How Clinical Pharmacology Can Support Clinical Trial Diversity and Inclusion

ABSTRACT

Enrolling diverse populations during early clinical trial development and planning for diversity plans could be challenging. In 2024, the Diversity and Inclusion Clinical Pharmacology Leadership Group Working Group (D&I CPLG WG) from The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) collaborated with the American Society for Clinical Pharmacology and Therapeutics (ASCPT) to develop a pre‐conference session with speakers from industry, regulators, and IQ to utilize clinical pharmacology tools and implement the guidance on diversity plans toward improving the participation of under‐represented populations in clinical trials. The pre‐conference was well attended by industry, academia, as well as regulators and led to robust presentations and panel discussions through speaker sessions and case studies. The three state‐of‐the‐art lectures and five case studies address key issues concerning the inclusion of underrepresented populations, as well as clinical pharmacology strategies to support the assessment of benefits and risks. The sessions offered insights into clinical pharmacology strategies for evaluating the effects of age, ethnic differences, organ impairment, drug metabolism, transporters, and translational pharmacogenetics approaches in clinical trials. They also highlighted the application of model‐informed drug development (MIDD)‐based extrapolation to bridge Phase III results to targeted subpopulations, thereby enhancing the efficiency of drug development. Additionally, the diverse formats of this pre‐conference, including a hands‐on workshop, breakout sessions, and panel discussions, provided an opportunity for the audience to discuss the practicalities of incorporating these principles in drug development settings. This conference reinforced that achieving diversity in clinical trials is a multifaceted challenge that requires sustained efforts across the clinical research ecosystem, guided by a commitment to equity and community engagement. As clinical pharmacologists, we are uniquely positioned to lead this transformation, ensuring future therapies are safe, effective, and equitable for all.

1. Introduction

Driven by growing awareness of health disparities and the need for equitable healthcare outcomes, the inclusion of previously underrepresented populations in clinical trials has been increasingly recognized as a critical component of drug development over the past few years [1]. Exclusion of such underrepresented demographic groups may result in post approval or post marketing requirements/commitments and challenges for providers when prescribing medications to these populations, especially if there is a high unmet need or a higher prevalence of an indication in such an underrepresented population [2]. Addressing this issue is a critical aspect of ensuring that clinical trial outcomes are generalizable to the population of interest and minimizing health disparities. In April of 2022, the Food and Drug Administration (FDA) issued a draft guidance underscoring the importance of diversity in clinical trials, which recommended that sponsors seek diversity in clinical trial enrollment inclusive of race and ethnicity and underrepresented populations defined by demographics such as sex, gender identity, age, socioeconomic status, disability, pregnancy status, lactation status, and co‐morbidity [3, 4]. The guidance calls for the creation of a diversity action plan (DAP) during early clinical development to communicate diversity goals and their implementation. However, there are challenges associated with generating a diversity plan in early clinical development, some of which, from a clinical pharmacology perspective, are outlined in a recent International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) White Paper [4]. Beyond the discipline of Clinical Pharmacology, in general, with the significant uncertainties associated with pharmacokinetics (PK), safety, efficacy, population enrollments, etc., these challenges often get compounded early on, limiting our understanding of differences in treatment across demographic subpopulations.

To a large extent, clinical pharmacology investigations offer a promising approach to overcoming these uncertainties and challenges through adaptive design, using virtual populations, modeling, and simulations. By leveraging clinical pharmacology principles and quantitative modeling approaches, researchers can gain a deeper understanding of how different populations may respond to a given therapy, thereby informing the design of clinical trials that are more inclusive. This principle was recently extensively discussed through efforts by the Clinical Pharmacology Leadership Group (CPLG) IQ working group on D&I: Role of clinical pharmacology. The efforts of this working group culminated in a white paper that was recently published on behalf of the IQ consortium [4]. This white paper provided challenges associated with the inclusion of broader populations and potential opportunities to close such gaps. For example, the use of model‐informed drug development (MIDD) may allow for better description and prediction of exposure–response in specific subgroups, which can guide dose adjustments and optimize safety profiles across diverse patient populations. Additionally, clinical pharmacology facilitates the understanding of the underlying mechanisms and the causal rather than correlative factors behind observed differences between subgroups defined by race, ethnicity, or age. This will help ensure drug developers plan appropriately to obtain sufficient clinical data to characterize safety, PK, pharmacodynamics, and responses in each subgroup before embarking on an inclusive pivotal clinical trial [5].

With these discussions in mind, and a follow‐up to the IQ efforts to bring this topic at a broader discussion level and an education forum at the Annual ASCPT meeting on March 26, 2024, the ASCPT Pre‐conference Workshop on “Clinical Trial Diversity & Inclusion: How Clinical Pharmacology Can Support the Implementation of Regulatory Guidance on Diversity Plans,” co‐sponsored by the IQ Consortium Clinical Pharmacology Leadership Group, took place.

The goals of this workshop were threefold:

• To provide education on the use of clinical pharmacology concepts to contribute to diversity plans in drug development.

• To share case studies for broadening enrollment of under‐represented populations.

• To familiarize participants with the concept of Diversity Plans at EoP2/pivotal trial design, using hands‐on cases and a breakout session.

The workshop started with three state‐of‐the‐art lectures on clinical trial diversity from industry and regulatory perspectives. Five case studies were presented outlining issues related to the inclusion of underrepresented populations, and clinical pharmacology approaches to support characterizing benefits and risks. The workshop attendees participated in breakout sessions to emulate a typical trial plan as part of a clinical development plan and co‐create a DAP for the development of hypothetical drugs for the treatment of cancer, infection, and inflammation in a hands‐on exercise. The workshop concluded with a panel discussion on perspectives pertinent to diversity and inclusion in clinical trials and case studies, reinforcing the key learning points of this pre‐conference workshop. As the industry continues to evolve, the collaborative efforts of regulators, academia, and industry stakeholders will be essential in implementing these strategies and advancing the field of precision medicine. This paper summarizes the proceedings and key learnings from the 1‐day workshop.

2. Introductory Lectures

2.1. Lecture 1: Advancing Health Equity Through Clinical Trial Diversity

The effectiveness and safety of a drug can be impacted by both extrinsic and intrinsic factors. Extrinsic factors such as food effects and drug–drug interactions can impact metabolism and response. Also, intrinsic factors such as disease state, age, sex, or genetic variation can lead to differential drug metabolism or therapeutic effects [6]. Considering the impact of intrinsic and extrinsic factors in drug response, enrolling clinical trial participants that reflect the diversity of the patient population that would use a medical product upon approval helps to build confidence in the generalizability of study results. FDA has a longstanding commitment to clinical trial diversity and increasing enrollment of participants who are members of historically underrepresented populations in clinical studies. This commitment has resulted in the issuance of guidance and policy development in this space and other initiatives related to health equity [7].

The FDA initiatives and activities in this space include public workshops, agency‐conducted and supported research, and patient and community education. For example, FDA centers and offices have ongoing public education and outreach related to enhancing the diversity of clinical trial participants by identifying barriers to enrollment and employing innovative strategies, training, education, and communication methods intended to increase clinical trial enrollment for historically underrepresented populations across varying categories, including ethnicity, race, age, disability, and geography. The FDA also has publicly available tools to provide insight into the demographic attributes of patients enrolled in clinical trials that support the approval of novel therapies, such as Drug Trials Snapshots, and recently the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health have published similar data [8].

The agency has issued several related guidance documents to provide insight into considerations for enrolling clinical trial participants that are representative of the population that would use a product if approved [7]. Examples include the International Council for Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) E5 guidance, which discusses intrinsic and extrinsic factors in the acceptability of foreign data, and the ICH E17 guidance related to planning multi‐regional clinical trials, which can be useful in examining the applicability of therapies to diverse populations [9, 10]. These documents may be of particular interest given the increasingly global nature of medical product development programs. An additional recent example is the draft guidance published in June 2024, Diversity Action Plans to Improve Enrollment of Participation from Underrepresented Populations in Clinical Studies [3] that replaced the April 2022 draft guidance for Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies. Publication of the former document was a requirement of the Food and Drug Omnibus Reform Act of 2022 (“FDORA”) that was part of the Consolidated Appropriations Act of 2023.

The FDORA legislation includes provisions related to the modernization of clinical trials and improving the enrollment and retention of a diverse clinical trial population [11]. Notably, FDORA requires the submission of DAPs for clinical investigations that support medical product marketing applications, where applicable. These plans provide enrollment goals disaggregated by race, ethnicity, sex, and age group that would generally be based on what is known about the disease or condition, the United States prevalence of the disease or condition, and the patient population. In addition, sponsors should consider non‐demographic factors (e.g., co‐morbidities affecting the patient population) and potential barriers to enrollment (e.g., geographic disparities in access to care, socioeconomic status) in developing DAPs. Engagement with the appropriate review divisions during drug development is recommended.

Strategies for enhancing participation for populations across a wide range of characteristics include attention to areas such as trial design, workforce diversity, broadening the range of providers and medical facilities that contribute to trial conduct, and incorporating digital health technology and decentralized trial elements where feasible and appropriate [12, 13, 14]. Also, there are pharmacokinetic (PK) and pharmacogenomic (PGx) tools that have the potential to provide insights for study design throughout product development and to inform enrollment of representative populations. In addition to the approaches that sponsors can leverage to facilitate the inclusion of diverse trial participants, other interested parties in the clinical research enterprise, such as Institutional Review Boards and trial sites, can further support this goal through attention to related considerations, including equitable selection of subjects and by recruiting and retaining a diverse workforce [12]. With proactive planning by sponsors and the engagement of others in the clinical research enterprise, there is a unique opportunity to advance the goal of enrolling more representative clinical trial populations and the inclusion of historically underrepresented participants.

2.2. Lecture 2: Diversity: From a Clinical Pharmacology Lens

Clinical pharmacology principles and translational science can be applied to improve the diversity of the study population and the generalizability of available information. Some patient subpopulations are frequently underrepresented in biomedical research, including clinical studies supporting the development of novel drugs [4]. This underrepresentation persists even when these patient subpopulations bear a disproportionate disease burden for certain diseases relative to their proportional representation in the general population [15]. This underrepresentation occurs despite the fact that clinical studies have become more global [8, 16]. Underrepresentation of certain racial and ethnic populations led to the publication of the Diversity Plan draft guidance in April 2022 intending to provide recommendations to sponsors to develop a Race and Ethnicity Diversity Plan to enroll adequate numbers of participants in clinical studies from underrepresented racial and ethnic populations in the United States. The “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies” draft guidance was published to provide recommendations to sponsors in submitting DAPs to support certain clinical studies [17]. The goal is to ensure that the drug development programs reflect the population who are most likely to use the drug if the drug is approved. The recommendation includes considerations for demographic characteristics of race, ethnicity, sex, and age. Additional demographic (e.g., geographic location) and non‐demographic (e.g., pregnancy, lactation, comorbidities) characteristics may also need to be considered in order to study a population that more accurately reflects the patients who are likely to use the drug. Diversity is context‐dependent; that is, the considerations may vary based on the disease and the indication for which the drug is being developed. Consequently, there is no one‐size‐fits‐all approach to developing DAPs [18].

Patients who are underrepresented or who are often excluded from clinical studies are typically considered as complex populations, such as pediatrics, older adults, pregnant and lactating females, and patients with compromised kidney or liver function [19, 20, 21]. There may be expectations of altered PK when compared to a “normal patient,” and at times, there may even be an altered exposure–response (E‐R) relationship in these populations [4]. Additionally, differences in pharmacodynamics (PD), effectiveness, and safety may not be studied sufficiently in these populations. Exposure and response information in these populations can be obtained by including a more heterogeneous population in late‐phase clinical studies. Clinical pharmacology and translational science play an important role in designing these studies. Understanding the impact of intrinsic (e.g., genetics, organ function) and extrinsic (e.g., concomitant medications) factors that affect drug exposure and response can be used to inform the inclusion and exclusion criteria and other design features (e.g., need for enrichment) of these clinical studies. Additionally, non‐clinical studies and modeling and simulation approaches can help us understand if there is a potential for exposure and response differences across populations [22, 23, 24].

2.3. Lecture 3: Ensuring Diversity in Clinical Trials: The Role of Clinical Pharmacology From the Industry Perspective

Clinical trials play a critical role in public health, informing patients and health professionals of the benefits and risks of new medicines. The real‐world performance of a drug (PK, safety, and efficacy) is best assured when a diverse population representative of the entire patient population for that disease is included in clinical trials [24]. Additionally, patient confidence in the safety and efficacy of medicines is increased when patients see themselves reflected in clinical trials.

Clinical Pharmacology plays a crucial role in ensuring that a diverse population can safely and efficiently be included into early‐phase clinical trials [5]. It begins with committing to broad representation in Phase I studies as part of the overall Diversity Plan for a new medicine. While data across various groups in Phase I is typically limited to drug exposure, evidence for target engagement, limited signs of clinical activity, and general safety across a range of doses, this information is critical to allow for broader inclusion criteria in early‐phase clinical trials. Direct evidence, even from a limited number of healthy participants and/or patients from various racial, ethnic, and age groups, along with our improved understanding of underlying genetic differences in metabolism that may impact drug metabolism, is often sufficient to allow for broad inclusion criteria in Phase II multi‐regional clinical trials where we can learn more.

A major limiting factor for underrepresented groups in clinical trials is accessibility and trial burden [25]. Clinical trials are often conducted at large regional urban hospitals, requiring participants to travel for multiple study visits. Few trials are conducted in rural communities, where some of the most underrepresented groups such as North American First Nations are located. The clinical trial burden introduced by travel and time requirements is much greater and limits participation. A key role for clinical pharmacology is to help bring clinical trials to those populations most underserved by embracing patient‐centric technologies such as patient‐centric micro‐sampling, digital vital assessments, wearable devices, etc. [26, 27, 28] Normalizing routine use of these technologies and approaches has the potential to lower the barrier for study participation and to improve study enrollment and retention, especially for underrepresented groups.

MIDD approaches play a key role in making clinical trial participation a more viable care option for underrepresented patient groups [22, 24, 29, 30, 31, 32]. Utilizing the totality of information available around the therapeutic area can improve the likelihood of a patient receiving benefit within a trial by augmenting or replacing within‐study control arms with external clinical evidence (i.e., data from similar studies conducted previously, real‐world data, natural history studies, patient registries, claims data, etc.). Trial simulations can accelerate bringing information to prescribers and patients for complex groups where, typically, limited information is available at the time of initial approvals and where enrollment may be slow or difficult, such as pregnancy and lactation and pediatrics.

3. Clinical Pharmacology Case Studies

3.1. Case Study 1: Representation of Elderly Patients in Clinical Trials—Can Clinical Pharmacology Improve the Situation?

By 2060, approximately a quarter of the United States population will be 65 years and older. The fastest rate of growth is among people 80 years and older, both in the United States and worldwide [33].

This suggests that in the majority of therapeutic areas, a larger proportion of the patients are at an older age. However, older adults, especially the oldest group (80 years or older) or those with multiple chronic health conditions, polypharmacy, or frailty, seem often underrepresented in clinical trials [19]. Therefore, an IQ Working Group (WG) was initiated to assess the status and potential root cause of the underrepresentation of older adults, particularly in pivotal clinical trials. This IQ WG conducted a survey across member companies.

An output of the IQ WG of elderly patients conducted a survey. The surveys comprised 51 randomized controlled registrational studies on 28 different compounds. Of the surveyed studies, 88% had no age restriction per protocol, and 86% reported data from patients older than 75 years [34]. A case study from the survey used the TriNetX, an electronic health record tool, analyzed information from a randomized controlled phase III trial in chronic kidney disease (CKD) and revealed the following:

• ○The base population of CKD patients in the case study in the TriNetX equal to or older than 80 years was 32% of adult CKD patients (> 18 years).
• ○The trial protocol did not have any age restrictions except for a minimum age of 18.
• ○After application of the exclusion criteria, the share of ≥ 80 years old CKD patients was only slightly reduced to about 25%.
• ○8.6% of all adult CKD patients screened for the trial were ≥ 80 years, and 8.3% were finally randomized.
• ○The participation to prevalence ratio was 8.3%/32% = 0.26.

This analysis suggests that age restrictions per protocol are the exception. The inclusion/exclusion criteria do not have a meaningful effect on the participation of elderly adult patients. Within the survey, this finding was also confirmed in other indications such as heart failure, macular edema, hepatitis‐C virus (HCV), and various pain indications (osteoarthritic pain, neuropathic pain, lower back pain). However, trial participation in the pivotal studies is much lower than it should be to represent the prevalence of the disease. Two factors for losing elderly patients after screening suggested to be the patient's wishes and the investigator's concern, which is to include elderly, potentially multi‐morbid patients. The question of how Clinical Pharmacology could improve the situation has to be seen under the following aspects:

1. Generate information in elderly adults addressing the concerns of investigators to include elderly adult—potential comorbidities associated within this population—patients in long‐term clinical trials.

2. Generate additional experimental data besides observed clinical data.

3. Evaluate PK, PD, or E‐R differences between younger and older adult patients.

The factors potentially modifying PK are most readily able to be characterized (e.g., higher gastric pH, lower organ blood flow, changes in serum protein and body composition, higher frequency of organ impairment in an elderly population) through dedicated clinical pharmacology studies and/or semi‐mechanistic or mechanistic modeling approaches [12, 29, 35, 36, 37]. Based on PK, the appropriate dose for elderly adult patients can be defined in most instances with reasonable precision and should pose no reason for concern.

Differences in PD, PK/PD, or E‐R have been reported in several disease areas, such as immunology, central nervous system, or cardiovascular, with a prominent example being anticoagulants [38]. Differences between younger and older patients seem to have a greater impact than PK, but they can generally only be identified from the data generated in patient trials or real‐world data [39]. Interestingly, from the survey presented above, of 51 pivotal phase III trials, population PK was applied in 75% of the trials, but E‐R analyses were only applied in 54%. The question of what data can be generated before the pivotal trial to alleviate any concerns of the investigators seems of utmost importance. Dedicated small PK/PD studies in elderly subjects, similar to the ethnic bridging studies, or a more targeted recruitment of elderly multi‐morbid patients into phase II trials, combined with MIDD, may improve the situation to have a more adequate representation of elderly patients in the pivotal trials defining benefit–risk. When sufficient numbers of elderly patients are represented in the pivotal phase III trials, E‐R analyses can identify differences in PK/PD and better inform benefit–risk and potential dose adaptations in elderly patients. While clinical pharmacology may help to generate data to allow the inclusion of elderly patients into pivotal phase III trials, or even may create information beyond pure clinical, observational data, other aspects, such as investigator, patient (or even sponsor) concerns, logistic hurdles, lack of caregiver engagement, and absence of endpoints relevant to elderly patients, seem the major barriers prohibiting adequate participation of elderly adult patients in clinical development [40].

