 capsules under &1 C7 *1Su$part 2 for the treatment of adult patients 8ith refractory anaplastic astrocytoma#i.e.# patients at first relapse 8ho have e)perienced disease progression on a drugregimen containing a nitrosourea and procar$a6ine.

,he 7DA approval 8as $ased on a surrogate endpoint !response rate% 8ith a post:approval commitment to conduct a study entitled4 FA 'hase 1(* randomi6ed study of radiation therapy and temo6olomide versus radiation therapy and BCN versusradiation therapy and temo6olomide and BCN for anaplastic astrocytomaG. ,hecommitment further stipulated that safety data from a 'hase 1 segment of the study8ould $e su$mitted to the 7DA 8ith agreement that initiation of the com$ination arm!BCN (temo6olomide% 8ould $e contingent on 7DA approval to proceed.7urthermore# Schering Corporation committed to completing the t8o monotherapyarms of the study in the event that the com$ination arm 8as stopped for any reason.

,8o "B- studies 8ere su$mitted in the original NDA. ,he first study# C(I9 :091#compared temo6olomide !11& patients% to procar$a6ine !11* patients%. ,he primaryendpoint of this study 8as progression free survival !'7S% 8ith overall survival !OS%as a secondary endpoint. '7S at months 8as &1@ !9+@ CI 1*:&9@% for temo6olomide versus 9@ !9+@ CI :1+@% for procar$a6ine !p?0.01 %. -edianoverall survival in this study sho8ed a trend favoring temo6olomide !/.* vs +.3&months p?0.0 /%.

,he second study !C(I9 :1&&% 8as a single arm study of 1*3 "B- patients in 8hich:month '7S 8as reported as 19@.

,he "B- claim from the August 1 1993 NDA 8as determined not to $e eligi$le for standard or accelerated approval.

.

II DESCRIPTION OF COMMITMENTS INCL'DING TITLES OFINDIVID'AL ST'DIES+

1. A 'hase 1(* randomi6ed study of radiation therapy and temo6olomide versus radiationtherapy and BCN versus radiation therapy and temo6olomide and BCN for anaplastic astrocytoma.

1.1. In addition# Schering:'lough esearch Institute !S' I% 8ill provide 'hase 1(&safety data of the a$ove study to support the dosing schedule in the com$inationarm of the trial# and agree that initiation of the com$ination arm 8ill $e contingenton 7DA approval to proceed.

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1.&. 7urthermore# S' I committed to completing the t8o monotherapy arms of thetrial in the event that the com$ination arm is stopped for any reason.

J eference 7DA 7a) dated >anuary &+# &001 !Attachment K1% and 7DA letter datedAugust *0# &001 !Attachment K&%L

&. Other ,E-ODA 5 Commitments4 On >anuary &+# &001# the 7DA issued a 'ediatricMritten eHuest and S' I su$mitted the reHuired studies on Septem$er 1 &00&. As aresult of this# pediatric e)clusivity 8as granted on Novem$er 1 &00& and thiscommitment is no8 completed.

III INFORMATION CONCERNING THE COMMITMENT ST'D)+

A E77e t$/#7 ! t5e St %6 De7$.

1 S / 6 ! t5e St %6 S$te7 (Ge!. / 56, N 8e &,here are 10* ,O" investigative sites ! S and Canada% and additional sites as partof the Intergroup net8or participating in this study 8hich is identified as ,O" 93:1*. See Attachment * for the geographic location of sites.

,he initial 'hase 1 safety study 8as conducted at the sites listed in Attachment .

2 P/t$e t P! #/t$! (E#$.$8$#$t6 E: # 7$! C $te $/&

,he adiation ,herapy Oncology "roup ! ,O"% 'rotocol 93:1* has $een revie8ed $y the 7DA on several occasions and in response to 7DA guidance# has $een amended

three times. ,he date!s% entered $et8een parentheses ne)t to section headings refer tothe dates of the protocol amendment.

