key: cord-0815124-iz70cqgk authors: Bime, Christian; Camp, Sara M.; Casanova, Nancy; Oita, Radu C.; Ndukum, Juliet; Lynn, Heather; Garcia, Joe G.N. title: The Acute Respiratory Distress Syndrome Biomarker Pipeline: Crippling Gaps between Discovery and Clinical Utility date: 2020-06-26 journal: Transl Res DOI: 10.1016/j.trsl.2020.06.010 sha: f0e9da21a23331797317313e6ba3c50c0692283b doc_id: 815124 cord_uid: iz70cqgk Recent innovations in translational research have ushered an exponential increase in the discovery of novel biomarkers, thereby elevating the hope for deeper insights into “personalized” medicine approaches to disease phenotyping and care. However, a critical gap exists between the fast pace of biomarker discovery and the successful translation to clinical use. This gap underscores the fundamental biomarker conundrum across various acute and chronic disorders: how does a biomarker address a specific unmet need? Additionally, the gap highlights the need to shift the paradigm from a focus on biomarker discovery to greater translational impact and the need for a more streamlined drug approval process. The unmet need for biomarkers in acute respiratory distress syndrome (ARDS) is for reliable and validated biomarkers that minimize heterogeneity and allow for stratification of subject selection for enrollment in clinical trials of tailored therapies. This unmet need is particularly highlighted by the ongoing SARS-CoV-2/COVID-19 pandemic. The unprecedented numbers of COVID-19-induced ARDS cases has strained health care systems across the world and exposed the need for biomarkers that would accelerate drug development and the successful phenotyping of COVID-19-infected patients at risk for development of ARDS and ARDS mortality. Accordingly, this review discusses the current state of ARDS biomarkers in the context of the drug development pipeline and highlight gaps between biomarker discovery and clinical implementation while proposing potential paths forward. We discuss potential ARDS biomarkers by category and by context of use, highlighting progress in the development continuum. We conclude by discussing challenges to successful translation of biomarker candidates to clinical impact and proposing possible novel strategies. Innovations in laboratory biochemistries, molecular biology, and "omics" medicine have ushered in an era with the potential to unravel the Gordian knot of identifying validated molecular markers of disease 1, 2 . The emergence of precision medicine and high throughput precision technologies elevated aspirations for defining novel biomarkers that would accelerate improved treatment of diverse adverse health conditions by facilitating the identification of responders to promising novel or repurposed therapeutic strategies 3, 4 . A cursory review of the medical literature [5] [6] [7] over the past three decades revealed the emergence of an increasing number of biomarker candidates. However, the exponential rate of initial discovery has now completely outpaced the ability of the biomedical community to successfully develop and validate the clinical utility of prospective biomarkers 7, 8 . In fact, only ~0.1% of potentially clinically-relevant biomarkers described in the literature have progressed to utility as a meaningful and routinely utilized clinical readout 9 . The reasons for this massive disconnect are multifactorial including the stark reality that the majority of biomarkers identified are by investigators in government-funded university laboratories that are ill-resourced to complete the biomarker development and validation continuum 5 . This realization led the U.S. Congress under the 21 st Century Cures Act of 2016, to encourage the U.S. Food and Drug Administration (FDA) to create the biomarker qualification program as part of the drug development toolkit, an effort to guide researchers and accelerate the development of promising biomarkers [10] [11] [12] [13] . Prior reviews of biomarkers in acute respiratory distress syndrome (ARDS), a serious critical care illness in dire need of validated and clinically useful biomarkers, have largely served as diligent but descriptive approaches outlining new technologies or summarizing the pathobiology of current biomarkers [14] [15] [16] [17] [18] [19] [20] . In contrast, this current review is highly divergent from prior reports and seeks to discuss the current state of ARDS biomarkers in the context of the drug development pipeline and to highlight the gaps between discovery and clinical implementation while proposing potential paths forward. Our intent is to shift the paradigm from a focus on biomarker discovery that is currently relegated to demonstrating a correlation between a specific biomarker and either the development of ARDS or ARDS severity, to a focus on the clinical utility and implementation of the biomarker within well-defined contexts of use including subject stratification in clinical trials 4, 5 . The need for such a translational focus is particularly highlighted by the ongoing SARS-CoV-2/COVID-19 pandemic. COVID-19-induced ARDS has strained health care systems across the world and exposed the need for biomarkers that would accelerate disease phenotyping and drug development. The clinical definition of the highly heterogeneous ARDS includes acute arterial hypoxemia and a ratio of partial pressure of arterial oxygen [PaO 2 ] to fraction of inspired oxygen [FiO 2 ] that is less than 300, bilateral pulmonary opacities, and the exclusion of cardiac failure or other reversible primary causes 21 . Since lung biopsies are not routinely obtained in ARDS, this clinical definition aims to identify patients with non-cardiogenic pulmonary edema, a process characterized by increased protein permeability of the alveolar-capillary membrane 22, 23 . Diagnostic uncertainty in ARDS further exacerbates disease heterogeneity and is a potential source of bias in conducting clinical trials 23 . There is a compelling unmet medical need to identify clinical and/or disease-specific biochemical parameters that risk-stratify patients for both accurate prognostication and clinical trial purposes. Stratification of ARDS patients with reliable biomarkers that are predictive of mortality would optimize participant selection for clinical trial enrollment by focusing