title: Assessing the clinical benefits of erythropoietic agents using area under the hemoglobin change curve.
abstract: BACKGROUND
  In assessing erythropoietic agents for chemotherapy-induced anemia, traditional single time-point end points (e.g., hematopoietic response [HR]) fail to reflect clinical benefits over the entire therapy course. Area under the hemoglobin change curve (Hb AUC) is introduced as an alternative measure, and its reliability, clinical significance, and superiority are assessed.
  
  
  METHODS
  Using data from a phase IV open-label epoetin alfa (EPO) trial, we tested Hb AUC reliability by comparing its values derived from primary patient data with those derived from aggregated data. Clinical significance of the Hb AUC was investigated in three phase IV EPO trials by examining the linear relationship between Hb AUC quartiles and established clinical end points. The superiority of the Hb AUC over HR in its association with blood transfusion was tested through logistic regressions and area under the receiver operating characteristic (ROC) curve analysis.
  
  
  RESULTS
  The Hb AUC values derived from patient and aggregated data were similar. Strong and statistically significant linear trends of decreasing transfusion requirements, increasing quality-of-life improvements, and decreasing time to HR were found across Hb AUC quartiles. The Hb AUC rendered the HR variable insignificant when both were present in the same model. Area under the ROC curve analysis supported the superior performance of the Hb AUC.
  
  
  CONCLUSIONS
  We found that the Hb AUC is an objective, reliable, clinically meaningful, and comprehensive summary statistic that may be used to quantify clinical benefits for patients receiving erythropoietic agents. Further prospective validation of the Hb AUC metric is recommended.
authors.affiliation: Analysis Group, Inc., 111 Huntington Avenue, Tenth Floor, Boston, Massachusetts 02199, USA. mduh@analysisgroup.com
authors.forename: Mei Sheng
authors.initials: MS
authors.lastname: Duh
authors.forename: Patrick
authors.initials: P
authors.lastname: Lefebvre
authors.forename: John
authors.initials: J
authors.lastname: Fastenau
authors.forename: Catherine Tak
authors.initials: CT
authors.lastname: Piech
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Waltzman
mesh_terms: D000740:Anemia / Q000139:chemically induced / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D017326:Clinical Trials, Phase III as Topic; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006397:Hematinics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006454:Hemoglobins / Q000187:drug effects*; D006801:Humans; D008297:Male; D011994:Recombinant Proteins; D015203:Reproducibility of Results; D012307:Risk Factors; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D006397:Hematinics; D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa