If Gertrude Stein had worried about her thyroid, she might have said “thyroxine is thyroxine is thyroxine is thyroxine.” But the drug, used to treat thyroid deficiency, is the second most prescribed in the U.S., doing hundreds of millions of dollars in business for its manufacturers. And when the U.S. Food & Drug Administration last year began allowing sodium levothyroxine, (the form of thyroxine most easily absorbed) in generic form to be interchangeable with brand-name versions, drug companies and many endocrinologists began waging a campaign to convince FDA that not all thyroxine (T4 ) is created equal.
Although it seems the issue should be cut and dry, determining whether or not different brands of T4 are therapeutically indistinct from each other is anything but. It’s true that the only thing chemically different about the pills is their inert ingredients, such as binders. But some drug companies and doctors say studies show that a combination of factors—including the inert ingredients, how T4 is treated and produced in the manufacturing process, as well as how long it’s been on the shelf—affect how fast and how much of the drug is absorbed. And that, they say, can create trouble for patients whose brand of T4 can now be switched by a pharmacist without their knowledge.
FDA maintains that numerous bioequivalence studies have shown that a number of T4 brands, manufactured under strict new standards, are essentially interchangeable. “FDA believes that whatever differences exist in rate and extent of absorption from different products are not clinically meaningful as long as the products have similar potency,” says David G. Orloff, director of FDA’s Division of Metabolic & Endocrine Drug Products.
In fact, Orloff says, even studies on the same drugs show absorption differences. “Those differences are related to the fact that bioavailability studies are conducted in people, as opposed to test tubes,” he says. “There’s some inherent variability that can’t be accounted for.”
Last month, FDA, members of several endocrinological and thyroid societies, and representatives from companies such as Abbott and Sandoz, held a workshop in Washington, D.C. “Both sides presented their views, and nobody changed their minds,” says Carlos R. Hamilton Jr., president of the American Association of Clinical Endocrinologists (AACE). “That didn’t come as a great surprise.”
What makes generic T4 distinct from other generic versions of big-name drugs? For one thing, according to John Leonard, vice president of medical and scientific affairs at Abbott, T 4 is an endogenous substance, like insulin and steroids, which is made by the body to control its normal function. The standard method of testing for bioequivalence—by observing blood concentrations of drugs in healthy volunteers—may be appropriate for exogenous drug like Prozac and Valium, but may not be so in the case of hormones that the body tightly regulates.
A related issue is that T 4 is one of a very few drugs with a so-called narrow therapeutic index. Doctors must work carefully with the patient to titrate an appropriate dose of these drugs, which include the blood thinner Coumadin (and its generic warfarin), as the differences between an ineffective, effective, or toxic dose is very small.
The dangers of an over- or underdose are hyperthyroidism, which can cause atrial fibrillation that can lead to stroke, or hypothyroidism, which could affect the mental development of a fetus in a pregnant woman. But, Hamilton says, most likely it interferes with attempts to stabilize the patient. “It could be life-threatening, but it’s usually not,” he says. “But it is inconvenient and aggravating—everything’s out of whack.”
Hamilton says the issue could be resolved by keeping patients on the same brand and requiring pharmacists to notify patients if a brand is switched.
T4 manufacturers such as Abbott, King Pharmaceutical’s subsidiary Jones Pharma (which makes Levoxyl) and Stevens (which makes Unithroid) insist that they, too, only have patients’ stability in mind. That altruistic stance, however, is tempered by the fact that generics being introduced by companies such as Mylan and Sandoz are poised to grab a formidable market share of a blockbuster drug. Abbott, whose Synthroid accounts for over 65% of T 4 sales, has particular reason to be concerned.
Thyroxine’s tortured regulatory history also adds to the context. In the 1980s, Flint Pharmaceuticals, Synthroid’s original manufacturer, commissioned a group at the University of California, San Francisco, led by pharmacologist Betty Dong, to compare Synthroid with other brands. When Dong’s research showed that four different brands of T4 were essentially bioequivalent, the company (which had since then been bought by Boots Pharmaceuticals) allegedly suppressed the study’s publication for seven years. The work was finally printed in the Journal of the American Medical Association in 1997, accompanied by a scathing editorial about academic freedom by a former JAMA editor, Drummond Rennie.
Because T4 had been available for decades, FDA in 1962 originally exempted the drug’s manufacturers from demonstrating its safety and efficacy. But evidence began piling up that there were serious inconsistencies from batch to batch in concentration, quality, and stability. FDA then changed its mind and required companies to submit New Drug Applications for T4 . Abbott filed an NDA in 2001, and in 2002, it received FDA approval for Synthroid. The result, FDA says, is a more consistent product.
“Products are light-years better than what they used to be in quality and potency,” Orloff says. “We believe endocrinologists have much better tools than they ever did for treating patients with thyroid hormone deficiency.”
And though the FDA is willing to keep talking, the agency considers the issue largely closed. “We have agreed to continue to engage in discussions to try to resolve the misunderstanding, but at this point, FDA has no question about its own standards,” Orloff says.
The lines are still clearly drawn, though. AACE recently conducted a survey of its members, in which over 90% of the more than 900 respondents said they supported more stringent bioequivalence standards for T4 products, as well as a limitation of pharmacists’ ability to substitute T4 brands.
Though AACE and other professional associations receive funding from drug companies like Abbott, Hamilton says preference for a particular brand isn’t the societies’ concern. “There’s no question that Abbott would love it if everybody took Synthroid. And King Pharmaceuticals would love everybody to take Levoxyl,” he says. “But we don’t take sides. We just want people to stay on what they’re already taking.”—ELIZABETH WILSON
Source:
American Chemical SocietyAnother good resource on this subject matter:
American Thyroid Association;
Medicine Net
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