Eligi$ility Criteria !3(1/(01% ,he protocol defined eligi$le patient population consists of histologically:confirmed unifocal

anaplastic astrocytoma as determined $y central revie8# or mi)ed oligodendroglial(astrocytictumors 8here the oligodendroglial component is less than &+@ of the tumor mass. 'atients 8ith

prior $iopsy:proven lo8 grade astrocytoma 8ho no8 have a $iopsy:proven anaplastic astrocytomaand have not $een previously treated 8ith either radiation or chemotherapy are eligi$le.

arnofs y performance status ! 'S% 0 . AdeHuate $one marro8 reserve hemoglo$in 10 grams# a$solute neutrophil count 1+00(mm *#

platelets 1+0#000mm * liver function tests !AS,(S"O,# al aline phosphatase# total $iliru$in% P& )upper limit of normal serum creatinine P1.+ ) normal.

,herapy must $egin 8ithin + 8ee s after tissue diagnosis. Diffusion =ung Capacity O)ygen !D=CO% /0@. 're: and post:op contrast:enhanced -agnetic esonance Imaging !- I%. If patient had only a stereotactic $iopsy# then a post $iopsy scan is not necessary. 'atient must sign a study:specific informed consent form prior to randomi6ation.

E)clusion Criteria !3(1/(01# &(13(0&% -a;or medical illnesses or psychiatric impairments# 8hich in the investigatorQs opinion 8ill prevent

administration or completion of the protocol therapy and (or interfere 8ith follo8:up.

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Any oligodendroglial component &+@. ,umor predominately located in the posterior fossa (i.e. brainstem or cerebellum). Spinal cord tumors. Evidence of spinal drop metastases or spread to non:contiguous meninges (MRI of the spine not

required in asymptomatic patient; patients will not be excluded based on pathologic evidence of local meningeal infiltration by underlying tumor) .

'rior malignancy (excluding in situ carcinoma of the cervix or non melanomatous s!in cancer)unless disease free for at least + years.

'rior radiation to the $rain or head(nec . 'rior chemotherapy. Active infectious process. 'regnant or nursing. ,he effects of protocol agents in the fetus are un no8n. Ina$ility or un8illingness to use effective contraception. ,his applies to $oth female and male

patients. no8n or suspected $y hypersensitivity to one of the components of BCN or temo6olomide or to

any other nitrosourea or Dacar$a6ine.

3 E % !$ t7 (; 1< 02& Overall Survival. ,ime to tumor progression. elative to)icities of the t8o regimens. Correlate molecular analysis 8ith overall survival and time to tumor progression.

4 T e/t e t S 5e / (; 1< 02&

S

,

A

,

I

7

Age

1. P+0&. +0

A

N

D

O

-

I

R

E

Arm 14 adiation ,herapy4 +9. "y ! ".# $y x %% fractions& ' daysa wee! x wee!s) plus ,emo6olomide &00 mg(m & daily on days1:+ of the first 8ee of radiotherapy. epeat ,emo6olomideevery &3 days for a total of 1& cycles.

'S

1. 0:30&. 90:100

Arm &4 adiation ,herapy4 +9. "y ! ".# $y x %% fractions& 'days a wee! x wee!s % plus BCN ! # mg*m+% on days 1# &and * of the first 8ee of radiotherapy and on days + # +/# and+3# then every eight 8ee s for four cycles for a total of si)cycles ! maximum ,- / dose "00 mg*m +%.

Surgery

1. Biopsy only&. esection

,he follo8ing & arms have $een closed4'ilotK1# Arm # 1+ patients4 adiation ,herapy4 +9. (".# $y x %%

fractions& ' days a wee! x wee!s % plus BCN &00 mg( m& on day 1of radiotherapy and ,emo6olomide 1+0 mg(m& on days 1:+ of the first

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TCasenum$er

Arm ,o)icity "rade -ost recent cycleof chemotherapy

Days fromStart of ,

* 'ilot K1# Arm 'ulmonary4 Dyspnea * 1 &3/ 'ilot K1# Arm Dermatology4

rash(desHuamation* & +

1* 'ilot K1# Arm Neurology4 confusion * &+9

1 'ilot K1# Arm Cardiovascular !"eneral%4throm$osis(em$olism + & n 1+ 'ilot K1# Arm Neurology4 vertigo * 199

As per the second annual report $y the ,O"# 8hich 8as su$mitted to the 7DA on >uly 11# &00 therehave $een no IND safety reports issued $y S' I.

,here 8ere 3 deaths reported during the first year of the study. Seven deaths 8ere attri$uted to disease.One death 8as a pulmonary em$olism.