3.2. Case Study 2. Impact of Ethnic Differences in PK on Drug Development and Significance of Phase I Studies in Different Regions

The Pharmaceuticals and Medical Devices Agency (PMDA) recognizes the significance of interethnic comparison of PK in new drug development using foreign clinical studies or Multi‐Regional Clinical Trials (MRCTs) data. In the ICH E5 guideline, “ethnic factors” are defined as factors relating to races or large populations grouped according to common traits and customs. The guideline also describes intrinsic and extrinsic factors that may affect the treatment effect [41]. Since intrinsic and/or extrinsic factors may impact treatment effects across regions, it is necessary to take the ethnic factors into account when planning MRCTs. There are examples of different doses applied between Japanese and White/European populations due to PK differences (Table 1). In a review of these drugs, the PK differences were concluded as significant and related to efficacy or safety differences [42, 43, 44, 45, 46].

TABLE 1.

Examples of approved drugs with dosing regimens differ between Japanese and Caucasian populations.

Drug	Indication	AUC ratio (Japanese/Caucasian)	Approved dose
			Upper: US
			Lower: Japan
Rosuvastatin	Hyper‐cholesterolemia	2	5–40 mg 2.5–20 mg
Eltrombopag olamine	Idiopathic thrombocytopenic purpura	2	50–75 mg (non‐East Asian) 12.5–50 mg
Simeprevir	Anti‐viral, HCV infection	1.5	150 mg 100 mg
Rivaroxaban	Non‐valvular atrial fibrillation	1.38	20 mg, 15 mg 15 mg, 10 mg
Opicapone	Parkinson's disease	2	50 mg 25 mg

It is important to conduct well‐planned clinical trials to investigate ethnic differences that may impact PK, PD, and/or dose selection before the start of the MRCT. The ICH E17 guideline says that to understand the impact of ethnicity on PK and/or PK‐PD, data may be obtained from single‐region trials in multiple regions, a trial with multiple ethnicities conducted in one region, or MRCTs [47]. Using phase I data from Japan and other countries, the impact of ethnic‐related factors such as race and body weight on PK can be investigated.

PMDA and the Ministry of Health, Labor and Welfare (MHLW) have developed guidelines to promote MRCTs and resolve the drug lag, which is the situation where drugs approved in Europe and the United States are not approved in Japan [48, 49, 50]. The former guidelines stated that a Japanese phase I trial prior to MRCTs was required in principle, but the necessity of conducting a Japanese phase I trial should be determined in consideration of the PK/PD properties and safety of the drug. In practice, for Japanese patients to participate in MRCTs without delay, PMDA has not always requested conducting a Japanese phase I trial prior to participating in MRCTs. However, in some cases, sponsors conducted the Japanese phase I trial on a voluntary basis without consulting the PMDA.

In recent years, cases have been identified in which early clinical development occurs outside Japan by overseas emerging companies, and development in Japan is being considered just before starting a confirmatory MRCT. In these cases, if the phase I trial in Japan is not conducted prior to initiating the confirmatory MRCT, Japan might not be able to participate in the MRCT. Based on these changes in the drug discovery and development environment, the “Basic principles for conducting phase I studies in Japanese participants prior to initiating MRCTs including Japan for drugs in which early clinical development is preceding outside Japan” has been issued on December 25, 2023 in order to minimize the disadvantages to Japanese patients due to delays in the approval of innovative drugs in Japan [51]. The new guideline states that, in principle, an additional phase I trial in Japanese participants is not needed unless it is deemed necessary after assessing whether the safety/tolerability of the dosage to be evaluated in the MRCTs in Japanese participants can be explained and the safety is clinically acceptable/manageable based on the data available prior to Japan's participation. On the other hand, the guideline also states that it remains desirable that Japan participates in the early phase of clinical development, considering the importance of identifying key ethnic factors early in drug development and improving Japan's capabilities in drug discovery and development. In addition to the basic principles, the guideline also shows examples where phase I trial in Japanese is not required, as below:

1. To minimize the disadvantages caused by the delay, in case of drugs with high unmet medical needs, such as drugs for rare diseases, refractory and serious diseases, or pediatrics, Japan can join MRCTs without conducting a phase I trial in Japanese participants.

2. Except for drugs described in (1), they will not be required to undergo a phase I trial if the safety of Japanese participants can be judged to be clinically acceptable/manageable considering facts such as PK and/or safety being less likely to be sensitive to ethnic factors based on clinical and nonclinical data, and existing knowledge.

3. Even for drugs that meet (1) or (2), the necessity of a phase I trial in Japanese participants should be judged more carefully if the drug is expected to frequently cause serious adverse events and has a narrow safety margin, as observed, for example, in anticancer drugs, with limited safety data such as no experience of administration in Japanese regardless of age and/or indication.

