Hi Beholder and all,

sorry that it took so long to get all permissions. The presentations are available as a zip-archive.]]>

Dear Obinoscopy,

thanks a lot for clarifying it this was really helpful!

Regards

Joose]]>

Dear Mittyri,

Your reply is very helpful.

I hope that I can fully understand what you mean, so I hope that I can repeat your point of view with my own words:

1. The meaning of the value of P should be stated in the hypothesis of my Protocol and set a significant level α, which I assume here α = 0.05:-).

2. For the Tmax test, I can use any test method for ordinal data as long as there is scientific evidence.

3. If I use the method of the paper to test Tmax, only the "3.2 treatment test" is meaningful when the P value of the "3.1 sequence test" sequence effect is >0.05. such as,

Scene 1: P value of sequence effect = 0.6, P value of treatment effect = 0.6

Scene 2: P value of sequence effect = 0.6, P value of treatment effect = 0.01

Scene 3: P value of sequence effect = 0.01, P value of treatment effect = 0.6

Scene 4: P value of sequence effect = 0.01, P value of treatment effect = 0.01

Among the above four scenarios, only the treatment effect of scene 1 is not significantly different.

Only the therapeutic effects of Scene 2 are significantly different,

Scene 3 and Scene 4 cannot determine whether the treatment effect is significantly different.

4. If I use the paper method to test Tmax, and if the P value of the "3.1 Sequence Test" sequence effect is <0.05, then I should use the "3.4 Treatment & Residual (simultaneous) test" instead of "3.2 treatment test".

5. I must assume that there is no significant difference between the sequence effect and the pairing effect before the "Wilcoxon signed rank test" method can be used.

6. Does it mean that the method in the paper as a whole is more extensive than the data applied by the "Wilcoxon signed rank test". In other words, the method in the paper has fewer assumptions than the "Wilcoxon signed rank test".:confused:

Kind regards,

0521]]>

Hi,

This paper is a reference to the Crossover object in the WinNonlin User Guide.

So I think I should follow the paper to interpret the results of the WinNonlin Crossover object.

I assume that the significance level is 0.05.

`no sequence effect (or drug residual effect) `

in WNL terminology.Does the first row of the effects sheet not indicate a test for sequence effects?

`No treatment effect given no sequence effect`

in WNL terminology.Does the second row of the effects sheet not indicate a test for treatment effects?

`Finally, it is appropriate to note here that if the residual effects cannot be deleted from the model, then the test procedures described in section 3.2 and 3.3 are no longer valid`

However, for this paper, 3.2 and 3.3 depend on 3.1, and only after the 3.1 test is passed, the tests of 3.2 and 3.3 can be performed.

Do you want to tell me this:-):

1. In the effect sheet, the P value judgment of the Treatment is independent of the sequence and the period.

2. All P values in the effect sheet are only statistically significant. The P value has no substantial clinical significance and should not be overly concerned. We should pay more attention to the results in the Confidence Intervals sheet.

3. For the effect sheet, we should pay attention to whether the median of Treatment_Diff_( T - R ) has clinical significance.

Other questions:confused::

1. For the nonparametric test of Tmax, is the only way to calculate the P value using "Mann–Whitney U test"?:confused:

2. For the non-parametric test of Tmax, can we use the "Wilcoxon signed rank test" to calculate the P value?:confused:

3. For the effect sheet, is the "Conclusion_Diff_(T - R)" confidence interval "0" necessary?:confused:

Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5 --> 16205! [Mittyri]]]>

Dear 0521,

`no sequence effect (or drug residual effect) `

in WNL terminology.`No treatment effect given no sequence effect`

in WNL terminology.I would follow the text of the article you referred:

`Finally, it is appropriate to note here that if the residual effects cannot be deleted from the model, then the test procedures described in section 3.2 and 3.3 are no longer valid`

Corresponding sequence test (unequal carry-over) in ANOVA couldn't be a reason for analysis interruption. Likely unequal carryover doesn’t exist in a properly designed study (sufficiently long washout), hence false positives could happen.

`3.3 Testing the equality of period effects when residual effects are absent`

3.4 Testing the equality of direct effects and residual effects simultaneous

(`[no period effect given no sequence effect] and [no treatment and no sequence effect]`

in WNL terminology)Yes, it could, but WNL does the trick with 3.4:

`Since the bivariate Wilcoxon test requires only an ordinal scale for ranking across subjects, it should be used instead of the sign test for general situations in which residual and/or period effects are unequal and within subject linear functions are invalid.`

Using the p-values from the Effects sheet is the same as using p-values from ANOVA: good exploratory analysis without any credible conclusions regarding bioequivalence.

It is better to compare CIs to some reference limits as Helmut noted here --> 18928.]]>

Hi Joose,

No I don't think so. This is because they are not pharmaceutically equivalent.

