Bioequivalence and Bioavailability Forum

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❝ 75/25, 90%CI was rocket science

Don’t forget #3 and #4 mentioned in this post.

The 75/75 rule was proposed in 1978 for tricyclic antidepressants.¹

(2) The test drug product shall be deemed to meet the bioequivalence requirement for in vivo testing in humans if the following conditions are met:
(ii) In at least 75 percent of the subjects administered the drug, the test drug product has a bioavailability of greater than 75 percent relative to that of the administered reference material utilizing each subject as his own comparison;

It was defended by the FDA² but immediately criticized³ because already earlier^4,5 it was shown to reject >50% of studies if the variability is large even for T/R=1.

The 80/20 rule (aka the “power approach”) was introduced by the FDA after a workshop in December 1971 (‼).⁶ Schuirmann showed why it is crap.⁷ Unfortunately (for historic reasons) it is still part of Phoenix/WinNonlin’s output and happily reported by some (see my rant, follow-up).

@John: The 90% CI was recommended in 1992.⁸

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1. Fed. Reg. 6913 (Feb. 17, 1978); §320.107:6968–9. free resource.
   
2. Cabana BE. Assessment of 75/75 Rule: FDA Viewpoint. J Pharm Sci. 1983;72(1):98–99. doi:10.1002/jps.2600720127.
   
3. Haynes JD. FDA 75/75 Rule: A Response. J Pharm Sci. 1983;72(1):99–100. doi:10.1002/jps.2600720128.
   
4. Haynes JD. Statistical Simulation Study of New Proposed Uniformity Requirement for Bioequivalency Studies. J Pharm Sci. 1981;70(6):673–5. doi:10.1002/jps.2600700625.
   
5. Metzler CM, Huang DC. 1983. Statistical methods for bioavailability and bioequivalence. Clin Res Pract Drug Reg Aff. 1983;1:109–132.
   
6. Skelly JP. A History of Biopharmaceutics in the Food and Drug Administration 1968–1993. AAPS J. 2010;12(1):44–50. doi:10.1208/s12248-009-9154-8. Free Full text.
7. Schuirmann DJ. A comparison of the Two One-Sided Tests Procedure and the Power Approach for Assessing the Equivalence of Average Bioavailability. J Pharmacokin Biopharm. 1987;15(6):657–80. doi:10.1007/BF01068419.
   
8. FDA/CDER. Guidance for Industry. Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design. Jul 1992. Internet Archive.