Log in
Register|
Ram14 ☆ India, 2014-12-25 19:24 (4197 d 19:30 ago) Posting: # 14174 Views: 6,516 |
|
|
Hi All, Question regarding the USFDA guideline for repeating a BE study. The study is a normal two-way crossover bioequivalence study. The study failed because the molecule degraded during bio-analysis and long-term stability was not proven. Because the Test product is from same exhibit batch a repeat study is demanded by sponsor. On what grounds can the study be repeated, or, what is the justification to repeat the study, such that it is acceptable by the FDA regulatory. Thank you Ram |
|
ElMaestro ★★★ Denmark, 2014-12-25 22:00 (4197 d 16:54 ago) @ Ram14 Posting: # 14175 Views: 5,903 |
|
|
Come on, Ram, ❝ The study is a normal two-way crossover bioequivalence study. The study failed because the molecule degraded during bio-analysis and long-term stability was not proven. Because the Test product is from same exhibit batch a repeat study is demanded by sponsor. From a GCP perspective you are on thin ice. You dosed drug to humans and the entire thing was futile because you hadn't done your homework. I am aware that some companies really conduct these studies when stability has not been investigated or proven and often with success and the partial benefit from hindsight but yours is an example which shows it can be a bad idea. At this point I hope both you (sounds like you are at a CRO?) and your sponsor will stop up and think. What got you into that mess? How do you avoid getting into one such mess again? And then I hope you'll wait with the next study until you have come up with something concreet and useful. ❝ On what grounds can the study be repeated, or, what is the justification to repeat the study, such that it is acceptable by the FDA regulatory. For a person or company in your situation that is the wrong question to ask at this point. Any IRBs and IECs reading this? How about making sure stability really has been proven before the next study is approved? — Pass or fail! ElMaestro |
|
Ram14 ☆ India, 2014-12-26 09:38 (4197 d 05:17 ago) @ ElMaestro Posting: # 14177 Views: 5,562 |
|
|
Thank you ElMaestro. ❝ From a GCP perspective you are on thin ice. You dosed drug to humans and the entire thing was futile because you hadn't done your homework. I am aware that some companies really conduct these studies when stability has not been investigated or proven and often with success and the partial benefit from hindsight but yours is an example which shows it can be a bad idea. The molecule showed no sign of degradation during method development and validation. Even during bioanalysis no difficulty was observed until repeat analysis. Upon investigation it was observed that the molecule degraded, and LTM confirmed it. ❝ At this point I hope both you (sounds like you are at a CRO?) and your sponsor will stop up and think. What got you into that mess? How do you avoid getting into one such mess again? ❝ And then I hope you'll wait with the next study until you have come up with something concreet and useful. To overcome the issue, we plan to re-develop and validate the method, and prove the stability for 80 days before re-conducting the study. Once we have proven stability and the molecule meets the bioequivalence criteria, we wish to submit it to FDA. ❝ For a person or company in your situation that is the wrong question to ask at this point. My point is, how can we justify to FDA to re-do the study. Should there be a change in exhibit batch used for dosing, the study can be re-done without objection. But because now, the same exhibit batch will be used for dosing, how do we justify to the regulatory. ❝ Any IRBs and IECs reading this? How about making sure stability really has been proven before the next study is approved? Yes, we will make sure that the method is robust before execution. Regards Ram |
|
Ohlbe ★★★ France, 2015-01-05 13:26 (4187 d 01:29 ago) @ Ram14 Posting: # 14218 Views: 5,207 |
|
|
Dear Ram, ❝ My point is, how can we justify to FDA to re-do the study. Should there be a change in exhibit batch used for dosing, the study can be re-done without objection. But because now, the same exhibit batch will be used for dosing, how do we justify to the regulatory. IMHO if you have a real, identified and documented reason to question the reliability of the first study you should be able to repeat it with the same batch. The problem you identified is independent from the formulation. ❝ The molecule showed no sign of degradation during method development and validation. Even during bioanalysis no difficulty was observed until repeat analysis. Upon investigation it was observed that the molecule degraded, and LTM confirmed it. That will be the more tricky part. You'll have to prove, and to convince them, that the problem indeed was a lack of stability - and to explain why you did not identify it initially. You can expect questions - and probably an inspection of both studies. — Regards Ohlbe |
|
Ram14 ☆ India, 2015-01-05 18:31 (4186 d 20:24 ago) @ Ohlbe Posting: # 14220 Views: 5,200 |
|
|