Questions and answers for the guideline were also issued by PMDA to help drug developers decide whether to conduct phase I studies in Japan [52]. A highlighted example question “What points should be considered to determine whether the safety of Japanese participants is clinically acceptable and manageable in the MRCT in which Japan will participate?” The answer is “The risks of the study drug should be comprehensively examined, mainly taking into account the safety profile of the study drug and the effect of ethnic factors on the study drug to confirm that there is a possibility that the risk for Japanese participants is greater than that for non‐Japanese participants.” However, the points to consider should be selected according to the characteristics of each study drug.

Evaluation of PK and safety in multiple regions and ethnic groups from the early development phase based on the characteristics of the study drug will provide useful information for the planning and implementation of subsequent MRCTs. Regardless of conducting a phase I trial in Japanese, it is important to assess the differences in PK and/or PD between Japanese and non‐Japanese through measures such as collecting PK and/or PD data in MRCTs for drug development in Japan. Appropriate assessment of ethnic factors is expected to reduce unnecessary trials and accelerate access to novel drugs worldwide. From early phase of drug development, it is recommended to consult and communicate with regulatory agencies. The new guidelines are expected to help resolve drug development delays in Japan.

3.3. Case Study 3: Enrolling Participants With Organ Impairment in Phase II/III Trials: Challenges and Potential Solutions

The conventional way to inform dosing in patients with organ impairment is through conducting pharmacokinetic studies in participants with organ impairment. The inclusion of participants with organ impairment in Phase II/III trials can be facilitated through the use of modeling and simulation, real world data, and improving the design of PK studies in participants with organ impairment (Figure 1).

FIGURE 1.

Ways to facilitate the inclusion of participants with organ impairment in Phase II/III clinical trials.

The advancement of modeling and simulation techniques allows the prospective prediction of exposure changes in participants with renal impairment, which can be used to facilitate the inclusion of participants with organ impairment in phase II/III trials. Good concordance in exposure changes due to renal impairment was reported when population PK analysis was used to predict exposure changes observed in dedicated renal impairment studies for 17 drugs [53]. The ability of physiologically‐based pharmacokinetic (PBPK) models to predict exposure changes due to renal impairment was demonstrated for 25 different drugs [54]. The utility of modeling and simulation techniques to predict exposure changes in participants with hepatic impairment is still evolving, and more work is needed to advance the field in this area.

In addition to modeling and simulations, real world data can be used to inform the need for organ impairment assessment and evaluate the feasibility of characterizing exposure differences of the investigational drug in target patient populations with organ impairment [24]. These data can be used to target clinical sites where the probability of enrolling participants with organ impairment is relatively high given the prevalence of organ impairment in the target population. Vora et al. reported the development of a user‐friendly dashboard utilizing the Flatiron Health electronic health records database to inform the prevalence of organ impairment among certain patient populations [32].

Improving the design of dedicated PK studies in participants with organ impairment can accelerate the availability of exposure data needed to inform the inclusion of participants with organ impairment in phase II/III trials. The use of a virtual or external control group can potentially shorten trial duration. Younis et al. coined this idea and demonstrated its feasibility among 7 drugs [23]. The utility of this approach was further demonstrated by Prybylski et al. [22] choosing the right criteria to assess renal impairment or hepatic impairment in these studies is key for obtaining more informative data [31, 55].

A recent survey by the IQ Clinical Pharmacology Organ Impairment Working Group indicated that enrolling participants with renal impairment in Phase II/III trials is largely dependent on the characteristics of the compound (small or large molecule), its renal clearance, and intended target population [56]. The typical approach would be to exclude severe renal impairment participants unless information is available from a dedicated renal impairment study or population PK model. Participants with renal impairment are included in Phase II/III trials for drugs developed to treat rare diseases or cancer. Model‐based approaches are used to facilitate the enrollment of participants with renal impairment in Phase II/III trials. The availability of predictive models at the time of protocol development is key to the success of this approach. Sponsors have experience filing initial New Drug Application/Biologics License Application (NDA/BLA) without conducting dedicated renal impairment studies. However, the experience with regulatory agencies has been mixed with regard to enrolling participants with renal impairment in Phase II/III, from encouraging to requiring such dedicated studies prior to Phase II/III trial enrollment.

Finally, several approaches have been proposed to enroll participants with organ impairment in phase II/III trials, including sequential evaluation, adaptive enrollment, enrollment in substudy, and open‐label extension [20].

