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Backup Slides. Physiology of Anemia. J&J Breast Cancer (EPO-ANE-3010). Design Features Excludes patients who ever had hormonal Rx or who are on anticoagulants Tumor Assessments and Follow Up are adequate Routine Assessment for TVEs included Dosing of epoetin alfa=Procrit label
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Reinforcement Slides

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Physiology of Anemia

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J&J Breast Cancer (EPO-ANE-3010) Design Features Excludes patients who ever had hormonal Rx or who are on anticoagulants Tumor Assessments and Follow Up are satisfactory Routine Assessment for TVEs included Dosing of epoetin alfa=Procrit name Stratified Randomization by Prior adjuvant anthracycline Her-2 Neu status DFS Interval between starting conclusion and metastatic illness

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GBR-7 (H/N) RTOG 9903 (H/N) GER-22 (NSCLC) CAN-20 (NSCLC) CAN-17 (Breast) AGO (Cervical) BEST (Breast) Supportive Safety Studies from J&J ODAC 2004 N93-004 (J&J PMC; SCLC) EPO-ANE-3010 (J&J PMC; Breast) 2001-0145 (SCLC) PREPARE (Breast) ARA-03 (Breast) DAHANCA (H/N) GELA (NHL) PMC Studies from Amgen Henke (Head/Neck)

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AGO Neoadjuvant Breast (PREPARE) Aranesp 1 ° Objectives RFS, OS EC → T q 21 SURGERY Transfusion Support Breast Cancer >2 cm N=720 2 ° Objectives pCR, LN status, in bosom repeat, reduction rate Aranesp Dose Dense + Intense E → T → CMF Transfusion Support Randomized, Open Label, Multifactorial 1 ° and 2 ° Endpoints: Q 21 versus Q 14 Dose Intense chemo Influence of Aranesp versus Supportive Care on 1 ° and 2 ° endpoints is likewise a 2 ° endpoint Target Hgb 12-13 Study DE2001-0033 E=epirubicin, C=cyclophosphamide, T=paclitaxel, M=MTX, F=5FU

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AGO Neoadjuvant Breast (PREPARE) Trial displayed at ODAC 2004 Accrual June 2002 - March 2005 Results not accessible Limitations Primary Data not gave to FDA Open Label Multifactorial M0 status affirmed by CXR, Abd US, Bone Scan Inadequate follow up reconnaissance for repeat Off-mark Aranesp measurement + measurements modification No standard appraisal of TVEs Study DE2001-0033

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WSG Adjuvant Breast (ARA-03) 1 ° Endpoint: EFS TAC or CEF x 6 Aranesp Breast Cancer T1-3 and >3 + LN N=690 of arranged 1234 RT+ Hormones 2 ° Endpoints: OS, Local Relapse TAC or CEF x 6 Transfusion Support Target Hgb >14 Randomized, Open Label Trial exhibited at ODAC 2004 Accrual started January 2004; as of now continuous TAC=Docetaxel, Doxirubicin, Cyclophosphamide CEF=Cyclophosphamide, Epirubicin, 5-FU Study DE 2002-0015

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WSG Adjuvant Breast (ARA-03) Limitations Heterogeneous chemotherapy regimens; no endeavor to stratify Open Label M0 status affirmed by CXR, Abd US, Bone Scan Inadequate follow up observation for repeat Off-name Aranesp measurement + measurement changes No normal evaluation of TVEs Study DE 2002-0015

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GELA DLBCL ( LNH03-6B ) 1 ° Objective EFS (Q 14 versus Q 21) Aranesp R-CHOP Q 14 x 8 + MTX IT x 4 Transfusion or Aranesp if Hgb ≤ 9 DLBCL N=328 of arranged 600 2 ° Objectives RR, DFS, OS, Progression rate, Relapse Rate Aranesp R-CHOP Q 21 x 8 + MTX IT x 4 Transfusion or Aranesp if Hgb≤9 Randomized, Open Label, Multifactorial 1 ° Endpoint: Q 21 versus Q 14 Dose Intense chemo Control arm could get Aranesp Target Hgb 13-15 Study FR 2003-2005

