Biomarker validation can be confusing. We constantly hear about qualification versus validation, fit-for-purpose validation, and context of use. Due to the ‘grey area’ nature of biomarker work, many companies interpret these concepts and approaches differently. As scientists working on biomarker projects, we have to deal with a lot of variability between reagent and kit lots, high or low biomarker endogenous levels, and how to precisely assess antibody specificity in commercial kits, among other things. In a perfect world, we would have decisive guidance on how to manage all of these factors. Today, there are a wide variety of opinions published in industry white papers, but no existing document provides clear and comprehensive guidance from regulatory agencies. Due to the complex nature of biomarker work, I do not believe we will ever see a detailed “cookbook” or singular answer, but I do think that we are getting closer to reaching common ground.
Biomarker Consensus in 2017
As challenging as the world of biomarkers can be, we have made a lot of positive progress in 2017. I genuinely believe we are beginning to come to some level of consensus as an industry, among pharma and biotech companies as well as regulatory bodies. I am very excited to see that institutions like FDA are working with industry leaders toward creating guidance on “Bioanalytical Assay Validation in Support of Clinical Biomarker Qualification”. This growing consensus was apparent at three of the events I attended this year, including the 11th WRIB, AAPS’ National Biotechnology Conference, and the biomarker public workshop held in June at the Duke Margolis Center on analytical validation of assays used in the qualification of biomarkers. Still, there are areas of biomarker development and testing that pose challenges for scientists.
Changing How We Think About Acceptance Criteria
In defining acceptance criteria for biomarker studies, you cannot have everything. As scientists, we have to pick and choose those most important to us, and as such we struggle with each project to balance quality, sample volume, time, cost, and risk. Your willingness to compromise on any of these items will depend entirely on your organization’s goals and priorities, as well as the context of the biomarker use. The appropriate error threshold can vary significantly between projects. The testing needs to be able to discriminate any changes that are clinically significant, so as long as you can see a change pre- and post-dose, a larger total error may not be a problem. I’ve participated in many studies where a larger total error still provided me with data in which I felt confident.
The Relative Accuracy of Assay Validation
When thinking about assay validation criteria, it is important to define what context of use and fit-for-purpose mean within your company. The industry’s way of thinking about “biomarker assay validation” has evolved over the last ten years. The way we thought about accuracy from the PK days is being replaced by relative accuracy in the biomarker world. In the words of Lauren Stevenson from Biogen, “It is crucial for us to remember that biomarkers are not PK assays.” PK assays have well-characterized reference materials that are available in pure forms and a simple buffer formulation. Conversely, biomarkers generally are recombinant reference materials, and the endogenous forms are usually not pure.
Harmonized Assays in the Future
Why don’t we have more uniform, commercial biological proteins to use as a calibrator? In short, it is because it is hard to characterize a constantly growing list of 700 biomarkers that biotech and pharma companies like to measure. With this number rapidly increasing, we can’t afford to wait for the official harmonized calibrator from organizations like WHO and NIBSC for each biomarker. This limitation has forced us as an industry to depend on new methods and practices for biomarker validation. For example, parallelism has gained a lot of traction in the past few years and will continue to be an essential parameter for assessment during biomarker assay development and subsequent validation. But, there is still no absolute consensus on how we should conduct the parallelism evaluation or what the right acceptance criteria should be. I don’t think we will ever reach a single conclusion, but I believe we can come up with viable, proven options.
I look forward to all the new challenges and biomarker discussions 2018 will bring!
Learn more about the innovative methods used in biomarker validation in the webinar I recently hosted by Bioanalysis Zone entitled “Challenges of single and multiplex biomarker validation on ‘planet Earth’ versus ‘planet Biomarkertopia”. I also encourage you to share your thoughts on biomarker validation best practices so that we can continue these important industry discussions. Please feel free to email me directly here to start a conversation.
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