Biomarker context-of-use: how organizational design can impact the implementation of the appropriate biomarker assay strategy

The European Bioanalysis Forum (EBF) has been playing a leading role in discussions with pharmaceutical and biotechnology companies, academia, health authority representatives and contract research organizations (CROs) on biomarker assay validation strategies and the principles of context-of-use (CoU) for many years, which has led to multiple contributions in international forums. These discussions and publications have included the recommendations from the 2012 and 2020 papers [1,2], workshops [3–5] and open symposia [6–8] on biomarker (BM) assay CoU. The goal of all of these interactions has been to focus on the scientific risk of applying Bioanalytical method validation (BMV) assay validation criteria related to pharmacokinetics (PK) for biomarker assays and to find a common understanding of CoU across organizations involved in biomarker bioanalysis, and a solution for cross-industry implementation of the CoU principles. The learnings from these cross-industry interactions have further shown that there remain fundamental challenges in the mindset and also in organizational design disfavoring and even preventing the implementation of CoU. As a result, the EBF biomarker team, involving many members from the EBF community, is regrouped to share and discuss how organizational design related to biomarker research (or the lack thereof) supports or in fact hampers the implementation of the CoU principles for biomarker assay validation and identify potential approaches that could be supportive of CoU implementation for companies.

CoU for biomarker assays is a detailed definition of the purpose of a biomarker assay for each analyte being investigated. This must be understood and agreed upon by all stakeholders, and documented, for example in method summaries, validation plans, and validation reports. It can be as simple as a few sentences, which define the biomarker to be assessed and why. Some of the key components to consider for a CoU statement include understanding the biology or pharmacological effect of the biomarker, including understanding the expected biological variability and why the data is needed. For example, what scientific or safety decisions could be taken based on the biomarker measurement. It is then possible to consider the options from a bioanalytical perspective, as the CoU statement supports the selection of the biomarker assay, and the corresponding assay validation strategy. Therefore, it is not a simple statement such as “to quantify the analyte”, and ultimately, the CoU will help ensure the appropriate collection and interpretation of data to serve patients.

In our 2020 recommendation paper [2], we re-emphasize the following for CoU implementation to be successful:

Documenting the CoU is critical not only to ensure the right assays are set up and used, but also because institutional knowledge may change over time, with incoming new team members, or with career changes as team members leave. In addition, the purpose of the biomarker results may change from one study to the next, or the types of decisions being made based on the biomarker assay results may vary, and this should be communicated before an analyte is measured. Fundamentally, without an agreed upon CoU, there is a risk of implementing the wrong assay, with inappropriate characterization and validation of the assay, and consequently a misinterpretation of the biomarker data. This in turn can lead to incorrect decisions based on that data, all of which could ultimately negatively impact patients. Thus, an agreement across the teams on the purpose of each biomarker assay, and documentation of that CoU for each analyte, are both essential. Biomarker assay selection and characterization should be an iterative process, with modifications driven by the CoU, with data generated during assay development potentially also having an influence.

We as an industry have begun to recognize that the bioanalytical scientist must take ownership and accountability to communicate with their stakeholders and provide adequate cross-functional education. We have echoed [2], along with other papers [9], that a BM assay is distinctly not a PK assay, and thus should not be characterized as one, due to the different scientific and analytical challenges encountered [2]. The default application of PK approaches and criteria as per BMV is wrong. We recognize that CoU as a principle is a game-changer for many bioanalytical laboratories, and this remains a major challenge to fully understand and subsequently implement. The EBF decided to reach out to stakeholders within and outside of the bioanalytical community to understand cross-functional implementation of CoU principles for biomarker assays, and to understand what stimulates or hinders approaching biomarker assay validation to start from the principles of CoU. We heard common statements such as:

And from a 2021 community poll, we still found these challenges remain: the wish for “proper guidance”, to understand what is expected for the various purposes; convincing stakeholders of applying the CoU process and receiving the correct feedback from stakeholders; the tendency to think in terms of broad categories (exploratory, and primary and secondary end point); and the expectation is that an off the shelf commercial kit or prior validated method will meet the requirements of the biomarker measurement, regardless of changes in its CoU. And all the meanwhile in an environment of potential scope creep by our industry, by our community in the lab and ultimately potentially by regulatory authorities in cross-industry discussions, through the stretching of the BMV guidance for PK assays onto BM assays.

EBF biomarker team

During 2021, the EBF biomarker team re-focused their discussion to take a deeper dive into aforementioned challenges, and to discuss what could be done about them. And most importantly, how do we as bioanalytical scientists keep the momentum going to reach a common agreement across the industry what CoU really is, and how to effectively implement CoU principles [5]. The biomarker team members involved in these discussions were representatives from across the industry, including the pharmaceutical industry, mid-sized and small biotech companies and CROs. Our focus was on how to change the way of thinking and how to effectively drive the topic of CoU, internally to our organizations as well as externally. The team viewed the goal as not a repackaging of the Jean Lee or subsequent fit-for-purpose (FFP) papers [16,17], but rather a deeper dive into the strategies that support CoU implementation. The intent is to engage with the health authorities and avoid inappropriate (new) draft guidance, or the continued inappropriate implementation of BMV guidance/guidelines on biomarker assays in general [10–15], and to work together to build clarity and alignment across the industry and health authorities more intensely.

