Defining the Path Forward for Biomarkers to Address Unmet Needs in Inflammatory Bowel Diseases

Abstract

Despite major advances in the inflammatory bowel diseases field, biomarkers to enable personalized and effective management are inadequate. Disease course and treatment response are highly variable, with some patients experiencing mild disease progression, whereas other patients experience severe or complicated disease. Periodic endoscopy is performed to assess disease activity; as a result, it takes months to ascertain whether a treatment is having a positive impact on disease progression. Minimally invasive biomarkers for prognosis of disease course, prediction of treatment response, monitoring of disease activity, and accurate diagnosis based on improved disease phenotyping and classification could improve outcomes and accelerate the development of novel therapeutics. Rapidly developing technologies have great potential in this regard; however, the discovery, validation, and qualification of biomarkers will require partnerships including academia, industry, funders, and regulators. The Crohn’s & Colitis Foundation launched the IBD Biomarker Summit to bring together key stakeholders to identify and prioritize critical unmet needs; prioritize promising technologies and consortium approaches to address these needs; and propose harmonization approaches to improve comparability of data across studies. Here, we summarize the outcomes of the 2018 and 2019 meetings, including consensus-based unmet needs in the clinical and drug development context. We highlight ongoing consortium efforts and promising technologies with the potential to address these needs in the near term. Finally, we summarize actionable recommendations for harmonization, including data collection tools for improved consistency in disease phenotyping; standardization of informed consenting; and development of guidelines for sample management and assay validation. Taken together, these outcomes demonstrate that there is an exceptional alignment of priorities across stakeholders for a coordinated effort to address unmet needs of patients with inflammatory bowel diseases through biomarker science.

Biomarkers are needed for prognosis, prediction of treatment response, and monitoring in inflammatory bowel diseases. The Crohn’s & Colitis Foundation launched the IBD Biomarker Summit to bring together stakeholders to prioritize unmet needs and approaches. This article summarizes the meeting outcomes.

INTRODUCTION

Gastroenterologists and drug developers lack minimally invasive validated and gold standard biomarkers to accurately diagnose inflammatory bowel diseases (IBDs), prognosticate its disease course, and predict and monitor treatment response. Inflammatory bowel disease is currently diagnosed and monitored using a combination of invasive endoscopic and histological measurements, nonspecific serologic and fecal markers, and nonspecific clinical parameters. In some cases, this leads to delayed conclusive diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC),¹ collectively known as IBD. More importantly, even after a correct diagnosis, current endoscopic, fecal, serologic, and clinical parameters are inadequate to accurately prognosticate disease course or predict response to treatment.² Addressing these issues is critical, as these diseases are very heterogeneous and exhibit a highly variable disease course, with some patients experiencing more aggressive disease than others, characterized by unremitting disease and the need for drug escalation and/or surgery.^{3, 4} For example, within the first 10 years after diagnosis of CD, about 53% of patients will experience severe stricturing or penetrating complications⁴ that dramatically impair quality of life; once these complications develop, they generally require surgery, and their recurrence after surgery is frequent.^{5, 6} Response to treatment is also variable among IBD patients, with an estimated 30%–40% of primary nonresponse and 30% of secondary nonresponse to biologics,^{7, 8} which are the most effective treatments available. Thus, given the heterogeneous disease course, variable patient response to treatment, and invasive assessment modalities, there is a pressing unmet need in IBD to identify, validate, and qualify noninvasive biomarkers with improved performance to provide optimal patient care and advance new drug candidates in biomarker-stratified clinical trials.²

Needed types of biomarkers include (1) prognostic biomarkers for prediction ​of quiescent, relapsing, or complicated disease course, and (2) biomarkers for prediction ​and monitoring of treatment response, which will enable more personalized treatments​ according to patients’ predicted outcomes and the design of efficient and impactful clinical trials (Fig. 1). Biomarkers to enable early classification of patients into subpopulations with different underlying biological mechanisms (endotypes) for more accurate diagnosis are also a priority. Additional types of biomarkers outside the scope of this review (eg, for safety and susceptibility) also are of significant interest. Discovering and qualifying these new biomarkers will require concerted scientific and operational efforts and resources from academia, pharmaceutical, and diagnostic industries, funders and regulatory agencies. Examples of such multi-institutional efforts to advance biomarkers to the clinic have been achieved in the fields of oncology, nephrology, and metabolic diseases,⁹ and we believe that the time is right to build a path for success in the IBD biomarker field.

FIGURE 1.

Biomarkers required to address unmet clinical needs in IBD. Prognostic biomarkers are needed to predict, early in the disease or at diagnosis, a quiescent or aggressive disease course characterized by continuous relapse, need for drug escalation, and development of penetrating and stricturing complications (left panel). Predictive biomarkers are required to identify, before treatment initiation, those patients likely to respond or not to drug treatment (center panel). Monitoring biomarkers are also needed to facilitate frequent and minimally invasive monitoring of patient response to treatment during drug trials and in clinical practice (right panel).

