186 CHAPTER 9 trials received a boost.38–42 Therefore, it is obvious that a uniform and international definition may boost the reversal of the ‘inverse research law’. Hence, providing a clear and internationally accepted definition is a crucial first step, albeit more is needed for substantial reversal. As a next step, we need to look critically at how research is conducted. At the moment, due to the lack of proper research in specific populations, existing clinical guidelines are largely based on expert opinions which are derived from results of RCTs that are generalised to other populations or from results of observational studies.43 However, as described in the General Introduction under the heading Frailty and the consistent lack of evidence and in the General Discussion under the heading The ‘inverse research law’, results from RCTs cannot simply be generalised to another population and observational studies often suffer from confounding bias. Therefore, this is not the solution to the reversal of the ‘inverse research law’. Another option is to develop an RCT for each research question and for each specific population group. In theory, this would be the best option, except for the fact that conducting so many different RCTs would be incredibly resource intensive. Currently, a lot of attention is given to diversity within RCTs to make the study population a reflection of the entire patient population in society. This, however, causes significant heterogeneity, which may eventually lead to difficulties in interpreting study results. The best way to reverse the ‘inverse research law’ in terms of conducting research is creating diversity between RCTs. As mentioned before, the four pivotal NOAC trials were performed in the same population. Testing medicines with a similar mechanism of action four times in a similar population might be considered ‘research waste’ and exposes more patients to a trial than necessary. Ideally, testing each medicine with a similar mechanism of action in a different population would enormously enrich the evidence, and thus clinical applicability. Imagine a series of trials would be organised differently: one medicine would be tested in men, a second in women and a third in frail older patients. Of course, such a trial strategy is only possible with medicines that have a similar mechanism of action. In addition, it is important that the study populations of the individual RCTs together properly reflect the whole population in society that is affected by the disease. In such a way organised, generalisation of results is based on evidence and no longer on speculations. However, history seems to repeat itself: the fact that the frail and old Mrs. de Jong is eligible to participate in a factor XI inhibitor RCT funded by the pharmaceutical industry appears to be an important development at first sight. But again, the inclusion and exclusion criteria of different RCTs testing a factor XI inhibitor with a similar mechanism of action are very similar.44–46 As described above, this will most likely lead to the inclusion of very similar populations of patients leading to ‘research waste’ and unnecessary patient exposure, while leaving society with similar questions for other specific populations. This hampers the reversal of the ‘inverse research law’.
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