Statistical Issues in Bioavailability/Bioequivalence Studies

ABSTRACTAs more and more generic (or biosimilar) drug products become available in the market place, it is a concern whether the approved generic (or biosimilar) drug products are safe and efficacious and hence can be used interchangeably. According to current regulation, most regulatory agencies such as the United States Food and Drug Administration (FDA) indicate an approved generic (or biosimilar) drug product can serve as a substitute for the innovative drug product. Bioequivalence (biosimilarity) assessment for regulatory approval among generic copies (or biosimilars) of the innovative drug product are not required. In practice, approved generic (or biosimilar) drugs are commonly used interchangeably without any mechanism of safety monitoring. In this article, current bioequivalence (or biosimilarity) limit is adjusted according to the observed geometric mean ratio and corresponding variability for development of safety margins for monitoring of drug interchangeability by minimizing the relative change in response with and without the switching.

Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.

The objective of this article is to discuss the similarities and differences in accepted bioequivalence (BE) approaches for generic topical dermatological drug products between international regulatory authorities and organizations. These drug products are locally applied and not intended for systemic absorption. Therefore, the BE approaches which serve as surrogates to establish safety and efficacy for topical dosage forms tend to differ from the traditional solid oral dosage forms. We focused on 15 different international jurisdictions and organizations that currently participate in the International Generic Drug Regulators Pilot Project. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association (EMA), Japan, Mexico, New Zealand, Singapore (a member of the Association of Southeast Asian Nations), South Africa, South Korea, Switzerland, the USA and the World Health Organization (WHO). Upon evaluation, we observed that currently only Canada, the EMA, Japan, and the USA have specific guidance documents for topical drug products. Across all jurisdictions and organizations, the three approaches consistently required are (1) BE studies with clinical endpoints for most topical drug products; (2) in vivo pharmacodynamic studies, in particular the vasoconstrictor assay for topical corticosteroids; and (3) waivers from BE study requirements for topical solutions. Japan, South Africa, the USA, and the WHO are also making strides to accept other BE approaches such as in vivo pharmacokinetic studies for BE assessment, in vivo dermatopharmacokinetic studies and/or BE studies with in vitro endpoints.

This chapter discusses the regulatory standards for approval of locally acting topical dermatological drug products based on the different types of submissions. Topical dermatological drug products are available in an array of dosage forms ranging from simple to complex. In the 1950s, manufacturers applied to the US Food and Drug Administration for approval to market topical dermatological corticosteroids as over-the-counter (OTC) products. An OTC monograph consists of the active ingredient specific, public and a “kind of recipe” book covering acceptable ingredients, doses, formulations, labeling and, in some cases, testing parameters. The drug application site and the disease state have a direct relation to the selection of the appropriate dosage form to elicit the desired therapeutic effect. OTC drug products can be brought to the market using the new drug application process or under an OTC monograph. Bioequivalence studies with clinical endpoints are commonly required for the approval of generic topical drug products.

Objective. The marketing authorization of generic and similar pharmaceutical drug products involves the analysis of proposing company's administrative aspects as well as drug product technical description and scientific evaluations. This study evaluated the main reasons for registration refusal of generic and similar pharmaceutical drug products in Brazil. The aim is to help future applicants to better organize the proposal. Methods. A retrospective search of drug products registration processes was performed on the Brazilian Government Official Gazette from January 1, 2015, and December 31, 2015. Results. Drug product quality control, drug product stability study, deadline accomplishment, API quality control made by drug manufacturer, active pharmaceutical ingredient (API), and production report were the main reasons for marketing authorization application refusal of generic and similar pharmaceutical drug products in 2015. Conclusion. Disclosure of the reasons behind failed applications is a step forward on regulatory transparency. Sharing of experiences is essential to international regulatory authorities and organizations to improve legislation requirements for the marketing authorization of generic and similar pharmaceutical drug products.

In recent years, as more generic drug products become available, it is a concern not only whether generic drug products that have been approved based on the regulation of average bioequivalence will have the same quality, safety and efficacy as that of the brand-name drug product, but also whether the approved generic drug products can be used interchangeably. In its recent draft guidance, the U.S. Food and Drug Administration (FDA) recommends that individual bioequivalence (IBE) be assessed using the method proposed by Hyslop, Hsuan, and Holder to address drug switchability. The FDA suggests that a 2x4 cross-over design be considered for assessment of IBE, while a 2x3 cross-over design may be used as an alternative design to reduce the length and cost of the study. Little or no information regarding the statistical procedures under 2x3 cross-over designs is discussed in the guidance. In this paper, a detailed statistical procedure for assessment of IBE under 2x3 cross-over designs is derived. The main purpose of this paper, however, is to derive an IBE test under an alternative 2x3 design and show that the resulting IBE test is better than that under a 2x3 cross-over design and is comparable to or even better than that under a 2x4 cross-over design. Our conclusions are supported by theoretical considerations and empirical results. Furthermore, a method of determining the sample sizes required for IBE tests to reach a given level of power is proposed.

Regulatory approval of complex generic drug products that are applied topically to treat skin disease can be challenging because a standard method to assess cutaneous pharmacokinetics in vivo is not available. As a result, expensive and prolonged clinical trials are often necessary, and this has proved to be a significant disincentive to generic product development and restrictive of patient access to more affordable medicines. Here Raman spectroscopy is used to quantify the relative spatiotemporal disposition of metronidazole (a drug used to treat rosacea) within the skin and proximal to its site of pharmacological action. Analysis of the data permits pharmacokinetic metrics to be extracted and compared between different gel and solution formulations with the potential to establish bioequivalence and enable more efficient complex generic drug product development.

