The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

A Survey of the Criteria Used for the Selection of Alternative Comparator Products by Participating Regulators and Organizations of the International Pharmaceutical Regulators Programme.

The safety and efficacy of a generic product are partly based on demonstrating bioequivalence to the innovator product; however, when the innovator product is no longer available as a comparator product, a survey conducted within the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP) indicated that the criteria for selecting an alternative comparator product varies. For most members of the BEWGG, an existing marketed generic that was approved based on a comparison with the locally registered innovator product can be used, contingent on criteria that ranges from allowing any generic to be used, to allowing only specific criteria-defined generics to be used. Notwithstanding the acceptability of a generic as an alternative comparator, it is not always the preferred comparator for several jurisdictions. Some jurisdictions require the use of a locally sourced alternative innovator comparator (e.g., the same medicinal ingredient manufactured by a different company) or a foreign innovator comparator. Unlike the other members of the BEWGG, the European Union (EU) has no such options available, rather mechanisms are in place to allow manufacturers to develop a new comparator. The criteria described herein regarding the use of an alternative comparator product can also be applied to scenarios where a specific strength of a series of strengths or an innovative fixed dose combination are discontinued. The results of the survey demonstrate that while criteria for selecting alternative comparator products are not harmonized among the BEWGG participants, the common concern for all jurisdictions is to select a comparator product that meets the safety and efficacy standards of the original innovator product.

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

A Survey of the Regulatory Requirements for the Waiver of In Vivo Bioequivalence Studies of Generic Products in Certain Dosage Forms by Participating Regulators and Organisations of the International Pharmaceutical Regulators Programme.

The requirements to waive in vivo bioequivalence studies for immediate release solid oral dosage forms based on the Biopharmaceutics Classifications System (BCS) are well known, and biowaivers[1] for other types of oral dosage forms based on pre-defined criteria may also be acceptable. Similarly, biowaivers for dosage forms such as injectable products may also be allowed if certain criteria are met. The current paper summarises the biowaiver requirements for oral solutions and suspensions, soft gelatin capsules and injectable products (intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection) among the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the requirements indicated that there was a trend towards convergence when the dosage form became less complex; however, the most common approach used by each of the jurisdictions was a case-by-case approach given that most jurisdictions do not have well defined guidelines to support all possible scenarios. Even in the simplest case of intravenous solutions, the acceptability of qualitative changes in excipients differ between the IPRP members.  Notwithstanding the differences, the dissemination of the information is a first step towards regulatory convergence regarding biowaivers for certain dosage forms and should be useful for pharmaceutical companies currently developing generic medicinal products for IPRP jurisdictions.

The global bioequivalence harmonisation initiative: Report of EUFEPS/AAPS third conference.

The European Federation of Pharmaceutical Sciences (EUFEPS) and American Association of Pharmaceutical Scientists (AAPS) have collaborated since 2015 to organize international conferences to support global harmonization of regulatory requirements for bioequivalence (BE) assessment. This collaboration has resulted in three Global Bioequivalence Harmonization Initiative (GBHI) workshops which provided a unique opportunity for scientists from academia, industry, and regulatory agencies to discuss current, complex BE issues. The 3rd GBHI workshop was held in April 2018 in Amsterdam/The Netherlands and covered the following topics: (a) the necessity of multiple-dose studies in BE testing; (b) BE of transdermal delivery systems, and (c) liposomal parenteral preparations. This report summarizes the extensive discussions that led to better understanding of the similarities and differences across the major regulatory agencies on these topics and paved the way for future international harmonization.

Overview of the European Medicines Agency's Experience With Biowaivers in Centralized Applications.

