Bioequivalence clinical trials

Although one cannot readily identify any comprehensive, official pronouncement on the topic of development bioequivalency, it is apparent that in many cases FDA officials have adopted a pragmatic and common-sense approach to problems of this type. Obviously, in development bioequivalency our fundamental objective should be, for example, to build an appropriate bridge between F3 and F3 and F2 and F3 such that it is legitimate to use data obtained in clinical trials with F3 and F2 to support a conclusion of safety and efficacy for F3. Depending on how substantial the differences are between Fi and F3 and F2 and F3, the required bridge can be very simple or possibly more elaborate. 

For development of bioequivalence studies (in which different formulations have been used in clinical trials), it would seem that normally there would be no need to conduct bioequivalency studies using a stereoselective assay for the evaluation of the concentrations of drug in the plasma samples. We would not usually expect any noticeable difference in the ratio of R to S isomer exiting in plasma samples derived at the same postdosing time point from different... 

It is conceivable that, in the not too distant future, biogenerics will be approved with applicants supplying certain preclinical data and clinical trial information to prove comparability and bioequivalence. At the same time, the regulatory authorities will rely on their experience and expertise in approving innovator biologies to guide them as they evaluate biogenerics. 

Bioequivalence of any particular formulation compared with standard formulation used in clinical trials... 

Frequently, the formulation used in clinical trials is not the one that is ultimately marketed. The pharmaceutical dossier is scrutinised for these variations and to ensure that studies have been carried out to prove the bioequivalence of the two. The same applies if more than one dose strength or dosage form is to be marketed, for example, tablets for adults and liquid preparations for use in children. 

All clinical trials, including bioavailability and bioequivalence studies, shall be designed, conducted and reported in accordance with the principles of good clinical practice. 

CPMP (2001) Note for Guidance on the Investigation of BioavaUabUity and Bioequivalence CPMP (2002) Points to Consider on Multiplicity Issues in Clinical Trials ... 

The development report has two main sections, one that addresses the dosage form and one that deals with the bulk drug substance The product development scientist compiles the experimental evidence to demonstrate bioequivalency for the first clinical trial lot through those lots that will be used for launch. The report further includes a description of the current process along with a description of the chemical/phys-ical characteristics, purity, related substances, specifications, and stability of the drug substance. 

The study design is dependent on the nature of the active drug. The bioequivalence study can be a comparative skin blanching study as in glucocorticoids (FDA, Topical Dermatological Corticosteroids In Vivo Bioequivalence, June 2,1995.) or a comparative clinical trial or any other appropriate vahdated bioequivalence study (e.g., dermatopharmacokinetic study) for the topical dermatological drug product. 

If the drug product in the registration stability study is not the same as the product used in the clinical trials, the differences must be assessed. Likewise, any differences between the drug product in the registration stability study and the product to be marketed must be assessed. All differences should be explained and justified. Release data comparisons and/or a bioequivalence study may be required, depending on the significance of the differences. 

Robust and rugged LC-MS/MS methods are essential in support of drug discovery, toxicology studies, and clinical trials, for the data generated from these bioanalytical methods is used to evaluate the bioavailability, bioequivalence, toxicokinetic, and pharmacokinetic parameters of drug candidates. Thus, it is critical to invest significant thought and effort in the method development process [25-27], Fast sample... 

Bioavailability/Bioequivalence studies are usually conducted in healthy subjects. Although the inclusion of women is now being encouraged, we enrolled only men. The study was the second clinical trial in this project. 

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