Bioequivalence of generics

Dong BJ et al Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997 277 1205. [PMID 9103344]... 

Current Rules Relating to Bioequivalence of Generic Drags... 

Ereshefsky L, Glazer W (2001). Comparison of the bioequivalence of generic versus branded clozapine. / Clin Psychol 62 (Suppl 5) 25-28. 

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. 

Fig. 1), these are adjudged to be bioequivalent. The FDA sets the degree of similarity needed to be so termed. This concept is of obvious importance for the acceptance of generic dmg products for marketing. 

The sponsor of an NDA will normally have extensive pharmacokinetic and pharmacodynamic information available at the time the NDA is submitted. It may be appropriate to use data such as the slope of the dose-response curve in support of a contention that, for example, dissolution testing may be, in some instances at least, be sufficient for the demonstration of development bioequivalency. Certainly, we may conclude that the requirements for development bioequivalence should never be more rigorous than those applied in consideration of generic bioequivalency. 

The topic of generic bioequivalence pertains to the relative bioavailability of different versions of the same drug product, all of which may be available in the marketplace at the same time. Thus, if we continue our consideration of the example introduced in the previous section of this chapter, let us suppose that the innovator did obtain approval to market F3. Initially F3 was the only product available in the marketplace. However, when the relevant patents held by the innovator have expired, other pharmaceutical... 

The methods used for the quantification of generic bioequivalence have evolved significantly in the past 15 years or so. There is no reason to believe that this evolutionary process will not continue. Thus, it is indeed likely that the present methods will be further refined. It is also likely that the processes of globalization and harmonization will assist in the further standardization of the methods approved for the determination of bioequivalence in different jurisdictions. 

For generic bioequivalence the generic manufacturer would be expected to use the same chiral material as the innovator (most probably a racemic mixture or pure active isomer, though it is possible that in some rare instances the innovator might have discovered a valid reason for using some mixture of R and S other than 50/50). Thus, as with development bioequivalency, it would not normally seem necessary to use stereoselective assays for the separate determination of R and S isomers. However, one can conceive of possible situations where clinically significant differences in R-to-S ratios could be caused by even relatively small differences in absorption rate [6,7]. 

The growth of generic prescribing and generic substitution will clearly increase the role and responsibilities of pharmacists in drug product selection. This movement will also stimulate in many regions of the world further debate about how bioequivalence should be quantified and when in vitro methods may, in some... 

W. P. Adams and G. J. P. Singh. Guidance Topical dermatology corticosteroids In vivo bioequivalents, Division of Bioequivalence, Office of Generic Drugs, Food and Drug Administration, 1995. 

The cost of generic substitutes is usually considerably less than that for the trade name psychotropic drugs, but issues of bioequivalence must also be considered (see the section The Four Primary Pharmacokinetic Phases in Chapter 3). Using the fewest tablets to achieve a targeted dose level is always less expensive. Unit dose systems, sustained release preparations, and concentrate forms all increase the cost ( 26). 

Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003 25 1578-1592. 

That documentation of pharmaceutical- and bio-equivalence should be provided to regulatory authorities is not at issue. However, the means by which these data can and should be demonstrated remain the subject of discussion. Political, economic and scientific hurdles pervade, and this issue remains unresolved. The imposition of existing small-molecule equivalence criteria on the registration of generic biologic drug products is unlikely to provide an acceptable degree of consumer protection. Likewise, the conventional bioequivalence trial used to infer therapeutic equivalence of different formulations based on the similarity of the phar-... 

For an ANDA, conducting an in vivo study on a strength that is not the highest may be appropriate for reasons of safety, subject to approval by the Division of Bioequivalence, Office of Generic Drugs, and provided that the following conditions are met. 

If drugs have the same bioavailability (i.e., the same AUC) they are said to be bioequivalent. This is a particularly important aspect in the development of generic drugs (discussed later). However, it should be appreciated that bioavailability refers ultimately to plasma concentration per se. It does not tell us anything about therapeutic... 

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