Abstract Pragmatic clinical research is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and precision medicine. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the pragmatic clinical research section is focused on highlighting gaps that need to be addressed in order to optimize and standardize IBD care. Identified gaps include: 1) understanding the incidence and prevalence of IBD; 2) evaluating medication positioning to increase therapeutic effectiveness; 3) understanding the utility of therapeutic drug monitoring (TDM); 4) studying pain management; and 5) understanding healthcare economics and resources utilization. To address these gaps, there is a need to emphasize the use of emerging data sources and real-world evidence to better understand epidemiologic and therapeutic trends in IBD, expanding on existing data to better understand how and where we should improve care. Proposed approaches include epidemiological studies in ethnically and geographically diverse cohorts to estimate incidence and prevalence of IBD and impact of diversity on treatment patterns and outcomes. The implementation of new clinical trial design and methodologies will be essential to evaluate optimal medication positioning, appropriate use of TDM in adults and children, and multidisciplinary approaches to IBD pain management and its impact on healthcare resources. Crohn’s disease, ulcerative colitis, randomized controlled trial, real-world evidence, pragmatic clinical research, observational studies, registries, epidemiology, clustered randomization, claims data Pragmatic clinical research is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms,1 environmental triggers,2 novel technologies,3 and precision medicine.4 Randomized controlled trials (RCTs) have been considered the gold-standard of trial design in medicine since their implementation in the 1940s.5 However, there are several key limitations of this study design.6 Firstly, patients enrolled in RCTs may not be representative of real-world treatment populations due to the strict exclusion of specific subgroups: pre-defined criteria may limit enrollment for patients due to prior medication exposures, age, or surgical history. Particular patient populations may also not be interested in participating, due to the need to continue beneficial medications or concerns regarding randomization to placebo. This has particularly impacted RCT enrollment rates for children, who are more challenging to recruit. Details of RCT protocols and outcomes are not always published in a timely manner. In addition, the conduct of these studies is quite costly. Lastly, RCTs for inflammatory bowel diseases (IBD) typically focus on one treatment effect over a relatively short follow-up period, as opposed to several possible clinical effects or treatment plans. Over the past 15 years, there has been a rapid expansion of clinical resources available to researchers in medicine and epidemiology. Pragmatic clinical trials, which may be defined as trials that are intended to “inform a clinical or policy decision by providing evidence for adoption of the intervention into real-world clinical practice,”6, 7 and observational studies conducted with these resources have the potential to address many knowledge gaps in the understanding of the epidemiology and management of IBD that have historically been challenging to assess through RCTs.7 There are several advantages to these approaches. The use of real-world populations allows for the measurement of real-world medication effectiveness. With a wide array of patients enrolled in large populations, there will be increased heterogeneity, allowing for the evaluation of specific subgroups, including difficult-to-recruit patient populations such as children or the elderly. Pragmatic and observational studies, conducted in the scope of routine care or with previously collected data, can be conducted at lower costs and produce findings more rapidly. Lastly, these studies have the potential to increase follow-up time, generating invaluable data on long-term medication effectiveness or rare adverse events. However, there have traditionally been several barriers to conducting pragmatic clinical research in IBD. Firstly, many of the methodologies may be unfamiliar to researchers, who may not be aware of clustered randomization for comparing treatment effects between two medications, or statistical methods such as risk or propensity score matching to compare “like” individuals, thereby approximating RCTs.8 Large datasets derived from claims-based data may not contain important confounders such as disease location, severity, or environmental factors. Linking datasets to include such variables has historically been challenging and costly. Despite these barriers, there is a growing acceptance of these methods and findings. There have been several prominent naturalistic observational study designs in cardiology and neurology.9 The Corticosteroid Randomisation After Significant Head injury, or MRC CRASH study, was a large, pragmatic trial with minimization of inclusion and exclusion criteria in order to maximize enrollment.10 Similarly, the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) utilized simplified enrollment criteria, a large national registry, and limited follow-up to minimize barriers to enrollment to assess the impact of thrombus aspiration prior to percutaneous interventions in ST-segment elevation myocardial infarction.11 The mHealth Screening to Prevent Strokes (mSToPS) trial combined direct-to-patient advertising, a large commercial registry, and minimal restrictions to providers caring for enrollees to assess a wearable technology for detecting atrial fibrillation.12, 13 Two recent studies in IBD also used pragmatic, cluster-based designs. De Jong and colleagues used a clustered design to study a telemedicine system and healthcare utilization, while the Randomised Evaluation of an Algorithm for Crohn’s Treatment, or REACT trial, compared early combination therapy to conventional treatment.14, 15 This approach has been extended to very large cohort study efforts such as NIH’s All of Us. The addition of new research resources in IBD make this an ideal time to further employ pragmatic clinical research methods to improve the care we provide for patients with IBD. There are an increasing number of large, merged datasets capable of better capturing the continuum of care in patients with IBD. There is also increasing interest in validating existing datasets that have not previously been used to study IBD, such as the Center for Disease Control and National Center for Health Statistics’ National Health Interview Survey (NHIS), one of the nation’s largest national surveys of health-related data.16 There have also been significant strides in the development of prospectively collected cohorts with highly granular patient data, such as SPARC IBD, IBD QORUS, RISK, and IBD Partners (for citations, see Table in Precision Medicine section of this Challenges document4). All of these resources will be invaluable for future IBD-related clinical research. In this section, we highlight how pragmatic research methods can be used in the coming years to address several key clinical questions regarding the natural history of IBD and the clinical care we provide to patients affected by these diseases. The main knowledge gaps (Fig. 1) that will benefit from a pragmatic clinical research approach were identified in the following areas: A) understanding the epidemiology of IBD, B) accurate medication selection to increase treatment effectiveness, C) defining how clinicians are utilizing therapeutic drug monitoring (TDM), D) study of pain management, and E) understanding the health economics and healthcare resources utilization. FIGURE 1. View largeDownload slide Pragmatic clinical research: current research gaps and steps forward to advance new clinical research methods reflecting real world evidence in order to standardize and optimize IBD care. FIGURE 1. View largeDownload slide Pragmatic clinical research: current research gaps and steps forward to advance new clinical research methods reflecting real world evidence in order to standardize and optimize IBD care. UNDERSTANDING THE INCIDENCE AND PREVALENCE OF IBD IN THE UNITED STATES The current incidence of Crohn’s disease (CD) in adults is estimated to be 6.3–23.8 per 100,000 person-years, while for ulcerative colitis (UC) it is estimated to be between 8.8–23.1 per 100,000 person-years.17 Incidence rates have historically been slightly lower in pediatric cohorts in the United states (CD incidence: 0.66–8.8 per 100,000 person-years; UC incidence 0.34–5.3 per 100,000 person-years).18 However, recent systematic reviews in both populations have demonstrated that worldwide IBD incidence and prevalence are likely changing over time, with some countries experiencing continued rapid increases in incidence and others with stabilization of rates.17, 18 In fact, a recent systematic review suggests that incidence rates in North American may be stabilizing, or even declining.17 However, these findings are derived from only four studies conducted in California, Olmstead county, and Rhode Island.19–22 In fact, a recent report by the Centers for Disease Control (CDC) utilizing the CDC’s NHIS suggests the prevalence of IBD in the United States was 3.1 million individuals in 2015,23 up to 3-fold higher than previously published estimates.24 As policy makers and funding bodies rely on these estimates, obtaining accurate data is important to ensure appropriate funding allocation. Observational studies have the potential to address this knowledge gap in the coming years. Prior epidemiologic research in the United States has been limited in part by the lack of comprehensive, longitudinal datasets, compared to data derived from more comprehensive systems such as the Vision computer system in the United Kingdom or Denmark’s nationalized healthcare system.25 This is in part secondary to the fragmented model of care delivered in the United States, with multiple private and federal payers, and a lack of a unified electronic medical record. However, merging of existing datasets may help to more comprehensively assess the shifting epidemiology of IBD in the United States. Several existing datasets may assist in estimating IBD incidence and prevalence rates. For example, while the CDC’s National Health Interview Survey has