Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Abstract

Discovery and development of new drugs for the treatment of inflammatory bowel disease (IBD) has intensified significantly within the past decade. However, numerous hurdles affect the pace and efficiency with which new drugs are developed. On March 20, 2019 the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) held a meeting entitled “Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design” in Miami, Florida. In addition to IOIBD members and IBD specialists, representatives from both industry and regulatory agencies were invited to speak and provide expert opinions and perspectives on the current landscape, factors influencing the evolution of IBD clinical trial design and endpoints, and potential novel approaches that may advance the field. The goal of this article is to provide a top-line summary of both materials presented by the invited speakers and the discussion that ensued after each of their talks. This article is not intended as a systematic or exhaustive review of the literature and should not be considered a guideline for clinical trials or practice. Rather, it should be viewed with the intent to provoke thought, stimulate research, and provide an impetus for continued discussion on more efficient and novel approaches to IBD clinical trial design. Select slides (developed by the speakers) presented during the meeting are included as supporting material. These slides are presented with minimal modification, except where additional context was required when viewed independently from the speaker’s original presentation. The meeting opened with an overview of some of the existing challenges and gaps associated with clinical trial design and drug development. Current rates of patient recruitment for participation in IBD clinical trials are low. This observation reflects both “competition” for patients that has occurred as a result of the myriad of clinical trials of potential new therapies as well as a reluctance to expose patients to placebo treatment considering the availability of multiple approved therapies. This situation is particularly problematic for enrollment of phase Ia and IIb proof-of-concept studies. Long timelines, invasive procedures, and changing regulatory recommendations have led to increased burdens for patients, investigators, and industry sponsors. Furthermore, contemporary clinical trial populations frequently include refractory patients who may have failed multiple medical therapies or who present late in their disease course. This observation is particularly relevant when considering Crohn’s disease (CD) trials, where patients may additionally enter studies with established bowel damage. These factors may affect trial outcomes in terms of both drug safety and efficacy. The proclivity toward enrollment of these patients is accompanied by a dearth of trials for rarely studied patient populations, such as those with early disease, external fistulas, strictures, stomas, postoperative disease, acute severe ulcerative colitis (UC), isolated proctitis, (solely) upper gastrointestinal disease, a history of (cured) cancer, and pouchitis. Historically, the lack of validated indices for measuring disease activity has contributed to the problem of studying these specific populations. Current approaches to measurement of disease activity, the most pressing limitations and pitfalls associated with these methods, and evolving approaches and regulatory recommendations for assessment of disease activity and its impact on patients (as discussed at the meeting) are summarized below. A number of modalities are available for objective measurement of disease activity (endoscopy, histopathology, imaging, biomarkers), some of which are particularly well suited to the disease process and have roles in patient management (eg, magnetic resonance imaging for CD). The goals of therapy, however, must also include improvements in disease characteristics important to patients—those that improve their function and well-being. This fundamental concept is reflected in regulatory guidance that recommends the inclusion of both objective measures of disease activity (currently endoscopy) and patient-reported outcomes (PROs) in registration trials of potential therapies for UC.1US Department of Health and Human Services Center for Drug Evaluation and ResearchUlcerative colitis: Clinical trial endpoints guidance for Industry. Food and Drug Administration, Silver Spring, MD2016Google Scholar,2European Medicines AgencyGuideline on the development of new medicinal products for the treatment of ulcerative colitis. CHMP/EWP/18463/2006 Rev 1.https://www.ema.europa.eu/en/development-new-medicinal-products-treatment-ulcerative-colitisDate accessed: November 1, 2019Google Scholar The US Food and Drug Administration (FDA) defines a PRO as “any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else.”3Food and Drug AdministrationGuidance for Industry. Patient-reported outcome measures: Use in medical product development to support labeling claims.https://www.fda.gov/media/77832/downloadDate accessed: November 23, 2020Google Scholar However, the current absence of well-defined, reliable, IBD-specific PROs and/or clinical outcome assessments that reflect the inflammatory burden of IBD and that also meet regulatory standards has led to challenges for design of pivotal trials. Interim solutions (eg, PRO2)4Khanna R. Zou G. D'Haens G. et al.A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity.Aliment Pharmacol Ther. 2015; 41: 77-86Crossref PubMed Scopus (99) Google Scholar have been developed that integrate patient-reported items (abdominal pain, stool frequency, rectal bleeding) present in the composite Crohn’s Disease Activity Index (CDAI)5Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's Disease Activity Index. National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2938) Google Scholar for CD and the Mayo Clinic Score6Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Scopus (1976) Google Scholar for UC. Although outcomes based on the CDAI have historically been used as the basis for drug approval, the CDAI has also faced criticism for its subjective nature and lack of correlation with more objective measures of disease activity. High placebo response rates when used as the sole criterion for patient selection and the inability to capture disease activity in certain patient subgroups (eg, fistulizing CD) are additional factors that initially led to regulatory recommendations to exclude the use of the CDAI in contemporary registration trials. Although the CDAI is currently considered an acceptable outcome measure for clinical trials, the FDA has consistently recommended the inclusion of endoscopic evaluation as a co-primary endpoint to ensure that a clinical improvement is accompanied by a benefit in the underlying disease process. Although some regulatory guidance exists for trial endpoints and definitions,1US Department of Health and Human Services Center for Drug Evaluation and ResearchUlcerative colitis: Clinical trial endpoints guidance for Industry. Food and Drug Administration, Silver Spring, MD2016Google Scholar there are some differences (Supplementary Table 1) between the FDA and the European Medicines Agency guidance for UC.7Reinisch W. Gottlieb K. Colombel J.F. et al.Comparison of the EMA and FDA guidelines on ulcerative colitis drug development.Clin Gastroenterol Hepatol. 2019; 17: 1673-1679Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Guidance for CD from the FDA is lacking. Furthermore, many questions remain regarding specific instruments and their validity, specificity, sensitivity, and clinical relevance. The implications for the use of combined outcomes in IBD clinical trials are also unclear. For example, (1) the appropriate ranges and scores for enrollment and endpoint assessment, (2) the effect of new endpoints on placebo responses and effect sizes and consequently on trial sample size and power, (3) the interaction between PROs and endoscopy when used as co-primary or composite scores (population- vs patient-level analyses), and (4) the generalizability of trial outcomes to the real world are as yet unknown. Importantly, these questions will need to be revisited once validated PROs (currently in development) are available and acceptable to regulatory agencies. Endoscopy has been the gold standard for objective assessment of UC disease activity in clinical trials since Truelove reported on the efficacy of cortisone in 1956.8Truelove S.C. Treatment of ulcerative colitis with local hydrocortisone.Br Med J. 1956; 2: 1267-1272Crossref PubMed Scopus (39) Google Scholar Numerous indices for measuring endoscopic disease activity in UC have since been developed9Samaan M.A. Mosli M.H. Sandborn W.J. et al.A systematic review of the measurement of endoscopic healing in ulcerative colitis clinical trials: recommendations and implications for future research.Inflamm Bowel Dis. 2014; 20: 1465-1471Crossref PubMed Scopus (52) Google Scholar; however, the endoscopic component of the composite Mayo Clinic Score is used most commonly in clinical trials. There is some evidence that the Mayo endoscopic subscore (MES) is a reliable measure,10Feagan B.G. Sandborn W.J. D'Haens G. et al.The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.Gastroenterology. 2013; 145: 149-157Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar although knowledge regarding the responsiveness or sensitivity of the MES to change with effective therapy is currently limited. Definitions for endpoints incorporating the MES are also changing (Supplementary Table 2), such that the FDA currently recommends that a MES equal to 1 should not include friability. Mucosal healing, which was previously assessed as a MES ≤ 1 (an outcome associated with high placebo response rates), is also evolving. Additional endpoints of interest include combined assessments of both endoscopic and histopathologic outcomes. Histopathologic disease activity persists in many patients despite a normal-appearing mucosa.11Riley S.A. Mani V. Goodman M.J. et al.Microscopic activity in ulcerative colitis: what does it mean?.Gut. 1991; 32: 174-178Crossref PubMed Scopus (414) Google Scholar The inclusion of histopathologic outcomes and evidence for the discordance between histopathologic and endoscopic appearance in UC can be found in studies dating back to the 1950s, and the association between persistent histopathologic disease activity and risk of disease relapse was first demonstrated over 50 years ago. Indeed, multiple lines of evidence support an association between improved outcomes in UC and histopathologic remission (ie, symptomatic remission and reduced risks for relapse, surgery/hospitalization, and development of colorectal cancer).12Peyrin-Biroulet L. Bressenot A. Kampman W. Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.Clin Gastroenterol Hepatol. 2014; 12: 929-934Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar Although guidelines support the value of histopathology as a sensitive measure of inflammation, they do not currently support treating patients to this target because of a lack of data demonstrating clinical utility.13Peyrin-Biroulet L. Sandborn W. Sands B.E. et al.Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target.Am J Gastroenterol. 2015; 110: 1324-1338Crossref PubMed Scopus (1065) Google Scholar Histopathologic outcomes are nevertheless being included in contemporary clinical trials to assess the anti-inflammatory properties of potential therapies. Numerous indices have also been developed to measure histopathologic disease activity14Mosli M.H. Parker C.E. Nelson S.A. et al.Histologic scoring indices for evaluation of disease activity in ulcerative colitis.Cochrane Database Syst Rev. 2017; 5: CD011256PubMed Google Scholar and have been used in clinical trials (including the commonly used Geboes score,15Geboes K. Riddell R. Ost A. et al.A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.Gut. 2000; 47: 404-409Crossref PubMed Scopus (578) Google Scholar Nancy Histological Index,16Marchal-Bressenot A. Salleron J. Boulagnon-Rombi C. et al.Development and validation of the Nancy histological index for UC.Gut. 2017; 66: 43-49Crossref PubMed Scopus (194) Google Scholar and the Robarts Histopathology Index17Mosli M.H. Feagan B.G. Zou G. et al.Development and validation of a histological index for UC.Gut. 2017; 66: 50-58Crossref PubMed Scopus (166) Google Scholar). Several indices were shown to be reliable and similarly responsive to change.18Jairath V. Peyrin-Biroulet L. Zou G. et al.Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial.Gut. 2019; 68: 1162-1168Crossref PubMed Scopus (32) Google Scholar Although histopathologic appearance is clearly an important determinant of disease behavior, critical questions remain regarding the use of this disease measure in clinical trials, including whether there are surrogate markers for histopathologic healing that would reduce the need for invasive procedures, the predictive value of histopathology, optimal disease cutoffs for available validated indices, and most appropriate contexts for use of the Geboes score, Nancy Histological Index, and Robarts Histopathology Index. Further study is also needed to determine the stability and reliability of a specific index in the same segment. Although central reading of histopathology slides has also been implemented in contemporary clinical trials to improve the reliability of assessment, there are multiple practical issues that require consideration before reading including biopsy location (prespecified, most severe, multiple segments), size, number and method for processing (both of which may vary according to planned assessments; ie, immunohistochemistry, RNA), and orientation and quality of section. Finally, central reader training and familiarity with the endoscopic and histopathologic indices used in clinical trials are critical to reduce variability and increase trial efficiency. As alluded to earlier, the path forward for assessment of CD activity is less well-defined and is complicated by the heterogeneous nature of the disease. Signs and symptoms may also vary based on disease location (ie, abdominal pain predominates in ileal disease, whereas increased stool frequency is more likely observed in patients with colonic disease), and endoscopic outcomes are currently favored in CD clinical trials. The move away from using solely nonspecific sign and symptom-based measures such as the CDAI toward the inclusion of more objective disease activity measures (ie, endoscopy, magnetic resonance imaging, biomarker) has been motivated by the deficiencies described above and, importantly, high placebo response rates, which are a particularly confounding factor for clinical trial design that results in reduced sensitivity to detect true differences between active drug and placebo, and the need for increased sample sizes to demonstrate treatment effects. High placebo response rates may also occur as a result of the inherent subjectivity of assessment of endoscopic appearance. In clinical trials, this variability is mitigated by blinded central reading of endoscopy videos,10Feagan B.G. Sandborn W.J. D'Haens G. et al.The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.Gastroenterology. 2013; 145: 149-157Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar a process that is recommended by both the FDA and European Medicines Agency when image interpretation is a critical component of trial eligibility or safety or efficacy endpoints. Both agencies also recommend adjudication for scoring discrepancies, although the most appropriate methodology for this process is a matter of debate,19Gottlieb K. Hussain F. Voting for image scoring and assessment (VISA)—theory and application of a 2 + 1 reader algorithm to improve accuracy of imaging endpoints in clinical trials.BMC Med Imaging. 2015; 15: 6Crossref PubMed Scopus (17) Google Scholar,20Reinisch W. Mishkin D.S. Oh Y.S. et al.Analysis of various central endoscopy reading methodologies in the BERGAMOT exploratory induction cohort evaluating etrolizumab in Crohn’s disease.J Crohns Colitis. 2018; 12: S161Crossref Google Scholar and empirical evidence is needed to support various approaches and reading paradigms. The most commonly used indices for endoscopic assessment of CD are the Crohn’s Disease Endoscopic Index of Severity (CDEIS)21Mary J.Y. Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).Gut. 1989; 30: 983-989Crossref PubMed Scopus (318) Google Scholar and the Simple Endoscopic Score for Crohn’s Disease (SES-CD).22Daperno M. D'Haens G. Van Assche G. et al.Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.Gastrointest Endosc. 2004; 60: 505-512Abstract Full Text Full Text PDF PubMed Scopus (975) Google Scholar The CDEIS and the SES-CD are similarly reliable and responsive instruments,23Khanna R. Zou G. D'Haens G. et al.Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease.Gut. 2016; 65: 1119-1125Crossref PubMed Scopus (52) Google Scholar,24Khanna R. Zou G. Stitt L. et al.Responsiveness of endoscopic indices of disease activity for Crohn's disease.Am J Gastroenterol. 2017; 112: 1584-1592Crossref PubMed Scopus (28) Google Scholar and both instruments are poorly correlated with symptoms. The SES-CD is currently favored over the CDEIS in clinical trials primarily because of ease of use, although variability in the assessment of lesions between segments/anastomosis, anal lesions, superficial ulcers, and stenosis can be problematic (Supplementary Figure 1). Standardized scoring conventions (Supplementary Table 3) have been proposed that improve the reliability of the SES-CD25Dubcenco E. Zou G. Stitt L. et al.Effect of standardised scoring conventions on inter-rater reliability in the endoscopic evaluation of Crohn's disease.J Crohns Colitis. 