= St/t$7t$ /# De7$.

2ample 2i3e

,he primary endpoint of ,O" 93:1* is survival. ,he standard arm is radiotherapy(R4) plus BCN . ,he e)perimental arm is , and temo6olomide. Assuming that the-edian Survival ,ime !-S,% for , BCN is * months and the , andtemo6olomide arm has a -S, of + months# then a sample si6e of &1 evalua$le

patients per arm 8ill provide overall statistical po8er of 90@ 8ith a one:sidedsignificance level of 0.0+. Since it is e)pected that +@ of the patients 8ill $eineligi$le# then a total of + randomi6ed patients 8ill $e reHuired. ,he primaryanalysis method 8ill $e aplan:-eier 8ith a stratified log ran test.According to Scott et al. +9 and Curran et al. 9 Jsuperscript num$ers indicate references

in the protocolL the recursive partitioning analysis ! 'A% classes are prognosticallyimportant. Based upon eligi$ility criteria# patients may $e in 'A classes I:IU 8hichhave decreasing estimated -S, from +3. to 11.1. ,he distri$ution of patients $y

'A class 8ill affect the e)pected num$er of deaths during the study. It is assumedthat /@ of the patients 8ill $e in class I# &+@ in class III# and 3@ in classes II andIU com$ined. If the percentage of 'A class II patients in the study sample issu$stantially higher than &+@# then the -S, 8ill $e lo8er than * months# or if the

percentage of 'A class I patients is higher than /+@# then the -S, 8ill $e higher than * months. In either case the sample si6e may need to $e ad;usted. !3(1/(01#&(13(0&%

'hase 1 Arm (#*"5* ")

Initially# fifteen patients 8ere accrued to the , temo6olomide BCN arm and thespecified num$er of dose limiting to)icities 8as not e)ceeded ! & patients 8ith grade

* pulmonary to)icity or + patients 8ith grade throm$ocytopenia or neutropenia%. 2o8ever# a sufficient num$er of patients had dose reductions resulting

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in protocol changes# nota$ly a reduction in the BCN dose from &00mg(m & to1+0mg(m &. In addition# the eligi$ility criteria 8ere also changed !patients 8itholigodendrogial(astrocytic tumors are eligi$le if the oligodendrogial component isless than &+@ pre:study liver and renal function limits added eligi$le D=COincreased from 0@ to /0@%.

'atient Accrual !Arm + 3(1+(0&%

An additional 1 patients 8ere accrued to assess further the com$ination of the, temo6olomide BCN . ,he dose of temo6olomide 8as 1+0 mg(m & p.o. daily on

days 1:+ 8ith BCN 1+0 mg(m & i.v. on day +. Accrual 8as suspended for * monthsto assess safety. Based on the high proportion of dose reductions seen and theto)icities encountered# the outcome of this safety assessment 8as that the phase *component of this study 8ill consist only of Arms 1 and & !see ,reatment Schema%.An additional + patients are to $e randomi6ed to these t8o treatment armsdiscussed in Section 1*.& of the protocol.

andomi6ation

'atients are to $e randomi6ed according to a permuted $loc design# $alancing $yinstitution 8ithin strata. ,he randomi6ation is stratified $y age !P ' vs ' %# 'S! # vs. 1 " %# and prior surgery ! resection vs. biopsy %. ,hese stratificationfactors ensure $alance $y 'A classes as 8ell.

Analyses 'lans

Interim 6nalyses of 7ndpoints (#*"'* +),hree interim analyses of the primary study endpoint !survival% are scheduled as per the follo8ing ta$le4

C #/t$ e E e t7 S$. $ $ / e Le e#* 0.00 1

1& 0.01+3133 0.0&3+

If a significance level is smaller than the 2 0 values# then the null hypothesis 8ill $ere;ected. ,hese significance levels 8ere calculated to ensure an overall significancelevel of 0.0+. ,here 8ill $e t8o stochastic analyses4 at +0@ accrual and /+@ accrual.If the stochastic analysis indicates less than 1+@ po8er to o$serve the alternativehypothesis# then the study 8ill $e recommended to $e closed. ,he results of theseinterim analyses 8ill only $e reported in a $linded fashion to the ,O" Data-onitoring Committee (8M-). A report 8ith recommendations 8ill $e given to the

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study chairman. Any pro$lems or recommendations identified $y the D-C# notresults# 8ill $e reported to the Brain Committee# 8hich is responsi$le for this studyand# if necessary# the ,O" E)ecutive Committee# so that corrective action can $eta en.

