Bioequivalence and Bioavailability Forum

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 [/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