Bioequivalent studies/trials

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... 

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

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. 

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. 

Design and conduct bioequivalence studies if drug product used in phase 2 is changed for phase 2 and 3 clinical trials. 

In Vivo Bioequivalence Studies In vivo studies are conducted to establish the biological availability or activity of the drug from a topically applied semisolid formulation. Dermatopharmacokinetic studies, pharmacodynamic studies, or comparative clinical trials are generally conducted to assess the bioequivalence of topical products [16,17]. 

R., Hauck, W.W. et al., An individual bioequivalence criterion regnlatory considerations, Stat. Med. 19, 2821-2842, 2000 Meyer, M.C., United States Food and Drug Administration requirements for approval of generic drug products, J. Clin. Psychiatry 62 (Suppl. 5), 4-9, 2001 Temple, R., Policy developments in regulatory approval, Stat. Med. 21, 2939-3048, 2002 Gould, A.L, Substantial evidence of effect, J. Biopharm. Stat. 12, 53-77, 2002 Chen, M.L., Panhard, X., and Mentre, F, Evaluation by simulation of tests based on nonlinear mixed-effects models in pharmacokinetic interaction and bioequivalence cross-over clinical trials, Stat. Med. 24,1509-1524,2005 Bolton, S., Bioequivalence studies for levothy-roxine, AAPS J. 7, E47-E53, 2005. 

Data from clinical trials or bioequivalence studies that indicate a bioequivalence problem. 

Clinical tricils can be done on imported formulations should the application be to import and market, then these studies are acceptable for registration. However, if the application is to manufacture cind market, the company would need to formulate the local product and perform bioequivalence studies to the imported formulation. In all likelihood, no trials would need to be conducted with the local formulation. The company can import the active substance to make the local formulation. 

In case of partial change in the formulations during the development stage, clinical data with the current formulation can be used for the application data if bioequivalence between both formulations is confirmed. In cases of a slight change in oral formulation such cis a vehicle before Phase II trials, the dissolution test can be acceptable instead of the bioequivalence study. 

For all clinical trials, including healthy volunteer bioequivalence studies, the principal investigator must also obtain prior approval from an ethics committee. The committee must be constituted cind operated according to the National Standard of Ethics Committees, and be accredited by the HRC s Ethics Committee or the Director-General of Health cis being qualified to review clinical trials involving human participants. 

The Clinical Trials Directive now requires the filing of a clinical trial application for bioequivalence studies in normal volunteers or patients. In the United States, an IND is always needed if the generic drug is without an approved innovator in the United States, is radioactive or is a cytotoxic. However, when single- or multiple-dose studies in normal volunteers do not exceed the approved clinical dose sizes and there will be retention samples available for inspection, then there can be exemption from the need to file an IND. An IND is needed for a multiple-dose bioequivalence study, when it is not preceded by a singledose study. The usual protections for human subjects are required, and, of course, these include an approval from the Institutional Review Board. 

Interchangeability Multisource (generic) bioequivalence study. Bioequivalence of all oral preparations except aqueous solutions. Orally or parenterally administered aqueous solutions chemical-pharmaceutical characteristics. Comparative clinical trial using clinical or pharmacodynamic end-points can be presented. End-points justified and validated for the compound and trial should be designed to show equivalence. Trial showing the absence of significant difference cannot be accepted Bioequivalence study report included ... 

To ensure interchangeability, the multisource product must be therapeutically equivalent to the comparator product. Types of in vivo bioequivalence studies include pharmacokinetic studies, pharmacodynamic studies and comparative clinical trials. Direct practical demonstration of therapeutic equivalence in a clinical study usually requires large numbers of patients. Such studies in humans can be financially daunting, are often unnecessary and may be unethical. For these reasons the science of bioequivalence testing has been developed over the last 40 years. According to the tenets of this science, therapeutic equivalence can be assured when the multisource product is both pharmaceutically equivalent/alternative and bioequivalent. Assuming that in the same subject an essentially similar plasma concentration time course will result in essentially similar concentrations at the site(s) of action and thus an essentially similar therapeutic outcome, pharmacokinetic data may be used instead of therapeutic results. In selected cases, in vitro comparison of dissolution profile of the multisource product with that of the comparator product, or dissolution studies, may be sufficient to provide indication of equivalence. 

For certain medicines and dosage forms, in vivo documentation of equivalence, through either a pharmacokinetic bioequivalence study, a comparative pharmacodynamic study or a comparative clinical trial, is regarded as especially important. In vivo documentation of equivalence is needed when there is a risk that possible differences in bioavailability may result in therapeutic inequivalence (2). Examples are listed below. 

Pharmacokinetic, pharmacodynamic and clinical studies are all clinical trials and should therefore be carried out in accordance with the provisions and prerequisites for a clinical trial, as outlined in the WHO guidelines for good clinical practice (GCP) for trials on pharmaceutical products (4). Additional guidance for organizations performing in vivo bioequivalence studies is available from WHO (5). 

---