Inclusive and safe clinical trials: Establishing race and time-specific reference intervals

Drugs administered in clinical trials may reduce the patients’ levels of white blood cells and render them vulnerable to infections. Thus, cell numbers are monitored to ensure that they comply with reference intervals. However, these intervals vary with race and hence setting a single range may exclude ethnic minorities. Dr Jörg Täubel of the Richmond Research Institute has analysed phase I trial results, in which blood samples were taken from members of different racial groups at different times. Dr Täubel has observed distinct reference intervals for black patients which, if utilised, will increase their participation in trials.

White blood cells are an important part of the body’s immune system. There is a risk during clinical trials that the drug given will reduce the patient’s white blood cell count and thereby increase the risk of infection. Clinicians monitor the levels of different types of white blood cells to ensure that they meet specified levels, which are called reference intervals.

Most UK hospitals, laboratories and research institutions use uniform reference intervals, but do not consider that reference intervals can vary depending on the patient’s race and the time of day that the blood was sampled. Thus, there is a risk of excluding suitable patients from ethnic minority groups from participation in clinical drug trials. This may raise questions regarding the validity of the trial and whether the trial results are applicable to certain ethnic groups.

Dr Jörg Täubel and colleagues at the Richmond Research Institute (RRI) have assessed the results of multiple phase I clinical trials, in which blood samples were taken from members of different racial groups at different times. They investigated whether there were any variations in reference intervals between patients of different races with the intention of increasing the inclusivity of clinical trials.

RRI has been born out of a partnership with St George’s University of London and is associated with Richmond Pharmacology, a clinical research organisation in the UK. RRI is a not-for-profit organisation dedicated to drug safety research to improve and save lives, and its researchers aim to explore the usefulness of potential new medicines, assess the safety of existing medicinal products, and provide scientific insights to improve clinical trial methodologies and strategies for personalised medicines.

Study group

The researchers analysed pooled data from 35 clinical trials conducted over a period of seven years (January 2010–January 2017) at Richmond Pharmacology, St George’s University of London.

They assessed the white blood cell count results from 13,332 blood samples (commonly 1 or 2 samples per patient) obtained from 7,157 healthy subjects (2,668 women and 4,489 men).

The patients were aged 18 to 76 years, were non-smokers and had not consumed caffeine over the preceding 48 hours. In addition, their urine tested negative for alcohol consumption and for other harmful drugs. Furthermore, a large proportion (96%) of samples came from patients who had fasted before giving blood.

Each patient in this study self-identified their ethnicity as being black African, black Caribbean, Caucasian or Asian (the researchers acknowledged that this self-ascription may have been a limitation of their study). Overall, 926 (13%) of these subjects were black (African or Caribbean) and 6,227 (87%) were non-black (Caucasian or Asian). Dr Jörg Täubel and colleagues have noted that this study group is unbalanced and skewed towards white and Asian males.

White blood cell analysis

In this study, the researchers measured the abundance of five types of white blood cell in each sample – neutrophils, eosinophils, basophils, monocytes and lymphocytes – in addition to the total number of white blood cells. In general, for a given blood sample, the neutrophil count represented roughly half of the total white blood cell count while lymphocytes comprised about 35% of the total. Monocytes (≈10%), eosinophils (2%–3%), and basophils (<1%) accounted for the remainder of the white blood cell numbers. The researchers also noted the time (between 8 am and 6 pm) that each blood sample had been obtained. The research team found that the white blood cell counts for Caucasians and Asians were similar and that white blood cell counts for black Africans and black Caribbeans were similar. Dr Täubel and colleagues did not report any differences in white blood cell counts between males and females.

“Total white blood cell counts from black volunteers were on average lower than those for non-black volunteers.”

The total white blood cell (neutrophil, eosinophil, basophil and monocyte) counts from black volunteers were on average lower than those for non-black volunteers. For example, for samples taken at 12 pm, the total white blood cell count was approximately 23% higher for the non-black participants. However, the average lymphocyte counts were higher in black participants than in non-black participants.

The total number of white blood cells was found to increase for all ethnicities during the day (an average increase of 20% for black individuals and of 29% for non-black patients) (Figure 1). In particular, there were increases in the number of neutrophils, monocytes and lymphocytes.

There were also smaller increases in the number of basophils, but this was not statistically significant. Eosinophil numbers decreased over this time, but this finding was only statistically significant for the Asian and Caucasian patients.

Why did patients differ?

The researchers do not consider the distinct white blood counts shown by black patients to be adverse reactions to drugs in clinical trials. They have pointed out that other scientists have also observed this phenomenon in healthy black individuals. For example, previous researchers have reported that people with African ancestry have lower white blood cell counts, including lower neutrophil counts, than individuals from other ethnic backgrounds (Chen et al, 2010). It has been suggested that this may have been a natural selection advantage associated with resistance to the development of malaria.

Selecting new reference intervals

A selection of reference intervals typically used in the UK are given in Table 1. The reference intervals proposed by the researchers based on the study results for both black and non-black patients are given in Table 2.

The data in these tables suggests that some black and non-black patients will be excluded from clinical trials based on their white blood cell counts, particularly if blood samples are taken early in the day. The authors have suggested that using reference intervals which take variations in race and time into account will be more inclusive and representative of local communities with regards to clinical trial patient recruitment.

“The main benefit of race-specific reference intervals is to enable more precise post-dose safety monitoring and reporting of clinical trials.”

It is the view of the researchers that the main benefit of race- and time-specific reference intervals is to facilitate accurate testing of drugs in development across a diverse population of healthy subjects and enable more precise post-dose safety monitoring and reporting of clinical trials.

Future work

The authors contend that their findings are further evidence that we need to consider ethnic origin in clinical research, so that the medical needs of multi-cultural societies can be addressed. With the development of personalised medicines, the impact of race, age, gender, smoking status, poor sleep and body mass index on white blood cell counts should be investigated.

Furthermore, these variables should be taken into account in any future studies which assess race and blood sampling times. The findings from this research are already being used in commercial research to increase the diversity of volunteers in clinical trials, with research physicians interpreting results on a case-by-case basis.

References

• Coates, S., Wang, D., Pierscionek, T., Fernandes, S., Djumanov, D., Lorch, U. and Täubel, J. (2020). Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data from Multiple Phase I Trials. Frontiers in Pharmacology, 11, Article 314. Available at: https://doi.org/10.3389/fphar.2020.00314
• Chen, W., Srinivasan, S., Xu, J. and Berenson, G. (2010). Black-White Divergence in the Relation of White Blood Cell Count to Metabolic Syndrome in Preadolescents, Adolescents, and Young Adults: The Bogalusa Heart Study. Diabetes Care, 33(11), 2474-2476. Available at: https://doi.org/10.2337/dc10-0619

Research Objectives

Dr Jörg Täubel researches variations in white blood cell counts which may lead to certain ethnicities being excluded from clinical trials.

Collaborators

Simon Coates, Duolao Wang, Tomasz Pierscionek, Sara Fernandes, Dilshat Djumanov, Ulrike Lorch

Bio

Dr Jörg Täubel is a scientific lead at Richmond Research Institute. He is an expert in clinical pharmacology having conducted over 500 early phase studies.

Dr Täubel is an honorary fellow at St George’s University and author of 140 publications. He has chaired 18 sessions and given 68 oral presentations.

Contact
Jörg Täubel
Richmond Research Institute
St George’s Hospital
University of London
Cranmer Terrace
Tooting, London
SW17 0RE

E: [email protected]
W: www.richmondresearchinstitute.org

Inclusive and safe clinical trials: Establishing race and time-specific reference intervals