The post hoc use of randomised controlled trials to explore drug associated cancer outcomes: Methodological challenges

Gudrun Stefansdottir, Sophia Zoungas, John Chalmers, Miriam J. Knol, Hubert G M Leufkens, Mark Woodward, Anushka Patel, Diederick E. Grobbee, Marie L. De Bruin

Research output: Contribution to journalArticle

Abstract

Introduction: Drug-induced cancer risk is of increasing interest. Both observational studies and data from clinical trials have linked several widely used treatments to cancer. When a signal for a potential drug-cancer association is generated, substantiation is required to assess the impact on public health before proper regulatory action can be taken. This paper aims to discuss challenges of exploring drug-associated cancer outcomes by post-hoc analyses of Randomised controlled trials (RCTs) designed for other purposes. Methodological Challenges to Consider: We set out to perform a post-hoc nested case-control analysis in the ADVANCE trial in order to examine the association between insulin use and cancer. We encountered several methodological challenges that made the results difficult to interpret, including short duration of exposure of interest, lack of power, and correlation between exposure and potential confounders. Considering these challenges, we concluded that using the data would not enlighten the discussion about insulin use and cancer risk and only serve to further complicate any understanding. Therefore, we decided to use our experience to illustrate methodological challenges, which need to be addressed when re-analysing trial data for cancer related outcomes. Conclusion: Substantial amount of information on cancer outcomes is available from RCTs. Hence, making use of such data could save time and spare patients from inclusion in further trials. However, methodological challenges must be addressed to enhance the likelihood of reliable conclusions. Advantages of post-hoc analyses of RCTs include quality of data collected and sometimes randomisation to exposure of interest. Limitations include confounding and sample size, which is fixed to suit the purposes of the trial, insufficient duration of exposure and identification of underlying biological mechanisms relating treatment to cancer to formulate the most appropriate post-hoc study design.

Original languageEnglish (US)
Pages (from-to)371-378
Number of pages8
JournalCurrent Drug Safety
Volume8
Issue number5
StatePublished - Dec 2013
Externally publishedYes

Fingerprint

Randomized Controlled Trials
Pharmaceutical Preparations
Insulin
Neoplasms
Public health
Random Allocation
Sample Size
Observational Studies
Public Health
Clinical Trials
Therapeutics

Keywords

  • ADVANCE
  • Cancer
  • Insulin
  • Methodological issues
  • Post-hoc analysis
  • Power

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Toxicology
  • Pharmacology

Cite this

Stefansdottir, G., Zoungas, S., Chalmers, J., Knol, M. J., Leufkens, H. G. M., Woodward, M., ... De Bruin, M. L. (2013). The post hoc use of randomised controlled trials to explore drug associated cancer outcomes: Methodological challenges. Current Drug Safety, 8(5), 371-378.

The post hoc use of randomised controlled trials to explore drug associated cancer outcomes : Methodological challenges. / Stefansdottir, Gudrun; Zoungas, Sophia; Chalmers, John; Knol, Miriam J.; Leufkens, Hubert G M; Woodward, Mark; Patel, Anushka; Grobbee, Diederick E.; De Bruin, Marie L.

In: Current Drug Safety, Vol. 8, No. 5, 12.2013, p. 371-378.

Research output: Contribution to journalArticle

Stefansdottir, G, Zoungas, S, Chalmers, J, Knol, MJ, Leufkens, HGM, Woodward, M, Patel, A, Grobbee, DE & De Bruin, ML 2013, 'The post hoc use of randomised controlled trials to explore drug associated cancer outcomes: Methodological challenges', Current Drug Safety, vol. 8, no. 5, pp. 371-378.
Stefansdottir G, Zoungas S, Chalmers J, Knol MJ, Leufkens HGM, Woodward M et al. The post hoc use of randomised controlled trials to explore drug associated cancer outcomes: Methodological challenges. Current Drug Safety. 2013 Dec;8(5):371-378.
Stefansdottir, Gudrun ; Zoungas, Sophia ; Chalmers, John ; Knol, Miriam J. ; Leufkens, Hubert G M ; Woodward, Mark ; Patel, Anushka ; Grobbee, Diederick E. ; De Bruin, Marie L. / The post hoc use of randomised controlled trials to explore drug associated cancer outcomes : Methodological challenges. In: Current Drug Safety. 2013 ; Vol. 8, No. 5. pp. 371-378.
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