cakhatri
★    

India,
2019-12-17 11:35
(316 d 18:10 ago)

Posting: # 20980
Views: 4,790
 

 Normal Reference Range Vs Pre-defined site normal values [Design Issues]

Dear All,

Below is the response from WHO for a protocol review for a BA/BE study on healthy volunteers and for submission to WHO. Request the members to clarify what WHO means for "Laboratory Reference Ranges or Interval"and "Pre-defined site normal values" or "Site normal range"

The list of laboratory reference ranges or intervals are included in Appendix 5. Please note that as this study is conducted in healthy volunteers, subjects should be recruited into the study only if their health is fully verified, including verification that serum biochemistry and haematology parameter values are within pre-defined normal ranges. The enrolment of a subject with measured values for the health verification parameters that fall outside the pre-defined site normal values should not occur, except on a rare, exceptional basis. On the rare occasion when a subject is enrolled in a study despite having a measurement outside the site normal range, the study physician should have a clearly documented and medically rigorous justification for making that exception. Good Clinical Practices (GCP) require that the rights, safety, and well-being of trial subjects be given top priority in every trial conducted.

My understanding on this is

The site can have a set of values pre-defined based on the reference ranges set by the clinical laboratory. These pre-defined values will be set by the Physician at his/her own discretion along with medical examination & medical history and can consider for enrollment of the volunteer into the study

To cite an example
A. Laboratory Reference range for Haemoglobin - 13-18 g/dL
B. Pre-defined Site Normal range for Haemoglobin - > 12.5 g/dL

B has been set by the physician at his/her own discretion

Can "B" value be used for enrollment of a volunteer into the study

Regards / Chirag


Edit: Category changed; see also this post #1[Helmut]
ElMaestro
★★★

Belgium?,
2019-12-17 23:21
(316 d 06:24 ago)

(edited by ElMaestro on 2019-12-17 23:41)
@ cakhatri
Posting: # 20988
Views: 3,998
 

 Normal Reference Range Vs Pre-defined site normal values

Hi all,

» rare, exceptional basis.

I have been involved in such discussions with WHO. A lot.
I pointed out to them that the reference range (which I would not myself define in a different manner than a normal range, but we can discuss that separately) usually involves 5% being outside even if normal. And an event which occurs with 5% frequency is not rare or exceptional, but "common", I think, when we talk the SPC definitions used for e.g. adverse events. So, there is some degree of word clutter here.

» To cite an example
» A. Laboratory Reference range for Haemoglobin - 13-18 g/dL
» B. Pr-defined Site Normal range for Haemoglobin - > 12.5 g/dL

It is not uncommon that labs have a reference range or a normal range or whatever you want to call it, and that the PI can decide to enroll someone who is outside if she/he is deemed healthy (if the protoco needs hevo's, etc). This is all at the PI's discretion or his/her delegate. However, if the phenomenon occurs frequently (let us say more than 5%, and no I am not goiing to comment on statistical testing for exactly that), then you are right in the middle of the trouble because thewn you are truly recruiting from a subject pool which does not reflect what's normal or what's reference and this is what the essence of WHO's publication is about, as far as I know.

As a results of WHO's publication some years ago some lab redefined their ref. range for hemoglobin, to get around the issue. Which is exactly what they were not supposed to do.
So even if WHO's choice of words was not optimal, the way it has been handled at CRO's is not ideal either.

Bottom line:
  1. The PI can deem a subject outside the ref. range enrollable.
  2. But if the PI does so too often, then it spells trouble.
  3. Recruit from a population which is truly reflecting what has been submitted to IEC/IRB and NCA, not a pool of subjects with lower hemoglobin or whatever range.
  4. Do not speculate too heavily into stats testing or multiplicity or correlation (there are usually 20-40 reference ranges in play in BE studies; there is always someone who has something which is outside; if HB is out then it is likely that e.g. Hematocrit is too).

Are you confused?
So am I.

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
Ohlbe
★★★

France,
2019-12-29 17:04
(304 d 12:42 ago)

@ cakhatri
Posting: # 21033
Views: 3,862
 

 Hb level

Dear Chirag,

Some thoughts, in addition to what ElMaestro already wrote.

» The list of laboratory reference ranges or intervals are included in Appendix 5. Please note that as this study is conducted in healthy volunteers, subjects should be recruited into the study only if their health is fully verified, including verification that serum biochemistry and haematology parameter values are within pre-defined normal ranges. The enrolment of a subject with measured values for the health verification parameters that fall outside the pre-defined site normal values should not occur, except on a rare, exceptional basis. On the rare occasion when a subject is enrolled in a study despite having a measurement outside the site normal range, the study physician should have a clearly documented and medically rigorous justification for making that exception.

I do not know whether the use of different terms by the WHO is intentional or not, but it certainly adds to the confusion.

» Good Clinical Practices (GCP) require that the rights, safety, and well-being of trial subjects be given top priority in every trial conducted.

Absolutely. And that's why I'm not too comfortable with this:

» To cite an example
» A. Laboratory Reference range for Haemoglobin - 13-18 g/dL
» B. Pr-defined Site Normal range for Haemoglobin - > 12.5 g/dL
»
» B has been set by the physician at his/her own discretion
»
» Can "B" value be used for enrolment of a volunteer into the study

It is fairly common for healthy volunteers in India to have a Hb level below 13 g/dl (I'd even say that based on ElMaestro's definition of "5% of normal folks are outside of the normal range", the normal range used by many labs in India does not seem to have been adapted to the population they usually serve). You can live a perfectly normal life with a Hb level between 12.5 and 13 g/dl. Where I become somewhat uneasy is that you are going to collect a few hundred ml of blood from these subjects. And that ethically and in the subject's best interest, you should avoid doing this from subjects who already have a borderline low Hb level. In France, you can only do a blood donation if your Hb level is at least 14 g/dl. I don't know whether there is an official limit in India.

Another aspect, again specifically for Hb: this can also be an indication of over-participation in BE trials / CRO shopping. I do not trust 100% the databases (OVIS and the like) which have been put in place against this.

This being said, and while mentioning Hb and collecting a large amount of blood from the subjects: many bioanalytical labs still use 500 µl of plasma when developing their methods, just like in the old days of HPLC/UV and though their LLOQ is now 3 logs lower thanks to LC/MS-MS. Using just 50 µl of plasma would be enough in most cases, which would allow to significantly reduce the blood volume collected (e.g. 2 ml per sample instead of 5), while keeping the possibility to re-analyse the samples multiple times if needed.

Regards
Ohlbe
Helmut
★★★
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Vienna, Austria,
2019-12-29 18:49
(304 d 10:57 ago)

@ Ohlbe
Posting: # 21034
Views: 3,851
 

 OT

Dear Ohlbe,

» I do not trust 100% the databases (OVIS and the like)…

SCNR.

[image]
Randall Munroe [CC BY-NC 2.5]

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Helmut Schütz
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nobody
nothing

2019-12-31 10:47
(302 d 18:59 ago)

@ Ohlbe
Posting: # 21039
Views: 3,816
 

 Hb level

» Another aspect, again specifically for Hb: this can also be an indication of over-participation in BE trials / CRO shopping. I do not trust 100% the databases (OVIS and the like) which have been put in place against this.

Absolutely justified, this does not work sometimes even in-house for a CRO ***cough***

Kindest regards, nobody
ElMaestro
★★★

Belgium?,
2019-12-31 15:19
(302 d 14:27 ago)

@ Ohlbe
Posting: # 21040
Views: 3,796
 

 Hb level

Hi Ohlbe,

» It is fairly common for healthy volunteers in India to have a Hb level below 13 g/dl (I'd even say that based on ElMaestro's definition of "5% of normal folks are outside of the normal range", the normal range used by many labs in India does not seem to have been adapted to the population they usually serve). You can live a perfectly normal life with a Hb level between 12.5 and 13 g/dl. Where I become somewhat uneasy is that you are going to collect a few hundred ml of blood from these subjects. And that ethically and in the subject's best interest, you should avoid doing this from subjects who already have a borderline low Hb level. In France, you can only do a blood donation if your Hb level is at least 14 g/dl. I don't know whether there is an official limit in India.

:-D
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.
We should also bear in mind that dietary habits and life style can play a role for HB. But there are very few answers on it.