2016; 10: 1006-1014Crossref PubMed Scopus (19) Google Scholar and should be adopted and implemented across clinical development programs. Historically, considerable variability has existed for the SES-CD and the CDEIS in terms of cutoffs used for defining disease activity both for trial eligibility and outcome assessment. The current regulatory recommendation for trial eligibility is an SES-CD score ≥ 6 (or ≥4 isolated ileal disease) to define baseline endoscopic disease severity. The recommended endpoint definitions for endoscopic remission is defined by an SES-CD score of 0 to 2, and endoscopic response is defined by a 50% reduction in the SES-CD score from baseline. Additional empirical data are needed to understand the operating properties of these indices when used as either dichotomous or continuous measures. Magnetic resonance imaging plays a critical role in both diagnosis and management of CD and is the only modality capable of detecting and monitoring all manifestations of disease activity as well as transmural complications (eg, perianal fistula, fibrosis). The 2 potential contexts for the use of magnetic resonance imaging in clinical trials are patient selection26Coimbra A.J. Rimola J. O'Byrne S. et al.Magnetic resonance enterography is feasible and reliable in multicenter clinical trials in patients with Crohn's disease, and may help select subjects with active inflammation.Aliment Pharmacol Ther. 2016; 43: 61-72Crossref PubMed Scopus (51) Google Scholar (confirmation of eligibility based on disease activity and exclusion for complications) and as a pharmacodynamic outcome measure.27Samaan M.A. Puylaert C.A.J. Levesque B.G. et al.The development of a magnetic resonance imaging index for fistulising Crohn's disease.Aliment Pharmacol Ther. 2017; 46: 516-528Crossref PubMed Scopus (35) Google Scholar Magnetic resonance imaging could potentially reduce the rate at which patients are excluded from clinical trials for failure to meet disease activity criteria because of its ability to identify disease in all segments; ileocolonoscopy may fail to identify up to 54% of active small bowel or upper gut CD.28Samuel S. Bruining D.H. Loftus Jr., E.V. et al.Endoscopic skipping of the distal terminal ileum in Crohn's disease can lead to negative results from ileocolonoscopy.Clin Gastroenterol Hepatol. 2012; 10: 1253-1259Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar,29Leighton J.A. Gralnek I.M. Cohen S.A. et al.Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn's disease.Clin Gastroenterol Hepatol. 2014; 12: 609-615Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar The Magnetic Resonance Index of Activity30Rimola J. Rodriguez S. Garcia-Bosch O. et al.Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn's disease.Gut. 2009; 58: 1113-1120Crossref PubMed Scopus (497) Google Scholar (MaRIA) score is evolving as a phamacodynamic outcome measure in clinical trials. The MaRIA score measures 4 disease components: wall thickening, hyperenhancement, edema, and presence of ulcers. For clinical use, active disease is determined by the presence of thickening and enhancement (segmental MaRIA score > 7), whereas severe disease is assessed as the presence of edema and ulcers (MaRIA score ≥ 11 at the segment level). The MaRIA score is well correlated to the CDEIS,30Rimola J. Rodriguez S. Garcia-Bosch O. et al.Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn's disease.Gut. 2009; 58: 1113-1120Crossref PubMed Scopus (497) Google Scholar,31Rimola J. Ordas I. Rodriguez S. et al.Magnetic resonance imaging for evaluation of Crohn's disease: validation of parameters of severity and quantitative index of activity.Inflamm Bowel Dis. 2011; 17: 1759-1768Crossref PubMed Scopus (358) Google Scholar has substantial inter-rater reliability,32Jairath V. Ordas I. Zou G. et al.Reliability of measuring ileo-colonic disease activity in crohn's disease by magnetic resonance enterography.Inflamm Bowel Dis. 2018; 24: 440-449Crossref PubMed Scopus (33) Google Scholar and is responsive to changes in endoscopic disease activity.33Ordas I. Rimola J. Rodriguez S. et al.Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn's disease.Gastroenterology. 2014; 146: 374-382Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar A simplified version of the MaRIA score, based on thickening, edema, fat stranding, and ulcers, that does not require the use of contrast has also been developed and shown to accurately detect changes in endoscopic disease activity in response to therapeutic intervention (Supplementary Figure 2).34Ordas I. Rimola J. Alfaro I. et al.Development and validation of a simplified magnetic resonance index of activity for Crohn's disease.Gastroenterology. 