Bioequivalence of Orally Administered Drugs algos
Generic drugs for oral administration that have no actual or potential bioavailable or pharmacologic differences compared with name brand drugs are designated AA equivalent (bio-identical). Drugs that use different manufacturing processes, have different excipients (fillers), or variations in the weight of the fillers, use different raw materials, or have other potential or actual differences composition are designated as AB equivalent.
In order to be considered bioequivalent (AB equivalent or same), several criteria must be met, all based on the original name brand applied drug. In order to be bioequivalent (AB), the generic drugs must have similar active ingredients (the FDA considers some of the salts such as hydrochloride vs. hydrobromide to be close enough to be considered the same), less than 10% weight difference in excipients (fillers), must have primarily the same excipients that result in similar absorption characteristics, and the raw materials used in manufacture must have the same quality as the name brand. Dissolution characteristics must be similar. The physical drug stability after manufacture must be assured by testing. Packing of the drugs must be regulated and equivalent, and package inserts equivalent, at least on initial release. Good manufacturing practice standards of the FDA must be employed. In vivo bioassays are performed in healthy volunteers that are tested with the generic, then with the name brand, and the AUC and Cmax are evaluated. By FDA rule, the log normalized AUC and Cmax are permitted to vary between 80 and 125% of the name brand (using 24-36 normal volunteers). This is equivalent mathematically of +/- 20% of the actual concentration of the drug. The critique of this is that the drug is only tested for bioavailability in normal volunteers whereas those who have various illnesses may have significant variation, and does not test variation in bioavailability in populations. Only the highest dosage of the drug is required to have bioavailability testing by the FDA: lower doses may undergo dissolution tests only (test tube in vitro dissolution).
Subsequent testing after generic approval is by the generic manufacturer. The active ingredient in the oral drugs is measured lot by lot against the name brand drug whereas bioavailability is only required initially on drug application. The lot by lot variation causes the generic manufacturers to hold release of lots due to variations in the name brand content. The generic manufacturers in such cases, must wait for a new lot of name brand drug to be manufactured so their drug will then fall within tolerance bands of approximately 15% compared to name brand drug. The testing by the manufacturer for active ingredient may make it possible to conceal excipient variations (eg. the generic manufacturer cannot obtain the stated excipient due to manufacturer shortages), which therefore affect the bioavailability of the drug.
Those drugs that are approved as not AB equivalent typically have the same active drug (or equivalent- eg. the FDA considers the hydrobromide and hydrochloride salts of some drugs to be equivalent), but different bioavailability absorption characteristics. Examples include Oramorph, that is not bioequivalent to MS Contin due to differences in the absorption curves. However, there are also examples where AB equivalence has been granted by the FDA in cases where clearly significant differences in both delivery technology and excipients exist such as Duragesic compared to the matrix formulations of transdermal fentanyl.
There have been concerns voiced about the generic manufactured drugs given the approval by the FDA of drugs from India in which the data supplied to the FDA was faked, and also concerns about the degree to which the FDA actually evaluates the bioequivalence. The manufacturers themselves are responsible for testing, leading to potential for subterfuge. In 2009, there was a wave of public criticism about generic quality, and the FDA responded by launching a multimillion dollar advertising campaign to assure the public about the equivalency of such drugs instead of increasing compliance monitoring. In 2006, Vancomycin was waived for bioequivalent testing requirements by the FDA, now only requiring test tube analysis. This was clearly a change in FDA rules that was unadvertised by the FDA and prompted litigation by the manufacturer of Vancomycin against the FDA. Also, the FDA does not require testing of generics for safety, efficacy, variations in delivery within populations (uses only a cross over test comparing name brand within individuals), and has no difference in requirements for critical drugs- those with a very low therapeutic index or in drugs in which a 20% variation in plasma concentration may result in toxicity or ineffectiveness. The latter two issues have been examined in several studies in which generic drugs for epilepsy led to a significant increase in seizure rate. Part of this may be due to bioavailability studies by the FDA due not take into account the Tmax but only the Cmax and AUC. The FDA has been accosted for these overly lax standards, especially when compared with all other Western nations that have far more stringent requirements.
Of concern for public safety is a 2011 US Supreme Court ruling that found generic manufacturers are not responsible for updating package inserts to supply information about serious side effects updates as required by the original manufacturers. This makes generics appear safer than the name brand drug.