» Another aspect, again specifically for Hb: this can also be an indication of over-participation in BE trials / CRO shopping. I do not trust 100% the databases (OVIS and the like) which have been put in place against this.

Zeba Ziddiqui from Reuters touched upon this topic in a little piece from 2016.

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
nobody
nothing

2019-12-31 15:46
(302 d 14:00 ago)

@ ElMaestro
Posting: # 21041
Views: 3,815
 

 Hb level

» Zeba Ziddiqui from Reuters touched upon this topic in a little piece from 2016.

...but you find this literally everywhere, not limited to a certain region...

Kindest regards, nobody
ElMaestro
★★★

Belgium?,
2019-12-31 17:21
(302 d 12:24 ago)

@ nobody
Posting: # 21042
Views: 3,787
 

 Hb level

Hi nobody,

» ...but you find this literally everywhere, not limited to a certain region...

I believe you. Truly I do.
Unfortunately money and ethics do not mix well. I think money is winning.....





































....by a very, very large margin, unfortunately.

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
nobody
nothing

2019-12-31 17:26
(302 d 12:19 ago)

@ ElMaestro
Posting: # 21043
Views: 3,797
 

 Hb level

I will start a year of meditation on "How to stop global idiotocracy" tonight...

Kindest regards, nobody
Helmut
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Vienna, Austria,
2019-12-31 18:01
(302 d 11:44 ago)

@ ElMaestro
Posting: # 21044
Views: 3,794
 

 Participation databases

Hi ElMaestro,

» Unfortunately money and ethics do not mix well. I think money is winning.....

Not only that. The volunteer-database of my CRO was linked (56k modem!) to “Cross-check” at the University Freiburg. Data shared: surname, given name, date & place of birth, nationality ([image] ISO 3166-1 alpha-2), sex, and date of last participation. Most German CROs used this database (we were the only one in Austria).
Was shut down in August 1997 since not compliant with the German data protection law… Yep, personal data, unencrypted transfer. Great.
Nowadays I would concatenate the information into one field (likely the initials instead of the full name are sufficient) and transfer only a [image] SHA-3. Everyone should be happy. Question: Where should such a system be located? At the EMA?

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.

Dif-tor heh smusma 🖖
Helmut Schütz
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ElMaestro
★★★

Belgium?,
2019-12-31 20:21
(302 d 09:25 ago)

@ Helmut
Posting: # 21045
Views: 3,778
 

 Participation databases

Hi Hötzi, and all,

» Everyone should be happy. Question: Where should such a system be located? At the EMA?

This would be an interesting discussion. A legal discussion, probably?


» 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.

This is much like Ovis and its siblings. A central database from which you get a single piece of info back and the submission is a fingerprint: Blocked or not (=can participate or not). It gives no personal info, no photo, no government ID, no birth date etc. It simply says yes or no given a "unique" identifier (such as the fingerprint), full stop.
In India, from the top of my head the general quarantine is 90days but the CRO can specify it to be longer.

However....

What do you do with the info? How do you record it?

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?

Then switch hats and assume you are the inspector or auditor.
  1. Can you ask the database if the CRO queried the guy having a fingerprint matching that of ID00012345? No, you can't.
  2. Can you ask the database if the CRO had any contact to it on the day of screening? No, you can't (=you actually do not know if the databse was online that day. Or if the CRO was, power outages and all. Now don't give me the usual spiel about UPS and stuff :-)).
  3. Can you audit the provider of OVIS, CTVS to check records at their end etc? No, you can't.
  4. 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.
  5. Can you somehow get hold of the subject and ask if she/he remembers anything about a fingerprint? As an inspector, possibly, but you may be in Ahmedabad and the volunteer in Bangalore. Phone home and tell your boss you will need two extra weeks and a budget for an interpreter. Good luck with that.
  6. Can you get actual info on 00012345's participation at other CROs? No, absolutely zero chance.

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?


§2.10: "All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification."

§2.13: "Systems with procedures that assure the quality of every aspect of the trial should be implemented."

Go figure....

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2020-01-01 10:23
(301 d 19:23 ago)

@ ElMaestro
Posting: # 21046
Views: 3,732
 

 Participation databases

Hi ElMaestro,

» » Where should such a system be located? At the EMA?
»
» This would be an interesting discussion. A legal discussion, probably?