This is even stated on the draft ICH M9 Guideline that you referenced. It can be found on lines 121 - 124 where eligibility for BCS based Biowaivers was discussed. Here's the excerpt:

For two products to be pharmaceutically equivalent, they must be of the same amount. I think some regulatory authorities allow a difference of 5% in the amount. But for 100% difference, no way.

The route you can go would be multiple strength biowaiver. However you have to check that the excipients are in the same proportion with the actives.

Regards]]>

Thanks Hötzi,

I applaud that move.

Bootstrapping has enormous potential, not just for dissolution. Sometimes the idea behind bootstrapping to me appears so simple and naïve that I am thinking it must be wrong :-|. Especially considering how often we complicate simple issues with fancy maths. :-D

So due to this step in the right direction I'll put flags on the table tonight and celebrate. :-)]]>

... and bootstraping is alive.

See Question and answer on the adequacy of the Mahalanobis distance to assess the comparability of drug dissolution profiles.]]>

Hi Hötzi,

Surely you can. Your only sin is that you have picked the wrong arbitrary value of k :-D:-D:-D:-D:-D:-D:-D]]>

Not only the two references I gave above but

Simple. Given the CDS's settings appropriate to integrate the

BTW, I'm curious how other members of the forum calculate the noise.]]>

*the signal
*

Is that somewhere stated, that peak height is the signal? You need a baseline (whatever that is) to establish this signal (as for the area, so both parameters don't fall out of the clear blue sky but might be considered convention methods, as the PO has noticed). Why not using the same signal as used for calculation of P/A, i.e. most often area? OR ratio of area with IS?]]>

Mainly the latter. However,

the signal

is the signal

is the signal

Hi ElMaestro,

Oh dear, I missed that for years. Biased perception.

Let me continue my series of methods. Number 3: A/P 10/10% but S:N 3:1. Although I have some doubts whether we can achieve such a nice A/P with such a bad S:N, let it be. I consider

Do you evaluate peak height as the signal for your assay? Or peak area?]]>

Dear all,

What are comparable the median of Tmax and the Tmax range for ibuprofen? Or it may be better to coin this way. What are non-comparable ones? This question has arisen because of http://www.ema.europa.eu/en/ibuprofen-product-specific-bioequivalence-guidance.]]>

Dear Helmut Schütz，

When using Phoenix WinNonlin Crossover object for Tmax testing, how can I judge whether it is equivalent by the result?:confused:

I read the "The Use Of Non-Parametric Methods In The Statistical Analysis" document（PMID: 4556704）, and I think he is doing the following steps to judge:

1. Determine if the P value of the sequence is greater than 0.05,

2. If the P value of the sequence is less than 0.05, the test of "Treatment" cannot be performed.

3. If the P value of the sequence is greater than 0.05, it is judged whether the P value of the treatment is greater than 0.05.

4. If the P value of the Treatment is greater than the equivalent, otherwise it is not equivalent.

5. If the P value of the sequence and the P value of the Period are both greater than 0.05, a sign test can be used instead of the rank sum test used in the above steps.

Assuming α = 0.05, all of the above P values are the results in the "Effects" table.

Is the above judgment process correct?:confused:

If not, what is the correct judgment process?:confused:

PARAMETER Test T_stat L_stat p_Value

Tmax Sequence 177.5 0.91791649

Tmax Treatment|(SEQ1=SEQ2) 220 0.021731156

Tmax Period|(SEQ1=SEQ2) 185 0.62428829

Tmax Treatment & Residual (simultaneous) 5.6567621 0.059108471

Best，

0521]]>

Hi Hötzi,

EMA: " (...) the analyte signal of the LLOQ sample should be at least 5 times the signal of a blank sample"

So, it becomes a choice between doing something meaningful or doing something that appears compliant with the guideline :-D]]>

Hello everyone,

I have already googled around the web but couldn't find any answers thus I'll see if anyone can help here!

ICH M9 draft guidance states that “BCS-based biowaivers are applicable to drug products where the drug substance(s) (thus APIs) in test and reference products are

My question now is, what about

More specifically our test product contains the exact double amount of APIs (both BCS Class I drugs) of the reference product (1000/130mg of paracetamol/caffeine TEST vs 500/65mg REFERENCE).

Given the API amount difference between T and R do you think a BCS based biowaiver application would still be applicable?

Thanks a lot in advance for the great support

Joosé]]>

Hi ElMaestro,

Sorry, my wording was not clear. I meant: Both methods fullfil the required conditions for (in)accuracy and precision at the LLOQ (20%). The first one is right at the border (20/20) but with a nice S:N of 10. The second one is better in terms of A/C (15/15) despite a worse S:N of 5.

I guess most people would prefer #2. I don't see the purpose of S:N. IMHO, it is nice to know only.]]>