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  1. Backup Slides

  2. Physiology of Anemia

  3. 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 • Stratified Randomization by • Prior adjuvant anthracycline • Her-2 Neu status • DFS Interval between initial diagnosis and metastatic disease

  4. 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)

  5. 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 breast recurrence, remission rate Aranesp Dose Dense + Intense E→T→CMF Transfusion Support • Randomized, Open Label, Multifactorial • 1° and 2° Endpoints: • Q 21 vs Q 14 Dose Intense chemo • Influence of Aranesp vs Supportive Care on 1° and 2° endpoints is also a 2° endpoint Target Hgb 12-13 Study DE2001-0033 E=epirubicin, C=cyclophosphamide, T=paclitaxel, M=MTX, F=5FU

  6. AGO Neoadjuvant Breast (PREPARE) • Trial presented at ODAC 2004 • Accrual June 2002 - March 2005 • Results not available • Limitations • Primary Data not provided to FDA • Open Label • Multifactorial • M0 status confirmed by CXR, Abd US, Bone Scan • Inadequate follow up surveillance for recurrence • Off-label Aranesp dose + dose adjustments • No routine assessment of TVEs Study DE2001-0033

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

  8. WSG Adjuvant Breast (ARA-03) • Limitations • Heterogeneous chemotherapy regimens; no attempt to stratify • Open Label • M0 status confirmed by CXR, Abd US, Bone Scan • Inadequate follow up surveillance for recurrence • Off-label Aranesp dose + dose adjustments • No routine assessment of TVEs Study DE 2002-0015

  9. GELA DLBCL (LNH03-6B) 1° Objective EFS (Q 14 vs Q 21) Aranesp R-CHOP Q 14 x 8 + MTX IT x 4 Transfusion or Aranesp if Hgb≤9 DLBCL N=328 of planned 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 vs Q 14 Dose Intense chemo • Control arm could receive Aranesp Target Hgb 13-15 Study FR 2003-2005

  10. GELA DLBCL (LNH03-6B) • Accrual began December 2003; ongoing • Interim results on 130 patients-1 yr OS, 1 yr EFS no difference observed • Design Problems • Control arm could receive Aranesp • Multifactorial • Open Label • Response Rate and DFS not clearly defined • Criteria for tumor response or progression not provided • Off-label Aranesp dose + dose adjustments • No routine assessment of TVEs Study FR 2003-2005

  11. 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)

  12. Common Limitations • Excessively high Target Hgb • Off Label Epoetin alfa dosage and dose adjustments • Inadequate radiological assessments to assess for recurrence • No routine assessment for TVEs • Open Label • Primary data not submitted to FDA on trials that have finished enrollment

  13. 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 presented at ODAC 2004 Accrual August 1999 – April 2002 Terminated early due to slow accrual (goal = 800 pts)

  14. EPO-GBR-7 Head/Neck Result summary from J&J, April 2006 • No significant differences for local recurrence in or outside the RT field, 1 yr OS, RR

  15. EPO-GBR-7 Head/Neck • Limitations • Primary Data not given to FDA • No result for Primary Endpoint, 2 yr local DFS • Assessment method and the frequency of testing for local recurrence was inadequate • Suspected recurrences did not need biopsy • Assessment of Survival was not required for subjects withdrawn from study • Response judged from clinical assessments only • Dose and dose adjustments off-label • Target Hgb excessively high • No routine TVE assessments

  16. 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 presented at ODAC 2004 Accrual June 2000-October 2003 Terminated early due to DMC trend to lower LRC and OS in Procrit arm (goal = 372 pts) LRF-loco regional failure; LRC-loco regional control

  17. RTOG 99-03 Head/Neck Result summary (abstract 2004): • Limitations • Primary Data not given to FDA • No result for Primary Endpoint, 2 yr LRF • Dose adjustments off-label • Frequency of testing for local recurrence inadequate • Target Hgb excessively high • No routine TVE assessments

  18. 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 presented at ODAC 2004 Accrual August 2001-December 2005 Terminated early due to slow accrual (Target = 612 patients)

  19. EPO-GER-22 NSCLC Result summary from J&J, April 2006 • Limitations • Primary Data not given to FDA • No result for Primary Endpoint, 2 yr OS • Dose and dose adjustments off-label • Target Hgb excessively high • No routine TVE assessments

  20. 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 presented at ODAC 2004 Accrual February 2002 – May 2003

  21. EPO-CAN-17 Breast • Results (J&J summary 4/06) Limitations • Primary Tumor Outcome or Survival data not given to FDA • Primary Endpoint: QOL • Open Label • Systematic tumor restaging in Stg IV dz not required post treatment • Length of f/u inadequate • Dose adjustments off-label • Target Hgb excessively high • No routine TVE assessments

  22. 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 presented at ODAC 2004 Accrual January 1999 – March 2001 RFS: Relapse Free Survival TTF: Time to Treatment Failure

  23. AGO/NOGGO Results (J&J summary 4/06) 5 year RFS (primary endpoint), OS, TTF: not reported • Limitations • Primary Data not given to FDA • Open Label • Dose adjustments off-label • Target Hgb excessively high • No routine TVE assessments