6nalysis for Reporting the Initial 4reatment Results (#*"'* +),his analysis is planned at the point 8here all patients have $een follo8ed for aminimum of * months# or a ma)imum of &+1 deaths have occurred. ,he anticipatedcomponents of this analysis are4

a% ta$ulation of all cases entered# and any e)cluded from the analysis 8ith reasonsfor the e)clusion

$% reporting institutional accrualc% distri$ution of important prognostic $aseline varia$les $y treatment arms

d% o$served results 8ith respect to the endpoints descri$ed in !need correctreference%

2urvival (#*"'* +)Survival is the primary endpoint. , BCN 8ill $e compared to , temo6olomide.A significance level of 0.0 0+ ! one sided % 8ill $e used# ad;usting for prior analyses.Analyses 8ithin 'A classes# or other prognostic groups# may $e performed if thereare sufficient num$ers of patients.

4umor 9rogression (#*"'* +),ime to tumor progression 8ill $e evaluated. Su$group analyses 8ithin 'A classes#or other prognostic groups# selecting the $est treatment# may $e performed if there aresufficient num$ers of patients.

4oxicityOverall to)icity 8ill $e compared across treatments. ,he comparison 8ill $e

performed using the 'earson chi:sHuare test.

Molecular 6nalyses'athologic samples 8ill $e analy6ed for chromosomes 1p and 19H and CD N&A.,he distri$ution of the outcome of molecular analyses 8ill $e e)amined $y treatment

arm to identify any im$alance. If there is no im$alance then the treatment arms 8ill $e collapsed and survival and time to tumor progression 8ill $e compared $y thegroups identified $y Cairncross et al. ,hese groups 8ill also $e correlated 8ith other

pretreatment characteristics.

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If the target of last patient enrollment $y the end of &00 is achieved# and the eventrate occurs as predicted# an analysis of survival could $e availa$le $y late &00/.

E E7t$ /te% T$ e#$ e7 ! S 8 $77$! ! St %6 Re7 #t7,he final study protocol has scheduled interim analyses $ased on a prespecifiednum$er of events 8hich may allo8 study results to $e shared 8ith the Agency inadvanced of >une &00/.

A report of the survival analysis# assuming the current initiatives to achieveaccelerated enrollment are successful# may $e availa$le $y late &00/.

IV OTHER ISS'ES+

A D$ $ #t$e7 e ! te e% $ ! % t / /# ! #et$! ! t $/#1 C5/ .e7 $ Me%$ /# P / t$ e

,emo6olomide is approved for patients 8ith relapsed anaplastic astrocytoma !AA%.,here is no standard chemotherapy for the treatment of patients 8ith ne8lydiagnosed AA. 2o8ever# from a survey of ho8 temo6olomide is $eing used inclinical practice in the nited States# it appears that there is a$out eHual use inrecurrent AA and ne8ly diagnosed AA. Mhile it is impossi$le to precisely predictthe effect of current clinical practice for AA on enrollment in the current ,O"study# the significant and gro8ing use of temo6olomide in first line treatment of

AA may 8ell $e an impediment to accrual to this trial.

2 N/t /# H$7t! 6 ! t5e D$7e/7e

'atients diagnosed 8ith anaplastic astrocytoma have a median survival of appro)imately * months. As a conseHuence# any randomi6ed survival study inthis population can $e pro;ected to reHuire at least * years !and longer if temo6olomide e)tends survival% after completion of enrollment to reach maturity.,he current ,O" study 8ith its targeted enrollment of + patients into t8o arms

8ill $e the largest randomi6ed comparative study ever conducted for first lineanaplastic astrocytoma. "iven these circumstances# the original target of initiatingand completing first a 'hase 1:safety evaluation and then a phase III study 8ithin /years 8as am$itious at the outset. 7urthermore# the necessity for a more e)tensivethan envisaged safety evaluation of the com$ination of temo6olomide and BCN #and the resulting time reHuired in this evaluation# ma e the >une# &00/ deadlineeven more am$itious.

