joyjac
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Philippines,
2006-07-19 07:10
(6097 d 21:05 ago)

Posting: # 179
Views: 10,630
 

 Add-on Studies / Sequential Design [Design Issues]

I have some questions regarding add-on studies /sequential design.
  1. Are these acceptable in bioequivalence studies if specified a priori in the protocol? Would you know if US FDA, EMEA, Canada, ASEAN accept such design?
  2. When an add-on study is conducted (and combined with the original study), what would be the statistical method of analysis?
  3. Can we still apply the 90% Confidence Interval criteria for bioequivalence or would it have to be more restrictive i.e. 95% CI?
  4. Could the first study be discarded if the second study passed the 90% CI BE criteria on its own?
  5. More importantly, what are its pros and cons with regards to consumer protection or risk.
Thank you so much for the knowledge sharing.
Ahmed meeran
●    

2006-07-27 10:56
(6089 d 17:18 ago)

@ joyjac
Posting: # 189
Views: 9,065
 

 Add-on Studies / Sequential Design

Dear joyjac

Only South Africa and Japan authorities approve such a study. Acc SA it should be stated in protocol before the beginning of the study. No of subjects should not exceed twice than orginal for eg if we begin the study with 12 volunteers then the maximum add ons permitted is 24. (Biostudies guidlines of SA and Addendum 5 to the biostudies). But what is not clear is whether we should do the clinical part for the entire study at first (eg for all the 24) and do the analytical part for the 12 only and to perfom the study on other 12 only if the study fails. If any body knows please clear.
Helmut
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Vienna, Austria,
2006-07-27 14:53
(6089 d 13:21 ago)

@ Ahmed meeran
Posting: # 190
Views: 8,945
 

 Add-on Studies in RSA

Dear Ahmed!

❝ Only South Africa and Japan authorities approve such a study.


...and Canada since 1991 ;-)

❝ Acc SA [...] is not clear is whether we should do the clinical part for the entire study at first (eg for all the 24) and do the analytical part for the 12 only and to perfom the study on other 12 only if the study fails.


IMHO it does not make sense to perform the clinical part of the maximum intended sample size first, because (staying with your example):
  1. evaluating part I, you calculate a necessary total sample size of 30.
  2. evaluating part I, you calculate a necessary total sample size of 16.
In case one, you have to stop the study (because you will not be able to demonstrate BE with n=24).
In case two, although you will be able to demonstrate BE, but like in case one, you unnecessarily have administered drugs to healthy subjects, which is considered unethical.

❝ If any body knows please clear.


A recent document (67kB zipped M$-Word)--for comment until 14 Aug 2006--is more precise:

3.2.1 Number of Subjects
[…] The provision for add-ons should be made in the protocol a priori clearly reflecting the maximum number of subjects to be included.
3.2.2 Drop-outs and withdrawals
[…] If the bioequivalence study was performed with the appropriate size but bioequivalence cannot be demonstrated because of a result of a larger than expected random variation or a relative difference, an add-on subject study can be performed using not less than half the number of subjects in the initial study. Combining is acceptable only in the case when the same protocol was used and preparations from the same batches were used.
Add-on designs must be carried out strictly according to the study protocol and SOPs, and must be given appropriate statistical treatment, including consideration of consumer risk.

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Ahmed meeran
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2006-08-03 16:38
(6082 d 11:36 ago)

@ Helmut
Posting: # 195
Views: 9,115
 

 Add-on Studies in RSA

Dear Mr Helmut,

Thanks for the clarification. This further reinforced in the USFDA guidlines

The US FDA guideline of "Statistical Approaches to Establishing Bioequivalence" mentions:
"If the study is carried out in two or more groups and those groups are studied at different clinical sites, or at the same site but greatly separated in time (months apart, for example), questions may arise as to whether the results from the several groups should be combined in a single analysis. Such cases should be discussed with the appropriate CDER review division."

THIS SHOWS FDA MAY NOT ENCOURAGE ADD ON

If clinical part of the study is conducted in 2 parts i.e. first in 12 subjects and then in 12 subjects (if required), there will be problem of group effect, sequence effect, period effect and subject effect.

The MCC South Africa guideline not clearly mentions about clinical or analytical conduct of the study and does not given any statement about statistical approach. Could u pl guide on statistical approach
Helmut
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Vienna, Austria,
2006-08-16 16:05
(6069 d 12:10 ago)

@ joyjac
Posting: # 219
Views: 8,965
 

 Add-on Studies / Sequential Design

Dear Joy,

sorry for the late reply ;-)

❝ 1. Are these acceptable in bioequivalence studies if specified a priori in the protocol? Would you know if US FDA, EMEA, Canada, ASEAN accept such design?

❝ 2. When an add-on study is conducted (and combined with the original study), what would be the statistical method of analysis?

❝ 3. Can we still apply the 90% Confidence Interval criteria for bioequivalence or would it have to be more restrictive i.e. 95% CI?


First a little review of international guidelines (maybe answering you questions #1-#3)

Canada
If BE is not shown, additional subjects are included. If an F-test (equality of variances) shows no significance, you may go for a pooled analysis. No alpha-adjustment needed.
Japan
If BE is not shown, a second part with sample size of at least half of the 1st part is initiated. Pooled analysis without alpha-adjustment.
South Africa
Maximum sample size must be stated a-priori; for details see Ahmed's post and the followings.
New Zealand
Group Sequential Design with alpha-adjustment (Gould's* method?).
USA
No way :-(

Second some notes on the European practice.

Add-On and Group Sequential Designs are not covered in the NfG on BA/BE.
Group sequential designs are standard in clinical research.
Although discussed at BioInternationals '89 to '96, no consensus about their application in BE was reached.

Personal Experience:
A proposed method* was not accepted in the planning phase (three cases by the German BfArM).
Gould's method is an adaption of 'classical' procedures in clinical research (e.g., P. Armitage, 1975; J. Whitehead, 1992).
With such a method you are penalized for 'looking' at the data, i.e., the combined sample size is always larger than the one of an optimal fixed-sized study.
Unfortunatelly both the deviation from the reference and the variability are not known with certainty; therefore such an optimal study may be an illusion (i.e., in the long run less subjects are needed with Group Sequential Designs).

The following Add-On design was accepted in the EU (two cases Germany, one case France):
Evaluation of first part by an independent statistician (calculation of CV only!), performance of a second part, evaluation of pooled data without alpha-adjustment (by another statistician). The maximum additional sample size (stop criterion) was stated in the protocol. Drawback: since no point estimate must be calculated for the first part, such a study may fail even after pooling (if your assumptions are not met).

❝ 4. Could the first study be discarded if the second study passed the 90% CI BE criteria on its own?


At the first glance I saw no practical application. But it may be possible (as always if stated a-priori) if the F-test (Canada!) rejects pooling, and the second part is large enough...

❝ 5. More importantly, what are its pros and cons with regards to consumer protection or risk.


With the exception of US-FDA, all other regulators are answering with a 'Positive Maybe' ;-)
I think it's hypocritical accepting Group Sequential Designs (or even Adaptive Designs) in phase III, but rejecting them in BE...


  • Gould LA. Group Sequential Extension of a Standard Bioequivalence Testing Procedure. J Pharmacokinet Biopharm. 1995;23(1):57-86.

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joyjac
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Philippines,
2006-08-18 04:35
(6067 d 23:39 ago)

@ Helmut
Posting: # 222
Views: 8,810
 

 Add-on Studies / Sequential Design

Dear HS,

I truly appreciate you for giving us greater understanding of the issues associated with bioavailability/bioequivalence. Thanks for the continued kind help.
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