2019; 157: 432-439Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Streamlined and validated endpoints are critical to the success of contemporary clinical trial design. However, the IOIBD meeting also highlighted the need for development and implementation of novel methods and designs for future clinical trials to improve the efficiency of drug development and address some of the current critical challenges. A general summary of potential novel approaches discussed at the meeting (without specific prioritization) follows. Surrogate biomarkers, for example, may eventually replace the need for invasive procedures currently required for endpoint evaluation. Predictive biomarkers may both enhance the power of studies (Supplementary Figure 3) and address current recruitment challenges by enrolling and stratifying patients based on risk of disease progression and/or likelihood for response, which may eventually involve the inclusion of patients based on genetic, genomic, proteome, or microbiome signatures. Further opportunities also exist to define and shape regulatory policy in this latter area, where the rapidly expanding knowledge of microbiome science and its role in the fundamental processes of human health and disease is leading to the development of novel microbiome-based therapies (Supplementary Figure 4). There is consistent evidence for microbiome dysbiosis in IBD (eg, reduced microbiome diversity, compositional instability, expansion of potential pathobiomes),35Imhann F. Vich Vila A. Bonder M.J. et al.Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease.Gut. 2018; 67: 108-119Crossref PubMed Scopus (356) Google Scholar and modulation of the microbiome represents a promising area for the treatment of IBD. Many questions remain, however, for drug development and regulatory bodies including (but not limited to) those relating to a more exact definition of dysbiosis, appropriate therapeutic targets (eg, those that are deficient vs those that are pathogenic), the goal(s) of therapy, and monitoring of microbiome restoration and/or efficacy of treatment. Innovative methods for data collection and sharing were also highlighted as having the potential to help drive research and drug development. Continuous data collection with prediction analysis could be beneficial to clinical management of IBD to minimize periods of disease progression (eg, before the onset of overt signs and symptoms) and to better predict disease relapse as well as for clinical trials to avoid the challenges associated with retrospective recall of subjective disease characteristics. The use of wearable sensors (eg, Fitbit) to continuously capture patient data (eg, sleep, physical activity, heart rate) that might reliably detect IBD relapse before the onset of symptoms is 1 example where currently available and widely adopted technology could be used to improve clinical trial data collection and disease management. Technologic advances in general have allowed for the collection of vast amounts of data from the general population that could potentially be shared and used for healthcare coaching, for trial recruitment, to inform epidemiologic studies, and for postmarketing analyses of drug safety and efficacy (Supplementary Figure 5). Sharing of data across clinical trials and standardized (boilerplate) informed consent would additionally advance the field and enable efficient trial design by allowing the use of trial data for multiple research initiatives, including assessment of the operating characteristics of evaluative instruments and a more accurate estimate of placebo response rates. Finally, innovation in trial design beyond the traditional placebo-controlled induction and maintenance paradigms currently used (particularly for proof-of-concept studies, which suffer from extended timelines) and advances in regulatory harmonization were also identified during the meeting as future goals necessary for the advancement of IBD research. Innovative trial design concepts discussed were the use of active comparators, shorter maintenance studies, greater use of adaptive designs (eg, those that allow for prospectively planned modifications to 1 or more aspects of the design based on data that accumulates during the trial), integrated (seamless) phase II and III trials, Bayesian approaches (eg, those that consider information from prior studies and new trial results as part of a continual data stream, in which inferences are being updated each time new data become available), and platform studies, the latter of which may allow the assessment of multiple interventions (potentially from multiple sponsors) in a single trial, guided by a master protocol, and intervention-specific indices.36Woodcock J. LaVange L.M. Master protocols to study multiple