Helmut
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Vienna, Austria,
2023-07-19 11:04
(268 d 04:32 ago)

Posting: # 23676
Views: 3,221
 

 Another one? [GxP / QC / QA]

Dear all,

see the CHMP’s Draft agenda for the meeting on 17–20 July 2023.

10.6.1. Synapse Labs Pvt. Ltd. – various – EMEA/H/A-31/1529

Article 31 procedure triggered by the Agency of Medicines and Medical Devices (AEMPS) in Spain, concerning the contract research organisation (CRO) Synapse Labs Pvt. Ltd., located in Kharadi, Pune, India


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Ohlbe
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France,
2023-07-21 14:59
(266 d 00:37 ago)

@ Helmut
Posting: # 23678
Views: 2,858
 

 Confirmed

Dear all,

Yes indeed, the referral is now confirmed.

The list of medicines concerned is massive.

According to the referral notification there were, again, duplicated subjects in over 20 different studies.

Regards
Ohlbe
Helmut
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Vienna, Austria,
2023-07-21 16:24
(265 d 23:12 ago)

@ Ohlbe
Posting: # 23679
Views: 2,830
 

 Who cares?

Dear Ohlbe,

THX for posting.

It seems that our members are not overly interested in these issues. Telling that only 2% of posts are in the category GxP / QC / QA.

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Ohlbe
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France,
2023-07-21 16:39
(265 d 22:57 ago)

@ Helmut
Posting: # 23680
Views: 2,797
 

 Who cares?

Dear Helmut,

❝ It seems that our members are not overly interested in these issues.


Too busy watching Virat's 29th test century, maybe ?

Regards
Ohlbe
Helmut
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Vienna, Austria,
2023-07-21 16:41
(265 d 22:55 ago)

@ Ohlbe
Posting: # 23681
Views: 2,800
 

 Expert

Dear Ohlbe,

❝ Too busy watching Virat's 29th test century, maybe?


I see that you a true expert in really important matters.:-D

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mittyri
★★  

Russia,
2023-07-22 21:57
(264 d 17:39 ago)

@ Ohlbe
Posting: # 23682
Views: 2,740
 

 Questions about data manipulation

Dear Ohlbe, Dear Helmut,

❝ According to the referral notification there were, again, duplicated subjects in over 20 different studies.


Could you please elaborate how is it possible?
What is the method CRO used for duplication? just copy all concentration points to another subject? what about chromatograms? Did they fake date/time of that?

Why experts didn't find it before? Are the methods of data manipulation recognition just implemented?

Kind regards,
Mittyri
Ohlbe
★★★

France,
2023-07-22 22:47
(264 d 16:49 ago)

@ mittyri
Posting: # 23683
Views: 2,726
 

 Data manipulation

Dear Mittyri,

❝ Could you please elaborate how is it possible?

❝ What is the method CRO used for duplication? just copy all concentration points to another subject? what about chromatograms? Did they fake date/time of that?


No. Simply re-analyse samples of subjects already analysed, under a different subject number. Your T/R is too high ? You want to bring it lower ? Select one previous subject with known expected concentrations, or periods from different subjects (let's say 10 and 14), write everywhere these were the samples of subject 45, and you're done. The first description I have seen of this was made in an inspection report, which somebody obtained under a freedom of information regulation and posted on internet. See document A3 - ANSM Preliminary Report. See also FDA's letter to Semler Research, a few years later.

❝ Why experts didn't find it before? Are the methods of data manipulation recognition just implemented?


Well, that French report from 10 years ago already described the general principle. A well-known usual suspect made a detailed publication describing tools and methods.

The problem is not just detecting data manipulation. The problem is collecting enough evidence. If you find signs of data manipulation in one study, you can reject that study. Triggering an article 31 referral to reject all studies from a given CRO probably requires a solid level of evidence. Not just to convince the CHMP: to convince lawyers.

Regards
Ohlbe
wienui
★    

Germany/Oman,
2023-07-23 19:29
(263 d 20:07 ago)

@ mittyri
Posting: # 23684
Views: 2,726
 

 Questions about data manipulation

Dear all,

I presented this topic at the GCC summit, which took place in Dubai in March of this year. Here is a summary:

The manipulation of a failing study involves performing an undocumented interim statistical analysis after unblinding the results, typically after half of the subjects have been analyzed. For example, if we have N=36 subjects, an interim analysis can be conducted after the analytical results of the first 18 subjects are known. If the point estimate (PE) or confidence interval (CI) after the first half of subjects is particularly low or high (e.g., GMR ~ 75%) and suggests that the bioequivalence (BE) study is failing, we identify those subjects that are causing the PE or CI to be skewed (high) and switch them.

As Ohlbe explained, the initially analyzed samples that do not fit will either be re-analyzed or diluted by a factor of 2. By doing this, the BE study will pass even if the product formulation is not bioequivalent, as there is a counterpart Y elsewhere in the data set with a T/R that eliminates or mitigates the issue with subject X.

Finding evidence of such manipulation is not easy because the paperwork, audit trials in the chromatographic system, audit trials in the statistical system, and plasma accountability are all clean. We can say that this switching process is an operation that leaves no classical trace, so it cannot be seen through audits or inspections. In other words, we don't have any evidence, only suspicions. Some of these suspicions include: 1) The manipulation revealing itself as trends (Cmax fingerprint), and 2) The manipulation revealing itself as profile similarities.

Dr. Anders Fuglsang has developed several software programs to detect such manipulation, including the Buster routines software, which detects the switch issue (trend manipulation), and the SaToWIB routines software, which detects profile similarities and issues with dilutions. For more details, you can refer to a published article by Dr. Fuglsang.

https://www.sciencedirect.com/science/article/abs/pii/S0928098720303833

Cheers,
Osama
Helmut
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Vienna, Austria,
2024-03-22 21:29
(20 d 17:07 ago)

@ Ohlbe
Posting: # 23917
Views: 325
 

 Update

Dear Ohlbe and all,

today’s update. No changes from the December 2023 statement except one; updated list.

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Ajay Gupta
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India,
2023-07-24 06:19
(263 d 09:18 ago)

@ Helmut
Posting: # 23685
Views: 2,591
 

 Another one?

Dear Sir,
This is wrt synapse CRO issue Article 31 is triggered by AEMPS, procedure being already started, impacting authorised MAA and ongoing procedures using Synapse BE study. We would like to know ur expert opinion on the MHRA authorisations in case of the negative outcome of this procedure (revocations/ suspensions of MAA), or how it was handled by MHRA in similar case of Synchron BE studies and EU suspended all the related product! May I request your kind advice wrt impact on UK licenses in this scenario ! Thank you!

Regards,
Ajay Gupta


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! [Ohlbe]
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