Biomarker Qualification at the European Medicines Agency: A Review of Biomarker Qualification Procedures From 2008 to 2020

Abstract

Regulatory qualification of biomarkers facilitates their harmonized use across drug developers, enabling more personalized medicine. This study reviews various aspects of the European Medicines Agency's (EMA's) biomarker qualification procedure, including frequency and outcome, common challenges, and biomarker characteristics. Our findings provide insights into the EMA's biomarker qualification process and will thereby support future applications. All biomarker-related "Qualification of Novel Methodologies for Medicine Development" procedures that started from 2008 to 2020 were included. Procedural data were extracted from relevant documents and analyzed descriptively. In total, 86 biomarker qualification procedures were identified, of which 13 resulted in qualified biomarkers. Whereas initially many biomarker qualification procedures were linked to a single company and specific drug development program, a shift was observed to qualification efforts by consortia. Most biomarkers were proposed (n = 45) and qualified (n = 9) for use in patient selection, stratification, and/or enrichment, followed by efficacy biomarkers (37 proposed, 4 qualified). Overall, many issues were raised during qualification procedures, mostly related to biomarker properties and assay validation (in 79% and 77% of all procedures, respectively). Issues related to the proposed context of use and rationale were least common yet were still raised in 54% of all procedures. While few qualified biomarkers are currently available, procedures focus increasingly on biomarkers for general use instead of those linked to specific drug compounds. The issues raised during qualification procedures illustrate the thorough discussions taking place between applicants and regulators-highlighting aspects that need careful consideration and underlining the importance of an appropriate validation strategy.

Figure 1

Selection of biomarker‐related qualification procedures at the EMA (European Medicines Agency). All procedures for qualification of novel methodologies that started between January 2008 and December 2020 were screened for eligibility according to the flowchart. FDA, US Food and Drug Administration; PRO, patient‐reported oucome.

Figure 2

Biomarker qualification procedures from 2008 to 2020. (a) All biomarker‐related qualification procedures are grouped according to the year in which the procedure was initiated: Stacked bars show the number of qualification advices (light gray) and qualification opinions (dark gray) for each year. (b) The type of applicant (company vs. consortium) and development context of the biomarker to be qualified were extracted for all 86 procedures. A distinction was made between biomarkers linked to a specific drug and clinical development program and those that were not. BM, biomarker; QA, qualification advice; QO, qualification opinion.

Figure 3

Main diseases or disease areas over time from 2008 to 2020. Number of biomarker procedures per disease or disease areas for which they were proposed over time. Diseases or disease areas for which only one procedure was started are grouped in the category “other.” In 2017 one procedure covered MS (multiple sclerosis) and two other diseases, and was therefore assigned to both categories MS and “other.” In 2020 one procedure covered MS, PD (Parkinson’s disease), and several other diseases. This procedure was counted for MS, PD, and “other.”

Figure 4

Different types of biomarkers in each CoU category. The stacked bars show the number of procedures in the three CoU categories for each type. BM, biomarker; CoU, context of use.