Patient Diversity in Global Industry Clinical Trials: Why It Matters, Who Should Be Concerned, and What Can Be Done?

Abstract

In their recent guidance to the industry the US FDA stated that it is concerned proposed the industry is rightfully concerned about patient diversity in industry-sponsored clinical trials (iCTs) due to a lack of attention on enrollment of representative numbers of participants from underrepresented racial and ethnic populations in the United States. Individuals from these populations are frequently underrepresented in biomedical research despite having a disproportionate disease burden for certain diseases relative to their proportional representation in the general population. However, the problem of insufficient representation of certain ethnic or racial groups in iCTs is not new and certainly should not be a concern to the US regulators only as there are nations/ethnicities with insufficient representation in global development of new drugs around the world. In this manuscript we examine qualifiable parameters of representation of countries in global iCTs and discuss some of the medical and ethical implications.

1. Introduction

In their recent guidance to the industry the US FDA expressed its concern about patient diversity in industry-sponsored clinical trials (iCTs) due to a lack of attention on enrollment of representative numbers of participants from underrepresented racial and ethnic populations in the United States. According to the US FDA, individuals from these populations are frequently underrepresented in biomedical research despite having a disproportionate disease burden for certain diseases relative to their proportional representation in the general population [1]. Without introducing corrective measures, the racial and ethnic underrepresentation in today’s iCTs in the US is likely to be further amplified in coming years, as the US is set to become “minority (non-Hispanic) White” by 2045 [2].

Therefore, FDA urged sponsors to develop and implement operational measures that would ensure diverse clinical trial participation and would improve the generation of evidence regarding safety and effectiveness across the entire population in the United States. The FDA provided examples of measures which could include but are not limited to offering financial reimbursement for expenses incurred by participation in a clinical trial or study (e.g., travel or lodging), providing language access to participants with limited English language proficiency, and partnering with community-based organizations to provide support to study or trial participants.

However, the problem of insufficient representation of certain ethnic or racial groups in iCTs is not new and certainly should not be a concern to the US regulators only as there are nations/ethnicities with insufficient representation in global development of new drugs around the world. In our previous publication which focused on this topic we have explored and attempted to quantify the magnitude of ethnic underrepresentation of the Middle Eastern populations (particularly Arabic) [3]. In this chapter we examine qualifiable parameters of representation of countries in global iCTs using more recent data and introducing some new parameters providing insights into countries’ representation in iCTs and discuss some of the medical and ethical implications.

2. Methods, data sources, and model assumptions

The following data sources and model assumptions have been used in this report:

LongTaal clinical trial informatics platform (www.longtaal.com) which combines, processes and enriches information downloaded from ClinicalTrials.gov [4], EUDRACT [5], has been utilized as the primary data source for comparative benchmarking analyses shown in this chapter.

2.1 Clinical trials market share

Unlike methodology used other authors which utilized number of newly submitted clinical trials sites into the registries (with considerable year-on-year changes) [6, 7, 8, 9], the methodology we developed and utilized also in this chapter enables determination of all active clinical trial sites in the country and has proven to be reliable source of determination of iCT market share of countries as a % of all active iCT sites in the country relative to all active iCT sites globally [3, 10, 11, 12, 13].

2.2 Accessibility to clinical trials

Accessibility to industry clinical trials is defined as the number of iCT sites per 1 million population. For comparative purposes, iCT Accessibility is expressed relative to the US levels (US iCT Accessibility level being 100%). Source of the population data was the World Bank population databank [14].

2.3 Participation to consumption ratio

Participation in iCT on a country level was approximated as country’s market share of global iCTs (see above). As a surrogate for the consumption of pharmaceuticals on a country level country’s market share of global prescription sales was used. Participation to Consumption Ratio (PCR) is a parameter introduced and coined by these authors to quantify adequacy of representation of countries’ populations in development of new pharmaceutical products relative to consumption of commercially available pharmaceutical products.

Participation to Consumption Ratio has been computed as follows:

$$\mathit{PCR}=\frac{\mathit{\text{Global}}\mathit{iCT}\mathit{\text{market share}}\left(\%\right)}{\mathit{\text{Global share of pharmaceutical consumption}}\left(\%\right)}$$E1

Where iCT market share is calculated as shown above and pharmaceutical consumption market share has been calculated from [15].

