The Beneficial Effects of Taking Part in International Research: an Old Chestnut Revisited

Two recent and well-written articles grapple with this question of whether or not clinical trials are beneficial, net of any benefit conferred by the therapeutic modalities evaluated in those trials.[1] [2]

The first study from the Netherlands concerns the effect of taking part in clinical trials where controls are made up of people not participating in trials (presumably because they were not offered entry in the trial).[1] This is the topic of a rather extensive literature, including a study to which I contributed.[3] The latter study found that the putative ‘trial effect’ applied only in circumstances where care given to control patients was not protocol-directed. In other words, our results suggested that the ‘trial effect’ was really a ‘protocol effect’. In that case the effect should be ephemeral and disappear as greater proportions of care become protocolised. And that is what appears to have happened – Lin, et al.[1] report no benefit to trial participants versus non-trial patients for the highly protocolised disease Hodgkin lymphoma. They speculate that while participation in trials does not affect individual patient care in the short-term, hosting trials does sensitise clinicians at an institutional level, so that they are more likely than clinicians from non-participating hospitals to practice evidence-based care. However, they offer no direct evidence for this assertion. Such evidence is, however, provided by the next study.

The effects of high participation rates in clinical trials at the hospital level is evaluated in an elegant study recently published in the prestigious journal ‘Gut’.[2] The team of authors (that includes prominent civil servants and many distinguished cancer specialists and statisticians) compared outcomes from colon cancer according to the extent to which the hospital providing treatment participated in trials. This ingenious study was accomplished by linking the NIHR’s data on clinical trials participation to cancer registry data and Hospital Episode Statistics. It turned out that risk-adjusted survival was significantly better in the high participation hospitals than in lower participation hospitals, even after substantial risk-adjustment. “Residual confounding” do I hear you say? Perhaps, but the authors have two further lines of evidence for the causal explanation. First, they documented a dose-response; the greater the level of participation, the greater the improvement in survival. Of course, an unknown confounder that was correlated with participation rates would produce just such a finding. The second line of evidence is more impressive – the longer the duration over which a hospital had sustained high participation rates, the greater the effect. Again, of course, this argument is not impregnable – duration might not serve as a good Instrumental Variable. How might the case be further strengthened (or refuted)? By unravelling the theoretical pathway between explanatory and outcome variables.[4] Since this is a database study, the process variables that might mediate the putative effect were not available to the authors. However, separate studies have indeed found an association between improved processes of care and trial participation.[5] Taken in the round, I think that a cause/effect explanation holds (>90% of my probability density favours the causal explanation).

— Richard Lilford, CLAHRC WM Director

References:

  1. Liu L, Giusti F, Schaapveld M, et al. Survival differences between patients with Hodgkin lymphoma treated inside and outside clinical trials. A study based on the EORTC-Netherlands Cancer Registry linked data with 20 years of follow-up. Br J Haematol. 2017; 176: 65-75.
  2. Downing A, Morris EJA, Corrigan N, et al. High hospital research participation and improved colorectal cancer survival outcomes: a population-based study. Gut. 2017; 66: 89-96.
  3. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”. J Clin Epidemiol. 2001; 54(3): 217-24.
  4. Lilford RJ, Chilton PJ, Hemming K, Girling AJ, Taylor CA, Barach P. Evaluating policy and service interventions: framework to guide selection and interpretation of study end pointsBMJ. 2010; 341: c4413.
  5. Selby P. The impact of the process of clinical research on health service outcomes. Ann Oncol. 2011; 22(s7): vii2-4.
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