Helmut
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2023-07-19 11:04
(371 d 16:03 ago)

Posting: # 23676
Views: 8,583
 

 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
(369 d 12:09 ago)

@ Helmut
Posting: # 23678
Views: 7,808
 

 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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2023-07-21 16:24
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@ Ohlbe
Posting: # 23679
Views: 7,779
 

 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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2023-07-21 16:39
(369 d 10:29 ago)

@ Helmut
Posting: # 23680
Views: 7,721
 

 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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2023-07-21 16:41
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@ Ohlbe
Posting: # 23681
Views: 7,729
 

 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
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Russia,
2023-07-22 21:57
(368 d 05:10 ago)

@ Ohlbe
Posting: # 23682
Views: 7,690
 

 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
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France,
2023-07-22 22:47
(368 d 04:20 ago)

@ mittyri
Posting: # 23683
Views: 7,654
 

 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
(367 d 07:39 ago)

@ mittyri
Posting: # 23684
Views: 7,693
 

 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
qualityassurance
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2024-04-30 13:38
(85 d 13:30 ago)

@ wienui
Posting: # 23967
Views: 4,491
 

 Questions about data manipulation

Dear Forum members,

❝ Dr. Anders Fuglsang has developed several software programs to detect such manipulation.


Is it advisable that CRO use this software (after implementing the SOP within the system) and prove that no such manipulation was done during BE study. By this way both sponsors and CROs are relaxed and regulatory authority will also have readily available data from the software.
The idea behind above approach is, there is no other way of finding such manipulation (profile duplication) during routine QA review or monitoring by sponsor.

Regards,
QA
Helmut
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2024-04-30 13:46
(85 d 13:21 ago)

@ qualityassurance
Posting: # 23968
Views: 4,508
 

 Questions about data manipulation

Hi QA,

❝ Is it advisable that CRO use this software (after implementing the SOP within the system) …

Yes, but…

❝ … and prove that no such manipulation was done during BE study.

Unfortunately you cannot prove that in the statistical sense (null hypothesis = no manipulation, alternative hypothesis = manipulation). The assessment contains still a subjective element. Sorry.

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qualityassurance
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2024-04-30 15:55
(85 d 11:12 ago)

@ Helmut
Posting: # 23969
Views: 4,447
 

 Questions about data manipulation

Hello Helmut,

Thank you for your input.

In this case there is always Sword of Damocles hanging over the sponsor head for their dossier because it can be affected by manipulation in another sponsor's BE study.
Of course there are system in place for CRO qualification, checking CRO accreditation (especially EU/USFDA) etc. and also monitoring done by sponsor to assure GCP/GLP and data integrity compliance in the BE study. But in nut shell it is not possible to identify profile duplication with such checkpoints and procedure.
There should be availability of some robust system (may be regulators should come forward) which prevents the risk of sponsor (often pharma companies) and common man (using the approved medicines) and at the same time CROs not involved in such practices would be benefited.

Regards,
QA
Helmut
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2024-04-30 16:52
(85 d 10:16 ago)

@ qualityassurance
Posting: # 23970
Views: 4,444
 

 Questions about data manipulation

Hi QA,

❝ In this case there is always Sword of Damocles hanging over the sponsor head for their dossier because it can be affected by manipulation in another sponsor's BE study.

Correct. This was the case in the Synapse story. AFAIK, some companies tried to support their arguments by software. None was accepted and they remained on the hook. Only one sponsor succeeded to get off the list. No idea how they did it. There were also cases where the reference is no more on the market and therefore, it’s no possible to repeat a study. Bad luck.

❝ […] But in nut shell it is not possible to identify profile duplication with such checkpoints and procedure.

Correct. The only possibility I can think of is that the sponsor hires a team (‼) of monitors which is 24/7 at the site. Yep, get camp beds and sleeping bags. Be present at all phases of the study (clinical, analytical, data transfer, statistics). :-D
Don’t think that this was ever done.

