tarak_desai
☆    

India,
2014-12-16 07:51
(3391 d 03:16 ago)

Posting: # 14076
Views: 8,969
 

 BE study with two different batches of the reference product [Study As­sess­ment]

Hello to all,

Need your guidance on following case.

In a two period, single dose, cross over, BE study, it was observd that after completion of period-I, there was insufficient quantity of the reference product available to dose subjects in period-II. sponsor also doesnt have same batch reference product availalbe with them.

can we use the different batch reference product in priod-II?
and what other measures to be taken in this case?
or redosing to be done using same batch in period-I and II or do we need to cancel study?

pls guide.

thanks.
tarak


Edit: Category changed. [Helmut]
cher0424
☆    

China,
2014-12-16 08:31
(3391 d 02:36 ago)

@ tarak_desai
Posting: # 14078
Views: 7,803
 

 BE study with two different batches of the reference product

Hello Tarak:

Reference product in BE study need can be different batch. It is provide more sufficient evidences for bioequivalence.
ElMaestro
★★★

Denmark,
2014-12-16 10:01
(3391 d 01:06 ago)

@ tarak_desai
Posting: # 14079
Views: 7,846
 

 BE study with two different batches of the reference product

Dear tarak_desai,

❝ In a two period, single dose, cross over, BE study,it was observd that after completion of period-I, there was insufficient quantity of the reference product available to dose subjects in period-II. sponsor also doesnt have same batch reference product availalbe with them.


❝ can we use the different batch reference product in priod-II?

❝ and what other measures to be taken in this case?


Forgive me for saying this, I know this could be seen as a negative comment; But do you really think it is a good idea to proceed with this trial if you realise halfway through it that you have not been able to plan it well enough to have the Ref available in quantities sufficing for the number of subjects?
It sounds to me like the planning is completely off. Think about responsibilities, futile trials, drug accountability, and GCP.
(let me add: an argument of having to involve a new Ref batch to avoid the trial becoming futile strikes me as backward)

Pass or fail!
ElMaestro
cher0424
☆    

China,
2014-12-16 10:31
(3391 d 00:36 ago)

(edited by Ohlbe on 2014-12-16 11:04)
@ ElMaestro
Posting: # 14080
Views: 7,771
 

 BE study with two different batches of the reference product

Hello ElMaestro:
It indeed haven't prepare well for the trial, but the different between two batch should be within 5%, so particularly no much influence in trial result. Unless the test product quality happen on the edge of 80%-125%. In that case the differences between two batch are essential to pass or fail.


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! [Ohlbe]
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2014-12-16 14:36
(3390 d 20:31 ago)

@ cher0424
Posting: # 14083
Views: 7,813
 

 Two different batches of R: bad idea

Hi cher0424 & Tarak,

I agree with what ElMaestro wrote about study planning etc.

❝ […] but the different between two batch should be within 5%, so particularly no much influence in trial result. Unless the test product quality happen on the edge of 80%-125%. In that case the differences between two batch are essential to pass or fail.


Let’s play the devil’s advocate. CVintra 25%, CVtotal 50%, expected T/R 95%, 2×2 crossover study planned for ≥80% power. We would design the study with 28 subjects (expected power 80.7%). Let’s further assume that both the measured content of the first batch of the reference (R1) and of the test (T) were 100%. The true – though unknown – bioavailability of T is 95%. You try hard to find a second batch of the reference which matches R1 but the only one you could get had a measured content of 95% (within ±5% of both R1 and T).
If you evaluate only the first period as a parallel design (bad idea, since Freeman* showed that you don’t get unbiased estimates if the study was planned a s a crossover):

T/R1  95.00% (90% CI: 60.57–148.99%)

Glorious failure since you are extremely underpowered with 14 subjects for a CVtotal of 50%.
Same story if you look only at the second period:

T/R2 100.00% (90% CI: 63.76–156.84%)

If you pool both periods you pass easily…

T/R   97.47% (90% CI: 87.12–109.05%)

…but through the backdoor (i.e., by introducing R2) shifted the result towards nicer results. If we would have had enough R1 for the entire study we would have got:

T/R1  95.00% (90% CI: 84.91–106.28%)


The CV employed in study planning was an assumption. What if it would be larger, say 40%? T/R1 (as planned) would fail with a lower CL of 79.70% but pass with T/R (lower CL 81.77%). Very bad idea. No regulator would buy that – for good reasons. :stop:


  • Freeman P. The performance of the two-stage analysis of two-treatment, two-period cross-over trials. Stat Med. 1989;8(12):1421–32.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
cher0424
☆    

China,
2014-12-17 02:49
(3390 d 08:18 ago)

@ Helmut
Posting: # 14088
Views: 7,768
 

 Two different batches of R: Analysis separately??

Dear Hulmet

Thank you for your vivid assumption. I still have one query. So if change the batch of Reference, the regulator need sponsor to provide separate and total analysis for each period ?
Ohlbe
★★★

France,
2014-12-17 14:45
(3389 d 20:22 ago)

@ cher0424
Posting: # 14092
Views: 7,626
 

 Two different batches of R: very bad idea

Dear cher0424,

❝ So if change the batch of Reference, the regulator need sponsor to provide separate and total analysis for each period ?


I think it is much, much simpler than that. If you change the batch of the reference product in the middle of the study, regulators are very likely to reject the study whatever analyses you provide.

Regards
Ohlbe
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2014-12-17 15:49
(3389 d 19:18 ago)

@ cher0424
Posting: # 14095
Views: 7,614
 

 Forget it!

Hi cher0424,

❝ Dear Hulmet


Helmut, if you don’t mind.

❝ So if change the batch of Reference, the regulator need sponsor to provide separate and total analysis for each period ?


My example demonstrates how different batches will influence the outcome. That’s exactly why I wrote:

❝ ❝ No regulator would buy that – for good reasons. :stop:


No way. Forget it!

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
cher0424
☆    

China,
2014-12-18 02:08
(3389 d 08:59 ago)

@ Helmut
Posting: # 14099
Views: 7,603
 

 Forget it!

:lookaround:Hi Helmut


❝ ❝ Dear Hulmet


Helmut, if you don’t mind.


SOOOO sorry for spelling your name wrong.
jag009
★★★

NJ,
2014-12-16 16:24
(3390 d 18:43 ago)

@ tarak_desai
Posting: # 14086
Views: 7,721
 

 BE study with two different batches of the reference product

Hi,

❝ In a two period, single dose, cross over, BE study, it was observd that after completion of period-I, there was insufficient quantity of the reference product available to dose subjects in period-II. sponsor also doesnt have same batch reference product availalbe with them.


FDA? Good luck.
Best thing to do is file a control correspondence and keep your fingers crossed.

John
felipeberlinski
☆    

Brazil,
2014-12-17 21:16
(3389 d 13:51 ago)

@ jag009
Posting: # 14098
Views: 7,593
 

 BE study with two different batches of the reference product

ANVISA? No way too :no:
UA Flag
Activity
 Admin contact
22,957 posts in 4,819 threads, 1,636 registered users;
105 visitors (0 registered, 105 guests [including 8 identified bots]).
Forum time: 11:07 CET (Europe/Vienna)

With four parameters I can fit an elephant,
and with five I can make him wiggle his trunk.    John von Neumann

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5