Helmut Schütz

Bioequivalence of a methylphenidate hydrochloride extended-release preparation: comparison of an intact capsule and an opened capsule sprinkled on applesauce.

OBJECTIVE To assess bioequivalence between an intact capsule and the content of a capsule sprinkled on applesauce. MATERIALS Medikinet retard 20 mg capsules were obtained from Medice (Iserlohn, Germany). METHODS This was a single-center, completely randomized, open, 2-period, 2-sequence, balanced crossover study with a washout period of 1 week between administrations, in 12 healthy male and female subjects, aged 18-45 years. Blood samples were collected over 24 hours and methylphenidate plasma concentration-time data were used to calculate pharmacokinetic parameters for both administrations. The main parameters were (confirmatory) AUC0-tz (extent of BA), Cmax, tmax (rate of BA) and (descriptively) AUC0-infinity and t1/2. Equivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was 0.80-1.25 (AUC0-tz). RESULTS All 12 dosed subjects finished both treatment periods and were included in pharmacokinetic and safety analyses. 90% geometric confidence intervals for AUC0-tz and Cmax data were well within accepted bioequivalence limits. The study has shown that both treatment modes lead to similar pattern of absorption and elimination following single-dose administration in the fed state. The test treatment (content of capsule sprinkled over 15 ml applesauce) is bioequivalent to the reference treatment (intact capsule) in terms of extent and rate of absorption. CONCLUSION Data collected from this study demonstrate that Medikinet retard capsules can be opened and the content sprinkled on a tablespoon of applesauce without influencing the rate and extent of bioavailability.

Lack of bioequivalence between two methylphenidate extended modified release formulations in healthy volunteers.

OBJECTIVE To assess bioequivalence between Equasym Retard and Medikinet retard containing 20 mg methylphenidate (MPH) hydrochloride in a fed state. MATERIALS Equasym Retard 20 mg capsules (UCB, Monheim, Germany) and Medikinet retard 20 mg capsules (Medice, Iserlohn, Germany). METHODS This was an open, single-center, randomized, 2-period, 2-sequence, balanced cross-over study with a wash-out period of 1 week between administrations in 14 healthy male and female volunteers, aged 18 - 45 years. Blood samples were collected over 24 hours and methylphenidate plasma concentration-time data were used to calculate pharmacokinetic metrics for both formulations. The main metrics were AUC0-t and Cmax. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was 80 - 125% (AUC0-t, Cmax). RESULTS All dosed subjects finished both treatment periods and were included in pharmacokinetic and safety analyses. The adverse events observed, mainly nervous system disorders (headache), were all mild or moderate in intensity and resolved without any action taken. The adverse event profile was consistent with the currently applicable SmPCs (Summaries of Product Characteristics) for Equasym Retard and Medikinet retard. Geometric means +/- SD for AUC0-t and Cmax were 35.5 +/- 10.1 ng x h/ml and 4.05 +/- 0.96 ng/ml (Equasym Retard) and 39.2 +/- 13.8 ng x h/ml and 5.26 +/- 2.11 ng/ml (Medikinet retard). The 90% geometric confidence interval for AUC0-t (extent of absorption) was within limits accepted for bioequivalence. Bioequivalence could not be demonstrated for the rate of bioavailability (Cmax); both the lower confidence limit and the point estimate were below 80% of the reference. The study has shown that both formulations lead to a similar pattern of absorption and elimination following single dose administration in the fed state, although the test formulation shows a somewhat slimmer profile, where the first peak is less pronounced. No bioequivalence could be shown within the first 4 hours. The second peak of the test was also lower than the one of the reference (both lower confidence limit and point estimate below 80%). CONCLUSIONS The two formulations are not bioequivalent, especially if the rate and values within the first four hours after administration are taken into account.

Two-stage designs in bioequivalence trials

PurposeThe aim of this study is to assess the current status of non-fixed sample size designs in bioequivalence trials with a focus on two-stage adaptive approaches.MethodsWe searched PubMed and Google Scholar from inception to October 2014. Regulatory guidelines were obtained from the public domain. Different methods were compared by Monte Carlo simulations for their impact on the patient’s and producer’s risks.ResultsAdd-on designs, group sequential designs and adaptive two-stage sequential designs are currently accepted to demonstrate bioequivalence in various regulations. All three approaches may inflate the patient’s risk if applied inconsiderately. Direct transfer of methods developed for superiority testing to bioequivalence is not warranted. Published two-stage frameworks maintain the type I error and generally the desired power. Adaptation based on the observed T/R ratio observed in the first stage should be applied with caution. Monte Carlo simulations are an efficient tool to explore the operating characteristics of methods.ConclusionsValidated two-stage frameworks can be applied without requiring the sponsor to perform own simulations—which could further improve power based on additional assumptions. Two-stage designs are both ethical and economical alternatives to fixed sample designs.

Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence, and a Method for its Control

PurposeTo verify previously reported findings for the European Medicines Agency’s method for Average Bioequivalence with Expanding Limits (ABEL) for assessing highly variable drugs and to extend the assessment for other replicate designs in a wide range of sample sizes and CVs. To explore the properties of a new modified method which maintains the consumer risk ≤0.05 in all cases.MethodsMonte-Carlo simulations of three different replicate designs covering a wide range of sample sizes and intra-subject variabilities were performed.ResultsAt the switching variability of CVwR 30% the consumer risk is substantially inflated to up to 9.2%, which translates into a relative increase of up to 84%. The critical region of inflated type I errors ranges approximately from CVwR 25 up to 45%. The proposed method of iteratively adjusting α maintains the consumer risk at the desired level of ≤5% independent from design, variability, and sample size.ConclusionsApplying the European Medicines Agency’s ABEL method at the nominal level of 0.05 inflates the type I error to an unacceptable degree, especially close to a CVwR of 30%. To control the type I error nominal levels ≤0.05 should be employed. Iteratively adjusting α is suggested to find optimal levels of the test.

Dissolution comparisons using a Multivariate Statistical Distance (MSD) test and a comparison of various approaches for calculating the measurements of dissolution profile comparison

The f2 test is generally used for comparing dissolution profiles. In cases of high variability, the f2 test is not applicable, and the Multivariate Statistical Distance (MSD) test is frequently proposed as an alternative by the FDA and EMA. The guidelines provide only general recommendations. MSD tests can be performed either on raw data with or without time as a variable or on parameters of models. In addition, data can be limited—as in the case of the f2 test—to dissolutions of up to 85% or to all available data. In the context of the present paper, the recommended calculation included all raw dissolution data up to the first point greater than 85% as a variable—without the various times as parameters. The proposed MSD overcomes several drawbacks found in other methods.

Reference Datasets for 2-Treatment, 2-Sequence, 2-Period Bioequivalence Studies

It is difficult to validate statistical software used to assess bioequivalence since very few datasets with known results are in the public domain, and the few that are published are of moderate size and balanced. The purpose of this paper is therefore to introduce reference datasets of varying complexity in terms of dataset size and characteristics (balance, range, outlier presence, residual error distribution) for 2-treatment, 2-period, 2-sequence bioequivalence studies and to report their point estimates and 90% confidence intervals which companies can use to validate their installations. The results for these datasets were calculated using the commercial packages EquivTest, Kinetica, SAS and WinNonlin, and the non-commercial package R. The results of three of these packages mostly agree, but imbalance between sequences seems to provoke questionable results with one package, which illustrates well the need for proper software validation.

Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII

Currently, no universally accepted definition of extended half‐life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half‐life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII.

Impact of Data Base Structure in a Successful In Vitro-In Vivo Correlation for Pharmaceutical Products

The in vitro-in vivo correlation (IVIVC) (Food and Drug Administration 1997) aims to predict performances in vivo of a pharmaceutical formulation based on its in vitro characteristics. It is a complex process that (i) incorporates in a gradual and incremental way a large amount of information and (ii) requires information from different properties (formulation, analytical, clinical) and associated dedicated treatments (statistics, modeling, simulation). These results in many studies that are initiated and integrated into the specifications (quality target product profile, QTPP). This latter defines the appropriate experimental designs (quality by design, QbD) (Food and Drug Administration 2011, 2012) whose main objectives are determination (i) of key factors of development and manufacturing (critical process parameters, CPPs) and (ii) of critical points of physicochemical nature relating to active ingredients (API) and critical quality attribute (CQA) which may have implications in terms of efficiency, safety, and inoffensiveness for the patient, due to their non-inclusion. These processes generate a very large amount of data that is necessary to structure. In this context, the storage of information in a database (DB) and the management of this database (database management system, DBMS) become an important issue for the management of projects and IVIVC and more generally for development of new pharmaceutical forms. This article describes the implementation of a prototype object-oriented database (OODB) considered as a tool, which is helpful for decision taking, responding in a structured and consistent way to the issues of project management of IVIVC (including bioequivalence and bioavailability) (Food and Drug Administration 2003) necessary for the implementation of QTPP.

Reference datasets for bioequivalence trials in a two-group parallel design.

In order to help companies qualify and validate the software used to evaluate bioequivalence trials with two parallel treatment groups, this work aims to define datasets with known results. This paper puts a total 11 datasets into the public domain along with proposed consensus obtained via evaluations from six different software packages (R, SAS, WinNonlin, OpenOffice Calc, Kinetica, EquivTest). Insofar as possible, datasets were evaluated with and without the assumption of equal variances for the construction of a 90% confidence interval. Not all software packages provide functionality for the assumption of unequal variances (EquivTest, Kinetica), and not all packages can handle datasets with more than 1000 subjects per group (WinNonlin). Where results could be obtained across all packages, one showed questionable results when datasets contained unequal group sizes (Kinetica). A proposal is made for the results that should be used as validation targets.

Adaptive two-stage bioequivalence trials with early stopping and sample size re-estimation

Bioequivalence between two products has to be demonstrated as an essential part of the generic approval process (new formulation vs. innovator product), bridging an innovator’s product from the formulation used in clinical phase III to the marketed formulation, or in case of major variations of an approved product. The most common design of bioequivalence studies is a twosequence two-period two-treatment crossover design, where inclusion of 90% confidence intervals of pharmacokinetic metrics in a pre-defined acceptance range has to be shown. Alternatively, bioequivalence can be established by using Two One-Sided Tests (TOST) each at an alpha level of 5%. However, this fixed sample approach offers no flexibility if in the planning phase parameters were misspecified. We propose a two-stage adaptive design based using combination tests to combine stagewise p-values. This will strictly control the type I error rate in case data-driven design modification have to be performed at an interim analysis. We derive 90%-repeated confidence intervals for the adaptive TOST approach. We investigate different sample size reassessment strategies using conditional power arguments. We discuss how futility stopping can be sensible implemented. The operating characteristics will be assessed by clinical trial simulations. Furthermore, the proposed adaptive design would allow to switch from a classical two-period design to a more complex replicate design if it turns out the reference product is highly variable and the within subject-variability has to be determined as well. Another application of the proposed method would be for establishing biosimilarity of two products. Authors’ details Lancaster University, Lancaster, UK. Medical University Vienna, Vienna, Austria. Baxter Innovations GmbH, Vienna, Austria. BEBAC Consultancy Services for Bioequivalence and Bioavailability Studies, Vienna, Austria. University Koln, Koln, Germany.