Toxicologic Pathology Forum*: Opinion on New Technologies and Trends Disrupting Drug Discovery and Development: How Can the Next Generation of Toxicologic Pathologists Be Prepared for Evolving Roles?

Abstract

The pace of technological innovation in the pharmaceutical industry, like in many other sectors, is accelerating rapidly. This is not only reshaping how pharmaceutical Research and Development (R&D) is conducted (e.g., introduction of novel models, endpoints, and instrumentation) but also influencing the types of therapeutic modalities being developed. In addition, societal and regulatory expectations have evolved to emphasize approaches that align with the 4Rs principles (Replacement, Reduction, Refinement, and Responsibility) and to encourage the replacement of animal testing with new approach methods (NAMs) through the FDA Modernization Act 2.0. While innovation, societal changes, and regulatory evolution are not new, what stands out is the unprecedented speed and scale at which these transformations are occurring. This acceleration is fueled predominantly by groundbreaking technological advancements (e.g., artificial intelligence, deep learning, communication tools, and digital pathology) in the context of rapidly changing societal dynamics such as globalization, social networking, and the increase in remote working. Given these potentially disruptive changes, it is essential to consider how toxicologic pathologists need to adapt. More importantly, how can they leverage these advancements to contribute even more significantly to the discovery and development of novel, safe, and effective medicines? In essence, what types of toxicologic pathologists will the pharmaceutical industry require in the future?

*This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the authors. It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

The Value of Toxicologic Pathologists in Pharmaceutical Development

Traditionally, toxicologic pathologists have primarily been employed in the pharmaceutical industry to perform histopathological evaluations of tissues from short- and long-term toxicology studies involving rodent or non-rodent species. This vital work has been essential to ensure the safety of clinical trial participants and patients, and it will remain crucial in the future. However, the advent of novel therapeutic modalities and complementary (non-in vivo) approaches is likely to lead to a significant reduction in the number of animal studies needed to support the development and approval of new experimental medicines. For example, the development of biologics often necessitates the use of only one species (non-human primate) due to the irrelevance of rodent models. Moreover, two decades of early involvement by safety scientists in drug discovery, coupled with advances in screening technologies, have substantially enhanced the quality of development candidates, especially small molecules, partly resulting in a lower attrition rate in Good Laboratory Practice (GLP) studies based on our own experience.^1,11 No robust data are available regarding the evolution of the GLP study success rate across the industry, and the few available data mainly reflect attrition of small molecules, which are increasingly becoming a smaller part of the industry pipeline. ⁵ Hence, a proper estimate of the change in GLP success rate in the industry is unknown. Finally, multiple precompetitive efforts within the pharmaceutical industry and by regulators have led to the acceptance of a weight-of-evidence (WoE) approach to help reduce the need for 2-year carcinogenicity studies in rats, which are resource-intensive and time-consuming for toxicologic pathologists (see ICH S1B(R1) guideline). ¹³ Likewise, a study for the IQ Consortium’s DruSafe Leadership Group suggests that a new paradigm using a single species in chronic toxicity studies may be warranted. ¹⁰ While these science-based “replacement” initiatives take time, experience with alternative protocols to the traditional mouse 2-year bioassay using the TgRasH2 model has shown that they can succeed and become industry standards. ³

Although these trends might suggest a reduced workload for toxicologic pathologists, they have also introduced opportunities and requirements to contribute in new and different ways. For example, the advancement of gene therapy modalities requires nonclinical safety assessments in combined pharmacology/safety studies, often utilizing genetically engineered mouse models. Interpreting these studies is particularly challenging due to background pathological changes that preferably need to be characterized before using the model to evaluate a new agent.^2,8 Likewise, new therapeutic modalities often lead to previously unrecognized histopathological changes. This is illustrated by studies with antibody-drug conjugates (ADCs), where unique findings such as hepatic sinusoidal obstruction syndrome, interstitial lung disease, or corneal microcysts have been observed.^7,9 These developments underscore the necessity for toxicologic pathologists to remain abreast of the emerging literature and science related to these new histological findings. They also reinforce the criticality of an in-depth experience in toxicologic pathology to appropriately characterize and interpret novel findings. In addition, they highlight the valuable contributions well-trained pathologists can make in characterizing, interpreting, and understanding the mechanisms behind these novel histopathological changes.

Embracing Technological Advancements in Pharmaceutical R&D: An Opportunity for Toxicologic Pathologists

The rapid and sometimes disruptive evolution of novel technologies has defined the last two decades; yet, its impact on pharmaceutical R&D has been limited, and the practical implementation of these technologies, particularly in the regulated domains of pharmaceutical R&D, remains a formidable challenge. The industry’s aspiration, along with that of regulators, to replace or refine certain existing nonclinical in vivo safety models with improved alternatives has yet to materialize. Several factors contribute to this slow adoption, especially the difficulties associated with validating technology in a regulated environment, the traditionally conservative outlook of nonclinical safety organizations, and the proven effectiveness of current in vivo methods in ensuring clinical trial subject and patient safety. ⁶ Nonetheless, there is an evident opportunity to enhance the efficiency and translatability of our current methodologies. Toxicologic pathologists, given their crucial role in both discovery support and nonclinical safety assessment, are strategically positioned to spearhead these improvements. For instance, the development and application of various new approach methods (NAMs), especially complex in vitro models, and analytical techniques such as spatial transcriptomics, could be significantly advanced through the active involvement of toxicologic pathologists. Based on our personal prior experience with genomics, molecular pathology, and imaging technologies, including toxicologic pathologists in the evaluation and implementation of new technologies is beneficial.

