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Patient burden and clinical advances associated with postapproval monotherapy cancer drug trials: a retrospective cohort study
  1. Benjamin Gregory Carlisle1,
  2. Adélaïde Doussau1,
  3. Jonathan Kimmelman2
  1. 1 Biomedical Ethics, McGill University, Montreal, Quebec, Canada
  2. 2 Biomedical Ethics Unit / SSOM, McGill University, Montreal, Quebec, Canada
  1. Correspondence to Dr Jonathan Kimmelman; jonathan.kimmelman{at}


Objectives After regulatory approval, drug companies, public funding agencies and academic researchers often pursue trials aimed at extending the uses of a new drug by testing it in new non-approved indications. Patient burden and clinical impact of such research are not well understood.

Design and setting We conducted a retrospective cohort study of postapproval clinical trials launched within 5 years after the drug’s first approval, testing anticancer drugs in monotherapy in indications that were first pursued after a drug’s first Food and Drug Administration (FDA) license, for all 12 anticancer drugs approved between 2005 and 2007. FDA, Medline and Embase search date 2019 February 12.

Primary and secondary outcome measures Our primary objective was to measure burden and clinical impact for patients enrolling in these trials. Each trial was sorted into a ‘trajectory’ defined by the drug and cancer indication. The risk was operationalised by proportions of grade 3–4 severe adverse events and deaths. The clinical impact was measured by estimating the proportion of patients participating in trajectories that resulted in FDA approval, uptake into National Comprehensive Cancer Network (NCCN) clinical practice guidelines or advancement to randomised controlled trials within 8 years.

Results Our search captured 104 published trials exploring monotherapy, including 69 unique trajectories. In total, trials in our sample enrolled 4699 patients. Grade 3–4 adverse events were experienced by 19.6% of patients; grade 5 events were experienced by 2.8% of patients. None of the trajectories launched after initial drug approval received FDA approval. Five trajectories were recommended by the NCCN within 8 years of the first trial within that trajectory. Eleven trajectories were advanced to randomised controlled testing.

Conclusions The challenges associated with unlocking new applications for drugs that first received approval from 2005 to 2007 were similar to those for developing new drugs altogether. Our findings can help inform priority setting in research and provide a basis for calibrating expectations when considering enrolment in label-extending trials.

  • research ethics
  • drug development
  • research efficiency
  • moral efficiency
  • cancer drug development

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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  • Contributors BGC and JK: designed this study; wrote the manuscript. BGC: collected data, performed analyses and produced the figure. AD: reviewed and edited the manuscript. All authors read and approved the final manuscript.

  • Funding This work was funded by CIHR (PJT-148726).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. Extra data can be accessed via the Dryad data repository at with the doi: 10.5061/dryad.zw3r22851.

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