Generic vs Name Brand L-Thyroxine Products: Interchangeable or Still Not?

Abstract

This issue of the JCEM provides us with new clinical data on L-thyroxine (LT4) equivalence (1, 2). The studies seem to reach opposite conclusions, but an understanding of the regulatory history shows us that they assess different aspects of the question. Before T4 was comprehensively regulated by the Food and Drug Administration (FDA), Hansen (3) asserted that the 2 leading name brand preparations of LT4 were equivalent. Within 5 years, no less than 10 studies assessed the “bioequivalence” of these 2 products using various methods and concluded that they either were or were not equivalent (4). In 1997, due to concerns with product potency and variability, the FDA declared LT4 preparations to be “new” drugs and required that all existing and future LT4 products be approved through the new drug application (NDA) process in order to remain on the US market (5, 6). This established uniform expectations for drug performance and resulted in a significant improvement in the LT4 products available for clinical use (7). The NDA products were unique formulations and were not considered interchangeable. This remained the case until the abbreviated NDA process of measuring relative bioavailability (bioequivalence) of LT4 products was implemented to provide a mechanism for assessing the potential interchangeability of generic and referenced name brand LT4 preparations (8). Shortcomings of the traditional pharmacokinetic method (9) resulted in a modification of the process to correct for endogenous T4 (10), but concerns remained that potentially clinically significant differences in a LT4 dose of 12.5% or more might not be recognized with the pharmacokinetic approach (9) in products designated as bioequivalent by the pharmacokinetic standard (11). Therapeutic equivalence codes were assigned once products met the bioequivalence specifications. The designation of AB was assigned if the standard for bioequivalence (8) was met, or products were rated as BX (not interchangeable) if this standard was not met (8). Current therapeutic equivalence ratings are summarized in Table 1 (12). The theoretical insensitivity of pharmacokinetics was confirmed when the reference drug, Synthroid, was compared to a generic candidate (13). The generic was recognized as therapeutically equivalent, given the AB2 designation, and was advertised as interchangeable (C. J. Worell, Sandoz Introduces Levothyroxine Sodium Tablets, USP, A Bioequivalent Alternative Product to Synthroid and Levoxyl. Sandoz, a Novartis Company: Advertisement to Physicians, 2004.). But the new generic was 12.5% more bioavailable than the referenced brand (13). Expert clinicians expressed great concern (11), and one of the studies in this issue of the JCEM directly assesses this same comparison (1). Further LT4 product improvement has occurred with the imposition of a narrower potency requirement by the FDA to minimize variability of the same LT4 product ingested from refill to refill (14, 15). To meet the new goal of 95–105% of labeled content (14), some products have been reformulated (16, 17). In both cases of reformulation, the FDA has been shown data documenting that the new formulations are therapeutically equivalent with the older versions of the same preparations by pharmacokinetic analysis (16, 17), but previous therapeutic equivalence ratings have not been reassessed. So now to the new work that advances our understanding of bioequivalence, therapeutic equivalence, and the potential interchangeability of LT4 products. The reports in the current issue of the JCEM appear to reach opposite conclusions on the interchangeability question, but in fact, differences in study design and execution result in the doc-