title: Benefit, Risk, and Outcomes in Drug Development: A Systematic Review of Sunitinib.
abstract: BACKGROUND
  Little is known about the total patient burden associated with clinical development and where burdens fall most heavily during a drug development program. Our goal was to quantify the total patient burden/benefit in developing a new drug.
  
  
  METHODS
  We measured risk using drug-related adverse events that were grade 3 or higher, benefit by objective response rate, and trial outcomes by whether studies met their primary endpoint with acceptable safety. The differences in risk (death rate) and benefit (overall response rate) between industry and nonindustry trials were analyzed with an inverse-variance weighted fixed effects meta-analysis implemented as a weighted regression analysis. All statistical tests were two-sided.
  
  
  RESULTS
  We identified 103 primary publications of sunitinib monotherapy, representing 9092 patients and 3991 patient-years of involvement over 10 years and 32 different malignancies. In total, 1052 patients receiving sunitinib monotherapy experienced objective tumor response (15.7% of intent-to-treat population, 95% confidence interval [CI] = 15.3% to 16.0%), 98 died from drug-related toxicities (1.08%, 95% CI = 1.02% to 1.14%), and at least 1245 experienced grade 3-4 drug-related toxicities (13.7%, 95% CI = 13.3% to 14.1%). Risk/benefit worsened as the development program matured, with several instances of replicated negative studies and almost no positive trials after the first responding malignancies were discovered.
  
  
  CONCLUSIONS
  Even for a successful drug, the risk/benefit balance of trials was similar to phase I cancer trials in general. Sunitinib monotherapy development showed worsening risk/benefit, and the testing of new indications responded slowly to evidence that sunitinib monotherapy would not extend to new malignancies. Research decision-making should draw on evidence from whole research programs rather than a narrow band of studies in the same indication.
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Carlisle
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Nadine
authors.initials: N
authors.lastname: Demko
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Georgina
authors.initials: G
authors.lastname: Freeman
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Amanda
authors.initials: A
authors.lastname: Hakala
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Nathalie
authors.initials: N
authors.lastname: MacKinnon
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Tim
authors.initials: T
authors.lastname: Ramsay
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Spencer
authors.initials: S
authors.lastname: Hey
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL).
authors.forename: Alex John
authors.initials: AJ
authors.lastname: London
authors.affiliation: Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, QC, Canada (BC, ND, GF, AH, NM, SH, JK); University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada (TR); Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SH); Department of Philosophy and Center for Ethics and Policy, Carnegie Mellon University, Pittsburgh, PA (AJL). jonathan.kimmelman@mcgill.ca.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kimmelman
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D017277:Drug Approval; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D018570:Risk Assessment; D000077210:Sunitinib; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib