Bioequivalence and Bioavailability Forum

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). 
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).

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.

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• 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. Open Access.

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.