Abstract
Background and Objectives:
The Best Pharmaceuticals for Children Act (BPCA) incentivizes the study of on-patent medicines in children and mandates that NIH sponsor research on off-patent drugs important to pediatric therapeutics. Failing to enroll cohorts that reflect the pediatric population at large restrict the generalizability of such studies. This investigation evaluates racial and ethnic (R/E) minority representation among participants enrolled in BPCA-sponsored studies.
Methods:
Data were obtained for all participants enrolled in 33 federally-funded studies of drugs and devices conducted from 2008 through June 2020. Observed R/E distributions were compared to expected by sampling Census data at the same geographic frequency as in the studies. R/E enrollment was examined by demography, geography, study type, study burden, and expected bias. Standard descriptive statistics, Chi-square, generalized linear models and linear regression were applied.
Results:
10,918 participants (51% male, 6.6 ± 8.2 years) were enrolled across 46 U.S. states and 4 countries. Studies ranged from treatment outcome reviews to randomized, placebo-controlled trials. Minority enrollment was comparable to, or higher than, expected (+0.1% to +2.6%) for all groups except Asians (−3.7%, p<0.001). American Indian/Alaskan Native and Multiracial enrollment significantly increased over the evaluation period (p<0.01). There were no significant differences in racial distribution as a function of age or sex, though differences were observed based on geography, study type, and study burden.
Conclusions and Relevance:
This study revealed no evidence of R/E bias in enrollment for pediatric studies conducted with funding from BPCA, fulfilling the legislation’s expectation to ensure adequate representation of all children.
Table of Contents Summary:
This paper examines 10,918 participants from 33 studies to investigate whether racial/ethnic minorities are adequately represented in federally-funded studies of drugs and devices in children.
Background
Since the mid-1970s, federal regulations have underscored the need for data on the safety and efficacy of medicines in children.[1–4] However, it took a 1990 workshop, convened by the Institute of Medicine, the National Institutes of Health (NIH), the American Academy of Pediatrics, the U.S. Food and Drug Administration (FDA), and representatives from the pharmaceutical industry, to spotlight prioritizing these efforts.[5] Pioneering legislation passed in 1997 by the US Congress (FDA Modernization Act) and supplemented in 2002 (Pediatric Research Equity Act; Best Pharmaceuticals for Children Act, BPCA) incentivized this activity and was successful enough to prompt 3 successive reauthorizations under the FDA Amendments Act, the FDA Safety and Innovation Act, and the FDA Reauthorization Act.[6–10] Though no commercial or economic incentives were put in place to study underrepresented minorities, BPCA did highlight that studies should “take into account adequate representation of children of ethnic and racial minorities” and ordered the Comptroller General to examine “the extent to which members of ethnic and racial minorities are underrepresented.”[7] This recommendation underscored the importance of ensuring that studies of drugs and devices, for which there is equal access across the general population, should enroll cohorts that mirror the population at-large. Failure to balance racial and ethnic distribution in these studies severely restricts the generalizability of their findings and serves as a missed opportunity to identify groups of individuals in whom safety or efficacy may be compromised.[11–14]
Under BPCA, drug companies can receive an additional 6 months of patent exclusivity for conducting studies in children. A 2003 General Accounting Office (GAO) report revealed that 23 medicines benefited from this legislation, having performed studies in a combined 6,952 children. However, only 7% of those children enrolled were Black, 5% were Hispanic, and 1% were Asian.[15] By 2016, over 42,000 children had been enrolled by the private drug-development sector in studies of medicines under this legislation, and gains were seen across all underrepresented groups though some minority populations still fell short of the proportions observed in the general population.[16]
Also nested within BPCA is a mandate for the NIH to sponsor research that generates data to guide the appropriate use of medicines in children for off-patent drugs important to pediatric therapeutics where there is no financial incentive for the pharmaceutical industry to fund the study. These studies, largely designed and conducted in the academic sector, are supported through the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) which is subject to the NIH Revitalization Act of 1993 that addresses diversity and inclusion in federally-funded clinical research.[17] In this paper, we explored the representation of racial and ethnic minority participants enrolled in BPCA-funded pediatric studies sponsored by NICHD.
Methods
The study population reflected all participants enrolled in completed or ongoing BPCA-funded studies occurring from 2008 through June 2020 whose data are maintained with the BPCA data coordinating center. No study had inclusion/exclusion criteria that explicitly referenced race or ethnicity. The data extracted included age, race, ethnicity, study site, study protocol, and the month and year of enrollment. Studies enrolling mother-infant dyads were retained in the analysis, but those enrolling adults only were excluded. The geographic site of enrollment was identified for each participant along with reference census data for the general population in that city as derived from the U.S. census bureau, World population review, Statistics Canada, United Kingdom Office for National Statistics, Israeli local council data, and Department of Statistics Singapore.[18–23] All participating study sites, irrespective of country, were required to record race and ethnicity according to the standards laid out by the Office of Management and Budget (OMB) as used by the U.S. Census Bureau.[24] The observed racial/ethnic enrollment distribution across all studies was compared to the expected racial/ethnic enrollment distribution determined by sampling the general population at the same geographic frequency as in the BPCA-funded studies.
Racial and ethnic enrollment was examined categorically by age, sex, and, geographic region while trends in minority enrollment were estimated over the entire evaluation period. Enrollment diversity in each state was explored by calculating the Simpson’s diversity index according to D=1-[( Σ n*(n-1))/(N*(N-1))] where n represents the total number of children for each racial/ethnic subgroup and N represents the total number of children for all groups.[25] The subgroups combine each of 7 racial groups (American Indian/Alaskan Native, Asian, Black, Hawaiian/Pacific Islander, Multi-racial, Not reported/Unknown, White) with 2 ethnic groups (Hispanic, non-Hispanic) for a total of 14 groupings as recorded in each of the studies. The calculated index “D” ranges from 0–100 and represents the probability that two randomly selected individuals, from the same area, belong to a different racial or ethnic group. Thus, zero represents no diversity and 100 suggests maximal diversity.
The studies from which the participants were drawn were subclassified to investigate comparisons of minority enrollment by study characteristic. Study “type” was categorized as interventional or non-interventional. The perceived burden of participating in the study for any participant (i.e. “study burden”) was classified as none, low, medium, or high; a rating reflecting the composite assignment of 3 pediatric clinician researchers, selected in a block randomized fashion from six in total. Raters evaluated each study according to their view on the burden of participation taking into consideration duration of participation, frequency of travel required for study visits, risks associated with study participation (i.e. physical, emotional, social), invasive nature of study procedures, and prospect for direct benefit. Discrepancies between raters were adjudicated by a seventh independent clinician researcher. Raters were also asked to classify (yes/no) whether they expected to see racial/ethnic biases in participant diversity for each study (e.g. “study bias”). Classification category was assigned by consensus of all raters based on peer-reviewed literature, publicly available reports, and disease-focused websites (e.g. Centers for Disease Control and Prevention, March of Dimes, NIH) that address racial/ethnic differences in disease epidemiology, healthcare utilization patterns, medication utilization, access to care, and prescriber treatment bias for the diseases under investigation.
Standard descriptive statistics were used to describe the study population. Comparison of proportions between observed and expected enrollment was accomplished using a Chi-square test or z-test. Generalized linear models were used to explore differences by sex, study type, and study burden. Linear regression was used to examine trends in enrollment over time. All statistical analyses were performed in SPSS v.23 (IBM SPSS, Armonk, NY).
Results
Data from 34 studies were available representing 11,045 participants. Enrollment occurred at 164 clinical study sites distributed across 46 U.S. states along with sites in Canada, England, Israel, and Singapore. One study that enrolled pediatric critical care providers (e.g. physicians, nurses, and emergency medical technicians; n=127) was excluded from the analyses leaving a final dataset constituted by 33 studies (Supplemental table) enrolling 10,918 participants (U.S.: 10,483, international: 435). Studies ranged from retrospective reviews of treatment outcomes to prospective, randomized, placebo-controlled investigations. Thirty studies represented investigations of drugs while the remaining 3 represented medical devices. The overall age of participants in these studies averaged 6.6 ± 8.2 years (range 0–45 years) and was evenly distributed among males and females (51% male vs. 49% female). However, when mothers from studies enrolling mother-baby dyads were removed (n=439), the participant age lowered to 5.5 ± 6.1 years (0–28 years, Figure 1).
