The challenges for implementing Good Clinical Practices in the bioanalytical laboratory: a discussion paper from the European Bioanalysis Forum

Abstract

This manuscript reports back from the discussion in the European Bioanalysis Forum community on the challenges observed when implementing Good Clinical Practices in the bioanalytical laboratory. It is not intended to challenge any regulatory requirements but to open a discussion on where the bioanalytical community sees ambiguities on implementing Good Clinical Practices or areas where expectations are either felt not being owned by Bioanalysis or where Good Clinical Practices requirements are at risk of getting contaminated with requirements originating from Good Laboratory Practices. In addition to this, the discussions focused on three additional main challenges: the informed consent withdrawal, expedited reporting of unexpected results and the risk-based approach to quality management, The European Bioanalysis Forum community is continuing discussions, but already this manuscript should help to appreciate the challenges and to try and resolve them, involving all stakeholders.

Implementation of Good Clinical Practices (GCP) in the bioanalytical laboratory has been discussed within the European Bioanalysis Forum (EBF) for almost 15 years. Key drivers for this discussion were

1.	EBF member companies based in the UK being inspected regularly by the Medicines and Healthcare products Regulatory Agency (MHRA) that combine GCP and Good Laboratory Practices (GLP) inspections
2.	Inclusion of a rather general expectation on compliance to GCP in the European Medicines Agency (EMA) guideline on bioanalytical method validation [1] on which the EBF commented earlier [2]
3.	Publication of the EMA reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples [3], for which the content was largely inspired by the MHRA process on the subject

In relation to the MHRA inspections in list item 1, while intended as separate (i.e., when a clinical bioanalytical study is selected during an inspection) the MHRA includes aspects of GCP. Equally, when a study performed under the Good laboratory Practices (GLP) regulations is audited, are GLP requirements being the regulations it is inspected against. Nevertheless, the EBF community sees the lines between GCP and GLP expectations blurring, also during MHRA inspections. At the 4th EBF open symposium there was already a presentation from one of the EBF member companies sharing feedback on their view on compliance to GCP for their bioanalytical laboratories [4].

More recently, from the public consultation of the ICH M10 guideline [5] onwards, where a similar general reference was made to GCP as in the EMA guideline, the EBF increased its focus on GCP; we formed a team to discuss the challenges related to GCP in the context of bioanalysis and what is needed to achieve a harmonized, compliant and efficient implementation of GCP in view of the lack of proper guidance from any guideline. Indeed, the ICH E6 (rev. 2) guideline [6] does not provide any reference to bioanalysis, creating a similar situation as for the compliance to GLP, where in Organisation for Economic Co-operation and Development 1–24 [7] bioanalysis is not specifically called out. Also for GCP, this has led to confusion in the bioanalytical community on, for example, not fully understanding which parts of the bioanalytical process are in the scope of GCP and which are not. Consequently, implementing GCP for bioanalysis is at risk of being subjective and prone to comparable individual interpretation, creating checklists and audit programs for which there is no reference point in any existing guideline. These challenges and how individual companies have implemented (or not) their interpretation of GCP for bioanalysis provided the EBF GCP team with a good starting point for discussions.

With the intention to invite for further discussion with all involved, we want to report back on the discussions related to GCP and regulated bioanalysis discussed in the EBF GCP team since 2019. This includes the discussion at and outcome of a recent Focus Workshop [8] and sessions at both the 15th and 16th EBF Open Symposium [9,10]. The challenges that have come to light can serve as a foundation for further discussions. We believe it is essential, initially within the industry, to reach consensus on diligent yet practical processes for complying with regulatory GCP expectations. From there, we can engage with health authorities.

Understanding the current regulatory landscape

One of the challenges we discussed is the large difference in GCP expectations in the regions represented in our member community. Bioanalytical laboratories operating in the UK are being inspected regularly by the MHRA with (increasing) focus on GCP. Recent feedback from our members is that these GCP requirements are increasingly becoming influenced by GLP guidelines. Further in this manuscript, we provide additional reflections on GCP versus GLP.

On the other hand, in bioanalytical laboratories operating in other regions (e.g., EMA, US FDA, Health Canada, Japanese Ministry of Health, Labour and Welfare and Swiss Medic), there is only limited focus on GCP during inspection of bioanalytical laboratories. This creates both a challenge and a concern: the challenge being the application of potentially different processes when analyzing samples in the UK versus outside the UK and the concern being that other health authorities may be tempted to copy the MHRA processes in the future without the desired a priori discussion with industry.

In our community, despite varying regulatory inspection scopes, there is a shared need and desire to enhance and align processes with what we perceive as GCP requirements. However, sharing these processes has revealed notable differences in interpretation and implementation. Some of these (self-imposed) processes may lead to bioanalytical laboratories' having difficulties complying with them. Indeed, we see processes being implemented due to MHRA inspection expectations, as well as expectations which are derived from GLP, the latter often via quality assurance (QA) audit programs performed by the GLP-QA unit.

