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Why Do We Need Patient Diversity in Clinical Trials?

Ensuring Drug Safety, First and Foremost, Even Ahead of Drug Efficacy

In the commercialisation of new medications, the paramount legal responsibilities of the pharmaceutical company are, firstly, to prove that the pharmacology is safe and well understood, and, secondly, to prove effective against the targeted disease. Within the European Union, for example, each pharmaceutical company has a Qualified Person for Pharmacovigilance (QPPV) representing them in each country in which they legally operate and market medications. The QPPV is legally responsible for the safety of a pharmaceutical product marketed for human usage in their country and does so by investigating adverse drug reactions (ADRs) – especially life-threatening ones – reported by patients or their physicians in the country, associated with the use of their product(s). The identification of these emerging ‘safety signals’ guarantees the safety profiles of products marketed in that country.

Pharmacovigilance consists of monitoring and ensuring drug safety across what are often diverse populations following a drug’s market authorisation. As an example, in oxidative metabolism (a mechanism by which compounds are broken down in the body), there are extensive population variability in the key cytochrome P450 (CYP450) liver enzymes. A medication’s metabolism and clearance (pharmacokinetics) are important factors when determining the appropriate dosage for clinical efficacy. If an individual patient´s CYP450 enzyme activity is lower than anticipated, they will receive a comparatively higher dose, as, for them, the molecule will be metabolised and excreted at a relatively lower rate. Hence, repeated administration of the medication could lead to the accumulation of the drug and increase the potential for toxicity.2,3

CYP450 enzymes are just one example of differential gene expression leading to varied pharmacodynamics and drug response. As drug treatments become increasingly personalised and often genetically focused, such as in cancer and many rare diseases, understanding genetic diversity across populations in countries in which the drug is marketed is increasingly critical. Taking it one step further, the relatedness of populations and genetic ancestry across borders are also becoming important to trait mapping and the understanding of underlying genetic dependencies in populations of target countries, especially those with mixed populations.

As an illustration, there are significant differences in optimal dosing for East Asian populations, compared to populations of European, Latino or African descent when prescribing Warfarin. The medication is widely prescribed as an anticoagulant to prevent thromboses and embolisms, but there are population differences associated with genetic polymorphisms in the Warfarin metabolic pathway. As an example, there can be significant variations in the Vitamin K epoxide reductase complex gene which regulates Vitamin K as part of the inverse clotting synthetic pathway. Individuals of Asian descent require a lower dose of Warfarin compared to Latinos, who are still more sensitive to the medication than patients of European and African descent, which results in the need for specific per-patient dosing and diet monitoring.4,5,6

Nature versus Nurture

Accounting for this genomic variability is therefore of importance for clinical trials, and the underlying reason for the need to ensure diversity in clinical trial patient populations. Additionally, the social and economic determinants of health must also be considered for the population of each country: there are significant differences in the incidence of disease because of location, race, social status, and proximity to care. As an example, the incidence of Chronic Obstructive Pulmonary Disease (COPD) and other respiratory diseases is higher in metropolitan areas with high smog and poor air quality than it is in rural areas. In many countries, there are persistent racial disparities in health coverage, chronic health conditions, mental health, and mortality. The COVID-19 pandemic is further highlighting significant social boundaries and differences in access to, and quality of, care based upon race, resulting in poor outcomes in racially and ethnically diverse communities, especially in the United States.7,8