Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases

Abstract

Advances in science have led to the development of multiple biologics and small molecules for the treatment of inflammatory bowel diseases (IBDs). This growth in advanced medical therapies has been accompanied by an increase in methodological innovation to study and compare therapies. Guidelines provide an evidence-based approach to integrating therapies into routine practice, but they are often unable to provide timely recommendations as new therapies come to market, and they have limited incorporation of real-world evidence when making recommendations. This limits the scope and usability of guidelines, and a gap remains in defining how best to position and integrate advanced medical therapies for IBD. In this review, we provide a framework for clinicians and researchers to understand key differences in sources of evidence, how different methodologies are applied to study the comparative effectiveness of advanced medical therapies in IBD, and considerations for how these sources of evidence can be used to better integrate current guideline recommendations. Over time, we anticipate this framework will allow for a transition to living guidelines and/or practice recommendations. Advances in science have led to the development of multiple biologics and small molecules for the treatment of inflammatory bowel diseases (IBDs). This growth in advanced medical therapies has been accompanied by an increase in methodological innovation to study and compare therapies. Guidelines provide an evidence-based approach to integrating therapies into routine practice, but they are often unable to provide timely recommendations as new therapies come to market, and they have limited incorporation of real-world evidence when making recommendations. This limits the scope and usability of guidelines, and a gap remains in defining how best to position and integrate advanced medical therapies for IBD. In this review, we provide a framework for clinicians and researchers to understand key differences in sources of evidence, how different methodologies are applied to study the comparative effectiveness of advanced medical therapies in IBD, and considerations for how these sources of evidence can be used to better integrate current guideline recommendations. Over time, we anticipate this framework will allow for a transition to living guidelines and/or practice recommendations. Inflammatory bowel diseases (IBDs)—ulcerative colitis (UC) and Crohn’s disease (CD)—are chronic immune-mediated disorders that often require long-term use of biologics and/or small molecules to achieve sustained disease remission. Substantial advances have been made in our understanding of disease mechanisms and the development of novel advanced medical therapies. With this increased therapeutic armamentarium comes a need to better understand how different levels of evidence should be used to integrate therapies in routine practice. Randomized controlled trials (RCTs) represent the most scientifically robust source of data to define treatment efficacy and comparative efficacy. RCTs form the basis for guidelines and societal recommendations, however, they have limitations for IBD specifically related to generalizability of study populations,1Ha C. Ullman T.A. Siegel C.A. et al.Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population.Clin Gastroenterol Hepatol. 2012; 10 (quiz e78): 1002-1007Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and feasibility for timely completion to inform utilization in the ever-evolving practice setting. Real-world evidence (RWE), the real-world setting investigation of therapies already found to be efficacious in RCTs, provides an understanding of effectiveness and safety when prescribed by licensed providers with varying degrees of expertise and practice patterns.2Makady A. de Boer A. Hillege H. et al.What is real-world data? A review of definitions based on literature and stakeholder interviews.Value Health. 2017; 20: 858-865Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar RWE is generated more rapidly within the first years of drug availability, offers an assessment of routine practice effectiveness and safety, and may help to identify populations in which the greatest potential benefit or risk may be seen. However, the uncontrolled environment within which these data are generated creates difficulties in making inferences about the validity of results. A critical gap remains in how we approach recommendations for advanced medical therapy positioning, and there is a need to bridge guideline recommendations informed by RCTs with practice-level data. In this review, we will discuss relative advantages and disadvantages of data sources for evidence generation, how these data sources can and have been applied to guide the integration of biologics and small molecules for IBD, and we will provide considerations for future efforts to assimilate the necessary evidence more rapidly for advanced medical therapies as they come to market for IBD. Finally, we provide an updated framework for advanced medical therapy positioning from the current American Gastroenterological Association (AGA) guidelines for both CD and UC for provider use. The underlying conceptual framework of “measurable” and “unmeasurable” confounders defines the core debate around RWE. Measurable confounders are any factors that can be directly quantified or assessed, and unmeasurable confounders are all other unknown factors that may or may not influence outcomes. The concept of measurable varies by data source, such as endoscopic disease activity, which might be a measurable confounder in an observational cohort in which endoscopy assessments are available but in a claims data set where the data cannot be ascertained, it becomes an unmeasurable confounder. Thus, the presence of unmeasurable confounders cannot be consistently or adequately accounted for and there are data set–specific limitations that need to be considered. In contrast, the act of randomly assigning participants to different interventions balances all confounders, measurable and unmeasurable, if sufficiently powered; this is why RCTs are felt to be the highest-quality evidence for comparisons3Collins R. Bowman L. Landray M. et al.The magic of randomization versus the myth of real-world evidence.N Engl J Med. 2020; 382: 674-678Crossref PubMed Scopus (265) Google Scholar, 4Armstrong K. in comparative effectiveness 2012; PubMed Scopus Google Scholar, et controlled trials versus magic PubMed Scopus Google Scholar C. Ullman T.A. Siegel C.A. et al.Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population.Clin Gastroenterol Hepatol. 2012; 10 (quiz e78): 1002-1007Abstract Full Text Full Text PDF PubMed Scopus (234) Google K. in comparative effectiveness 2012; PubMed Scopus Google Scholar, et controlled trials versus magic PubMed Scopus Google Scholar, M. 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