Lucas
★    

Brazil,
2014-03-17 16:27
(3663 d 18:27 ago)

Posting: # 12637
Views: 18,007
 

 Approved Pilot and Failed Pivotal Study [Study As­sess­ment]

Hello.

There have been two strange similar cases recently where I work, and we have been discussing it for a while now. For both cases, a pilot study was conducted with 28 subjects, and bioequivalence was achieved through the 90% CIs (For drug A: Cmax 88.74% - 124.54% with ISCV of 36.88% and AUClast 87.10% - 113.39% with ISCV of 28.33%. For drug B: Cmax 89.34% - 119.35% with ISCV of 31.90% and AUClast 91.67% - 116.96% with ISCV of 26.64%). The sponsor could submit those studies to the regulator with no problem, but they haven’t done all the in vitro studies required. Based on the ISCV estimated on the pilot study they decided the sample size for the pivotal studies (64 for drug A and 56 for drug B). The problem is that the pivotal studies for both drugs failed (For drug A: Cmax 75.39% - 100.88% with ISCV of 52.49% (!!) and AUClast 72.70% - 87.57% with ISCV of 32.33%. For drug B: Cmax 74.01% - 90.26% with ISCV of 31.22% and AUClast 79.34% - 92.71% with ISCV of 24.26%). Same analytical methods were applied, the only thing that changed from pilot to pivotal was the sample size, and the batch of the reference in the study of the drug A.
What is to make of that? I mean, those products could have been in the market if the pilot study was submitted and a pivotal study was not conducted and I know that the results from the pivotal studies must be more reliable than the pilot's. How would we evaluate the reliability of the study?

Best regards.

Lucas


Edit: Category changed. [Helmut]
nobody
nothing

2014-03-17 17:02
(3663 d 17:52 ago)

@ Lucas
Posting: # 12638
Views: 16,327
 

 Approved Pilot and Failed Pivotal Study

Apparently the point estimates have changed quite a bit! Could you compare Reference-pilot and Reference-pivotal to get a feeling for these products?

Replicate designs employed?

Kind regards

Kindest regards, nobody
Lucas
★    

Brazil,
2014-03-17 18:51
(3663 d 16:03 ago)

@ nobody
Posting: # 12639
Views: 16,265
 

 Approved Pilot and Failed Pivotal Study

Hi!

❝ Apparently the point estimates have changed quite a bit! Could you compare Reference-pilot and Reference-pivotal to get a feeling for these products?


Yes, they've changed a lot, but not only the point estimate, the geometric means aswell. In the drug B studies the Cmax geo mean for the reference treatment changed 45% from the pilot to the pivotal. For drug B the major difference was for the Cmax of the test treatment, which changed 23%.
So when I compare RxR for drug A I get a positive result, but for drug B this does not happen, since they have a ratio of 145% for Cmax. It is noteworthy that for drug A a different batch of the reference was used in the pivotal study, but Cmax was very similar and for drug B with the same batch we got very different values for the plasma concentrations.

❝ Replicate designs employed?


Standard 2x2 Xover actually.
nobody
nothing

2014-03-17 19:38
(3663 d 15:16 ago)

@ Lucas
Posting: # 12640
Views: 16,279
 

 Approved Pilot and Failed Pivotal Study

❝ For drug B the major difference was for the Cmax of the test treatment, which changed 23%.


...should read "For drug A...", or?

Which agency do you wanna go with these data?

Experienced CRO? Some sponsor audits throughout the studies or after obtaining such results?

Kindest regards, nobody
Lucas
★    

Brazil,
2014-03-17 19:55
(3663 d 14:59 ago)

(edited by Lucas on 2014-03-17 20:13)
@ nobody
Posting: # 12641
Views: 16,661
 

 Approved Pilot and Failed Pivotal Study

❝ ...should read "For drug A...", or?


No. For the test treatment of drug A the difference between the two studies was actually lower than that.

❝ Which agency do you wanna go with these data?


❝ Experienced CRO? Some sponsor audits throughout the studies or after obtaining such results?


What I'm questioning is not even the results from this specific study, but yes, it was audited and no problem was found. I'm trying to understand whether that is a concern point for bioequivalence in general. The big question would be "how many studies have passed with 28 subjects or less and shouldn't pass actually?" or "how many studies have failed with 28 subjects or less and should pass actualy?". You see that the variability for both drugs in the pilot studies was not very high for the N used, so we would expect it to be predictive.
kumarnaidu
★    

Mumbai, India,
2014-03-18 06:03
(3663 d 04:51 ago)

@ Lucas
Posting: # 12642
Views: 16,180
 

 Approved Pilot and Failed Pivotal Study

Hi all,
In this case reference drug itself behaving as a variable drug. Also the inrasubject CV was also > 30%. According to me one should go for the replicate design (reference replicate)in pivotal study. Lets take other members opinion.

Kumar Naidu
Dr_Dan
★★  

Germany,
2014-03-18 12:30
(3662 d 22:23 ago)

@ Lucas
Posting: # 12648
Views: 16,219
 

 Approved Pilot and Failed Pivotal Study - same test?

Dear Lucas
It is hard to believe especially for Drug B that the only thing that changed from pilot to pivotal was the sample size since you have nearly the same intra-subject variability in the pivotal study as in the pilot study but the overlap of the 90% CI for AUC and Cmax is very small. You state that the sponsor could not submit the pilot studies to the regulator because not all the in vitro studies required were performed. I cannot follow this argumentation. Please correct me if I am wrong but I guess the pilot studies were performed with a lab scale batch of the test formulation whereas the pivotal studies were performed with one of the validation batches, right? Otherwise you would be able to provide the requested results of in vitro studies (o.k. the data would have been collected after the conduct of the BE study but they would still demonstrate the quality of the test formulation). Differences in production between the lab scale batch and the validation batches led to a slightly different formulation and consequently to different study results. I am looking forward to your reply.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Lucas
★    

Brazil,
2014-03-18 14:38
(3662 d 20:16 ago)

@ Dr_Dan
Posting: # 12656
Views: 16,214
 

 Approved Pilot and Failed Pivotal Study - same test?

Hello Dr Dan!

❝ It is hard to believe especially for Drug B that the only thing that changed from pilot to pivotal was the sample size...


I myself have the same doubts, but that's what they tell us, that the same batch was used in both studies. It's the same batch number.

❝ You state that the sponsor could not submit the pilot studies to the regulator because not all the in vitro studies required were performed. [...](o.k. the data would have been collected after the conduct of the BE study but they would still demonstrate the quality of the test formulation).


The in vitro studies must be conducted before the in vivo study as far as I know.

❝ Differences in production between the lab scale batch and the validation batches led to a slightly different formulation and consequently to different study results. I am looking forward to your reply.


It seems to me that they have done exactly that.

My position to the sponsor is to run the pilot having all the data necessary for submission, but due to internal procedures they can't always do that by motives not known by me.
Tina
★    

India,
2014-03-18 11:28
(3662 d 23:26 ago)

@ Lucas
Posting: # 12646
Views: 16,238
 

 Approved Pilot and Failed Pivotal Study

Dear Lucas,

Why cant the sponsor submit the pilot data for MAA and do the relevant invitro studies for MAA? I know Iam going off topic...that could be a solution.

Though regulators advise us for taking innovator from different batches, we know the pain of establishing BE if variability change for a different batch of the innovator. The regulators arent keen on suing the reference innovator until and unless it comes to light. May be you could share the entire data with the regulatory body and discuss on the BE and non-BE with different batch and have the regulators give a solution to it.

All the best.

Kind regards,
Tina
Ohlbe
★★★

France,
2014-03-18 12:15
(3662 d 22:38 ago)

@ Tina
Posting: # 12647
Views: 16,169
 

 Approved Pilot and Failed Pivotal Study

Dear Tina,

❝ Why cant the sponsor submit the pilot data for MAA and do the relevant invitro studies for MAA? I know I am going off topic... that could be a solution.


They could have done that before, rather than running new studies. Now it's too late: the new studies are there, and they fail, whatever the reason. Applicants have to submit all data available, whether passing or failing, and I don't see how they could defend submitting with a passing pilot but a failing pivotal, unless they find a very, very good explanation. Hiding the failing studies is no option.

Regards
Ohlbe
Helmut
★★★
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Homepage
Vienna, Austria,
2014-03-18 14:06
(3662 d 20:48 ago)

@ Tina
Posting: # 12653
Views: 16,257
 

 Approved Pilot and Failed Pivotal Study

Hi Tina,

are you suggesting to submit the smaller – passing – study and sweep the larger – failing – one below the carpet? Telling.

