title: Assessing the benefit-risk of new treatments using generalised pairwise comparisons: the case of erlotinib in pancreatic cancer.
abstract: BACKGROUND
  Efficacy and safety are the two considerations when characterising the effects of a new therapy. We sought to apply an innovative method of assessing the benefit-risk balance using data from a completed randomised controlled trial that compared erlotinib vs placebo added to gemcitabine in patients with advanced pancreatic cancer (NCIC CTG PA.3).
  
  
  METHODS
  We applied generalised pairwise comparisons with several prioritised outcome measures (e.g., one or more benefit outcomes and one or more risk outcomes). Here, the first priority outcome was overall survival (OS) time. Differences in OS that exceeded 2 months were considered clinically meaningful. The second priority outcome was toxicity. The overall treatment effect was quantified using the proportion in favour of erlotinib, which can be interpreted as the net proportion of patients who have a better overall outcome with erlotinib as compared with placebo. Sensitivity analyses were performed.
  
  
  RESULTS
  In this trial 569 patients were randomly assigned in a 1 : 1 ratio to receive gemcitabine plus either erlotinib or a matched placebo. Overall, the method indicated no statistically significant overall treatment effect in favour of erlotinib; if anything, the point estimate of the net proportion leaned in favour of the placebo group (overall proportion in favour of erlotinib=-3.6%, 95% CI, -14.2- 7.1%; P=0.51). The net proportion was never in favour of the erlotinib group throughout all sensitivity analyses.
  
  
  CONCLUSIONS
  Generalised pairwise comparisons make it possible to assess the benefit-risk balance of new treatments using a single statistical test for any number of prioritised outcomes. The benefit-risk assessment was not in favour of adding erlotinib to gemcitabine for the treatment of patients with advanced pancreatic cancer.
authors: 1] Service de biostatistiques, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite F-69310, France [2] CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Université Lyon 1, Villeurbanne, France.
authors: J
authors: J
authors: Péron
authors: 1] Service de biostatistiques, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite F-69310, France [2] CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Université Lyon 1, Villeurbanne, France.
authors: P
authors: P
authors: Roy
authors: NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.
authors: K
authors: K
authors: Ding
authors: NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.
authors: W R
authors: WR
authors: Parulekar
authors: 1] Service de biostatistiques, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite F-69310, France [2] CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Université Lyon 1, Villeurbanne, France.
authors: L
authors: L
authors: Roche
authors: International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.
authors: M
authors: M
authors: Buyse
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D018570:Risk Assessment; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000700:Analgesics; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine