Helmut
★★★

Vienna, Austria,
2021-04-08 19:09
(715 d 23:57 ago)

Posting: # 22305
Views: 19,348

## Requesting data for a publication 📥 ♻️ 🚀 [General Sta­tis­tics]

Dear all,

we are collecting data for a publication about the annoying ‘Group-by-Treatment interaction’ (for some thoughts see this article).
Below what we have so far in a small meta-analysis of multi-group studies:

To make a long story short: As expected, significant Group-by-Treatment interactions were detected at approximately the level of the test (0.1). Hence, based on our observations in well-controlled studies likely they are mere ‘statistical artifacts’, i.e., false positives. The Kol­mo­go­rov–Smirnov tests were not significant, accepting the expected standard uniform distribution of $$\small{p(G\times T)}$$.

Any type of comparative BA study (BE, food-effect, DDI, dose-proportionality) is welcome.
Of course,  data will be treated strictly confidential and not published . The preferred data format is CSV (though xls(x), ODS, SAS XPT or Phoenix project files would serve as well).

Columns (any order is fine):
1. Company or individual (text)
2. Study code (text)
3. Analyte (text) if you don’t want to give this information, use not spec. X, where X is an integer 1 … number of analytes
4. Design (2x2x2, 3x6x3, 3x3, 4x4, 2x2x4, 2x2x3, 2x3x3)
Simple crossover, 6-sequence 3-period Williams’ design, 3-period Latin Squares, 4-sequence 4-period Williams’ design or 4-period Latin Squares, 2-sequence 4-period full replicate, 2-sequence 3-period full replicate, partial replicate; no parallel design
5. Drug (integer) 1 … number of analytes
6. Subject (integer or text) min(n) … max(n); missings due to dropouts not a problem
7. Group or Site (integer) 1 … number of groups / sites
8. Sequence (character or integer), e.g., TR, RT or AB, BA or 1, 2 (simple crossover), e.g., TRTR, RTRT or TRT, RTR (full re­pli­cate designs), TRR, RTR, RRR (partial re­pli­cate design), ABC, BCA, CAB (Latin Squares), ABC, ACB, BAC, BCA, CAB, CBA (Williams’ design)
Essentially any kind of coding is possible, as long as it is unambiguous.
9. Treatment (character) mandatory T or R (not A or B)
10. Period (integer) 1 … number of periods
11. AUC (numeric); for single dose AUC0–t or AUC0–72, for multiple dose AUC0–τ.
Missing values should be coded with NA (preferred) or Missing.
12. Cmax (numeric)
Optional columns:
• Interval (integer) days separating groups; only if equal across groups
• Sex (character) f or m
If you want to participate, please send data to [email protected].
No cherry-picking, otherwise we will fall into the trap of selection bias and the outcome will be useless. Hence, if you decide to provide data, please do so irrespective of whether you ‘detected’ a significant Group-by-Treatment interaction or not.
We are primarily working on 2×2×2 crossover designs. How­ever, if you have data of replicate designs, fine as well. In Higher-Order crossover designs indicate which of the treatments is the test and the reference.
If possible, give the analyte. Once we have enough data sets, we will perform sub-group analyses.

So far we have only data of one multi-site study. If you could share some data, great.

Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Helmut
★★★

Vienna, Austria,
2023-02-23 11:46
(30 d 06:20 ago)

@ Helmut
Posting: # 23471
Views: 3,997

## Requesting data for a presentation

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? We have only few anecdotal reports and small meta studies with contradicting results. Nevertheless, authors of the largest one concluded:1

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

In the past 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…2

I will give a presentation at Medicines for Europe’s 2nd BE Work­shop. This is what I have so far (205 mixed-sex datasets, 170 passing BE for AUC; 3,380 males, 2,778 females):

Preliminary results:
• Similar within-subject CV in males (x̃ 12.4%) and females (x̃ 12.0%).
• No evidence that medians of Point Estimates of subgroups differ (notches of box plots overlap).
• Difference in PEs of males and females > ±20% in 3.5% of datasets.
• Difference in PEs of males and females ≤ ±10% in 77.1% of datasets.
• S × F uniformly distributed (Kol­mo­go­rov–Smirnov p 0.6101).
• Significant (p < 0.1) S × F interaction in 12.4% of datasets.

1. 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.
2. 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.

Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes