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Amira Gouda ☆ Egypt, 2020-03-01 21:28 (1735 d 23:51 ago) Posting: # 21191 Views: 5,818 |
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Dears Good evening Is it applicable to use the same volunteers in fast and fed studies for the same product separated with adequate wash out period? Is there any reference in guidelines for such? Thanks Amira |
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alghazam ☆ Jordan, 2020-03-03 11:24 (1734 d 09:55 ago) @ Amira Gouda Posting: # 21193 Views: 4,253 |
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Dear Amira, It is clearly stated in EMA guidance of 2010 on page 10/27 (lines 6-7) that "In cases where information is required in both the fed and fasted states, it is acceptable to conduct either two separate two-way cross-over studies or a four-way cross-over study." hope this helps. Mutasim |
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Ohlbe ★★★ France, 2020-03-03 12:58 (1734 d 08:21 ago) @ Amira Gouda Posting: # 21195 Views: 4,255 |
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Dear Amira, ❝ Is it applicable to use the same volunteers in fast and fed studies for the same product separated with adequate wash out period? Is there any reference in guidelines for such? If you run two separate studies, I'm not aware of any provision in guidelines that would prevent to re-use the same subjects in the second study, if you respect a wash-out period and if the blood loss remains reasonable. In most protocols (and IIRC, in the ANVISA guidelines) there are criteria for a minimum time between two studies (e.g. 2 or 3 months) and this would have to be respected too. But if you run two separate studies I would not make it a strict requirement that it should only be the same subjects participating in both: there would be a higher risk of drop-out. Helmut would explain you that the loss of power due to a couple of drop-outs is minimal, but if there are many subjects missing you could get in trouble. If you fear a high drop-out rate, you would need to enrol more subjects in the first study in order to still have enough in the second. The longer the time between the two studies, the higher the risk of loosing subjects. If you insist on having the same subjects in both trials: you should make it clear in the protocol of the second study, so that the Ethics Committee can check the time between studies and the cumulative blood loss. — Regards Ohlbe |
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Helmut ★★★   Vienna, Austria, 2020-03-04 15:15 (1733 d 06:04 ago) @ Ohlbe Posting: # 21200 Views: 4,252 |
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Dear Ohlbe & Amira, ❝ But if you run two separate studies I would not make it a strict requirement that it should only be the same subjects participating in both: there would be a higher risk of drop-out. Helmut would explain you that the loss of power due to a couple of drop-outs is minimal,…  ❝ … but if there are many subjects missing you could get in trouble. OK, OK. ❝ If you insist on having the same subjects in both trials: you should make it clear in the protocol of the second study, so that the Ethics Committee can check the time between studies and the cumulative blood loss. I submitted a comment (which never will be published) to the drafted MR-GL. We should keep in mind that only T vs. R in fasting and fed state are required. The assessment of food effects of T and R is only “nice to know”.a If you run two separate studies there are two issues:
Tfed – Rfed – Tfasting – Rfasting In one study (where I expected higher variability in fed state) I opted for a TSD. In the interim assess the CVs (separate for the fed and fasting parts) and initiate the second stage with potentially different sample sizes. The fed and fasting parts are simple 2×2×2 crossovers. The evaluation of the food effect follows #2 above. Assuming lacking period effects is common practice in assessing linear PK of new drugs (MD AUC0–τ vs. SD AUC0–∞). We gave that as a justification in the protocol, which was accepted by the German BfArM in 2015.
