This article is about AI-enabled digital twins in biomedical domains. Abstract: "The use of synthetic data is recognized as a crucial step in the development of neural network-based Artificial Intelligence (AI) systems. While the methods for generating synthetic data for AI applications in other domains have a role in certain biomedical AI systems, primarily related to image processing, there is a critical gap in the generation of time series data for AI tasks where it is necessary to know how the system works. This is most pronounced in the ability to generate synthetic multi-dimensional molecular time series data (SMMTSD); this is the type of data that underpins research into biomarkers and mediator signatures for forecasting various diseases and is an essential component of the drug development pipeline. We argue the insufficiency of statistical and data-centric machine learning (ML) means of generating this type of synthetic data is due to a combination of factors: perpetual data sparsity due to the Curse of Dimensionality, the inapplicability of the Central Limit Theorem, and the limits imposed by the Causal Hierarchy Theorem. Alternatively, we present a rationale for using complex multi-scale mechanism-based simulation models, constructed and operated on to account for epistemic incompleteness and the need to provide maximal expansiveness in concordance with the Principle of Maximal Entropy. These procedures provide for the generation of SMMTD that minimizes the known shortcomings associated with neural network AI systems, namely overfitting and lack of generalizability. The generation of synthetic data that accounts for the identified factors of multi-dimensional time series data is an essential capability for the development of mediator-biomarker based AI forecasting systems, and therapeutic control development and optimization through systems like Drug Development Digital Twins."