Equivalence bioequivalence

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

For dmgs approved originally between 1938 and 1962, the FDA has utilized the Abbreviated New Dmg AppHcation (ANDA) for review of generic products that are pharmaceutical equivalents of the initially approved products. In this way, costiy dupHcation of animal and human experimentation is avoided. The new manufacturer has to show only that its manufacturing methodology, specifications, quaUty control, and labeling are acceptable. In some cases, the FDA does require proof of bioequivalence. 

More important than bioequivalence is the therapeutic equivalence of LT4 products. Will patients have the same outcomes if bioequivalent products are used The study by Dong... 

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. 

Another collateral effect of the DESI project was the development of the abbreviated NDA, by which a generic version of the innovator product could satisfy the statutory preconditions for entering the market, without repeating the preclinical and clinical studies of the innovator. This administrative creation, designed to assure that generics were both pharmaceutically equivalent and bioequivalent to the pioneer product, was endorsed by Congress in 1984. As will be seen, this development had a staggering impact on the business model of the pharma industry. 

Brand interchange - The metolazone formulations are not bioequivalent or therapeutically equivalent at the same doses. Mykrox is more rapidly and completely bioavailable. Do not interchange brands. 

Bioequivalency The sprinkle formulation is bioequivalent to the immediate-release tablet formulation and, therefore, may be substituted as therapeutically equivalent. 

Bioequivalence problems have been documented in the past for products marketed by different manufacturers however, studies in patients have shown comparable clinical efficacy between brands based on the results of thyroid function tests brand interchange should be limited to products with demonstrated therapeutic equivalence... 

Tablets and solution are not bioequivalent (tab has 27% > bioavailability) however, 2-mg tabs clinically equivalent to 2 mg oral sol not known if higher doses of oral sol are clinically equivalent to higher doses of tabs... 

In an equivalence trial we are looking to show that we are similar to some reference treatment, bioequivalence trials are the most common examples of this type of trial. 

Equivalence trials are, of course, routinely used in the evaluation of bioequivalence and the methodology there is well established, both European and FDA guidelines exist. More recently we have seen the need to establish therapeutic equivalence and Ebbutt and Frith (1998) provide a detailed case study in the development of an alternative propellant for the asthma inhaler. More usually,... 

Although conventional p-values have no role to play in equivalence or noninferiority trials there is a p-value counterpart to the confidence intervals approach. The confidence interval methodology was developed by Westlake (1981) in the context of bioequivalence and Schuirmann (1987) developed a p-value approach that was mathematically connected to these confidence intervals, although much more difficult to understand It nonetheless provides a useful way of thinking, particularly when we come later to consider type I and type II errors in this context and also the sample size calculation. We will start by looking at equivalence and use A to denote the equivalence margins. 

One of the most difficult aspects of the design of equivalence and non-inferiority trials, with the exception of bioequivalence, is the choice of the margin(s). 

The equivalence margins for bioequivalence specified by both the FDA (2001) Statistical Approaches to Establishing Bioequivalence and the CPMP (2001) Note for Guidance on the Investigation of Bioavailability and Bioequivalence require that the ratio of the geometric means, for the two treatments lie between... 

The rules for therapeutic equivalence are different from those for bioequivalence. The choice of margin will be a mixture of statistical and clinical reasoning. Strict equivalence is appropriate when we want to consider essential similarity or where the test treatment is to be used as an exact replacement for the new treatment. In these cases A should be chosen to be a completely irrelevant difference from a clinical point of view. Ebbutt and Frith (1998) based their choice of A= 15l/min on several considerations ... 

Bioequivalence (e.g. equivalence of efficacy) of two different galenical formulations of the same compound as measured by maintained remission rates in schizophrenic patients after an oral or depot antipsychotic formulation. 

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