Levothyroxine bioequivalence - Journal Club

Journal of Family Practice, July, 1997 by Kenneth G. Schellhase, Allan Ellsworth

Reference Dong BJ, Hauck WW, Gambertoglio JG, Gee L, White JR, Bubp JL, Greenspan FS. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997; 277:1205-13.

Clinical question Can different commercial preparations of levothyroxine be used interchangeably in the treatment of hypothyroidism?

Background An estimated 8 million prescriptions for thyroid replacement are written yearly in the United States. Most of these prescriptions are written for the Synthroid brand of levothyroxine because of perceived lack of quality or therapeutic equivalency of generic versions. In vitro bioequivalency data are available for several brand-name products, but the bioequivalence of generics has not been tested. In this in vivo study, therapeutic equivalency of two brand-name and two generic levothyroxine preparations was compared.

Population studied Twenty-four women taking either 0.1 mg or 0.15 mg of levothyroxine were studied. Inclusion criteria included at least two sets of normal thyroid function tests performed at least 6 weeks apart. Exclusion criteria included conditions known to interfere with the metabolism, absorption, or measurement of levothyroxine. Two subjects were excluded from the final analysis because of protocol violations.

Study design and validity The study was a randomized, single-blind (primary investigators only) four-way crossover trial comparing bioavailability of two brand-name versions of levothyroxine (Synthroid and Levoxyl) and two generic products (distributed by Geneva Generics and Rugby Laboratories, though manufactured by the same company). Subjects were assigned to one of four distinct four-drug sequences. Each product was taken for a minimum of 6 weeks. Thyroid indices were determined at 3-week intervals, and conventional bioavailability values were obtained at the end of each 6-week block Medication and protocol compliance was monitored.

The crossover study design, in which each patient served as her own control, is very strong and allows conclusions to be drawn from a small number of patients. Generalization to other brands of levothyroxine that were not a part of this study, however, may not be valid.

Outcomes measured The main outcomes were conventional bioavailability values at steady state of total thyroxine, triiodothyronine, and resin thyroxine uptake, as well as thyrotropin levels. Dosage forms of the same drug are considered bioequivalent when they yield neither clinically nor statistically significant differences in these values.

Results There were no statistically significant differences between these four levothyroxine products at either dose for total thyroxine, total triiodothyronine, and free thyroid index. Moreover, all four preparations produced substantially less variation in bioequivalence (-5% to 7%) than the standard of -20% to 25% allowed by the US Food and Drug Administration. The statistical power of this study was high enough to find a difference among the products if one truly existed.

Recommendations for clinical practice This well-executed study provides strong evidence for the bioequivalence of common name brands and generic forms of levothyroxine. Although the study reports disease-oriented rather than patient-oriented evidence, it is clearly of clinical interest. Practitioners can now prescribe these generic formulations with confidence that they will provide reliable, effective, and equivalent therapy.

The financial impact of this study could be substantial. The authors estimate that if generics or Levoxyl (which is close to generic cost) were used for roughly one half of levothyroxine prescriptions each year, more than $350 million could be saved. The financial ramifications of this study were not lost on the study sponsor, the manufacturer of Synthroid. An editorial with this study details how publication of this work was delayed for 6 years by a dizzying variety of specious complaints from the manufacturer, ranging from flaws in study design to vague suggestions of ethical misdoings.[1] The results of this study were improperly published by the company in another journal, complete with a conclusion more favorable to Synthroid but failing to acknowledge the original investigators.[2]

Sadly, this cautionary tale does not represent mere anecdote. As Blumenthal et al[3] showed, academic-private sector partnerships are significantly associated with delays in publication. While the withholding of research results is far from commonplace, the increasing frequency of academic-private partnerships may merit greater scrutiny to ensure that academic freedom is not impaired.

References

[1.] Drummond R. Thyroid storm [editorial]. JAMA 1997 277:1238 43.

[2.] Mayor GH, Orlando T, Kurtz NM. Limitations of levothyroxine bioequivalence evaluation: analysis of an attempted study. Am J Ther 1995; 2:417-32.

[3.] Blumenthal D, Campbell KG, Anderson MS, Causino N, Louis KS. Withholding research results in academic life science. JAMA 1997; 277:1224-8.