Abstract
The Food and Drug Administration (FDA) Guidance for Bioavailability and Bioequivalence Studies for Levothyroxine has been challenged by companies that manufacture brand-name products. Their contention is that the current guidance does not adequately address the endogenous background levels of the drug, and that the ratios of the PK parameters, a basis for approval of equivalence, are not assessed correctly. In particular, they conclude that products that have a potency differing by 12.5% cannot be differentiated using the present guideline and criteria for acceptance of bioequivalence. They claim that such a difference can be a public health hazard because of the perception among practitioners that levothyroxine is a narrow therapeutic index drug. This article describes the procedure recommended in the current Guidance for Levothyroxine and demonstrates that the methods recommended are adequate and will accept products that are therapeutically equivalent. To date, no generic product accepted as equivalent using FDA Guidances has been shown to result in a safety and efficacy profile different from its brand counterpart.
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References
- 1.Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry Levothyroxine Sodium Tablets—In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing. Rockville, MD: February 2001.
- 2.Citizen's Petition. Jones Pharma, Inc. March 28, 2003.
- 3.Citizen's Petition. Abbott Laboratories. August 25, 2003.
- 4.Blakesley V, Awni W, Locke C, Ludden T, Granneman GR, Braverman LE. Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable? Thyroid. 2004;14:191–200. doi: 10.1089/105072504773297867. [DOI] [PubMed] [Google Scholar]
- 5.Food and Drug Administration. FDA Advisory Committee for Pharmaceutical Science.Briefing Document From Abbott Laboratories. Rockville, MD; May 12–13, 2003. Available at: http://www.fda.gov/ ohrms/dockets/ac/03/briefing/3926B1_02_A-Abbott%20.htm. Accessed March 23, 2005.
- 6.Levothyroxine Sodium Tablets. Canonsburg, PA: Mylan Laboratories, Inc; 2000. pp. 76–187. [Google Scholar]
- 7.Food and Drug Administration. FDA Advisory Committee for Pharmaceutical Science. Record of Proceedings. March 13, 2003. Available at: http://www.fda.gov/ohrms/dockets/ac/cder03.html# Pharmaceutical Science. Accessed March 23, 2005.
- 8.Citizen's Petition. Abbott Laboratories. August 25, 2003.
- 9.Food and Drug Administration. FDA Response to Abbott Petition, Citizen's Petition #2003P-0126/CP1, Document PDN 1. June 29, 2004.
- 10.Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. J Clin Endocrinol. 1988;28:325–333. doi: 10.1111/j.1365-2265.1988.tb01219.x. [DOI] [PubMed] [Google Scholar]
- 11.Food and Drug Administration. Code of Federal Regulations. Title 21, Volume 5: CFR 320.33. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfefr/CFRSearch.cfm?fr=320.24. Accessed: March 23, 2005.
- 12.Bolton S, Bon C. Pharmaceutical Statistics, Practical and Clinical Applications. 4th ed. New York, NY: Marcel Dekker; 2003. [Google Scholar]
- 13.Health Canada. Expert Advisory Committee on Bioavailability. Record of Proceedings. April 16, 2003. Available at http://www.hc-sc.gc.ca/hpfbdgpsa/tpd-dpt/2003-04-16_e.html. Accessed March 23, 2005.