The Crohn’s & Colitis Foundation, cognizant of the current lack of adequate biomarkers for clinical practice and drug development and of the complexities of biomarker research, decided to convene the key stakeholders in IBD biomarker discovery, development, and qualification in a collaborative, precompetitive environment to foster discussions, scientific collaborations, and actionable decisions to advance the field. Therefore, the Crohn’s & Colitis Foundation, in collaboration with the Foundation for the National Institutes of Health (FNIH) and the Critical Path Institute (C-Path), launched the IBD Biomarker Summit in 2018. This annual summit brings together representatives from pharmaceutical and diagnostic companies, regulatory agencies, academic clinical and research centers, and nonprofit organizations to discuss advances, challenges, and collaborative opportunities in the IBD biomarker field.

The specific objectives for the 2018 and 2019 summits were to: (1) assess the state of the field, focusing on critical gaps and promising approaches for identification and validation of IBD biomarkers; (2) develop a consensus problem statement and roadmap to address critical gaps; and (3) propose approaches to optimize harmonization of research activities. Topics included biomarkers in IBD clinical practice and drug development, mucosal healing, quantitative imaging and endoscopy, molecular biomarkers, data integration, and decision-modeling. In conjunction with the summit, the Crohn’s & Colitis Foundation and summit participants also conceived the publication of this special IBD biomarkers issue, in which scientific and clinical leaders in the field would delineate current challenges and opportunities for different biomarker modalities. In this review article, we summarize the key themes and ideas that emerged at the summits held in 2018 and 2019, to be further developed at the 2020 meeting. In addition, we describe ongoing activities addressing biomarker development in the areas of prognostic, predictive, and monitoring needs of IBD clinicians and drug developers. Finally, we report on a roadmap discussed at the 2019 summit toward harmonization and coordination of data and sample collection across studies, which would accelerate the progress of the community overall toward biomarker discovery, validation, and qualification.

IBD BIOMARKER DEVELOPMENT: FUNDAMENTALS, REGULATORY FRAMEWORK , AND UNMET NEEDS

Although the content of the Biomarker Summit and this special issue of Inflammatory Bowel Diseases demonstrate the exciting recent progress in IBD biomarker research, there clearly remains a critical, unmet need for validated and precise biomarkers to realize the potential for precision medicine for IBD. Here, we summarize the defining features of biomarkers needed to accomplish this goal, the regulatory framework in which they are evaluated, and certain critical unmet needs—both within clinical practice and drug development—that could be addressed by advances in biomarker science within the IBD field.

Biomarker Fundamentals

A biomarker has been defined by the FDA-NIH Biomarker Working Group as “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions. . . . A biomarker is not an assessment of how an individual feels, functions, or survives.” ¹⁰ As such, biomarkers are the foundation of precision medicine and comprise a broad and diverse set of indicators including molecular, histologic, radiographic, endoscopic, physiologic and combinatorial types, but excluding patient-reported outcomes and physician global assessments. Biomarkers may be used for clinical management or to advance research and development, particularly clinical trials intended to evaluate the safety and efficacy of an investigational drug in a specific patient population. Biomarkers can also advance understanding of environmental exposures and their impact on disease onset and progression.¹¹ From a clinical perspective, the use of any biomarker should, ideally, be limited to a specific context within which the use of the biomarker has been demonstrated to confer benefit for patient experience and/or outcomes.^{10, 12} The discovery of a novel biomarker can emerge from multiple approaches including, but not limited to, omics-based screening^13–15 or hypothesis-driven interrogation of candidate markers.^{16, 17} Mining of real-world data for biomarker discovery might provide another exploratory approach.¹⁸

Once a candidate biomarker has been identified and an appropriate assay has been developed, its validation must progress in several stages. Analytical validation refers to the characterization of a specific assay or set of assays in terms of reliability, precision, reproducibility, and additional performance metrics.¹⁹ The variability and sources of bias should be sufficiently well understood to ensure that the results of the assay can be meaningfully interpreted in the context in which the assay will be used.²⁰ The level of analytical validation required depends on the setting in which the assay will be used. For example, an assay that will be operated in routine clinical settings to support critical medical decisions needs to be exceptionally robust, whereas an assay used to address an exploratory research question would not typically require the same level of analytical validation.²¹

Clinical validation is the process of confirming that a candidate biomarker is reliably associated with a clinically meaningful outcome or condition within a representative patient population, preferably across multiple independent cohorts. The validity and discriminatory power of a biomarker is typically quantified using standard statistical constructs including area under the receiver-operator curve (AUROC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value.²² Clearly defining the context in which the biomarker will be used is also critical, as the clinical validation of the biomarker depends on the patient population and clinical situation in which it can be applied. Finally, clinical utility evaluation refers to the process of demonstrating that implementation of a biomarker in clinical management results in improved outcomes and/or cost-effectiveness relative to management not informed by use of the biomarker.²³ Effective clinical use of a biomarker requires an overall acceptable risk-benefit profile and an assay that is not prohibitive in terms of adverse events, cost, or time required to perform the assay.¹²

Regulatory Framework

The use of biomarkers to accelerate drug development has been accelerated by the development of a formal regulatory process, authorized through recent legislation and developed by a multidisciplinary working group, for the regulatory acceptance (qualification) of the use of a biomarker in the context of a drug development objective.^{10, 12, 24} This process, the Biomarker Qualification Program, is administered by the Center for Drug Evaluation and Research and considers the data available in support of a specific biomarker within a specific drug development context. Criteria for qualification include the reproducibility of data across multiple studies and cohorts, analytical reliability of the assay or range of assays that will be used, and feasibility of the biomarker’s use should a drug be approved (ie, whether the biomarker could be practically implemented in the context of the drug’s use within clinical practice). Biomarker qualification can also be proposed for preclinical applications relating to investigational new drug (IND) designations. To date, no biomarker has been qualified for any use specific to clinical trials for IBD field, despite the substantial investment in drug development and biomarker research within this field and despite the fact that certain biomarkers, such as fecal calprotectin, are widely used clinically.

Biomarker qualification is meant to complement but not exclude other uses of biomarkers within research and clinical practice. It is important to note that use of a biomarker in clinical practice does not require qualification under the Biomarker Qualification Program, and conversely, qualification of a biomarker does not imply that a product (eg, drug or device) based on an assay for that biomarker has been approved for clinical use.²⁵ The regulatory framework governing marketing approval for products based on biomarker assays will depend on legal jurisdiction and on the type of assay and instrument. For example, within the United States, a laboratory test would be regulated under the Laboratory-Developed Test (LDT) framework²⁶ and/or the FDA’s In Vitro Diagnostic (IVD) device pathway.²⁷ In the case of a companion diagnostic, for an in vitro diagnostic specifically approved for use in conjunction with a specific drug, market approval requires a coordinated drug approval and IVD device approval. The FDA qualification of validated biomarkers, or approval of specific diagnostic devices utilizing biomarkers, would be most impactful; however, even in the absence of such approvals, novel biomarkers could accelerate progress in the IBD field. For example, availability of validated biomarkers targeting patients likely to respond to a new therapy could enable more effective and innovative drug development through implementation of biomarker-stratified clinical trial design.

Biomarker Needs in IBD

Prognostic biomarkers to optimize clinical management

IBD is a progressive disease. Over time, uncontrolled inflammation, which will affect a subset of patients, causes repeated damage to the bowel wall, increasing risk for complications and deterioration of long-term bowel function.^{3, 28} There may be a window of opportunity, after initial diagnosis but before the onset of severe intestinal inflammation, to aggressively intervene in the disease and potentially modify its long-term course in high-risk patients.³ However, for those patients at lower risk of severe or complicated disease, aggressive therapy may expose them to unnecessary risk. At the present time, biomarkers are not available to readily stratify patients, at or after diagnosis, who will or will not experience severe disease and complications later. Such prognostic biomarkers could be highly valuable to optimize treatment early in the disease course to improve long-term outcomes and quality of life. For example, early administration of antitumor necrosis factor (anti-TNF)-α therapy may significantly reduce the incidence of penetrating inflammation (B3 phenotype) in pediatric Crohn’s disease.²⁹ A biomarker that would stratify patients at the time of diagnosis who are likely to develop B3 complications would also identify those patients as very likely to benefit from anti-TNF-α therapy.

Novel biomarkers to enable accurate classification of patients into subpopulations with distinct disease features and biology (endotypes) could have implications for both diagnosis and prognosis. For example, diagnosis of CD vs UC is currently based in part on the presence and location of intestinal inflammation at the time of diagnosis, both of which can fluctuate over time, requiring changes in diagnosis and clinical management. Moreover, fistulizing and stricturing CD are currently diagnosed using the Montreal classification system once the phenotype is evident.³⁰ Novel biomarkers could enable clinicians and researchers to classify and diagnose such patients earlier and more precisely based on the biological drivers underlying these phenotypes, facilitating proactive management. It is important to note that there is likely to be overlap between prognostic biomarkers and diagnostic biomarkers for IBD. In fact, molecular biomarkers indicative of altered inflammation,³¹ immune response to microbial antigens,^32–34 and altered mucosal gene expression³⁵ are already used clinically for differential diagnosis of IBD and noninflammatory bowel disease or of CD and UC. Some of these same markers have also been shown to be have prognostic value.^{22, 29, 32, 33, 36}

Biomarkers for monitoring disease activity and predicting treatment response

Improved monitoring methods to assess disease activity and treatment response represent another important need. Though physician assessment and patient reporting of clinical symptoms are important, there can be a significant discordance between how a patient feels and how the disease process is progressing within the affected tissue.^37–43 In fact, persistent mucosal inflammation can persist even if clinical symptoms improve^{38, 39} and is independently associated with poor long-term outcomes, such as the need for hospitalization, treatment escalation, or surgery.^37–40 On the other hand, healing of the intestinal mucosa and reduction in mucosal inflammation, as assessed through a variety of methods, is associated with improved long-term clinical outcomes.^37–40 This concept, referred to in the literature and in a regulatory guidance⁴⁴ as mucosal healing, is increasingly important as a treatment target, but currently there is not a definitive consensus on a precise definition or best method of assessment.⁴⁵ Clinicians rely on several methods to directly assess inflammation and mucosal healing within the intestine, principally via endoscopic examination of the intestinal wall and histological assessment of mucosal biopsies. Radiological imaging of the bowel is also used to assess inflammation and healing.⁴⁶

At present, all of these methods depend on qualitative image review by one expert observer and are limited by poor intra- and interobserver reliability, limited dynamic range, and potential for significant bias. Centralized reading, where images are read by multiple expert readers in a blinded fashion, can reduce variation, but it is not feasible in routine clinical care due to the high cost and labor required. The outcome of histological assessment is, notably, highly dependent on the locations and density of biopsies, especially in Crohn’s disease where inflammation can be highly segmented and localized.^{47, 48} None of these methods can be used to readily quantify and track the global burden of disease across the gastrointestinal (GI) tract. Finally, there is a lack of extensive validation or consensus regarding the most accurate and clinically meaningful method to score disease activity using these methods for UC⁴⁹ (despite an agreement about the key parameters⁵⁰) and particularly for CD.^{51, 52}

Furthermore, available radiological imaging modalities may have underutilized the potential to quantify not only overall disease burden in IBD but also pathology and healing that may occur deep in the intestinal tissue (referred to as transmural healing) in CD.⁵³ There is also a need for novel imaging tools to detect and quantify fibrosis and inflammation within a stricture; this is of great clinical importance due to implications for choice of therapy. If the stricture is driven by inflammation, anti-inflammatory modalities may be optimal, whereas if the stricture is driven primarily by fibrosis, balloon dilation or surgery may be required.⁵⁴

Fluid biomarkers such as C-reactive protein (CRP) and fecal calprotectin are also used clinically to monitor disease activity and treatment response.²² Importantly, these markers may perform well only in a subset of patients, but the relevant patient subsets are not fully defined at present. For example, calprotectin has been suggested to have a tighter association with inflammation in patients with colonic disease location, but this remains unclear.^{55, 56} In addition, common alleles of CRP locus have been shown to be independently associated with elevated CRP levels in IBD⁵⁷ and non-IBD^{57, 58} populations, including 2 variants that are much more common in individuals of African ancestry,⁵⁸ suggesting that genotypes in specific patient populations may need to be considered to appropriately interpret CRP levels; however, the significance of CRP genotype for the interpretation of this biomarker in IBD also remains unclear.⁵⁹

Thus, there is a critical need for more precise, robust, and standardized methods to assess disease activity and monitor treatment response. A biomarker or set of biomarkers better able to identify and quantify mucosal healing and inflammation, both at specific locations in the bowel and in terms of overall disease burden for the patient, would be highly valuable. Further, noninvasive or minimally invasive biomarkers for monitoring disease activity and treatment response, such as those based on blood, urine, stool, or ultrasound imaging that could be repeated more frequently than endoscopy, would have the potential to improve the utility of available therapies in a patient-friendly and cost-effective manner.

Another important unmet need is for predictive biomarkers that can stratify patients into those likely to respond or not respond to a specific therapy or set of therapies. Earlier identification of optimal therapy, as noted previously, has the potential to improve long-term patient outcomes and quality of life. With the expanding therapeutic toolkit and concerns regarding cost-effectiveness of novel therapies, earlier stratification of responders and nonresponders, which may allow more efficient allocation of resources and improved patient experience, becomes particularly important.² Biomarkers to predict pharmacokinetics or safety liabilities of drugs in specific patients can also inform personalized treatment. A recent advance from the PANTS (Personalising Anti-TNF Therapy in Crohn’s Disease) study suggests that human leukocyte antigen genotyping could predict development of antidrug antibodies against anti-TNF-α, which can lead to secondary loss of response.⁶⁰ Regarding prediction of toxicity, certain mutations are associated with increased risk of thiopurine toxicity.⁶¹ Biomarkers to predict adverse effects to biologics remain an unmet need.

Considerations for drug development

There is a consensus among regulatory agencies and the clinical community that demonstration of efficacy in CD or UC should include a combination assessment of clinical signs and symptoms and demonstration of mucosal healing.⁴⁴ However, design of trial end points is currently a major challenge for clinical development in the IBD field. Though improved longer-term outcomes (such as survival, reduction in flare frequency, and avoidance of need for repeated surgeries) are clearly the eventual goal of therapy, such outcomes are difficult to evaluate within the time frame of a typical clinical trial for IBD, usually no longer than 52 weeks. As a result, methods to assess the underlying disease processes (eg, mucosal inflammation) or recovery from such processes (eg, mucosal healing) have primary importance as “surrogate” end points (eg, markers that correlate with clinical benefit).⁴⁴ Current methods of assessing mucosal healing are variable, costly, and invasive. End point definitions are also highly heterogeneous, as described in a recent systematic review of published CD trials,⁴⁵ reflecting a lack of consensus among clinicians and regulators; in fact, no method has yet been qualified by the FDA. The validation, standardization, and qualification of treatment response biomarkers as surrogate end points with superior performance would be an important advance. Such biomarkers could enable investigators to measure response earlier and more accurately after treatment administration; this would also improve early go/no-go decisions regarding which programs to advance to later-stage clinical trials.