Figure 1.
Distribution of pediatric participants in BPCA-funded studies by age (the single 28-year old reflects a neurology patient being managed at one institution).
Enrollment across all studies paralleled the expected enrollment based on estimates from the general population (Table 1). Though minimal with respect to percentage points, significantly higher than expected enrollment was observed in White, Multi-racial, American Indian, Hawaiian and Hispanic children ranging in absolute increases over expected from +0.2% to +2.6% (p<0.05). Asian children enrolled in lower absolute proportions than expected (−3.7%, p<0.001) while essentially no difference between observed and expected enrollment was found for Black children (24.6% vs. 24.5%, p=0.864). There were no significant differences in racial distribution as a function of sex (p=0.214), nor were any significant differences observed between the largest of the enrolled populations (infants < 3 months, n=3,139) and children older than 3 months of age (p=0.769).
Table 1.
Observed versus expected enrollment by race and ethnicity for 33 BPCA-funded studies conducted from 2008–2020.
| Race/Ethnicity | Expected n=10,918 |
Observed n=10,918 |
difference | 95% CI | p-value |
|---|---|---|---|---|---|
| White | 61.5% | 63.1% | +1.60% | 0.31 to 2.88% | 0.015 |
| Black or African American | 24.5% | 24.6% | +0.10% | −1.04 to 1.24% | 0.864 |
| Multi-race, not specified | 3.2% | 3.7% | +0.50% | 0.02 to 0.99% | 0.043 |
| Asian | 6.0% | 2.3% | −3.70% | 3.18 to 4.23% | <0.001 |
| American Indian or Alaskan Native | 0.5% | 0.8% | +0.30% | 0.09 to 0.52% | 0.006 |
| Hawaiian or Pacific Islander | 0.1% | 0.3% | +0.20% | 0.08 to 0.33% | 0.001 |
| Not reported/Unknown | 4.2% | 5.2% | +1.00% | 0.44 to 1.56% | 0.001 |
| Hispanic or Latino | 13.2% | 15.8% | +2.60% | 1.67 to 3.53% | <0.001 |
Not surprisingly, enrollment in the U.S. varied widely by Census Region and Division (Table 2a). A comparison with the expected racial and ethnic distribution by geographic region when sampled at the same frequency, from the same locations, as study participants reveals a net neutral balance for most population groups. However, absolute percentage deviations of more than 5% and 10% were observed in 7/9 and 4/9 census divisions, respectively. Only the W.N. Central Midwest and the W.S. Central South saw enrollment parallel the general population with deviation under 5% across all racial and ethnic groups. The one exception to otherwise balanced enrollment across the U.S. was observed for the Asian population. As illustrated in Table 2a, statistically fewer Asian children were enrolled in all but one Census Division and this was most pronounced in Western Divisions where a higher overall proportion of the population originates from Asian ancestry.
Table 2a.
Racial and ethnic distribution in enrollment by U.S. census region and division for BPCA-funded studies from 2008–2020.
