Biopharmaceutical equivalence

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

Calculation of the starting dose in first-in-human trials with biopharmaceuticals requires a good understanding of the science behind both the mechanism of action and the mechanism of toxicity of the test article. The FDA has provided an algorithm in its MRSD guidance to calculate a human equivalent... 

Biogenerics per se, that is, protein drug products approved via 505(j)(l), would need to demonstrate their bioequivalence to the innovator protein. Flowever, due to their complexity and heterogeneity, the classical biopharmaceutical principles upon which the current ratings of therapeutic equivalence are based do not apply in their current language to complex macromolecules. For example, due to the nature and complexity of an immunogenic response, one concern would be if traditional bioequivalence appropriately addresses the complex safety issues associated with biologies. 

The application of modern biopharmaceutic principles to assure the equivalent performance of immediate-and modified-release drug products. 

Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. Journal of Pharmacokinetics and Biopharmaceutics, 1987, 15 657-680. 

Lobenberg R, Amidon GL. Modern bioavailability, bio-equivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm 2000 50 3-12. 

On the other hand, biopharmaceuticals are difficult to characterize. Therefore under certain conditions a product may be defined by its manufacturing process, and the final product may be linked to a specific process. Additionally, it is challenging -both in scientific and regulatory terms - to determine if complex dmg substances are comparable before and after manufacturing changes, or to decide if they are therapeutically equivalent when made by different companies. 

The problem with biopharmaceuticals is that these are generally characterized by properties that may complicate the demonstration of equivalence because of the difficulty of characterizing the physico-chemical makeup [115]. The product... 

Grieve AP (19 9 8) Joint equivalence of means and variances of two populations. Journal of Biopharmaceutical Statistics 8 377-390. 

Hauck WW, Anderson S (1984) A new statistical procedure for testing equivalence in two-group comparative bioavailability trials. Journal of Pharmacokinetics and Biopharmaceutics 12 83-91. 

Figure 8.15 Effect of dissolution rote on the absorption and biological response of tolbutamide (I.Ogj and sodium tolbutamide (1. Og equivalent) when formulated in compressed tablets. From Wagner JG (1961). Biopharmaceutics absorption aspects. J. Pham. Sci. 50 359. Reprinted with permission John Wiley Sons, Inc.

Holmgren, E.B. Establishing equivalence by showing that a sp>ecified percentage of the effect of the active control over placebo is maintained. Journal of Biopharmaceutical Statistics 9 651-659,1999. 

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