estimated a significantly higher prevalence of IBD than prior studies conducted in Olmstead County or California,23 this survey-based dataset requires validation of IBD diagnoses to ensure they are accurate. Larger federal or commercially based claims datasets, alone or in combination, could also be used to confirm these estimates. Costs have historically been a barrier to these efforts. Additionally, each dataset may contain or lack specific coding, such as inpatient information or specific medication recording. These databases are also sensitive to patients entering or leaving due to insurance status or geographic relocation. However, as they often include tens of millions of patients, they could prove to be an important resource. There have also been multiple recent advances in merging secondary datasets. Researchers in pharmacoepidemiology have recently created several distributed data networks, collating data from multiple sources to study rare diseases or rare medication- or device-related adverse events.26 Examples of such networks include the Food and Drug Administration’s Sentinel System,27 the Accelerating Data Value Across a National Community Health Center Network, or ADVANCE network,28 and National Patient-Centered Clinical Research Network (PCORnet).29 These networks can contain hundreds of millions of patient-lives. Significant data curation, including the development of common data models, ensuring anonymity, and data quality assessments are required in order to develop these “data lakes”, increasing the costs of these resources. However, these datasets have already allowed for assessments of the rare risk of intussusception with pentavalent rotavirus vaccination,30 comparing bariatric surgical approaches in pediatric patients,31 and assessing the appropriate aspirin dosing for cardiac event prevention.29 There have been limited attempts to use such data in IBD, however. One particular example is the use of a distributed network to assess the incidence of IBD in pediatric populations in Canada. Using collated data from all 5 provinces in Canada, which typically employ separate data warehouses, Benchimol and colleagues were able to appreciate a rapidly rising IBD incidence in those <5 years of age.32 Researchers should emulate similar efforts in both pediatric and adult patient populations in the United States. UNDERSTANDING HOW TO MORE ACCURATELY SELECT MEDICATION FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE TO INCREASE TREATMENT EFFECTIVENESS Over the past two decades, the available agents to treat IBD have rapidly expanded, progressing from anti-tumor necrosis factor agents (anti-TNFs) to anti-leukocyte adhesion agents, biosimilars, anti-IL-12/23 biologics, and most recently the small molecule tofacitinib.33–39 These medical therapies still do not address all patient needs: Primary non-response rates to anti-TNFs range from 10 to 30%, while secondary loss of response rates are considerably higher, with up to 46% of patients experiencing recurrence of symptoms at the end of 1 year.40 These estimates are potentially inaccurate due to heterogenous follow-up periods during induction or maintenance phases; different clinical, endoscopic, and adverse event-related outcome measures.41 Even when considering these differences in trial design, clinical trials do not account for gaps between clinical trial efficacy and real-world effectiveness.42 Therefore, clinicians are often presented with the conundrum of determining in whom we should use which agents as first-line therapy. As previously noted in the Precision Medicine section, there are limited data providing clinical guidance on this topic. Additional research is required to identify serologic, biochemical, or genetic markers that may predict which medications are ideal for specific patient subgroups. This is the unifying goal of personalized medicine, with fields like oncology at the forefront of applying these methods. New, highly granular observational clinical research datasets, combined with advances in predictive modeling, may aid in helping to identify in whom we should initiate specific therapies. Current initiatives within the Crohn’s & Colitis Foundation will soon provide the large, comprehensive datasets required for this research. One such dataset is the Study of a Prospective Adult Research Cohort with IBD, or SPARC IBD cohort. This initiative is prospectively collecting highly detailed clinical and laboratory data, in combination with biospecimens, on up to 7000 patients with IBD from a wide array of centers of excellence across the United States. These data will provide us with the opportunity to analyze an atypically large number of covariables to identify who might best respond to particular classes of medications. In pediatrics, a similar corollary is the RISK study cohort,43 the first of its kind with regards to both size and granularity of collected data. The use of advanced statistical methods will be necessary to take full advantage of these datasets and to explore all potential predictors. Machine learning (ML) and propensity score-based methodologies are two examples that have been increasingly utilized within IBD-related epidemiologic research over the