Bioequivalence and Bioavailability Forum

Hi all,

It looks like I've opened a can-o'worm discussion here...

❝ I think it is an area where inspectors can do very little and where the need for doing something is pronounced (ElMaestro)

Yep. The thing is, who should do something about it, and what ? There are things that should be done not because inspectors ask for them, but because national regulations ask for them. But when national regulations don't even consider BE trials to be clinical trials, you are a long way behind.

❝ BTW, I like ANVISA’s system. The database is run by the agency and volunteers are blocked from participation in another study for six months. No fret, no pain (Helmut)

They're not the only country with a national system. That's also the case in Jordan, Tunisia... and France. OK, we don't have that many phase I units left in the country...

Our database is managed by the Ministry of Health. It includes the family name, first name, date and place of birth, gender, start and stop date of participation in the trial, end of the exclusion period (defined trial-wise in the protocol approved by the IEC), amount of money paid to the subject (there is a maximum of 4500 € per 12-month period, which has not been modified since 2006 !).

The thing is, that this requires the subject to have a reliable proof of his ID. No problem in France, where everybody carries a picture ID card. That's not the case in every country, and everybody can come with a school leaving certificate pretending that's his - and of course, with a different school leaving certificate for each trial and at each CRO. Hence the need for a fingerprint system.

❝ Question: Where should such a system be located? At the EMA? (Helmut)

Or at the Commission ? Ideally the EU would have a single database, in order to prevent cross-participation in various countries. But it would be more likely to be considered a matter of national competence, with national databases.

❝ Let us say you are a CRO and you are screening and enrolling subjects. Where would you record whether ID00012345 (CRO ID, not official ID) is blocked? A checkbox on a CRF? A screenshot from Ovis etc documenting time and block/no-block? Great eh? (ElMaestro)

Doable when you query the database with information such as names or initials. Impossible when what you submit is a fingerprint (you would not get the fingerprint on the screenshot).

❝ Can you somehow enter a discussion of false positive and false negative finger print matches? No, you can't. I have had my fair share of false ID's with CRO finger print scanners when we use a 'naïve' finger, i.e. a finger which the reader has never seen (ElMaestro)

In this setting I'm more concerned about false negatives (non-naive fingers not being recognised). And there we move to a different field: computerised system validation. Who should do it (vendor, CRO, both) ? How could inspectors access the documentation ? Would inspectors be willing to review it anyway, considering the limited amount of time they have during their inspections and the huge amount of other things that can go wrong and that they need to look into ?

❝ So, in the study you are looking at 2 of every 5 having lower than normal HB and HTC, 3 of 5 have at least one of them low, all of them are cleared by the PI as NCS, and you only have a checkbox stationg the database check has been done, or you have a screenshot. Both the screenshot option and the checkbox-on-CRF option provide wide open opportunities for tampering. So you still sit there with an inkling.... could 00012345 have been cross-participating? (ElMaestro)

Yep. My point precisely, and one of the reasons why I would not widen the limits for Hb.

❝ We should also bear in mind that dietary habits and life style can play a role for HB (ElMaestro)

With cross-participation being part of the life style...

❝ Without pointing fingers anywhere, I'd say you'll be really lucky to have just 1 out of 50 with that hemoglobin level in certain regions from which many, many EU-approved BE dossiers originate (ElMaestro)

Sure. But what is the usual Hb level in these regions amongst people who do not cross-participate and who respect a 90-day exclusion period ?

❝ I was in Ahmedabad in July 2019, right after a volunteer had lost his life after being sent home from a BE trial. [...] I had brief dialogue with EU regulators about it - the consensus was that in the absence of proof that the death related to a dossier submitted in EU, no EU regulators could take any action (ElMaestro]

I think the idea here is that India is not a colony of the EU and that this would be for the Indian authorities to investigate, not EU inspectors.

Of course, this unfortunate serious adverse event should be reported as such in the study report (not as "did not report for period 2" or "withdrew consent for his own personal reason").