Log in
RegisterUpdate [Study Assessment]
Hi Helmut!
Hey they pay for for my bills, food, sports car etc etc
Remember I told you about my case a month or so ago? I had to deal with a drug product having ISCV~60% and T/R Ratio ~120% from a pilot study! They wanted me to go for a pivotal and also low-balled my sample size recommendation to ~70% of the computed sample size!
Found the rechallenge study... Yes it was accepted by the FDA and the original results were very similar to what Sam has (79.xx% as the lower limit of the 90% CI, in my case it was Cmax). Here goes:
Original fasting study was n=47, rechallenge was n=8 with 5 questionable subjects + 3 controls; The 5 questionable subjects were suspected as outliers because their Cmax ratios were greater than ± 2 standard deviations from the mean ratio. AUCs were fine. All subjects were from the original study population. The rechallenge study was successful so the original study data was re-evaluated with n=42 (minus the 5 weirdos) and bioequivalence was concluded. How did we conclude that the 5 weirdos were enigmatic? Well their ratio observed from the rechallenge study were within ± 2 SD of the mean observed from the original study. Note that this assessment was made for Cmax and AUCs ratios.
So n=8/n=47 → ~ 17% of the original study population.
The final report has 3 parts: Final bioequivalent results after removal of outliers (n=42) with explanation of why the removal was justified, original results (n=47), rechallenge results (n=8)
Mind you this study didn't fail because of incomplete AUCt though. The drug product was not highly variable, CV was about 18%. Why the criteria was ± 2 SD? I don't have the real justification and there's none written on the report.
Now I don't know if there was communication with FDA(OGD) before we went ahead to conduct the rechallenge study though since this happened before I joined the company. In Sam's case, if it is in my shoes, I would go ask FDA first and tell them why I suspect the AUCt issue was attributed to subject variation rather than inadequate sampling time period since AUCt was sufficiently captured in almost all subjects (yes present the AUCt/AUCinf ratio, show a table of the half-life values, throw all possible presentations that you can think of including a kitchen sink). I would do this rather than spending the $ on a rechallenge study and later on receiving a middle finger salute from the FDA (Mean haha tough luck, we don't accept it!). Maybe FDA will buy your reason(s) for the AUCt problem and accept the analysis excluding those subjects.
Hope this helps
John
❝ ❝ I don’t have other option as the management wanted to go with this study
❝
❝ Splendid! Given your results chances that the product does not show a lower BA than the reference are ~0.00005%. Four questions:
❝ • Would you take the drug yourself?
❝ • Would you give it to your wife and/or children?
❝ • Would your boss take it him/herself?
❝ • Would your boss give it to his wife / her husband and/or children?
Hey they pay for for my bills, food, sports car etc etc
Remember I told you about my case a month or so ago? I had to deal with a drug product having ISCV~60% and T/R Ratio ~120% from a pilot study! They wanted me to go for a pivotal and also low-balled my sample size recommendation to ~70% of the computed sample size!
Found the rechallenge study... Yes it was accepted by the FDA and the original results were very similar to what Sam has (79.xx% as the lower limit of the 90% CI, in my case it was Cmax). Here goes:
Original fasting study was n=47, rechallenge was n=8 with 5 questionable subjects + 3 controls; The 5 questionable subjects were suspected as outliers because their Cmax ratios were greater than ± 2 standard deviations from the mean ratio. AUCs were fine. All subjects were from the original study population. The rechallenge study was successful so the original study data was re-evaluated with n=42 (minus the 5 weirdos) and bioequivalence was concluded. How did we conclude that the 5 weirdos were enigmatic? Well their ratio observed from the rechallenge study were within ± 2 SD of the mean observed from the original study. Note that this assessment was made for Cmax and AUCs ratios.
So n=8/n=47 → ~ 17% of the original study population.
The final report has 3 parts: Final bioequivalent results after removal of outliers (n=42) with explanation of why the removal was justified, original results (n=47), rechallenge results (n=8)
Mind you this study didn't fail because of incomplete AUCt though. The drug product was not highly variable, CV was about 18%. Why the criteria was ± 2 SD? I don't have the real justification and there's none written on the report.
Now I don't know if there was communication with FDA(OGD) before we went ahead to conduct the rechallenge study though since this happened before I joined the company. In Sam's case, if it is in my shoes, I would go ask FDA first and tell them why I suspect the AUCt issue was attributed to subject variation rather than inadequate sampling time period since AUCt was sufficiently captured in almost all subjects (yes present the AUCt/AUCinf ratio, show a table of the half-life values, throw all possible presentations that you can think of including a kitchen sink). I would do this rather than spending the $ on a rechallenge study and later on receiving a middle finger salute from the FDA (Mean haha tough luck, we don't accept it!). Maybe FDA will buy your reason(s) for the AUCt problem and accept the analysis excluding those subjects.
Hope this helps
John
Complete thread:
- AUCextrap more than 20% sam 2013-08-01 06:15
![[Mix]](https://static.bebac.at/img/mix.png "open in Mix view")
- AUCextrap more than 20% ElMaestro 2013-08-01 10:29
- AUCextrap more than 20% sam 2013-08-01 11:21
- AUCextrap more than 20% ElMaestro 2013-08-01 11:39
- AUCextrap more than 20% sam 2013-08-01 12:01
- AUCextrap more than 20% Helmut 2013-08-01 12:52
- AUCextrap more than 20% sam 2013-08-01 12:01
- forced BE d_labes 2013-08-01 11:59
- Gambling ♠ ♣ ♥ ♦ Helmut 2013-08-01 13:31
- AUCextrap more than 20% ElMaestro 2013-08-01 11:39
- AUCextrap more than 20% sam 2013-08-01 11:21
- AUCextrap more than 20% Helmut 2013-08-01 12:32
- AUCextrap more than 20% sam 2013-08-01 12:55
- 46% power in study planning? Helmut 2013-08-01 13:18
- 46% power in study planning? sam 2013-08-01 13:40
- 46% power in study planning? jag009 2013-08-01 20:04
- Re-dosing Helmut 2013-08-02 03:32
- 46% power in study planning? sam 2013-08-02 07:00
- Carved in stone? Helmut 2013-08-02 03:22
- Carved in stone? sam 2013-08-02 07:02
- Carved in stone? luvblooms 2013-08-02 08:37
- Carved in stone? sam 2013-08-02 09:01
- Ethics (again) Helmut 2013-08-02 14:53
- Updatejag009 2013-08-02 17:25
- Update Helmut 2013-08-02 18:11
- Update jag009 2013-08-02 20:11
- Outliers (CAN) Helmut 2013-08-02 20:56
- Outliers (CAN) jag009 2013-08-02 22:23
- OT: Expert Helmut 2013-08-03 10:11
- Outliers (CAN) jag009 2013-08-02 22:23
- Outliers (CAN) Helmut 2013-08-02 20:56
- Update jag009 2013-08-02 22:29
- Update jag009 2013-08-02 20:11
- Update luvblooms 2013-08-05 06:02
- Update jag009 2013-08-05 20:14
- Update Helmut 2013-08-02 18:11
- Updatejag009 2013-08-02 17:25
- Ethics (again) Helmut 2013-08-02 14:53
- Carved in stone? sam 2013-08-02 09:01
- Carved in stone? luvblooms 2013-08-02 08:37
- Carved in stone? sam 2013-08-02 07:02
- 46% power in study planning? jag009 2013-08-01 20:04
- 46% power in study planning? sam 2013-08-01 13:40
- 46% power in study planning? Helmut 2013-08-01 13:18
- AUCextrap more than 20% sam 2013-08-01 12:55
- AUCextrap more than 20% ElMaestro 2013-08-01 10:29
Ing. Helmut Schütz