The waiver of the in vivo demonstration of bioequivalence (biowaiver) is an established tool in drug development and regulatory assessment. This study reviews the use of different biowaiver approaches in centralized applications for marketing authorization to the European Medicines Agency for generic and innovator medicinal products in 2016 and 2017. The focus was to provide insight into the applicability of biowaivers for medicines development. The results show that as expected, biowaivers were most frequently used in applications for generic medicines, in particular for the approval of additional strengths when in vivo bioequivalence has been demonstrated using a single, usually the highest, strength. Biowaivers have, however, also been used in applications for innovator medicines in different phases of clinical development. This review confirms the existing key roles and further potential for biowaivers in regulatory submissions in that they are useful in streamlining the often challenging processes of clinical development.

The Requirements for Additional Strength Biowaivers for Immediate Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

In relation to the registration of generic products, waivers of in vivo bioequivalence studies (biowaivers) are considered in three main cases: certain dosage forms for which bioequivalence is self-evident (e.g. intravenous solutions), biowaivers based on the Biopharmaceutics Classification System and biowaivers for additional strengths with respect to the strength for which in vivo bioequivalence has been shown. The objective of this article is to describe the differences and commonalities in biowaivers for additional strengths of immediate release solid oral dosage forms between the participating members of the International Pharmaceutical Regulators Program (IPRP). The requirements are based on five main aspects; the pharmacokinetics of the drug substance, the manufacturing process, the qualitative and quantitative composition of the different strengths, and the comparative dissolution profiles. For the pharmacokinetic aspects, many regulators/agencies have the same requirements. All strengths must be manufactured with the same process, although a few regulators/agencies accept small differences. In relation to the formulation aspects, the data required breaks down into three major approaches based initially on one of those of the EU, the USA or Japan, but there are some differences in these three major approaches with some country specific interpretations. Most regulators/agencies also have the same requirements for the dissolution data, though there are some notable exceptions.

Summary report of second EUFEPS/AAPS conference on global harmonization in bioequivalence.

The Global Bioequivalence Harmonization Initiative (GBHI) was launched by the Network on Bioavailability and Biopharmaceutics (BABP) under the auspices of European Federation for Pharmaceutical Sciences (EUFEPS) several years ago. Since 2015, EUFEPS in collaboration with the American Association of Pharmaceutical Scientists (AAPS) has organized three international conferences to support global harmonization of regulatory requirements for bioequivalence (BE) assessment. These conferences provided an open forum for pharmaceutical scientists from academia, industry and regulatory agencies to discuss various BE topics at issue. The current report summarizes the discussion of BE issues at the 2nd GBHI conference held in 2016, Rockville, USA. Three important BE topics were discussed at the meeting: (a) prodrugs and compounds with pre-systemic extraction, (b) scaling procedures and two-stage designs, and (c) exclusion of pharmacokinetic data in BE assessment. The presentations and discussions of these issues have enhanced the mutual understanding of scientific background for BE evaluation and further facilitated harmonization of regulatory approaches for establishing BE of multisource drug products.

The Global Bioequivalence Harmonization Initiative: Summary report for EUFEPS international conference.

Bioequivalence (BE) is considered one of the key questions in new and generic drug product development and registration worldwide. However, the regulations and jurisdiction vary from country to country and continent to continent. Harmonization of regulatory requirements and criteria for BE determination may avoid unnecessary repetition of BE studies and minimize drug exposure to humans. Harmonization around the globe may be achieved by a better understanding of scientific principles and expectations from different regulatory authorities. To facilitate global harmonization, the Network on Bioavailability and Biopharmaceutics (BABP) under the European Federation for Pharmaceutical Sciences (EUFEPS) launched a Global Bioequivalence Harmonization Initiative (GBHI) several years ago. This international conference was the first in a series of workshops organized by EUFEPS/BABP under GBHI. The workshop provided a forum for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on selected BE issues in the hope of identifying common ground and arriving at a harmonized view on these topics.

Interchangeability between first-line generic antiretroviral products prequalified by WHO using adjusted indirect comparisons.