— 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 |
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Shuanghe ★★ Spain, 2020-03-04 17:13 (1733 d 04:06 ago) @ Helmut Posting: # 21203 Views: 4,180 |
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Dear Helmut ❝ If T shows a substantially lower food effect than R that’s good for the patients. However, if you want to state that in the label/SmPC (“can be taken with or without food”) you have to switch from a generic to a hybrid application. The EMA welcomes that. Whether the additional clinical studies are worth the efforts is another story. What happens if T is BE to R under fasting and fed but T has much more food effect than R? Will "nice-to-know" become "but-now-I-know-so-you-are-fucked"? What's your experience from regulation perspective? — All the best, Shuanghe |
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jag009 ★★★ NJ, 2020-03-04 20:25 (1733 d 00:54 ago) @ Shuanghe Posting: # 21204 Views: 4,192 |
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Hi, ❝ What happens if T is BE to R under fasting and fed but T has much more food effect than R? Will "nice-to-know" become "but-now-I-know-so-you-are-fucked"? What's your experience from regulation perspective? With FDA → In general they don't care but if they look at your data and see that you borderline past fed (or fast), then they might raise an issue. J |
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Helmut ★★★ Vienna, Austria, 2020-03-05 12:50 (1732 d 08:29 ago) @ Shuanghe Posting: # 21206 Views: 4,115 |
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Hi Shuanghe, ❝ What happens if T is BE to R under fasting and fed but T has much more food effect than R? Will "nice-to-know" become "but-now-I-know-so-you-are-fucked"? By “much more” you mean that the 90% CI is entirely outside the 80-125% limits, right? This means only that you have to forget the idea of a hybrid application. Everything else (CI overlapping the limits) is indecisive and would not worry me. Even if you are completely outside (T demonstrated a larger food effect than R) – since both fasting and fed passed BE – stay with the generic pathway and you should be fine. ❝ What's your experience from regulation perspective? Nil – also for the “nice” case. Though the EMA stated in various conferences to welcome such a hybrid application, I haven’t seen one so far. Any experience from the members? — 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 |
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Shuanghe ★★ Spain, 2020-03-05 17:02 (1732 d 04:17 ago) @ Helmut Posting: # 21208 Views: 4,107 |
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Hi Helmut, ❝ By “much more” you mean that the 90% CI is entirely outside the 80-125% limits, right? Not necessarily. Yesterday when I was asking the question I was thinking about 90% CI partially out, e.g., T fed/T fasting is 60%--85%, and R fed/R fasting is 115%--130%. So food increase the reference but decrease the test absorption. Or vice versa. But what if 90% CIs are within 80%--125%? e.g., T fed/T fasting 80.1%--90% (which is statistically significant different but is BE) and R fed/R fast about 115%--124% (similarly, there's statistically significant difference but is BE), or vice versa. Clearly, food effect is huge and there's something wrong here... Of course, this is just pure speculation. I'm not even sure if the scenario is remotely possible given that T fed/R fed and T fast/R fast are assumed within 80%--125%  ... ❝ Everything else (CI overlapping the limits) is indecisive and would not worry me. If the scenario above is possible, I would worry about it... But again, maybe it's just my silliness. I cannot think straight right now. ❝ Nil – also for the “nice” case. Though the EMA stated in various conferences to welcome such a hybrid application, I haven’t seen one so far. Any experience from the members? Yes, let's hear other opinion/experience. — All the best, Shuanghe |
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Marcelo Davanco ☆ Campinas, SP, Brazil, 2020-03-06 14:35 (1731 d 06:44 ago) @ Shuanghe Posting: # 21221 Views: 4,108 |
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Hy everyone, ❝ ❝ By “much more” you mean that the 90% CI is entirely outside the 80-125% limits, right? ❝ Not necessarily. Yesterday when I was asking the question I was thinking about 90% CI partially out, e.g., T fed/T fasting is 60%--85%, and R fed/R fasting is 115%--130%. So food increase the reference but decrease the test absorption. Or vice versa. ❝ ❝ But what if 90% CIs are within 80%--125%? e.g., T fed/T fasting 80.1%--90% (which is statistically significant different but is BE) and R fed/R fast about 115%--124% (similarly, there's statistically significant difference but is BE), or vice versa. Clearly, food effect is huge and there's something wrong here... ❝ ❝ Of course, this is just pure speculation. I'm not even sure if the scenario is remotely possible given that T fed/R fed and T fast/R fast are assumed within 80%--125% I think this scenario would be rare to happen. Unless the matrices of the generic and RLD formulations are totally different, impacting on excipient solubilitY under fed condition and, consequently, different drug release rate would be obtained (e.g., hydrophilic vs lipophilic matrix). In any case, if the health authority will evaluate the two studies separately (if the two studies were perfomed as two independently studies:Fasting 2x2x2 and Fed 2x2x2 - scenario considered by ANVISA), I do not believe there is a problem with that if both studies were BE. — Marcelo Davanço |
Ing. Helmut Schütz