therapies, multiple diseases, or both.N Engl J Med. 2017; 377: 62-70Crossref PubMed Scopus (433) Google Scholar Although operationally complex, the advantages of such an approach have been demonstrated in the I-SPY2 breast cancer study,37Quantum Leap Healthcare CollaborativeThe I-SPY 2 trial.https://www.ispytrials.org/i-spy-platform/i-spy2Date accessed: November 1, 2020Google Scholar where timeframes for proof-of-concept studies were reduced from 40 to 18 months. These concepts and the perspective gained from the significant advances of the past decade will help shape the future of clinical research and drug development. A summary of potential opportunities for a path forward in IBD research is shown in Supplementary Table 4. The IOIBD Defining Endpoints and Biomarkers in Inflammatory Bowel Disease Writing Group represents expert speakers and panelists who participated in the meeting and who also served as authors in the development of the Meeting Summary. Members are as follows: Fabio Cataldi, AbbVie Inc; Geert D'Haens, Amsterdam UMC/AMC; Brian G. Feagan, University of Western Ontario, Robarts Clinical Trials, Inc; Stephen Hanauer, Northwestern University; Vipul Jairath, University of Western Ontario, Robarts Clinical Trials, Inc; Peter Lakatos, McGill University Health Center; Christopher Leptak, US Food and Drug Administration; Dermot McGovern, Cedars-Sinai Medical Center; Andrew Mulberg, Amicus Therapeutics, Inc; Julian Panes, Hospital Clinic Barcelona, IDIBAPS, CIBERehd; Asit Parikh, Takeda Pharmaceuticals; Laurent Peyrin-Biroulet, CHU de Nancy; Walter Reinisch, Medical University of Vienna; Robert Riddell, Mount Sinai Hospital; David Rubin, University of Chicago; Bruce Sands, Icahn School of Medicine at Mount Sinai; Johannes Spleiss, Tillotts Pharma AG; Richard Strauss, Janssen Research Development; Swati Tole, Genentech Inc; Juli Tomaino, US Food and Drug Administration. Maria T. Abreu and William J. Sandborn drafted the manuscript, and all authors critically reviewed, contributed important intellectual content, and approved the final draft for submission. Supplementary Table 1Concordance of FDA and EMA GuidelinesPoint of Agreement Between the EMA and FDAPoint of Divergence Between the FDA and EMAPoint Addressed Only by the FDAPoint Addressed Only by the EMAFDAEMAPrimary endpointAssessment of disease activity by modified version of the Mayo Score/Ulcerative Colitis Disease Activity IndexRejection of Physician’s Global Assessment for primary endpointClinical remission based on stool frequency, rectal bleeding, and endoscopy scores (composite endpoint)Significant effect on symptoms and mucosal healing is required (co-primary endpoints)Composite endpoint possibleRecommends standardizing the Mayo ScoreAdvocates corticosteroid-free induction endpointRecommends validation of patient-reported outcome instruments for use as a primary outcome parameter to gauge symptomatic reliefEndoscopyCentral reading of endoscopyHistologyHistologic confirmation of diseaseHistologic grading scales and scoring techniques should be discussed with the agencyStudy designNeeds to reflect clinical treatment goals, moderated by the capabilities of the drug, and the particular needs of the patient populationProvides detailed advice for study design based on the induction-maintenance paradigmOthersNeed for pharmacokinetic and pediatric studiesAcute severe colitis, extraintestinal manifestations, and pouchitis are coveredUse of the Montreal classification is advocatedCorticosteroid-free dependency is defined according to European Crohn’s and Colitis Organization guidelinesNOTE. EMA, European Medicines Agency.Adapted from Reinsich et al. Comparison of the EMA and FDA guidelines on ulcerative colitis drug development. Clin Gastroenterol Hepatol 2019;17:1673–1679. Open table in a new tab Supplementary Table 2Endoscopic Endpoints in UCEndpointDefinitionClinical remissionComposite term that includes both symptomatic remission AND endoscopic improvement (Mayo endoscopic subscore of 0 or 1)Endoscopic improvementMES equal to 0 or 1 (when starting at a score of 2 or 3)Endoscopic remissionMES equal to 0Mucosal healingHistorically defined as a MES equal to 0, NOW defined as a composite term of endoscopic improvement and histologic remission Open table in a new tab Supplementary Table 3Standardized Scoring Conventions for SES-CD Assessments Associated With Poor ReliabilityArea of Poor ReliabilityScoring ConventionImpassable stricture with a view to the next segmentScoring ulceration or affected surface beyond an impassable stricture is not performed