Systems Pharmacovigilance (Panvigilance): Thinking Beyond Location on the Planetary Map in Global Clinical Trials

To the Editor:

Clinical trials are fast-paced time-sensitive operations that generate timely evidence on safety and efficacy of new drug candidates in development. In this context, globalization over the past several decades has promised, in theory, the prospects for inclusion of additional world populations in clinical trials beyond North America and Western Europe. In practice, however, globalization of clinical trials has had mixed motives and drivers.

Expanding the clinical trial participant pool on a planetary scale is laudable for the ethical principle of inclusion and better forecasting of drug pharmacokinetics and pharmacodynamics in diverse populations worldwide. In contrast, sponsor motives for global clinical trials can also be shaped by expediency so as to escape high costs and poor enrollment in a developed country setting and achieve greater speed for participant enrollment. Even in the presence of identical inclusion and exclusion criteria, heterogeneity across geographic sites in worldwide clinical trials and clinical outcomes is very common.

There is emerging evidence that heterogeneity in global clinical trials cannot be narrowly explained by geographic variation. In the case of heart failure trials, for example, country-level income inequality has been noted as an important dimension of variation within global heart failure trials (Greene and Califfe, 2019). Social determinants of health (SDH) (Donkin et al., 2017; Marmot and Bell, 2019) vary both across and within populations worldwide, and thus can result in differences in clinical trial outcomes, despite employing identical inclusion and exclusion criteria.

Global action on the SDH is required to reduce health inequities (Donkin et al., 2017). I suggest that SDH such as income inequality and economic factors, among others, are taken into account in scientific design and multivariate statistical analyses and interpretation of global clinical trials so as to better forecast and explain outcome variance across trial sites.

Integration of biological and SDH is one of the key focus areas for OMICS: A Journal of Integrative Biology as highlighted in numerous articles in the journal over the past many years. Hence, the recent introduction of the concept of panvigilance for pharmaceutical and medicinal product safety is very much in the spirit of in-depth knowledge integration across social and biological determinants of health to achieve systems pharmacovigilance (Şardaş and Kendirci, 2019).

Panvigilance invites the global clinical trial community to rethink the ways in which participants are enrolled in clinical trials to expeditiously obtain the estimates for upper and lower bound limits for pharmacokinetic and pharmacodynamic variability. In practice, panvigilance involves “proactive ‘stress testing’ of new drug candidates in panels of patients or healthy volunteers identified by biomarkers, and who are situated in population edges in terms of pharmacokinetic and/or molecular target interindividual variability” (Şardaş and Kendirci, 2019).

Taken together, although panvigilance encourages integration of biomarkers in global clinical trial design, considering, additionally, that the SDH in clinical trial design and multivariate data analyses would further strengthen drug safety, systems pharmacovigilance, and quality of evidence generated by global clinical trials.

Panvigilance, with its broad mandate for systems thinking and systems pharmacovigilance, is well suited to include biomarkers and SDH in future clinical trial designs and thus rethink participant enrollment including and beyond location on the planetary map.