Biomarker Qualification Process Research Articles

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

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.

Perspectives on statistical strategies for the regulatory biomarker qualification process.

Qualification of a biomarker for use in a medical product development program requires a statistical strategy that aligns available evidence with the proposed context of use (COU), identifies any data gaps to be filled and plans any additional research required to support the qualification. Accumulating, interpreting and analyzing available data is outlined, step-by-step, illustrated by a qualified enrichment biomarker example and a safety biomarker in the process of qualification. The detailed steps aid requestors seeking qualification of biomarkers, allowing them to organize the available evidence and identify potential gaps. This provides a statistical perspective for assessing evidence that parallels clinical considerations and is intended to guide the overall evaluation of evidentiary criteria to support a specific biomarker COU.

Osteoarthritis: Current Molecular Biomarkers and the Way Forward

The ultimate hope of researchers and patients is a pathway to development of treatments for osteoarthritis to modify the disease process in addition to the symptoms. However, development of disease modifying drugs requires objective endpoints such as measures of joint structure, joint tissue homeostasis and/or joint survival-measures such as provided by imaging biomarkers, molecular biomarkers and joint replacement frequency, respectively. Although biomarkers supporting investigational drug use and drug approval include surrogate endpoints that may not necessarily reflect or directly correlate with the clinical outcome of interest, a formal biomarker qualification process currently exists that is a rigorous three stage process that yields biomarker approvals (or denials) for specific contexts of use. From a cost perspective, biochemical biomarkers are the 'ones to beat'; however, even well-validated biomarkers may not cross the translation gaps for eventual use in healthcare unless they offer an advantage in terms of cost per quality adjusted life year. This review summarizes the case FOR and AGAINST biomarkers in drug development and highlights the current data for a subset of biomarkers in the osteoarthritis research field informing on cartilage homeostasis, joint inflammation and altered subchondral bone remodeling.

The Autism Biomarkers Consortium for Clinical Trials (ABC-CT): Scientific Context, Study Design, and Progress Toward Biomarker Qualification.

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA’s Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.

STRATEGIES AND CHALLENGES IN METHOD DEVELOPMENT AND VALIDATION FOR THE ABSOLUTE QUANTIFICATION OF ENDOGENOUS BIOMARKER METABOLITES USING LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY.

Metabolomics is a dynamically evolving field, with a major application in identifying biomarkers for drug development and personalized medicine. Numerous metabolomic studies have identified endogenous metabolites that, in principle, are eligible for translation to clinical practice. However, few metabolomic-derived biomarker candidates have been qualified by regulatory bodies for clinical applications. Such interruption in the biomarker qualification process can be largely attributed to various reasons including inappropriate study design and inadequate data to support the clinical utility of the biomarkers. In addition, the lack of robust assays for the routine quantification of candidate biomarkers has been suggested as a potential bottleneck in the biomarker qualification process. In fact, the nature of the endogenous metabolites precludes the application of the current validation guidelines for bioanalytical methods. As a result, there have been individual efforts in modifying existing guidelines and/or developing alternative approaches to facilitate method validation. In this review, three main challenges for method development and validation for endogenous metabolites are discussed, namely matrix effects evaluation, alternative analyte-free matrices, and the choice of internal standards (ISs). Some studies have modified the equations described by the European Medicines Agency for the evaluation of matrix effects. However, alternative strategies were also described; for instance, calibration curves can be generated in solvents and in biological samples and the slopes can be compared through ratios, relative standard deviation, or a modified Stufour suggested approaches while quantifying mainly endogenous metabolitesdent t-test. ISs, on the contrary, are diverse; in which seven different possible types, used in metabolomics-based studies, were identified in the literature. Each type has its advantages and limitations; however, isotope-labeled ISs and ISs created through isotope derivatization show superior performance. Finally, alternative matrices have been described and tested during method development and validation for the quantification of endogenous entities. These alternatives are discussed in detail, highlighting their advantages and shortcomings. The goal of this review is to compare, apprise, and debate current knowledge and practices in order to aid researchers and clinical scientists in developing robust assays needed during the qualification process of candidate metabolite biomarkers. © 2019 John Wiley & Sons Ltd. Mass Spec Rev.

Shear Wave Elastography as a Quantitative Biomarker of Clinically Significant Portal Hypertension: A Systematic Review and Meta-Analysis.