3.4. Case Study 4: Drug Metabolism and Transporter Considerations for Diversity and Inclusion in Clinical Trials

The field of drug metabolism and transporters is well‐positioned to support the discovery, development, and optimal utilization of technologies to support the growth of multiple modalities across therapeutics [57]. Clinical pharmacology profiling is critical for elucidating the mechanism of drug responses and understanding variabilities that differ across patient populations with diverse backgrounds. It is pivotal for assessing the impact of genomics on drug efficacy and safety [58]. Genomic variation (in drug‐metabolizing enzymes and drug transporters) has been associated with variability in both the efficacy and toxicity of drugs. Mutations can impact drug metabolism, efficiency, and safety and are often the most underlying cause of pharmacokinetic variability [59, 60].

Despite growing trends in variability due to patient background, there are still opportunities to increase patient representation across diverse ethnic origins and not depend on data predominantly from single ancestry. Furthermore, appropriate utilization of emerging translational advancements to identify new associations within genomic studies requires clinical data from various ethnicities to inform all appropriate drivers of variability and inform clinical utility [61].

Improving the broad representation in clinical trials and widening the inclusion and exclusion criteria are some of the important steps to enhance trial representation. Individual and community factors are often cited as reasons for the lack of inclusion of underrepresented and excluded populations in clinical trials. For example, in 2020, only 8% of participants in new drug trials were Black, 6% were Asian, 11% were Hispanic, and 30% were age 65 and older, which is not the true representation of the American population. Furthermore, racial disparity in drug disposition may lead to significant variability in drug exposure in different races. For example, it was reported that CYP3A4 activity in white populations was different from that in South Asian populations, resulting in a difference in plasma exposure (AUC) of midazolam when the drug was administered at the same dose [62]. Another example showed that due to higher glucuronidation rates, the clearance of morphine in African‐American pediatrics was significantly higher than that in white pediatrics, so the authors suggested that dose adjustments for morphine may be needed for perioperative patients of different races [63]. These examples suggest that racial disparity in drug disposition and response has been realized, and racial contributions to drug efficacy and safety are important considerations in drug development that need to be considered across the entire drug development continuum.

3.5. Case Study 5: Translational Approaches to Promote Equity: A Focus on Precision Medicine

Translational studies include computational modeling, experimental cell or animal studies, epidemiologic studies, or dedicated clinical trials. These studies can be conducted at all stages of drug development to inform a variety of decisions related to clinical trial enrollment criteria or the generalizability of results. They can help identify factors that inform dosing, trial design, inclusion criteria, and site selection. For example, in vitro metabolism studies are routinely performed to inform clinical trial exclusion criteria and the need for dedicated studies [64]. Additionally, translational models may characterize treatment effects in unstudied or understudied populations not captured in pivotal efficacy and safety trials. For instance, extrapolation to pediatric populations involves considering various evidence sources to support the similarity of disease and drug response in adults and pediatrics [30]. Translational studies can also be used to explain observed heterogeneity in treatment effects. For example, genomic studies may explain differences in PK or treatment response based on race, ethnicity, or geography [65].

Various examples in the context of targeted drug development, where clinical trial enrichment is common, illustrate the importance of different translational approaches. In targeted cancer therapies, patients whose tumors have specific mutations are often the focus of clinical trials. In this context, epidemiologic studies of tumor molecular features are important for understanding the spectrum of molecular diversity, as are basic pharmacology studies evaluating drug activity in different genetic contexts. For example, in lung cancer patients of African ancestry, compared with the therapeutic targets KRAS, EGFR, and ROS1 to those of European ancestry, KRAS G12C and EGFR L858R mutations are less common, while ROS1 fusions are more prevalent [66]. Therefore, in clinical trials of KRAS G12C‐targeted therapies, the representation of African ancestry patients with KRAS G12C mutations will naturally be lower. To ensure characterization of effects in African ancestry patients, perhaps due to differences in co‐occurring alterations, site distribution may need to be adjusted to increase enrollment from this population. In some cases, generalizability can be supported by studies other than clinical trials. For example, nonclinical studies of specific variants present in more diverse populations—who may not be enrolled due to regional targeting—can provide evidence to support the generalizability of trial results to other mutations and demographic subgroups. Regulators have historically relied on nonclinical evidence of response across different tumor variants to inform the indicated population for various drugs [67].

Although less common outside oncology, clinical trials in other therapeutic areas may also focus on the population most likely to benefit, even though other patients may respond to the drug based on its mechanism. For example, during the development of the cystic fibrosis drug ivacaftor, a chloride transport modulator, multiple variants were found to respond to the drug in vitro. The initial program targeted patients with the G551D variant, the most prevalent responsive variant. The drug was initially approved for this population, and additional trials were conducted for patients with other responsive variants, expanding the indication to include eight additional variants. As confidence in the in vitro model grew, further expansions to the eligible population were based solely on in vitro data, without the need for additional clinical trial data. Ultimately, this covered 23 additional variants. Understanding the robustness of the in vitro system, coupled with the challenges of conducting clinical trials in small patient populations, supported the use of this model. A similar approach was used in the design of trials and approval of migalastat for Fabry disease [68].