on those subjects most likely to benefit from novel clinical interventions 24, 25 . More than 45 promising candidate biomarkers in ARDS have been described in the medical literature, however, to date no biomarker has been successfully developed as an accepted point of care surrogate marker of disease 14, 15 . The heterogeneity of the ARDS phenotype, the variability of candidate biomarkers, and the focus on biomarker discovery without consideration of biomarker development, are all serious contributors to the abysmal record for ARDS biomarker development and the poor performance record of ARDS clinical trials. Biomarkers, objectively measured as characteristic of clinical, pathologic, or physiologic processes, can be bioanalytical (proteins, metabolites, DNA genetic variants, RNA types), histologic, or radiographic 12, 26 . The ideal bioanalytical biomarker is easily measured in blood or in other bodily fluids, has an excellent analytical sensitivity, high statistical sensitivity and specificity, varies rapidly in response to impactful therapies, aids in subject stratification, and exhibits biologic plausibility 26 . Although traditional clinical or laboratory variables such as blood pressure readings, PaO 2 , hemoglobin A 1C , and glomerular filtration rates are examples of "biomarkers", in the context of translational research, the term often refers to a marker used to provide insight into a "personalized medicine" approach to phenotyping and care 27 . In this review, we have attempted to summarize the current state of ARDS biomarkers based upon FDA-proposed categories with assessment of the advancement of each ARDS biomarker in the drug development continuum. Finally, we have sought to identify potential challenges to the successful translation of candidates through the pipeline of biomarker development. Of note, the biomarkers covered in this review is not an exhaustive list of possible ARDS biomarkers. The pathogenesis of ARDS includes a combination of endothelial injury, epithelial injury, an intense inflammatory cascade, dysregulated coagulation, fibrosis, and apoptosis in response to diverse stimuli 14 (Figure 1 ). This acute dysregulation of various biochemical and cellular pathways allows for the generation of numerous potential biomarkers associated with risk or severity of ARDS 14, 15 . However, to address the specific unmet medical needs in ARDS, biomarkers must provide specific contexts such as early However, initial reports correlating high plasma levels of SP-A and SP-B or reduced BAL levels of SP-D with a diagnosis of ARDS have not been confirmed 35, 40 . Selectins. These membrane-associated glycoproteins mediate the adhesion of leukocytes and platelets to the vascular endothelium 41 . Plasma levels of P-selectin and E-selectin are elevated in patients with acute lung injury compared to those with sepsis without lung injury 42, 43 . However, these initial reports have not been robustly replicated. glycoprotein that is expressed on the endothelial cell surface 65 . Levels of sICAM-1 are upregulated during inflammation in response to stimulation by interferon-γ (IFN-γ) or IL-1 66 . In multiple studies, elevated baseline levels of sICAM have been associated with increased mortality from ARDS 67-69 . on cell surface to its active form by the thrombomodulin-thrombin complex 70, 71 . with anti-inflammatory properties that can improve endothelial permeability 72 , and exert antiapoptotic effects 73 . Activated protein C also inactivates PAI-1 thus promoting fibrinolysis 74 . Low plasma levels of protein C have been associated with higher ARDS mortality 75 . Mendelian randomization analysis with genetic variation as an instrumental variable linked to plasma levels of a biomarker can infer causal inference under certain assumptions 78, 86 . Plasma levels of Ang-2, sRAGE and S1P3 have been identified as potential casual biomarkers in sepsis-associated ARDS using these techniques 87, 88 . Combining biomarkers to improve diagnostic, predictive and prognostic value. The biomarker development pipeline can be divided into the following phases: Validation for clinical utility should distinguish between at-risk ICU controls and ARDS patients and between ARDS survivors and non-survivors. Ideally, validation for clinical utility should include an assessment of performance against clinically meaningful outcomes in multiple prospective cohort studies. For ARDS, mortality is the universal endpoint, however, the context of use determines the endpoint chosen. As noted above, the historical focus in the ARDS biomarker research community has been on discovery. No ARDS biomarker candidate has cleared regulatory qualification and approval. As noted above, general biomarker development, including specific utility in ARDS, remains a limited priority and pales in comparison to efforts in government-funded university laboratories where novel biomarker discovery is the focus and centers on demonstrating disease associations 5 but do not address issues of clinical validation. The focus of these laboratories is entirely understandable given the lack of capacity and resources to undertake the stringent biomarker profiling required to attract investment in clinical trials 5 concern is the relative absence of multidisciplinary coordinated efforts in the ARDS research community to address the unmet need for ARDS biomarkers which requires integrative and collaborative approaches. In order to address the major barriers of moving forward beyond association and towards causation, mechanism, and predicting response, researchers need to veer from working in "silos" and instead move to the forging of new collaborative, integrative approaches to biomarker development 5 . This is important because specific failures of biomarkers begin at the discovery and analytical validation phases. The need for broadly accepted standards to inform every module and decision point of biomarker development cannot be overemphasized 5 therapies for specific endotypes as suggested by biomarkers, and a more streamlined drug approval process. This will require multilateral collaboration and, while challenging, has never before been as within reach as it is today. Genomics-Inspired Biomarkers and Diagnostics-Where Are They? 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