3. Results and discussion

The US regulators (FDA) in their recent guidance to the industry flagged the problem of underrepresentation of certain racial and ethnic populations in iCTs in the United States [1].

The root causes to this phenomenon are multiple. First and foremost, we need to acknowledge the contribution of deplorable historical practices, where ethnic minorities and/or vulnerable populations were involved in research we now consider unethical [16, 17].

The impact of this legacy continues to affect the inclusion of iCT subjects today in two significant ways:

• Mistrust in the healthcare system among ethnic minorities, thus lowering their willingness to participate in CTs offered to them [18].

• Reverse selection bias among healthcare professionals, who are sensitized about potential ethical risks. Well-meaning health professionals may limit subjects’ participation in a study involving vulnerable populations under the guise of protecting these individuals from harm [19].

Other factors may be at play as well, and their collective manifestation is the underrepresentation of certain socioeconomic or ethnic groups in iCTs not only in the US. In their 2013 paper, Noor et al. studied access to early-phase cancer trials in the UK as a factor of the socioeconomic statuses of patients, finding that the least deprived patients were almost twice as likely to be referred for an early-phase oncology clinical trial. Ethnicity analysis demonstrated that the non-white population was less likely to be recruited [20]. In another study, Godden et al. analyzed the effect of the ethnicity of patients recruited to cancer clinical trials of all phases in one hospital trust in England, finding that non-white minorities were 30% less likely to be recruited than were white patients [21].

However, gaps in the access to and participation in iCTs also exist on a global scale, as accessibility to iCTs for patients in several ethnically and culturally distinct global geographies lags substantially behind the countries in North America and Europe [3]. Thus, patient diversity and adequate representation of certain ethnic groups in development of new drugs should not only be a concern to the US regulators, but also to regulators, health professionals, and patients in the countries underrepresented in global drug development.

Figure 1 shows Accessibility to iCTs (for definition and calculation see Methods) for patients in countries around the world.

Figure 1.

Accessibility to clinical industry clinical trials, calculated as number of clinical trial sites per 1 m population relative to the US levels (US = 100%). Data source: LongTaal Clinical Trials Landscape dashboard/Clinical Trials Indices (www.longtaal.com).

Population-adjusted Accessibility to iCTs indicates high levels of accessibility in North America and Europe, as well as Israel and Australia, with lower accessibility levels in Latin America, and dropping below 5% of the US levels in India, the Arabic Middle East as well as Africa (with South Africa being an exception).

While Accessibility data are indicative of potential underrepresentation in iCTs, they do not reflect an important variable, i.e., consumption of pharmaceuticals. Super-imposing Consumption of pharmaceuticals data over iCT Participation data helps us identify countries, which are underrepresented in development of pharmaceuticals (i.e., in iCTs) relative to pharmaceutical consumption.

To assess these imbalances, we have introduced the so-called Participation to Consumption Ratio (PCR) (see Methods). Consumption of developed pharmaceuticals was expressed as global market share of pharmaceutical sales of prescription pharmaceuticals, while participation in development of novel biopharmaceutical products was expressed as a global share of active iCTs sites (iCT market share).

PCR index has been adopted and modified from the so-called Participation to Prevalence ratio (PPR) used by Saltzman et al. to assess proportionality of demographic representation of certain patient groups in clinical trials for cell-based therapy [22].

Before discussing the results, it is important to provide to the reader guidance to these results. We consider a “normal” or acceptable range of PCR = <0.5; 2>, while countries with PCR index >10 are, with a high degree of certainty, substantially underrepresented in the development of novel pharmaceuticals, and thus potentially consuming medications in development of which patients with similar ethnic or cultural¹ profiles have not been adequately represented.

Graphical presentation of the PCR data by country is shown in Figure 2: global heat map of PCR index by country, with darker tones of red showing the problem “out of balance” areas, with country-level details shown in Table 1.

Figure 2.

Global heat map of Participation to Consumption Ratio (PCR). For definitions and methodology see Methods. Data source: LongTaal Clinical Trials Landscape dashboard, 2019 data.

