title: The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?
abstract: BACKGROUND
  The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT-drug development programmes before patent expiration.
  
  
  METHODS
  We identified novel drug-radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time.
  
  
  RESULTS
  The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001).
  
  
  CONCLUSIONS
  Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug-RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes.
authors.affiliation: 1] Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA [2] Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Blumenfeld
authors.affiliation: 1] Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel [2] Department of Radiation Oncology, Sheba Medical Center, Ramat Gan, Israel [3] MSR School of Radiotherapy, Ramat Gan, Israel.
authors.forename: R M
authors.initials: RM
authors.lastname: Pfeffer
authors.affiliation: 1] Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel [2] Department of Radiation Oncology, Sheba Medical Center, Ramat Gan, Israel [3] MSR School of Radiotherapy, Ramat Gan, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Symon
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Denver, CO, USA.
authors.forename: D
authors.initials: D
authors.lastname: Raben
authors.affiliation: 1] Department of Radiation Oncology, Sheba Medical Center, Ramat Gan, Israel [2] MSR School of Radiotherapy, Ramat Gan, Israel [3] Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Y R
authors.initials: YR
authors.lastname: Lawrence
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D059248:Chemoradiotherapy; D017321:Clinical Trials, Phase I as Topic; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D058996:Quality Improvement; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents