Response to Klintmalm on the Use of Generic Immunosuppression

To the Editor: I read with great interest the editorial about the use of generic immunosuppression by Klintmalm in response to the study by Momper et al. (1, 2). I believe some points must be clarified so that readers have a better understanding of the generic drug approval process. Klintmalm states that a patient taking a generic may be exposed to more than a 50% increase in the amount of drug compared to the brand (1). This is a common misconception of health care providers and the public alike. In reality, this would almost always result in failure to meet the Food and Drug Administration (FDA) requirements for bioequivalence (BE) because not only does the geometric mean ratio of the maximum observed concentration (Cmax) and area under the curve (AUC) have to fall between 80 and 120%, but the 90% confidence interval (CI) has to as well (3). Because the 90% CI must fall within this range, the geometric mean ratio rarely differs from the brand formulation by more than 10% (3). In fact, a study conducted by the FDA over a 12-year period including 2070 BE studies found the average difference in Cmax and AUC between brand and generic to be 4.35% and 3.56% (3). Klintmalm also states that there is no comparable data in regards to the current generic tacrolimus products on the market (1). This data can easily be obtained by simply contacting the manufacturer. Klintmalm makes the argument that BE testing should be required to be conducted in organ transplant patients rather than healthy individuals (1). One must realize that this introduces a significant amount of confounders that can result in variations in tacrolimus serum concentrations. It is well-known that there is a significant amount of drug interactions with tacrolimus, which would be difficult to control for. In fact, Momper et al. failed to comment on the addition or subtraction of interacting medications during their study (2). In addition, without a control group it is unknown if we would have seen the same small variation in serum concentrations in patients taking brand due to differences in lots or daily variations in the assay. As a result, conducting BE studies in organ transplant patients would make it extremely difficult to detect a true difference in drug formulations (4). Brand name manufacturers are required to conduct the same BE testing in healthy individuals as generic manufacturers when attempting to market new formulations of their brand name medication. This has not always been successful as in the case of sirolimus (Rapamune, Wyeth-Ayerst Laboratories, St. Davids, PA USA) in which the liquid and tablet formulations were not found to be bioequivalent but were later found to be therapeutically equivalent (4). Additional studies are needed to assess the true impact of generic immunosuppression. Although small dose titrations may be needed, it seems these are not clinically significant (2, 5). Health care providers need to continue to educate themselves about the generic drug approval process and be aware of common misconceptions so that we can properly educate our patients about the use of generic immunosuppression. The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.