BACKGROUND: The scaling-up of access to antiretroviral therapy, particularly in low- to middle-income countries, was facilitated by the introduction and widespread use of generic antiretroviral medicines and fixed-dose combinations. Generic medicines are approved by regulatory authorities based on the demonstration of bioequivalence with the innovator or reference product, as well as meeting quality standards. In clinical practice, however, it is not unusual for generics to be interchanged between each other. This study investigated the differences in bioavailability between WHO-prequalified first-line antiretroviral generics by means of adjusted indirect comparisons to ensure interchangeability between these generics. METHODS: Data on 34 products containing emtricitabine, tenofovir disoproxil fumarate, lamivudine and efavirenz in single formulations or fixed-dose combinations were included in the analysis. The 90% CI for the adjusted indirect comparisons was calculated using the homoscedastic method that uses the conventional t-test, and assumes homogeneity of variances between the studies and small sample sizes. The combined standard deviation of both bioequivalence studies was calculated from the variability of each individual study. RESULTS: The adjusted indirect comparisons between generics showed that the differences, expressed as 90% CIs, are less than 30%. Confidence in the interchangeability of two generic products was reduced if the mean difference between the test and reference in the original studies is more than 10%. CONCLUSIONS: From a bioequivalence perspective, the generic antiretroviral medicines prequalified by WHO are interchangeable with the reference, as well as between each other without safety or efficacy concerns.

Influence of point estimates and study power of bioequivalence studies on establishing bioequivalence between generics by adjusted indirect comparisons.

PURPOSE: Adjusted indirect comparisons can be used to investigate bioequivalence between generic products that are bioequivalent with a common reference product. In previous work with generic tuberculosis medicines prequalified by the WHO, it was observed that although indirect comparisons are an effective approach for confirming the interchangeability of generics, the approach is subject to less precision than direct comparisons. The objective of this investigation was to explore this by examining the influence of point estimates and power of bioequivalence studies versus the reference on the ability to show equivalence in indirect comparisons. METHODS: Power was considered as a determining factor instead of variability and sample size, because sample size is calculated based on variability and desired power. Scenarios were computed combining a range of point estimate differences (0-14 %) and statistical power of the studies (50-99.99 %). RESULTS: The indirect comparisons could conclude equivalence between generics only when (a) point estimate differences between generics were low (≤ 5.5 %) for any sufficiently powered study (> 80 %), or (b) the differences were large (but less than 14 %) and both bioequivalence studies were overpowered (e.g., 10 % difference and power ≥ 95 %). CONCLUSIONS: In summary, the ability to demonstrate interchangeability between generics is dependent not only on the real differences between the products but also on the design of the original generic vs. reference bioequivalence studies being combined, as earmarked by their respective power.

Clinical pharmacology of tyrosine kinase inhibitors becoming generic drugs: the regulatory perspective.

Over the last decades, billions have been spent and huge efforts have been taken in basic and clinical cancer research [CA Cancer J Clin63:11-30]. About a decade ago, the arms race between drugs and cancer cells reached a new level by introduction of tyrosine kinase inhibitors (TKI) into pharmacological anti-cancer therapy. According to their molecular mechanism of action, TKI in contrast to so-called "classic" or "conventional" cytostatics belong to the group of targeted cancer medicines, characterized by accurately fitting with biological structures (i.e. active centers of kinases). Numerous (partly orphan) indications are covered by this new class of substances. Approximately ten years after the first substances of this class of medicines were authorized, patent protection will end within the next years. The following article covers clinical meaning and regulatory status of anti-cancer TKI and gives an outlook to what is expected from the introduction of generic anti-cancer TKI.

Regulatory status on the role of in vitro dissolution testing in quality control and biopharmaceutics in Europe.

An overview is provided regarding the different use of in vitro dissolution and particular related regulatory aspects. The overview attempts to clarify the regulatory requirements in all contexts in which in vitro dissolution data are employed. The different areas comprise the development of new and generic products as well as bioequivalence between different formulations. In vitro dissolution is no longer one issue among others in terms of specifications and batch release only, but is aimed to be a relevant tool for describing biopharmaceutic product characteristics for different purposes in the regulatory environment. Accordingly, the extent of the experiments will depend on the purpose of the in vitro dissolution data.

