FDA: Mini-study (retesting) [Outliers]
Dear all,
at the last two conferences in Budapest I discussed the issue of retesting subjects with (former) employees of the FDA.
at the last two conferences in Budapest I discussed the issue of retesting subjects with (former) employees of the FDA.
- The FDA discourages exclusion of outliers (especially of the “no profile” type) in 2×2 crossover studies.
- Performing “mini-studies” (aka retesting) was never an official recommendation. The commonly quoted sizes (at least six subjects or 20% of the main study – which ever is larger) are also an urban myth.
- The FDA allowed exclusion of outlying subjects only if
- retesting was already stated in the protocol as some kind of contingency plan,
- any post hoc procedure was not accepted, and
- not more than 1–2 outliers were excluded.
- I never (!) saw a protocol where re-testing was planned.
- Some studies were quite large (60–80 subjects). When asked why they didn’t opt for reference-scaling the answer was “FDA’s guidance requires a two-way crossover!” It turned out that high variability is well documented in the literature (well, that’s why the sample size was large). The FDA started updating their product specific guidances (allowing RSABE) in 2010. The one for this product was from 2007. Unlike for the EMA (where a clinical justification is needed), there are no problems expected using RSABE for both AUC and Cmax.
- Even if no scaling is intended, a fully replicated design could rule a product failure and explore a potential subject-by-formulation interaction. Much easier to deal with “no profiles”. That was already stated in the 2001 biostat’s guidance.
- Given the advanced technology in bioanalytics accessible today – requiring much smaller sampling volumes than a decade ago – the main obstacle (total blood loss limited to ~500 mL) in many cases is not issue any more. It is true that more periods increase the chance of drop-outs – but the loss in power is smaller than most people believe. Example: T/R 0.95, CV 35%, target power 90%, expected drop-out rate 5% / washout phase.
2×2 cross-over: Dose 70, complete 67+, power 89.30%+.
2×2×4 replicate: Dose 36, comlete 30+, power 86.18%+.
If the drop-out rate is 10%, power in the replicate design would still be >80%…
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Complete thread:
- FDA: Mini-study (retesting)Helmut 2014-05-26 17:50
- FDA: Mini-study (retesting) jag009 2014-05-27 21:52