In recent years, “diversity” has often been discussed in societal and political contexts, sometimes creating misconceptions about its role in science and technology. However, within the field of preclinical drug development, patient diversity is not a political buzzword - it is a scientific imperative. Understanding and accounting for the biological and physiological differences between individuals ensures that new therapies are both effective and safe across the diverse populations they are intended to treat. For drug developers, this concept is integral to reducing late-stage failures, regulatory setbacks, and adverse events. At InSphero, our commitment to getting the right drugs to the right patients at the right time is emphasized by the core strength of our 3D InSight™ microtissue platform, reflecting patient diversity, which we believe is critical to the future of therapeutic development.
What does “Diversity” in preclinical research look like?
In preclinical research, patient diversity refers to the inclusion of biological variability that reflects differences in genetics, sex, age, ethnicity, and disease backgrounds among human populations, taking into consideration the effect of the patient’s environment as well. This approach ensures that preclinical models better represent the diversity of real-world patients, leading to less attrition in clinical trials due to more accurate predictions of drug efficacy and safety across different groups.
In the context of 3D in vitro models, patient diversity can be integrated by using cells from multiple donors exhibiting that variability, incorporating genetic variations, and designing models that mimic diverse disease states and co-morbidities. This helps identify population and person-specific drug responses, reduce clinical trial failures, and promote more equitable drug development.
The challenge of representing the patient population in preclinical models
Human populations are inherently diverse, and this diversity extends to how individuals metabolize drugs, experience toxicity, and respond to therapies. Genetic variability, differences in enzyme activity, metabolic capacity, and immune responses mean that a drug proven effective in one subset of the population may be less effective - or even harmful - than in another. For example, variations in liver enzyme activity (e.g., cytochrome P450 polymorphisms) can lead to differences in drug clearance, potentially causing toxicity or therapeutic failure.
Historically, preclinical research has relied on animal models and a limited set of 2D cultures of human cell lines that often fail to reflect this biological complexity. As a result, drugs that perform well in early testing may fail in clinical trials, where human diversity can reveal previously undetected risks. According to a study by the Biotechnology Innovation Organization, over 40% of drug failures in Phase II and III trials are due to issues with efficacy or unexpected safety concerns — problems that could often be anticipated if preclinical models were more representative of patient populations.
The value of microtissues derived from diverse patient samples
At InSphero, we address this challenge through our ability to rapidly generate 3D microtissues derived from a range of human donors. Unlike traditional 2D cell models, our microtissues maintain key physiological features, such as liver-specific metabolic function, and can be produced using cells from multiple individuals, each with their own unique genetic and metabolic profile. This capability enables drug developers to test compounds across different patient-specific contexts without the need for large, costly clinical cohorts during early research stages.
How this approach translates into value for drug developers:
- Uncovering inter-individual variability in drug response: By testing drugs on microtissues derived from different donors, researchers can identify subpopulations that are more susceptible to toxicity or exhibit differential drug efficacy. For instance, in liver toxicity studies, we can detect differences in how individuals metabolize a drug and flag compounds likely to cause patient-group-specific drug-induced liver injury (DILI).
- De-risking clinical trials: Preclinical models that incorporate patient diversity provide a clearer picture of how a drug is likely to perform in diverse populations. This can inform better trial design, patient stratification, and early identification of at-risk groups, reducing costly late-stage failures and enhancing the likelihood of regulatory approval. Furthermore, in keeping with the draft guidance released by the FDA in 2016, 2020, 2022 and most recently in 2024, the necessity to match diversity in clinical trials with matching diversity in preclinical models is imperative. Unfortunately, while these documents are no longer available online, there are plenty of references to the Diversity Action Plans (DAPs) referenced in those documents available elsewhere. However, in an unprecedented move, unlike other FDA draft recommendations, which are usually never legally binding, this particular draft guidance, emphasizing the necessity of patient diversity in clinical trials, was designed to create legally binding guidelines that would be expected of the sponsor, enforceable 180 days after the guidance was slated to be finalized in June 2025.
- Tailoring therapies for personalized medicine: With the rise of precision medicine, understanding which patient subgroups will benefit most from a treatment is becoming increasingly important. Our platform allows drug developers to evaluate biomarkers, genetic polymorphisms, and other factors relevant to patient stratification, supporting the development of targeted therapies.
Beyond “one-size-fits-all” safety testing
One dangerous common pitfall in preclinical research is the assumption that a drug’s safety profile, once established in one model, applies universally. However, toxicological outcomes often vary based on patient-specific biology. For example, a compound that appears safe in a donor with high drug-metabolizing capacity may accumulate to toxic levels in a donor with slower metabolism. By testing drugs across multiple patient-derived microtissues, we can help drug developers avoid these blind spots, making their safety assessments more robust and comprehensive.
Furthermore, regulators are paying closer attention to the representation of patient diversity in preclinical safety studies. In the context of drug-induced liver injury - a leading cause of drug withdrawal - agencies such as the FDA are emphasizing the importance of predictive models that account for individual differences. InSphero’s approach aligns with this trend, providing drug developers with the data they need to meet regulatory expectations while safeguarding patients.
Addressing concerns about diversity misconceptions
Given recent shifts in the political landscape, particularly in the U.S., there may be concerns that focusing on diversity is a “woke” agenda rather than a scientific necessity. It is critical to separate these narratives. Diversity means different things in different contexts. In preclinical research, diversity is not about ideology - it is about ensuring that therapies work for all patients, regardless of their genetic or metabolic differences. Differences in race, ethnicity, sex and age tremendously affect response and resistance to therapeutics and consequently the effectiveness of an approved drug for a particular indication. Neglecting this diversity is irresponsible and introduces significant risks to patient safety and drug efficacy, potentially leading to catastrophic outcomes such as undetected adverse effects or poor therapeutic performance.
A strategic advantage for drug developers
Incorporating patient diversity into preclinical workflows is not merely about meeting regulatory demands — it is a strategic decision that can provide a competitive edge. By leveraging InSphero’s advanced 3D microtissue models, our partners gain access to a scalable, reproducible platform that mirrors the complexity of the real-world patient population. This capability translates into:
- Faster identification of lead compounds with the highest likelihood of success
- Reduced time and cost by identifying potential failures early
- Stronger data packages to support regulatory submissions
Patient diversity is not a passing trend - it is a fundamental aspect of successful drug development. While patient diversity has always been recognized as a tenet of genetic and rare diseases, it is important to acknowledge that this diversity is equally important to consider in developing drugs for other mainstream disease areas like oncology, metabolic syndromes, and many more. As drug developers face increasing pressure to improve clinical success rates and deliver precision-medicine treatments, integrating diverse, human-relevant models into preclinical research will be essential. InSphero is committed to supporting our partners by providing biologically relevant models that reflect the complexity of human populations, helping them bring safer, more effective therapies to market.
We invite our customers and collaborators to explore how our 3D InSight™ platform can enhance their R&D programs, minimize risks, and unlock new therapeutic opportunities. For more information, contact us today to discuss how patient diversity can drive your next breakthrough.