Observations by the EBF team on organizational design: sponsor perspective

We found that the following does not work in sponsor organizations toward supporting the implementation of CoU principles for all biomarker assays:

We found that the following key approaches do work for pharmaceutical and biotech organizations:

The EBF biomarker strategy team has proposed a simple cross-functional team structure, that could easily support and ensure the consistent implementation of CoU principles (Figure 2). Here, we depict a translational biomarker team of representative key experts. The team lead would ensure that a BM “integrator”, who ensures the biomarker strategy is discussed, and a BM technology lead, who ensures the appropriate BM platforms and technologies are discussed, are a part of this team. This cross-functional BM team would work closely with members of the “discovery” and “development” teams and meet regularly through “touchpoint meetings”, to ensure the BM strategy meets the goals of the drug development team in general.

The CRO perspective

The CRO perspective was also discussed by the EBF biomarker team, recognizing that CROs are a key stakeholder in implementing CoU principles and considering all the challenges that come with this. Once again, communication is key and is often the biggest issue when trying to ensure CoU principles are being followed. Optimally in a sponsor to CRO relationship, there would be an explanation of the CoU for the biomarker, to inform the decision on the biomarker assay to be used for that particular CoU, which is then followed by the selection of the analytical technology to answer the specific question. Only then would the fit-for-purpose validation parameters be defined, as well as acceptance criteria for the assay to support the analysis of any study samples. Unfortunately, the reality is usually that the initial discussion does not occur – the team found through their discussions that normally, if the CoU statement exists for any biomarker, that is not always shared with the CRO, let alone openly debated, and this often can be related to either IP concerns, or trust issues, both combined, or just simply omitted and not requested during outsourcing process. The sponsor also often suggests or recommends a commercially available kit and expects a “full validation” according to BMV principles “to be on the safe side”, rather than a fit-for-purpose approach. This then removes the opportunity to select the appropriate technology to address a specific question. And in the rare instances when a CoU statement is disclosed to the CRO, it is often not truly a CoU statement. Typically, it is an oversimplified purpose statement like “exploratory”, “I got this list of biomarkers to measure”, or “the CoU will be shared before sample analysis”. Also, the challenge in getting a CoU statement from a sponsor can be due to challenges in contracting. Operationally, a CRO can often get locked into an initial cost proposal and subsequent contract, so that having the CoU discussion ultimately becomes “out-of-scope”. Alternatively, the operational team is not aware of or does not request the CoU. And finally, every client is different, and it is often a challenge to have specific business processes in place when the sponsor does not adhere to them, and to generate business it's often needed to keep the contracting process as simple as possible.

Ideally, the sponsor to CRO dynamic over biomarker assay CoU implementation should be optimized according to at least these following principles:

The sponsor and bioanalytical scientist at the CRO both need to insist on a clearly written rationale for any requested analysis. A written statement on the purpose of the biomarker data must be documented, at least in the validation and sample analysis reports. Only when the CoU is clear will the sponsor and CRO be confident that the data will fit the purpose.

Conclusion

CoU is critical for patients, but it remains as a challenge to properly implement. The omission of CoU for biomarker assays is dangerous: the wrong CoU can lead to inappropriate assay acceptance criteria, poor use of resources and time, wrong decisions and ultimately failed drug development. In the regulated bioanalytical community, we must take ownership for implementing CoU principles and influence our stakeholders to do the same. As a community of scientists, we are responsible for the validity of the biomarker data, which includes ensuring that we are implementing CoU principles properly, that the CoU information is accurate and practical to implement, and understanding how that information directly affects what will be done in the lab. Analytical decisions need to be driven by science, not following a framework or categories, as the diversity and complexity of biomarker assays are wide. A framework may stifle the crucial conversations that are needed for defining the assay purpose. In addition, CoU must be re-evaluated as the purpose of the biomarker data changes and will dictate assay characterization and much later validation. In addition to previous EBF recommendations on CoU, we recognize the importance of how an organization is built around promoting and supporting CoU as a steppingstone to its successful implementation. The suggestions discussed in this manuscript can help organizations change the mindset toward CoU and show how it can be implemented through thoughtful organizational design. Going forward, the EBF will continue to support the bioanalytical and drug development community in the implementation of CoU principles for biomarker assays and connect with all stakeholders as necessary, as we believe it will improve the quality and value of the biomarker data in support of efficacious and safe drugs for patients.