“The whole is greater than the sum of its parts” is often quoted to inspire teamwork and synergy but it can also apply to drug development. Studies that assess endpoints in isolation have value and can achieve the desired outcome. Yet, many times a more complicated picture emerges and assessing multiple endpoints in a combined study reveals a more holistic view.
Inspired by the 3Rs—reduction, refinement and replacement of animals used in safety testing—the possibility of integrating multiple endpoints into one study is shaping new best practices in early drug development. Integrated solutions can maximize the value of each study to provide a better understanding, reveal earlier decision points and produce greater confidence in clinical outcomes.
While the concept seems straightforward, it’s not only a combination of otherwise standalone studies. Integrated solutions require a unique blend of fit-for-purpose experimental strategies tailored to each unique drug development program and the relevant endpoints.
The process starts by understanding the big picture—historical challenges and future goals. This background helps pave the path forward to design meaningful studies that both meet regulatory needs and alleviate business risk.
Integrated solutions in action
Safety Pharmacology is one area ripe for integration – where we are starting to see the assessment of multiple pharmacology endpoints during a toxicology study. This has been referred to as Safety Pharmacology in Toxicology (SPiT) or Value-added Safety Pharmacology in Toxicology (VAST). It is especially helpful in situations where unexpected adverse events appear – such as for cardiovascular, respiratory or CNS. Here, a traditional safety assessment study can be enhanced with multiple endpoints to gain additional experimental results. This novel technique can yield new insights, uncovering perspectives that focus on potential issues of concern from a variety of angles.
Likewise, the same principles can apply by integrating metabolite identification into safety assessment trials from rodent and non-rodent species with comparison to clinical results. As part of Metabolites in Safety Testing (MIST) strategy, developing acceptable exposure data and understanding the potential safety margin—before later-stage trials start—can help de-risk a program, address issues earlier and build more confidence into the data package. An example of this integrated study approach will be presented at the Society of Toxicology Annual Meeting.
Considerations in study design
The art behind integrating multiple endpoints into one study requires knowing which studies to combine that will both wisely use resources and extract the most value, taking into account the target and its expression, modality and pharmacology.
At the assay level, it’s important to understand the tradeoffs between sensitivity and specificity among models and their contribution to the overall clinical plan. Here, integrating data with clinical endpoints is not only crucial to interpreting exposures and how they translate to downstream phases—it can also create stronger predictive values.
The timing of the particular studies within the overall drug development journey is also a critical consideration. By integrating earlier what would traditionally be done later in the early development phase, such as safety pharmacology or metabolism endpoints, the results can guide earlier go/no-go decisions and redirect resources to studies that make the most impact and maximize overall efficiency.
Proceeding with confidence
In the ever-evolving drug development journey, the path ahead must be planned purposely and thoughtfully. Translating meaningful results toward clinical outcomes requires both the insight and know-how to choose the right studies at the right times.
Not every situation warrants multi-endpoint studies. However, partnering with Covance can help you determine when it’s the right solution, and help you receive a stronger data package, mitigate risk and get the most value out of your program.
Join the conversation
We want to know your thoughts on the following:
- What do you think is the greatest challenge in de-risking programs with Metabolites in Safety testing (MIST) and why?
- Pro or Con – what is your perspective on adding safety pharmacology endpoints into your toxicology studies and why?