Model-Informed Bioequivalence & Biosimilarity

The challenge

Our solution

Optimizing bioequivalence success

Whether you are developing a generic, a biosimilar, or innovating a new formulation for an existing product, demonstrating bioequivalence can be of essence.

Recognizing the limitations of standard methods, such as NCA and the two one-sided t-tests (TOST) procedure, regulatory agencies like the U.S. Food and Drug Administration (FDA) are encouraging alternative methods and are sponsoring the development of these new methodologies.

By leveraging all available data, we build a comprehensive and defensible scientific and regulatory package to either justify avoiding a clinical study – supporting a bioequivalence waiver, or ensuring the success of a necessary one.

Our services

A renewed approach to drug development and regulatory submissions

Model-Based Bioequivalence (MBBE)

Model-Based Bioequivalence (MBBE) is a collection of methods for designing and analyzing data from bioequivalence trials. Instead of relying on conventional NCA, it uses population PK (PopPK) modeling and simulations to analyse the data and conclude bioequivalence.

Examples of when MBBE is essential:

Studies with sparse sampling designs, provided the design is optimized to be informative. In these situations, conventional NCA approaches may demonstrate low power.
Products containing a highly variable drug (HVD), where standard designs would require a very large number of subjects.
Drugs with a very long half-life or prolonged release, such as long acting injectables (LAIs) and monoclonal antibodies, where cross-over standard designs are not feasible.
Ophthalmic drugs, where traditional sampling from the aqueous humor is inherently sparse and difficult.

Our expertise in this area is validated by collaborative research showing that model-integrated approaches show markedly higher statistical power than NCA-based methods while maintaining controlled type I error.

Enabling virtual Bioequivalence (vBE)

Virtual Bioequivalence (vBE) is a simulation-based approach, either conducted entirely in-silico before any clinical trial is performed, or leveraging reference clinical data, using PBPK or PBBM modeling. PBBM modeling mechanistically links a formulation’s physical attributes (e.g., particle size, dissolution) to its predicted in-vivo performance allowing for critical de-risking and strategic planning early in development.

We apply Virtual Bioequivalence (vBE) using PBPK or PBBM models to answer critical development questions such as:

To assess the bioequivalence probability of success: We run virtual trials to evaluate the likelihood of demonstrating bioequivalence between two formulations before you commit to a costly and time-consuming clinical study.
To support a biowaiver strategy: vBE can provide the evidence needed to build a scientific case that a clinical trial is unnecessary, hence supporting a waiver.
To guide early formulation development: In silico studies are used for formulation bridging between different product versions, assessing risks and predicting exposure changes without requiring a new study for every minor change.
To solve impossible scenarios: vBE is often the only viable path forward when a standard clinical BE study cannot be conducted safely or ethically,

Model-informed biosimilarity

Model-based bioequivalence and virtual bioequivalence can be used to assess pharmacokinetics equivalence of biosimilars.

The regulatory pathway for biosimilar approval relies on the “totality of evidence”. Regulators like the U.S. FDA are intensifying their focus on high analytical similarity and, most critically, pharmacokinetic equivalence to infer clinical efficacy. This shift, highlighted by the FDA’s 2024 proposal to remove switching study requirements for interchangeability, makes a robust demonstration of exposure similarity more critical than ever to a successful submission.

Why Pharmetheus

We gained expertise from our involvement in the foundational methodology development sponsored by the U.S. FDA

From left: Prof. Andrew Hooker, Ph.D., Moriah Pellowe, Ph.D., Henrik Bjugård Nyberg, Ph.D., Prof. France Mentré, Ph.D.

Novel methodology through foundational research

We gained expertise in this field through our involvement in collaborative research with academia and regulatory agencies. In 2018, the FDA awarded grants to standardize model-based BE approaches, and our advisors and colleagues were central to that work. We don’t just apply standard methods; we help develop them. Our strategic research partnerships for MBBE include world-renowned institutions and key opinion leaders:

INSERM: Through our work with Pharmetheus advisor France Mentré and her research group.
Uppsala University: Led by advisor Andrew Hooker, with significant, published contributions from our colleague Henrik Bjugård Nyberg as part of his thesis work.