last several years. For example, Waljee and colleagues recently applied random forest modeling to assess predictors of response to vedolizumab in CD and UC within 6 weeks of initiating therapy.44 This is just one subtype of ML, which includes regression subtypes, spline-based analyses, and neural networking. Utilizing these methods in combination with ensemble machine learning, which can create a weighted model among many of these different ML methods, may help to even further refine these methods as they are applied to new datasets in IBD.45 Another potential methodology that can be applied with combined large datasets is high-density propensity score matching.46 Using a large amount of available variables to identify like individuals for comparison allows one to emulate a randomized controlled trial in observational datasets. This was recently demonstrated in a combined cohort of Medicare and Medicaid patients to compare the effectiveness of early anti-TNF use compared to repeated corticosteroid utilization.47 Propensity-score methods were also employed to compare early anti-TNF therapy to thiopurine monotherapy in the pediatric RISK cohort.48 Another important challenge that may be amenable to pragmatic clinical research methods is determining how we ideally position different medication classes and surgery when considering sequential therapies. As noted, the majority of the patients will not respond or lose response to their initial therapy. Research to date has employed simulation or network meta-analytic methods to attempt to determine ideal sequences of therapies in CD and UC.38, 49–51 While these studies are an important step, they are also limited for several reasons. Firstly, they combine data from studies with different outcome measures or different follow-up periods. Secondly, these studies often do not incorporate all potential therapy sequences, given heterogeneity in clinical practices. Thirdly, these studies cannot accurately assess particular patient subgroups: there are limited randomized controlled trial data on many of these agents in pregnant women and pediatric and elderly populations, for example. Lastly, there may be practice heterogeneity in how drugs are used, particularly regarding dose modifications among community providers and those at specialized academic medical centers, or across different regions due to differences in resources and reimbursement practices. Obtaining more accurate effectiveness estimates should be a primary short-term goal of clinical studies in IBD over the coming years. Large observational cohorts are well-positioned to assess sequential medication effectiveness as new medications or medication classes come to market, though there may be an initial delay in data acquisition. These data may also potentially be used to expand the knowledge base regarding how to best use these medications in the post-operative setting.52, 53 Larger datasets also have the potential to help address questions regarding practice or geographic heterogeneity and how that may influence medication effectiveness or sequencing. Recent data suggest geographic variation likely affects IBD outcomes.54 While larger cohorts will also likely accrue data in subgroup populations, data collected prospectively by RISK, Improve Care Now (ICN), a pediatric quality improvement network, or SPARC IBD will provide much needed granularity to also address how we employ our newest therapies in IBD. BETTER DEFINING HOW CLINICIANS ARE UTILIZING THERAPEUTIC DRUG MONITORING IN IBD There has been growing interest in utilizing therapeutic drug monitoring (TDM) to optimize the effectiveness of immunosuppressive medications in IBD. However, several questions remain. In adult populations, there is an active debate regarding the ideal timing of measuring biologic drug levels and anti-drug antibodies. “Reactive monitoring”, or using TDM when individuals have lost response or have not responded to therapy, has been accepted as an important component of using biologics.55 The available data assessing “proactive monitoring”, or the use of TDM to assess drug levels in those with an appropriate clinical response, are considerably murkier, however. While several observational studies have demonstrated a potential benefit of proactive monitoring for both adalimumab and infliximab,56, 57 this approach was not prospectively validated in two large RCTs, which were unable to demonstrate a significant clinical benefit. However, critics have highlighted some potential design flaws in these RCTs.58, 59 It also remains unclear to what extent TDM is being employed both at and outside of academic medical centers. Identifying inappropriate or inadequate use of reactive TDM would allow organizations such as the Crohn’s & Colitis Foundation to provide educational outreach to providers in order to ensure patients have the best chance of response to their therapy. Patterns of test utilization will likely be readily available in claims-based datasets in the next few years. Datasets such as SPARC IBD will also allow us to assess the effectiveness of both reactive and proactive interventions on a larger scale than previously performed. Furthermore, it is unclear what barriers