Individual bioequivalence testing under 2x3 designs.

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.

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 U.S. Food and Drug Administration (FDA) has proposed new regulations that address the 'prescribability' and 'switchability' of new formulations of already-approved drugs. These new criteria are known, respectively, as population and individual bioequivalence. Two methods have been proposed in the bioequivalence literature for assessing population and individual bioequivalence that calculate an upper 95 per cent confidence bound for the bioequivalence criterion in question, and then test bio-equivalence by comparing this bound to the limit established by the FDA. In this paper we propose applying the generalized test function (GTF) methodology of Tsui and Weerahandi (Journal of the American Statistical Association 1989; 602-607) to this problem to produce tests based on a generalized p-value (GPV). This methodology allows us to construct hypothesis tests in the presence of nuisance parameters. Using simulation we show that these tests perform well in comparison to the confidence interval methods and have superior power for assessing population bioequivalence.

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.

Since the vast majority of prescription drugs consumed by Americans are off patent (‘generic’), their regulation and supply is of wide interest. We describe events leading up to the US Congress's 2012 passage of the Generic Drug User Fee Amendments (GDUFA I) as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). Under GDUFA I, generic manufacturers agreed to pay approximately $300 million in fees each year of the five-year program. In exchange, the US Food and Drug Administration (FDA) committed to performance goals. We describe GDUFA I’s FDA commitments, provisions, goals, and annual fee structure and compare it to that entailed in the authorization and implementation of GDUFA II on October 1, 2017. We explain how user fees required under GDUFA I erected barriers to entry and created scale and scope economies for incumbent manufacturers. Congress changed user fees under GDUFA II in part to lessen these incentives. In order to initiate and sustain user fees under GDUFA legislation, FDA requires the submission of self-reported data on generic manufacturers including domestic and foreign facilities. These data are public and our examination of them provides an unprecedented window into the recent organization of generic drug manufacturers supplying the US market. Our results suggest that generic drug manufacturing is increasingly concentrated and foreign. We discuss the implications of this observed market structure for GDUFA II’s implementation among other outcomes.

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.

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.

Med Check

*Director, Drug Information Group and Prior Authorization Services, Clinical Associate Professor, Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, Illinois In June 2015, the bipartisan Fair Access for Safe and Timely (FAST) Generics Act was reintroduced in the House of Representatives.1 This Act was developed in response to accusations that manufacturers of brand name medications are “abusing restricted access programs” in order to delay the entry of generic products into the pharmaceutical market.2 In 2007, the US Food and Drug Administration (FDA) was given the authority to require a Risk Evaluation and Mitigation Strategy, or REMS, from pharmaceutical manufacturers.3 A REMS is essentially a risk management plan that is developed by the manufacturer, approved by the FDA, and implemented by health care providers. This plan helps providers manage a known or potential serious safety risk associated with a medication and enables patients to have appropriate and safe access to the medication. REMS may involve patient or provider education, medication guides, restricted distribution programs, or required medical interventions or other actions providers need to perform prior to prescribing or dispensing a medication (ie. elements to assure safe use or ETASU). Approximately 40% of all new drug approvals are subject to REMS, and the number of REMS that restrict medication distribution in some manner has increased dramatically over recent years.4 The FAST Generics Act aims to amend the federal Food, Drug, and Cosmetic Act so that “eligible product developers have competitive access to approved drugs and licensed biological products.”5 Basically, passage and approval of the FAST Generics Act would result in the closing of a loophole. This loophole currently allows pharmaceutical manufacturers to utilize aspects of REMS programs, such as restricted distribution networks, to deny generic and biosimilar manufacturers access to samples of brand name reference products. These samples are needed in order for the generic or biosimilar manufacturer to conduct appropriate studies comparing its proposed product to the brand name reference medication for FDA approval.2 In normal situations, obtaining a brand name reference product sample is fairly easy; however, products that are available through a restricted distribution program have access tightly controlled.6 In July 2014, a report on the impact of using REMS programs to delay generic market entry was published by the economic policy consulting firm, Matrix Global Advisors.4 This report, which was sponsored by the Generic Pharmaceutical Association, estimated lost savings on 40 generic smallmolecule products whose market entry was delayed by misuse of REMS or other restricted access programs, according to a survey of generic manufacturers. Specifically, the analysis found that the use of such programs to create barriers for generic competition costs the US health care system an estimated $5.4 billion annually. Passage of the FAST Generics Act is not only meant to be a potential cost-saving measure, but also to engage the Department of Health and Human Services (HHS) as the “go-between” between generic and brand name manufacturers.7 The generic manufacturer would have to receive authorization from HHS prior to requesting a reference product sample from the brand name manufacturer. The Act would also allow for injunctive relief and damages if a generic manufacturer is inappropriately denied access to needed samples. Opponents of the FAST Generics Act focus on the importance of REMS programs with regard to protecting patients from serious harm.1 They note that many of these medications have extensive safety concerns and that the Act may “dilute important safety mechanisms.”7 Opponents also note that the mere existence of a REMS program, even with the more restrictive ETASU requirements, does not eliminate the approval of a generic product. In fact, generic products exist for medications with REMS including medications with ETASU provisions. Hosp Pharm 2016;51(1):42–43 2016 © Thomas Land Publishers, Inc. www.hospital-pharmacy.com doi: 10.1310/hpj5101-42

IN 1984, Congress enacted a new law that greatly affected the economics of the pharmaceutical industry in the United States. It has been characterized as the most important legislation affecting competition in the pharmaceutical industry since the 1962 Kefauver-Harris Amendments to the Food and Drug Act. This 1984 law, known as the Drug Price Competition and Patent Term Restoration Act (hereinafter the 1984 Act), facilitated the entry of generic drug products after patent expiration while it also restored part of the patent life lost during the premarket regulatory process for new introductions.1 Market entry by generics was relatively limited prior to 1984 because of costly Food and Drug Administration (FDA) requirements that had to be met by the imitative products. That is, generic drugs often would have to duplicate many of the pioneer's tests to gain market approval after patent expiration. As a result of the 1984 law, generic products need only demonstrate bioequivalence to the pioneer's brand, and generic entry has increased significantly. This has provided a body of very interesting data to analyze the pattern of entry and the pricing strategies followed by the entrants and incumbents. In this article, we make use of data covering the sales and prices of the pioneer and generic products for eighteen drug products, generally over the time period 1984-88. A number of issues are examined. First,

FDA's role in anesthetic drug development.

Bioequivalence studies are conducted to demonstrate equivalence in the bioavailability of the active ingredient in different formulations. The U.S. Food and Drug Administration (FDA) requires pharmaceutical companies to show bioequivalence between different formulations or generic companies to show bioequivalence between generic drugs and brand drugs before approval. A recent FDA guidance on bioequivalence proposes criteria for assessment of population bioequivalence (PBE) and individual bioequivalence (IBE) in a four-period cross-over design. In this paper, computer simulation is used to compare modified large sample (MLS) upper bounds with those proposed by the FDA to test for both PBE and IBE. The comparison criteria are the ability to maintain the stated test size and the simulated power of tests based on these bounds.

For the approval of generic drug products, bioavailability/bioequivalence studies are often conducted to demonstrate that the drug absorption profiles in terms of the extent and rate of absorption of test products are bioequivalent to those of the innovative drug product. The bioavailability/bioequivalence studies are often conducted under a standard two-sequence, two-period (2x2) crossover design. Under the standard 2x2 crossover design, statistical methods are well established for the assessment of bioequivalence. However, it is a concern whether approved generic drug products can be used safely and interchangeably. In this article, drug interchangeability under a replicated crossover bioavailability/bioequivalence study is discussed. Several controversial statistical issues that are commonly encountered in the assessment of bioequivalence are discussed. In addition, some frequently asked questions during regulatory submissions are reviewed. Recommendations regarding possible resolutions are made whenever possible. Some concluding remarks on the feasibility of the application of current methods for bioequivalence to the assessment of biosimilarity of follow-on biologics are also presented.

Low-Field NMR in Nondestructive Quantitative Inspection of Drug Products

Background: Generic drugs are those that are identical or bioequivalent to a brand name drug or innovator drug in active ingredient(s), dosage form, strength, route of administration, intended use, quality, safety and performance characteristics. Pharmaceutical companies need to submit Abbreviated New Drug Application (ANDA) to the US Food and Drug Administration (FDA) for approval to market a generic product in the US. After a drug product is marketed, it is mandatory for pharma companies to report adverse events occurring due to their drug products to the FDA and this is done by the Pharmacovigilance department. The objective of this article is to provide an understanding of the pharmacovigilance department and the activities conducted by them to report adverse events to the FDA and the challenges faced by them while carrying out these activities. Keywords: US FDA, safety reporting, pharmacovigilance, individual case safety report, periodic adverse drug experience report.