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GELA DLBCL ( LNH03-6B ) Accrual started December 2003; progressing Interim results on 130 patients-1 yr OS, 1 yr EFS no distinction watched Design Problems Control arm could get Aranesp Multifactorial Open Label Response Rate and DFS not plainly characterized Criteria for tumor reaction or movement not gave Off-name Aranesp dosage + measurement conformities No standard appraisal of TVEs Study FR 2003-2005

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GBR-7 (H/N) RTOG 9903 (H/N) GER-22 (NSCLC) CAN-20 (NSCLC) CAN-17 (Breast) AGO (Cervical) BEST (Breast) Supportive Safety Studies from J&J ODAC 2004 N93-004 (J&J PMC; SCLC) EPO-ANE-3010 (J&J PMC; Breast) 2001-0145 (SCLC) PREPARE (Breast) ARA-03 (Breast) DAHANCA (H/N) GELA (NHL) PMC Studies from Amgen Henke (Head/Neck)

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Common Limitations Excessively high Target Hgb Off Label Epoetin alfa dose and measurement alterations Inadequate radiological appraisals to survey for repeat No standard evaluation for TVEs Open Label Primary information not submitted to FDA on trials that have completed enlistment

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EPO-GBR-7 Head/Neck 1 ° Endpoint: 2 yr Local DFS Definitive RT Eprex Head/Neck Cancer (Stage II/III) N=301 2° Endpoint: 1, 2, 5 yr OS Definitive RT Transfusion Support Target Hgb 14.5-15 Randomized, Open Label Trial introduced at ODAC 2004 Accrual August 1999 – April 2002 Terminated ahead of schedule because of moderate collection (objective = 800 pts)

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EPO-GBR-7 Head/Neck Result synopsis from J&J, April 2006 No huge contrasts for neighborhood repeat in or outside the RT field, 1 yr OS, RR

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EPO-GBR-7 Head/Neck Limitations Primary Data not given to FDA No outcome for Primary Endpoint, 2 yr nearby DFS Assessment strategy and the recurrence of testing for neighborhood repeat was lacking Suspected repeats did not require biopsy Assessment of Survival was not required for subjects pulled back from study Response judged from clinical evaluations just Dose and measurements modification off-name Target Hgb unreasonably high No routine TVE appraisals

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RTOG 99-03 Head/Neck 1 ° Endpoint: 2 yr LRF Definitive RT or chemoRT Procrit Head/Neck Cancer (Stage I-IV) N=148 2° Endpoint: OS Definitive RT or chemoRT Transfusion Support Target Hgb 13.5-16 M, 12.5-14 F Randomized, Open Label Trial displayed at ODAC 2004 Accrual June 2000-October 2003 Terminated right on time because of DMC pattern to bring down LRC and OS in Procrit arm (objective = 372 pts) LRF-loco provincial disappointment; LRC-loco territorial control

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RTOG 99-03 Head/Neck Result rundown (conceptual 2004): Limitations Primary Data not given to FDA No outcome for Primary Endpoint, 2 yr LRF Dose changes off-name Frequency of testing for neighborhood repeat deficient Target Hgb unnecessarily high No routine TVE evaluations

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EPO-GER-22 NSCLC 1 ° Endpoint: 2 yr OS Weekly chemo →RT Eprex NSCLC (Stage IIIA/IIIB) N=389 2° Endpoint: Remission Rate, Local Control Weekly chemo→RT Transfusion Support Target Hgb: 12-13 Randomized, Open Label Trial exhibited at ODAC 2004 Accrual August 2001-December 2005 Terminated right on time because of moderate accumulation (Target = 612 patients)

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EPO-GER-22 NSCLC Result outline from J&J, April 2006 Limitations Primary Data not given to FDA No outcome for Primary Endpoint, 2 yr OS Dose and measurement modification off-name Target Hgb exorbitantly high No routine TVE evaluations

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EPO-CAN-17 Breast 1 ° Endpoint: QOL Chemo Eprex Breast Ca (Stage I-IV) N=354 2° Endpoint: RR, OS Chemo Transfusion Support Target Hgb: 12-14 Randomized, Open Label Trial displayed at ODAC 2004 Accrual February 2002 – May 2003