❝ There should be availability of some robust system (may be regulators should come forward) which prevents the risk of sponsor (often pharma companies) and common man (using the approved medicines) and at the same time CROs not involved in such practices would be benefited.

You’re an optimist. Regulators will never share such information (i.e., tell who are the bad and good guys).

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Ohlbe
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France,
2024-06-05 14:45
(49 d 12:22 ago)

@ Helmut
Posting: # 24022
Views: 1,996
 

 Assessment report published

Dear Helmut,

❝ Only one sponsor succeeded to get off the list. No idea how they did it.


The assessment report has now been published. Mystery solved. The MAH had submitted the same response as other MAH for the same product: Synapse only did a fed study, a fasting study was done elsewhere and is sufficient according to EMA's product-specific guideline. Due to a "technical issue" this response had not been considered during the initial assessment.

Regards
Ohlbe
Ohlbe
★★★

France,
2024-04-30 20:25
(85 d 06:43 ago)

@ qualityassurance
Posting: # 23971
Views: 4,446
 

 Questions about data manipulation

Dear QA,

❝ Is it advisable that CRO use this software (after implementing the SOP within the system)...


Anders will be delighted to do that for them :-)

❝ and prove that no such manipulation was done during BE study.


Well, what you will "prove" is that either:
  1. there was no manipulation, or
  2. the CRO was smart enough to do it in a way that will fool the software, or
  3. they manipulated the study in a totally different manner, which the software cannot detect...
My concern is that by using the software, bad CROs will just learn how not to get caught. You will not uproot cheating, only change the way cheaters operate.

❝ By this way both sponsors and CROs are relaxed and regulatory authority will also have readily available data from the software.


Yes, until someone comes with evidence of 2 or 3.

❝ The idea behind above approach is, there is no other way of finding such manipulation (profile duplication) during routine QA review or monitoring by sponsor.


Agree (especially if, as suggested in some older cases, the sponsor was perfectly aware of what was going on, and even selected the CRO for that exact reason). By the way, remember that profile duplication and trends in the PK data are two sides of the same coin.

Regards
Ohlbe
ElMaestro
★★★

Denmark,
2024-05-01 09:10
(84 d 17:58 ago)

@ Ohlbe
Posting: # 23972
Views: 4,387
 

 Questions about data manipulation

Hi all,

lots of good info here but also a few details that deserve commenting, in my opinion.

There have now been several cases where an authority directly requested -in a DCP- the outcome of Buster and SaToWIB (or similar software) along with its assessment. In the cases I know of and was involved in, the dossier sailed through to approval after a subjective assessment was sent along with B&S analyses.

❝ Well, what you will "prove" is that either:

❝    1. there was no manipulation, or

❝    2. the CRO was smart enough to do it in a way that will fool the software, or

❝    3. they manipulated the study in a totally different manner, which the software cannot detect...

❝ My concern is that by using the software, bad CROs will just learn how not to get caught. You will not uproot cheating, only change the way cheaters operate.


Well, look what happens if we do nothing. We've had hundreds upon hundreds of retracted MAs from various CROs. Can someone tell me how that is a preferable scenario to one where we use software routinely?
If we look at some of the concern through the years in the area of BE, then some of ships on the regulatory waters were somehow set afloat on basis of somewhat hypothetical fear. It starts with "what if…?" and then the ball starts rolling. Dose dumping comes to mind. It found its way into guidance even though noone actually had good proof for it.
The Tmax worry for select APIs… "What if…?"…And then we suddenly had Tmax requirements without clinical proof. All that existed was indicator of Tmax differing between formulations but not an absence of efficacy/safety similarity. And then we got guidance that was – as Helmut Schütz showed very elegantly – solving a hypothetical problem in such a way that it was all but impractical for an applicant to plan and dimension a study.
So, now the "what if…?" for the use of software. Are we hypothetically worried or are we concretely worried? Show me the concrete worry and I will deal with it. Possibly with software :-)

The next (or a new) frontier is when CROs are taking an aliquot of, say, x mL S13P2 and y mL S25P1 and mixing them. Then extracting and injecting. You will get a new profile that does not resemble any other profile much and you can completely steer the T/R in the direction you want. Software can detect it, though. In a study with 36 subjects Subj 31, 32, 33, 34, 35, 36 came out at the top of the sorted list, that is, they were apparently constructed from profile combinations of subjects 1–30 without T and R switched.

