pash413
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India,
2012-03-28 18:04
(4496 d 06:09 ago)

Posting: # 8343
Views: 6,087
 

 Drop out handling in Europe Submission Study [Regulatives / Guidelines]

Dear All
We are planing to conduct biostudy for EU submission and we need some clarity regarding below mentioned points:
  1. As per current EU guideline statistical evaluation of Tmax is not require, if our drug is not rapid release formulation. In old guidance it was mentioned as “if appropriate to the evaluation the analysis technique for Tmax should be non-parametric and should be applied to un-transformed data”.
    Is it required to performed statistical evaluation of Tmax in studies conducted after implementation of new guideline? Our formulation is not rapid release formulation.
  2. If during conduction of two way crossover bio study some of the subject(S) withdraw or dropped before check-in of period 2 but they had completed period 1 successfully.
    As pr current EU Guidance "Drop-out and withdrawal of subjects should be fully documented. If available, concentration data and pharmacokinetic parameters from such subjects should be presented in the individual listings, but should not be included in the summary statistics". and as per old guidance "All the results should be clearly presented and should include data from subjects who eventually dropped-out. Drop-out and withdrawal subjects should be fully documented and accounted for".

Should we have to analyze (bioanalysis) plasma samples of that dropped/withdraw subject(s)? We are confusing with the statement of current guidance "if available...."
Helmut
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Vienna, Austria,
2012-03-28 18:27
(4496 d 05:45 ago)

@ pash413
Posting: # 8344
Views: 5,316
 

 Tmax, drop-outs (EMA)

Dear Pash!

❝ 1. As per current EU guideline statistical evaluation of Tmax is not required, if our drug is not rapid release formulation. In old guidance it was mentioned as “if appropriate to the evaluation the analysis technique for Tmax should be non-parametric and should be applied to un-transformed data”.


You are mixing things up. Both quotes come from IR guidelines.

A statistical evaluation of tmax is not required. However, if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, there should be no apparent difference in median tmax and its variability between test and reference product.

  • Comparison only required if clinically relevant:
    □ No apparent difference in median tmax between test and reference product.
    No apparent difference in its variability.
BTW, in my studies I run nonparametrics on tmax essentially ignoring the guideline. :-D

❝ Is it required to performed statistical evaluation of Tmax in studies conducted after implementation of new guideline?


No. But don’t ask me how to assess the variability if required. F**ing boxplots again (like in the assessment of outliers in replicate studies)?

❝ Our formulation is not rapid release formulation.


So what is it exactly? CR, DR, multiphasic, pulsatile,…? Tmax is not mentioned in the MR guidance from 1999. Not even for MR formulations where rapid onset is of importance tmax is required (see here).

❝ Should we have to analyze (bioanalysis) plasma samples of that dropped/withdraw subject(s)?


Yes.

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pash413
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India,
2012-03-28 19:04
(4496 d 05:08 ago)

@ Helmut
Posting: # 8345
Views: 5,261
 

 Tmax, drop-outs (EMA)

Dear HS
Thanks for your quick reply
  1. Our formulation is IR formulation, but the reported Tmax is around 6-10 hours.
  2. Further we want to know the the reason/regulatory expectation behind the analysing the drop out/ withdrawal subjects. Will it be useful to establish any correlation between adverse events with the plasma concentration data and may be used to rule out formulation performance as the reason of adverse events? then what about it's applicability for subject who dropout due to personal reason? Please share your view, as USFDA does not require analysis of such dropout subjects.
Helmut
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Vienna, Austria,
2012-03-28 19:49
(4496 d 04:23 ago)

@ pash413
Posting: # 8346
Views: 5,447
 

 Tmax, drop-outs (EMA)

Dear Pash!

❝ 1. Our formulation is IR formulation, but the reported Tmax is around 6-10 hours.


So I assume that rapid onset most likely is neither a clinical claim nor related to AEs. Assessment of tmax is not required.

❝ 2. […] Will it be useful to establish any correlation between adverse events with the plasma concentration data and may be used to rule out formulation performance as the reason of adverse events?


Exactly (see here). Sometimes even a subpopulation of ultraslow metabolisers turn up. See the end of this post.

❝ then what about it's applicability for subject who dropout due to personal reason?


You never know. Sometimes volunteers don’t report AEs and withdraw consent “for personal reasons” fearing that otherwise they won’t be included in future studies. We once performed a multiple dose PK interaction study on orphenadrine where a volunteer dropped out after the 4th dose. No AEs reported, but trough values were rising significantly faster than in any other subject of the study and would have lead to 10fold higher concentrations in steady state…

❝ […] as USFDA does not require analysis of such dropout subjects.


Here I fully agree with EMA’s position.

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