| Census Region | Northeast | Midwest | South | West | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Census Division (number) |
New Engl. (187) |
Mid-Atl. (1,348) |
Overall (1,535) |
E.N. Cent. (2,095) |
W.N. Cent. (1,763) |
Overall (3,858) |
S. Atl. (2,598) |
E.S. Cent. (318) |
W.S. Cent. (984) |
Overall (3,900) |
Mntn. (346) |
Pacf. (889) |
Overall (1,235) |
| White | 68.8% | 65.8% | 66.1% | 70.9% | 66.0% | 68.7% | 47.6% | 69.6% | 58.4% | 52.1% | 76.9% | 73.4% | 74.4% |
| Black or African American | 12.9% | 22.8% | 21.6% | 19.7% | 26.1% | 22.6% | 38.8% | 24.7% | 31.2% | 35.7% | 5.3% | 4.4% | 4.7% |
| Multi-race, not specified | 9.7% | 3.9% | 4.6% | 3.0% | 3.4% | 3.2% | 3.4% | 3.5% | 3.8% | 3.5% | 3.6% | 5.8% | 5.2% |
| Asian | 2.2% | 3.9% | 3.7% | 1.5% | 2.0% | 1.7% | 1.2% | 0.0% | 1.5% | 1.2% | 0.0% | 5.3% | 3.9% |
| American Indian or Alaskan Native | 0.5% | 0.5% | 0.5% | 0.1% | 0.2% | 0.2% | 0.7% | 0.3% | 1.3% | 0.8% | 5.3% | 1.4% | 2.5% |
| Hawaiian or Pacific Islander | 0.0% | 0.1% | 0.1% | 0.2% | 0.4% | 0.2% | 0.0% | 0.0% | 0.2% | 0.1% | 1.5% | 1.5% | 1.5% |
| Not reported/Unknown | 5.9% | 3.0% | 3.3% | 4.5% | 2.0% | 3.3% | 8.5% | 1.9% | 3.5% | 6.7% | 7.4% | 8.2% | 8.0% |
| Hispanic | 19.4% | 10.8% | 11.9% | 26.2% | 16.4% | 21.7% | 7.4% | 3.8% | 18.9% | 10.0% | 22.8% | 24.2% | 23.8% |
| Absolute Difference (% Observed - % Expected) | |||||||||||||
| White | 9.3% | −7.9%c | −5.9%c | 20.4%c | −0.4% | 10.9% c | −10.4%c | 10.3%b | 1.9% | −5.6%c | 6.5% | 4.7%a | 5.2% b |
| Black or African American | −3.1% | 7.6%c | 6.3% c | −14.3%c | 3.5%a | −6.2%c | 8.0%c | −10.2%b | −1.3% | 4.1% c | −0.9% | −1.6% | −1.4% |
| Multi-race, not specified | 5.7%a | 1.7%a | 2.2% c | −0.2% | −0.6% | −0.3% | 0.7% | 1.2% | 1.0% | 0.8% a | −0.5% | −0.4% | −0.5% |
| Asian | −7.4%b | −1.9%a | −2.5%b | −3.3%c | −0.5% | −2.1%c | −4.6%c | −2.2%b | −2.4%b | −3.8%c | −5.1%c | −9.5%c | −8.2%c |
| American Indian or Alaskan Native | −0.1% | 0.3% | 0.3% | −0.2% | −0.4% | −0.3%a | 0.4%a | 0.1% | 0.7% | 0.5% b | 3.5%a | 0.8% | 1.6% b |
| Hawaiian or Pacific Islander | −0.1% | 0.1% | 0.1% | 0.2%a | 0.3% | 0.1% | 0.0% | −0.1% | 0.1% | 0.1% a | 0.6% | 0.8% | 0.7% |
| Not reported/Unknown | −4.3% | 0.0% | −0.6% | −2.7%c | −1.8%b | −2.3%c | 6.1%c | 0.9% | −0.2% | 4.1% c | −4.1% | 5.2%c | 2.6% a |
| Hispanic | −6.4% | 2.9%b | 1.8% | 7.0%c | 4.6%c | 5.9% c | −2.6%c | −1.3% | 0.7% | −1.7%a | −4.8% | 10.3%c | 6.1% b |
p< 0.05
p<0.01
p<0.001
A more granular look at enrollment diversity by state, as represented by the Diversity Index, is presented in Figure 2. The shading cutoffs employed in this figure reflect those that have been used, by others, to describe population diversity in counties across the U.S.[26] In non-U.S. study settings, the diversity was far less varied (Table 2b), though wholly aligned with expectations for those regions. Calculated diversity index was highest in Canada (D=54.0, n=386) followed by England (D=32.4, n=21) with essentially no diversity in Israel (D=0.0, n=13) and Singapore (D=0.0, n=15).
Figure 2.
Enrollment diversity by U.S. state.
Table 2b.