Discussions in the EBF GCP team

The EBF GCP team was assigned to highlight and discuss the challenges around GCP for the bioanalytical lab. In addition to the above-mentioned challenge of GCP versus GLP, the team identified a broad array of areas needing further discussion, most of them finding their origins in the ICH E6 (rev. 2) GCP guideline [6]. As mentioned previously, with no reference to bioanalysis or sample analysis of pharmacokinetic or biomarker samples originating from humans, little room has been left for interpretation or (inaccurate or inappropriate) copying from other procedures and guidelines. Our team discussed the areas where challenges are faced and intends to present these areas in meetings or discussions with stakeholders, aiming to find a common ground. As stakeholders or partners in industry, we identified a need to collaborate with QA groups and clinical operations, both being critical partners to move the discussion in the right direction. We are actively inviting both partners in our team. Recently, we increased our team membership to include QA representatives, and we hope to do the same for clinical operation units. Naturally, the regulators are the most important stakeholders, and we have and will continue to share all the details of our discussions.

To date, and after internal discussion in the team, the themes we have identified for further discussion in industry currently are

-	Communication, with a focus on protocol deviation reporting requirements for bioanalytical laboratory and issue communication
-	Informed consent form (ICF) status and the process in the case of withdrawal of consent
-	Fit-for-purpose GCP training
-	Differences in QA activities between GLP and GCP with a focus on QA involvement, the risk-based approach (RBA) to quality management [11], computer system validation and archiving
-	Accountability of the bioanalytical team with a focus on sample disposition and data management plans, expedited reporting and contracting

At the Focus Workshop in Málaga [7], all of the above items were discussed in six interactive round tables. The outcomes of these discussions, presented at the 15th EBF Open Symposium, are available on the EBF website [8]. From these discussions, two themes were identified as critical for further discussion, as they risk clogging the bioanalytical motor if implemented in their current thinking in some laboratories or regions (i.e., the responsibility of the bioanalytical team with respect to ICF status and expedited reporting due to unexpected results observed). In this manuscript, we dedicate a paragraph to each. Together with the discussion around GCP versus GLP and the RBA, we feel these topics are essential for understanding the challenging environment for GCP in bioanalysis.

GCP versus GLP

As alluded to in the previous paragraph, the EBF community feels there is a risk of GLP regulations and expectations contaminating the bioanalytical process with respect to GCP, which in turn may instigate the regulatory authorities to adapt their expectations, too. Discussions in the EBF confirm the need to understand that GLP and GCP are two different sets of regulations originating from different needs (i.e., ensuring transparent documentation and communication to prevent fraud for GLP and ensuring the integrity of patient information and safety for GCP). Translating the GLP requirements into a standard operating procedure (SOP) for GCP may be efficient if a lab already operates with GLP-compliant processes. This is also the feedback from our community that it is more efficient to use the same SOPs and processes if your lab supports both GLP and GCP studies. However, it should always be clear that some of the specific GLP requirements should not and even cannot be complied with for GCP studies, and any audit or inspection should be taking this into account. Most examples are related to the clear requirements on communication with the study director, protocol deviations, communication of changes to the method, aspects of multisite studies, QA study audits and reporting thereof and aspects of computer system validation, to name a few. Already, these examples clearly illustrate the differences between GLP and GCP and that GCP should not blend into GLP. These examples, however, also show the need for a specific quality system for bioanalytical laboratories not involved in supporting GLP studies. Implementing the GLP quality system into their laboratories will distract from the essence of the task, will be very resource intensive and therefore requires a fresh discussion.

Informed consent form

Managing the status of the ICF was identified as one of the biggest challenges in managing for GCP in the bioanalytical lab. Currently, the issue is limited to GCP inspections in test facilities of laboratories under the MHRA rule, but it is getting attention as part of inter-regional sharing of processes. Hence, there is a growing fear that the (regulatory) expectation on the responsibilities of the bioanalytical lab with respect to the ICF status (e.g., full or partial withdrawal of a subject's consent) will spill over into other regulatory regions without the necessary discussion on the impact on the bioanalytical laboratory. In turn, this is already leading to some bioanalytical laboratories installing procedures to comply with self-defined unclear expectations, which is always the fastest route to unrealistic procedures being put in place, or implementing procedures trying to defer this responsibility back to clinical operations or data management, who are reluctant to sign off on any SOP identifying them as the final owners of this process. The current outcome of the discussions in the EBF community doesn't ignore the importance of all aspects of the ICF. However, there is a growing concern that being held accountable for a process that is not owned by the bioanalytical laboratory (i.e., having all current information on the status of the informed consent prior to the analysis of the study samples or at reporting of the concentration data) is not practical and likely not the intention of the ICF. A process to defer this accountability to groups closer to this process (e.g., data management or clinical operations) via a service agreement, SOPs, communication plans or the equivalent should be considered. Also coming into play are the specific challenges of contract research organizations, which are doing the bulk of the analysis of clinical trial samples. They will have additional challenges to have all the ICF information at hand, nor may they be allowed to have full access due to patient confidentiality requirements or issues related to unblinding of the study samples. Versions of a workable process have already been put in place in some members of the EBF and have been accepted during regulatory inspections by the MHRA as part of their regular GLP/GCP site inspections of bioanalytical laboratories. These examples could serve as a starting point for a template to manage the ICF in our area. The EBF hopes that a discussion can take place involving all stakeholders in industry and the regulatory authorities so we find a consensus to manage this issue.

Expedited reporting

A second theme for discussion, which received and continues to receive a lot of attention during both the discussion within the EBF and at our meetings, is the process of expedited reporting due to unexpected bioanalytical pharmacokinetic results (i.e., measurement of drug in human samples). These discussions currently focus on trying to define what would be an unexpected result calling for expedited reporting for the bioanalytical scientist. Indeed, it may be very difficult and even not allowed for the bioanalytical laboratory to classify a pharmacokinetic result as unexpected (and potentially impacting patient safety) for various reasons. Also, a typical clinical study protocol has insufficient details pertaining to performance of bioanalytical services on what deviation should be reported and when. This may need more debate, if not alone to manage the concern of a growing desire by regulators to push for a position that borrows from GLP, where a lot of bioanalytical details are typically included in a GLP toxicology study protocol.

Risk-based approach

As GCP gain prominence in bioanalytical audits, both within and outside MHRA-inspected labs, there is a need to collaboratively establish the appropriate audit criteria. As already referred to earlier in this manuscript, adopting expectations from GLP into GCP should be avoided, as they will lead to processes being implemented which are not required or intended for clinical studies from a GCP regulations requirement.

One of the processes applied in GLP QA audit is the RBA to quality management. Where it had the noble intention of lowering the burden and resources spent in audits by focusing on those items critical to quality and with the highest risk of either noncompliance or impacts on patient safety, we observe an opposite effect. When defining a risk as part of RBA quality management, our industry's fear for noncompliance identifies more items as high risk than needed, leading to increasing the workload rather than lowering it.

Hence, we continue to discuss how applying RBA for a bioanalytical laboratory involved in GCP can add value instead of potentially raising the bar as we currently observe. The consequences of using an RBA in the bioanalytical laboratories involved in GLP needs further discussion with all involved – that is, what would a pragmatic RBA look like?

Conclusion & future perspective

In this manuscript, we reported back from the recent discussion in the EBF on understanding the GCP requirements for the bioanalysis of samples from clinical patient and healthy volunteer studies. Although we have already been actively discussing this in the EBF for many years, the discussions have been intensified within our community as part of the publication of the ICH M10 guideline.

At this stage, the EBF is not ready to make any recommendations but is calling for further discussions to prevent GCP expectations for bioanalytical laboratories becoming unrealistic and procedures to comply with them going overboard. Currently, we see that the lack of clarity of expectations is leading to individual interpretation of GCP requirements for bioanalysis, both by industry (the bioanalytical laboratory, QA units auditing and clinical operations) and by regulators. In turn, this is already leading to a resource-intensive process, partially adopted from GLP, which may become virtually impossible to comply with realistically. Hence, the EBF calls for an open discussion involving all stakeholders in all regions to come to an agreement on the requirements for GCP to which the bioanalytical lab can comply to in a resource-efficient way.

Acknowledgements

The authors acknowledge additional members of the EBF GCP team for their contribution to the discussions: Mathias Salger (Boehringer Ingelheim Pharma GmbH and Co.), Sarah Ball (Labcorp Drug Development), Jelena Popov-Čeleketić (Genmab B.V.), Herlind Biedert and Michaela Golob (Nuvisan GmbH), Giancarlo Sabattini (Idorsia), Martin Rieger (Morphosys), Elizabeth Wilson-Kruchen (Biotest AG), Kay Sommerville (Charles River Laboratories), Janett Schwarz (Bioagilytix), Uwe Schwahn (Sanofi), Isabelle Atlan and Delphine Maux (Syneos Health), Henriet Meems (Ardena), Valeria Castagna and Diana Knapp-Buehle (Merck KGaA), Stephanie Vauleon (F. Hoffmann–La Roche) and Alexandros Vegiopoulos (Abbvie).

Disclaimer

The views and conclusion presented in this paper are those of the European Bioanalysis Forum and do not necessarily reflect the representative affiliation or company's position on the subject.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.