unless the bowel mucosa is properly visualizedImpassable strictureIf screening endoscopy for trial eligibility requires dilation is to be completed, the patient should not be considered eligible. If not for screening, after balloon dilation of the stenosis upstream, segments may be scored provided that a sufficient proportion of the mucosa is observed (ie, enough to reliably score “ulcerated” or “affected” surface).Contiguous ulceration involving 2 segmentsContiguous ulceration at the junction of 2 colonic segments, with minimal extension into either segment, is scored once on the side that appears most affected. If contiguous ulceration extends clearly over a long distance over the 2 segments, then ulceration can be scored for 2 segments.Ulceration at the ileocecal valve or ileocolic anastomosisUlceration at the ileocecal valve or ileocolic junction (regardless of whether there is suspicion that these are ischemic) is scored in the ileal segment. Ulceration on the colonic surface of the ileocecal valve but not in the ileum itself is scored as right colon.Aphthoid ulcerationAphthous ulceration is scored as superficial ulceration and contributes to the estimate of the ulcerated surface area.Anal canal ulcers and stricturesAnal canal ulcers and strictures as well as other anal lesions are included in the score and scored as part of the rectum.Stenosis between 2 segments or ileocecal valve or ileocolic anastomosisStenosis is scored only once in the distal segment when it is located at the junction between 2 segments, including anal stenosis that is scored at the rectum. Stenosis of the ileocecal valve or ileocolic junction is scored as ileal. Open table in a new tab Supplementary Table 4Opportunities for a Path Forward in IBD Research•Streamlined, validated endpoints•Aligning and incorporating clinical research with clinical practice to bridge research and health care•Development of novel methods of endpoint collection (wearable devices and digital medicine)•Development of predictive biomarkers to enhance study power•Validation of inflammatory biomarkers as surrogate endpoints•Microbiome-based and other novel therapeutics•Sharing of data across sponsors•Innovative study and program design○Active comparator studies○Shorter maintenance studies○Adaptive study designs○Seamless phase II→III studies○Bayesian studies○Platform studies•Regulatory harmonization, innovation, and reform Open table in a new tab Supplementary Figure 2Correlation between (A) changes in the simplified MaRIA score and changes in endoscopic disease activity and (B) accuracy of the simplified MaRIA score to predict changes in endoscopic disease activity in response to treatment. Data are based on 37 patients with active CD who underwent magnetic resonance imaging and endoscopy at baseline and after 12 weeks of treatment with corticosteroids (n = 12) or tumor necrosis factor inhibitors (n = 25). Adapted from Ordas I, Rimola J, Alfaro I, et al. Development and validation of a simplified magnetic resonance index of activity for Crohn's disease. Gastroenterology 2019;157:432–439. AUC, area under the curve.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 3Theoretical benefit of patient stratification to improve clinical trial efficiency. The ability to stratify and accurately predict the proportion of patients who will respond to therapy based on a particular biomarker- or gene-based signature (ie, based on the biology of the patient’s underlying disease) will reduce the number needed to treat and improve the efficiency of clinical trials. Sequential stratification of patients based on biologic signatures may eventually reduce populations to levels consistent with orphan disease status. CR, clinical response; NNT, number needed to treat; SNP, single nucleotide polymorphism.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 4Microbiome-based therapeutic approaches. A wide range of microbiome-based approaches (above and below line) are being considered to transform the treatment of IBD.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 5Potential utility of shared data sources. Vast amounts of patient- and population-level data exist in multiple sources that could be used for a multitude of purposes, including trial recruitment and postmarketing analyses of drug safety and efficacy.View Large Image Figure ViewerDownload Hi-res image Download (PPT) NOTE. EMA, European Medicines Agency. Adapted from Reinsich et al. Comparison of the EMA and FDA guidelines on ulcerative colitis drug development. Clin Gastroenterol Hepatol 2019;17:1673–1679.