Until fairly recently, most clinical trials largely recruited people of European descent. However, it doesn’t automatically follow that most approved drugs work better on them nor that they work worse on those of other ethnicities. Rather, empirical evidence suggests a mixed bag with examples of some drugs proving harmful but others working even better in other ethnicities.
Genetic polymorphisms are present in different ethnic groups in different proportions and can influence drug effectiveness in unpredictable ways. In any case, due to very real cost constraints, varying effectiveness is baked into the drug approval process, whether or not ethnic differences are taken into consideration during drug development,
- On their path to regulatory approval, drugs are tested on merely a few thousand people (see below from ). Drug development costs having already increased greatly, testing on many more would drive costs up to an unsustainable level and entirely stop new drug development in its tracks.
- Current drug approval is still largely based on group averages, not on their effectiveness at the individual level. Largely in that in recent years, patient stratification, , has emerged as an approach to extract data on drug effectiveness within patient subsets, subsets being defined not just by age, gender and ethnicity but also by genetic polymorphisms such as cancer-specific mutations.
Drug Effectiveness Varies Widely
A 2015 comment piece by Nicholas J. Schork in Nature highlighted the fact that the then top ten best-selling drugs in the US alleviated symptoms in at best 1:4 (Humira, Enbrel, Remicade) to at worst 1: 25 (Nexium) (see below from).
Again, this shouldn’t be surprising either since individual variations are to be expected,
- Different individuals taking the same drug at even the same dose may concurrently have other diseases or be taking other drugs.
- Humans are considerably diverse genetically in terms of individual gene polymorphisms (in the lingo, outbred species unlike experimental animals such as mice which tend to be inbred).
- Genetic factors are estimated to account for 20 to 95% of the variability in response to drugs ( ). Whether variations in response to drugs should be so large is another matter.
: Higher Frequency Of Serious Side-Effects Among African Americans
Inhaled corticosteroids are now a mainstay in managing asthma symptoms. However, symptoms persist in some patients. This drove development of secondary drugs,, a (LABA) being one such drug. However, independent analysis of the data from a phase IV, i.e., post-marketing, trial that included as many as 18% African Americans in the study population found them to be at much higher risk of life-threatening events and death, which forced the FDA to recommend additional safety warning emphasizing ‘small but significant risk in asthma related deaths‘ (4, 5).
Genetic Variations Influence Effectiveness & Side-effect Severity Of Some Standard Cancer Chemotherapies: Some Examples Of Inter-ethnic Differences In Their Prevalence
Side-effects of many standard cancer chemotherapies are often more severe in African Americans compared to people of European descent while their effectiveness also varies between ethnic groups (see below from).
Enzyme Variants Can Enhance Drug Effect Or Toxicity: Some Examples Of Inter-ethnic Differences In Their Prevalence
Enzyme variants that metabolize many standard drugs are present in varying proportions of people of different ethnicities. As a result some drugs can be either more effective or more toxic in different ethnicities (see below from).
- Schork, Nicholas J. “Personalized medicine: time for one-person trials.” Nature 520.7549 (2015): 609-611.
- Weinshilboum, Richard. “Inheritance and drug response.” New England Journal of Medicine 348.6 (2003): 529-537.
- Currie, Graeme P., Daniel KC Lee, and Brian J. Lipworth. “Long-Acting β 2-Agonists in Asthma.” Drug safety 29.8 (2006): 647-656.
- Shah, Rashmi R. “Inter-ethnic differences in drug response: implications for drug development and complying with drug regulation.” Clinical Research and Regulatory Affairs 32.3 (2015): 88-98.
- O’Donnell, Peter H., and M. Eileen Dolan. “Cancer pharmacoethnicity: ethnic differences in susceptibility to the effects of chemotherapy.” Clinical Cancer Research 15.15 (2009): 4806-4814.