How to address the challenges of evaluating treatment benefits-risks in rare diseases? A convergent mixed methods approach applied within a Merkel cell carcinoma phase 2 clinical trial

Orphanet J Rare Dis. 2018 Jun 18;13(1):95. doi: 10.1186/s13023-018-0835-1.


Background: Demonstrating treatment benefits within clinical trials in the context of rare diseases is often methodologically and practically challenging. Mixed methods research offers an approach to overcome these challenges by combining quantitative and qualitative data, thus providing a better understanding of the research question. A convergent mixed methods design in the context of Merkel cell carcinoma, a rare skin cancer, was used during the JAVELIN Merkel 200 trial (NCT02155647).

Methods: Nine patients receiving avelumab in the JAVELIN Merkel 200 trial were interviewed at baseline prior to receiving study treatment, and at 13 weeks and 25 weeks after first avelumab administration. Key concepts of interest identified from the baseline interviews were physical functioning, fatigue/energy, and pain. Patient perceptions of the overall change in their cancer-related health status since starting study treatment were also recorded. During qualitative analysis, at each time-point, each concept of interest was assigned a category describing the trend in change (e.g. newly emerged, no change/stable, improved, worsened, ceased/disappeared). In parallel, patients' tumour status was determined by the clinical overall response status as per the clinical trial protocol.

Results: A high concordance between patient-reported qualitative data and assessed tumour response was observed. All eight patients who clinically improved had perceived a subjective improvement in their disease since the beginning of the study; the single patient whose disease worsened had a perceived deterioration. Patient perceived benefit in physical functioning, fatigue/energy and pain was subsequent to the measured change in clinical status as assessed by tumour response. This suggests that patient-reported assessment should be examined over the long term in order to optimally capture meaningful treatment effect.

Conclusion: Embedding qualitative research in clinical trials to complement the quantitative data is an innovative approach to characterise meaningful treatment effect. This application of mixed methods research has the potential to overcome the hurdles associated with clinical outcomes assessment in rare diseases.

Keywords: Merkel cell carcinoma; Mixed methods research; Qualitative outcomes; Quantitative outcomes; Treatment meaningfulness.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Carcinoma, Merkel Cell / drug therapy*
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Rare Diseases / drug therapy*
  • Risk Assessment
  • Skin Neoplasms / drug therapy*


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • avelumab

Associated data