The tendency to group and categorize phenomena in dichotomies seems to be an inherent feature of our species. We have even dichotomized our bodies into the mind and the body. Other dichotomies such as nature/nurture, emotional/rational, induction/deduction, learn/instinct ossify into naturalized and distinct categories. The consequence of this naturalization is that they operate at below the level of consciousness and we forget that they are normative and represent range limits. At best, they are immensely contextual and optimally should be judged by the criteria of fitness for purpose. Ancient Greek skepticism and Buddhist logic provided an antidote to this trap. The fourfold negation or the tetralemma is a “meta”-framework that not only expands the range of possibilities and diminishes the effects of false dichotomies, but also lays stress on the investigation of causes and relations. It nudges our mental framework away from if-then boundaries, categories, and universals and into nuance, context, and continuums. The basic structure of the tetralemma is such:
A is true
B is true
Neither A or B are true
Both A and B are true
In the last two essays, I discussed the advantages and disadvantages of big real world evidence (RWE) and double blind randomized clinical trials (dbRCT). Proponents and naysayers lie on both ends of the choice. However, this might represent a false dilemma: both sources of evidence generation may be valuable, one may be more valuable than the other in certain contexts, or neither may be valuable as a hybrid methodology.
The pragmatic clinical trial (PCT) is just such a hybrid methodology of evidence generation. While not a new methodology, it has not been adopted widely thus far. Nonetheless, as push and pull incentives favor real world evidence generation, the PCT has increasingly gained prominence in the biomedical research community. PCT combines elements of RCT – treatments assigned by protocol, randomization, data collection on report forms – with elements of non-interventional studies from real clinical settings, more representative (ie multimorbid) patient populations, and passive and unsupervised data collection typical of RWE. Although unknown to most outside the research community, the effectiveness of vaccines was validated by such a trial. In 1954, the polio vaccine trial randomized nearly 650,000 children to a treatment and a placebo arm while simultaneously following more than a million children as “observed” controls. Evidence for the effectiveness of the polio vaccine was generated by a PCT and the use of the dual protocol ensured internal and external validity of the results. Thus there was robust evidence to extrapolate the results to the population in large.
The philosopher Michael Serres writes that the task of the philosopher is to “keep open and explore the spaces that otherwise would be left dark and unvisited…since new forms of knowledge might arise out of these spaces.” The tetralemma is such an exploration – a framework that serves as a reminder to look around, between, and beyond the static, naturalized, and reified dichotomies that pervade our world. If real world evidence borne on real world big data and protocolled, double blinded randomized clinical trials represent the ends of the polarity, then a pragmatic clinical trial is a hybrid – representing the “both” in the tetralemma. Optimally, evidence should be considered by each – either individually or in combination – for specific use cases and particular contexts. As medicine moves towards the cadence and volume of data inherent in the realm of big data, a static evidence hierarchy represented by the evidence pyramid as a marker for evidence quality might be relegated to the “ash heap of history.”