Breaking New Ground: EMA Qualification of the Simcyp® Simulator Ushers in a New Era for PBPK Modeling

Let’s step back to understand why this is such a big deal. In 2019, the EMA published its guideline on the use and reporting of PBPK modeling in regulatory submissions. While the guidance outlined expectations, many sponsors found their PBPK-based DDI assessments rejected on the grounds that “the platform has not been qualified.”The burden this action placed on sponsors was a driving force behind our pursuit of qualification. We wanted to remove the subjectivity from the review process and give sponsors a more predictable path for leveraging PBPK in DDI risk assessment.

EMA qualification is often granted for a single method or approach. In our case, the scope is broader: six CYP enzymes and two inhibitory, spanning over 60 compounds. The qualification covers three defined contexts of use:

• Victim drugs: Predicting the impact of weak/moderate CYP inhibitors on a new drug’s exposure using verified clinical data for a strong inhibitor.
• Competitive inhibitors: Estimating a drug’s effect on the exposure of CYP substrates using verified clinical data for a sensitive substrate.
• Mechanism-based inhibitors: Evaluating long-lasting inhibition on sensitive substrates.

Each of these use cases allows Simcyp simulations to replace dedicated clinical DDI studies, accelerating development and reducing patient burden.

As someone who has worked on the Simcyp platform since its early days, helping to develop both the software and many of the compound and population files, this moment is deeply personal. I’ve experienced firsthand how mechanistic modeling has evolved from a research tool to a regulatory asset. Achieving EMA qualification is the culmination of decades of science, innovation, and regulatory dialogue.

Importantly, the qualification process was not just a Certara effort involving a great team of scientists (notably Masoud Jamei, Iain Gardner, Sibylle Neuhoff and Frederic Bois) and software developers. It also prompted the EMA to assemble their PBPK experts and recruit additional expertise to establish best practices for assessing PBPK modeling submissions. In my view, the outcome is a more robust and transparent review process, which benefits not just us, but the entire PBPK community, and more importantly patients.

For sponsors using Simcyp v19, EMA qualification means a faster, more efficient path for CYP-mediated DDI submissions in the EU. Instead of needing to defend the platform, the focus can shift to the science of the model itself (for the test drug), its assumptions, parameters, and data sources. Sponsors using newer versions can build upon this foundation, as long as they can demonstrate that their submission remains within the qualified scope.

This EMA qualification is only the beginning. We’re already exploring qualification for additional mechanisms such as enzyme induction, complex DDIs and transporter-mediated interactions, as well as applications in specific populations. Both Masoud Jamei and I will be presenting at the EMA workshop where these areas of application will be discussed along with issues such as how the current EU regulatory framework can be adapted to facilitate future regulatory qualification of mechanistic models.

Our long-term vision is a future where PBPK modeling is not just accepted but an expected part of every drug development strategy for all of the above scenarios. Personally, the most gratifying part of this achievement is knowing that it will help bring medicines to patients, especially in underserved populations, more quickly. Regulatory trust is the cornerstone of that progress, and this qualification is a powerful step in the right direction.