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 A. J. et al.Development and of the Nancy histological for 2017; PubMed Scopus Google Scholar and the M.H. B.G. Zou G. et al.Development and of a histological for 2017; PubMed Scopus Google indices were to be reliable and to V. L. Zou G. et of histological disease activity indices in ulcerative colitis: a data from the controlled 2019; PubMed Scopus Google Scholar Although histopathologic appearance is an important of disease questions remain regarding the use of this disease measure in clinical trials, there are for histopathologic healing that the need for invasive procedures, the value of histopathology, disease for available validated and most appropriate for use of the Geboes Nancy and Index. is also to the and of a specific in the Although reading of histopathology slides has also been in contemporary clinical trials to improve the of assessment, there are multiple that reading most multiple number and for of which may to and and of and with the endoscopic and histopathologic indices used in clinical trials are to and trial to the for assessment of CD activity is and is by the nature of the and may also based on disease (ie, in disease, increased stool is more in patients with and endoscopic outcomes are currently in CD clinical trials. The from and measures such as the CDAI toward the inclusion of more objective disease activity measures (ie, magnetic resonance imaging, has been by the high placebo response which are a particularly for clinical trial design that in reduced sensitivity to differences between active drug and and the need for increased sample sizes to treatment High placebo response rates may also as a result of the of assessment of endoscopic In clinical trials, this is by reading of endoscopy 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 interpretation is a component of trial or safety or efficacy agencies also for scoring although the most appropriate for this process is a of K. for scoring and assessment and of a 1 to improve of imaging endpoints in clinical Med 2015; PubMed Scopus Google W. et of endoscopy reading in the in Crohn’s 12: Google Scholar and evidence is to support approaches and reading The most commonly used indices for endoscopic assessment of CD are the Crohn’s Disease Index of R. and of an endoscopic of the for Crohn's a PubMed Scopus Google Scholar and the Score for Crohn’s Disease D'Haens G. G. et al.Development and of a endoscopic activity for Crohn's the Full Text Full Text PDF PubMed Scopus Google Scholar The and the are reliable and R. Zou G. D'Haens G. et in the evaluation of endoscopic from patients with Crohn's PubMed Scopus (52) Google R. Zou G. L. et of endoscopic indices of disease activity for Crohn's J Gastroenterol. 2017; PubMed Scopus Google Scholar and both instruments are with The is currently over the in clinical trials because of of although in the assessment of between and can be problematic (Supplementary scoring (Supplementary Table have been that improve the of the Zou G. L. et of scoring on in the endoscopic evaluation of Crohn's PubMed Scopus Google Scholar and should be and clinical development Historically, has for the and the in terms of used for disease activity both for trial and outcome The current regulatory for trial is an isolated to endoscopic disease The recommended endpoint for endoscopic remission is by an of to and endoscopic response is by a in the from Additional data are to the properties of these indices when used as or resonance imaging a role in both and management of CD and is the of and of disease activity as well as (eg, The potential for the use of magnetic resonance imaging in clinical trials are patient J. et resonance is and reliable in clinical trials in patients with Crohn's disease, and may with active Pharmacol Ther. PubMed Scopus Google Scholar of based on disease activity and for and as a outcome M.A. B.G. et al.The development of a magnetic resonance imaging for Crohn's Pharmacol Ther. 2017; PubMed Scopus Google Scholar resonance imaging the at which patients are from clinical trials for to meet disease activity because of its to disease in may to to of active bowel or upper et of the in Crohn's disease can to from Gastroenterol Hepatol. Full Text Full Text PDF PubMed Scopus Google S.A. et endoscopy is to and to in Crohn's Gastroenterol Hepatol. 2014; 12: Full Text Full Text PDF PubMed Scopus Google Scholar The Index of J. et resonance for assessment of disease activity and in Crohn's PubMed Scopus Google Scholar is evolving as a outcome measure in clinical trials. The measures disease and of For clinical active disease is by the of and severe disease is assessed as the of and at the The is well to the J. et resonance for assessment of disease activity and in Crohn's PubMed Scopus Google J. et resonance imaging for evaluation of Crohn's of of and of Bowel Dis. 17: PubMed Scopus Google Scholar has V. Zou G. et of measuring disease activity in disease by magnetic resonance Bowel Dis. PubMed Scopus Google Scholar and is to in endoscopic disease J. et of magnetic resonance in response to therapy and healing in patients with Crohn's 2014; Full Text Full Text PDF PubMed Scopus Google Scholar A of the based on and that does not the use of has also been developed and to in endoscopic disease activity in response to therapeutic (Supplementary J. et al.Development and of a magnetic resonance of activity for Crohn's 2019; Full