Racial and ethnic distribution in enrollment by non-U.S. country for BPCA-funded studies from 2008–2020.
| Country | Canada (386) |
England (21) |
Israel (13) |
Singapore (15) |
|---|---|---|---|---|
| White | 71.2% | 81% | 100% | 0% |
| Black or African American | 10.4% | 0% | 0% | 0% |
| Multi-race, not specified | 3.6% | 0% | 0% | 0% |
| Asian | 5.4% | 0% | 0% | 100% |
| American Indian or Alaskan Native | 2.1% | 0% | 0% | 0% |
| Hawaiian or Pacific Islander | 0.0% | 0% | 0% | 0% |
| Not reported/Unknown | 7.3% | 19% | 0% | 0% |
| Hispanic | 6.2% | 0% | 0% | 0% |
| Absolute Difference (% Observed - % Expected) | ||||
| White | −0.6% | −7.8% | 3.3% | 0.0% |
| Black or African American | 2.1% | −1.9% | 0.0% | 0.0% |
| Multi-race, not specified | 3.2%b | −2.1% | −3.3% | 0.0% |
| Asian | −8.7%c | −6.0% | 0.0% | 3.3% |
| American Indian or Alaskan Native | 0.8% | 0.0% | 0.0% | 0.0% |
| Hawaiian or Pacific Islander | 0.0% | 0.0% | 0.0% | 0.0% |
| Not reported/Unknown | 3.2% | 17.9% | 0.0% | −3.3% |
| Hispanic | 2.8% | 0.0% | 0.0% | 0.0% |
p< 0.05
p<0.01
p<0.001
When examining trends in racial/ethnic enrollment across the 13-year timeframe, we observed wide fluctuation from year to year, though the rank order between racial/ethnic groups stayed relatively consistent (Table 3). In 5 racial groups (Asian, Black, Hawaiian/Pacific Islander, Not reported/Unknown, White), there was no significant trend in enrollment over time as evidenced by confidence intervals for the slope that span zero (Table 3). Similarly, there was no trend in enrollment among Hispanic participants. By contrast, enrollment among American Indian/Alaskan Native and Multiracial children significantly increased during this time frame at rates of 0.17% and 0.36% per year, respectively (p<0.01). Nevertheless, the absolute numbers enrolled for these population subgroups remain modest.
Table 3.
Trends in racial and ethnic pediatric study enrollment over time for BPCA-funded studies.
| Year | AI/NA | Asian | Black | HI/PI | Multi | NR | White | Hispanic |
|---|---|---|---|---|---|---|---|---|
| 2008 | 0.8% | 3.4% | 29.7% | 2.5% | 2.5% | 4.2% | 56.8% | 19.5% |
| 2009 | 0.0% | 0.7% | 28.3% | 0.3% | 1.7% | 5.3% | 63.7% | 16.0% |
| 2010 | 0.0% | 5.3% | 17.1% | 0.3% | 2.6% | 6.6% | 68.1% | 22.7% |
| 2011 | 0.6% | 1.7% | 29.4% | 0.6% | 2.3% | 6.2% | 59.3% | 20.9% |
| 2012 | 0.0% | 1.9% | 22.9% | 0.2% | 2.4% | 3.9% | 68.7% | 13.0% |
| 2013 | 0.5% | 1.6% | 18.0% | 0.5% | 1.9% | 3.7% | 73.8% | 14.0% |
| 2014 | 0.7% | 1.4% | 38.1% | 0.2% | 1.5% | 9.2% | 48.8% | 10.5% |
| 2015 | 0.4% | 2.1% | 27.2% | 0.4% | 3.2% | 3.9% | 62.9% | 18.5% |
| 2016 | 1.1% | 2.6% | 15.3% | 0.3% | 4.2% | 8.2% | 68.3% | 14.4% |
| 2017 | 1.0% | 2.7% | 19.5% | 0.1% | 7.1% | 3.7% | 66.0% | 18.1% |
| 2018 | 0.9% | 1.7% | 16.3% | 0.1% | 4.9% | 7.0% | 69.1% | 12.9% |
| 2019 | 1.8% | 3.5% | 25.0% | 0.2% | 5.6% | 5.0% | 58.9% | 15.6% |
| 2020 | 3.2% | 2.7% | 18.6% | 0.9% | 5.4% | 2.7% | 66.5% | 18.1% |
| Min | 0.0% | 0.7% | 15.3% | 0.1% | 1.5% | 2.7% | 48.8% | 10.5% |
| Max | 3.2% | 5.3% | 38.1% | 2.5% | 7.1% | 9.2% | 73.8% | 22.7% |
| Slope | 0.17% | 0.00% | −0.67% | −0.07% | 0.36% | −0.04% | 0.26% | −0.28% |
| Lower CI | 0.07% | −0.20% | −1.74% | −0.17% | 0.17% | −0.37% | −0.85% | −0.85% |
| Upper CI | 0.27% | 0.20% | 0.40% | 0.03% | 0.55% | 0.29% | 1.37% | 0.29% |
| p-value | 0.003 | 0.986 | 0.196 | 0.161 | 0.001 | 0.787 | 0.622 | 0.306 |
AI/NA- American Indian/Native Alaskan, HI/PI- Hawaiian/Pacific Islander, Multi- Multiracial, NR- Not reported, CI- 95% confidence limit.
When explored by study type, the only significant racial and ethnic differences observed were lower enrollment for American Indian/Alaskan Natives and higher enrollment for Hispanics in the interventional studies (p<0.05, Table 4). More differences in racial/ethnic distribution were observed by study burden; however, these were largely influenced by the higher proportion of participants in the “zero” burden studies where information on race and ethnicity was incompletely captured (Table 5). When focusing on the studies with some degree of participant burden (i.e. those scored in the range of 1–3), White children were represented to a lower extent in moderate burden studies whereas the inverse was observed for Black children. A higher proportion of Multi-racial children were enrolled in high burden studies (vs. low/moderate burden) and a higher proportion of American Indian children were enrolled in moderate vs. low burden studies.
Table 4.
Racial and ethnic distribution in enrollment by study type for BPCA-funded studies from 2008–2020.
| Overall | Non-Interventional | Interventional |
|---|---|---|
| White | 63.3% | 61.9% |
| Black or African American | 24.4% | 26.1% |
| Multi-race, not specified | 3.8% | 3.4% |
| Asian | 2.4% | 1.9% |
| American Indian or Alaskan Native* | 0.8% | 0.3% |
| Hawaiian or Pacific Islander | 0.3% | 0.4% |
| Not reported/Unknown | 5.1% | 6.1% |
| Hispanic or Latino* | 15.3% | 18.2% |
p<0.05
Table 5.
Racial and ethnic distribution in enrollment by study burden for BPCA-funded studies from 2008–2020.
| Overall | No burden (0) |
Low burden (1) |
Moderate burden (2) |
High burden (3) |
|---|---|---|---|---|
| White | 44.8% a | 67.1% c | 55.4% f | 64.6% |
| Black or African American | 40.7% a | 21.3% c | 30.8% f | 21.4% |
| Multi-race, not specified | 1.1% a | 3.8% d | 3.1% f | 9.6% |
| Asian | 2.3% | 2.3% | 2.7% | 1.6% |
| American Indian or Alaskan Native | 0.7% | 0.7% c | 1.3% | 0.8% |
| Hawaiian or Pacific Islander | 0.0% b | 0.4% | 0.2% | 0.0% |
| Not reported/Unknown | 10.4% a | 4.4% e | 6.6% f | 2.0% |
| Hispanic or Latino | 10.0% a | 16.6% | 15.3% | 16.3% |
| Not reported/Unknown | 15.5% a | 2.5% | 3.3% f | 1.4% |
difference between 0 vs. 1/2/3, p<0.05
difference between 0 vs. 1, p<0.05
difference between 1 vs. 2, p<0.05
difference between 1 vs. 3, p<0.05
difference between 1 vs. 2/3, p<0.05
difference between 2 vs. 3, p<0.05
Finally, we explored whether observed enrollment tracked with the over- or under-representation bias that we predicted based on reported epidemiologic, sociodemographic, and healthcare utilization patterns. For studies of conditions where we expected higher enrollment in the Black population (e.g. prematurity, obesity, sickle cell disease), we observed that the proportion of Black children enrolled was nearly 10 percentage points higher than seen in studies where no bias between black and non-Black children was expected (33% vs. 24.3%, p<0.001). In contrast, assumptions for studies where we expected disproportionate enrollment in White (e.g. mental health, infantile hemangioma) or Hispanic (e.g. status epilepticus, renal transplant, obesity) children proved largely incorrect. For example, in studies where a higher proportion of White children were expected, enrollment percentages were nearly 6 points lower than in studies where no bias in White representation was expected (58.2 vs. 63.9%, p<0.001). Similarly, studies in which we predicted lower Hispanic enrollment demonstrated a near doubling in the opposite direction as compared to studies where bias was not expected (29.8% vs. 15.3%, p<0.001).
