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ElMaestro
Hero

Denmark,
2019-01-20 11:42

Posting: # 19787
Views: 678
 

 GLP or GCP for bioanalysis? [GxP / QC / QA]

Hi all,

more confusion at my end, it is something very basic.

EU guideline on BE: "The bioanalytical part of bioequivalence trials should be performed in accordance with the principles of Good Laboratory Practice (GLP)"

EU guideline on method validation: "The validation of bioanalytical methods and the analysis of study samples for clinical trials in humans should be performed following the principles of Good Clinical Practice (GCP)"

So, which guideline(s) must a CRO follow for sample analysis for EU studies: GLP or GCP or both?
Does validation "only" need to comply with GCP and if yes, can you give a practical example of the real difference?

If you are saying both GLP and GCP need to be observed in some cases then I may have a natural question about the meaning of the term "principal investigator"....:-)

if (3) 4

x=c("Foo", "Bar")
b=data.frame(x)
typeof(b[,1]) ##aha, integer?
b[,1]+1 ##then let me add 1



Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
nobody
Senior

2019-01-20 13:47

@ ElMaestro
Posting: # 19788
Views: 630
 

 GLP or GCP for bioanalysis?

sensu strictu GLP applies to preclinicl/tox studies, and GCP does not cover(bio)analytical methods, so neither (really) applies and therefore in the end both.

Don't get confused, get drunk...

Kindest regards, nobody
ElMaestro
Hero

Denmark,
2019-01-20 13:54

@ nobody
Posting: # 19789
Views: 630
 

 GLP or GCP for bioanalysis?

Dear nobody,

here I think you are going astray.

it is true the OECD GLP guidance was developed for nonclin./tox studies and this is stated in the preamble section of the document, but there is nothing, not one single paragraph anywhere in Eudralex or any other collection of legal or regulatory documents, which precludes regulators from applying the same standard (or another) in any field.

if (3) 4

x=c("Foo", "Bar")
b=data.frame(x)
typeof(b[,1]) ##aha, integer?
b[,1]+1 ##then let me add 1



Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Ohlbe
Hero

France,
2019-01-20 23:11

@ ElMaestro
Posting: # 19790
Views: 595
 

 Both, Cap't'n !

Gentlemen,

I think you are both right... And a little bit of history may help understand. This is gonna be a lengthy post, sorry.

GLP first made it to the EMA BE guideline in its previous version (when was it ? 2001 ? I've got it on my computer at the office but not at home). It came as a surprise to everybody: it was not in the draft published for consultation. As EMA did not publish any overview of comments at that time, there is no information on where it came from. Actually, I should be more specific: this was the first time it was mentioned in the human BE guideline, but it was already in the vet guideline (and nobody seemed to mind then). Still is.

This requirement for GLP compliance triggered some rather strong reactions. Strangely enough, not really from industry (after all, most CROs were already claiming GLP compliance in their reports), but from some regulators. The MHRA was particularly pissed off, and eventually their GLP inspectors issued a clarification statement, according to which there was no need for labs analysing BE samples to be part of a GLP monitoring programme. The MHRA shared nobody's opinion that GLP is strictly and only applicable to preclinical safety studies, and actually threatened to prosecute any UK lab that might claim GLP compliance for other activities. Some other regulators shared ElMaestro's opinion: GLP is mandatory for preclinical safety studies, but it's written nowhere that you can't claim GLP compliance for anything else. Actually I've heard that some EU monitoring authorities (Spain and a few others) did perform GLP inspections and issued GLP compliance statements for labs analysing BE samples, but no preclinical samples. So much for EU harmonisation.

When the BE guideline was revised in 2008-2009, the GLP thing remained (difficult to appear to lower existing requirements), and the clarification on the GLP monitoring programme was incorporated in the text.

When the bioanalytical guideline was published for consultation, it attempted to widen the application of GLP to all bioanalytical work. In an attempt to satisfy the MHRA, it also mentioned that clinical work additionally had to comply with GCP (fine, but as mentioned by nobody there is not much applicable to bioanalysis in GCP (apart from section 2)). The MHRA was actively communicating on GCP compliance for bioanalytical labs at that time, and ended up publishing a guidance for labs analysing clinical samples in 2009.

This was actively (that's an understatement) debated at the EBF/EUFEPS meeting in Brussels in April 2010, where the 3 authors of the guideline explained why they wanted it, and industry explained why they didn't. Everybody agreed on the main GLP principles: data should be reconstructible, generated by qualified people, with qualified equipment, following valid SOPs, but industry wanted to avoid some of the surrounding paperwork (and QA audits).

Another factor is that bioanalytical method validation is used to support preclinical safety studies, but are not by themselves preclinical safety studies, so some argued that they do not need to follow GLP. I've been told that GLP monitoring authorities accept this position.

The compromise that was eventually found is the following:
- preclinical safety studies: no discussion. GLP.
- method validation for preclinical safety studies: should "normally" follow GLP. If not, clearly identify deviations and provide an impact analysis.
- clinical studies: follow GCP + the "reflection paper" adopted by the GCP inspectors working group.
- method validation for clinical studies: also GCP + reflection paper, though one could develop the same argument as for preclinical: method validation is not a clinical trial by itself, so it is not subject to GCP.
- BE trials: the BE guideline requires GLP compliance, and this has not been repelled by the publication of the BMV guideline. So: GCP + GLP + reflection paper.

The reflection paper derives from the guidance published by the MHRA in 2009. It is a common sense blend between GCP and GLP. However I would consider its legal value as rather weak.

[off topic] I'm not too fond of blends. I prefer single malt. Which is fully compatible with nobody's final wise words :-D [/off topic]

» If you are saying both GLP and GCP need to be observed in some cases then I may have a natural question about the meaning of the term "principal investigator"... :-)

We'll need rum for this one, Cap't'n :-D

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2019-01-21 09:42

@ Ohlbe
Posting: # 19791
Views: 571
 

 Both, Cap't'n !

Hi Ohlbe,

thanks for the insight.

» This requirement for GLP compliance triggered some rather strong reactions. Strangely enough, not really from industry (after all, most CROs were already claiming GLP compliance in their reports), but from some regulators. The MHRA was particularly pissed off, and eventually their GLP inspectors issued a clarification statement, according to which there was no need for labs analysing BE samples to be part of a GLP monitoring programme. The MHRA shared nobody's opinion that GLP is strictly and only applicable to preclinical safety studies, and actually threatened to prosecute any UK lab that might claim GLP compliance for other activities. Some other regulators shared ElMaestro's opinion: GLP is mandatory for preclinical safety studies, but it's written nowhere that you can't claim GLP compliance for anything else. Actually I've heard that some EU monitoring authorities (Spain and a few others) did perform GLP inspections and issued GLP compliance statements for labs analysing BE samples, but no preclinical samples. So much for EU harmonisation.

Is there anything in the public domain about the threat to prosecute? Does it mean in the UK you cannot write in a MV for BE or in a BE SR that you comply with GLP?

Also,I think that when regulators can disagree so much in the meaning and interpretation of guidance then there is a clear and present need for a radical update -at least a major revision- of the documents. No wonder, in light of this, that some companies are very uncertain as to what they need to do in order to comply EU-wide with guidelines. I had no idea this was so controversial; I only saw it as a big confusion.
Thanks again.

if (3) 4

x=c("Foo", "Bar")
b=data.frame(x)
typeof(b[,1]) ##aha, integer?
b[,1]+1 ##then let me add 1



Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
nobody
Senior

2019-01-21 10:25

@ ElMaestro
Posting: # 19792
Views: 565
 

 Both, Cap't'n !

...who controls the fear and the bread is in charge. ;-)

If there are divergent opinions and no one is in the position to tell "right" from "wrong" there is obviously not way forward to any kind of consensus. No difference if it's in politics (but usually the lawyers will tell you, who REALLY is the one to decide....) or in guidelines nonsense discussions.

Kindest regards, nobody
Ohlbe
Hero

France,
2019-01-21 11:05

@ ElMaestro
Posting: # 19793
Views: 557
 

 Both, Cap't'n !

Hi ElMaestro,

» Is there anything in the public domain about the threat to prosecute?

Not that I know of. That's what I was told at the time, but I didn't ask for any written source.

» Does it mean in the UK you cannot write in a MV for BE or in a BE SR that you comply with GLP?

I don't know what the current status is in the UK.

In France, what I've been told is that GLP inspectors will react if a bioanalytical report of clinical work refers to the French GLP texts which they are supposed to enforce, but will accept a reference to the OECD text. Very hypocritical, considering that the French text is directly derived from the OECD text. I guess that's the compromise that was found between GCP inspectors, who want GLP for BE trials, and the GLP inspectors who don't want to be asked to inspect them.

» Also, I think that when regulators can disagree so much in the meaning and interpretation of guidance then there is a clear and present need for a radical update -at least a major revision- of the documents.

It seems to me that the disagreement is not in the meaning and interpretation, but in the contents. The majority voted for something which is not accepted by a minority. The fact that those who disagree most are soon to leave the EU is of little comfort.

» No wonder, in light of this, that some companies are very uncertain as to what they need to do in order to comply EU-wide with guidelines.

They will have no problem if they go back to basics. Write what you will do, do as you wrote, write what you did. Qualify your equipment. Use qualified staff. Have a QA in place.

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2019-01-21 11:28

@ Ohlbe
Posting: # 19794
Views: 548
 

 Both, Cap't'n !

Thanks Ohlbe,

» They will have no problem if they go back to basics. Write what you will do, do as you wrote, write what you did. Qualify your equipment. Use qualified staff. Have a QA in place.

...and don't sign form 1572.:-D:no::lol::ponder:

if (3) 4

x=c("Foo", "Bar")
b=data.frame(x)
typeof(b[,1]) ##aha, integer?
b[,1]+1 ##then let me add 1



Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Ohlbe
Hero

France,
2019-01-21 11:51

@ ElMaestro
Posting: # 19796
Views: 543
 

 Both, Cap't'n !

» ...and don't sign form 1572.:-D:no::lol::ponder:

OMG. Another can'o'worm discussion. Isn't it a bit early for rum ?:party:

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2019-01-22 22:39

@ Ohlbe
Posting: # 19798
Views: 485
 

 A great idea

Just sayin',

» - BE trials: the BE guideline requires GLP compliance, and this has not been repelled by the publication of the BMV guideline. So: GCP + GLP + reflection paper.

Assessment report template from CMD(h), updated long after the MV guideline was published, page 7 of 11:
Assessor's comment: Is the analytical method acceptable, validated (pre-study and within study), handling of samples adequate. Is there a statement on GLP compliance? Protocol deviations/violations? Are reasons for reanalysis of samples acceptable?

It ain't all easy to comprehend.

All this means to me that finding the right way through this ...erm... situation... implies that one must involve some degree of decision-making on basis of facts that are not in the public domain.

Is the template based on a semantic brilliancy - Perhaps they truly want compliance with GLP and GCP for bioanalysis but for some reason or other the CRO isn't supposed to actually spell out the latter?

I have a great idea. Why don't we include a standardised formulation in all reports, to replace all other compliance statements: "The bioanalytical part of this study was conducted in compliance with GCP and GLP, except GCP (where applicable)".
Less confusing, right?:-)

You can thank me later. :-D:cool::lol:

if (3) 4

x=c("Foo", "Bar")
b=data.frame(x)
typeof(b[,1]) ##aha, integer?
b[,1]+1 ##then let me add 1



Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Ohlbe
Hero

France,
2019-01-23 00:29

@ ElMaestro
Posting: # 19799
Views: 479
 

 Statements of GCP and GLP compliance

Dear ElMaestro,

» Assessment report template from CMD(h) [...] Is there a statement on GLP compliance?

» Is the template based on a semantic brilliancy - Perhaps they truly want compliance with GLP and GCP for bioanalysis but for some reason or other the CRO isn't supposed to actually spell out the latter?

I think it is actually very simple:
- OECD GLP, section II, § 1.2.2.h, require the study director to sign and date the final report to indicate acceptance of responsibility for the validity of the data and to indicate the extent to which the study complies with these principles of good laboratory practice. Consequence: the bioanalytical report needs to include a statement of GLP compliance signed by the study director.
- GCP does not require anybody (sponsor, investigator or whoever, let alone anybody at labs) to sign any kind of statement of GCP compliance.
- AFAIK, the only reference text applicable in the EU that mentions a statement of compliance with GCP is ICH E3 on the structure and contents of clinical trial reports, according to which (section 1) the title page of a study report should include a statement indicating whether the study was performed in compliance with Good Clinical Practices (GCP), including the archiving of essential documents. Not the bioanalytical report, the cover page of the study report, to which the bioanalytical report is appended.

So IMHO the reason why the assessment report template does not include a reference to a GCP compliance statement in the bioanalytical report is simple: as far as I know, there is no legal requirement to have one :crying:

Regards
Ohlbe
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