Comment from Alcyomics

We strongly support the U.S. Food and Drug Administration’s (FDA’s) move towards New Approach Methodologies (NAMs) for nonclinical safety assessment of oncology products. This guidance represents an important step towards a framework that prioritises scientific relevance, human biology and patient safety. For almost 20 years, Alcyomics has been developing and applying human-specific, non-animal methodologies to assess immunotoxicity and efficacy of novel pharmaceuticals. Our platforms utilise human tissue and immune cells to generate data that reflects human biology. We particularly champion models that combine biological complexity with practical usability, a hallmark of human explant systems. We have evaluated a wide range of oncology therapeutics, including biologics, antibody-based therapies, nanomedicines, and other immune-modulating medicines, supporting drug developers in the assessment of potential human safety risks before clinical investigation. We also expect that as reconstituted 3D tissue models continue to mature, their biomarker profiles can be more confidently aligned with human tissues, creating a complementary suite of human-relevant bioscreening tools. Our experience has consistently demonstrated that well-designed human-based assays can provide clinically relevant information that is not always captured by traditional animal studies. We have observed correlations between responses measured in our human-based systems and safety outcomes observed in patients. While no single model can answer every scientific question, this reinforces the idea that evidence generated from human-relevant systems can provide information that is applicable to predicting human responses. We therefore support the guidance's emphasis on a weight-of-evidence approach, allowing decisions to be informed by all available scientific evidence rather than relying on traditional animal studies. Human-relevant in vitro models, mechanistic understanding, computational approaches, existing nonclinical and clinical data and other NAMs should all be considered as complementary sources when evaluating the safety of investigational oncology products. We believe that the future adoption of NAMs should be guided by context of use. Different methodologies are designed to answer different scientific questions, and their suitability should be assessed according to the question. Regulatory confidence should be based on whether a NAM is fit for purpose. A context-of-use framework provides the flexibility to incorporate innovative technologies while maintaining scientific standards. As NAMs become more widely integrated into regulatory decision-making, continued emphasis on validation, standardisation and evidence generation will be essential. We encourage the FDA to support validation strategies that focus on demonstrating clinical relevance and correlate with clinical data, giving predictive performance for the intended context of use. While comparisons with historical whole animal data may sometimes remain informative, greater emphasis should be placed on establishing how well a methodology predicts human outcomes. In our experience, direct comparison of NAM-generated data with clinical observations has been important in building confidence in the predictive capability of human-based approaches. We particularly support the guidance's recognition that extensive non-human primate studies may not always be scientifically justified for oncology biologics and conjugated products. We have found that human-based assays can predict safety concerns observed in humans while also reproducing findings identified in non-human primate studies. These data demonstrate that human-relevant approaches could provide sufficient evidence to identify potential safety risks, reducing the need for non-human primate studies. We encourage the FDA to: Continue to promote a weight-of-evidence approach that integrates NAMs alongside mechanistic, computational and existing clinical evidence. Explicitly recognise that human-specific NAMs may provide information that is more clinically relevant than animal data. Encourage the adoption of context-of-use frameworks when evaluating the suitability and credibility of NAMs. Support validation approaches that prioritise clinical relevance, predictive performance and reproducibility for the intended application. Overall, this draft guidance represents an important milestone in the evolution of nonclinical safety assessment. By encouraging scientifically robust, human-relevant approaches alongside traditional methods where appropriate, the FDA is helping to create a regulatory framework that is better aligned with advances in biomedical science and more likely to improve the prediction of human safety. Prepared by: Emerita Professor Anne Dickinson Dr Katie Smith Dr Abbas Ishaq On behalf of Alcyomics Ltd. The Biosphere Draymans Way, Newcastle Helix, Newcastle upon Tyne NE4 5BX Contact: info@alcyomics.com