Discussion
This study reveals that the pediatric investigators responsible for executing federally-funded drug and device studies under BPCA have ensured ethnic and racial representation among study participants. The minority enrollment observed in these studies was comparable to, or greater than, would be expected based on estimates from the general population. Thus, while the legislation never required pre-specified racial and ethnic representation in pediatric studies, legislators may be reassured that racial and ethnic minorities are appropriately represented in trials supported by the off-patent component of BPCA which is required by law to be reviewed and renewed by the US Congress every 5 years.
It is possible that the equity observed in this study arose because federally-funded investigators are attuned to NIH initiatives surrounding race and ethnicity. However, the wide range of minority representation reflected in the most recent triennial inclusion reports for the various NIH institutes argues that this is unlikely the sole reason for our findings.[27] It is also possible that pediatric-trained, clinician-investigators feel a greater sense of responsibility to ensure that broad enrollment is sought from all eligible participants and families for whom they care. Though, this remains speculative as, to our knowledge, this is has not been documented quantitatively for other large NIH-sponsored pediatric clinical trial programs. Another possibility is that multi-disciplinary, pediatric, clinician-investigator teams that are experienced in the conduct of drug and device trials, approach trial design with an eye toward simplifying inclusion/exclusion criteria, eliminating undue emotional distress, and minimizing participation burden wherever possible. However, we would be remiss not to acknowledge that the findings might simply reflect the balance of children presenting to the participant institutions. If this latter explanation were proven to be the case, it would underscore the need to purposefully select study sites that serve a broad cross-section of the population.
The one exception in these studies was children of Asian ancestry who were represented at significantly lower proportions than the census would have suggested. Reasons for this finding remain unclear. With no significant disparity in overall rates of medically uninsured among Asian-Americans, economic factors may not serve as the primary explanation.[28] It is well described that cultural norms influence health care seeking behaviors in the Asian community resulting in lower healthcare utilization,[29–33] and this appears to extend to Asian-American children as well.[34,35] However, without the demographic distribution of patients receiving care at each of the 164 participating study sites, this theory cannot be confirmed. It is also possible that limited English proficiency, coupled with a lower likelihood of permission/assent and consent (PAC) forms being translated into Asian languages versus more prevalent languages (e.g. Spanish), could have played a role. Unfortunately, we did not have access to the PAC forms created for these studies to explore this theory.
We observed no discernible trends in participation by study burden across the entire cohort though unique differences were noted within populations. However, the conclusions that can be drawn from these findings are limited by the fact that our views of research burden (i.e. the views of clinical investigators with extensive clinical trials experience) may be different than those of participants. Where medical and economic risks to clinical study participation are objectively easy to identify, psychological burdens are perhaps less so.[36] In the context of pediatric research, it is unclear whether concerns of the parent/guardian are projected onto the child. On a separate note, the over representation of unknown/unreported participants in the zero burden studies which largely reflect retrospective chart reviews, speaks to the inherent limitations of research conducted using Electronic Health Record systems where race and ethnicity are incompletely captured.
