Introduction

This white paper focuses on the critical issue of inclusivity and diversity in clinical trials. We propose innovative solutions to bridge the gap between research and real- world healthcare with particular emphasis on the importance of these factors in improving patient safety and healthcare outcomes. Regulatory bodies will also be featured as playing a pivotal role in promoting inclusivity and diversity through the development of new guidance and legislation. Our objective is to leverage technology and real-world data, to enhance the inclusion of underrepresented groups in clinical research studies.

Understanding the scope of the problem

Inclusivity is a key factor in clinical trials, to ensure that research findings are representative of the population and applicable to all patients, who may eventually receive the treatment. Clinical trials involve testing new medications, therapies, or medical devices to determine their safety and effectiveness. However, a lack of inclusivity in clinical trials can have negative consequences and hinder the progress of medical research.

The INCLUDE project examined underrepresentation in clinical design and delivery, and identified a range of underserved groups, and highlighted common barriers to participation. The project identified key groups such as older people, ethnic minorities, and women who continue to be underrepresented in clinical trials today [1].

Implications of underrepresentation

The involvement of women, ethnic minorities, and older adults is essential to the scientific, economic, and ethical value of clinical trials. Failure to include such individuals can lead to under diagnosis, undertreatment, and a lack of understanding of how certain medical therapies may affect specific groups of people.

For example, clinical trials investigating treatments for ischemic heart disease (IHD) often exclude older individuals despite their higher susceptibility of developing the disease [2]. To assess whether a drug is safe and effective for use by the elderly, a sufficient number of elderly patients are needed to be included in drug trials. Evaluation of the exclusion of elderly adults from 839 randomised controlled trials studying drug interventions for IHD concluded that, from these trials, 446 (53%) explicitly excluded elderly adults. The estimated proportion of participants aged 65 and older was 42.5%, and the estimated proportion aged 75 and older was 12.3% [2]. As such, these trials create challenges for treating clinicians in evaluating the risk benefit of medications in their older patients.

Physiological variations can translate into differences in pharmacokinetics and/or pharmacodynamics for specific drugs, meaning that medications can work or be processed differently in people of different sexes [3]. For example, the medication Dofetilide was approved by regulators in 1999, to help control irregular or fast heart rhythms (atrial fibrillation). Despite this, it was only in 2018, that a subsequent study found that the recommended twice daily dose was too high in over half of female participants, as they developed other abnormal heart rhythms and had an increased risk of cardiac arrest. This study highlighted the importance of having adequate representation of women in trials, as in the original phase III DIAMOND study, females constituted less than a quarter of all trial participants [4], clearly demonstrating the serious consequences of underrepresentation in clinical trials.

There have been several studies suggesting that pulse oximetry may not be as accurate in certain populations, particularly in individuals with darker skin pigmentation, including those of black ethnicity. This discrepancy in accuracy could result in an overestimation of oxygen saturation levels. The lack of diversity in the patient populations studied in clinical trials has been identified as a contributing factor to this issue. Consequently, there is a growing call for prospective studies to investigate the impact of ethnicity on the accuracy of pulse oximetry to ensure care is optimised for all [5].

These examples highlight the major consequences of not adequately representing these diverse groups in clinical trials, resulting in a lack of understanding of the drug’s true impact, leading to potentially harmful consequences for those affected.

The Food and Drug Administration (FDA) recognises that some eligibility criteria have become commonly accepted by sponsors over time and used as a template across trials, sometimes excluding certain populations from trials without strong clinical or scientific justification (e.g., older adults, those at the extremes of the weight range, those with malignancies or certain infections such as HIV, and children) [6].

Exclusion of these populations from clinical trials not only propagates inequalities in healthcare but, also puts these groups at higher risk of experiencing adverse effects to medical interventions once they have reached the market.

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