## meta analysis? [Regulatives / Guidelines]

Dear Martin, dear all,

I'm not a statistician. But as a "lay person" my question would be: what do we need to demonstrate ? The problem raised by the assessor is not that one study shows bioequivalence but a previous study was inconclusive (that's the situation where there were discussions about meta analysis at some point in time, if I'm not mistaken). The problem is rather that there are fluctuations in the point estimates between different studies, and I'm not sure what new information a meta analysis will bring.

When reading the objection from the assessor, it seems to me that he/she is considering the point estimate to be a "true value", not an experimental value affected by some level of uncertainty. This is reflected in the statement

I would see two possible ways out:

Regards

Ohlbe

I'm not a statistician. But as a "lay person" my question would be: what do we need to demonstrate ? The problem raised by the assessor is not that one study shows bioequivalence but a previous study was inconclusive (that's the situation where there were discussions about meta analysis at some point in time, if I'm not mistaken). The problem is rather that there are fluctuations in the point estimates between different studies, and I'm not sure what new information a meta analysis will bring.

When reading the objection from the assessor, it seems to me that he/she is considering the point estimate to be a "true value", not an experimental value affected by some level of uncertainty. This is reflected in the statement

*"This fluctuation can not be explained through the "intra-subject variability" as the latter influences Cmax and hence justifies the widening of the acceptance range for Cmax but not the fluctuating point estimates which are independent of this variability. This fluctuation is also independent of the number of subjects in the studies".*This statement is not correct: the number of subjects in your study will directly influence the "reliability" of your experimental determination of the point estimate. Particularly with a high intra-CV. Actually, that level of uncertainty is precisely what the confidence interval represents, isn't it ?I would see two possible ways out:

- disregard the pilot studies (insufficiently powered, poor estimate of the point estimate, test 1 was lab scale) and focus on the two pivotals. There is an overlap between the 90 % CI of the two studies, which, if I'm not mistaken, could be considered as meaning that the two point estimates are not statistically different;

- argue that there were also differences in the batch number of the reference product and that the difference in point estimates cannot be attributed
*a priori*to the test product alone. Now let's first restrict the comparison to study 1 vs. study 3, which used different test batches but the same reference batch. OK, both studies fail to demonstrate BE, but that's not the question here: let's just focus on the point estimates. They're very close, right ? Now let's compare studies 2 and 3: same test batch, different reference batch. There we have much larger differences in point estimates. Conclusion: it seems that there is a batch-to-batch difference in the reference product, not in yours .

Regards

Ohlbe

—

Regards

Ohlbe

Regards

Ohlbe

### Complete thread:

- inter-batch variability? Dr_Dan 2010-08-04 10:29 [Regulatives / Guidelines]
- inter-batch variability? Pavidus 2010-08-04 11:57
- inter-batch variability? d_labes 2010-08-04 13:58
- inter-batch variability? ElMaestro 2010-08-04 17:09
- Between study variability common for HVDs Helmut 2010-08-04 19:45
- Between study variability common for HVDs ElMaestro 2010-08-04 21:01
- Representative batches? Helmut 2010-08-04 23:42
- Representative batches? ElMaestro 2010-08-05 08:40
- Representative batches? Helmut 2010-08-05 12:30

- Representative batches? Dr_Dan 2010-08-05 08:58
- Representative batches? Helmut 2010-08-05 12:45
- Confidence intervals vs. point estimators Dr_Dan 2010-08-06 09:55
- Confidence intervals vs. point estimators ElMaestro 2010-08-06 12:34
- Confidence intervals vs. point estimates Helmut 2010-08-06 13:20
- Confidence intervals vs. point estimators Dr_Dan 2010-08-06 14:44
- Confidence intervals vs. point estimators ElMaestro 2010-08-06 15:01
- meta analysis? martin 2010-08-06 17:25
- meta analysis? ElMaestro 2010-08-06 17:57
- meta analysis? Helmut 2010-08-06 18:31

- meta analysis?Ohlbe 2010-08-06 23:21
- No chance against RMS? Dr_Dan 2010-08-10 12:27
- No chance against RMS? ElMaestro 2010-08-10 16:26

- No chance against RMS? Dr_Dan 2010-08-10 12:27

- meta analysis? ElMaestro 2010-08-06 17:57

- meta analysis? martin 2010-08-06 17:25

- Confidence intervals vs. point estimators ElMaestro 2010-08-06 15:01

- Confidence intervals vs. point estimators ElMaestro 2010-08-06 12:34

- Confidence intervals vs. point estimators Dr_Dan 2010-08-06 09:55

- Representative batches? Helmut 2010-08-05 12:45

- Representative batches? ElMaestro 2010-08-05 08:40

- Representative batches? Helmut 2010-08-04 23:42

- Between study variability common for HVDs ElMaestro 2010-08-04 21:01
- Batch-to-Batch Pharmacokinetic Variability kumarnaidu 2016-07-20 07:16
- tlast (Common) Helmut 2016-07-20 10:48
- tlast (Common) nobody 2019-02-21 15:20
- tlast (Common) ElMaestro 2019-02-21 16:32
- tlast (Common) nobody 2019-02-21 17:02
- tlast (Common) ElMaestro 2019-02-21 18:02
- tlast (Common) nobody 2019-02-21 18:17

- tlast (Common) ElMaestro 2019-02-21 18:02

- tlast (Common) nobody 2019-02-21 17:02

- tlast (Common) ElMaestro 2019-02-21 16:32

- tlast (Common) nobody 2019-02-21 15:20

- tlast (Common) Helmut 2016-07-20 10:48

- Between study variability common for HVDs Helmut 2010-08-04 19:45