Virtual patients, digital twins and causal disease models: Paving the ground for in silico clinical trials.

Computational models are being explored to simulate in silico the efficacy and safety of drug candidates and medical devices. Disease models that are based on patients' profiling data are being produced to represent interactomes of genes or proteins and to infer causality in the pathophysiology, which makes it possible to mimic the impact of drugs on relevant targets. Virtual patients designed from medical records as well as digital twins are generated to simulate specific organs and to predict treatment efficacy at the individual patient level. As the acceptance of digital evidence by regulators grows, predictive artificial intelligence (AI)-based models will support the design of confirmatory trials in humans and will accelerate the development of efficient drugs and medical devices.

Innovative medicine development.

BACKGROUND: In recent years the global landscape of pharmaceutical development has evolved drastically in order to adapt to innovative products such as immunotherapy, regenerative medicines and cell and gene therapy, all offering the hope to cure numerous untreated diseases. The global COVID-19 pandemic also led competent authorities in charge of approval of new medicines to implement adapted regulatory pathways allowing early access to innovative treatments and vaccines. New challenges are to be overcome, it is the short development time, or the small patient populations, or again drug product features requiring complete new production, testing and distribution strategies. OBJECTIVE: This paper provides a short overview of the different adaptations required to allow the development of such innovative medicines. METHOD: Several drug development strategies for products under clinical development or recently approved were assessed. RESULTS: Fully integrated strategies encompassing research, non-clinical, clinical and product manufacturing development along with adapted regulatory pathways, anticipation of market access and supported by risk based are important. In such fast pace, the development of relevant manufacturing processes and test methods assessing quality, safety and efficacy of new drugs falls on the critical path and requires particular attention, anticipation and detailed planning as early as possible in order to ensure successful filing and approval. CONCLUSION: Insights within innovative products approved recently reveal the importance of defining a solid chemistry manufacturing and control strategy early on as part of clinical development. Interactions with agencies at key milestones of development are also essential to reduce risks, prioritize development to support safety and allow early access to patients.

Possible Contexts of Use for In Silico Trials Methodologies: A Consensus-Based Review.

The term "In Silico Trial" indicates the use of computer modelling and simulation to evaluate the safety and efficacy of a medical product, whether a drug, a medical device, a diagnostic product or an advanced therapy medicinal product. Predictive models are positioned as new methodologies for the development and the regulatory evaluation of medical products. New methodologies are qualified by regulators such as FDA and EMA through formal processes, where a first step is the definition of the Context of Use (CoU), which is a concise description of how the new methodology is intended to be used in the development and regulatory assessment process. As In Silico Trials are a disruptively innovative class of new methodologies, it is important to have a list of possible CoUs highlighting potential applications for the development of the relative regulatory science. This review paper presents the result of a consensus process that took place in the InSilicoWorld Community of Practice, an online forum for experts in in silico medicine. The experts involved identified 46 descriptions of possible CoUs which were organised into a candidate taxonomy of nine CoU categories. Examples of 31 CoUs were identified in the available literature; the remaining 15 should, for now, be considered speculative.

Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: Building model credibility.

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk-based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick-start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts.

Maternal effects as drivers of sibling competition in a parent-offspring conflict context? An experimental test.

Maternal effects occur when the mother's phenotype influences her offspring's phenotype. In birds, differential allocation in egg yolk components can allow mothers to compensate for the competitive disadvantage of junior chicks. We hypothesize that the parent-older chick conflict peaks at intermediate conditions: parents benefit from the younger chick(s) survival, but its death benefits the older chick in terms of growth and survival. We thus expect maternal compensation to follow a bell-shaped pattern in relation to environmental conditions. We studied a black-legged kittiwake (Rissa tridactyla) population where previous results revealed increased allocation of yolk testosterone in younger as compared to older chicks in intermediate conditions, in line with our theoretical framework. We therefore predicted a maternally induced increase in aggressiveness, growth, and survival for younger chicks born in intermediate environmental conditions. Controlling for parental effects and chick sex, we manipulated food availability before egg laying to create a situation with intermediate (Unfed group) and good (Fed group) environmental conditions. Within each feeding treatment, we further created experimental broods where the natural hatching order was reversed to maximize our chances to observe an effect of feeding treatment on the younger chicks' aggressiveness. As predicted, we found that chick aggressiveness was higher in younger chicks born from the Unfed group (i.e., in intermediate environmental conditions), but only when they were put in a senior position, in reversed broods. Predictions on growth and survival were not confirmed. Mothers thus seem to favor the competitiveness of their younger chick in intermediate conditions via egg yolk components, but our study also suggests that hatching asynchrony need to be small for maternal compensation to be efficient. We emphasize the need for further studies investigating other chick behaviors (e.g., begging) and focusing on the relative role of different yolk components in shaping parent-offspring conflict over sibling competition.

Accelerating development, registration and access to medicines for rare diseases in the European Union through adaptive approaches: features and perspectives.

There is growing recognition that the current research-and-development (R&D) and innovation-regulation ecosystem could be made more efficient to stimulate and support access to innovative therapies for those patients with rare, life-threatening diseases for which there are no adequate licensed therapies. New and progressive thinking on the principles and processes of drug development and regulation are needed in rare disease settings in order to ensure developments are financially sustainable. This paper presents perspectives on the current and emerging schemes for accelerating development of and access to medicines for rare diseases in the European Union.