Showing that a medicine is safe and effective is a scientific task; but what determines under which conditions and how this evidence is to be produced is the regulatory framework. Bioequivalence studies are conducted within this framework. For a generic medicine to reach the market, it must prove that it is equivalent to the reference product, and the rules for this proof are carefully defined by the authorities. In this article we look at the regulatory framework of bioequivalence and at how the approaches of different countries are converging toward common ground.
The origin of the rules
Bioequivalence took shape as a regulatory requirement over the past fifty years. In the 1960s, researchers noticed that the same active ingredient could behave differently in different products. This observation soon prompted regulatory authorities to act, and the first bioavailability requirements emerged. In the following years, together with legislation that opened the way for generic medicines, manufacturers were required to prove that their products were equivalent to the reference drug. This requirement gradually spread around the world.
The United States approach
In the United States, the general principles of bioavailability and bioequivalence studies are defined in comprehensive guidances published by the relevant authority.¹ These guidances set out the study design, the quantities to be measured, and the acceptance criteria. The basic acceptance rule is that the ninety percent confidence interval calculated for the ratio of the geometric means of two products must fall between eighty percent and one hundred twenty-five percent. This criterion forms the scientific basis on which generic medicines are safely brought into use.
The European approach
In Europe, bioequivalence studies are conducted within the framework of the bioequivalence guideline published by the European Medicines Agency.² The European guideline shares the same scientific backbone as the United States approach in terms of study design and evaluation; the crossover design, the logarithmic transformation, and the same acceptance range are parts of this shared backbone. Although there are differences in the details, the underlying logic of the two frameworks overlaps.
Harmonization: toward a common guideline
For many years, each authority’s own rules meant that different studies had to be conducted for the same product in different regions. This both increased costs and led to unnecessary duplication. To address this problem, international harmonization efforts were carried out and a common bioequivalence guideline was prepared for orally administered immediate-release solid dosage forms.³ By reducing the differences between regions, this guideline opens the way for a single study to be accepted by more than one authority. The United States and Europe have gradually incorporated this common guideline into their own systems, moving toward a more consistent framework on a global scale.
The Turkish approach
In Türkiye, the field of bioavailability and bioequivalence is regulated by the Turkish Medicines and Medical Devices Agency. The qualifications that the centers conducting these studies must hold are defined in a dedicated guideline published by the agency.⁴ This guideline is an adaptation of the World Health Organization’s guidance for organizations performing bioequivalence studies.⁵ This shows that the framework in Türkiye is aligned with internationally accepted principles. A center’s meeting of the conditions defined in this guideline is a precondition for the data it produces to be regarded as reliable at both the national and the international level.
Why so many rules?
Behind all these rules lies a single aim: to safeguard the reliability of the medicine that reaches the patient. When a generic medicine is approved in a country, the physician and the patient trust that the product will produce the same effect as the reference drug. This trust can only be protected through common and strict rules. Although different authorities have their own requirements in the details, they all rest on the same scientific foundation and are increasingly converging. Harmonization efforts allow this trust to cross borders.
NanoTox’s place within this framework
As a bioavailability and bioequivalence center authorized by the Turkish Medicines and Medical Devices Agency, NanoTox meets the conditions required by this regulatory framework. Being an authorized center is not merely a permission; it is confirmation that the data produced complies with defined rules, traceable conditions, and internationally accepted principles. The results obtained with the LC-MS/MS infrastructure and the experience in bioanalytical method validation carry the scientific robustness this framework expects.
In the final article of this series, we will examine in detail the bioanalytical method validation that lies at the foundation of this entire process and the role of LC-MS/MS in these studies.
References
¹ U.S. Food and Drug Administration. Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations. https://www.fda.gov/files/drugs/published/Bioavailability-and-Bioequivalence-Studies-Submitted-in-NDAs-or-INDs-%E2%80%94-General-Considerations.pdf
² European Medicines Agency. Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1). https://www.ema.europa.eu/en/investigation-bioequivalence-scientific-guideline
³ ICH M13A. Bioequivalence for Immediate-Release Solid Oral Dosage Forms. https://www.ema.europa.eu/en/ich-guideline-m13a-bioequivalence-immediate-release-solid-oral-dosage-forms-scientific-guideline
⁴ Turkish Medicines and Medical Devices Agency. Guideline on the Centers Where Bioavailability and Bioequivalence Studies Are Conducted (TİDD-KLVZ-19, Rev. 01, 15.11.2022). https://titck.gov.tr/storage/Archive/2026/contentFile/DD-KLVZ19%20Biyoeşdeğerlik%20Merkezleri%20Hakkında%20Kılavuz%20R.01_b7f60da8-9039-4e70-b8d3-19f0b9b48d37.pdf
⁵ World Health Organization. Annex 9: Guidance for organizations performing in vivo bioequivalence studies. WHO Technical Report Series No. 996, 2016. https://www.who.int