Integrated regulatory strategy

Our support goes beyond the technical analysis. We partner with clients from identifying waiver opportunities all the way through direct regulatory interactions using the appendix 1 of the ICH M15 for structured and efficient communication. Our senior colleagues bring significant experience to these meetings, including participation in the FDA’s MIDD (Model-Informed Drug Development) paired program, ensuring your modeling strategy is effectively communicated to regulators.

A collaborative, multidisciplinary team

Our team is a diverse, global group with deep competencies across many therapeutic areas. With several colleagues who have spent decades inside pharmaceutical companies, we understand your challenges from both the inside and outside. We recognize that our clients come from a variety of backgrounds, and we tailor our communication to meet you where you are, whether you are an experienced pharmacometrician or in any position where you need us to support you.

FAQ

Frequently asked questions

What is the strategic difference between vBE and MBBE?

vBE is a simulation-based approach used before a clinical trial to predict outcomes, support biowaivers, or guide formulation development. MBBE is a method for analyzing data from an actual clinical trial. A strategy is to first attempt to use vBE to justify a waiver; if a study is still required, MBBE can be used to allow for a reduced sample size and/or less cumbersome study design.

Can Pharmetheus support our team in defining a model-integrated evidence strategy for a bioequivalence waiver?

Our team has knowledge and experience in performing standard NCA and Two One-Sided Tests (TOST) procedures, as well as Model-Informed Bioequivalence and Biosimilarity approaches. We can also give early advice on strategies for optimizing bioequivalence success.

How does model-informed BE help with biosimilars specifically?

The regulatory paradigm for biosimilars is shifting to a “totality of evidence” framework, where regulators increasingly accept that if a product has high analytical similarity and equivalent PK exposure, its clinical efficacy can be inferred. This makes the robust demonstration of PK equivalence — the specialty of our model-informed approaches—more critical than ever for reducing the need for large, expensive confirmatory efficacy trials.

What is the advantage with model-based approaches over a standard bioequivalence study with NCA analysis?

For complex drugs or sparse data situations, NCA suffers from comparably low statistical power. Our model-based approaches, which have been developed and validated in collaboration with academic and regulatory partners, are proven to have significantly higher power to establish BE while adequately controlling for type I error (the risk of approving a non-equivalent drug). They allow for a more precise estimation of BE metrics by accounting for multiple sources of variability and uncertainty. The model based analysis also opens possibilities for alternative study designs with features such as shorter trial duration and less frequent plasma samples.

Can bioequivalence be assessed with sparse PK data?

Yes, MBBE methods can be successfully applied to sparse data, provided the study design has been optimized to ensure it is informative for the modeling analysis.

What kind of regulatory interaction experience does Pharmetheus have?

Several of our senior colleagues have significant experience from interacting with regulatory agencies; some have even been assessors during their career. We can support you through direct participation in FDA MIDD paired meetings, and help you present and defend a model-informed approach to regulators.

Does Pharmetheus run the clinical bioequivalence studies?

No, Pharmetheus is not a clinical trial center. We provide services in the realm of model-informed drug development that inform the design of those trials and the interpretation of their results for regulatory decisions.

Can Pharmetheus support standard bioequivalence study design and analysis (i.e., NCA and TOST)

Our focus is on advanced modeling and simulation that informs trials and regulatory decisions, not on performing standard NCA and Two One-Sided Tests (TOST) procedures, although our team of course has knowledge and experience of standard approaches.

Our collaboration solutions

Supporting resources

Key publications

Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic end points

Evaluation of model-integrated evidence approaches for pharmacokinetic bioequivalence studies using model averaging methods

These works, co-authored by Henrik Bjugård Nyberg and Pharmetheus scientific advisors, presents novel model-integrated evidence (MIE) approaches that demonstrate significantly higher power than conventional NCA-based methods, particularly in studies with sparse sampling, while maintaining acceptable type I error rates.

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Ready to de-risk your development program and accelerate your product’s path to market?

Whether you are in early-stage strategic planning or preparing for regulatory submission, our experts are ready to discuss how our PK modeling for bioequivalence can optimize your program.