History lessons - FDA BE 90% CI [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2019-02-26 00:44  – Posting: # 19974
Views: 1,720

Γεια σου, λακωνικό Οδυσσέα!

» 75/25, 90%CI was rocket science :-D

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 earlier4,5 it was shown to reject >50% of studies if the variability is large even for T/R=1.

I don’t know when the 80/20 rule (aka the “power approach”) was introduced (mid-1980s?). Schuirmann showed why it is crap.6 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 1992.7


  1. Fed. Reg. 6913 (Feb. 17, 1978); §320.107:6968–9. [image] 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. 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.
  7. FDA/CDER. Guidance for Industry. Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design. Jul 1992. [image] Internet Archive.

Cheers,
Helmut Schütz
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