4. Panel Discussion and Overall Summary

It was acknowledged that clinical pharmacology plays an essential role in achieving increasing diversity and inclusion in clinical trials. The discussion stressed the importance of awareness, strategic planning, and the commitment of all stakeholders to foster equitable access to clinical trials. Overall, drug development should consider factors that can influence exposure or response from the earliest stages. When these factors are identified, controlled evaluations should be performed to anticipate potential issues that might alter the benefit–risk profile. Regardless, clinical trials with adequate representation of diverse patient subsets—whether based on demographic or clinical factors—should always be attempted to explore intrinsic and extrinsic factors, such as organ function, weight, age, sex/gender, comorbidities, race/ethnicity/ancestry, molecular characteristics, and disease severity. Any subgroups demonstrating different responses compared to the general population should be further evaluated. These studies can support broad dosing and administration instructions for diverse populations or lead to strategies for managing clinically relevant differences.

The implementation of organizational‐level practices to improve trial diversity was another significant focus [69]. It was argued that achieving equitable access and participation requires a strong organizational commitment, beginning with senior leadership and involving the allocation of resources to support diversity initiatives. These efforts include hiring dedicated personnel, training staff, and building systems to sustain long‐term diversity practices. Partnerships with community groups, patient organizations, and clinical trial operators were identified as essential to tailoring trials to meet the needs of historically underrepresented populations [70].

A key point of the discussion was the responsibility of clinical pharmacology in not only ensuring the safety and efficacy of medicines across diverse populations but also in facilitating broader access to clinical trials. This involves ongoing efforts beyond initial drug approvals, as continued studies in real‐world settings are necessary to expand treatment information for underrepresented groups such as participants of certain races and ethnicities, older adults, those with organ impairment, those with differential genetic traits pertinent to disease, pregnant individuals, and pediatric patients. The consensus was that a framework led by the clinical pharmacology community is vital for advancing equity and diversity in clinical trials [4].

Moreover, the conversation acknowledged the broader benefits of diversifying clinical trial participation, not only for improving health outcomes but also for building trust within underserved communities. Although some scholars argued that diversification might accelerate innovation by enabling quicker participant recruitment, the discussion recognized that the value lies in fostering trust and fairness, which are fundamental to the integrity of biomedical research and will influence healthcare delivery and outcomes [21]. The discussion underscored the need for data‐driven approaches, using quantitative clinical pharmacology modeling and simulations to justify the incorporation of special populations and impacting the drug label.

5. Conclusion

In conclusion, the ASCPT 2024 pre‐conference workshop, co‐sponsored by the IQ Clinical Pharmacology Leadership Group, underscored the indispensable role of clinical pharmacology in operationalizing regulatory expectations for diversity in clinical trials. The three lectures and five case studies highlighted persistent gaps in inclusion, from older adults and racially diverse groups to patients with organ impairment and those with pharmacogenomic differences. Participants engaged in hands‐on exercises to construct DAPs aligned with early‐phase development, focusing on enhancing representation at pivotal trial stages.

The pre‐conference workshop reinforced that diversity is not just a regulatory checkbox but a scientific imperative. Achieving diversity in clinical trials is a multifaceted challenge that requires sustained efforts across the clinical research ecosystem, guided by a commitment to equity, trust, and community engagement. Looking forward, drug developers must embed inclusive design principles from first‐in‐human studies through post‐marketing surveillance. This requires early and iterative engagement with key stakeholders, robust clinical pharmacology frameworks to characterize exposure–response in special populations, and sustained investment in community partnerships and decentralized technologies to reduce access barriers.

As clinical pharmacologists, we are uniquely positioned to lead this transformation, ensuring future therapies are safe, effective, and equitable for all.

Conflicts of Interest

M.Z.L. is an employee of Third Arc Bio and holds shares in Third Arc Bio. He was an employee of Genentech, a company of the Roche family, and held stocks at the time the conference was conducted. A.S. is an employee of AstraZeneca and holds stocks in AstraZeneca. B.C. is an employee of Metrum RG. He is a retired employee of Pfizer and holds shares in Pfizer. S.H. is an employee of Boehringer‐Ingelheim Pharma GmbH & Co. KG. Y.O. has no competing interests for this work. I.R.Y. is an employee of Merck and Co. Inc. and holds shares in Merck and Co. Inc. S.K. is an employee of Gilead Sciences and holds shares in Gilead Sciences. R.M. is an employee of GSK and holds shares in GSK.

Liao M. Z., Sawant A., Corrigan B., et al., “How Clinical Pharmacology Can Support Clinical Trial Diversity and Inclusion,” Clinical and Translational Science 18, no. 9 (2025): e70332, 10.1111/cts.70332.