may exist for patients who have been advised to perform therapeutic drug monitoring. Future qualitative research using IBD Partners to determine what insurance or cost related factors may influence testing will be vital. Given likely wide variation in care coupled with the minimal prospective data currently available, this is also an area for potential prospective pragmatic clinical trials assessing different algorithms of reactive and proactive TDM. Previously published TDM research has been conducted primarily in adults. There remain limited data for pediatric patients, in whom pharmacokinetics may be quite different. Using highly granular data with serum drug levels may better help to determine if target trough ranges are similar in pediatrics, and how TDM may be best utilized in these patients. STUDYING PAIN MANAGEMENT, OPIOID USE AND CANNABIS Another important area in IBD care is pain management, and related to this, opioid use. The relationship between opioid use and increased risks of both morbidity and mortality in IBD is well-established.60, 61 Despite these risks, there are concerning data that the same epidemic trends in opioid use affecting the general population are affecting both adult and pediatric patients with IBD,62, 63 and that prescriptions of opioids to IBD patients during a flare is associated with a higher likelihood of persistent opioid use, as were co-morbid conditions including depression.64 One potential means for combating opioid misuse would be the inclusion of pain medicine specialists in IBD care. Addressing co-existent mental health problems and understanding pain medicine utilization patterns, and how they may impact urgent care resource use would allow for future targeted interventions for both patients and providers. Referrals to pain medicine and anesthesia can be readily tracked in claims-based data, and prescribing patterns can be assessed in large secondary datasets with pharmacy files, as well as new datasets. Finally, another major trend in IBD management is marijuana legalization and the potential for increased use in the IBD patient population.65 Currently, medicinal marijuana (and cannabinoid derivatives) is legal in 9 states in the U.S. and multiple additional jurisdictions including Canada, with legislature pending in numerous others. Many patients with IBD are already using or inquiring about the use of cannabis and its derivatives. While there are no proven anti-inflammatory effects, marijuana use may impact opioid use: In Colorado, cannabis legalization resulted in a statistically significant reduction of opioid-related overdoses.66 Marijuana use itself is difficult to track in observational data, though state-specific time-series analyses in relation to time of legalization may help to better assess if there are changes in opioid use over time. More in-depth data will be needed, however, to accurately measure the use and impact of marijuana use over the coming years. Additionally, prospective observational studies such as CANDID at the University of Colorado, are crucial first steps in assessing this. Future prospective data collection using existing patient reported research networks across multiple geographic regions will also be vital. This topic is covered further in a recent Crohn’s & Colitis Foundation commissioned publication on the topic.67 UNDERSTANDING OF HEALTH ECONOMICS AND HEALTHCARE RESOURCES UTILIZATION Over the past 15 years, the utilization of large claims- or electronic medical record-based datasets has allowed us to begin to grasp the economic impact of caring for patients with IBD. In one such study, estimated annual direct charges of IBD exceeded $6.3 billion dollars in 2003.68 Even after adjustment for inflation, this is likely an underestimate of today’s costs, as biologics have become an ever-growing component of IBD care and related expenditures.69 These burdens affect pediatric populations as well, with national estimates of $2.9 billion.70 The out of pocket expenses of these medications can be burdensome to patients and their families.71 Patients with IBD also often have increased costs associated with co-morbidities, including mental health disorders. Therefore, there is increased interest in providing comprehensive IBD care, which involves a multi-disciplinary approach, comprised of more than gastroenterology visits and related laboratory studies, imaging, and procedures. For example, we are only beginning to understand the importance of screening for depression, anxiety, and other psychiatric disorders, with growing data suggesting an intrinsic relationship between IBD-related outcomes and depressive symptoms.72 Despite increasing screening recommendations for depression and anxiety, little is known at this time about geographic or center-based disparities in psychiatric screening, related referrals, or the availability of these resources. Identifying gaps in education or access related to depression and anxiety in IBD, and expanding telemedicine to improve access to complementary services, would allow us to improve patient care and compliance, potentially reducing hospitalizations and improving quality of life. Using larger data sources with greater geographic coverage