To qualify shear wave elastography (SWE) as a biomarker for clinically significant portal hypertension (CSPH) beyond proof of concept, we aimed to accumulate and summarize the current evidence through systematic review and meta-analysis. A computerized literature search was performed to identify studies from MEDLINE and EMBASE up to February 9, 2017. Studies on the diagnostic performance of liver stiffness measurements using SWE for CSPH with hepatic venous pressure gradient (HVPG) as the reference standard were included. Various aspects of SWE were comprehensively assessed. The summary diagnostic performance of SWE for the diagnosis of CSPH and the summary correlation coefficient between liver stiffness measured using SWE and HVPG were evaluated through a meta-analysis. Nine articles (including 746 patients) were retrieved. The diagnostic performance of SWE for the diagnosis of CSPH was fairly good, with a summary sensitivity of 85% (95% CI, 75-91%; I2 = 78.56%) and summary specificity of 85% (95% CI, 77-90%; I2 = 0%); the area under the ROC curve was 0.88 (95% CI, 0.85-0.91). The summary correlation coefficient between liver stiffness and HVPG measurements was 0.741 (95% CI, 0.658-0.825; I2 = 0%). These results support the value of SWE as a diagnostic biomarker for CSPH. However, there was significant heterogeneity in the imaging devices, protocols, liver stiffness measurement methods, and cutoff values used, which suggests that standardization is required. The consistent evidence favoring SWE as a biomarker for CSPH should be considered in the biomarker qualification process and management of patients with CSPH.

Preclinical biomarker qualification.

Biomarkers are ubiquitously used within drug development programs in both nonclinical species and in humans to assess safety and efficacy of novel compounds. To routinely apply such novel biomarkers with certainty, a well-defined data package is necessary for review and endorsement by regulatory agencies including the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. This type of endorsement is known as regulatory qualification. Novel approaches are being applied to speed the process, lower the resource intensity, and increase the accessibility of biomarker qualification data and it is likely that consortia will continue to play a fundamental role in the qualification process by bringing together like-minded stakeholders focused on specific tools to accelerate drug development. This article will focus on learnings from the previous three nonclinical biomarker qualification projects, as well as discuss the progression of preclinical biomarker projects into the clinical qualification space and the current strategy for the use of nonclinical biomarker data in the translational qualification of clinical biomarkers; much like nonclinical information is used in the approval of drug development candidates. Impact statement This minireview provides an overview of the history of preclinical biomarker qualification by summarizing the three examples of this type of qualification with US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. In addition, an overview of the biomarker qualification process is included to educate key stakeholders with links to relevant white papers that provide information on current evidentiary considerations. The manuscript also provides new information on the evolution of the role that preclinical qualification plays in clinical qualification of biomarkers and the novel approaches that are being utilized to improve the process.

The Predictive Safety Testing Consortium: safety bio-markers, collaboration, and qualification

The Predictive Safety Testing Consortium (PSTC) is one of nine consortia comprising the Critical Path Institute (C-Path), a non-profit organisation launched in 2005 and dedicated to playing the role of a catalyst in the development of new approaches that advance medical innovation and regulatory science. C-Path achieves this by lead-ing teams that share data, knowledge and expertise resulting in sound, consensus-based science. PSTC is a unique, public-private partnership that brings pharmaceutical companies together to share and validate safety testing methods under the advisement of worldwide regulatory agencies, including the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). The eighteen corporate members of PSTC share a common goal: to find improved safety testing methods and approaches utilizing fluid-based safety biomarkers which accurately predict drug-induced tissue injury. Specifically, the primary goal of PSTC is the qualification of novel translational safety biomarkers for use in early clinical trials in order to ena-ble safer investigations and development of new drug candidates. This manuscript describes the critical importance of improved safety biomarkers to the drug development process and the present state of the biomarker qualification process with regulatory agencies. In addition, the work that the PSTC and its collaborative partners have done and con-tinue to do to identify and qualify more selective and specific safety biomarkers is highlighted. Finally, successes in-cluding the recently adopted regulatory Letter of Support and ongoing efforts to better define the regulatory qualifica-tion process and an integrated translational safety strategy are also discussed.