  24. 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

  25. 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

  26. Non-Myeloid Malignancy (2003-0232) • Results (FDA review of primary data) • No significant difference in OS ( HR 0.82 [95% CI 0.43, 1.57]). • Limitations • Primary endpoint: % transfusions • Data collection not adequate • No long term follow-up plan • Dosing was off-label in dose (300 µg Q3W) and adjustments • Heterogeneous cancer types • Target Hgb excessively high • No routine TVE assessments

  27. 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 type and hormonal status Accrual November 2002 – June 2004

  28. BRAVE (Breast) • Results (summary results) • OS no significant difference (HR 1.07, 95% CI 0.87, 1.33; p=0.522) • PFS no significant difference (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 data not supplied to FDA • Protocol not submitted to FDA • Target Hgb 13-15 • No routine TVE assessments

  29. 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 recurrence (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

  30. Moebus (Breast) • Results • 5 yr OS and DFS: no significant difference • ↑ TVE in ESA arm (3.0% vs 1.7%) • Limitations • Primary data not submitted to FDA • Inadequate study endpoints • Multifactorial • Inadequate frequency of radiographic assessments • Dosing adjustments off label • No routine TVE assessments

  31. TVE Risks • There are increased risks of TVE with the use of ESAs • Evidence: • EPO-CAN-15 (SCLC) • PR00-03-006 (Gastric/Rectal cancer) • GOG 191 (Cervical cancer) • Rosenzweig (Breast) • Bohlius meta-analysis JNCI April 2006 • SPINE Study • With the exception of EPO-ANE-3010, tumor promotion studies discussed do not routinely assess patients for TVE, & did not specify TVE as prespecified endpoint. • Safety signals for increased risk may be missed

  32. EPO-CAN-15 (SCLC) 1° Endpoint: PFS Chemo Epoetin SCLC (Limited Stg)N=106 2° Endpoints: RR, OS, median survival, LC Chemo Placebo Target Hgb: 14-16 Terminated early due to TVEs TVE OR 7.74 (ESA vs Control) ↑ Mortality (40% vs 19%) in ESA arm

  33. PR 00-03-006 (Gastric/Rectal) 1° Endpoint: % transfusion ChemoRT→surgery Epoetin Gastric/Rectal Ca N=59 2° Endpoints: RR, pCR ChemoRT →surgery Placebo Target Hgb: 14-15 Terminated early due to TVEs TVE OR 3.79 (ESA vs Control)

  34. GOG 191 (Cervical) 1° Endpoint: PFS ChemoRT Epoetin Cervical Ca N=113 2° Endpoints: OS, LC ChemoRT Transfusion Support Target Hgb: 13-14 Terminated early due to TVEs TVE OR 2.65 (ESA vs Control)

  35. Rosenzweig (Breast) 1° Endpoint: Unclear Unclear Epoetin Breast Ca (Stg 4) N=27 2° Endpoints: Unclear Unclear Transfusion Support Target Hgb: Unclear Terminated early due to TVEs TVE 29% vs 0% (ESA vs Control)

  36. JNCI Meta Analysis 2006: TVE

  37. JNCI Meta Analysis 2006: OS

  38. JNCI Meta Analysis • 2005 OS: HR 0.81 (95% CI: 0.67 to 0.99) • 2006 OS: HR 1.08 (95% CI: 0.99 to 1.18)

  39. Final Data/Study Report not received 2008 2007 2003 2006 2009 2001 2012 2004 2002 2010 2005 2011 GBR-7 RTOG 9903* GER-22 CAN-17† AGO* 232‡ PREPARE ARA-03 GELA *=Data never submitted to FDA =Last pt accrued †=Received limited safety data (no efficacy data) ‡=Received primary data =Final Data/Study Report Anticipated

  40. Final Data/Study Report not received *=Data never submitted to FDA †=Received limited safety data (no efficacy data) ‡=Received primary data

  41. Non Inferiority Trials • Purpose is to rule out a prespecified margin of inferiority between ESA and control • In trials with ESAs in cancer pts specifically designed to look for safety signals, non-inferiority design preferable over superiority design Prespecified Margin Inferior Non-inferior 1.0 Worse for Control Worse for ESA Hazard Ratio

  42. Studies Initiated by Amgen or J&J Epoetin alfa Studies ODAC 2004 EPO-ANE-3010 (J&J PMC; Breast) N93-004 (PMC; SCLC) Other Studies Aranesp Studies

  43. Completed studies w/summary results + no reported safety signal • 5 epoetin alfa studies have been completed, and have had summary results submitted to FDA either by a J&J report or by literature publication, and have not reported safety signals • Both FDA and J&J have not analyzed data from these trials • Study Limitations • 3 of the 5 studies have inadequate design to address risk of tumor promotion

  44. Completed studies w/summary results + no reported safety signal Epoetin alfa Studies ODAC 2004 Other Studies Aranesp Studies

  45. Hazards Ratios for Overall Survival by Studies

  46. Meta-Analysis results • Amgen meta analysis used Peto odds ratio, which: • Is based solely on the # of known deaths and total # of pts in each arm • Does not consider pt follow-up and survival times • Is not interpretable since study patients do not have the same study start day