Bioequivalence, definition

Kararli, T. T., Comparative models for studying absorption, A APS Workshop on Permeability Definitions and Regulatory Standards for Bioequivalence, Arlington, Aug. 17-19, 1998. 

The 505(b)2 application raises some patent issues beyond the scope of this book but that need to be considered if the option is under review. Generally, the 505(b)2 provides a patent exclusivity if (and only if) the applicant conducts one or more critical studies in support of the application. If all support studies are referenced from published literature of Agency findings, the patent exclusivity will not apply. While the definition of critical studies is subject to some interpretation, in this context, it most commonly refers to studies that demonstrate the link between the applicant drug and other formulations used in outside studies or previously approved by the Agency. These studies fall under the headings of Bioequivalence (BE) or Bioavail-... 

So how would FOPs be classified using conventional definitions of bioequivalence To answer this question, it is necessary to review current legal definitions of bioequivalence terms [19] ... 

On the contrary, the new formulation might be deliberately designed not to be bioequivalent. Slow-release formulations are, by definition, not bioequivalent but often associated with therapeutic superiority due to reduced probability of C -related adverse events and better compliance because of reduced dosage frequency. In this case, efficacy data will normally be required of the scale and rigor of the earlier phase III program. 

The following relevant definitions have been provided by the Code of Federal Regulations to understand the principles behind bioavailability and bioequivalence testing ... 

By definition, sustained release formulations differ pharmaceutically and pharmacokinetically from the innovator drug. Delayed or sustained release oral formulations are used for chronic therapy, and may have two principal advantages (a) reduction in dose frequency (and thus, hopefully, improved compliance see Chapter 21) and (b) reduction of Cmax for a standard AUC, which can improve tolerability when adverse events are plasma concentration-related. The demonstration of bioequivalence usually hinges on the following factors (a) equivalence of AUC to an innovator drug at steady state (b) the absence of any chance of dose dumping (c) consistency of performance from dose to dose [see 21CFR320.25(f)]. 

The US Food and Drug Administration (FDA) definition was not well received by many experts and scholars in this field, particularly among the academic community, for the reasons that drug concentrations are seldom monitored at the site of action in bioavailability studies and, very frequently, the site of action may not even be known. Furthermore, current guidelines of the FDA require manufacturers to jrerform bioavailability and bioequivalence studies by monitoring drug in plasma and/or urine. 

Please compare the definition of therapeutic equivalence with the definition of bioequivalence and examine the differences, if any, between these two definitions. Would you consider them to be the same Would bioequivalent products guarantee or assure therapeutic effectiveness Please discuss these issues in a study group. 

A related problem concerns a scientifically defensible definition of the lower limit of quantitation (LLOQ). This is sometimes referred to simply as the LOQ but in fact the upper limit of quantitation (ULOQ) can also be an important parameter for validated analytical methods (see Chapter 9). A very important definition of LLOQ is that of the US FDA with regard to bioan-alytical data used in human clinical pharmacology and in bioavailabihty and bioequivalence studies requiring pharmacokinetic evaluation (FDA 2001) this guidance also applies to bioanalytical methods used for non-human pharmacology-toxicology studies and preclinical studies. According to this protocol, the LLOQ is accepted as the lowest standard on the cahbration curve provided that (a) the analyte response for this concentration (amount)... 

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