Abstract
Bioavailability and/or bioequivalence studies play a key role in the drug development period for both new drug products and their generic equivalents. For both, these studies are also important in the postapproval period in the presence of certain manufacturing changes. Like many regulatory studies, the assessment of bioavailability and bioequivalence can generally be achieved by considering the following three questions. What is the primary question of the study? What are the tests that can be used to address the question? What degree of confidence is needed for the test outcome? This article reviews the regulatory science of bioavailability and bioequivalence and provides FDA's recommendations for drug sponsors who intend to establish bioavailability and/or demonstrate bioequivalence for their pharmaceutical products during the developmental process or after approval.
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REFERENCES
Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications. National Institutes of Health and the Food and Drug Administration Conference. April 15–16, 1999, Bethesda, Maryland.
L. B. Sheiner. Learning versus confirming in clinical drug development. Clin. Pharmcol. Ther. 61:275-291 (1997).
Drug Bioequivalence Study Panel. Drug bioequivalence. Office of Technology Assessment, Superintendent of Documents, U.S. Government Printing Office, Washington DC 20402 (1974).
U.S. Food and Drug Administration, Title 21 Code of Federal Regulations (CFR) Part 320, Office of Federal Register, National Archives and Records Administration (2001).
Food and Drug Administration Modernization Act, Public Law No. 105–115, 111 Stat. 2296, 1997 (http://www.fda.gov/opacom/7modact.html).
U.S. Food and Drug Administration, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research. Guidance for Industry—Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products. Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, Rockville, Maryland 20857, May 1998.
U.S. Food and Drug Administration, Title 21 CFR 21 CFR 314.50(d)(1)–(6), Office of Federal Register, National Archives and Records Administration (2001).
U.S. Food and Drug Administration, Title 21 CFR 314.94, Office of Federal Register, National Archives and Records Administration (2001).
R. L. Williams, W. P. Adams, M.-L. Chen, D. Hare, A. Hussain, L. Lesko, R. Patnaik, V. Shah, and the FDA Biopharmaceutics Coordinating Committee. Where are we now and where do we go next in terms of scientific basis of regulation of BA and BE? Eur. J. Drug Metab. Pharmacokinet. 25:7-12 (2000).
B. S. Schug, M. Elze, and H. H. Blume. Bioequivalence of highly variable drugs and drug products: steady state studies. In K. K. Midha and T. Nagai (eds.), Bioavailability, Bioequivalence and Pharmacokinetics Studies, Business Center for Academic Societies, Tokyo, 1996 pp. 101-106.
A. A. el-Tahtawy, A. J. Jackson, and T. M. Ludden. Evaluation of bioequivalence of highly variable drugs using Monte Carlo simulations. I. Estimation of rate of absorption for single and multiple dose trials using Cmax. Pharm. Res. 12:1634-1641 (1995).
A. A. el-Tahtawy, T. N. Tozer, F. Harrison, L. Lesko, and R. Williams. Evaluation of bioequivalence of highly variable drugs using clinical trial simulations. II. Comparison of single and multiple-dose trials using AUC and Cmax. Pharm. Res. 15:98-104 (1998).
A. A. el-Tahtawy, A. J. Jackson, and T. M. Ludden. Comparison of single and multiple dose pharmacokinetics using clinical bioequivalence data and Monte Carlo simulations. Pharm. Res. 11:1330-1336 (1996).
T. N. Tozer, F. Y. Bois, W. W. Hauck, M.-L. Chen, and R. L. Williams. Absorption rate vs. exposure: which is more useful for bioequivalence testing? Pharm. Res. 13:453-456 (1996).
M.-L. Chen, L. J. Lesko, and R. L. Williams. Measures of exposure versus measures of rate and extent of absorption. Clin. Pharmacokinet. 40:565-572 (2001).
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations, Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, Rockville, Maryland 20857, October 2000.
E. R. Juniper, D. W. Cockcroft, and F. E. Hargreave. Histamine and methacholine inhalation tests: tidal breathing method. Laboratory procedure and standardisation. Astra Draco, Lund, Sweden (1991).
P. J. Sterk, L. M. Fabbri, Ph. H. Quanjer, et al. Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Official statement of the European Respiratory Society. Eur. Respir. J. 6(Suppl. 16):53-83 (1993).
N. H. G. Holford and L. B. Sheiner. Understanding of the dose-response relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokinet. 6:429-453 (1981).
W. R. Gillespia. Bioaquivalance assessment based on pharmacodynamic response-bioequivalence on the dose scale: rationale, theory and methods. Presentation to a joint session of the Advisory Committee for Pharmaceutical Science and Pulmonary-Allergy Drugs Advisory Comittee, Gaithersburg, Maryland, October 16, 1996, Transcript, pp. 40-52.
International Conference on Harmonisation: Choice of Control Group in Clinical Trials (E10), Internet www.ifpma.org/inchse.html
G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutics drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413-420 (1995).
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, Rockville, Maryland 20857, August 2000.
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence, Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, Rockville, Maryland 20857, January 2001.
M.-L. Chen, R. Patnaik, W. W. Hauck, D. J. Schuirmann, T. Hyslop, R. L. Williams, and the FDA Population and Individual Bioequivalence Working Group. An individual bioequivalence criterion: regulatory considerations. Stat. Med. 19:2821-2842 (2000).
U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of Biopharmaceutics, Guidelines for the Evaluation of Controlled Release Drug Products, 1984.
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance: Oral Extended (Controlled) Release Dosage Forms: In Vivo Bioequivalence and In Vitro Dissolution Testing, Office of Training and Communications, Division of Communications Management, Drug Information Branch, HFD-210, Rockville, Maryland 20857, 1993.
World Health Organization. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. WHO Technical Report Series, No. 803 (1996).
World Health Organization. Guidance on the Selection of the Comparator Pharmaceutical Product for Equivalence Assessment of Interchangeable Multi-Source (Generic) Products, (in press).
The International Conference on Harmonization. The Common Technical Document (M4). (Internet) http://www.ifpma.org/ich5c.html.
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Chen, ML., Shah, V., Patnaik, R. et al. Bioavailability and Bioequivalence: An FDA Regulatory Overview. Pharm Res 18, 1645–1650 (2001). https://doi.org/10.1023/A:1013319408893
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DOI: https://doi.org/10.1023/A:1013319408893