The development of treatments for rare diseases remains a significant challenge, with approximately 95% of such conditions still lacking approval from the U.S. Food and Drug Administration (FDA). Progress in this field has been slow, largely due to the regulatory practice of evaluating each treatment on an individual basis.
Certara, a company specializing in optimizing drug development processes, is advocating for a new approach known as the "sandbox" strategy. This method draws inspiration from digital innovation, creating a controlled environment where regulators, industry sponsors, patients, and academic experts can collaborate to test and refine new methodologies in real time.
"The sandbox approach, borrowed from digital innovation, refers to a controlled, collaborative space where regulators, industry sponsors, patients and academic experts can test and refine new methodologies in real time. In rare disease treatment development, this method offers an environment to trial novel endpoints, adaptive designs and statistical approaches without the rigidity of traditional regulatory frameworks," Certara stated.
Under current procedures, developers typically engage in separate meetings with the FDA at different stages of clinical trials. The sandbox model proposes continuous collaboration among stakeholders throughout all phases of drug development—from nonclinical studies through pivotal Phase 3 trials—with ongoing data review by regulators rather than waiting for milestone meetings.
This strategy also involves grouping treatments into different sandboxes based on how they are manufactured: small synthetic molecules ("small sandbox"), well-characterized biologics like monoclonal antibodies ("bio sandbox"), and complex cell or gene therapies ("complex sandbox"). The goal is to align product development requirements according to product type while maintaining consistency within each group.
Certara acknowledges potential skepticism about simplifying regulatory processes but notes that recent changes—such as the FDA's plan to phase out animal testing requirements for monoclonal antibodies—make now an opportune time to explore new models. The FDA and National Institutes of Health (NIH) have announced plans to reduce animal research requirements for certain therapies. While some researchers see promise in organoid and artificial intelligence-based methods as alternatives to animal testing, concerns remain regarding safety and practical implementation (https://www.biospace.com/article/fda-nih-accelerate-shift-away-from-animal-research-as-experts-warn-of-limitations/).
The sandbox framework could be particularly useful for developing monoclonal antibodies for rare diseases by eliminating nonhuman primate use in research and implementing robust alternative models. Certara believes that piloting this approach could provide valuable insights applicable to more common diseases.
A further enhancement involves integrating Model-Informed Drug Development (MIDD), which uses data-driven models across biology, pharmacology, and clinical sciences. Regulatory agencies such as the FDA and European Medicines Agency have shown increased openness toward MIDD through pilot programs designed to improve engagement between developers and regulators.
In rare disease contexts—where patient populations are small—MIDD allows developers to maximize limited clinical trial data through modeling techniques that inform dose selection and trial design. When applied within a sandbox setting with early stakeholder involvement, these strategies can validate innovative approaches while meeting regulatory standards.
For example, developers working on gene therapies for pediatric neuromuscular disorders may lack long-term outcome data; using MIDD within a sandbox enables them to build disease progression models validated by natural history data under regulator guidance. These tools help justify surrogate endpoints or dosing strategies needed for accelerated approvals.
Combining MIDD with the sandbox approach also supports platform development across related diseases by facilitating structured data sharing and standardization. Certara emphasizes that success will depend on transparent communication among stakeholders, robust model validation practices, continued investment in infrastructure—and crucially—regulatory support alongside active patient participation.
Looking forward, advancements such as real-world evidence collection and AI-driven modeling may further expand possibilities within these frameworks by simulating outcomes or identifying subgroups who might benefit from targeted therapies.
"Together, MIDD and the sandbox approach represent a paradigm shift in rare disease drug development. By merging rigorous quantitative science with regulatory flexibility and stakeholder collaboration, they offer a viable path forward for overcoming the inherent limitations of traditional drug development in small, heterogeneous populations. Their combined use promises to accelerate innovation, reduce uncertainty and ultimately bring much-needed therapies to patients who have long been underserved," Certara concluded.
