Immunosuppression, Generic Drugs and the FDA

Abstract

We respectfully disagree with some points voiced in Dr. Klintmalm's editorial regarding generic immunosuppression (1).(1) Regardless if a generic or brand immunosuppressant is used, significant variation in calcineurin inhibitors' trough concentrations must be considered in the context of patient-specific therapeutic ranges. For example, a 25% fluctuation in tacrolimus trough concentrations in a patient whose target is 4-6 ng/mL may not be considered as clinically significant as the same percent change in a patient whose target is 8-12 ng/mL. Moreover, intrasubject variability in exposure to calcineurin inhibitors is commonplace in patients maintained on innovator products. These pharmacokinetic variations are secondary to: impact of food on drug exposure, fluctuations in renal and/or hepatic function, alterations in administration times and timing of trough levels. Although the inception of generic immunosuppressants introduces one additional variable, the clinical significance of this variable is not well defined. (2) Misinformation continues to be disseminated regarding the interpretation of confidence interval (CI) bioequivalence testing (1,2). In order for a generic medication to be considered bioequivalent, the 90% CI of the geometric, not arithmetic, mean of the ratio of the generic compared to the innovator product of the maximum concentration and area under the curve (AUC) values must lie between 80% and its reciprocal, 125% (3). In contrast to an arithmetic mean, which represents the midpoint of the range of values, a geometric mean mutes the contributing effect of extreme low and high values, respectively. If the true (arithmetic) mean exposure of a generic approaches ±20%, then one or both of the 90% CI is likely to fall outside the bioequivalence limits (4). The actual mean differences of four Food and Drug Administration (FDA)-approved tacrolimus generics in healthy volunteers is 4% (range 0-11%) for AUC fasting and 4.5% (2-6%) for AUC fed. (3) The degree of cost savings associated with generic immunosuppressants, and the benefactor of that savings, is multifactorial. For example, a patient's copay will vary depending on the type of billable insurance they possess (private vs. federally funded Medicare Part B or D vs. state funded Medicaid) and may change throughout the year (5). We agree that savings associated with the use of generic immunosuppressants should be countered by the associated cost of increased laboratory monitoring.We acknowledge that further research is necessary to determine the pharmacoeconomic impact of generic immunosuppressants. Future studies performed in transplant recipients will help answer these questions, as well as provide pharmacokinetic data comparing innovator to generic immunosuppressive products. Currently the FDA is considering potential refinements in bioequivalence criteria for narrow therapeutic index drugs and we expect that selective immunosuppressant agents will be included in this new classification. Transplant clinicians can advocate for policy changes reg...

Treat Patients, Not Statistics

“…Hence, there are reasons to use the target population for testing of new generic drugs. This may yield substantially different results than those obtained after the testing described in detail by the authors (2,3) for FDA approval of a generic drug, which is done in healthy volunteers as a single‐dose administration. The drug interval of 80–125% does not even have to include 100% of the brand name concentration.…”

“…It was with great interest that I read the responses to my recent editorial regarding generic immunosuppression (1) by Dr. Latran (2) and Drs. Trofe‐Clark, Gabardi, McDevitt‐Potter and Alloway (3).…”

Generics: Are all immunosuppression agents created equally?

“…In 2003, the American Society of Transplantation published a position paper on generic immunosuppression conversion, including the use of generic cyclosporine and tacrolimus. [9][10][11] This position paper advocated transplant physicians should initiate and supervise their conversion followed by close interval trough monitoring. A subsequent editorial in the European Journal of Hospital Pharmacy agreed with this strategy but further warned of the perils of repetitive and consecutive substitutions.…”

Use of Generic Tacrolimus in Elderly Renal Transplant Recipients

“…[1][2][3][4][5][6][7] Bioequivalence investigations for marketing authorization applications of generics are generally performed in small populations of healthy young adult volunteers, using a single-dose crossover design where both the rate (defined by maximum concentration, C max ) and the extent of absorption (defined by the area under the curve [AUC]) of the generic drug cannot differ significantly from the original drug. The use of generic drugs is increasing, and because of cost-saving opportunities, authorities approve and applaud their introduction.…”