From: Braverman, Lewis [Lewis.Braverman@bmc.org]
Sent: Friday, November 21, 2003 9:13 AM
To: fdadockets@oc.fda.gov
Subject: Comments to FDA -- Docket # 2003P-0387

Dear Gentleman:

	I have spent my entire academic career focusing on various aspects of thyroid physiology and pathophysiology and caring for patients with thyroid disease.  Levothyroxine (L-T4) administration in the therapy of hypothyroidism has been the standard of care for over 40 years.  L-T4 has a narrow therapeutic index and small changes in dosage can adversely affect a patient's well being resulting in symptoms of either hyper/or hypothyroidism, and would have adverse effects on cardiac, bone and mental function.

	The current FDA standards for bioequivalence, even with the new guidelines to determine bioequivalence of different L-T4 formulations by subtracting off the endogenous L-T4 concentrations, still do not permit differentiation of products that differ as much as 12.5%, a difference which is biologically important.  The ideal way to determine bioequivalence would be to study patients who have overt primary hypothyroidism and monitoring both serum L-T4 and TSH concentrations obviating the problem of endogenous L-T4 concentrations.

	I would suggest that further discussions with leaders in the field be done to further explore the ideal way to determine bioequivalence of various L-T4 products.

Most sincerely yours,


Lewis E. Braverman, M.D.
Professor of Medicine
Boston University School of Medicine
Chief, Section of Endocrinology, Diabetes & Nutrition
Boston Medical Center