Many ongoing Alzheimer's disease central nervous system clinical trials are being disrupted and halted due to the COVID-19 pandemic They are often of a long duration' are very complex;and involve many stakeholders, not only the scientists and regulators but also the patients and their family members It is mandatory for us as a community to explore all possibilities to avoid losing all the knowledge we have gained from these ongoing trials Some of these trials will need to completely restart, but a substantial number can restart after a hiatus with the proper protocol amendments To salvage the information gathered so far, we need out-of-the-box thinking for addressing these missingness problems and to combine information from the completers with those subjects undergoing complex protocols deviations and amendments after restart in a rational, scientific way Physiology-based pharmacokinetic (PBPK) modeling has been a cornerstone of model-informed drug development with regard to drug exposure at the site of action, taking into account individual patient characteristics Quantitative systems pharmacology (QSP), based on biology-informed and mechanistic modeling of the interaction between a drug and neuronal circuits, is an emerging technology to simulate the pharmacodynamic effects of a drug in combination with patient-specific comedications, genotypes, and disease states on functional clinical scales We propose to combine these two approaches into the concept of computer modeling-based virtual twin patients as a possible solution to harmonize the readouts from these complex clinical datasets in a biologically and therapeutically relevant way
A modeling informed quantitative approach to salvage clinical trials interrupted due to COVID-19