Interestingly, our predictions of enrollment bias, as informed by the medical literature, were largely incorrect. While we did see higher Black participant enrollment in studies where bias in favor of Black participation was expected, this was not reproduced for the White and Hispanic populations. A posteriori examination of our miscalculations for expected bias in White participants appeared to be influenced by the inclusion of studies dealing with pregnancy and lactation where our perceptions were driven by reported racial differences related to adequate prenatal care. However, we were unable to account for the composition of the population served by the enrolling centers. When these studies were removed from the analysis, we did observe bias in the predicted direction (69.1% vs. 63.9%, p=0.009) albeit moderate. Our findings in the Hispanic population, where lower estimates of enrollment were expected, may also be driven by patient demographics at the enrolling centers. However, it is more likely that our predictions reflect an incomplete understanding of the factors that influence the rate and extent to which patients present for care.
Despite perpetuated myths about minority participation in clinical research,[37] our data do not indicate that under-represented pediatric populations are less likely to participate in clinical research. However, we cannot discriminate between the rate at which families from racial/ethnic minorities were approached for participation in these studies and the proportion that elected to participate. Nevertheless, these data reassure us that minority children have not been overlooked in the pediatric studies conducted with funding from BPCA.
Based on the nature of this investigation, we were unable to identify whether the individual studies were powered to explore the impact of race and ethnicity on study outcomes and whether such analyses were undertaken. However, ensuring balance in the acquisition of knowledge and the generation of evidence will be an important initiative as we look to refine our understanding of drug and device response as it shapes the risk-benefit balance for these interventions in children of different racial/ethnic backgrounds. Failure to do so will only serve to exacerbate the health disparities that exist among racial and ethnic minorities.[38]
Conclusions
Historically, the biomedical research community has done an inadequate job of ensuring the broad and balanced enrollment of underrepresented minorities in drug and device trials.[39–44] This study revealed no evidence of racial/ethnic bias in pediatric clinical trial enrollment for investigator-initiated studies conducted with funding from the BPCA; a reassuring finding in light of the racial and ethnic disparities that persist in healthcare. However, these findings are not reflective of all contexts wherein pediatric clinical research takes place. In clinical research settings where similar findings have not been observed, or in settings where clinical trial planning is ongoing and adequate racial representation is paramount (e.g. COVID therapeutic trials), collaborative discussions between stakeholders may offer solutions to resolve these disparities.
Supplementary Material
What’s Known on This Subject:
The federal government has purposefully investigated the impact of pediatric legislation on the inclusion of children in studies of on-patent drugs and concomitantly reported on racial/ethnic inclusion. However, minority representation in legislatively-mandated, federally-funded studies of off-patent medications is yet undescribed.
What This Study Adds:
This study highlights the extent to which pediatric investigators, overseeing drug and device trials, are ensuring balanced ethnic and racial representation among study participants. To our knowledge, similar findings have not been reported for other large Government-sponsored pediatric trial programs.
Acknowledgements
We gratefully acknowledge Gina Simone and Dr. Ravinder Anand at the BPCA data coordinating center and Dr. Perdita Taylor-Zapata at NICHD for their assistance and input on the execution of this study.
Funding Support:
Funded, in part, by the Marion Merrell Dow/Missouri Chair in Pediatric Clinical Pharmacology held by Dr Abdel-Rahman.
Conflict of Interest Disclosures:
Authors Abdel-Rahman, Delmore, Hornik, Paul, Sullivan, Wade, and Zimmerman serve as members of the steering committee for the Pediatric Trials Network (PTN), which receives BPCA funding from the NICHD. Dr. Benjamin serves as the PI of the PTN. At the time of writing Dr. Sharma was employed by the BPCA data coordinating center.
Abbreviations:
- BPCA
Best Pharmaceuticals for Children’s Act
- FDA
U.S. Food and Drug Administration
- NICHD
Eunice Kennedy Shriver National Institute for Child Health and Human Development
- NIH
National Institutes of Health
- PTN
Pediatric Trials Network
Footnotes
Presentation
This work has been accepted as a poster presentation at the 2021 annual meeting of the American Society for Clinical Pharmacology and Therapeutics planned for March 2021.
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