Hence, we suggest that pathologists be actively involved at the earliest stages in the adoption of any technology aimed at enhancing our assessment of human risk for novel therapeutics. Their expertise is crucial, ranging from selection of relevant model systems (e.g., identifying pertinent cell types for toxicity studies), validation of models (e.g., confirming that cells form a biological interface in an organ-on-a-chip), understanding differences of response, physiological or anatomical differences between species, ensuring the translatability of in vitro findings to in vivo conditions to interpreting the relevance of nonclinical data to humans. Importantly, the etiopathogenesis and morphology of phenotypical and pathological changes observed in animal models remain the foundation and gold standard around which all of these technologies can be validated for their proper context of use. Therefore, pathologists’ involvement must remain crucial to these efforts and can best contribute to the successful implementation of novel technologies by working in close collaboration with bench scientists, biologists, bioengineers, clinical veterinarians, and data scientists. To facilitate and encourage these collaborations, appropriate organizational design should be considered to address the hurdles inherent to traditional organizational structures.

The emergence of accessible artificial intelligence (AI) and machine learning (ML) tools further amplifies these opportunities for the profession. At AbbVie, we have championed this by supporting a veterinary pathologist’s leadership role in our R&D-wide digital transformation efforts. These AI/ML opportunities span from straightforward productivity enhancements, such as digital pathology and structured document authoring, to ambitious projects like biology knowledge generation through inference, automated digital slide reading and interpretation, computational molecular design, and the creation of virtual human and animal models. ⁴ For toxicologic pathologists, the potential to contribute to these initiatives is immense, not only in the application of the technology, but also in the critical oversight of the context of use. However, achieving this necessitates not only a cultural shift within R&D but also a foundational understanding by some of our peers of AI/ML principles complemented by a unique ability to collaborate with computationally inclined colleagues.

The Future of Toxicologic Pathologists: A Vision Beyond Predictions

Envisioning the future is always a challenge, and history has shown us that even the most brilliant minds can be mistaken in their forecasts. Take, for example, Lord Kelvin’s famous 1895 declaration that “heavier-than-air flying machines are impossible.” Clearly, being too specific in our descriptions of the future of toxicologic pathologists risks inaccuracy. However, there are several enduring principles that we believe will shape the profession.

• Foundational knowledge and training. First and foremost, a deep understanding of disease mechanisms and pathology will remain essential for toxicologic pathologists. Robust academic training programs with high credentialing standards coupled with on-the-job mentoring are vital. ¹² These training programs must create environments that stimulate scientific curiosity, foster collaboration across disciplines, and instill a sound experimental mindset. In addition, they must attract talent in a field that will require several additional years of training. In the fast-paced world of pharmaceutical R&D, a strong scientific foundation, emotional intelligence, and collaborative skills are critical for success. Several challenges currently impede the support and training of toxicologic pathologists, including the general lack of toxicologic pathology in pathology residency curricula, the student debt crisis, the desire for work-life balance, and the decline in government funding for graduate programs. Therefore, creating training programs that are adequately aligned with the expectations of the next generation of toxicologic pathologists has become increasingly urgent.

• Adapting to the digital transformation. The rapid digital transformation of our industry brings new requirements. Skills that were not critical in the recent past, such as data analytics proficiency and familiarity with various computational platforms, are becoming indispensable. Flexibility and adaptability, as well as resilience, and the ability to contextualize complex datasets, will be crucial as we navigate these changes.

• Complexity of drug discovery and development. New toxicologic pathologists will need to quickly acclimate to the growing complexity of the drug discovery and development process. A pathologist in this new paradigm must integrate large and diverse datasets, such as information about the therapeutic target, the modality and delivery system, properties of distribution and metabolism that drive exposure, clinical imaging data, molecular pathology, and “-omics” data. This is in addition to the already complex pathology dataset that encompasses clinical observations, clinical pathology, gross, microscopic, and ultrastructural pathology. Pathologists working in this environment must adapt and think creatively as unfamiliar models and data types will regularly arise. For example, a current gap in our own organization, and perhaps others, is the shortage of experienced critical thinkers to manage complex projects, especially those involving novel experimental modalities with no established development paths. Closing this gap will require not only internal training resources and time for knowledge development but also a willingness from individuals to acquire this new knowledge.

• Cultivating positive attitudes and willingness to expand. Finally, maintaining a positive attitude and a willingness to step outside one’s comfort zone are crucial to long-term success in pharmaceutical R&D. The learning agility, flexibility, stamina, and resilience honed during graduate training are critical. Unstoppable curiosity and embracing challenges and opportunities for growth will define the future success of toxicologic pathologists.

In conclusion, there is a clear and pressing need for toxicologic pathologists to embrace and drive the implementation of new technologies. By doing so, they can ensure that our industry advances in applying advanced technological solutions to improve the safety and efficacy of new drug candidates while honoring our 4Rs commitments. While the exact future of the evolving role of toxicologic pathologists is unknowable, several guiding foundational principles will likely be crucial: strong academic and practical training, embracing the digital transformation, successfully navigating the complexities of drug discovery and development, and cultivating a growth mindset. By embracing these principles, the profession will not only endure but also thrive in the rapidly changing landscape of pharmaceutical R&D.