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Tina
★    

India,
2014-03-18 14:24
(3662 d 20:30 ago)

@ Helmut
Posting: # 12654
Views: 16,102
 

 Approved Pilot and Failed Pivotal Study

No no no I am not suggesting to submit pilot passed without the pivotal. I was saying that the company could submit the entire information to the regulatory body for the regualtors to advise.

❝ Though regulators advise us for taking innovator from different batches, we know the pain of establishing BE if variability change for a different batch of the innovator. The regulators arent keen on suing the reference innovator until and unless it comes to light. May be you could share the entire data with the regulatory body and discuss on the BE and non-BE with different batch and have the regulators give a solution to it.


I wouldnt have thought of a pivotal if the pilot study had passed. It would have been up to justifying in the clinical overview of the bioequivalence established with the pilot and the associated non-requirement of pivotal study with completion of all other required invitro-studies

Kind regards,
Tina
nobody
nothing

2014-03-18 14:31
(3662 d 20:23 ago)

@ Tina
Posting: # 12655
Views: 16,138
 

 Approved Pilot and Failed Pivotal Study

❝ ... I was saying that the company could submit the entire information to the regulatory body for the regualtors to advise.


If I was the poor guy at the agency to catch such a project I would reply: Do your homework and then come back with a good explanation. Something has gone REALLY wrong with your Test/Reference/Clinics...

Kindest regards, nobody
Lucas
★    

Brazil,
2014-03-18 15:03
(3662 d 19:51 ago)

@ nobody
Posting: # 12657
Views: 16,078
 

 Approved Pilot and Failed Pivotal Study

❝ If I was the poor guy at the agency to catch such a project I would reply: Do your homework and then come back with a good explanation.


Yes, I also think so. They did not expect that the pivotal study would fail at all, that's why they didn't at least tried to submit the pilot. Once the pivotal study was done and failed, there's nothing to do, IMHO.

But once again, my doubts about this matter is how we determine a product as bioequivalent (and so efficient and safe) but that depend on the batch? If I were to test the equivalence of all the batches, would it be equivalent? Or is the N of 28 subjects not enough to safely determine the equivalence?
nobody
nothing

2014-03-18 16:55
(3662 d 17:59 ago)

@ Lucas
Posting: # 12658
Views: 16,060
 

 Approved Pilot and Failed Pivotal Study

This is not about the methodology of BE-testing.

The Test product might have changed (scale-up), the clinics might have screwed up (so so many possible ways...).

You need a lot of detailed data (from in vitro to clinical records) to learn what went wrong in such a case.

Kindest regards, nobody
luvblooms
★★  

India,
2014-03-19 06:16
(3662 d 04:37 ago)

@ Lucas
Posting: # 12661
Views: 16,092
 

 Approved Pilot and Failed Pivotal Study

Dear Lucas

As per my experience, this is a clear case of Scale-up gone bad (assuming that the Pilot was sone on Lab batch and Pivotal was done on Exhibit batches)

First attempt should be to do some proper in vitro studies to find out the differences between both the batches and then to take a call.

For better understanding could you confirm
a) BCS class of drug (impact of PSD)
b) type of formulation (IR /ER)
c) pH solubility and degradation profile
d) Variations in DT/dissolution observed for both the batches?
e) Any changes in pilot and pivotal study sites?

Regards

~A happy Soul~
kumarnaidu
★    

Mumbai, India,
2015-12-08 08:02
(3033 d 02:52 ago)

@ luvblooms
Posting: # 15706
Views: 14,085
 

 Approved Pilot and Failed Pivotal Study

Dear all,

Recently I came across the situation where pilot study passed and pivotal study failed. The different batches of reference drug were used in both the study due to unavailability.

Pilot study (3 way reference replicate): N = 21
Cmax-99.8 (87.8 - 113.4) and AUC-99.9 (88.2 - 113.2)

Pivotal study (3 way reference replicate): N = 42
Cmax-83.3 (77.2 - 89.9) and AUC-85.2 (79.0 - 91.9)

Here I compared reference and test drug used in pilot and pivotal study

Reference
Cmax- Pivotal/Pilot = 127.2 (105.3 - 153.6)
AUC- Pivotal/Pilot = 112.5 (91.9 - 137.7)

Test
Cmax- Pivotal/Pilot = 107.2 (89.4 - 128.6)
AUC- Pivotal/Pilot = 96.7 (78.7 - 118.7)

From the above data can we say that the reference drug used in pivotal study shows more release as compared to the used in pilot study? And I think this can be the probable reason for failure of pivotal study.:confused:

Please give your suggestions.

Kumar Naidu
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