Generic drugs are a mainstay of patient treatment, representing more than 90% of medicines dispensed in the US and approximately two-thirds in Europe. Because generics are copies of innovative drugs with proven safety and efficacy, they are not required to undergo the same extensive clinical trials as a new medicine. Regulators do, however, require companies to prove that a new generic drug is just as safe and efficacious as the originator product. The bioequivalence study is a critical part of this process.
What is a Bioequivalence Study?
Comparative bioavailability studies, also known as bioequivalence studies, are designed to demonstrate that the outcomes of treatment would be the same for a patient, regardless of whether they were given the originator or the generic version. These trials compare the rate and extent of absorption of the two products into the bloodstream.
If the results of bioequivalence studies for generic drugs are comparable, regulators accept that the therapeutic outcome will also be equivalent. This avoids the need for more extensive and costly efficacy studies, based on the assumption that similar absorption leads to similar efficacy. While not all products require clinical equivalence studies, as scientific data from lab experiments can sometimes suffice, in most cases a formal bioequivalence study is required.
The Strategic Importance of Study Design
Careful and experienced study design is essential for a successful outcome. At the heart of the design process is a deep understanding of what regulators will look for when they review the submission. When we prepare a development proposal, we design a complete pathway that should lead to approval, identifying and mitigating potential risks along the way.
Pilot vs. Pivotal Studies
In some cases, particularly for complex dosage forms or molecules with inherent variability, running a pilot study first is a wise decision. A pilot study helps to reduce development risk by providing an early indication that a larger, pivotal study is likely to succeed. However, in other situations, it may be feasible to proceed directly to the pivotal study without incurring significant risk.
Key Design Considerations
Various choices must be made when finalising the trial design. How many subjects are required? Will the products be administered under fasting or fed conditions? Will a simple crossover study be sufficient, or will a more complex replicate design be necessary to demonstrate bioequivalence?
There is no substitute for experience when deciding which studies are needed. For example, if the drug is marketed at multiple strengths, will a study using just the highest dose be enough, or will a range of doses need to be investigated? Likewise, will a single study in fasted patients suffice, or will studies under fed or steady‑state conditions also be required?
Executing the Pivotal Bioequivalence Study
Typically, a pivotal bioequivalence study will include 24 to 32 subjects for a simple protocol. However, for some products, 100 or even 200 subjects may be necessary to prove that the bioavailability of the two products is comparable. Subjects are given either the originator product or the generic, often after an overnight fast, and blood samples are taken at specified time intervals for analysis.
Core Bioequivalence Parameters: AUC and Cmax
The analysis focuses on critical pharmacokinetic parameters. These include the area under the curve (AUC), which indicates the total extent of drug absorption, and the maximum concentration (Cmax), which shows the rate of absorption. If these key figures are similar between the two products, they are deemed to be bioequivalent.
Application Across Dosage Forms
This process is similar for all orally administered small‑molecule drugs, regardless of the format, such as a tablet, capsule, or liquid. Even a topical product may follow a similar bioequivalence process, though the focus shifts from systemic absorption to local absorption at the site of application. For topical drugs, parameters like skin penetration or local drug concentration may be measured to determine equivalence.
Managing the Development and Regulatory Pathway
Most steps in the development programme require specialised outside providers. At our Adragos facility in Athens, we act as project managers, coordinating the entire process. This includes oversight of work done in a generic lab, designing the clinical protocol, and preparing the final report on the bioequivalence study.
Project Coordination and Manufacturing
The dosage forms for the studies must be made under GMP conditions. This can happen at another Adragos site or at an external contract manufacturer, and we collaborate with dozens of different CMOs across Europe. We also assemble all the documentation for the regulatory application to run the trial and, following the study’s completion, prepare the paperwork for the marketing authorisation application.
Development Timelines
The timescale for the development process depends on project complexity. It typically takes six to nine months to design the dosage form and evaluate its stability. Manufacturing can then begin, with preparations starting while the dosage form is still in development. The bioequivalence study follows, with or without a preceding pilot study. With careful design and preparation, this clinical phase can often be completed within six months.
An experienced team can move a product from concept to submission in approximately 18 months. Regulators then typically take another 12 to 18 months to grant approval, giving an overall project timescale of about three years. More complex products might take longer, but this is still significantly shorter than the decade or more required for a new chemical entity (NCE).
Navigating Intellectual Property and Market Entry
A generic drug cannot enter the market until the originator product’s intellectual property has expired. The development work, however, can take place while this protection is still intact. In the US, market entry is largely driven by patent expiry, as the data exclusivity period is shorter. In Europe, it relies more on data and market exclusivity, though patent laws must still be obeyed.
In either case, once competition is permitted, the generic launch provides more affordable alternatives for patients and healthcare systems. Careful development and planning ensure the generic is ready to enter the market as soon as this is allowed. At Adragos, we are proud to help our clients bring their generic products to patients quickly and effectively.
