FDA urged to rethink its method of determining bioequivalence

Results of a pharmacovigilance trial have the Endocrine Society concerned about the adverse health effects of switching L-T4 sources.

In a position statement released in June, the Endocrine Society asked the FDA to reverse its ruling on the substitution of sodium levothyroxine.

“The FDA has been using a technique for assessing bioequivalence for decades that not only the Endocrine Society, but also professional endocrinology associations agree is an antiquated method that is being inappropriately applied to the bioequivalence for thyroxine,” Leonard Wartofsky, MD, MPH, MACP, chairman of the Department of Medicine at Washington Hospital Center, told Endocrine Today.

The adverse health effects associated with substituting L-T4 prompted the Endocrine Society’s position statement. Currently, the FDA allows certain manufacturer doses of L-T4 to be considered bioequivalent to those from other makers. This allows patients to switch between sources of L-T4 without the physician’s awareness.

According to the statement, the Endocrine Society, American Association of Clinical Endocrinologists and the American Thyroid Association conducted a pharmacovigilance study in 2007. Researchers sent adverse event surveys to 210 users of prescription L-T4. They reported 160 adverse events related to a change in type of L-T4; 87.6% of changes were made by pharmacists with the knowledge of the prescribing physician. Thirty-one percent of those surveyed reported adverse events related to switching.

Current system is not working

The FDA’s current “one size fits all” method of determining bioequivalence cannot be applied to L-T4 for several reasons, according to the society. Those reasons include: the natural properties of L-T4, the delicate balance of the thyroid system and the possibility of small changes in thyroid hormones upsetting the balance, which may not be recognized by measurements of thyroid hormone levels.

The society is also concerned that serum TSH levels may change if measurable changes in L-T4 levels are absent, which would cause problems when evaluating a patient’s thyroid status.

“Bioequivalence as determined by the FDA is not therapeutic equivalence — a much more clinically important measure,” according to the statement.

Recommendations for a reversed ruling

The Endocrine Society recommends that the FDA be cautious when determining bioequivalence due to its importance in the role of patient safety. According to the society’s position statement, other recommendations include:

• Devise and execute a system to determine therapeutic bioequivalence of L-T4 that will consider TSH levels over time.
• Retract the current methods used to determine the bioequivalence of L-T4 products and declare that the products have not been shown to be bioequivalent.
• Require the inclusion of patient warning information in L-T4 products to emphasize the importance of consulting a prescribing physician if the source of the product is changed.
• The possible consequences of slightly altered L-T4 products must be made clear to physicians who are not thyroid specialists. L-T4 product information should clearly convey the potential problems with slight alterations in dose and the need for patient reevaluation upon substitution.

“As clinicians, we depend on the TSH yet, paradoxically, the FDA ignores TSH and they do not, when they conduct bioequivalent studies, take into account what affect the dosages have on TSH. So it has been the position of these organizations that the FDA should abandon the chemical bioequivalence technique and look instead at pharmacodynamics and pharmacokinetics,” Wartofsky said. – by Stacey L. Adams

The FDA methodology is probably not optimal and likely would be improved by using TSH concentrations over time as the measure of bioequivalence. In fact, such a study has been done by Betty Dong et al (JAMA. 2007;277:1205-1213). They showed that two of the most widely used brands of L-T4 were equivalent to two generics. Publication of that study was suppressed for a time by the manufacturer of Synthroid who threatened to sue the authors and did everything possible to prevent its publication indefinitely. However, the paper was finally published because the company received such bad publicity.

Despite what the Endocrine Society, the American Thyroid Association and the Association of Clinical Endocrinologists state, there is, as yet, no published evidence that indicates a serious problem at this time. The professional organizations mention only anecdotal data and results of a survey to conclude that more people are out of range with generic switching and suffer adverse health issues. That is no solid data from a controlled study that is peer reviewed and published.

Cross-sectional studies have repeatedly shown that when groups of patients are treated mostly with major branded products, about 20% are over-treated and 20% are undertreated; only 60% are within the target reference range for serum TSH. To my knowledge, there are no similar observations for those on generics and for those who are switched from brand to generic. What is needed is a prospective controlled study in this area.

My own experience in a middle class community in Bronx, N.Y., which is not a controlled study, is that most patients are switched from brand to generic products by the pharmacist. My assessment is that the percentage of patients who are out of range on annual checkups is around 15%, not that different from when brand name products dominated the market. Also, I have not seen any drug related adverse health issues in these patients, as mentioned by the Society's document.

– Martin I. Surks, MD, MACP

Program Director for the Division of Endocrinology and Metabolism,

Montefiore Medical Center, Bronx, N.Y.