The Predictive Safety Testing Consortium: safety biomarkers, collaboration, and qualification

The Predictive Safety Testing Consortium (PSTC) is one of nine consortia comprising the Critical Path Institute (C-Path), a non-profit organisation launched in 2005 and dedicated to playing the role of a catalyst in the development of new approaches that advance medical innovation and regulatory science. C-Path achieves this by lead-ing teams that share data, knowledge and expertise resulting in sound, consensus-based science. PSTC is a unique, public-private partnership that brings pharmaceutical companies together to share and validate safety testing methods under the advisement of worldwide regulatory agencies, including the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). The eighteen corporate members of PSTC share a common goal: to find improved safety testing methods and approaches utilizing fluid-based safety biomarkers which accurately predict drug-induced tissue injury. Specifically, the primary goal of PSTC is the qualification of novel translational safety biomarkers for use in early clinical trials in order to ena-ble safer investigations and development of new drug candidates. This manuscript describes the critical importance of improved safety biomarkers to the drug development process and the present state of the biomarker qualification process with regulatory agencies. In addition, the work that the PSTC and its collaborative partners have done and con-tinue to do to identify and qualify more selective and specific safety biomarkers is highlighted. Finally, successes in-cluding the recently adopted regulatory Letter of Support and ongoing efforts to better define the regulatory qualifica-tion process and an integrated translational safety strategy are also discussed.

A 20 years of progress and future of quantitative magnetic resonance imaging (qMRI) of cartilage and articular tissues-personal perspective.

In 1994, the first article on quantitative magnetic resonance imaging (qMRI) of articular cartilage was published, and tremendous progress in image acquisition, image analysis, and applications has since been made. The objective of this personal perspective is to highlight milestones in the field of qMRI of cartilage and other articular tissues over these past 20 years. Based on a Pubmed search of original articles, the authors selected 30 articles which they deemed to be among the first to provide an important technological step forward in qMRI of cartilage, provided a first application in a particular context, or provided mechanistic insight into articular cartilage physiology, pathology, or treatment. This personal perspective summarizes results from these 30 articles. Further, the authors provide examples of how qMRI of cartilage has translated to quantitative analysis approaches of other articular tissues, including bone, meniscus, and synovium/edema. Eventually, the report provides a summary of how the lessons learned might be applied to future clinical trials and clinical practice. Over the past 20 years, quantitative imaging of articular tissues has emerged from a method to a dynamic field of research by its own. Continuing the qMRI biomarker qualification process will be crucial in convincing regulatory agencies to accept these as primary outcomes in phase 3 intervention trials. Once successful structural intervention will actually become available in OA, qMRI biomarkers may play an essential role in monitoring response to therapy in the clinic, and in stratifying disease phenotypes that respond differently to treatment.

Building a roadmap to biomarker qualification: challenges and opportunities.

The traditional route for regulatory acceptance of biomarkers in drug development is through submission of biomarker data in drug approval submissions in the context of a single drug development program. The US FDA's Critical Path Initiative called for establishment of a biomarker qualification process to enable progress in the drug development paradigm. In response to this, the Center for Drug Evaluation and Research (CDER) established a Biomarker Qualification Program (BQP) to qualify a biomarker for a specific context of use (COU). The qualified biomarker can then be used in multiple drug development programs for this COU without re-review. Here, we describe some of the features of the BQP and two new initiatives that have the potential to aid biomarker development through early interactions with the FDA. Finally, we discuss some of the feedback the FDA has received from submitters and the BQP's actions to strengthen the program.

No seven year itch for Metabolomics

Welcome to the Eighth Volume of Metabolomics! It continues to be an exciting journey for the journal and I hope you are as pleased as I to see that after seven publication years that the impact of the journal remains very healthy. This is of course due to the great papers, reviews and opinion articles that we publish and I thank these Authors very much for choosing Metabolomics as the home for their exciting and interesting work. It goes without saying that a very big thank you also goes to the many Reviewers and Editorial Board who spend some of their valuable time assessing these articles and doing such a good job. Unfortunately as some of you know we now reject just over half of the papers that are submitted for review and we expect this rejection rate to increase over the coming years. Again we have a nice front cover from Drs Rick Beger and Thomas Colatsky highlighting the biomarker qualification process at the US FDA. It is appropriate that the journal features some of the most important work on the front of the journal and I hope you find these informative. This year we are increasing our publication frequency from four to six issues per annum, and this is a reflection of the fact that last year the number of manuscripts submitted to the journal has more than doubled; importantly without a drop in scientific quality. When appropriate Metabolomics publishes themed or what we refer to as Special Issues and these are edited by Guest Editors. In 2011 we are publishing two of these: the first Special Issue covers Data Analysis for Metabolomics and is edited by Drs Johan Westerhuis and Jeroen Jansen; the second is edited by Drs Rick Dunn and Thomas Hankemeier and the theme is Mass Spectrometry for Metabolomics. I am very grateful to all these Guests Editors for their hard work and commitment to delivering a great line up of primary papers, reviews and tutorials. If any of you have thoughts on future special issues I would be very interested to hear about them, as I would be to hear about potential review articles or tutorials. I can be contacted at the coordinates below. I remind you that Metabolomics also has a twitter presence (http://twitter.com/metabolomics) and there are regular updates on the Journal tweeted there. I hope as ever that you enjoy this issue and continue to read and send your best work to Metabolomics. I wish you all the very best for a successful and peaceful 2012.