If we want the trouble to continue, then out of hypothetical fear we can just decide to do nothing and we will be blessed with a continuation of the current mess.

If the software is not so appropriate then why are regulators using it? How is that "something else" in reality? The regulatory use of Dabers is no issue, but applicant's or CRO' use of SaToWIB & Buster & & Effiou is?

If the subjective aspect is the issue then why don't we collaborate towards finding a way to make it all less subjective and more objective? Wouldn't that be a solution?


My own experience from being a regulator: Solution based on actual problem and facts are good solutions. Solutions that are founded solely in fear, "what if…?" and hypothetical scenarios tend to be not so good solutions.

Finally, FDA's new data integrity guidance calls for a proactive approach without being specific. Someone, please tell me how the use of software that has the potential to detect bioinequivalent products prior to submission is not a proactive approach. I am dying to hear it. :-)

Pass or fail!
ElMaestro
Helmut
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2024-05-01 22:42
(84 d 04:26 ago)

@ ElMaestro
Posting: # 23973
Views: 4,227
 

 OT

Hi ElMaestro,

❝ […] And then we got guidance that was […] solving a hypothetical problem in such a way that it was all but impractical for an applicant to plan and dimension a study.


Reminds me on Individual / Population Bioequivalence, which was regarded* a

‘theoretical’ solution to a ‘thoretical’ problem.


BTW, at the GBHI-2024 in April I tried to squeeze information from the FDA’s participants about DABERS (Data Anomalies in Bio­Equi­va­lence R Shiny). Nada.
Edit: Same at the SAAMnow Spring Work­shop on Data Inte­grity in BE Stu­dies in June.


  • Patterson S. A Review of the Development of Biostatistical Design and Analysis Techniques for Assessing In Vivo Bio­equi­va­lence: Part Two. Ind J Pharm Sci. 2001; 63(3): 169–86. [image] Open Access.

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Ohlbe
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France,
2024-05-01 22:58
(84 d 04:10 ago)

@ ElMaestro
Posting: # 23974
Views: 4,234
 

 Questions about data manipulation

Hi ElMaestro,

Please don't misunderstand me. I'm not in any way saying that sponsors, applicants or CROs should not use tools such as Busters, SaToWIB, Effiou or whichever. I'm not trying to discourage anybody willing to do such analyses. They're useful tools in the toolbox.

But they're just one tool in the toolbox, and should not be used to replace the others. Because the fact that there is no signal in your study, does not mean that the CRO did not manipulate other studies, and that you will not get in trouble in the next Art. 31 referral. And reading anything which sounds like "we can be sure of" or "we can prove that" makes me a bit nervous.

So if the Man in the Armani suit thinks that data analyses will spare the expenses of doing proper CRO selection audits and proper monitoring (for the sponsor - and btw, if bioanalysis represents half the study, how comes it does not get half the QC/QA efforts ?) or proper due diligence (if buying a dossier), then he's wrong. And for as long as he, himself, will continue to think "oh our last study at that CRO failed, they're not good, let's go somewhere else for the next", he will send out the wrong signal and will actually encourage them to cheat, to keep their customers happy and retain them.