Statistical approaches to indirectly compare bioequivalence between generics: a comparison of methodologies employing artemether/lumefantrine 20/120 mg tablets as prequalified by WHO.

PURPOSE: The objective of this study was to compare different methods of adjusted indirect comparisons that can be used to investigate the relative bioavailability of different generic products. To achieve this goal, generic artemether/lumefantrine 20/120 mg tablets that have been prequalified by the World Health Organization (WHO) were selected as model products for study. METHODS: Data from three bioequivalence studies conducted independently that compared three generics with the same reference product were used to indirectly determine the relative bioavailability between the generics themselves. RESULTS: The different methods of indirect comparison examined in this study provide consistent results. Methods based on the assumption of a large sample size give slightly narrower 90 % confidence intervals. Therefore, the use of methods based on the t test is recommended. Given the precision of the area under the time-concentration curve (AUC) data, it is possible to conclude that the extent of exposure of artemether and lumefantrine is bioequivalent between the different generics studied. However, given the precision of the drug peak concentration (C(max)) data, it is not possible to demonstrate equivalence within the conventional acceptance range for all comparisons; it is possible to conclude bioequivalence within the widened acceptance range 75-133 %. CONCLUSIONS: From a clinical viewpoint, not only are these prequalified generics bioequivalent and interchangeable with the reference product (Coartem, Novartis), but also the existing indirect evidence makes it possible to conclude that these WHO prequalified products are bioequivalent between themselves with respect to the AUC. The lack of the necessary precision to demonstrate bioequivalence between generics with respect to the C(max) within the conventional acceptance range does not preclude considering them as interchangeable, if necessary, since C(max) is considered to be of less clinical relevance for the relevant therapy.

Investigation on the possibility of biowaivers for ibuprofen.

The aim of the study was to investigate the ability of in vitro dissolution to ensure bioequivalence of ibuprofen products. Ibuprofen is a Biopharmaceutics Classification System (BCS) class II drug with low solubility at pH 1.2 and 4.5 and high solubility at pH 6.8. The possibility of extending the "BCS biowaivers" to weak acidic compounds has been suggested. Three ibuprofen formulations were compared in vitro and in vivo with the reference. Dissolution profiles in several pH buffers showed similarity at 75 and 50 rpm. However, the bioequivalence studies showed that two formulations were not equivalent in C(max) because of a statistically significant difference. Conversely, another formulation was bioequivalent both in AUC and C(max) in a pilot study (n = 10) and a final study (n = 18), demonstrating that the previous failures were not due to lack of statistical power, but due to a different absorption rate that cannot be detected in vitro. In conclusion, "biowaivers" for this type of class II drugs are not feasible because the dissolution tests do not detect differences in absorption rate. Differences in absorption rate cannot be neglected, not only because absorption rate has clinical relevance but also because the clinical importance of the differences cannot be assessed if they are not quantified.

Biopharmaceutical characterization of sotalol-containing oral immediate release drug products.

The objective of this study was replacing an in vivo bioequivalence study by generating suitable in vitro data in order to get generic marketing authorisation. Solubility and permeability of sotalol hydrochloride were determined thereby achieving classification of this compound according to the biopharmaceutical classification system. In addition comparative investigation of in vitro dissolution properties of different Sota-saar formulations and the reference product provided satisfying justification to waive in vivo bioavailability (BA)/bioequivalence (BE) studies. The investigations on solubility were performed considering the highest dose strength in aqueous media (250 ml) with pH conditions between pH 1.0 and 7.5. Permeability was studied using the human colorectal carcinoma cell line Caco-2. In vitro as well as in vivo data suggest high permeability of the drug compound through the intestinal membrane. Thus, evaluation of solubility and permeability allow sotalol hydrochloride to be classified as biopharmaceutics classification system class I drug. In vitro dissolution profiles demonstrate comparable rapid dissolution (more than 85% in 15 min) for test and reference products. Summarizing, relevant prerequisites are fulfilled to waive BA/BE studies.