In recent years, the pharmaceutical industry has witnessed a dramatic acceleration in the adoption of New Approach Methodologies (NAMs) for drug safety testing. This surge, often perceived as an overnight revolution driven by regulatory shifts like the FDA Modernization Act 2.0 in 2022, is, in fact, the culmination of over a decade of rigorous scientific development, cross-sector collaboration, and evolving regulatory frameworks. The Act, which notably removed the statutory requirement for animal testing and explicitly permitted non-animal alternatives, served not as the genesis of NAMs but as a legislative acknowledgment of the robust scientific and technical groundwork already established. For leaders in drug safety, the critical question now revolves around identifying which NAM platforms are sufficiently validated, trusted, and prepared for integration into regulatory-facing applications.
The Imperative for Innovation: Addressing Traditional Model Limitations
The journey toward NAMs began with a profound recognition of the inherent limitations of traditional animal-based safety models. Despite decades of refinement and significant investment, these models frequently struggled to accurately predict human physiological responses, leading to persistently high rates of late-stage drug attrition due to safety liabilities. This challenge was particularly acute in areas like cardiac risk assessment, where adverse events could be rare but catastrophic. The discrepancies between animal and human physiology often translated into costly failures in clinical trials, prolonged drug development timelines, and, in some cases, severe patient harm or market withdrawals. The economic burden of these failures, estimated to be in the hundreds of millions of dollars per failed drug candidate, alongside growing ethical concerns regarding animal testing, underscored the urgent need for more predictive, human-relevant alternatives.
Early-to-mid 2010s saw the emergence of foundational initiatives designed to bridge this predictive gap. Programs such as Tox21 (Toxicity Testing in the 21st Century) and ToxCast (Toxicity Forecaster), spearheaded by U.S. government agencies, aimed to revolutionize chemical toxicity testing by developing high-throughput, in vitro assays. These programs explored thousands of chemicals across a multitude of biological pathways using human cells and cell-free systems, laying the groundwork for mechanism-based toxicology. Simultaneously, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative began to address the specific challenge of drug-induced arrhythmias, a leading cause of cardiovascular drug failure. CiPA’s premise was groundbreaking: human-relevant, mechanism-based assays, particularly those focusing on cardiac electrophysiology, could not only equal but potentially surpass the predictive power of traditional animal models when applied appropriately.
Building Trust: From Internal Use to Regulatory Acceptance
Despite these promising scientific advancements, the initial adoption of NAMs remained cautious. Pharmaceutical companies often leveraged these novel methods internally for early-stage screening and decision-making, but hesitated to rely on them for formal regulatory submissions. This reticence stemmed primarily from a lack of clear regulatory pathways and established guidelines for how NAM data would be evaluated and accepted by agencies. The scientific community and industry stakeholders understood the potential, but the absence of a structured dialogue with regulators created a barrier to widespread implementation.
This landscape began to shift significantly with the development of formal regulatory engagement mechanisms. A pivotal example is the U.S. Food and Drug Administration’s (FDA) Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program, launched in 2019. ISTAND was designed to create a structured framework for dialogue and collaboration, allowing technology developers, industry researchers, and regulators to align on what constitutes "fit-for-purpose" evidence for novel methodologies. By providing a clear channel for feedback and acceptance, ISTAND began to demystify the regulatory pathway for NAMs, fostering an environment of increased confidence and collaboration. This program signaled a proactive stance from regulatory bodies, acknowledging the scientific evolution and the need to integrate modern, human-relevant approaches into drug development and safety assessment.
Cardiac Safety: A Model for NAM Maturity and Success
Cardiac safety has emerged as a vanguard in demonstrating the practical utility and regulatory readiness of NAMs. This area of drug development inherently highlights the value of functional, human-derived physiological models in making critical safety decisions. The heart’s complex electrophysiology, which can be exquisitely sensitive to drug interference, makes it a particularly challenging organ to model accurately using non-human systems. Functional NAMs, especially those employing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), offer an unprecedented level of human relevance.
A significant regulatory milestone reflecting this progress was the recent acceptance of a Letter of Intent submitted by Axion BioSystems for a human iPSC-derived cardiomyocyte microelectrode array (MEA) assay into the FDA’s ISTAND program. This achievement is not merely a corporate success but a testament to years of sustained, collaborative investment across industry, academia, and regulatory science. It underscores a broader, concerted effort to translate sophisticated human-relevant physiology into robust, standardized tools capable of supporting regulated safety workflows. This acceptance into ISTAND reflects a growing confidence within regulatory bodies in functional assays that can directly measure human cardiac electrophysiology in vitro.
MEA technology, particularly when paired with hiPSC-CMs, has been central to this evolution. Platforms such as the Maestro MEA system enable continuous, noninvasive monitoring of complex cardiac electrophysiology. These systems provide real-time functional data, including beating rate, field potential duration, and detection of arrhythmogenic events, offering insights that are both physiologically relevant and operationally practical for the high-throughput demands of pharmaceutical and contract research organizations (CRO) environments. The scalability and reproducibility of MEA assays have been critical factors in their increasing adoption.
The CiPA Initiative: A Collaborative Breakthrough
The credibility of hiPSC-CM MEA assays for cardiac safety was largely forged through extensive collaborative initiatives, most notably the CiPA program. Two seminal multicenter CiPA studies, involving a consortium of pharmaceutical companies, CROs, and regulators worldwide, played a pivotal role. These studies rigorously demonstrated that hiPSC-CM MEA assays could reliably detect delayed repolarization and arrhythmia-like events—key indicators associated with the risk of torsades de pointes (TdP), a rare but potentially fatal ventricular arrhythmia. These findings were instrumental in shaping the updated ICH E14/S7B Questions & Answers document, finalized in 2022. This crucial international guideline formally recognized hiPSC-CM data as supportive evidence for proarrhythmic risk assessment, marking a watershed moment for the regulatory acceptance of NAMs.
