Bioequivalence (BE) studies have long relied on well-established assumptions about how drugs are administered, absorbed, and measured in the body. Traditional solid oral dosage forms such as tablets and capsules produce relatively predictable pharmacokinetic (PK) profiles that align well with conventional crossover BE designs and standard plasma sampling strategies.
However, drug developers are increasingly moving away from these traditional formats. Oral thin films, transdermal patches, sublingual sprays, long-acting injectables, and other novel delivery systems are now being used to improve adherence, enable faster onset of action, reduce gastrointestinal side effects, and support differentiated product positioning. While these technologies offer clear clinical and commercial advantages, they also introduce significant complexity into BE study design.
These newer formats do not behave like conventional immediate-release or modified-release tablets. Their absorption kinetics, site of uptake, and release profiles often violate the assumptions built into standard BE models, requiring sponsors and CROs to rethink how equivalence is demonstrated.
Conventional BE studies were designed around oral dosage forms that follow a familiar pathway: ingestion, gastric dissolution, intestinal absorption, first-pass metabolism, and systemic circulation. This predictable sequence allows PK metrics such as Cmax, Tmax, and AUC to be compared between a test and reference product using well-validated statistical approaches.
For immediate-release and many modified-release tablets, the relationship between formulation, dissolution, and plasma exposure is sufficiently stable that small formulation changes can be reliably assessed through standard two-way crossover designs. Regulators have decades of experience evaluating these studies, and sponsors have clear expectations for how to demonstrate equivalence.
Novel delivery systems disrupt this framework. They bypass or alter key physiological steps that traditional models assume are present, which changes both the shape of the PK curve and the variability around it.
Oral thin films dissolve on the tongue or buccal mucosa, delivering drug through the oral cavity rather than through the gastrointestinal tract. This creates two potential absorption pathways: direct transmucosal uptake and swallowed drug that enters the gut.
The relative contribution of these two pathways can vary based on formulation composition, saliva flow, film thickness, and patient behavior. Small differences in film disintegration or adhesion to the mucosa can meaningfully alter early exposure and peak concentrations.
From a BE perspective, this creates challenges in:
Traditional BE designs were not built to separate or control for these overlapping absorption routes, making it harder to interpret whether observed differences are formulation related or simply driven by biological variability.
Transdermal systems introduce an entirely different kinetic profile. Instead of a bolus dose entering systemic circulation, patches provide continuous delivery across the skin over many hours or days. Drug input is governed by skin permeability, patch adhesion, and local blood flow rather than gastrointestinal physiology.
This leads to flatter, prolonged concentration-time curves that challenge traditional BE endpoints. Small differences in patch formulation, backing materials, or adhesives can produce large differences in cumulative exposure over time even if short-term concentrations appear similar.
In these systems, AUC becomes more sensitive to wear time, patch placement, and removal procedures, while Cmax may be less informative than in oral products. Designing BE studies that capture meaningful equivalence without excessive noise requires careful control of application conditions and often longer sampling windows.
Beyond films and patches, sponsors are increasingly developing:
Each of these introduces unique PK patterns that do not map cleanly to traditional BE assumptions. For example, depot formulations may exhibit flip-flop kinetics, where the absorption rate rather than elimination governs the terminal slope of the PK curve. This complicates half-life estimation and bioequivalence interpretation.
With novel delivery systems, the timing and frequency of blood sampling becomes far more important. Rapid-onset products require dense early sampling to accurately characterize peak exposure, while sustained-release products require extended sampling to capture full AUC and late-phase behavior.
Insufficient sampling can mask true formulation differences or create artificial variability that undermines BE conclusions. In many cases, standard sampling templates developed for tablets are no longer adequate.
Regulators recognize that novel delivery systems require tailored BE approaches. Guidance increasingly emphasizes the need to justify sampling schedules, PK endpoints, and statistical methods based on the specific delivery technology rather than relying on legacy templates.
Sponsors who apply tablet-based BE logic to films, patches, or injectables often encounter delays, requests for additional data, or study redesigns late in development. Early alignment between formulation scientists, PK experts, and regulatory teams is now essential.
As delivery technologies become a core part of product differentiation, BE studies move from being a routine regulatory hurdle to a strategic design exercise. The way equivalence is demonstrated can influence development timelines, approval risk, and even labeling outcomes.
Sponsors that treat novel delivery systems as simple reformulations of existing tablets risk underestimating the complexity of the data package required to support them.
Novel drug delivery systems are redefining how medicines reach the body, but they are also redefining how bioequivalence must be demonstrated. Oral thin films, transdermal patches, and other emerging formats do not fit neatly into the PK and statistical frameworks built for traditional tablets and capsules.
Successful BE programs in this new environment depend on delivery-specific study design, thoughtful sampling strategies, and early regulatory alignment. As innovation in formulation continues to accelerate, so too must the science and strategy behind BE studies that support these products.
