Bioequivalence studies measures

Obviously, if the clinical mirror approach to bioequivalency testing gains momentum, we may expect to see more quantification of clinical response in bioequivalency studies. In some instances pharmacodynamic parameters that are amenable to precise quantification are easily identified. Thus, if we are working with an antihypertensive drug, measurement of blood pressure using an electronic sphygnomanometer is an obvious option. However, for many drugs there is no simple way to quantify pharmacodynamic response. In some cases we may have to rely, to some extent at least, on patient diaries [41]. Such techniques are open to criticism of subjectivity and imprecision. 

How the baseline measurement will be used in relation to the critical evaluable endpoints must be determined before analysis. Comparison of two or more treatments usually takes into account the differences between baseline values between treatment groups at the point of randomisation. The way in which the analysis will influence the report and publications needs to be decided, as some regulatory authorities have their own statistical criteria that need to be observed (e.g. for bioequivalence studies ). 

Stereoisomer Assays. There are many drugs that are administered as racemic mixtures. They may undergo stereoselective metabolism and/or elimination, and one isomer may be more active than the other. Therefore, there is the need to develop and validate bioanalytical assays for stereoselective determination in bioavailability/bioequivalence studies. All methods used for measurement of stereoisomer should be validated (with emphasis on stereospecificity). For bioequivalence studies of an existing racemic product, a stereospecific assay is not required if the rate and extent of profiles are superimposable (within the usual statistical boundaries) [3,23]. 

Pivotal Bioequivalence Studies General recommendations for a standard BE study based on pharmacokinetic measurements are provided in Attachment A. 

When ethical drugs are to be manufactured by contract, the reason for the contracted manufacture, measured values, accelerated test, bioequivalence study, list of literature, etc., should be attached. It is necessary to attach a copy of the approval cancellation form for contracted manufacture and make a new application when changing from contracted mcmufacture to complete manufacture (See section Repackaging and Contracted Mcmufacturing). 

A single-dose cross-over pharmacokinetic bioequivalence study of an orally administered product with a long elimination half-life can be conducted provided an adequate wash-out period is used between admnistrations of the treatments. The interval between study days should be long enough to permit elimination of essentially all of the previous dose from the body. Ideally, the interval should not be less than five terminal elimination half-lives of the active compound or metabolite, if the latter is measured. Normally the interval between study days should not exceed 3-4 weeks. If the crossover study is problematic, a pharmacokinetic bioequivalence study with a parallel design may be more appropriate. 

Tucker G, Rostami A, Jackson P. Metabolite measurement in bioequivalence studies theoretical considerations. In Midha KK, Blume HH, eds. Bio-Intemational Bioavailability, Bioequivalence and Pharmacokinetics. Stuttgart Medpharm Scientific Publishers, 1993 163-170. 

Common study designs for assessing bioequivalence of MDIs are multiperiod crossover. Responses to the test and reference products of each subject are measured at baseline, at one or two doses of the test drug, and at two doses of the reference product. Due to the complexity of conducting MDI bioequivalence studies. 

The acceptance limit X varies depending on the requirements of the laboratory and the intended use of the measured results. The objective is to link this acceptance limit to the requirements usually employed in specific applications. For example, this might be 1% or 2% on bulk drug, 5% on pharmaceutical specialties such as tablets, 15% for biological samples in a bioequivalence study, 1% for clinical applications where X depends on factors such as the physiological variability and the intent of use. 

A bioequivalence study was conducted in nonhuman primates to assess in vivo equivalence for the two forms of the drug. In preparation for sample analysis, the assays were optimized and standard curves were prepared using each form of the protein in study matrix. In addition, spiked controls were serially diluted and each series was measured in the N-and C-terminus-specific assays. The results for the C-terminus assay were equivalent, as shown in Fig. 9.3, demonstrating acceptable dilutional linearity with either sample type. However, as one can see in Fig. 9.4, the N-terminus assay clearly does not equivalently recognize the two forms of the drug. 

This sort of choice between models occurs all the time in PK/PD work. This is because even where, and unlike the example above, a subject or patient is given a single treatment, repeated blood samples are taken and we wish to use the observed concentration -time profiles to estimate particular parameters. We thus have a repeated-measures problem. Often a summary-measures approach is used. For example, in bioequivalence studies AUCs are compared for different formulations. These AUCs are always calculated first for each subject before proceeding to the modelling process. On the other hand, in certain applications it is not possible to cover all desired blood sampling points in all patients. Different times are used for different patients to minimize the number of samples taken. The only way in which this can be drawn together is via a random-effects approach. 

For bioavailability studies, the parent compound or the active moiety and the active metabolites should be measured if analytically feasible. For bioequivalence studies, the measurement of the parent compound is desirable, unless the parent drug levels in the plasma or serum are too low to allow reliable measurements. In addition to measuring the parent, the measurement of the metabolite is important when it contributes to either safety or efficacy of the drug product. The bioequivalence criterion is applied to the parent with supportive evidence from the metabolite measurements. Similarly, measurement of enantiomers or racemate may be necessary as appropriate. 

This issue has been addressed in detail in the next chapter. However, a brief overview is presented here. Recent guidance [29] by the FDA issued in October 2000 discusses when an enantiospecific assay may be used in bioequivalency studies. The FDA recommendations are that nonstereospecific assay may be used for bioequivalency assessment of most racemic drug formulations. Measurement of individual enantiomers in bioequivalency studies is recommended only when all of the following conditions are met ... 

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