Abstract
Real-life clinical research may be more valuable to achieve the aspirations of personalised medicine than the traditional “regulatory style” randomised clinical trials http://bit.ly/2M7vnYT
To the Editor:
The manifesto proposed by Roche et al. [1] is a most important plan to revolutionise respiratory clinical research.
It also prompts a key question about the balance between the effort spent on randomised clinical trials (RCTs) versus real-life research (RLR), particularly in an era where frequent monitoring of patients capturing their real life, using wearable devices, home diagnostics, smartphones, smart inhalers, collections of contextual information, cloud connectivity and the ability to analyse large complex datasets is becoming increasingly feasible [2].
The promise of the perfect RCT is to provide reliable information on whether the use of a new therapy in a well-defined population of subjects provides a significant benefit versus the same population receiving a control. The fundamental conflict of this approach vis a vis the aspirations of personalised medicine is that the “real-life” subject is unlikely to be anything like the hypothetical “mean” or “median” patient in the RCT, even if that real-life subject were to satisfy all the inclusion/exclusion criteria for the population in the RCT. Furthermore, many RCTs fail to use some form of integrated assessment of efficacy and safety, and therefore do not address the possibility that the “responders” to the therapy may be also experiencing undesirable side-effects. Indeed, this is a deficiency fundamentally inherent in the current regulatory approval process in which the individual benefit/risk ratio is rarely evaluated or used as the primary criterion for approval.
RLR is defined by Roche et al. [1] as “research that includes the widest possible range of the target patients population, cared for in naturalistic conditions, with an intensity of follow-up that does not exceed what is provided in routine care”. Such research, if conducted in large numbers of subjects, is eminently suitable to provide the type of information that enables personalised medicine in real-life clinical practice. If the numbers of subjects in such research are sufficiently large to be able to match each patient in the treatment group and control group for many more risk factors than a realistic size RCT would afford, then one can assess prospectively with much greater degree of reliability whether a future subject with the same risk factors is likely to get an attractive benefit/risk ratio from the new intervention. In fact, one could argue that such RLR is more controlled than the traditional RCT, because it controls for many more risk factors! It also removes a key artefact of a typical RCT, which often results in patients in both the treatment and reference groups “feeling better” than they would if they were not in an RCT.
It would seem that much greater investment into RLR associated with collection of the information from such trials into large databases together with analytical tools to extract information from them, will assist in much better decision-making for a personalised approach to respiratory healthcare. This approach may provide a very attractive return on investment for development of new therapies as well and certainly enable their more effective use post-approval through a greater granularity of information about the non-responders and subjects likely to develop side-effects.
While retrospective in its nature, the use of a large registry using “real-life data” enabled Konstan et al. [3] to provide evidence of benefits from the chronic use of ibuprofen in well-defined cystic fibrosis patients through propensity matching while also identifying the group that would unlikely derive a positive benefit to risk ratio [3]. This illustrates well the value of RLR-based databases.
Prospective design of such trials can further improve their credibility. RLR can and should be used to create a seamless continuum between therapeutic development and optimisation of the use of therapies post-approval.
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Supplementary Material
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Footnotes
Conflict of interest: I. Gonda was, until February 2018, the President and CEO of Aradigm Corporation, which has been developing a new treatment for bronchiectasis patients; it was the recognition of the heterogeneity of these patients and the consequent differences in their response to the new therapies that prompted these thoughts about new ways to conduct drug development and the use of new products in clinical practice.
- Received September 20, 2019.
- Accepted October 2, 2019.
- Copyright ©ERS 2020