Clinical Endpoint Bioequivalence Studies Research Articles

An Adaptive Three-Arm Comparative Clinical Endpoint Bioequivalence Study Design With Unblinded Sample Size Re-Estimation and Optimized Allocation Ratio.

A three-arm comparative clinical endpoint bioequivalence (BE) study is often used to establish bioequivalence (BE) between a locally acting generic drug (T) and reference drug (R), where superiority needs to be established for T and R over Placebo (P) and equivalence needs to be established for T vs. R. Sometimes, when study design parameters are uncertain, a fixed design study may be under- or over-powered and result in study failure or unnecessary cost. In this paper, we propose a two-stage adaptive clinical endpoint BE study with unblinded sample size re-estimation, standard or maximum combination method, optimized allocation ratio, optional re-estimation of the effect size based on likelihood estimation, and optional re-estimation of the R and P treatment means at interim analysis, which have not been done previously. Our proposed method guarantees control of Type 1 error rate analytically. It helps to reduce the average sample size when the original fixed design is overpowered and increases the sample size and power when the original study and group sequential design are under-powered. Our proposed adaptive design can help generic drug sponsors cut cost and improve success rate, making clinical study endpoint BE studies more affordable and more generic drugs accessible to the public.

O-PTIR spectroscopy for characterizing active pharmaceutical ingredient specific particle size distributions of nasal spray suspension products

Evaluation of the particle size distribution (PSD) of active pharmaceutical ingredients (APIs) in nasal suspension products is challenging due to the presence of both API and excipients. To characterize these intricate formulations, it is essential to have sophisticated analytical methods that offer high spatial resolution and the ability to chemically pinpoint and map out the presence of API particles. However, such advanced techniques have not been documented for nasal formulations yet.In this proof-of-concept study, we investigated the utility of optical photothermal infrared spectroscopy (O-PTIR) to analyze the PSD of commercially available Nasonex® and its generic Azonaire® nasal mometasone furoate (MM) suspensions. Simultaneous O-PTIR and Raman spectra, as well as IR chemical maps, were collected from the particles in both formulations. Spatially resolved spectra from the particles confirmed the presence of peaks related to MM (1727 cm−1, 1661 cm−1, and 1122 cm−1) and excipient microcrystalline cellulose (MCC) (1061 cm−1). The PSD of MM particles was characterized using chemical maps specific to MM (1661 cm−1) and automated imaging. Results confirmed that the PSD of both formulations were comparable. Spectral analysis also revealed the presence of free MM, free MCC, and particles containing co-localized MM and MCC.For suspension-based nasal products, O-PTIR enables the measurement of API PSD, which is critical for formulators in developing nasal suspension products. This approach holds potential as an innovative complimentary analytical tool that could diminish the need for extensive clinical endpoint bioequivalence studies when evaluating the comparability of generic and brand-name nasal suspension products.

Topical Semisolid Drug Product Critical Quality Attributes with Relevance to Cutaneous Bioavailability and Pharmacokinetics: Part I—Bioequivalence of Acyclovir Topical Creams

PurposeTo develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT).MethodsProduct attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system.ResultsA toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams.ConclusionsThis research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.

Considerations for the Forced Expiratory Volume in 1 Second-Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products.

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV1 ) are often the recommended clinical endpoints. However, the use of FEV1 can pose a challenge due to its large variability and a relatively flat dose-response relationship for most OIDPs. The utility of applying dose-scale analysis was also investigated by the FDA but often not recommended, due to either flat dose-response relationships or insufficient clinical study data. As a potential way to reduce sample size, we found adapting covariate analysis only explained a limited portion of the variation based on further investigation. The FDA continues to develop alternative methods to make BE assessment of OIDPs more cost- and time-efficient. Prospective generic drug applicants and academia are encouraged to participate in this effort by proposing new approaches in pre-abbreviated new drug application meeting requests and collaborating in the form of grants and contracts under the Generic Drug User Fee Amendments (GDUFA) Regulatory Science and Research Program.

A Systematic Approach in the Development of the Morphologically-Directed Raman Spectroscopy Methodology for Characterizing Nasal Suspension Drug Products

Demonstrating bioequivalence (BE) of nasal suspension sprays is a challenging task. Analytical tools are required to determine the particle size of the active pharmaceutical ingredient (API) and the structure of a relatively complex formulation. This study investigated the utility of the morphologically-directed Raman spectroscopy (MDRS) method to investigate the particle size distribution (PSD) of nasal suspensions. Dissolution was also investigated as an orthogonal technique. Nasal suspension formulations containing different PSD of mometasone furoate monohydrate (MFM) were manufactured. The PSD of the MFM batches was characterized before formulation manufacture using laser diffraction and automated imaging. Upon formulation manufacture, the droplet size, single actuation content, spray pattern, plume geometry, the API dissolution rate, and the API PSD by MDRS were determined. A systematic approach was utilized to develop a robust method for the analysis of the PSD of MFM in Nasonex® and four test formulations containing the MFM API with different particle size specifications. Although the PSD between distinct techniques cannot be directly compared due to inherent differences between these methodologies, the same trend is observed for three out of the four batches. Dissolution analysis confirmed the trend observed by MDRS in terms of PSD. For suspension-based nasal products, MDRS allows the measurement of API PSD which is critical for BE assessment. This approach has been approved for use in lieu of a comparative clinical endpoint BE study [1]. The correlation observed between PSD and dissolution rate extends the use of dissolution as a critical analytical tool demonstrating BE between test and reference products.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Current Regulation for Bioequivalence Evaluations of Generic Ophthalmic Dosage Forms in Japan.

In Japan, the revised version of bioequivalence (BE) evaluations for generic drug products was made available in 2012; however, the scope of this guideline is mainly oral solid dosage forms. Other dosage forms have to be discussed regarding how to evaluate BE by applicants and regulators during consultation meetings or the review process. Recently, there has been an increase in developing generic drug products in various dosage forms in Japan. Therefore, the Pharmaceuticals and Medical Devices Agency (PMDA) must strengthen their efforts to establish methodologies for BE evaluations for various dosage forms, including those of ophthalmic drugs. In 2016, the Japanese Ministry of Health, Labour and Welfare (MHLW) issued "The basic principles of bioequivalence evaluations of generic ophthalmic aqueous solutions." This document presents recommendations for clinical endpoint BE studies or biowaiver options to evaluate the BE of generic ophthalmic aqueous solutions. However, this document has brought other issues to the forefront, such as the lack of feasibility of human BE studies for certain indications. Therefore, the PMDA, Japan Ophthalmic Pharmaceutical Manufacturer's Association, and BE experts discussed these issues for 2years, which led to an update by MHLW in 2018 entitled "The basic principles of bioequivalence evaluations of generic ophthalmic dosage forms." This document describes methodologies for evaluating the BE of ophthalmic dosage forms including suspensions. This article introduces recently approved generic products of ophthalmic dosage forms in Japan, the basic principle of which was issued in 2018, and compares the BE evaluations between the PMDA and U.S. Food and Drug Administration.

Assessing the ratio of means as a causal estimand in clinical endpoint bioequivalence studies in the presence of intercurrent events.

In clinical endpoint bioequivalence studies, the observed per-protocol (PP) population (compliers and completers in general) is usually used in the primary analysis for equivalence assessment. However, intercurrent events, ie, missingness and noncompliance, are not properly handled. The resulting estimand is not causal. Previously, we proposed the first causal framework to assess equivalence in the presence of missing data and noncompliance. We proposed a causal survivor average causal effect (SACE) estimand for the difference of means (DOM). In equivalence assessment, DOM is not as widely used as the ratio of means (ROM). However, no existing formula links the observed PP estimand to the SACE estimand for ROM as exists for DOM. Herein, we propose a similar causal framework for ROM using the principal stratification approach, one of the strategies recommended by the International Conference on Harmonisation (ICH) E9 R1 addendum. We quantify the bias of the observed ROM PP estimand for the SACE estimand, which provides a basis to identify three conditions under which the two estimands are equal. We propose a sensitivity analysis method to evaluate the robustness of the current PP estimator to estimate the SACE estimand. We extend Fieller's confidence interval for the SACE estimand using ROM, which can be applied to many settings. Simulation demonstrates that the PP estimator is biased in either directions and may inflate type 1 error and/or change power when the three identified conditions are violated. Our work can be applied to comparative clinical biosimilar studies.

Adaptive clinical endpoint bioequivalence studies with sample size re-estimation based on a nuisance parameter

ABSTRACTA clinical endpoint bioequivalence (BE) study is often used to establish bioequivalence (BE) between a locally acting generic drug (T) and an innovator drug (R), which is a double-blind, randomized three-arm (T, R and placebo: P) parallel clinical trial. BE is established if two superiority tests (T vs. P, R vs. P) and one equivalence test (T vs. R) all pass. An accurate estimate of the nuisance parameter (e.g. variance) is vital in determining an accurate sample size to attain sufficient power. However, due to potential study design variations between NDA and Abbreviated NDA (ANDA) studies and high variability of clinical endpoints, variance may be over- or under-estimated, resulting in unnecessary extra costs or underpowered studies. Traditionally, clinical endpoint BE studies use a fixed study design. In this work, we propose four sample size re-estimation approaches based on a nuisance parameter and recommend one approach after comparing various operating characteristics by simulation.The proposed adaptive design with sample size re-estimation provides a more accurate estimate of sample size without wasting resources or under-powering the study and controls the Type 1 error rate under a negligible level, both for the family-wise alpha and individual alpha for superiority and equivalence tests.

A Clinical Endpoint Bioequivalence Study of "Oxymetazoline Hydrochloride Cream"

A Clinical Endpoint Bioequivalence Study of "Oxymetazoline Hydrochloride Cream"

Decision Science for Generic Drug Development and Review.

Decision Science for Generic Drug Development and Review.

Scientific Considerations for the Review and Approval of First Generic Mometasone Furoate Nasal Suspension Spray in the United States from the Bioequivalence Perspective.

In 2016, the US Food and Drug Administration (FDA) approved the first Abbreviated New Drug Application for Mometasone Furoate Nasal Suspension Spray. To establish the bioequivalence of this generic nasal suspension spray with the reference listed drug product (RLD), Nasonex®, a "weight-of-evidence" approach was utilized by the applicant that included formulation and device similarities, equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition to these testing for comprehensive evaluation of the drug product, FDA also considered supportive data generated by a novel in vitro method, Morphologically-Directed Raman Spectroscopy (MDRS), to characterize the particle size distribution (PSD) of active pharmaceutical ingredient (API) in the drug product. In this case, MDRS data eliminated the need for a comparative clinical endpoint bioequivalence study. The approval of the first generic Mometasone Furoate Nasal Suspension Spray is precedent-setting and paves a new pathway to establish bioequivalence for generic nasal suspension sprays. This approval also exemplifies FDA's commitment to advance regulatory science for evaluation of generic drug products.

Common Filing Deficiencies in Abbreviated New Drug Applications Containing Clinical Endpoint Studies.

The objective of this report is to summarize common deficiencies identified in the filing reviews of abbreviated new drug applications (ANDAs) with clinical endpoint bioequivalence studies and skin irritation, sensitization, and adhesion (I/S/A) studies received by the US Food and Drug Administration (FDA) between 2007 and 2017, to help applicants avoid common deficiencies, minimize "refuse-to-receive" (RTR) actions, "information requests," and ANDA approval delays. Multiple internal FDA databases were searched to evaluate and summarize common deficiencies identified in ANDA submissions containing clinical endpoint studies and skin I/S/A studies that required review by the Division of Clinical Review. A total of 275 ANDA submissions with filing reviews from January 2007 to June 2017 were analyzed in this report. Two hundred eighteen (79.3%) filing reviews contained one or more deficiencies. Seventy-nine (28.7%) ANDAs were issued RTR letters because of major clinical deficiencies, specifically bioequivalence and clinical deficiencies, accounting for 9% of overall identified deficiencies. Twenty-two other categories of deficiencies are summarized into 4 main categories: missing information related to the clinical studies other than data sets (38%), missing data sets (35%), formulation issues (12%), and organization/format issues (6%). The most common deficiency in the "missing information related to the clinical studies other than data sets" category was "missing clarification of information" (22%). We also noted that the Division of Filing Review has identified these same types of deficiencies since assuming responsibility of the filing assessment for ANDAs with clinical endpoint BE studies and skin I/S/A studies. In conclusion, to minimize "refuse-to-receive" actions, "information requests," and approval of ANDA delays for generic drug products, applicants should submit full clinical study reports, including all data sets for drug products recommending clinical studies.

Protocol for evaluation of topical ophthalmic drug products in different compartments of fresh eye tissues in a rabbit model

Topical ophthalmic drugs are the most commonly used dosage form to treat diseases of the anterior segment of the eye. Although this dosage form has the advantages of ease of application, small volume dose, and rapid action and is largely devoid of systemic adverse effects, the bioavailability is low due to pre-corneal anatomical barriers and the nature of the drug formulation itself. Some complex generic formulations (suspensions, ointments, gels) for topical ophthalmic products face impediments to rapid regulatory approval because of the complex nature of the formulations and difficulties in determining bioequivalence with the innovator product. Clinical endpoint bioequivalence studies of ophthalmic products in humans are challenging due to inaccessibility of internal compartments of eye, large inter-subject variability that reduces study sensitivity, patient safety issues, and the prohibitively high costs of these types of clinical studies. Because of its ocular anatomical similarity to human eye, rabbits are frequently used as a model in early product development. Generating appropriate animal model data can inform physiological-based pharmacokinetic (PBPK) model building that might eventually replace the need for extensive, expensive preclinical and clinical testing. Little detail was found in the existing literature on sampling and bioanalytical protocols for determining drug concentration in different compartments of fresh eye tissues. This study describes in detail a sampling protocol for evaluating dexamethasone concentration in different tissues of freshly harvested eyes using TobraDex ST topical ophthalmic drug product in a rabbit model.

An Exact Method for Power Calculation for a Three-arm Clinical Endpoint Bioequivalence Study

A clinical endpoint bioequivalence (BE) study aims to establish BE between a generic drug (TEST) and an innovator drug (REF). A placebo (PLB) is usually included to demonstrate the sensitivity of the study. BE is established if TEST is shown to be superior to PLB, REF superior to PLB, and TEST equivalent to REF. Therefore, an overall BE test for a clinical endpoint BE study is composed of two superiority tests (TEST vs. PLB and REF vs. PLB) and one equivalence test (TEST vs. REF).
 Previously, Chang et al (2014) calculated the sample size and power for an overall BE test based on one superiority test (TEST vs. PLB) and an equivalence test (TEST vs. REF) using the joint distribution of sample means and sample variances because ’it is not easy to derive the sample size based on the multivariate t-distribution’ (we call this a ZChiSquare method). In this paper, we propose an exact method to calculate the power and sample size for an overall BE test based on two superiority tests (TEST vs. PLB, REF vs. PLB) and one equivalence test (TEST vs. REF) using a multivariate non-central t distribution directly, which we call an Exact-t method. We also extended the Z-ChiSquare method to an overall BE test with two superiority tests and one equivalence test, rather than one superiority and one equivalence test as in Chang et al’s paper.
 Simulation shows that our proposed Exact-t method is computationally more efficient than the Z-ChiSquare method without self-writing codes to numerically calculate the conditional expectation of a multivariate normal distribution conditional upon a truncated Chi-Square distribution. When sample size is small, the Exact-t method generates more accurate results than the Z-ChiSquare method.
 The Exact-t method is recommended when calculating power and determining sample size for a three-arm clinical endpoint BE study.

Clinical Endpoint Bioequivalence Studies Are Needed: A Perspective From Brand Drugs.

Clinical Endpoint Bioequivalence Studies Are Needed: A Perspective From Brand Drugs.

Estimation of causal effects in clinical endpoint bioequivalence studies in the presence of intercurrent events: noncompliance and missing data

ABSTRACTIn clinical endpoint bioequivalence (BE) studies, the primary analysis for assessing equivalence between a generic and an innovator product is based on the observed per-protocol (PP) population (usually completers and compliers). However, missing data and noncompliance are post-randomization intercurrent events and may introduce selection bias. Therefore, PP analysis is generally not causal. The FDA Missing Data Working Group recommended using “causal estimands of primary interest.” In this paper, we propose a principal stratification causal framework and co-primary causal estimands to test equivalence, which was also recommended by the recently published ICH E9 (R1) addendum to address intercurrent events. We identify three conditions under which the current PP estimator is unbiased for one of the proposed co-primary causal estimands – the “Survivor Average Causal Effect” (SACE) estimand. Simulation shows that when these three conditions are not met, the PP estimator is biased and may inflate Type 1 error and/or change power. We also propose a tipping point sensitivity analysis to evaluate the robustness of the current PP estimator in testing equivalence when the sensitivity parameters deviate from the three identified conditions, but stay within a clinically meaningful range. Our work is the first causal equivalence assessment in equivalence studies with intercurrent events.

A Case Study of Clinical Endpoint Bioequivalence Study with Missing Data and Non-compliance Data

Missing data and non-compliance data questions are especially important in evaluating locally acting generic drugs because primary equivalence analyses in clinical endpoint bioequivalence (BE) studies are based on the per-protocol (PP) population (generally, completers and compliers). However, no case studies have been reported to address the status of missing data and non-compliance in clinical endpoint BE studies. A case study using a clinical endpoint study for topical drugs for treatment of acne vulgaris was used to illustrate the extent and pattern of drop out and non-compliance reported in the Sun et al. meta-analysis results, and whether drop out and non-compliance are random or not random, independent or correlated with each other, balanced or not balanced between the generic (TEST) and the innovator drug, i.e., the reference listed drug (RLD).

A Meta-Analysis of Missing Data and Non-Compliance Data in Clinical Endpoint Bioequivalence Studies

ABSTRACTMissing data and noncompliance data questions are especially important in evaluating locally acting generic drugs because primary equivalence analyses in clinical endpoint bioequivalence (BE) studies are based on the per-protocol (PP) population (generally, completers and compliers). A meta-analysis using six clinical endpoint BE studies for topical drugs reveals the following: (1) An average of 22% (95% CI: 15–29%) of randomized subjects are excluded from the PP population. (2) Of these excluded subjects, half (10.6%, 95% CI: 8.3–12.8%) dropped out. Most who dropped out (6.9%, 95% CI: 5.0–8.8%) did not specify reasons. (3) Noncompliance categories include out-of-window visits (7.7%, 95% CI: 5.5%–9.8%), dosing noncompliance (<75% or >125% of dose) (5%, 95% CI: 2.7%–7.4%), and restricted medication use (3.2%, 95% CI: 1.8%–4.7%). (4) Drop out and noncompliance are not completely at random: a better treatment effect is associated with less drop out and less noncompliance. (5) Drop out and noncompliance are correlated: noncompliers are more likely to drop out, and vice versa. These results will help regulators better understand the extent and pattern of drop out and noncompliance and shed light on designing appropriate analysis population, endpoints, estimands, and investigating primary and sensitivity methods for equivalence in clinical endpoint BE studies in presence of missing and noncompliance data.

Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products

This review presents considerations which can be employed during the development of a semi-solid topical generic product. This includes a discussion on the implementation of quality by design concepts during development to ensure the generic drug product has similar desired quality attributes to the reference-listed drug (RLD) and ensure batch to batch consistency through commercial production. This encompasses the concept of reverse-engineering to copy the RLD as a strategy during product development to ensure qualitative (Q1) and quantitative (Q2) formulation similarity, as well as similarity in formulation microstructure (Q3). The concept of utilizing in vitro skin permeation studies as a tool to justify formulation differences between the test generic product and the RLD to ensure a successful pharmacodynamic or clinical endpoint bioequivalence study is discussed. The review concludes with a discussion on drug product evaluation and quality tests as well as in vivo bioequivalence studies.