Bioequivalence study

Cross-over study designs are typically employed in bioequivalence trials. Imagine that the new formulation is called N and the existing formulation is called R (the reference formulation). The two order possibilities for receiving the two drug treatments are NR and RN. Typically, healthy male and female adults participate in these studies, and the treatment orders are appropriately controlled and balanced. Pharmacokinetic parameters are used to represent both safety and efficacy. 

To demonstrate equivalence in plasma concentration profiles, rate and extent of availability must be assessed and compared. The parameters Cmax and AUC are typically used here, and they are regarded as surrogate markers for clinical safety and efficacy. If they are too much higher in the new drug formulation N, they could lead to unwanted side effects. On the other hand, if they are too much lower, the new formulation may be less effective in treating the condition. The definition of too much in this context is not simple, and we will not discuss the details here (see Patterson and Jones, 2006, for more details). 

In this case, a double-barreled approach is taken. Both of these hypotheses need to be rejected in order for N to be deemed bioequivalent to R. If the data lead to the failure to reject one or both of the hypotheses, N is not deemed to be bioequivalent to R (see Hauschke et al., 2007, for additional discussion). 

which was strange, the one so like the other As could not be distinguished but by names 

Most commonly, a single dose of each of test and reference is given on particular days well separated by a wash-out period of at least five half-lives of the drug and a number of blood (or possibly urine) samples are taken until at least three half-lives of the drug have been passed or sometimes until the concentration has passed the limits of detection. These samples are analysed before breaking the blind and the concentration for a given time point is obtained for each individual. Summary statistics such as the area under 

Statistical Issues in Drug Development, 2nd Edition. Stephen Seim 2007 John Wiley Sons, Ltd. ISBN 978-0-470-01877-4 

A crucial assumption in the analysis of many experiments is that there are no versions of the treatment (Rubin, 1980) in clinical trials, for example, we assume that a drug 

The fact that I regard this problem as being difficult and important has been coloured by my experience with two trials which I myself have helped design. Both were to 

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Generic applications for chiral medicinal products should be supported by bioequivalence studies using enantiospecific bioanalytical methods unless both products contain the same, stable, single enantiomer or both products contain a racemate where both enantiomers show linear pharmacokinetics. 

The procedure for introducing changes to an approved drug in the US is dictated by type of data that must be submitted to support the alteration. Changes that require review of new investigations to approve the modification, other than bioavailability or bioequivalence studies, must be submitted as supplementary ND As/NAD As, as they... 

A discussion of the statistical methods used in analyzing the data from bioequivalence studies is beyond the scope of this chapter. For a discussion of these considerations, the reader is referred to a description by Westlake [6]. 

Hard gelatin capsules are uniquely suitable for blinded clinical tests and are widely used in preliminary drug studies. Bioequivalence studies of tablet formulations may be conveniently blinded by inserting tablets into opaque capsules, often along with an inert filler powder. Even capsule products may be disguised by inserting them into larger capsules. 

Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a biopharmaceutics classification system. Center for Drug Evaluation and Research, Food and Drug Administration, issued 8/2000, posted 8/31/2000. http //www.fda.gov/cder/guidance/ index, htm... 

There are occasions when it is not possible to use a cross-over design in a bioequivalency determination. For example, if the half-life of the drug is very long, the required washout period between the two treatment periods may be several months. Obviously, it is quite impracticable to consider such a long washout period. Test subjects are unlikely to wait patiently for long periods of time, and thus if we tried to conduct a bioequivalency study with, say, a 3-month washout period, we would probably find that a significant number of our test subjects would not be available for the second dose. 

OTCs) are used as subjects in bioequivalency studies. Such persons, often, university students, have been regarded as human test tubes in whom bioequivalency is evaluated. However, with the emergence of a school of thought that believes that bioequivalency should be a clinical mirror for the behavior of the test and reference products, this situation may change. Pregnant and nursing females are normally excluded from all bioequivalency studies. 

The question that must be addressed is which molecular species should be quantified in a bioequivalency study of a product containing a chiral drug ... 

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... 

F. Bioequivalency Studies for Drugs with Active Metabolites... 

Also, if conversion of drug to active metabolite shows significant departure from linear pharmacokinetics, it is possible that small differences in the rate of absorption of the parent drug (even within the 80-125% range for log transformed data) could result in clinically significant differences in the concentration/ time profiles for the active metabolite. When reliable data indicate that this situation may exist, a requirement of quantification of active metabolites in a bioequivalency study would seem to be fully justified. 

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. 

When pharmaceuticals are administered to feed animals there is a special concern about the possible accumulation of drug residues in the animals tissues. Thus, in these bioequivalency studies it may be appropriate to carefully monitor parameters that define possible tissue accumulation [45]. 

Other issues in veterinary bioequivalence which merit attention include policies to be followed when a product is to be used by more than one animal species. Is it sufficient to perform a bioequivalence study in only one species, or should studies be carried out in most or all the species for which the drug is recommended [46] There may be reason to believe that bioequivalence problems exist in some veterinary products [47,48]. 

C. T. Rhodes, Acceptable limits in bioequivalence studies, Clin., Res. Drug Reg. Affaris, 14, 127 (1997). 

Which bioequivalence study for racemic drug , Eur. J. Drug Metab. Pharmacokinet., 23, 166 (1998). 

I. Mohmood and H. Mahayni, A limited sampling approach in bioequivalence studies application to long half life drugs and replicate design studies, Int. J. Clin. Ther, 37, 275 (1999). 

I. Mahmood, Assessment of metabolites in bioequivalence studies Should bioequivalence criteria be applied on the sum of parent compound and metabolite , Int. J. Clin. Pharmacol Ther, 36, 540 (1998). 

H. Vergin, G. Mahr, R. Metz, A. Eichinger, V. Nitsche, and H. Martens, Analysis of metabolites—a new approach to bioequivalence studies of spironolactone... 

C. T. Rhodes, Bioequivalence studies for veterinary drug products, Clin. Res. Drug. Affairs, 9, 1 (1992). 

FDA Guidance for Industry Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Containing Certain Active Moieties/ Active Ingredients Based on a Biopharmaceutics Classification System, CDER-GUID 2062dft.wpd Draft, Jan. 1999. 

CDER Waiver of in vivo bioavailability and bioequivalence studies for... 

Grahnen, A., The impact of time dependent phenomena on bioequivalence studies in Topics in Pharmaceutical Sciences, Elsevier, Amsterdam, 1985, pp. 179-190. 

Crison, G. L. Amidon. pH and surfactant-facilitated in vitro solubilization and dissolution of ketoprofen, a class II drug. Implications for waiver of bioavailability and bioequivalence studies (Unpublished). 

The BCS has been developed primarily for regulatory applications, although its use has been extended beyond this area (as discussed in more detail below). The aim of the BCS in a regulatory context is to provide a basis for replacing certain bioequivalence studies by equally or more accurate in vitro dissolution tests. This could reduce costs and time in the development process as well as reducing unnecessary drug exposure in healthy volunteers, which is normally the study population in bioequivalence studies. 

CDER Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system Food and Drug Administration, 2000. 

Bioequivalence studies come into play if any change in product production/delivery systems was being contemplated. These studies would seek to identify whether such modifications still yield a product equivalent to the original one in terms of safety and efficacy. Modifications could include an altered formulation or method of administration, dosage regimes, etc. 

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