Given the European GDPR of 2016 for sure.

» » 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.
»
» This is much like Ovis and its siblings.

THX for your summary. I was much too naïve. What a nightmare for inspectors!

Dif-tor heh smusma 🖖
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
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ElMaestro
★★★

Belgium?,
2020-01-01 12:23
(301 d 17:23 ago)

@ Helmut
Posting: # 21047
Views: 3,730
 

 Participation databases

Hi Hötzi,

happy new year.

» THX for your summary. I was much too naïve. What a nightmare for inspectors!

Actually I don't think anything is naïve.
I think it is an area where inspectors can do very little and where the need for doing something is pronounced.

So I welcome any and all discussion and I'd be very happy to hear suggestions how to fix things so that it is possible to safeguard against cross-participation. I believe at the moment there is next to no prospects for doing anything with the system (like national data protection laws), and software providers who program and maintain the databases are not too keen on entering a discussion of the functionality at their end. Can something be done then?

I have been thinking a lot about it, but as you know my walnut-sized brain is much better at creating trouble than solving it, so I have only drawn a blank. I believe many regulators would appreciate dialogue and suggestions too. I think some of them are a bit frustrated about the limited options.

I was in Ahmedabad in July 2019, right after a volunteer had lost his life after being sent home from a BE trial. During lunches, dinners, breakfasts, breaks, in the hotel lobby at the Courtyard and Hyatt Vastrapur everyone seemed be discussing whether the guy had been crossparticipating. There was a lot of speculation in the air. Noone could get info on which trial he had participated in, the nature of the study drug, or who the sponsor was. The CRO's name was made public. 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. It makes lot of sense, technically and formally. But it is worrying as hell that this is how it works.
I asked if an EU regulator could ask the CRO if the person who died had participated in an EU trial (and when, relative to the time of death etc). As far as I understood, no CRO was obliged to answer a question like that. Again this quickly becomes a legal discussion whe outcome has to do with the industry protecting itself rather than a discussion of the protection of the trials subjects, present as well as future.
It was hinted to me that no regulator of e.g. the inspectors working group etc can ask such a question of behalf of others. It can perhaps be asked as a purely national matter, but then 20 regulators may need to ask and it is still doubtful if the CRO is under obligation to answer :-) The overarching role of EMA only goes so far.

§2.3: The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
nobody
nothing

2020-01-02 10:35
(300 d 19:10 ago)

@ ElMaestro
Posting: # 21048
Views: 3,622
 

 Participation databases

» happy new year.

same!

To be honest: This all is not a bug but a feature. You get what you pay for and if you go remote with your studies, sponsors know why...

Kindest regards, nobody
Ohlbe
★★★

France,
2020-01-02 12:18
(300 d 17:27 ago)

@ ElMaestro
Posting: # 21049
Views: 3,627
 

 Participation databases

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").

Regards
Ohlbe
Helmut
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Vienna, Austria,
2020-01-02 13:06
(300 d 16:40 ago)

@ Ohlbe
Posting: # 21050
Views: 3,609
 

 National databases‽

Hi Ohlbe,

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

Those are the best ones!

» » 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.
»
» They're not the only country with a national system. That's also the case in […] France.
» Our database is managed by the Ministry of Health. It includes […] amount of money paid to the subject (there is a maximum of 4500 € per 12-month period, which has not been modified since 2006 !).

Adjusting for the annual inflation rates in France it should be ~5,355 €, right?

» » Question: Where should such a system be located? At the EMA?
»
» Or at the Commission ? Ideally the EU would have a single database, in order to prevent cross-participation in various countries.

What else? That’s why Europol runs one database which is accessible by all member states.

» But it would be more likely to be considered a matter of national competence, with national databases.

Freedom of travel is one of the basic principles in the EU. In order to prevent “volunteer-tourism” national databases would have to synchronize their data pools – probably on a daily basis. With – soon – 27 members states + Norway, Iceland, Liechtenstein we end up with \(\frac{n!}{(27+3-2)!2!}=435\) 1:1 connections.
If we consider only the EU, still 351. Not joking.

I’m pretty sure that at least one of Murphy’s laws will hit. IMHO, national databases wouldn’t make any sense.

Dif-tor heh smusma 🖖
Helmut Schütz
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ElMaestro
★★★

Belgium?,
2020-01-02 16:31
(300 d 13:14 ago)

@ Helmut
Posting: # 21051
Views: 3,589
 

 Great discussion

Hi all,

interesting discussions here.

» Question: Where should such a system be located? At the EMA?

Is a crossparticipation effort truly necessary across EU?

Some pros and cons as I see the issue and I am not talking legal affairs here:

Pros:
  1. If we require /enforce/inspect/question anything about it in region A (like India), then we should do so also in region B (like EU).
  2. EU would be forerunners. Someone in a penguin suit would have an opportunity to go on TV and brag about initiaties and patient concerns and sip champagne out of a tall glass, display friendly handshakes, canapes, live webinars with agency employees who read from a script and that kinda stuff. The opportunity to get good press is something that means a lot to the heads of agencies.
Cons:
  1. Is there a need? ICF is always in layman's national language. I did not hear much of crossparticipators across borders in EU, as far as I recall. It cannot be compared so well to India, where ICF's are usually in at least 3 languages (Hindi, English, and (the most common) state language(s)).
    But on the other hand, being proactive -if anyone wants to be so?- means you address an issue before the need arises. What if it turns out in 5 years there are current crossparticipators gaming the systems in Austria/Germany, or the Francolophystic countries? Do you wish to wait until you learn about them or do you want to do something to prevent it before it happens? After all, CAPA's are part of general GCP which regulators seem to like, right?
  2. Expand a little further on Pros pt 1. and you will need to discuss China. A diplomatic crisis waiting to happen.

By the way: I do not know of any other indicator -should I call it biomarker??- of crossparticipation than HB (or hematocrit, RBC count etc). Do you know of any?
Of course DNA traces present in plasma are direct markers of subject identity posing huge technical and practical difficulties and that in itself is a discussion for another thread.
Can you guys think of any other biomarker/indicator unrelated to blood loss or the regenerative process?

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
Ohlbe
★★★

France,
2020-01-02 16:57
(300 d 12:48 ago)

@ ElMaestro
Posting: # 21053
Views: 3,576
 

 Great discussion

Dear ElMaestro,

» Can you guys think of any other biomarker/indicator unrelated to blood loss or the regenerative process?

Needle prick marks in the forearm veins, if the subject is so greedy (or hungry :-() that he does not even wait for them to heal ? Well, actually it would be relevant, if I am to believe Zeba Ziddiqui's paper which you mentioned earlier (with subjects participating in 3 or 4 trials in the same month). I never saw a protocol with a non-inclusion criterion "Subject with needle marks in the forearm". So I never saw a tick box anywhere in the screening documentation with this criterion.

I'm not aware of any other indicator, unfortunately.

By the way, I really don't see how a subject could participate in 3 or 4 trials in the same month without the CRO(s) being aware of it. I'm really not sure whether some of the CROs are really willing to know whether the subjects cross-participate.

[image] © Roberto Mangosi

Regards
Ohlbe
ElMaestro
★★★

Belgium?,
2020-01-02 18:19
(300 d 11:26 ago)

@ Ohlbe
Posting: # 21055
Views: 3,564
 

 Great discussion

Hello Ohlbe,

» By the way, I really don't see how a subject could participate in 3 or 4 trials in the same month without the CRO(s) being aware of it. I'm really not sure whether some of the CROs are really willing to know whether the subjects cross-participate.

A sore issue.
I think, and I cannot back this up with facts, that in some cases CROs are desperate to enroll subjects because they have signed a contract with all sorts of penalties for not initiating dosing on some specific date. I had several cases in 2019 of studies being postponed. The thing is, if one study gets postponed due to low enrollments, then it is not easy just to postpone the dosing a few days. You actually need serious rescheduling because you have several studies lined up. It is a nightmare and this is why a study where dosing is postponed due to slow enrollment is often not just postponed "a few days" but rather weeks.
I had several cases where I looked at the incidence of a PI or delegate NCS'ing subjects with low HB prior to studies. One case that stands out was one where the rate of NCS'ed subjects was extremely high -certainly higher than "normal" (as perceived by me)- on the last three days prior to dosing. This study included a HEVO male who had low:

HB
RBC
HCT
MCV
MCH
WBC

I am trying to say that sometimes I think CROs are in need of subjects. I would not protest to anyone hinting that possibly a CRO here or there is putting pressure on PIs or delegates to enroll the enrollables.
Also, there are companies in Ahmedabad, Bangalore and Mumbai specialising in finding volunteers. Since there is no crosstalk between OVIS in Gujarat and similar software in e.g. Karnataka, you can rather safely take someone who is a recent participator from Gujarat to Bangalore without flags showing up.
This traffic of volunteers is big business. As in, really really big business.

