Toward Inclusivity in Preclinical Drug Development: A Proposition to Start with Intestinal Organoids

Abstract

Representation of humans from diverse backgrounds in the drug development process is key to advancing health equity, and while clinical trial design has recently made strides toward greater inclusivity, preclinical drug development has struggled to make those same gains. One barrier to inclusion is the current lack of robust and established in vitro model systems that simultaneously capture the complexity of human tissues while representing patient diversity. Here, the use of primary human intestinal organoids as a mechanism to advance inclusive preclinical research is proposed. This in vitro model system not only recapitulates tissue functions and disease states, but also retains the genetic identity and epigenetic signatures of the donors from which they are derived. Thus, intestinal organoids are an ideal in vitro prototype for capturing human diversity. In this perspective, the authors call for an industry‐wide effort to leverage intestinal organoids as a starting point to actively and intentionally incorporate diversity into preclinical drug programs.

Assessment of Colorectal Cancer Risk Factors through the Application of Network-Based Approaches in a Racially Diverse Cohort of Colon Organoid Stem Cells

“…Importantly, the biracial nature of this dataset helped to address key racial and data availability disparities for AA populations. Indeed, our work is in line with calls for action from a recently published review that highlighted the need for additional consideration of underserved communities in preclinical research [97]. This would lead to more targeted approaches in the future.…”

Integrating Diversity, Equity, and Inclusion into Preclinical, Clinical, and Public Health Mathematical Models

“…Advances in organoids and 3D bioprinting require an improved comprehension of their effects of the model system itself on outcomes. By considering diversity in various facets—from biobanks to cells to organoid systems (Co et al 2023 ) to animals—preclinical mathematical models can be used to improve the success of candidate molecules and increase the successful transition into clinical trials. Historically, clinical trials, especially early-phase, have been run in a homogenous group of individuals (Merkatz 1998 ) (typically younger, Caucasian men) without the integration of gender, racial, ethnic, age, and other forms of diversity (Corneli et al 2023 ).…”

From Organ-on-a-Chip to Human-on-a-Chip: A Review of Research Progress and Latest Applications

“…This milestone event highlighted the FDA's strong endorsement of the credibility of research on organoids. 2 The innovative development of organoids has made it feasible to replace animal experiments. 3 An organoid is a three-dimensional (3D) tissue formed by stem, progenitor, or differentiated cells that self-organize through cell sorting and space-constrained lineage differentiation.…”

“…In a significant development in December 2022, the U.S. Congress approved the FDA Modernization Act 2.0, which eliminated the mandatory requirement for animal tests of new drugs and encouraged the gradual adoption of alternative models when possible. This milestone event highlighted the FDA’s strong endorsement of the credibility of research on organoids . The innovative development of organoids has made it feasible to replace animal experiments …”