In addition, biomarkers that enable enrollment of patients likely to respond to a specific therapy could enable smaller trials with higher rates of response, which would be exceptionally valuable in advancing truly differentiated treatment approaches suitable for specific patient segments. Even in the absence of biomarkers to predict response to specific therapies, prognostic biomarkers could also be highly useful for IBD trials. For example, enriching the study population with patients who are more likely to experience severe disease could improve the likelihood of detection of beneficial effects of a therapy intended for severe disease. Prognostic biomarkers would be particularly important for studies related to complications of IBD. In the case of stricturing disease, at present it would be exceptionally challenging to demonstrate efficacy for an antifibrotic therapy in CD patients because only a small proportion of patients enrolled would experience strictures during a feasible observation period. A prognostic biomarker to enrich the study population of CD patients at high risk for strictures, along with improved biomarkers to quantify fibrosis, would critically enable clinical development in this area.

OPPORTUNITIES TO ADDRESS VITAL UNMET NEEDS IN THE IBD FIELD

The outcomes of the 2018 and 2019 IBD Biomarker Summits clearly demonstrated an exceptional alignment among key stakeholders regarding needs, priorities, and ongoing efforts within the IBD biomarker field. In this section, we review these specific opportunities. To advance these efforts and to optimize future efforts, the IBD Biomarker Summits identified the need for more harmonization and coordination across studies of different biomarker technologies, which is discussed in the subsequent section.

Assessment of Mucosal Healing: Toward Validation and Automation

The IBD field currently lacks a well-validated, agreed-upon, gold-standard end point to assess disease burden and define response to treatment, creating barriers for advancing clinical efficacy trials and treat-to-target clinical approaches. The absence of a clearly defined comparator, against which one can benchmark novel biomarkers, also limits discovery and validation efforts. In addition to introducing uncertainty regarding the interpretation of novel biomarker data, imprecise or variable comparators can also lead to artifactual degradation of the observable performance of a novel biomarker.⁶² As a result, a critical first step in advancing the IBD biomarker field is to validate a consensus-driven method to assess mucosal healing and treatment response.

The FNIH Biomarkers Consortium, in collaboration with the Crohn’s & Colitis Foundation and leading researchers from academia and the pharmaceutical industry, has developed a framework for a consortium-based project to address this important need. The initial focus is on histological assessment in UC, given scientific agreement regarding the relative strengths of histological scoring systems (relative to those available for CD) and the FDA’s emphasis on the importance of histopathology as a clinical trial end point related to mucosal healing.⁴⁴ Histopathology images, histological scoring reports, and/or slide specimens are to be aggregated from biorepositories generated in the course of industry-sponsored clinical trials. We will aggregate these data and samples, in addition to longitudinal clinical response data (based on patient-reported outcomes and endoscopy), data regarding longer-term outcomes such as steroid free remission, hospitalizations, and time to surgery where applicable. Multiple scoring methods will be applied to compare the performance of each of these scores with regard to clinical outcomes and correlation with endoscopy measurements. A specific histological scoring protocol, recommended by consensus among the consortium participants, will be considered for submission as a surrogate end point via the FDA’s Biomarker Qualification Program. This is intended to be a key enabling step in the further discovery and development of novel biomarkers. Eventually, noninvasive biomarkers for mucosal healing may outperform histological methods and thus could serve as a new, improved, gold standard.

The development of automated scoring systems using machine learning will also be explored within the FNIH proposal. Automated scoring of endoscopic, radiologic, and histopathological data has the potential to revolutionize these modalities and could also lead to a new and improved gold-standard end point. Algorithms developed using machine learning have the potential to match the discriminatory power of trained expert observers with higher reliability and reproducibility.^{63, 64} It may be possible for automated image analysis algorithms to detect features not identifiable by human observers or otherwise improve upon expert observers. In fact, the FDA has recently approved an artificial intelligence-based medical device that detects retinopathy in adults with diabetes.⁶⁵ Within the GI field, a recently launched clinical laboratory test integrates protein expression and tissue structure information to predict risk of progression to esophageal adenocarcinoma.⁶⁶ Approaches to automate and standardize endoscopy and histology in the IBD field are discussed by Syed and colleagues in this issue.⁶⁷

Prognostic Biomarkers Based on Gene Expression Profiles

Biomarkers based on gene expression have demonstrated potential for the prognosis of IBD and are being intensively studied as potential predictors of treatment response. Notably, a clinical test based on a gene expression signature in the blood has recently been validated to accurately discriminate at diagnosis the IBD patients likely to experience a severe disease course in the subsequent 18 months; ¹³ this test is being further evaluated in a United States observational clinical validation study (PRECIOUS) and a biomarker stratified interventional trial (PROFILE).⁶⁸ Moreover, analysis of gene expression in biopsies has demonstrated potential to provide prognostic information regarding risk of developing stricturing and penetrating complications in pediatric CD.²⁹ Those advances are reviewed in this issue by Haberman and colleagues.⁶⁹

Fluid Biomarkers for Monitoring and Prognosis

Periodic endoscopy or histology to assess mucosal healing requires waiting months for information regarding whether a treatment is having a positive impact on disease progression. As noted by the Crohn’s & Colitis Foundation’s Challenges in IBD working group, methods to track inflammation and healing more frequently and less invasively have great potential to positively impact patient care.⁷⁰ The lack of qualified biomarkers for monitoring treatment response also impacts clinical trials. A reduction in the number of endoscopy procedures needed to evaluate efficacy would reduce trial cost and improve protocol acceptance by patients, as recently reported in a conjoint analysis initiated by the Crohn’s & Colitis Foundation.⁷¹ Fluid biomarkers, particularly CRP and fecal calprotectin, are already widely used in the clinic and in clinical trials for this purpose, and novel biomarkers have been proposed to address this need, including a urine-based metabolite^{72, 73} and several plasma protein panels.^{16, 17} However, gaps remain regarding the validation of the performance of described markers and the understanding of how they perform within specific patient segments.