Qualifying biomarkers for use in drug development: a US Food and Drug Administration overview

Despite huge investments, there are still difficulties in the development of novel therapies. This has led to a growing interest in the use of new tools, such as biomarkers, that can help overcome development hurdles while providing increased certainty about drug safety and efficacy. Until recently, no formal process has existed for qualifying biomarkers for regulatory decision making. The FDA's Center for Drug Evaluation and Research (CDER) has initiated such a process, which has led to the recent qualification of two biomarker sets for use in regulatory decisions. This article provides the reader with an overview of the CDER Biomarker Qualification Process and is shaped by the recent regulatory developments in biomarker qualification and the consideration of frequently asked questions in the area. The Biomarker Qualification Process is intended to be a mission-critical, value-added CDER program. The success of this effort will depend on the willingness of pharmaceutical and diagnostic companies, consortia, the FDA and other regulatory agencies to continue to work together, motivated by the benefits that can accrue to public health through the increasing availability of qualified biomarkers for use in drug development.

Metabolomics data and the biomarker qualification process

Since its initial applications in healthcare research over a decade ago, metabolomics has matured into a technology that can now reliably detect and quantify hundreds of metabolites in biofluids and tissue samples. With substantial improvements in analytical capabilities in recent years, metabolomics now has the potential to provide sensitive and specific biomarkers of health and disease status, drug toxicity and therapeutic efficacy. Although many of the clinical biomarkers currently in use are metabolites such as glucose, cholesterol, and creatinine, few, if any, new metabolites (or panel of metabolites) derived from metabolomic analyses have been submitted to the FDA as biomarker candidates. Under a recent FDA draft Guidance for Industry from the Center for Drug Evaluation and Research (CDER), biomarkers discovered using metabolomics, like those derived from genetic, transcriptomic, and proteomic studies, may be submitted to CDER for consideration as new drug development tools and entered into a formal biomarker qualification process. The qualification process begins with a letter of intent from the submitter, followed by discussions with FDA and then the submission of data supporting the performance of the biomarker within a specific context of use. CDER forms a Biomarker Qualification Review Team at the start of the interactive process to advise the biomarker developer on the type of information important to support the proposed context of use, and review the data that evaluates the biomarker for the proposed context of use when the biomarker development appears complete and the full supporting data are submitted. Once qualified, a biomarker can be used in drug development within the qualified context of use without requesting additional regulatory review concerning its suitability.

Comparative profile of commercially available urinary biomarkers in preclinical drug-induced kidney injury and recovery in rats

We designed a study to provide reversibility and comparative injury data for several candidate urinary biomarkers of kidney injury in the United States Food and Drug Administration biomarker qualification process. The nephrotoxin gentamicin was given to rats once on each of three days and the animals were killed during dosing or over the following 42 days. Between days one and three, all biomarkers except albumin were elevated, peaked at day 7, and returned to control levels by day 10 (μ- and α-glutathione S-transferases, and renal papillary antigen-1) or day 15 (kidney injury molecule-1, lipocalin-2, osteopontin, and clusterin). All biomarkers performed better during injury than during recovery except osteopontin, which performed equally well in both time periods. During the evolution of injury, kidney injury molecule-1, renal papillary antigen-1, and clusterin best mirrored the histopathologic lesions. During injury resolution, kidney injury molecule-1, osteopontin, and blood urea nitrogen best reflected recovery. Based on histopathology, necrosis, or apoptosis scoring, kidney injury molecule-1 was the best biomarker of overall renal injury. Evaluation by regeneration score showed that renal papillary antigen-1 best reflected tubular and/or collecting duct regeneration, especially during recovery. Thus, these biomarkers performed with different effectiveness when evaluated by individual pathological processes such as necrosis, apoptosis, and regeneration.