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B Ot5e A #$ / t C! e 7

A#te /t$ e A !/ 5e7

,he sponsor 8ould li e to e)plore 8ith the Agency possi$le alternative means tomeet the post:approval commitment !confirmation of clinical $enefit%# foremostamong them su$mission of the results of an EO ,C randomi6ed study in first line"B- comparing radiotherapy 8ith temo6olomide to radiotherapy alone.

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Att/ 5 e t 1

>AN &00f

-AV > E N-

DIUISION O7 ONCO=O" D " ' OD C,S Center for Dmg Evaluation and esearch# 27D:1+0 Moodmont Office Comple) : ,8o 1 +1 oc vMc 'i e#. ac vi c# A- &03+&

,O4 -ary >ane NehOng 7ronu Sean Bradley

7a? 903:/ 0:&& * 7s?*10:3&/: +90

'h88. 903:/ 0: /1* 'hom *01:+9 :+/+0

pages# Including c8or shoot4 & Datei >anuary & # &001

o4 NDA &1:&09# 'ostappmvM commentB

1* rgent J* par evie8 Oplonge Comment 0'lease eply 0'lease ecycle

,2IS DOC -EN, IS IN,ENDED ON= 7O ,2E SE O7,2E 'A , ,OM2O- rrIS ADD ESSED AND -A CON,AN IN7O -A,ION ,2A,ISW' IUI=ECED. CON7IDEN,IA= AND ' O,EC,ED 7 O- DISC=OS E NDE A''=ICAB=E =AM. Ifyou are not the addressee# or aperson authori6ed to doiivcr the doc8nent to the addressee# youam here$ynotified ftt any mvie8# disclosam. disscmination or other action $ased on the content of the communication is not authori6ed. If youhave received this documetit inerror#please immediatelynotify us $y telophone and return itto us at the a$ove addmss $y mail. 0 Cominents: 'lease refer to your >anuary 1 # &001 su$missionregarding your drugproduct ,emodarOD !temo6olomide% C psulcs.

'er your reHues here amthe post approval comments# 8hich8ere included 8ith the August II# 1999 approval letter for ,omodar Capsides.

Schering8ill conduct a study according to the follo8ingprotocol4

VAphase UI2 randomi6ed study of radiation therapy and temo6olomide versus radiation therapy and BCN versus mdiadon therapy and temo6olomide and BCN for miaplasfic astrocytotnaXW. ,he stagstical muslysis plonfor this study 8ill $e performed according to your su$mission dated >uly 19#1999.

In addition# as agreed upon inyour letter dated August 1999# you 8ill provide the 'hase 1(11 safety data to support the dosing schedule in the com$ination armof the trial and agree that initiation ofthe com$ination arin 8ila $e contingeat on 7DAapproval toproceed. 7urthennore#

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NDA &1:0&9 'age & >anuaiy &+# &001

Ou COmmitted to completing the t8o mcinOthOrO' ams of the trial inthe event that the c:om$inafion arm is stopped for any remn. 7inal stMy reports should $e su$mitted to ENS NDAas a supplemental application. 7or tidministrative purposes# all su$missions relating to this 'hase commitmont must $e clearly designated VSu$'art 2 'hme Commitments.:

If ou have any Huestions regarding this trammission# please contact me at *01:+9 :+/+0.

Sean Bradley# .'h.

"g:ulatory 'r:o;ect- Ygcr

Att/ 5 e t 1 ( ! t&

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Att/ 5 e t 2

DE'A ,-EN, O7 2EA=,2 Y 2 -AN SE UICES 'u$lic 2ealth Service

7oodand $rug Administration oc ville# -D &03+/

NDA:&1:0&9 -A y ;Ai#ZEt Jv; iN" Schering Corporation &000 "alloping 2ill oad enil8orth# N> 0/0** 99

Attention4 -ary >ane Nehring Senior Director -at eted 'roducts Support

Dear -s. Nehring4

Me refer toyour ne8 dnig apphcation!NDA% su$mitted under section+0+!$% of the 7ederal 7ood# Drug# and Cosmetic Act for ,emodar !temo6olomide% capsules.

Me have received your su$missiondated -ay 9# &001# mgarding the follo8ing postmar eting study commitrnents.

