The ATA Unveils New Data to FDA On Bioequivalence of Levothyroxine

The ATA Unveils New Data to FDA On Bioequivalence of Levothyroxine

Physician survey reveals significant adverse events in patients

On Oct. 4, 2006, the Food and Drug Administration (FDA) heard data presented by James Hennessey, MD, representing the American Thyroid Association (ATA), at a joint meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Advisory Committee for Pharmaceutical Science.  Data collection was spearheaded by the ATA in an effort to quantify the harmful impact of the FDA 1994 ruling that all levothyroxine (L-T4) preparations are therapeutically equivalent. Dr. Hennessey is professor of medicine at Brown University, Providence, R.I. and a member of the ATA public health committee.

The data shows that changes in levothyroxine preparation in a small fraction of patients were associated with significant adverse events. The information was collected via survey by members of the ATA, the American Association of Clinical Endocrinologists (AACE), and The Endocrine Society.  

“In 1997, the FDA changed the process for approving levothyroxine preparations after receiving 58 adverse drug event reports over a seven-year period on the potency of levothyroxine products,” said Dr. Hennessey. “In contrast, in 2006, in a period of a few weeks, we have through our survey, received 210 reports of suspected adverse events resulting from both super- and sub-potency. The majority of these reports were associated with a switching of levothyroxine preparations.  Somehow, we’ve yet to get the FDA’s full attention to this matter.”

Of the 1,421 physicians who responded to the survey, 210 levothyroxine prescribers suspected an adverse event and completed additional information. Of these responders, 160 provided information indicating that switching of levothyroxine preparations had occurred. Eighty-eight percent reported that their patients were switched without their knowledge. Of these patients who were switched, 31% experienced a significant adverse event, such as an urgent clinic visit, emergency room visit, hospitalization, and missed work.

Specific examples provided by physicians include:

  • Failure to achieve target TSH levels in a thyroid cancer patient, an important goal to prevent tumor recurrence, due to the sub-potency of a substituted thyroxine preparation;
  • Reoccurrence of heart disease symptoms, which abated after switching back to the original name brand preparation;
  • Previously stable hypothyroidism becoming unstable on a new preparation; and
  • Development of atrial fibrillation in a thyroid cancer patient due to the super-potency of a substituted preparation.

“The three endocrine societies have been voicing their concerns to the FDA for more than two years,” says Gregory Brent, MD, the ATA’s secretary & chief operating officer and professor of medicine and physiology, David Geffen School of Medicine at UCLA. “The primary concern, reiterated during the public comment period at this meeting, is that the method used by the FDA to compare the different levothyroxine products — and which has identified them as equivalent — is not sensitive enough to detect important differences in levothyroxine preparations.”

“While the meeting was a step in the right direction, we hope that our ongoing collaboration with the ATA will effectively address our concerns about the FDA’s current approach to assessing bioequivalence,” said AACE Representative Jeffrey Garber, MD, treasurer of AACE and chief of endocrinology at Harvard Vanguard Medical Associates, Boston.  

The societies also contend that that the FDA policy generates additional cost and inconvenience because patients are encouraged to return for additional blood tests and clinical assessment to determine the need for potential dose adjustments after being switched to a different levothyroxine preparation. Moreover, the thyroid experts pointed out that the FDA is not using the TSH test to assess and adjust levothyroxine dose in patients.

“For several years now, The Endocrine Society, ATA, and AACE have maintained that the FDA is insufficiently protecting millions of Americans who take levothyroxine by continuing to follow outdated standards,” said Leonard Wartofsky, MD, MPH, president of The Endocrine Society, past-president and past-secretary of the ATA, and chairman of the department of medicine at the Washington Hospital Center in Washington, D.C.

“This problem is multifaceted and relates to the FDA’s: (1) reliance on pharmacokinetic parameters to determine bioequivalence of different preparations; (2) failure to incorporate a pharmacodynamic parameter of levothyroxine action, i.e., serum TSH, in comparing products; (3) inadequate enforcement of “do not substitute” guidance to pharmacists; and (4) failure to acknowledge that levothyroxine, as a narrow therapeutic index medication, will be associated with adverse clinical outcomes, due to existing variations in marketed branded and generic preparations when products are “switched,” said Dr. Wartofsky. “We endocrinologists are not advocating one brand over another, but rather that the FDA employs and enforces modern bioequivalence standards. Until different products can be truly proven to be bioequivalent, patients must remain on the same consistent brand of product.”

In 1997, the FDA revised the drug approval process for levothyroxine after receiving 58 adverse drug event reports over a period of seven years. As part of this change in the approval process, the FDA issued standards for thyroxine bioequivalence, deeming that levothyroxine preparations that meet these standards have the same clinical effect and safety profile as the reference product to which they are compared. This then allows pharmacists to switch to generic versions of levothyroxine for another — not necessarily with the knowledge of the patient or the physician. Of concern is that levothyroxine is a drug known to have a narrow toxic-to-therapeutic ratio, with the potential for significant clinical consequences of even minor excessive or inadequate dosing.

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