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EPO-CAN-17 Breast Results (J&J outline 4/06) Limitations Primary Tumor Outcome or Survival information not given to FDA Primary Endpoint: QOL Open Label Systematic tumor restaging in Stg IV dz not required post treatment Length of f/u insufficient Dose alterations off-name Target Hgb too much high No routine TVE evaluations

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AGO/NOGGO Cervical 1 ° Endpoint: 5 yr RFS Chemo →RT Eprex SURGERY Cervical Ca (Stage Ib-IIb) N=264 2° Endpoint: OS, TTF Chemo →RT Transfusion Support Target Hgb: 13 Randomized, Open Label Trial displayed at ODAC 2004 Accrual January 1999 – March 2001 RFS: Relapse Free Survival TTF: Time to Treatment Failure

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AGO/NOGGO Results (J&J synopsis 4/06) 5 year RFS (essential endpoint), OS, TTF: not reported Limitations Primary Data not given to FDA Open Label Dose modification off-name Target Hgb too much high No routine TVE appraisals

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Supportive Safety Studies from J&J GBR-7 (H/N) RTOG 9903 (H/N) GER-22 (NSCLC) CAN-20 (NSCLC) CAN-17 (Breast) AGO (Cervical) BEST (Breast) ODAC 2004 N93-004 (J&J PMC; SCLC) EPO-ANE-3010 (J&J PMC; Breast) Other Studies 2001-0145 (SCLC) PREPARE (Breast) ARA-03 (Breast) DAHANCA (H/N) GELA (NHL) PMC Studies from Amgen Henke (Head/Neck) Anemia of Cancer Lymphoid Malignancy Non-Myeloid Malignancy Moebus

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Non-Myeloid Malignancy (2003-0232) Chemo Aranesp 1 ° Endpoint: % transfusion Non-Myeloid Ca N=391 Chemo Placebo Target Hgb: 12-13 Randomized, Double-Blind, Placebo Controlled Stratified by Tumor Type Accrual February 2004 – October 2004 Primary Data submitted March 2007

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Non-Myeloid Malignancy (2003-0232) Results (FDA audit of essential information) No huge contrast in OS ( HR 0.82 [95% CI 0.43, 1.57]). Impediments Primary endpoint: % transfusions Data accumulation not sufficient No long haul follow-up plan Dosing was off-mark in measurement (300 µ g Q3W) and conformities Heterogeneous malignancy sorts Target Hgb too much high No routine TVE evaluations

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BRAVE (Breast) 1 ° Endpoint: OS Chemo Epoetin beta Breast Ca (Stage IV) N=463 2° Endpoint: PFS Chemo Transfusion Support Target Hgb: 13-15 Randomized, Open Label Stratified by chemo sort and hormonal status Accrual November 2002 – June 2004

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BRAVE (Breast) Results (synopsis comes about) OS no noteworthy distinction (HR 1.07, 95% CI 0.87, 1.33; p=0.522) PFS no critical contrast (HR 1.07, 95% CI 0.89, 1.30; p=0.448) TVE higher in ESA arm (13% v 6%, RR 2.36, 95% CI 1,23, 4.55; p=0.01) Limitations Primary information not provided to FDA Protocol not submitted to FDA Target Hgb 13-15 No routine TVE appraisals

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Moebus (Breast) 1 ° Objective: EFS (Q14 v Q21) ∆Hgb Eprex Dose Dense/Intense ETC + GCSF 2 ° Objectives: 5 yr OS and DFS (Q14 v Q21), Intramammary repeat (ESA v control) Transfusion Support Breast Ca (Adjuvant Node +) N=1284 Standard EC->T Multifactorial Accrual January 1999 – March 2001 Target Hgb 12.5-13 Study

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Moebus (Breast) Results 5 yr OS and DFS: no huge contrast ↑ TVE in ESA arm (3.0% versus 1.7%) Limitations Primary information not submitted to FDA Inadequate study

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