I . Acommitment for a 'hase I(11 randomi6ed study ofradiation therapy and temo6olomide versus radiation therapy aiid BCN versus radiation therapy and temo6olomide and BCN for anaplastic astrocytoma. ,he statistical analysis plan for this study 8ill $e performed according tofirmWs su$mission dated >uly 19# 1999.

S,A, S4 gtudy ongoing scheduled cotnpletion is >une *0# &00/.

&. Acommitment to# provide the 'hase 1(11 safety data to support the dosing schedule in the com$ination armof the trial aiid agree that initiation ofthe com$inationarm8ill$e contingent on 7DAapproval to proceed. 7urthermore# the 7irmconu:nits to completing the t8o monotherapy arms of the trial inthe event that the com$ination armis stopped for any reason.

S,A, S4 Study ongoing scheduled completion is >une *0# &00 1.

*. 'ediatric :1&0 day committnent

S,A, S4 7DA issued 'ediatric Mritten eHuest >anuary &+# &001. Applicant reHuested revision onApril &/# &00 1 VgrantedV letter issued August & # &001.

'age 1 of &0


19/22


20/22

Att/ 5 e t 3+ Ge!. / 5$ #! /t$! ! 7$te7 (St %6 9;-13&G ! N/ e C$t6 St/te C! t 6

ansas City CCO' ansas City -OUirginia -ason -edical Center Seattle MAMest -ichigan Cancer Center CCO' alama6oo -I

-etro:-N CCO' -inneapolis -NCancer esearch for the O6ar s Springfield -O-t. Sinai Comprehensive Cancer Center CCO' -iami 7=-ayo Clinic ochester -NOncology Institute of "reater =afayette =afayette =A,he Mendt egional Cancer Center of the 7inley 2ospital Du$uHue IA

a ima Ualley -emorial 2osp a ima MA'rovidence Cancer ,herapy Center Anchorage A Sutter 2ealth Mestern Division Cancer esearch "roup "reen$rae CA'eninsula 2ospital Y -edical Center Burlingame CA

niversity of ochester ochester N7inger =a es adiation Oncology 'C Clifton Springs N

niversity of entuc y 2ospital =e)ington

Southeast Cancer Control Consortium# Inc. CCO' Minston:Salem NC,homas >efferson niversity 2ospital 'hiladelphia 'A=utheran "eneral 2ospital 'ar idge I=

niversity of Misconsin 2ospital -adison MI-arshfield Clinic -arshfield MIColum$ia 2ospital:St. -aryWs -il8au ee MIUirtua -emorial 2ospital Burlington County -ount 2olly N>2alifa) 2ospital OC Dayton Beach 7=-c"ill niversity -ontreal Canada

Notre Dame 2ospital( niversity of -ontreal -ontreal CanadaMyoming Ualley 2ealth Care System : 2ospital Mil es Barre 'A-ontefiore -edical Center Bron) NA ron City 2ospital A ron O2Emory niversity Affiliated 2ospitals Atlanta "ABeth Israel -edical Center Ne8 or N&1st Century Oncology# Inc. 7t. -yers 7=

niversity of =ouisville =ouisvilleUander$ilt niversity -edical Center Nashville ,N

niversity of -iami -iami 7=Mashington niversity St. =ouis -O

niversity of Ala$ama at Birmingham -edical Center Birmingham A=niversity of Cincinnati Cincinnati O2

St =ouis niversity 2ospitals St. =ouis -Opstate Carolina CCO' Spartans$urg SC

-c=aren egional Cancer Center 7lint -Iniversity 2ospitals of Cleveland Cleveland O2

7o) Chase Cancer Center 'hiladelphia 'A-ercy 2ospital Scranton 'A7lorida adiation Oncology "roup >ac sonville 7=St -ary egional Cancer Center =anghorne 'A

eading 2ospital and -edical Center eading 'ADela8are County -emorial 2ospital Dre)el 2ill 'ASt. Eli6a$eth -edical Center Edge8oodSouth >ersey 2ospital Systems Camden N>-onmouth -edical Center =ong Branch N>

'age 13 of &0


21/22

G ! N/ e C$t6 St/te C! t 6niversity of California San 7rancisco San 7rancisco CAniversity of California Davis -edical Center Sacramento CA