The Critical Path Institute (C-Path) recently convened the Crohn’s Disease Biomarker Preconsortium to assess the Crohn’s disease fluid biomarker landscape and define a roadmap to qualify select biomarkers and reduce regulatory uncertainty related to the use of biomarkers for clinical development. A multidisciplinary working group performed an in-depth evaluation of the maturity of individual biomarkers in terms of clinical validity, analytical assay validity, and availability of patient-level clinical data. The preconsortium concluded that 2 biomarkers, fecal calprotectin and CRP, are “regulatory-ready” with sufficient data generated to advance toward qualification as pharmacodynamic biomarkers able to identify patients experiencing endoscopic healing.⁷⁴ The Critical Path Institute is proposing to accomplish this by aggregating and reanalyzing patient-level data from clinical trials and longitudinal observational studies and expanding this approach from CD to UC. With technological advances in proteomics, transcriptomics, microbiomics, and machine learning, the discovery of novel fluid biomarkers has the potential to accelerate rapidly within the IBD field to address the needs for improved and less invasive monitoring and prognosis and treatment response prediction. Within this issue, Sauer and colleagues discuss the C-Path effort and the landscape of fluid biomarkers for Crohn’s disease,⁷⁴ and Ashwin Ananthakrishnan and colleagues review the emerging field of microbiome-based biomarkers in IBD.⁷⁵

Imaging in IBD: Validation of Established Modalities and Application of Novel Approaches

Clinically used radiological imaging modalities, including magnetic resonance enterography and ultrasound, have the potential to provide less invasive and more accurate monitoring of disease activity and treatment response, particularly for Crohn’s disease and pediatric disease, as discussed by Greer and colleagues in the present issue.⁷⁶ As in the case of endoscopy and histology, despite the progress of multicenter prospective cohort studies, there is not a clear consensus regarding specific scoring systems, and there has not been a successful regulatory qualification.⁷⁰ Validation and implementation of consensus-based scoring systems and development of quantitative analytic tools are important priorities.

In addition, there is an opportunity to advance promising novel imaging technologies to address additional unmet medical needs, particularly the detection and quantification of fibrosis. Stricturing complications will affect a significant proportion of CD patients over their lifetime; ⁵ however, clinicians currently lack the tools to identify patients at high risk of strictures and do not have adequate methods to detect or quantify fibrosis or to differentiate it from inflammation. In particular, assessing risk of fibrosis could enable earlier informed therapeutic decisions, especially for vulnerable populations such as children and patients recovering from resection surgery.²⁹ To address this gap, the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium has formed to define a stricture radiological index as a clinical trial end point, measuring 3 parameters: prestenotic dilation, wall thickness, and luminal diameter.^{54, 77} Magnetic resonance imaging technologies such as diffusion-weighted imaging, delayed enhancement imaging, and magnetization transfer ratio and ultrasound technologies such as shear wave elastography and photoacoustic imaging are particularly promising for detection and quantification of fibrosis.⁷⁰ Additional next-generation molecular imaging technologies for IBD are discussed in this issue by Canavan and colleagues.⁷⁸

HARMONIZATION TO ACCELERATE IBD BIOMARKER DEVELOPMENT

Outcomes of the IBD Biomarker Summit and the Foundation’s Challenges in IBD process indicate that a lack of harmonization has limited progress in this field.² Harmonization in this context refers to a consensus-based adoption of a range of unified research procedures with the goal of enabling data to be compared across studies. Confounding factors that may limit such comparisons include inconsistent nomenclature, insufficient protocol detail, and inconsistent reporting units.⁷⁹ At present, there is also a lack of broad consensus regarding the most important clinical data elements, samples, and documentation to include in biomarker studies in IBD. If key elements are omitted or misconstrued early in a study, the eventual utility of data for regulatory submissions may be compromised. This is especially problematic for IBD studies that may require multiyear observation periods to track disease progression. With multiple biomarker research programs and consortia focusing on related objectives and technologies, improved harmonization has the potential to maximize collective productivity and potential for integration of data and insights across studies. Consistent with this concept, the Crohn’s & Colitis Foundation’s IBD Plexus is a research platform that integrates harmonized data and samples from multiple large cohort studies with a process for data and samples to be effectively obtained, stored, and analyzed by many researchers from academia and industry.

The need for harmonization must be balanced with an imperative to avoid inhibiting innovation. For example, overly rigid standards could limit implementation of novel analytical approaches. An effective harmonization strategy must also offer efficiencies and value to drive adoption across research and clinical settings. Here, we focus on pragmatic harmonization approaches for biomarker discovery that could be advanced in the near term (Fig. 2).

FIGURE 2.

