Use of in vitro-in vivo correlation to predict the pharmacokinetics of several products containing a BCS class 1 drug in extended release matrices.

PURPOSE: To determine if an IVIVC model can predict PK profiles of varying formulations of a BCS Class 1 drug that is a salt of a weak base. METHOD: An IVIVC model (Level A) was created by correlating deconvoluted in vivo absorption data obtained from oral administration of 50 mg, 100 mg, and 200 mg fast and slow extended release formulations with in vitro percent dissolved using residual regression analysis. The model was then used to predict the in vivo profile of five test products that varied in formulation characteristics. RESULTS: The model passed internal validation for predicted Cmax and AUC. For external validation, in vitro data of five different test formulations was utilized. The model passed external validation for two test formulations that were different but belonging to the same release mechanism as that of the reference formulation. Three formulations failed external validation because they belonged to either a mixed or different release mechanism. The model and results were further confirmed using GatstroPlus™ simulation software. CONCLUSIONS: These observations indicate that an IVIVC model for a BCS class I drug may be applicable to varying formulations if the principle of the drug release is similar.

Impact of Biopharmaceutics Classification System-based biowaivers.

The Biopharmaceutics Classification System (BCS) is employed to waive in vivo bioequivalence testing (i.e. provide "biowaivers") for new and generic drugs that are BCS class I. Granting biowaivers under systems such as the BCS eliminates unnecessary drug exposures to healthy subjects and provides economic relief, while maintaining the high public health standard for therapeutic equivalence. International scientific consensus suggests class III drugs are also eligible for biowaivers. The objective of this study was to estimate the economic impact of class I BCS-based biowaivers, along with the economic impact of a potential expansion to BCS class III. Methods consider the distribution of drugs across the four BCS classes, numbers of in vivo bioequivalence studies performed from a five year period, and effects of highly variable drugs (HVDs). Results indicate that 26% of all drugs are class I non-HVDs, 7% are class I HVDs, 27% are class III non-HVDs, and 3% are class III HVDs. An estimated 66 to 76 million dollars can be saved each year in clinical study costs if all class I compounds were granted biowaivers. Between 21 and 24 million dollars of this savings is from HVDs. If BCS class III compounds were also granted waivers, an additional direct savings of 62 to 71 million dollars would be realized, with 9 to 10 million dollars coming from HVDs.

Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Generic drugs--safe, effective, and affordable.

This article discusses the history and evolution of the process for generic drug evaluation and approval in the United States, with emphasis on locally acting dermatologic products. The requirements for in vivo bioequivalence (BE) testing and the statistical criteria for BE are discussed, and an example of a topical antifungal dermatologic product is used to demonstrate the BE determination for locally acting drugs. Other factors in the dispensing of prescription medications that are not within the Food and Drug Administration regulatory authority are also mentioned.

BCS Biowaivers: Similarities and Differences Among EMA, FDA, and WHO Requirements.

The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has enjoyed wide use since 1995 as a mechanism for waiving in vivo bioavailability and bioequivalence studies. In 2000, the US-FDA was the first regulatory agency to publish guidance for industry describing how to meet criteria for requesting a waiver of in vivo bioavailability and bioequivalence studies for highly soluble, highly permeable (BCS Class I) drugs. Subsequently, the World Health Organization (WHO) and European Medicines Agency (EMA) published guidelines recommending how to obtain BCS biowaivers for BCS Class III drugs (high solubility, low permeability), in addition to Class I drugs. In 2015, the US-FDA became better harmonized with the EMA and WHO following publication of two guidances for industry outlining criteria for obtaining BCS biowaivers for both Class I and Class III drugs. A detailed review and comparison of the BCS Class I and Class III criteria currently recommended by the US-FDA, EMA, and WHO revealed good convergence of the three agencies with respect to BCS biowaiver criteria. The comparison also suggested that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators. It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach.

Analysis of imprecision in incurred sample reanalysis for small molecules.

Over the years, incurred sample (IS) reanalysis (ISR) has become a tool to confirm the reliability of bioanalytical measurements. The recommendation for ISR acceptance criterion for small molecules is at least 67% of ISR samples that have reanalyzed concentrations within 20% of their original concentrations when normalized to their means. To understand the relevance of the ISR acceptance criterion and sample size requirements, simulated ISR studies evaluated the probability of ISR studies passing the acceptance criterion (ISR pass rate) as a function of IS imprecision and sample size. When IS imprecision (percent coefficient of variation: %CV) is low (≤ 10 or 1-10% CV), high ISR pass rate (≥ 99%) is attained with <50 samples. At intermediate IS imprecision (e.g., 12% CV or 7-12% CV range), 80-160 samples are required for a high ISR pass rate. When IS imprecision is at the higher end of the acceptance limit, ISR pass rate decreases significantly, and increasing sample size fails to achieve high ISR pass rate. The effect of systematic bias (e.g., instability, interconversion) on ISR pass rate is strongly dependent on sample size at intermediate IS imprecision. The results provide an understanding of the effect of IS imprecision on ISR pass rates and a framework for selection of ISR sample sizes.

Survey of international regulatory bioequivalence recommendations for approval of generic topical dermatological 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.

Common bioanalytical deficiencies with bioequivalence submissions in Abbreviated New Drug Applications.

BACKGROUND: The US FDA published A Guidance for Industry: Bioanalytical Method Validation in May 2001. Despite the publication of the guidance, companies continue to submit bioequivalence studies with bioanalytical deficiencies that preclude Abbreviated New Drug Application approval. The Divisions of Bioequivalence in the FDA's Office of Generic Drugs conducted a survey of the bioequivalence submissions over a 10-year period (2001-2011) to identify the most commonly occurring bioanalytical deficiencies. RESULTS: Data from a total of 4028 Abbreviated New Drug Application submissions were collected to identify bioanalytical deficiencies. Of the three categories of bioanalytical deficiencies (method, validation and report), the majority of the deficiencies were from the bioanalytical method validation section. Globally, the percentage of bioanalytical method validation deficiencies was 62%. CONCLUSIONS: The approval of generic drugs would be accelerated if these deficiencies were avoided by generic companies by adhering to the guidance and therefore submitting a more complete application.

Bioequivalence study designs for generic solid oral anticancer drug products: scientific and regulatory considerations.

The demonstration of bioequivalence (BE) between the test and reference products is an integral part of generic drug approval process. A sound BE study design is pivotal to the successful demonstration of BE of generic drugs to their corresponding reference listed drug product. Generally, BE of systemically acting oral dosage forms is demonstrated in a crossover, single-dose in vivo study in healthy subjects. The determination of BE of solid oral anticancer drug products is associated with its own unique challenges due to the serious safety risks involved. Unlike typical BE study in healthy subjects, the safety issues often necessitate conducting BE studies in cancer patients. Such BE studies of an anticancer drug should be conducted without disturbing the patients' therapeutic dosing regimen. Attributes such as drug permeability and solubility, pharmacokinetics, dosing regimen, and approved therapeutic indication(s) are considered in the BE study design of solid anticancer drug products. To streamline the drug approval process, the Division of Bioequivalence posts the Bioequivalence Recommendations for Specific Products guidances on the FDA public website. The objective of this article is to illustrate the scientific and regulatory considerations in the design of BE studies for generic solid oral anticancer drug products through examples.

Common reasons for "for-cause" inspections in bioequivalence studies submitted to the Food and Drug Administration.

"For-cause" inspections are initiated during the review of bioequivalence (BE) data submitted to Abbreviated New Drug Applications when possible scientific misconduct and study irregularities are discovered. We investigated the common reasons for initiating "for-cause" inspections related to the clinical, analytical, and dissolution study sites associated with BE studies. This information may help the pharmaceutical industry to understand the root causes of compliance failures in BE studies and help them to improve compliance with FDA's regulations, thereby facilitating more rapid approval of safe and effective generic drugs.

Statistics on BCS classification of generic drug products approved between 2000 and 2011 in the USA.

The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period.

Common deficiencies with bioequivalence submissions in abbreviated new drug applications assessed by FDA.

PURPOSE: A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence. These approvals may be delayed if the BE portion of the submission is determined to be deficient. Many of these BE deficiencies recur commonly and can be avoided. METHOD: We conducted a survey of the BE submissions to abbreviated new drug applications (ANDAs) over years 2001 to 2008 to identify the most commonly occurring BE deficiencies. RESULTS: Recurring deficiencies are found in a majority of the ANDAs reviewed by FDA's Division of Bioequivalence. The most common deficiencies were the two deficiencies related to dissolution (method and specifications) found in 23.3% of the applications and analytical method validation and/or report found in 16.5% of the applications. The approval of generic drugs would be greatly accelerated if these deficiencies could be avoided.

Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs 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's Office of Generic Drugs 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 generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

Summary workshop report: Facilitating oral product development and reducing regulatory burden through novel approaches to assess bioavailability/bioequivalence.

This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro-in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen C (max) acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).

Dissolution testing for generic drugs: an FDA perspective.

In vitro dissolution testing is an important tool used for development and approval of generic dosage forms. The objective of this article is to summarize how dissolution testing is used for the approval of safe and effective generic drug products in the United States (US). Dissolution testing is routinely used for stability and quality control purposes for both oral and non-oral dosage forms. The dissolution method should be developed using an appropriate validated method depending on the dosage form. There are several ways in which dissolution testing plays a pivotal role in regulatory decision-making. It may be used to waive in vivo bioequivalence (BE) study requirements, as BE documentation for Scale Up and Post Approval Changes (SUPAC), and to predict the potential for a modified-release (MR) drug product to dose-dump if co-administered with alcoholic beverages. Thus, in vitro dissolution testing plays a major role in FDA's efforts to reduce the regulatory burden and unnecessary human studies in generic drug development without sacrificing the quality of the drug products.

Utility of physiologically based absorption modeling in implementing Quality by Design in drug development.

To implement Quality by Design (QbD) in drug development, scientists need tools that link drug products properties to in vivo performance. Physiologically based absorption models are potentially useful tools; yet, their utility of QbD implementation has not been discussed or explored much in the literature. We simulated pharmacokinetics (PK) of carbamazepine (CBZ) after administration of four oral formulations, immediate-release (IR) suspension, IR tablet, extended-release (XR) tablet and capsule, under fasted and fed conditions and presented a general diagram of a modeling and simulation strategy integrated with pharmaceutical development. We obtained PK parameters and absorption scale factors (ASFs) by deconvolution of the PK data for IR suspension under fasted condition. The model was validated for other PK profiles of IR formulations and used to predict PK for XR formulations. We explored three key areas where a modeling and simulation approach impacts QbD. First, the model was used to help identify optimal in vitro dissolution conditions for XR formulations. Second, identification of critical formulations variables was illustrated by a parameter sensitivity analysis of mean particle radius for the IR tablet that showed a PK shift with decreased particle radius, C (max) was increased and T (max) was decreased. Finally, virtual trial simulations allowed incorporation of inter-subject variability in the model. Virtual bioequivalence studies performed for two test formulations suggested that an in vitro dissolution test may be a more sensitive discriminative method than in vivo PK studies. In summary, a well-validated predictive model is a potentially useful tool for QbD implementation in drug development.

The role of predictive biopharmaceutical modeling and simulation in drug development and regulatory evaluation.

Advances in predicting in vivo performance of drug products has the potential to change how drug products are developed and reviewed. Modeling and simulation methods are now more commonly used in drug product development and regulatory drug review. These applications include, but are not limited to: the development of biorelevant specifications, the determination of bioequivalence metrics for modified release products with rapid therapeutic onset, the design of in vitro-in vivo correlations in a mechanistic framework, and prediction of food effect. As new regulatory concepts such as quality by design require better application of biopharmaceutical modeling in drug product development, regulatory challenges in bioequivalence demonstration of complex drug products also present exciting opportunities for creative modeling and simulation approaches. A collaborative effort among academia, government and industry in modeling and simulation will result in improved safe and effective new/generic drugs to the American public.

Highly variable drugs: observations from bioequivalence data submitted to the FDA for new generic drug applications.

INTRODUCTION: It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions. MATERIALS AND METHODS: We collected data from all in vivo bioequivalence studies reviewed at FDA's Office of Generic Drugs (OGD) from 2003-2005. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within-subject variability. A drug was considered highly variable if its RMSE for C (max) and/or AUC was > or =0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance. RESULTS AND DISCUSSION: In 2003-2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs. CONCLUSION: About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability.