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Back to the forum  Query: 2017-10-19 00:16 CEST (UTC+2h)
 
K Vishal
Junior

India,
2017-07-07 11:17

Posting: # 17517
Views: 846
 

 Pivotal and pilot BE Study [Study As­sess­ment]

My pilot bio study passed which was single dose,single treatment cross -over study with 90% CI 87 - 118% on 16 subjects but pivotal bio study of same fails i.e 82 - 147 %, the dissolution profiles, physicochemical properties were also same,there is no any significant difference between both batches, analytical method validation was also up to the mark, then please tell me what are the potential factors for passing and failure of same formulation.


Edit: Please follow the Forum’s Policy. Category changed (see this post #1). Please give complete information about the pivotal study; see also this post #4. [Helmut]
ElMaestro
Hero

Denmark,
2017-07-07 12:05

@ K Vishal
Posting: # 17518
Views: 745
 

 Pivotal and pilot BE Study

Hi K Vishal,

there could be a ton of reasons.

But the one thing I'd check first and above all in exactly this situation is if the right randomization code was applied in the pilot (i.e. was the (single) generated code used for dispensing? Was the code used for stats?

Go onsite to check it yourself. Don't ask the CRO to send you the documentation.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
Ohlbe
Hero

France,
2017-07-07 18:29

@ K Vishal
Posting: # 17520
Views: 706
 

 Pivotal and pilot BE Study

Dear K Vishal,

» My pilot bio study passed which was single dose,single treatment cross -over study with 90% CI 87 - 118% on 16 subjects but pivotal bio study of same fails i.e 82 - 147 %,

How many subjects in your pivotal study ?

It looks like the intra-subject variability is much higher compared with the pilot. Any outlier / subject with "strange" results in the pivotal study ?

Were both studies done by the same CRO ?

Regards
Ohlbe
K Vishal
Junior

India,
2017-07-08 09:23

@ Ohlbe
Posting: # 17521
Views: 667
 

 Pivotal and pilot BE Study

» How many subjects in your pivotal study ?
» It looks like the intra-subject variability is much higher compared with the pilot. Any outlier / subject with "strange" results in the pivotal study ?
» Were both studies done by the same CRO ?

Dear Ohlbe,

Thanks for your reply, the pivotal was done on 36 subjects and done by same CRO, with same Bio parameters as that of pilot study, the release was found to be on higher side as that of Innovators i.e 147 (>125) what are the potential causes and in this even i can not change formulation whether study on more subjects i.e 40 + will solve this issue. Since i am purely from formulation development dont know much about statistical bio designs.

Regards


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! [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-08 14:23

@ K Vishal
Posting: # 17522
Views: 663
 

 Pivotal and pilot BE Study

Hi K Vishal,

please answer Ohlbe’s question:
» » Any outlier / subject with "strange" results in the pivotal study ?

» […] what are the potential causes

As ElMaestro’s wrote above: “a ton of reasons”. Please answer his questions:
» » check […] if the right randomization code was applied in the pilot (i.e. was the (single) generated code used for dispensing?
» » Was the code used for stats?

» and in this even i can not change formulation …

Why not? But in your case I suspect bad study conduct rather than formulation problems.

» … whether study on more subjects i.e 40 + will solve this issue.

No. The intra-subject coefficient of variation (CV) in the pilot was 25% and in the pivotal 84% (the ratio of standard deviations was 3). If you assume that you will get exactly the same CV and geometric means ratio (GMR 110%) in the next study, you would need ~400 (‼) subjects for 80% power (π). Since the probability of a Type II Error (β) is 1 – π the chance of failing to demonstrate bioequivalence for a product which is BE is 20%. Forget it.
Try to find out why the variabilities in the two studies differed so much (as advised by Ohlbe and ElMaestro already).

» Since i am purely from formulation development dont know much about statistical bio designs.

I strongly suggest to get some training if you want to design further studies. Without sufficient knowledge (GCP, GLP, bioanalytical method validation, medical ethics, and – yes, biostatistics) you place yourself entirely in the hands of greedy CROs which are always eager to repeat studies – especially with high sample sizes. Increases their profits. And Indian CROs are not the best on the planet. Sorry to say.

Remember that administering drugs to volunteers always carries some risk. Before you plan the next study, ask yourself these questions:
  1. Would I take the drug myself?
  2. Would I give it to my wife/husband/spouse?
  3. Would I give it to my children?
If the answer to any is “No!” reconsider what you are doing. Humans  guinea pigs.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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ElMaestro
Hero

Denmark,
2017-07-08 17:01

@ K Vishal
Posting: # 17525
Views: 648
 

 Retained samples?

Hi Vishal K,

furthermore, if by any chance the CRO has retained samples from the two trials (i.e. units that were undispensed, unused) then I would ask those back and subject them to the usual in vitro tests that you use for the CoA, most importantly
1. potency or content.
2. the release profiles in suitable dissolution media.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
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