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Regulatory Guidance (regulatory + guidance)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Perspectives on ecological risk assessment of chiral compounds

INTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT, Issue 3 2009
Jacob K Stanley
Abstract Enantiomers of chiral contaminants can significantly differ in environmental fate as well as in effects. Despite this fact, such differences are often ignored in regulation and in practice, injecting uncertainty into the estimation of risk of chiral compounds. We review the unique challenges posed by stereochemistry to the ecological risk assessment of chiral contaminants and existing regulatory guidance for chiral pharmaceuticals and pesticides in the United States. We identify the advantages of obtaining data on fate and effects of each individual enantiomer of chiral contaminants that are either distributed as or may end up as enantiomer mixtures in the environment due to enantiomerization. Because enantiomers of the same compound are highly likely to coexist in the environment with each other and can result in nonadditive effects, we recommend treatment of enantiomers as components of a mixture using widely accepted mixture models from achiral risk assessment. We further propose the enantiomer hazard ratio for retrospectively characterizing relative enantiomer risk and examine uncertainty factor magnitudes for effects analysis. [source]

Comparing Methods of Measurement for Detecting Drug-Induced Changes in the QT Interval: Implications for Thoroughly Conducted ECG Studies

ANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2004
Nkechi E. Azie M.D.
Background:,The aim of this study was to compare the reproducibility and sensitivity of four commonly used methods for QT interval assessment when applied to ECG data obtained after infusion of ibutilide. Methods:,Four methods were compared: (1) 12-lead simultaneous ECG (12-SIM), (2) lead II ECG (LEAD II), both measured on a digitizing board, (3) 3-LEAD ECG using a manual tangential method, and (4) a computer-based, proprietary algorithm, 12SLÔ ECG Analysis software (AUT). QT intervals were measured in 10 healthy volunteers at multiple time points during 24 hours at baseline and after single intravenous doses of ibutilide 0.25 and 0.5 mg. Changes in QT interval from baseline were calculated and compared across ECG methods, using Bland,Altman plots. Variability was studied using a mixed linear model. Results:,Baseline QT values differed between methods (range 376,395 ms), mainly based on the number of leads incorporated into the measurement, with LEAD II and 3-LEAD providing the shortest intervals. The 3-LEAD generated the largest QT change from baseline, whereas LEAD II and 12-SIM generated essentially identical result within narrow limits of agreement (0.4 ms mean difference, 95% confidence interval ± 20.5 ms). Variability with AUT (standard deviation 15.8 ms for within-subject values) was clearly larger than with 3-LEAD, LEAD II, and 12-SIM (9.6, 10.0, and 11.3 ms). Conclusion:,This study demonstrated significant differences among four commonly used methods for QT interval measurement after pharmacological prolongation of cardiac repolarization. Observed large differences in variability of measurements will have a substantial impact on the sample size required to detect QT prolongation in the range that is currently advised in regulatory guidance. [source]

Variability and Impact on Design of Bioequivalence Studies

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010
Achiel Van Peer
Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75,133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003,2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe. [source]

Virus susceptibility of Chinese hamster ovary (CHO) cells and detection of viral contaminations by adventitious agent testing

BIOTECHNOLOGY & BIOENGINEERING, Issue 4 2010
Andreas Berting
Abstract Biopharmaceuticals are of increasing importance in the treatment of a variety of diseases. A remaining concern associated with their production is the potential introduction of adventitious agents into their manufacturing process, which may compromise the pathogen safety of a product and potentially cause stock-out situations for important medical supplies. To ensure the safety of biological therapeutics, regulatory guidance requires adventitious agent testing (AAT) of the bulk harvest. AAT is a deliberately promiscuous assay procedure which has been developed to indicate, ideally, the presence of any viral contaminant. One of the most important cell lines used in the production of biopharmaceuticals is Chinese hamster ovary (CHO) cells and while viral infections of CHO cells have occurred, a systematic screen of their virus susceptibility has never been published. We investigated the susceptibility of CHO cells to infection by 14 different viruses, including members of 12 families and representatives or the very species that were implicated in previously reported production cell infections. Based on our results, four different infection outcomes were distinguished, based on the possible combinations of the two factors (i) the induction, or not, of a cytopathic effect and (ii) the ability, or not, to replicate in CHO cells. Our results demonstrate that the current AAT is effective for the detection of viruses which are able to replicate in CHO cells. Due to the restricted virus susceptibility of CHO cells and the routine AAT of bulk harvests, our results provide re-assurance for the very high safety margins of CHO cell-derived biopharmaceuticals. Biotechnol. Bioeng. 2010;106: 598,607. © 2010 Wiley Periodicals, Inc. [source]