Yes, plausibility matters, but biological plausibility is not everything

As explained in my previous post, plausibility matters. The post was predominantly about biological plausibility – but things can be a little more complex, and it would be foolish to deny the fact that there are two kinds of plausibility; biological and clinical.

Biological plausibility concerns compatibility with established physiology, biochemistry, and pathology. It asks whether a credible pathway exists by which an assumed cause could produce an effect. And it takes into account current knowledge from biology and other natural sciences. Within the Bradford Hill framework, biological plausibility helps distinguish mere statistical associations from actual causes. For more details see my previous post.

Clinical plausibility, by contrast, is based on much softer criteria, such as clinical observation and real-world outcomes. Here, the core question is whether a claimed effect fits observed patient patterns, e.g.:

• temporal relationships,
• dose-response gradients,
• reproducibility across cohorts,
• alignment with known clinical phenotypes.

Supported by case series, observational studies, clinical trials, or epidemiological studies, an intervention can be clinically plausible long before its underlying biology is understood. This has historically been the case for many drugs; an apt example is aspirin which has been used clinically long before a biologically plausible mechanism was discovered..

The two forms of plausibility should be complementary. Ideally, a robust causal claim satisfies both mechanistic logic and clinical observation. Biological plausibility without clinical evidence remains speculative. Clinical plausibility without a known mechanism invites skepticism and further inquiry.

The deficit of biological plausibility is a major indictment of many forms of so-called alternative medicine (SCAM). They often offer no tenable mechanism and fail under rigorous testing. Conversely, demanding full mechanistic clarity before accepting consistent clinical data is likely to hinder progress in healthcare.

In relation to so-called alternative medicine (SCAM), the issue was summarised more than 20 years ago as follows:

In summary, the way to prove the efficacy of most CAM therapies is with well-designed RCTs, and there is no reason to believe that clinical trial designs cannot be developed that allow even complex CAM therapies to be evaluated. The procedures involved can be sophisticated, complex and expensive, however, and this confronts investigators with the challenge of identifying which of the myriad of existing and future CAM therapies merit the effort and expense of definitive RCT evaluation. The challenge should be met as it is in conventional drug discovery, through plausibility-building research. Whenever possible, efforts should be made to establish a credible mechanism of action for a candidate CAM therapy, because this will increase its biological plausibility and reduce the risk of false-negative RCT results. When biological plausibility is lacking, clinical plausibility alone must be the basis for determining whether or not to proceed to the costlier phase of definitive RCTs. The creation of a plausibility-building CAM research strategy will require thought, instruction, funding, and collaboration among conventional clinical investigators and CAM advocates. The advantages are many: fairness, low cost and the creation of rules of engagement for CAM evaluation that foster balanced partnerships between CAM advocates and mainstream clinical scientists.

Ultimately, in my view, not a dogmatic stance but a balanced integration of both biological and clinical plausibility should underpin rational decisions about which medical hypotheses to pursue, adopt, or discard.