Regulators in Europe and US are sending CROs (and sponsors who may select a CRO because they know they will do whatever it takes to make their study pass) a harsh message, which they hope is deterrent: if you manipulate data, it may take years for us to detect it, but whenever we get enough evidence that's the end of your company. Unfortunately that's not enough: OK the company shuts down, but what about its owners/managers ? Well, they will just set up another business, in a different field, and live happily ever after. When GVK Bio got burnt, they were heavily defended by the Indian authorities, who created a diplomatic incident with the EU. Indian authorities then kept silent for Synchron, Panexcell and Synapse (can't remember about Semler), but if they have taken any action to help clean the mess and sweep their own backyard, and prosecute the managers who ordered or endorsed the manipulations, they have kept extremely silent about it. If any forum member has any information on this, please post it.

Years ago, after the GVK Bio case, the EMA and the EGA (now Medicines for Europe) organised a workshop where they discussed how to avoid this to ever happen again. One of the suggestions from regulators was to improve communication between sponsors or applicants, and between them and authorities. It is in everybody's best interest to identify black sheep as early as possible and stop them before it's too late and hundreds of marketing authorisations have to be suspended. If your audit shows that CRO A is f*cking up, or going back to this discussion, if you find manipulated data at CRO A with whatever tool you're using, spread the word. OK, the other guys are your competitors - but if public confidence in generics drops because of these cases, or if you can't find a slot at your preferred CRO because they're too busy repeating studies for others, then you will be suffering too. And if authorities never get to hear of what you found and where, then it may take another 2, 3 or 5 years before they identify it themselves, and even more products will be affected - and patients, at the end of the day.

Unfortunately, lawyers blocked the idea: oh no we can't do that, the CRO might prosecute us. Man, come on, make my day, you manipulated my study, try and take me to court, I'll be more than happy to discuss the case there ! Things would be so much easier if lawyers didn't have to get involved.

Regards
Ohlbe
Helmut
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2024-03-22 21:29
(124 d 04:39 ago)

@ Ohlbe
Posting: # 23917
Views: 5,304
 

 Update

Dear Ohlbe and all,

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

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Helmut
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2024-06-09 11:16
(45 d 15:51 ago)

@ Helmut
Posting: # 24026
Views: 1,779
 

 Health Canada recalls

Dear all,

on 7 June Health Canada recalled Accel-Ondansetron ODT, Mint-Betahistine and PMS-Pirfenidone tablets due to data integrity concerns.

Health Canada’s authorization of the affected products relied on the bioequivalence test data. Bioequivalence data is used to demonstrate that generic drugs are equivalent to their brand-name counterparts.
The bioequivalence tests were conducted by Synapse Labs Pvt. Ltd., a contract research organization in Pune, Maharashtra, India. An inspection by a member of the
European Medicines Agency, a trusted regulatory partner, found that data produced by Sy­na­p­se Labs can no longer be relied upon to show this bioequivalence. As a result, the affected products can no longer be considered safe and effective. At Health Canada's request, the companies have stopped sale and have recalled all lots of the affected products until they can provide additional information to demonstrate that the products are safe and effective.


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Helmut
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2024-06-19 13:22
(35 d 13:46 ago)

@ Helmut
Posting: # 24031
Views: 1,217
 

 And the FDA…

Dear Ohlbe and all,

Notification to Pharmaceutical Companies: Clinical and Bioanalytical Studies Conducted by Synapse Labs Pvt. Ltd. are Un­ac­cept­able (June 18, 2024)

FDA is notifying sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) that clinical and bioanalytical studies conducted by Synapse Labs Pvt. Ltd. (Synapse)—a contract research organization (CRO) based in Pune, India—are not acceptable because of data integrity concerns. Studies conducted by Synapse must be repeated.
(my emphasis)

More details. Overlapping profiles, small differences in individual concentrations, etc. One study was performed in four groups and the FDA assessed a group-by-treatment interaction followed by Bayesian Shrinkage.

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Ajay Gupta
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India,
2023-07-24 06:19
(366 d 20:49 ago)

@ Helmut
Posting: # 23685
Views: 7,519
 

 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]

wrt ur… The forum is not SMS, WhatsApp, Telegram, Signal, Threema. Please take your time and use words.
See also there[Helmut]
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