may help to answer these utilization questions, though more granular data may be required to assess the frequency of actual screening practices among gastroenterologists. Steps Forward From a methodologic standpoint, we are at the forefront of an exciting era in IBD research in the US and worldwide. Access to larger patient populations is rapidly expanding, both secondary to the emergence of large claims datasets over the past decade, and the development of new merged databases. Recently developed initiatives such as RISK, fielded through the PRO-KIIDS network, and SPARC IBD will provide researchers not only with broad patient data across thousands of lives, but do so with a depth and granularity that has not been achieved previously, merging deep clinical phenotyping with laboratory data and biosamples. IBD researchers have also become versed in the necessary statistical methods to optimally utilize these data, emulating prospective RCTs to predict potential outcomes or adverse events. It is therefore important, among this rapid proliferation of resources and skills, that potentially attainable clinical goals be highlighted for the research community embarking on pragmatic clinical research over the coming years. Throughout this section, we have highlighted several research topics that are either readily amenable to research in existing datasets, or soon will be as new data are collected. These tools will allow us, in the next several years, to better understand trends in incidence and prevalence of IBD, both in adult and pediatric patient populations. As more patients are exposed to newer agents and their data are accrued in claims and observational data, we will have the ability to better assess patterns and algorithms of care, measuring real world effectiveness in a manner that has not been achievable before. These findings will lead to better drug selection and optimization. Lastly, these data will allow us to best understand how patients are utilizing healthcare resources outside of their gastroenterologists’ offices. Understanding psychiatric or pain medicine resource use, how this is changing over time, and how it can impact urgent or emergent care access is vital to providing integrated, comprehensive care for our patients. To specifically address these research goals over the next several years, the following focuses of pragmatic clinical research should be considered: (1) Emphasize the use of emerging data sources to better understand epidemiologic and therapeutic trends in IBD, expanding on existing data to better understand how and where we should improve care. (2) Better characterize how we can best position medical therapies as new medications and medication classes come to market. These research efforts should include both identifying which therapies are best utilized as first-line treatment, and in whom; as well as those sequences of therapies and timing of therapy that are most effective should treatment failure and/or the need for surgery occur. (3) Describe provider and geographic variation in the utilization and effectiveness of both proactive and reactive TDM in adult and pediatric patient populations. (4) Identify the impact of ethnic diversity and geographic variation in IBD care in the US, including medication treatment patterns, access to support services, psychiatric utilization and comprehensive IBD center of excellence referrals and use. An additional goal would be to determine how access to these resources influences medication persistence and clinically relevant outcomes in IBD. (5) Support and promote future prospective pragmatic studies with clustered randomization to assess: i) positioning of therapeutic options, especially new classes of agents and timing around surgery ii) TDM algorithms and their impact on durability of response, cost, healthcare utilization iii) Impact of multi-disciplinary psychiatric care/pain support services on outcomes such as emergency room and urgent care utilization, pain management, medication compliance, rates of hospitalization, and medication persistence. Supported by: Crohn’s & Colitis Foundation ACKNOWLEDGMENTS The authors thank Rosemary Bianculli for design of figures; Orna Ehrlich for coordination with the publisher; Rebecca Kaplan for facilitating public comments; and the following individuals for review and recommendations on the manuscript: Robert Hinton; Douglas Levine; Jeremy Adler; Neil Hyman; Sridhar Mani; Antonina Mikocka-Walus; Chao Li; Carolina Ciacci; Damian Garcia-Olmo; J. Todd Kuenstner; Maria Lia Scribano; Alan Baird; Emina Huang; Giovanni C. Actis; Harris Ahmad; Herbert Van Kruiningen; J.M. Mullin; Pietro Tonelli; Richard M Soll; Simone Saibeni and Ulla Knaus. REFERENCES 1. Pizarro TT , Stappenbeck TS , Rieder F et al. Challenges in IBD Research: Preclinical Human IBD Mechanisms . Inflamm Bowel Dis . 2019 ; 25 ( Suppl 2 ): S5 – S12 . 2. Ho SM , Lewis JD , Mayer EA et al. Challenges in IBD Research: Environmental Triggers . Inflamm Bowel Dis . 2019 ; 25 ( Suppl 2 ): S13 – S23 . 3. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
Inflammatory Bowel Diseases – Oxford University Press
Published: May 16, 2019
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