Bioequivalence of generic and brand-name levothyroxine

Authors: Dong B, Hauck W, Gambertoglio J, Gee L, White J, Bubp J, Greenspan F.
Source: JAMA . 277:1205-13. April 16, 1997.
Institution: University of California Medical Center, San Francisco.
Financial support: Boots Pharmaceuticals.

Summary

Background

This article has generated considerable controversy in the medical and in the general press, because of attempts to prevent its publication by pharmaceutical industry sponsors.

Apart from this controversy, the topic of brand/generic equivalence is an important one.

Methods

The study compared four different levothyroxine formulations, two brand and two generic products:

Patients previously stable on l-thyroxine replacement (either at a dose of 0.100 mg or 0.150 mg) were given each of the four preparations for at least 6 weeks, and biochemical measurements were obtained in order to compare the products. Furthermore, the four products were subjected to biochemical assays.

Results

Authors' Discussion

The authors make a number of points in their discussion, including:

The publication controversy

This study became the object of much controversy and publicity when it was revealed that the pharmaceutical industry sponsors of the work (Knoll pharmaceuticals), unhappy with the results, suppressed its publication and then published the same data elsewhere with a different analysis and interpretation.

The exact sequence of events is complicated and fascinating, and is described in detail in the same issue of JAMA in a long editorial by Dr. Drummond Rennie. I strongly recommend reading this editorial, which is available at JAMA's website.

Knoll pharmaceuticals present their side of the publication controversy in a letter to the editor published in the same issue of JAMA, to which the authors respond.

Furthermore, Knoll presents a factual critique of the methods and results of the study in another letter to the editor, to which the authors also respond.

Comment

Whether or not to prescribe generic drugs for an individual patient is obviously an important question, with significant financial ramifications. The biggest concern is with drugs that have a narrow therapeutic index which need to be carefully titrated to blood levels and/or to therapeutic effect (such as digoxin, coumadin, anti-convulsants, anti-arrhythmics).

In my opinion, this study is reassuring concerning the bioequivalence of brand and generic l-thyroxine preparations, but there are a few caveats. Not all generic formulations were tested here, so equivalence of other products cannot be strictly inferred. Also, the significance of a difference in serum TSH levels between the products remains unclear to me. The authors state that this difference did not reach statistical significance and that all products produced a circadian drop in TSH that was comparable. The analysis presented by Knoll in their paper (see their letter to the editor) came to a different conclusion, but they seem to have performed a statistical manipulation by "normalizing" the baseline TSH, a procedure that is rejected by the authors of the present study. Presumably, if their was a difference in TSH levels between the different products, it was not a major one.

The fact that only two specific generic formulations were studied here raises another issue: why don't physicians order specific "brands" of generic medicine? This would maintain much of the cost savings of generic prescribing, while greatly reducing the potential for inter-product variability. The choice of the specific generic product chosen for a patient now lies with the pharmacist, as a rule. In order to remain price-competitive, pharmacists will presumably choose the least expensive brand, which may vary from time to time. Perhaps "branding" individual generic products would be a cost-effective solution for medications with a narrow therapeutic index, such as l-thyroxine.

Finally, as health care takes on more and more of an "industrial" flavor, controversies surrounding corporate sponsorship of medical research and pressure on the authors of such research are likely to become a more pervasive problem.

May 23, 1997


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