Research Bias		Normal iCT Distribution		Consumption Bias		Substantial Consumption Bias
PCR > 2	PCR value	2 ≥ PCR ≥ 0.5	PCR value	PCR < 0.5	PCR value	PCR < 0.1	PCR value
Ukraine	7.42	Belarus	1.97	Slovenia	0.483	Kenya	0.095
Czech Republic	7.32	Argentina	1.95	India	0.442	Senegal	0.093
Hungary	6.84	South Korea	1.83	Tunisia	0.413	Sierra Leone	0.078
Bulgaria	6.80	Portugal	1.77	Puerto Rico	0.388	Mali	0.070
Serbia	5.69	Malaysia	1.77	Mongolia	0.360	Saudi Arabia	0.067
Georgia	5.45	Bosnia and Herz.	1.77	China	0.359	Morocco	0.067
Israel	5.07	Finland	1.72	Jordan	0.306	Kazakhstan	0.065
Poland	4.87	Greece	1.67	Iceland	0.290	Zambia	0.064
Estonia	4.40	Canada	1.59	Gabon	0.286	Niger	0.063
Belize	4.13	United Kingdom	1.57	CAR	0.273	Kyrgyzstan	0.059
Latvia	3.93	Italy	1.44	Armenia	0.262	Cyprus	0.057
Slovakia	3.68	Peru	1.41	Venezuela	0.210	Bahrain	0.053
Lithuania	3.45	Sweden	1.39	Uganda	0.204	Iran	0.051
New Zealand	3.31	France	1.35	Vietnam	0.201	Uruguay	0.047
Belgium	3.08	Chile	1.32	Oman	0.193	Algeria	0.044
Croatia	3.03	Turkey	1.27	Burkina Faso	0.181	Cuba	0.041
Taiwan	2.68	Ireland	1.24	Mauritius	0.168	Paraguay	0.041
Romania	2.67	Germany	1.21	Luxembourg	0.159	Indonesia	0.038
Netherlands	2.41	Hong Kong	1.05	Qatar	0.136	Mozambique	0.037
Spain	2.31	Mexico	1.03	Egypt	0.133	Ghana	0.036
Australia	2.30	Thailand	0.90	Sri Lanka	0.133	Ecuador	0.033
South Africa	2.29	Norway	0.85	Albania	0.126	Madagascar	0.032
Russia	2.16	Colombia	0.82	Rwanda	0.126	UAE	0.031
Moldova	2.12	United States	0.76	Zimbabwe	0.124	Benin	0.031
Singapore	2.09	Japan	0.71	Bolivia	0.111	Cameroon	0.030
Austria	2.06	Bahamas	0.65	Swaziland	0.102	Malta	0.027
Denmark	2.05	Jamaica	0.60	Dominican Rep.	0.100	Botswana	0.024
		Switzerland	0.59			Guinea	0.021
		Lebanon	0.57			Pakistan	0.019
		Philippines	0.55			Kuwait	0.019
		Gambia	0.53			Malawi	0.015
		Brazil	0.51			Tanzania	0.012
						Bangladesh	0.002

Table 1.

Participation in development of pharmaceuticals relative to consumption of developed pharmaceuticals (PCR index). Data source: LongTaal Clinical Trials Landscape dashboard, 2019 data.

As seen from Figure 2 and Table 1 majority of the countries with the highest imbalances between participation in consumption of marketed products relative to participation in development of new products are from Africa and the Arabic Middle East.

We recognize the following limitations of such a top-level approach to assess representation of countries in development of novel pharmaceuticals:

• Significant pricing differences between countries, i.e., typically lower pricing for the same compound in lower income countries.

• Analysis was not done at the level of the product and/or therapeutic area.

These limitations notwithstanding, PCR index can serve as a helpful and rapid identifier of significant imbalances. It is safe to assume that countries with PCR index >10 are substantially underrepresented in the development of novel pharmaceuticals, and thus potentially consuming medications in development of which patients with similar ethnic or cultural profiles have not been adequately represented.

Why is insufficient ethnic representation in development of novel pharmaceuticals a problem? Let us start with biological differences. Examples below illustrate how racial, ethnic, and cultural factors impact the safety and efficacy profile of drugs and medical devices. Such factors must be therefore taken into considerations both during products’ development stage and after their launch, including:

• Skin pigmentation: Pulse oximeters function less accurately in patients with higher levels of skin pigmentation (darker skin), resulting in a risk of missing clinically important hypoxia [23]. This is possibly one of the contributing factors that led to the disproportionally high COVID-19 related death rates among Black or African American, as well as Hispanic or Latino populations in the US [24].