-t. Dia$lo -edical Center Concord CA>oe Arrington Cancer esearch Y ,reatment Center =u$$oc ,\=DS 2ospital Salt =a e City ,

7oundation for Cancer esearch and Education 'hoeni) ARDi)ie -edical Cancer Center East St. "eorge ,-emorial 2ospital Colorado Springs CO

North8est Community Clinical Oncology 'rogram ,acoma MA>ohn 7 ennedy -edical Center Edison N>Al$ert Einstein -edical Center 'hiladelphia 'AMa e 7orest niversity Baptist -edical Center Minston:Salem NCIngalls -emorial 2ospital 2arvey I=Central Illinois CCO' Decatur I=,he Schiffler Cancer Center Mheeling MU=ehigh Ualley 2ospital Allento8n 'AAnne Arundel -edical Center Annapolis -D

niversity of ,e)as:-D Anderson Cancer Center 2ouston ,\

"ulf Coast -BCCO' -o$ile A=St. Anthony Cancer Care Institute at St. Anthony 2ospital O lahoma City O ,he Christ 2ospital Cincinnati O2-D Anderson Cancer Center : Orlando Orlando 7=-ary Bird 'er ins Cancer Center Baton ouge =ACleveland Clinic 7oundation Cleveland O2

Natalie Marren Bryant Cancer Center at St. 7rancis 2ospital ,ulsa O niversity of ,e)as -edical Branch "alveston ,\

-edical College of Misconsin -il8au ee MICommunity -emorial 2ospital -enomoee 7alls MI"underson Clinic =acrosse MI-ethodist Cancer Center Omaha NEMestern 'ennsylvania 2ospital 'itts$urgh 'ASt. Uincent egional Cancer Center CCO' "reen Bay MICross Cancer Institute : niversity of Al$erta Al$erta Canada2enry 7ord 2ospital Detroit -IMayne State niversity Detroit -I

North8est Community 2ospital Arlington 2eights I=-ichigan Cancer esearch Consortium CCO' Ann Ar$or -I

niversity of tah 2ealth Science Center Salt =a e City ,"reen -ountain Oncology "roup Bennington U,

niversity of South Ala$ama Cancer Center CCO' -o$ile A=Dartmouth 2itchcoc -edical Center 2anover N2Baptist 2ospital of -iami -iami 7=Christiana Care 2ealth Services# Inc. Christiana DE

Dayton CCO' Dayton O2Bay Area ,umor Institute CCO' Oa land CAniversity of Mestern Ontario =ondon# Ontario Canada

Alta Bates 2ospital Comprehensive Cancer Center Oa land CACalifornia 'acific -edical Center San 7rancisco CACancer Care Center# Inc Salem O2-ayo adiation Oncology Center >ac sonville 7=Cancer ,reatment Center Mooster O2Cotton8ood 2ospital -urray ,

'age 19 of &0


22/22

Att/ 5 e t 4+ S$te7 / t$ $ /t$ . $ t5e 7/ et6 /77e77 e t (St %6 9;-13&G ! N/ e C$t6 St/te

ansas City CCO' ansas City -O-etro:-N CCO' -inneapolis -NCancer esearch for the O6ar s Springfield -O

Southeast Cancer Control Consortium# Inc. CCO' Minston:Salem NC,homas >efferson niversity 2ospital 'hiladelphia 'A=utheran "eneral 2ospital 'ar idge I=

ochester "eneral 2ospital ochester Nniversity of Misconsin 2ospital -adison MI

Uander$ilt niversity -edical Center Nashville ,Nniversity of California Davis -edical Center Sacramento CA

>oe Arrington Cancer esearch Y ,reatment Center =u$$oc ,\7oundation for Cancer esearch and Education 'hoeni) ARDi)ie -edical Cancer Center East St. "eorge ,Ma e 7orest niversity Baptist -edical Center Minston:Salem NCIngalls -emorial 2ospital 2arvey I=

Central Illinois CCO' Decatur I=Cleveland Clinic 7oundation Cleveland O2

Natalie Marren Bryant Cancer Center at St. 7rancis 2ospital ,ulsa O niversity of ,e)as -edical Branch "alveston ,\niversity of tah 2ealth Science Center Salt =a e City ,

Dayton CCO' Dayton O2

3936B2 04 Schering-Temodar

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