Dear Ohlbe, Thank you for the reply. ❝ IMHO if you have a real, identified and documented reason to question the reliability of the first study you should be able to repeat it with the same batch. The problem you identified is independent from the formulation. The execution of the clinical part of the study is absolutely fine. But the study failed because of the Bioanalytical issues which were not able to define the stability of the molecule. The molecule showed stability until 55 days, where after it showed degradation. Possible reasons incurred are - (1) improper mixing of blood and anti-coagulant at time of blood collection, (2) samples where not stored at prescribed temperature, (3) method was not robust. ❝ That will be the more tricky part. You'll have to prove, and to convince them, that the problem indeed was a lack of stability - and to explain why you did not identify it initially. You can expect questions - and probably an inspection of both studies. Are there any guidelines related to this part. Thank you |
|
Ohlbe ★★★ France, 2015-01-05 19:34 (4186 d 19:20 ago) @ Ram14 Posting: # 14221 Views: 5,143 |
|
|
Dear Ram, ❝ But the study failed because of the Bioanalytical issues which were not able to define the stability of the molecule. When you say that the study failed, do you mean to say that it failed to demonstrate bioequivalence ? Or just that as the bioanalytical results are not reliable you can't use them for PK / stats ? If you performed the stats and the study failed it will become difficult to convince the regulators that you are repeating the study because of a bioanalytical issue unseen before. ❝ The molecule showed stability until 55 days, where after it showed degradation. Shit happens. But storage over 55 days in a BE study is already quite long. ❝ Possible reasons incurred are - (1) improper mixing of blood and anti-coagulant at time of blood collection,(2) samples where not stored at prescribed temperature, (3) method was not robust. (1): OK, could be, but not my first hypothesis. And you would not see it with your stability QC samples. (2): yes, possible. You're supposed to have temperature records to confirm the storage conditions. (3): unless the problems happened during sample processing (bench top stability, dry extract stability) or added up to the degradation over time during long term storage, no. Stability is a characteristic of the analyte under specific conditions and is independent from the method used. I would add reason 4: the analyte is not stable for more than 55 days in matrix at that temperature... Solutions: analyse faster; store at lower temperatures; add agents to stabilise. ❝ ❝ That will be the more tricky part. You'll have to prove, and to convince them, that the problem indeed was a lack of stability - and to explain why you did not identify it initially. You can expect questions - and probably an inspection of both studies. ❝ ❝ Are there any guidelines related to this part. I don't think this is a matter of guideline... It also goes back to the first question: - if you did not run the PK / stats but just stopped the analysis because of the stability issues, the study did not really "fail"; - if you did the PK / stats and the study failed to show BE, and now you say there were stability issues, you can expect questions. Especially if there were no problems in your temperature records, the drug is described as stable in the literature, and you now have 80 days stability data. — Regards Ohlbe |
|
Ram14 ☆ India, 2015-01-06 08:40 (4186 d 06:14 ago) @ Ohlbe Posting: # 14224 Views: 5,204 |
|
|
Dear Ohlbe, ❝ When you say that the study failed, do you mean to say that it failed to demonstrate bioequivalence ? Or just that as the bioanalytical results are not reliable you can't use them for PK / stats ? If you performed the stats and the study failed it will become difficult to convince the regulators that you are repeating the study because of a bioanalytical issue unseen before. The PK/Stats analysis without repeat concentration data showed bioequivalence. The same with repeat concentration data did not prove bioequivalence, failing on lower side of AUC0-t. To investigate, the ISR was performed and majority of samples were not meeting the ISR acceptance limits. ❝ Shit happens. But storage over 55 days in a BE study is already quite long. Long term stability results were not within acceptance limits and the molecule was found unstable in plasma, which was again confirmed by ISR. ❝ (1): OK, could be, but not my first hypothesis. And you would not see it with your stability QC samples. (2): yes, possible. You're supposed to have temperature records to confirm the storage conditions. (3): unless the problems happened during sample processing (bench top stability, dry extract stability) or added up to the degradation over time during long term storage, no. Stability is a characteristic of the analyte under specific conditions and is independent from the method used. ❝ ❝ I would add reason 4: the analyte is not stable for more than 55 days in matrix at that temperature... Solutions: analyse faster; store at lower temperatures; add agents to stabilise. I agree that the analyte is not stable in plasma. The stabilising agent was either incorrect or insufficient to maintain stability. ❝ I don't think this is a matter of guideline... It also goes back to the first question: ❝ - if you did not run the PK / stats but just stopped the analysis because of the stability issues, the study did not really "fail"; ❝ - if you did the PK / stats and the study failed to show BE, and now you say there were stability issues, you can expect questions. Especially if there were no problems in your temperature records, the drug is described as stable in the literature, and you now have 80 days stability data. The study failed because of bioanlaytical issues - lack of stability and improper stabilising agent. Required temperature was maintained all through. Would you be able to suggest a way forward. Thank you Regards Ram |
Ing. Helmut Schütz