Requesting data for another publication [General Sta­tis­tics]

posted by Helmut Homepage – Vienna, Austria, 2023-02-23 11:46 (367 d 04:16 ago) – Posting: # 23775
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Dear all,

I’m also collecting data to assess a ‘Sex-by-Formulation interaction’ because in Section 2.1.1 of ICH M13A we find:

Subjects should be at least 18 years of age and preferably have a Body Mass Index between 18.5 and 30.0 kg/m2. If a drug product is intended for use in both sexes, it is recommended the study include male and female subjects. […] Subjects should preferably be non-nicotine users.

Obviously there are no concerns about extrapolating results to patients < 18 years, to obese patients (in the US a whopping 42% of the adult population), or to 23% of adults smoking tobacco. However, this sentence is similar to what the FDA recently recommended but is not stated in any other of the global guidelines. Where does this come from and why? Science or rather (gender)politics?1,2 We have only few anecdotal reports and small meta studies with contradicting results. Nevertheless, authors of the largest one concluded:3

There is no evidence to require studies in both sex groups, combined or separately.

In the past – at least in Europe – the majority of studies were performed in males only. We know that pharmacovigilance is not very sen­sitive. However, in 23.8 million drug switches in The Netherlands only 1,348 ADRs were reported (i.e., in 0.006% of switches)…4

Recently I gave presentations on the topic.5,6 In the meantime I have more data (228 mixed-sex datasets, 190 passing BE for AUC; 3,970 males, 3,302 females):



I had only limited information about the subjects’ bodyweight. However, if the AUC was adjusted by bodyweight, the apparent difference between sexes mainly disappeared.


  1. Criado Perez C. Invisible Women: Exposing data bias in a world designed for men. New York: Random House; 2019.
  2. Senn S. Randomisation Versus Random Sampling: Clinical Trials and the Representation Fallacy. Presentation at the Center for Me­di­cal Data Science of the Medical University of Vienna. 20 October 2023.
  3. González-Rojano E, Marcotegui J, Ochoa D, Román M, Álvarez C, Gordon J, Abad-Santos F, García-Arieta A. Investigation on the Existence of Sex-By-Formulation Interaction in Bioequivalence Trials. Clin Pharm Ther. 2019; 106(5): 1099–112. doi:10.1002/cpt.1539.
  4. Glerum PJ, Neef C, Burger DM, Yu Y, Maliepaard M. Pharmacokinetics and Generic Drug Switching: A Regulator’s View. Clin Phar­ma­co­kin. 2020; 59: 1065–9. doi:10.1007/s40262-020-00909-8.
  5. Schütz H. Statistical challenges and opportunities in ICH M13A. Presentation at: 2nd Bioequivalence Workshop, Brussels. 26 April 2023. Online.
  6. Schütz H. Sex– and group–related problems in BE. A delusion. Presentation at: BioBridges, Prague. 21 September 2023. Online.
  7. Alosh M, Fritsch K, Huque M, Mahjoob K, Pennello G, Rothmann M, Russek-Chen E, Smith E, Wilson S, Yiu L. Sta­tis­tical Con­si­de­ra­tions on Subgroup Analysis in Clinical Trials. Stat Pharm Res. 2015; 7(4): 286–304. doi:10.1080/19466315.2015.1077726.
  8. Sun W, Schuirmann D, Grosser S. Qualitative versus Quantitative Treatment-by-Subgroup Interaction in Equivalence Studies with Mul­tiple Subgroups. Stat Pharm Res. 2023; 15(4): 737–47. doi:10.1080/19466315.2022.2123385.

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