title: From bench to bedside: a review of the clinical trial development plan of drotrecogin alfa (activated).
abstract: OBJECTIVE
  To provide a comprehensive overview of the various clinical trials of drotrecogin alfa (activated) (DrotAA) completed by Eli Lilly and Company over the past 10 years.
  
  
  METHODS
  Eli Lilly and Company data from phase 1 through phase 4 trials, observational studies, and compassionate-use studies of DrotAA were reviewed. Safety, efficacy, and pharmacokinetic data were included. The review excluded pediatric studies and studies recently concluded where the manuscript was in press. All studies included in the review were approved by the ethical review boards at the participating institutions.
  
  
  RESULTS
  Over 9000 adults with severe sepsis have been enrolled in DrotAA clinical trials through December 2005 and the results of the clinical evaluation of DrotAA have been widely disseminated in publications. Analyses of the data indicate that the pharmacokinetics of DrotAA are both linear and dose-proportional. The phase 2 and phase 3 studies of administration of DrotAA to patients with severe sepsis demonstrated a significant reduction in mortality and were associated with a favorable benefit/risk profile. Three of these trials (a phase 2 and two phase 3, PROWESS and ENHANCE) evaluated the effect of DrotAA in adult patients with sepsis associated with acute organ dysfunction (severe sepsis) while another phase 3 trial (ADDRESS) was conducted in the non-indicated population of adult patients with severe sepsis associated with a lower risk of death. A phase 4 trial demonstrated no significant difference in steady-state plasma concentrations or elimination half-life of DrotAA between patients < or =135 kg and >135 kg, indicating that DrotAA should be dosed by actual body weight.
  
  
  CONCLUSIONS
  The challenges and limitations of the clinical development plan for DrotAA are discussed.
  
  
  CONCLUSIONS
  DrotAA is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death. DrotAA is not indicated in adult patients with severe sepsis and low risk of death. The clinical plan for DrotAA continues with a focus on tailored therapy and identifying the most appropriate patients for DrotAA treatment.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Short
authors.forename: Douglas
authors.initials: D
authors.lastname: Schlichting
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Qualy
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D005500:Follow-Up Studies; D006801:Humans; D011486:Protein C / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy*
chemical_list: D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated