Bioequivalence and Bioavailability Clinical Trials: A Status Report from the National Institutes of Health ClinicalTrials.gov Registry (original) (raw)
Related papers
Demonstrating bioequivalence using clinical endpoint studies
Journal of veterinary pharmacology and therapeutics, 2012
Bermingham, E., del Castillo, J. R. E., Lainesse, C., Pasloske, K., Radecki, S. Demonstrating bioequivalence using clinical endpoint studies. J. vet. Pharmacol. Therap.35 (Suppl. 1), 31–37.For drug products not amenable to blood level studies, clinical endpoint studies have been used as an indirect measure of formulation difference in bioavailability between test and reference products. However, clinical endpoint studies are not as sensitive in detecting formulation differences as blood level studies and offer numerous challenges to both regulatory authorities and sponsors. The objective of this article is not to suggest new regulatory policies, but to explore new methodologies and alternative solutions to clinical endpoint bioequivalence (BE) studies, which are used when a blood level study is not considered to be appropriate. To achieve this objective, this article identifies situations where a clinical endpoint study might be appropriate, lists the advantages and disadvantages of this type of study design, and discusses possible alternative solutions. It is concluded that future evidence-based research is needed to explore new methodologies such as clinical trial simulations of various study designs, new statistical methods, and new in vitro methods to demonstrate BE.
Guidelines for bioavailability and bioequivalence studies: A review
The Pharma Innovation Journal, 2018
Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two drugs are bioequivalent it means that they would be expected to be, for all intents and purposes, the same. In determining bioequivalence between two drugs such as a reference drug (Brand) and potential to be test drug (marketed generic drug), pharmacokinetic studies are conducted whereby, each of the drugs are administered in a cross over study to volunteers subjects (healthy individuals). Serum/plasma are obtained at regular intervals and assayed for parent drug (metabolites) concentration. Blood concentration levels are neither feasible nor possible to compare the two drugs, then pharmacodynamic endpoints rather than pharmacokinetic end points are used for comparison. For a pharmacokinetic comparison, the plasma concentration data are used to assess key pharmacokinetic parameters such as area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), and absorption lag time (tlag). Testing should be conducted at several different doses, especially when the drug displays non-linear pharmacokinetics. If 90% Confidence interval for the ratio of the geometric least square means of natural log transformed Cmax, AUC0-t and AUC0-inf of Test and Reference drugs are within 80.00% to 125.00%, then bioequivalence will be establish.
Journal of Pharmacy & Pharmaceutical Sciences
The requirements to waive in vivo bioequivalence studies for immediate release solid oral dosage forms based on the Biopharmaceutics Classifications System (BCS) are well known, and biowaivers[1] for other types of oral dosage forms based on pre-defined criteria may also be acceptable. Similarly, biowaivers for dosage forms such as injectable products may also be allowed if certain criteria are met. The current paper summarises the biowaiver requirements for oral solutions and suspensions, soft gelatin capsules and injectable products (intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection) among the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the requirements indicated that there was a trend towards convergence when the dosage form became less complex; however, the most common approach used by each of the jur...
Translational and Clinical Pharmacology
Because bioequivalence studies are performed using a crossover design, information on the intrasubject coefficient of variation (intra-CV) for pharmacokinetic measures is needed when determining the sample size. However, calculated intra-CVs based on bioequivalence results of identical generic drugs produce different estimates. In this study, we collected bioequivalence results using public resources from the Ministry of Food and Drug Safety (MFDS) and calculated the intra-CVs of various generics. For the generics with multiple bioequivalence results, pooled intra-CVs were calculated. The estimated intra-CVs of 142 bioequivalence studies were 14.7±8.2% for AUC and 21.7±8.8% for C max. Intra-CVs of C max were larger than those of area under the concentrationtime curve (AUC) in 129 studies (90.8%). For the 26 generics with multiple bioequivalence results, the coefficients of variation of intra-CVs between identical generics (mean±sd (min ~ max)) were 38.0±24.4% (1.9 ~ 105.3%) for AUC and 27.9±18.2% (4.0 ~ 70.1%) for C max. These results suggest that substantial variation exists among the bioequivalence results of identical generics. In this study, we presented the intra-CVs of various generics with their pooled intra-CVs. The estimated intra-CVs calculated in this study will provide useful information for planning future bioequivalence studies. (This is republication of the article 'Transl Clin Pharmacol 2017;25:179-182' retracted from critical typographic errors. See the 'Retraction and Republication section of this issue for further information)
Journal of Pharmacy & Pharmaceutical Sciences, 2013
The US Food and Drug Administration (FDA) has recently suggested that the bioequivalence (BE) for products of drugs with narrow therapeutic indices (NTI) be assessed by the approach of reference-scaled average BE (SABE). Subsequently, in December, 2012, the FDA issued draft guidances for the comparison of products of warfarin sodium and of tacrolimus. The guidances expect that 4-period studies be performed, that the results be evaluated by SABE, and that the analysis include also unscaled average BE as well as the comparison of the estimated within-subject variations (sW) of the test and reference drug products. This communication discusses the new guidances and suggests considerations to reduce the regulatory burden. It is demonstrated that SABE could be applied when the within-subject variation of the reference product is not higher than 21.42%. Beyond this variation, the BE limits would remain 80% to 125%, as usual. No further testing by unscaled average BE is needed. It is also ...
Bioavailability, Bioequivalence, and Pharmacokinetics: Clinical Effectiveness in Drug Development
Acta Scientific Pharmaceutical Sciences, 2021
Bioequivalence has also been referred to as comparative bioavailability. The concept of bioequivalence started gaining an increased attention during the last three decades, after it became evident that some marketed products containing the same amount of drug and marketed in the same dosage form exhibited marked differences between their therapeutic responses. In many instances, different therapeutic responses observed with these products were correlated successfully to dissimilar levels of drug concentration in the plasma, which was caused mainly due to differences in the rate of absorption of drug from these products. It is now very well established that the rate and extent to which an administered drug dose, to cause a systemic effect, must reach systemic circulation first, therefore its bioavailability depends on a number of very important factors. Although, the previous revisions specifies comparison of pharmaceutical equivalents. It is obvious that pharmaceutical alternatives are also included because the comparison here is also between therapeutic drug ingredients as well. Conclusion: Bioavailability testing for all products is economically difficult, and for some drugs such studies may not necessarily be essential. The question of determining bioavailability, however, is of particular interest for drug products which fall into distinct categories.