March 2003 -- On March 13, 2003, the FDA's Advisory Committee for Pharmaceutical Science met to consider an issue of importance to thyroid patients -- the availability of generic -- and likely less expensive versions -- of popular hormone replacement drugs, drugs, including thyroid drug Synthroid.
The consideration of the issue was triggered by Abbott Laboratories, manufacturer of Synthroid, which was trying to argue the case that the means by which the FDA currently designates bioequivalent levothyroxine products is flawed, and presents a possible danger to patients if generic levothyroxine products are approved. Abbott was proposing that multi-dose studies involving patients with no thyroid function be done in order to establish bioequivalence.
Abbott -- as well as other manufacturers of brand name levothyroxine products, have not had to face generic competition because thyroid replacement drugs -- even those that are synthetic versions of natural hormones -- are considered "endogenous hormones."
In a telephone interview with Mary Shomon, Abbott Labs' endocrinologist Dr. Vickie Blakesley explained that endogenous hormones -- which include thyroid, estrogen, testosterone, insulin, and others -- replace something that is naturally found in the body, rather than introduce something that doesn't naturally occur in the body.
The three top-selling brands thyroid hormone replacement -- Synthroid, Unithroid and King Pharmaceutical's Levoxyl -- are all levothyroxine, but as endogenous hormones, the three drugs are not considered interchangeable. To date, only Mylan Laboratories Inc. has received approval for a generic version of Unithroid in 2002. This is first and only generic version of a brandname, newly approved levothyroxine to date.
According to Abbott, tests were conducted on more than 30 people with thyroid problems who each received identical amounts of Synthroid. Two groups each received 600 or 400 micrograms of Synthroid, and then blood levels evaluated a fixed time period later. After their first course cleared the bloodstream, a second course was given using the larger or smaller dosage, and again, the levels were tested. According to Abbott spokespeople, the T4 levels detected in the bloodstream of test subjects varied by such a degree that according to the FDA's methodology, two different dosages of Synthroid could actually be considered bioequivalent, based on how much circulating levothyroxine is measured in the bloodstream.
According to Abbott's Dr. Blakesley, bioequivalence testing standards for thyroid drugs require that tests be done on healthy patients without any thyroid problems. But optimally, such tests should be done on patients who have no functioning thyroid, because those without a particular endogenous hormone process it quite differently than healthy subjects who already have circulating levels of the hormone.
She also indicated that under the current FDA methodology, if a generic version of Synthroid were approved, a patient on a particular dose of Synthroid could be switched to the same dose of a generic, and face as much as a 30% increase or decrease in the potency of the medicine. This is of particular concern with the elderly, those with a history of heart disease, and with thyroid cancer patients who depend on consistent dosages to suppress their thyroid function and prevent cancer recurrence.
The current FDA bioequivalence testing for levothyroxine also measures T4, when most conventional endocrinologists feel that the Thyroid Stimulating Hormone (TSH) is a better measure for evaluation.
What Did the FDA Decide?
In the March 13th meeting, the FDA determined that testing for levothyroxine bioequivalence in patients with no thyroid activity was unrealistic.
Office of Clinical Pharmacology & Biopharmaceutics Reviewer Steven Johnson said, "We felt that it was an unrealistic study type just to do it in athyreotic patients...The recruitment process, and second of all, if we're taking into consideration [TSH], the number of subjects would be astronomical."