Text Full Text PDF PubMed Scopus Google Scholar and validated endpoints are to the of contemporary clinical trial design. However, the IOIBD meeting also the need for development and of novel and for future clinical trials to improve the efficiency of drug development and some of the current A summary of potential novel approaches discussed at the meeting specific for example, may the need for invasive currently required for endpoint may both the of studies (Supplementary and current recruitment challenges by and patients based on risk of disease and/or for which may the inclusion of patients based on or also to and regulatory in this where the knowledge of and its role in the fundamental of health and disease is to the development of novel therapies (Supplementary There is evidence for in IBD (eg, reduced of potential A. M.J. et of and underlying the and clinical of inflammatory bowel PubMed Scopus Google Scholar and of the a for the treatment of questions however, for drug development and regulatory not those to a more of appropriate therapeutic (eg, those that are vs those that are the of therapy, and of and/or efficacy of for data and were also as the potential to and drug development. data with be to clinical management of IBD to of disease (eg, the of and and to disease relapse as well as for clinical trials to the challenges associated with retrospective of subjective disease The use of (eg, to capture patient data (eg, activity, that IBD relapse the of is 1 where currently available and be used to improve clinical trial data and disease in have for the of of data from the that be and used for for trial to and for of drug safety and efficacy (Supplementary of data clinical trials and additionally advance the and efficient trial design by the use of trial data for multiple assessment of the characteristics of instruments and a more of placebo response in trial design the and currently used for proof-of-concept which from and in regulatory were also during the meeting as future goals for the of IBD trial design discussed were the use of active use of (eg, those that for to 1 or more of the design based on data that during the phase and trials, approaches (eg, those that from studies and new trial as of a data in which are being each new data and the of which may the assessment of multiple from multiple in a by a and J. to multiple multiple or Engl J Med. 2017; PubMed Scopus Google Scholar Although the of such an have been demonstrated in the accessed: November 1, 2020Google Scholar where for proof-of-concept studies were reduced from to These and the from the of the past will the future of clinical and drug development. A summary of potential for a in IBD is in Table The IOIBD Endpoints and Biomarkers in Inflammatory Bowel Disease expert speakers and who in the meeting and who also as in the development of the are as G. of Clinical of Clinical Health US Food and Drug Clinic of of of at US Food and Drug and J. Sandborn the and contributed important and approved the for Table of FDA and EMA of the EMA and of the FDA and by the by the of disease activity by of the Mayo Disease Activity of for remission based on stool frequency, rectal and endoscopy scores effect on and healing is required endpoint the Mayo of patient-reported outcome instruments for use as a outcome to symptomatic reading of of grading and scoring should be discussed with the to reflect clinical treatment by the of the and the of the patient for design based on the for and severe and are of the is is to European Crohn’s and Organization European Medicines from et of the EMA and FDA guidelines on ulcerative colitis drug development. Gastroenterol in a new Table Endpoints in that both symptomatic remission endoscopic improvement endoscopic subscore of or equal to or 1 at a of or equal to as a MES equal to as a composite of endoscopic improvement and remission in a new Table for of with a to the or an is not the bowel is endoscopy for trial is to be the patient should not be considered not for after of the may be that a of the is (ie, to or at the of with minimal is once on the that most over a over the can be for at the or at the or of there is that these are is in the on the of the not in the is as is as and to the of the and and as well as are included in the and as of the between or or is once in the when it is at the between that is at the of the or is as in a new Table for a in IBD validated and incorporating clinical with clinical to and health of novel of endpoint and of to of inflammatory as and novel of data and phase and in a new between in the and in endoscopic disease activity and of the to in endoscopic disease activity in response to are based on patients with active CD who magnetic resonance imaging and endoscopy at and after of treatment with or from et and of a magnetic resonance of activity for Crohn's the benefit of patient to improve clinical trial The to and the of patients who will to therapy based on a or (ie, based on the of the underlying will the number to and improve the efficiency of clinical trials. of patients based on may populations to with disease clinical number to therapeutic A of approaches and are being considered to the treatment of of data of and data in multiple that be used for a of trial recruitment and of drug safety and European Medicines from et of the EMA and FDA guidelines on ulcerative colitis drug development. 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