• The effects of race and ethnicity on drug metabolism: Significant racial and ethnic variations in the pharmacokinetics, efficacy, and toxicity of drugs have been reported [25, 26].

• Religious and cultural practices: Drug metabolism rates could also be influenced significantly by environmental and nutritional factors such as fasting (e.g., during Ramadan). The resulting changes in drug metabolism may result in treatment failure or, conversely, in increased side effects or toxicity. Studies have shown that fasting alters drug metabolism by modulating the activity of the drug metabolizing enzymes involved [27].

However, as a recent MRCT Center guidance document on patient diversity emphasized, inclusion of diverse representation in clinical trials is not simply a matter of biology, but a matter of health equity, fairness, and public trust [28].

Let me touch here on a few additional factors that may play a significant role in alleviating the existing diversity gaps:

3.1 Ethnically diverse iCT workforce as enablers of patient diversity

Lack of adequate racial/ethnic diversity radiation oncology physician workforce in the United States has been called out as potential contributing factor to the racial/ethnic disparities in cancer outcomes [29]. Recently the US NIH identified workforce diversity as a key to expanding the reach of clinical trials and inclusion of diverse populations [30]. Similarly, Bierer et al. in the MRCT Center Guidance document on diversity, inclusion, and equity in clinical research identified lack of cultural competence and diverse staff (investigators/referring physicians/site staff) as one of the structural barriers to improving patient diversity in clinical research [28].

The role of technology:

• Decentralized or virtual CT solutions have been finally embraced by the industry during the COVID-19 pandemic and supported by processes and technologies enabling telemedicine and remote patient visits. Some leaders in innovative technology-based solutions enabling and supporting DCTs are Science 37, Medable, and Lightship. While such technologies hold a lot of promise, the practical impact on improving patient diversity in CTs is yet to be determined.

• EHR mining with technology-based EHR-mining solutions for clinical trials, such as those offered by TriNetX or Clinerion, appear to be uniquely suited for the identification of trial sites with access to diverse patient populations.

Patient expense reimbursement:

The US FDA in its guidance to the industry specifically called out offering financial reimbursement for expenses incurred by participation in a clinical trial or study (e.g., travel or lodging) as a tool to improve patient diversity [1]. If handled well, this indeed can be an effective tool. However, as a recent article points out, there is an acute lack of uniform approach, including among regulators, globally [31]. As a result of these differences, some geographies and regulatory jurisdictions offer no reimbursement of (often very significant) travel expenses, and/or no compensation of lost wages; alternately, the process of reimbursement of these expenses may be ineffective or slow. This naturally impacts low earners disproportionally, thus reducing their interest to participate in a CT or increasing their trial drop-out rates, both adversely impacting patient diversity in iCTs.

4. Conclusions

This chapter illustrated another dimension of patient diversity gaps in global iCTs: patients from countries/regions around the world which appear to be underrepresented in development of novel pharmaceutical relative to consumption of marketed products, and thus potentially consuming medications in development of which patients with similar ethnic or cultural profile have not been adequately represented. The most impacted global regions are Africa and the Middle East with most countries with the highest global imbalances. In these regions as well other countries with significantly skewed CPR balances. This problem should be further analyzed at a product level and based on the findings a robust solution-oriented discussions involving country regulators, health policy experts, insurance providers, and biopharma representatives should take place. Possible options include e.g., requiring a sub-study on a representative population of ethnically identical or similar patient groups as part of the product marketing authorization, and/or mandatory post-launch real-world data collection allowing assessment of product safety and efficacy in local populations.

We believe that in the wake of the recent US FDA guidance flagging the lack of adequate ethnic diversity in iCTs, there is an opportunity to initiate discussions around this problem globally, and particularly in the affected geographies. In this context it is important to emphasize that inclusion of diverse representation in clinical trials is not simply a matter of biology, but a matter of health equity, fairness, and public trust [28]. It remains to be seen, however, whether the market significance of the impacted markets is such that biopharma companies as sponsors of iCTs are prepared to play a more active role at driving change.

Acknowledgments

Customized clinical trial analytics for this chapter were prepared by and provided as a courtesy of LongTaal (www.longtaal.com).

Conflict of interest

The authors declare no conflict of interest.