Consistent quality and performance characteristics for the innovator (brand name) drug products and their generic (multisource) equivalents are explicit objectives of the drug approval process in the US. Statutory and regulatory requirements supporting these objectives are based on the bioavailability and bioequivalence Regulations (1), the amendments to the Food, Drug and Cosmetic Act (2), and the implementing regulations to the amendments. These objectives are based on the concept that an innovator drug exists with reproducible quality and performance characteristics that are maintained throughout the marketing life. Following termination of the patent or the exclusivity period for an innovator drug product, its generic pharmaceutical equivalents may be marketed. These generic drug products are expected to demonstrate comparable quality and performance characteristics to those of the innovator product throughout the marketing period. In addition, both innovator and generic drug products may undergo several post-approval changes in formulation and manufacturing processes, change of manufacturing site, and increase in batch size, etc., that may warrant demonstration of sustained quality and performance characteristics. Several drug application and compendial tests and specifications exist to assure the overall objective of stability in the quality and the performance characteristics of the innovator and

Highly variable (HV) drugs are defined as those for which within-subject variability in bioequivalence (BE) measures is 30 % or greater. Studies designed to show whether a test highly variable drug product (either a generic or reformulated new drug) is bioequivalent to its corresponding reference highly variable drug product may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration (FDA) developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV drug product must meet the scaled BE limit and a geometric mean ratio (GMR) constraint. The approach has been implemented successfully by the FDA, to date supporting approvals of both new generic drug products and reformulated modified-release (MR) new drug products.

Objectives To explore the issues involving generic versus brand antimicrobial drug products and provide an overview of assessments of equivalence and their potential relevance to health outcomes. Methods In April and May 2010, literature searches were performed in MEDLINE and EMBASE for studies involving antimicrobial drug products that convey equivalence or non-equivalence of generic and brand-name drugs. Key findings Sixty-six studies involving antibiotics, antifungals, antivirals and antimalarials were identified for analysis. The types of studies were categorized into microbial assays, pharmaceutical assays, bioequivalence and those that assess clinical endpoints. Studies varied markedly on equivalence measures between generic and brand drug products. Thirty-four of 66 (52%) were primarily bioequivalency studies with 30 of 34 (88%) demonstrating positive outcomes for equivalency. Two of 22 studies (9%) involved microbial and/or pharmaceutical assays for quality assurance testing and presented the largest disparity in equivalence. Ten studies compared outcomes of a clinical nature and concluded no significant difference in outcome between generic and brand products. Ten of 66 (15%) studies were published before 2000 and 11 (17%) were conducted in the USA. Conclusions In the USA, it is unlikely that use of generic antibiotics and antimicrobials pose a problem for patients with infectious diseases, where quality safeguards exist and patients are informed when generic substitution occurs. However, with expansion of international markets and questionable drug supply chains – particularly with the advent of the internet – consumers and providers should be aware of drug product quality differences that may impact patient outcomes.

In the US, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the generic formulation provides the same rate and extent of absorption as (ie, is bioequivalent to) the innovator drug product. Thus, most orally administered generic drug products in the US are approved based on results of one or more clinical bioequivalence studies. To evaluate how well the bioequivalence measures of generic drugs approved in the US over a 12-year period compare with those of their corresponding innovator counterparts. This retrospective analysis compared the generic and innovator bioequivalence measures from 2070 single-dose clinical bioequivalence studies of orally administered generic drug products approved by the Food and Drug Administration (FDA) from 1996 to 2007 (12 y). Bioequivalence measures evaluated were drug peak plasma concentration (C(max)) and area under the plasma drug concentration versus time curve (AUC), representing drug rate and extent of absorption, respectively. The generic/innovator C(max) and AUC geometric mean ratios (GMRs) were determined from each of the bioequivalence studies, which used from 12 to 170 subjects. The GMRs from the 2070 studies were averaged. In addition, the distribution of differences between generic means and innovator means was determined for both C(max) and AUC. The mean +/- SD of the GMRs from the 2070 studies was 1.00 +/- 0.06 for C(max) and 1.00 +/- 0.04 for AUC. The average difference in C(max) and AUC between generic and innovator products was 4.35% and 3.56%, respectively. In addition, in nearly 98% of the bioequivalence studies conducted during this period, the generic product AUC differed from that of the innovator product by less than 10%. The criteria used to evaluate generic drug bioequivalence studies support the FDA's objective of approving generic drug formulations that are therapeutically equivalent to their innovator counterparts.

Bioequivalence of defferent products of the same drug is very important where many generic drug products are on the market. Data of bioequivalence tests have been analyzed using pharmacokinetic model independent parameters. However, model dependent methods merit being considered as an analysis method to assess bioequivalence/bioavailability. We have studied the application of NONMEM to evaluation of bioequivalence/bioavailability, which is one of the methods used for analysis of population pharmacokinetics. In this paper, decision-making rules in bioequivalence assessment, an application method of NONMEM to the evaluation of bioequivalence and the relationship between a decision-making rule and the NONMEM method were shown. The results of comparison of the confidence intervals for the difference in bioavailability estimated by NONMEM and a model independent method were summarized, which indicated the usefulness of the NONMEM method for evaluation of bioequivalence using experimental and obsevational data. Merits and demerits of NONMEM for assessing bioequivalence/bioavailability were discussed.

Advance in bioequivalence assessment of topical dermatological products

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