CiPA’s success validated the scientific premise that mechanistic, functional assays could significantly enhance proarrhythmia risk prediction beyond the limitations of traditional hERG (human Ether-à-go-go-Related Gene) channel assays and animal studies. The subsequent challenge was to translate this scientific breakthrough into workflows that were reproducible, scalable, and readily usable across diverse organizations, a challenge largely met by commercial MEA platforms and the collaborative spirit of the industry.
Accelerated Adoption and Enhanced Predictive Power
The impact of these advancements is now evident in drug development pipelines. A 2025 study authored by FDA scientists revealed a consistent increase in the number of Investigational New Drug (IND) applications submitted with hiPSC-CM data over the past decade. Notably, the period between 2020 and 2023 saw a doubling of submissions including hiPSC-CM MEA assays compared to the total number submitted prior to 2020. This trend reflects a clear acceleration in the industry’s adoption of these advanced approaches.
Further reinforcing the predictive power of these methods, a new paper, currently under peer review, presents compelling evidence of hiPSC-CM data’s strong concordance with clinical QT outcomes. The study demonstrated a higher predictive performance compared to commonly used methods such as hERG assays, multi-ion channel approaches, and traditional animal QT studies. Perhaps most significantly, the research indicated that integrating hiPSC-CM data with other in vitro assays substantially reduced nonclinical QT false negatives. Crucially, it provided predictive value comparable to multiple animal studies, opening a viable pathway to potentially replace a significant number of animal studies in the future. This represents not only an ethical advancement but also a strategic one, promising to streamline drug development and reduce costs associated with extensive animal testing.
What makes this adoption particularly striking is its voluntary nature. HiPSC-cardiomyocyte MEA data are not currently mandated for IND submissions. Yet, drug sponsors are proactively including these studies, recognizing the immense value they offer. This voluntary uptake is further evidenced by the fact that at least 16 contract research organizations (CROs) now offer CiPA-style hiPSC-CM assays as a standard service, frequently utilizing the Maestro Pro MEA system. This widespread, unmandated adoption signals that these assays are delivering tangible value: reducing uncertainty in safety assessments, enabling better-informed decision-making, and ultimately de-risking drug candidates earlier in the development process.
Ensuring Consistency: The Role of Standardization
As functional NAMs transition from validation into broader regulatory use, a new challenge emerges: ensuring consistency. Variability in model performance, assay protocols, and data interpretation could quickly erode the confidence built over years of development. To address this, initiatives like the Axion iPSC Model Standards (AIMS) have been launched. AIMS represents a collaborative effort with leaders in the safety field to define meaningful functional standards for hiPSC-CM MEA assays. The goal is to establish clear benchmarks for baseline electrophysiological performance, acceptable levels of variability, and expected responses to known reference compounds. Such standardization is critical for NAMs to scale responsibly, ensuring reproducibility across different labs and systems, and to underpin future regulatory frameworks. This commitment to standardization is vital for fostering continued trust and facilitating the seamless integration of these advanced tools into global drug development paradigms.
Collectively, these efforts—from the scientific rigor of CiPA to the increasing inclusion in INDs, from the structured dialogue of ISTAND to the standardization goals of AIMS—illustrate how cardiac safety has become a leading model for NAM maturity. More importantly, they demonstrate what successful NAM adoption looks like when it is built upon robust scientific evidence, proactive regulatory engagement, and a shared commitment to standards grounded in human-relevant physiology.
A Managed Transition for Safety Organizations
For safety leaders within pharmaceutical organizations, the current inflection point in NAM adoption presents both an unparalleled opportunity and a significant responsibility. The opportunity lies in leveraging tools that provide earlier, more accurate, and human-relevant insights into cardiac risk, potentially saving time, resources, and lives. The responsibility, however, is to implement these sophisticated methodologies thoughtfully, ensuring they integrate seamlessly into existing decision processes without introducing new layers of uncertainty or complexity.
The true risk today may not be in adopting new approaches, but in clinging to outdated models that have not kept pace with the profound advancements in our understanding of human cardiac biology. The narrative of a "sudden" NAM shift is therefore misleading; the tools now entering mainstream safety workflows are the product of years of meticulous validation, extensive cross-sector collaboration, and substantial investment in regulatory science. Platforms that offer a combination of proven performance, established regulatory engagement, and a clear commitment to standardization represent an evolutionary rather than disruptive path forward. This strategic integration of functional NAMs promises to usher in an era of more efficient, ethical, and ultimately safer drug development, profoundly redefining how cardiac safety assessment is approached globally.
Mike Clements, PhD, is the SVP Scientific Partnerships & Strategy at Axion BioSystems. His work focuses on initiatives advancing the use of human stem cell-derived models in drug discovery and toxicology. Dr. Clements earned his PhD in neuropharmacology from the University of Oxford, followed by postdoctoral training in both the UK and the US. In 2014, he authored the first study to utilize the Maestro multielectrode array (MEA) system with stem cell-derived cardiomyocytes, pioneering their potential as predictive tools for preclinical cardiac safety screening. This foundational research significantly contributed to the development and understanding of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. He also served as the editor of "Stem Cell-Derived Models in Toxicology," a comprehensive resource reviewing next-generation in vitro toxicology platforms, and previously held the position of president of the stem cells specialty section of the Society of Toxicology.
