This publication includes answers to the following questions:

• The required scope of pivotal clinical trials of generic products;

• Regulations supporting equivalence by pharmacodynamic, pharmacokinetic and clinical trials;
• When biowaiver is possible and where it is not.

On November 3, 2016 Rules for bioequivalence studies of medicinal products within the framework of the Eurasia Economic Union were approved by the Decision of the Council of the Eurasian Economic Commission No 85 (hereinafter referred to as the Rules).

A Generic Drug is defined by article 11 of the Rules as follows:

• The equivalent qualitative and quantitative composition of the active ingredients (active pharmaceutical substances) and the same dosage form as the reference product;
• And its bioequivalence to the reference product is supported by the corresponding bioavailability studies.

Bioequivalence studies prove the equivalence of the generic drug to reference product in its quality to extrapolate results of preclinical and clinical trials of the reference product to the generic product.

According to Article 2 of the Rules, two drugs with the equivalent amounts of the active ingredient, are considered bioequivalent if

• They are pharmaceutically equivalent or pharmaceutically alternative and
• Their bioavailability characteristics (rate and extent) after administration in the same molar dose are within the predefined acceptable limits. The specified limits are established for assurance of comparability of the biopharmaceutical properties of the dosage form in vivo (i.e. their equivalence for efficacy and safety).

The studies of bioequivalence may be conducted (Article 11 of the Rules):

• in vivo — pharmacokinetic, pharmacodynamic and clinical studies
• in vitro — for example, comparative dissolution kinetics test

According to Article 4 of the Rules, its scope covers medicinal drugs in the form of solid immediate release dosage forms for parenteral use. Bioequivalence studies of other dosage forms are described in Appendix 1 to the Rules.

No in vivo bioavailability studies within the biowaiver procedure is required in the following cases:

• for additional dosages — according to subclause 7, clause III of the Rules (articles 58-67);
• for specific types of dosage forms — according to Appendix No 1 of the Rules;
• for the biowaiver procedure based on the biopharmaceutics classification system (BCS) — according to Appendix No 4 of the Rules.

Determination of equivalence through Pharmacokinetic Studies

The concentration-time curve is usually used for determination of the rate and extent of absorption in the bioequivalence studies (Article 3 of the Rules).

The pharmacokinetic parameters shown below and the predefined acceptable limits provide a means for bioequivalence assessment of the drugs being compared by comparative bioavailability assessment:

• the area under the concentration-time curve (AUC) reflecting the exposure;
• the maximum blood, plasma or serum concentration (С_max) (hereinafter – plasma, bioliquid);
• time to maximum concentration in the bioliquid (t_max).

Moreover, С_max and t_max are parameters affecting the rate of absorption of the active substance from the dosage form.

Development of design and conducting studies, comparative bioavailability study analysis to support bioequivalence are conducted according to the requirements of section III of the Rules.

If bioequivalence cannot be supported with bioavailability studies, pharmacodynamic or clinical studies are to be conducted according to the requirements specified in Appendices 2 and 3. (Article 4 of the Rules)

Determination of equivalence through Pharmacodynamic Studies

See Appendix 2 to the Rules for the requirements to pharmacodynamic studies within the framework of the bioequivalence studies.

Pharmacodynamic studies in healthy volunteers or patients may be used for establishing the equivalence between the two medicinal drugs if the pharmacokinetic approach is not applicable.

A  pharmacodynamic equivalence study may be required unless an assay of the active substance and(or) its metabolites plasma or urea levels can be performed with sufficient sensitivity and precision.

Besides pharmacodynamic equivalence studies in humans are required if the active substance level cannot be used as surrogate end points to support the efficacy and safety of the specific product, e.g. for a topical medicinal product.

BUT at certain circumstances (e.g. for liposomal drugs) the plasma concentration-time curves are not applicable for the medicinal drug equivalence assessment.

Although pharmacodynamic studies can be suitable for establishing the equivalence, sometimes, the specified studies cannot be used because of lacking pharmacodynamic parameters to be reliably measured. In that case, clinical studies may be required to support the equivalence of two medicinal drugs (Article 1, Appendix 3 to the Rules)

Determination of equivalence through Clinical Trials

(Appendix 3 to the Rules)

Comparative clinical trials, described in these Requirements, are conducted according to 2 basic designs:

• clinical equivalence design

and

• noninferiority design.

If the clinical study is conducted to support the clinical equivalence, the same statistical principles should be used as for the bioequivalence study. Moreover, 95% confidence intervals should be used for the pharmacodynamic and clinical endpoints instead of the 90% confidence intervals commonly used for the pharmacokinetic trials. The number of patients included into the clinical trial will depend on the variability of the measurable parameters and the acceptable variation range, usually significantly exceeding the bioequivalence study requirements.

The following statements must be clearly defined in the equivalence study protocol:

• significant clinical endpoints are chosen as reference parameters, they can be used to calculate the start point of the body reaction (if measurable and clinically significant) and its severity;
• the equivalence limits should be based on the situation analysis, considering specific clinical conditions, e.g. natural course of the disease, effects of the available treatment options and the study parameters chosen. Unlike bioequivalence studies (where a standard acceptance range is used), the acceptance limits in clinical trials cannot be standard for all product groups, and is determined for each therapeutic class (and indication) individually;
• currently the statistical methods based on confidence intervals are commonly used for the specified clinical trials of equivalence. The key objective is to assure that the difference between the study drug and the reference drug does not exceed the predefined limits.

A placebo product should be used in design of such studies (whenever appropriate).

In certain cases, safety endpoints should be included into the final comparative analysis.

The generic and reference products must comply to the requirements of Subsection 2, section III of the Rules for the comparative clinical study of bioequivalence.

Determination of Bioequivalence by Biowaiver Based on the Biopharmaceutics Classification System

(Appendix No 4 to the Rules)

The Biopharmaceutics Classification system (BCS) is a scientific approach enabling to classify the active substances of the medicinal products based on their water solubility and intestinal permeability properties. Biowaiver based on the Biopharmaceutics Classification System (BCS) is designed to decrease the number of in vivo bioequivalence studies.

Together with the dissolution kinetics test for the medicinal product, BCS considers 3 basic factors affecting the rate and extent of absorption of the active substances from the immediate release oral dosage forms:

• dissolution,
• solubility
• intestinal permeability

A BCS-based biowaiver is limited on the solid systemic dosage forms for immediate release, containing highly soluble active substances with predictable absorption in humans, on condition that these substances are characterized by a wide therapeutic range.

Such approach is not applicable to sublingual, buccal dosage forms and modified release products, as well as for orally dispersible dosage forms, if unless oral absorption is not excluded.

Biowaiver as a replacement for the in vivo bioequivalence studies is possible if the active substances of the test and reference drugs are similar and belong to BCS class I or III (if requirements of section II, Appendix No 4 are met).

Biowaiver is also possible if the study and reference drugs contain various salts on condition of belonging to BCS class I (high solubility and full absorption). The active substance should not be of a narrow therapeutic range according to requirements of subsection 11, section III of the Rules.

Biowaiver is not possible, if the study medicinal product contains compound ethers, stereoisomers or their combinations, mixtures or derivatives of the reference product active substance, as such differences may lead to variable bioavailability which cannot be detected through the tests used for the BCS-based biowaiver concept.

December 26, 2022