FDA scaling for NTIDs [Design Issues]
❝ As per the recent guideline of FDA for warfarin sodium Tablets, they designed the BE acceptance criteria assuming all NTIs are low variable.
Likely they are. From a presentation by Lawrence Yu:1
Residual variability (%CV) from ANDAs reviewed between 1996–2008
AUC0-t Cmax
Drugs Mean Range Mean Range
Warfarin (n=29) 5.7 3.3, 11.0 12.7 7.7, 20.1
Levothyroxine (n=9) 9.3 3.8, 15.5 9.6 5.2, 18.6
Carbamazepine (n=15) 8.0 4.4, 19.4 8.7 5.2, 17.6
Lithium Carbonate (n=16) 7.8 4.5, 14.0 13.5 6.4, 24.4
Digoxin (n=5) 21.7 13.1, 32.2 21.0 14.3, 26.1
Phenytoin (n=12) 9.2 4.1, 18.6 14.9 7.4, 20.0
Theophylline (n=3) 17.9 12.8, 24.2 18.2 11.8, 25.8
❝ I have gone thorough the guideline it is very stringent to rest of regulatory.
Agree. I think it is an attempt to avoid arbitrary limits ignoring potential differences in variances – important if formulations are switched under treatment. Reminds me somehow on IPE/PBE of the late 1980s.
❝ […] Suppose if the full replicated study results are like for Cmax: 86.00 (80.00 - 93.00) with %CV: 26
Hhm, \(\small{\sqrt{0.80\times 0.93}\neq 0.86}\).

❝ […] then the study passing with SABE, also with ABE and test variability is less than the Refe variability.
The study passes all criteria. What is the problem?
❝ Even, in the guideline they didn't mention about cut off for maximum sigmaR.
- A cutoff on sWR (the estimate of σWR) and switch to conventional unscaled ABE. Donald Schuirmann explored values of 0.21179 (CV 21.42%) and 0.21 (CV 21.23%).
- A “Must Pass Both” criterion: RSABE + ABE
❝ So, what is the advantage of above stringent criteria in this case?
The replicate design allows comparison of σWT with σWR. Arbitrary narrowing the AR does not take the actual variance into account.
Not an advantage but an obstacle: sample size estimation. Simulations are required and IMHO a pilot study is unavoidable.
- Yu LX. Approaches to Demonstrate Bioequivalence of Critical Dose Drugs. Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 13 April, 2010.
webarchive.
- Schuirmann DJ. Evaluation of Scaling Approaches to Demonstrate BE of NTI Drugs – OGD Simulation Efforts. Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 26 July, 2011.
webarchive.
P.S.: Nice to know:
- Simulations were carried out in the S-Plus, R [sic], or APL computer programming languages
- Each estimated probability based on one million (1,000,000) simulated studies
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Science Quotes
Complete thread:
- NTIDs with high variability ioanam 2010-06-07 13:52 [Design Issues]
- NTIDs # HVDs (or not?) Helmut 2010-06-07 14:18
- NTIDs # HVDs (or not?) ioanam 2010-06-07 18:17
- Complicated ElMaestro 2010-06-07 18:28
- NTIDs # HVDs (or not?) Dr_Dan 2010-06-08 12:24
- Switch over Helmut 2010-06-08 12:34
- NTIDs # HVDs (or not?) Relaxation 2010-06-09 22:38
- FDA scaling for NTIDs krishna 2013-01-07 14:01
- FDA scaling for NTIDsHelmut 2013-01-12 20:06
- FDA scaling for NTIDs krishna 2013-01-18 10:04
- FDA scaling for NTIDs Helmut 2013-01-20 12:46
- FDA scaling for NTIDs krishna 2013-02-01 12:20
- FDA scaling for NTIDs Helmut 2013-01-20 12:46
- FDA scaling for NTIDs krishna 2013-01-18 10:04
- FDA scaling for NTIDsHelmut 2013-01-12 20:06
- FDA scaling for NTIDs krishna 2013-01-07 14:01
- NTIDs # HVDs (or not?) Relaxation 2010-06-09 22:38
- Switch over Helmut 2010-06-08 12:34
- NTIDs # HVDs (or not?) ioanam 2010-06-07 18:17
- NTIDs # HVDs (or not?) Helmut 2010-06-07 14:18