Harmonization needs and approaches for IBD biomarker discovery and qualification. Unification of research procedures that facilitate comparisons across studies remains an outstanding challenge to advance IBD biomarker science. Three main approaches are proposed that, if implemented, could have a transformative impact on this field. First, general adoption of the IBD SmartForm would unify clinical parameters and measurements used in the clinic to phenotype patients (left panel). Second, implementation of a standard informed consent template would facilitate broad use of data, samples, and recontacting of subjects (middle panel). Third, generalized use of a biomarker readiness checklist that includes unified procedures, criteria, and measurements for sample collection, storage, and assay development would enhance data comparability and reproducibility (right panel).

Harmonization in Disease Phenotyping

The identification, validation, and implementation of a biomarker depend critically on a specific and reproducible definition of the relevant patient population and clinical context.⁹ Clinical assessment of phenotype and treatment response in IBD are variable due to their subjective and qualitative nature; this challenge is confounded by heterogeneous and inconsistent clinical definitions,⁴⁵ resulting in a “confluence of imprecision.” ² Even if the biology of a candidate biomarker is robust, validation may fail if clinical definitions are applied inconsistently across sites or across studies. Although improved biomarkers for clinical assessment can eventually address this barrier,² in the interim, the lack of harmonized clinical definitions will hamper the discovery and validation of such biomarkers. The Clinical Data Interchange Standards Consortium (CDISC) is developing a comprehensive set of clinical data standards specifically for Crohn’s disease, which will be an important resource to address this issue. The implementation of CDISC standards is required by FDA and other regulatory agencies for the conduct of clinical trials intended to support regulatory approvals⁸⁰ and have enabled biomarker data integration efforts.⁸¹ However, adoption of standardized clinical phenotyping is resource intensive and requires continuous training of study investigators and coordinators. For example, investigators responsible for the Study of a Prospective Adult Research Cohort in IBD study and adult cohort within IBD Plexus recently performed a quality study to determine the level agreement between investigators for common phenotyping characteristics and to optimize training materials based on a phenotyping manual developed by the IBD Genetics Consortium.⁸²

There is clearly a need and opportunity for data collection software tools that can be used broadly and easily in different research settings, with common elements and concepts, to facilitate comparability across studies in which patients may be phenotyped at different levels of depth and complexity. Such software tools facilitate the capture of structured clinical data, resulting in harmonized data sets amenable to integration. For example, the IBD SmartForm, a module within the Epic electronic medical record platform, has been implemented in Study of a Prospective Adult Research Cohort in IBD and additional real-world cohort studies (Fig. 2). The SmartForm is used to populate the clinical record using data and checklists collected during a research visit. Efficient integration into the clinical workflow will be important to drive broad adoption. These software tools could incorporate validated scoring systems such as the Mayo index or validated simplified versions suitable for routine clinical use,^{83, 84} allowing for improved comparability between data sets obtained in clinical trials and observational studies.

Harmonization in Informed Consent

Informed consent is another critical element of clinical research with implications for the utilization and aggregation of data and samples collected across different cohort studies. Certain studies in the IBD field incorporate consenting for broad research use of data and samples, including those initially collected for clinical purposes, which is desirable from a biomarker research perspective. However, expectations and practices regarding the appropriate uses of patient data and samples vary widely, particularly for industry-sponsored studies. A more efficient and harmonized approach would utilize standardized consenting templates, allowing for broad use of data, samples, and recontacting of subjects, as is the case for several adult research cohorts within IBD Plexus (Fig. 2). Ethical issues must be proactively and openly discussed and addressed to preclude exploitation of subjects or any semblance of exploitation. Engaging with patients throughout the research process, including consideration of patient priorities in clinical protocol design and transparent communication regarding governance of sample and data use and reuse, may alleviate these concerns via “respect through engagement,” as recommended in an Institute of Medicine consensus report.⁸⁵ Patient advocacy organizations can play an important role in facilitating such processes, as illustrated by a recent collaboration between the Alzheimer’s Drug Discovery Foundation and C-Path.⁸⁶

Harmonization in Sample Management & Assay Development

Pre-analytical factors (eg, how a sample is collected, stored, and annotated) can introduce significant artifactual variability and confounding comparisons across studies.²¹ There is a need for consensus-driven protocols for sample collection and management. One approach to address this barrier would be the development of a “biomarker readiness checklist” enumerating consensus-based, unified, pre-analytical procedures for IBD biomarker studies (Fig. 2). These conventions should be flexible and adaptable, specifying minimal but significant criteria to be considered depending on the research objective, with a focus on principles that would be most informative to improve comparability of results across studies. Guidelines should also consider linkage to key clinical metadata, clinical phenotyping procedures, and best practices for documentation, particularly when biomarker data will be critical for regulatory approvals or clinical decisions. Consensus is also needed regarding the appropriate validation of analytical assays reported in the IBD biomarker field. For assays developed to the point where they can be evaluated within a specific clinical context, consistent reporting of standard performance metrics (such as AUROC, sensitivity, specificity, PPV, and NPV) would facilitate comparisons across studies. Investment in formal quality control procedures should be considered as an integral element in the planning and execution of any long-term biomarker project. For projects involving multiple research sites, assignment of assays to specific, qualified core laboratories can also support harmonization, as in the case of IBD Plexus; participating researchers have full freedom to design experiments independently, but assays are performed by core laboratories whenever possible.

Dedicated projects focused on establishing best technical practices for sample collection, sample processing, and analytical assays are also needed. For example, the location where an intestinal biopsy is collected has been shown to impact disease severity scoring and gene expression results; ⁴⁷ in another study, significant differences in histologic appearance were observed between different biopsies from the same patient, indicating that multiple biopsies are needed for accurate scoring of overall disease severity.⁴⁸ Uniform standards for biopsy sampling in therapeutic drug trials are lacking; accordingly, the FNIH Mucosal Healing working group has proposed a prospective study to develop an optimal biopsy protocol for accurate scoring of disease severity, which would have implications for many studies. Preferably, such projects should be supported collectively by coalitions of stakeholders with a precompetitive interest in addressing inefficiencies in the field. Coalition projects should address comparability of commercially available assays and the development of reference standards to assess assay performance in advance of clinical validation, as illustrated by a multidisciplinary consortium focused on complex genomic biomarkers in immuno-oncology.^{87, 88}

These also apply to the collection and analysis of imaging data sets such as magnetic resonance imaging, with the added challenge that assessment of a particular biomarker relies upon the specific instrument used in a given clinical setting. Instruments from different manufacturers may have distinct biases, and commercial incentives may work against efforts to harmonize data produced using proprietary instruments.⁸⁹ Patient advocacy organizations may be in a position to encourage precompetitive alignment to address this barrier.

PATH FORWARD

Advances in biomarker research have the potential to address many of the challenges facing IBD patients and clinicians, including earlier diagnosis, prognosis/prediction and monitoring of disease course, and response to therapy. Such advances would also accelerate the development of novel and improved therapies. Precise and minimally invasive biomarkers are needed for monitoring of disease activity and response to treatment, enabling effective treat-to-target clinical strategies, reducing variability in clinical trials, and fascilitating further biomarker discovery by providing a gold standard for clinical validation. Biomarkers to prognosticate disease course and predict response to specific therapies would enable more personalized and effective management and more efficient and impactful clinical trials. Biomarkers related to severe or complicated disease are especially needed to optimize timing and access to care and to accelerate development of novel solutions for the most at-risk patients. Multiple technological approaches show great potential to address these needs, including gene expression analysis, novel imaging modalities, and machine learning. Realizing this potential will require collaborative engagement of academic researchers, clinicians, regulators, funders, and patients to deliver the resources and efforts needed to discover and validate biomarkers (Fig. 3).

FIGURE 3.

Path forward to IBD biomarker discovery and qualification. The end goal of the IBD biomarker field will be to enable precision medicine in clinical practice and effective clinical trials. This will be possible throughout a concerted effort among different stakeholders who will establish effective collaborations for biomarker discovery, validation, and qualification. These coalitions will utilize harmonized processes and data from real-world longitudinal cohorts, which will be critical for the identification of biomarkers with reproducible, generalizable, and enhanced performance in diverse IBD patient populations. Given the variety of biomarker needs in IBD, the implementation of diversified technological and analytical platforms, including machine learning, will be essential not only to identify novel biomarkers but also to define a gold-standard measurement that can be used as a comparator benchmark for novel biomarkers.

Data and samples from longitudinal cohorts of well-phenotyped patients are the critical foundation of IBD biomarker research. Industry-sponsored clinical trials can be an important source of this type of data, whether accessed through specific IBD biomarker projects such as those under development by C-Path and FNIH or through disease-agnostic platforms.^{90, 91} However, individual clinical trials cannot capture the diverse needs, experiences, and outcomes within the IBD patient population.⁹² Large and diverse real-world cohorts are needed, and mechanisms to enable harmonized data from these cohorts should be generated and disseminated to researchers in academia and industry. The Crohn’s & Colitis Foundation’s IBD Plexus initiative is designed to address these needs by providing a collaborative infrastructure for investigators from academia and industry to contribute to and exploit these resources.

Finally, the collective impact of IBD biomarker research efforts depends critically on harmonization of research practices to enable results to be more effectively compared across studies. Feasible and attractive approaches to address this barrier include standardization of informed consenting language and utilization of software tools, such as the IBD SmartForm, to improve consistency of disease phenotyping. Development and adoption of flexible but rigorous standards for sample management, assay development, and reporting would also improve the overall impact of research in this field. Finally, there is an opportunity to leverage the Crohn’s & Colitis Foundation’s annual IBD Biomarker Summit to establish consensus, alignment, and commitment regarding critical data elements and harmonization strategies to be implemented for IBD biomarker consortia moving forward.

Supported by: The content of this review is based on the IBD Biomarker Summit conference series hosted in 2018 and 2019, with the financial support of the Crohn’s & Colitis Foundation; the Biomarkers Consortium of the Foundation for the National Institutes of Health; Celgene; Genentech, a member of the Roche Group; Janssen Pharmaceutical Companies; Lilly; Prometheus Therapeutics & Diagnostics; UCB; Arena Pharmaceuticals; Abbvie; Gilead; Shire; and the Critical Path Institute.