As inspector or auditor I never had a chance to approach them. I have helped TV crews get inroads, but the people who are connected to these "humanitarian recruiters" are specifically people who do not like people like concepts like ethics, inspectors, auditors, and GCP. I have no doubt some of these people will happily break your leg and threaten to do stuff to members of your family in order to shut you up :-)
"Humanitarian recruiters" is a term I heard first during 2018. These people should apparently be awarded a Nobel Prize. They see themselves as career facilitators - poor people in remote areas who are in possession of valuable resources (think plasma and health) have a way to build a career and earn a living by signing up for trials (not to be confused with the ICF) via those people, who thereby help the local economy and so forth. Yes, these people are veritable saints, who get a cut like 50% of the volunteer compensation.
Some CROs are collaborating with these trafficking companies. I heard one guy saying they have no choice. In Ahmedabad the CRO industry has outgrown the volunteer pool. It is a rather precarious situation.

I heard of someone who was transported 450 km on top of a lorry from a remote area to CRO. If he was found enrollable but did not sign the ICF he would not be transported back to his village. He'd be stuck without a penny (rupee) in his pocket far away from home, and he did not know this condition before he departed. Now, try and see what GCP mentions about coercing someone to participate.
All this is of course completely off the radar for all formalised GCP activity and we can discuss wording of 4.8.3 and such but we will not be getting anywhere.

That is no way to treat humans. It royally pisses me off and I feel I can do absolutely nothing.


Bottom line: I am guessing that
  • in some cases CROs may know about the risk of crossparticipation,
  • in some cases they close their eyes to it,
  • in some cases they don't know anything,
  • in some cases they go above and beyond to make sure it does not happen by avoiding the humanitarian recruiters.

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
Helmut
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2020-01-02 18:42
(300 d 11:04 ago)

@ ElMaestro
Posting: # 21056
Views: 3,546
 

 WTF 😡

Hi ElMaestro,

nothing more than
[image]

Dif-tor heh smusma 🖖
Helmut Schütz
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Helmut
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Vienna, Austria,
2020-01-02 17:14
(300 d 12:32 ago)

@ ElMaestro
Posting: # 21054
Views: 3,576
 

 Great discussion

Hi ElMaestro,

» Is a crossparticipation effort truly necessary across EU?

Yes. In my CRO we had occasionally volunteers from Budapest (2:40 by train), Brno (2:10), and Bratislava (1:10).

» Of course DNA traces present in plasma are direct markers of subject identity posing huge technical …

No cellular compounds in plasma → bad luck. DNA identification was our first idea when we suspected a case of sample mix-up. Well, …

» … and practical difficulties …

Not to forget legal issues. Even if you manage to get a blood sample, in Germany & Austria you can’t simply start sequencing. Needs another ICF.

» … and that in itself is a discussion for another thread.

Yep.

» Can you guys think of any other biomarker/indicator unrelated to blood loss or the regenerative process?

No, sorry.

Dif-tor heh smusma 🖖
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Ohlbe
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France,
2020-01-02 16:36
(300 d 13:09 ago)

@ Helmut
Posting: # 21052
Views: 3,583
 

 National databases‽

Dear Helmut,

» » Our database is managed by the Ministry of Health. It includes […] amount of money paid to the subject (there is a maximum of 4500 € per 12-month period, which has not been modified since 2006 !).
»
» Adjusting for the annual inflation rates in France it should be ~5,355 €, right?

[nitpicking] 5,189.66 € using the official, most used "excluding tobacco" index, between May 2006 (the text establishing the limit was dated 26 April 2006) and December 2019 [/nitpicking].

Regards
Ohlbe
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