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Lifestyle modification is the foundation of treatment recommendations for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The design of clinical trials in NASH may be impeded by the lack of a systematic approach to identify and evaluate how lifestyle changes and/or modifications influence clinical trial outcomes and associated endpoints. Furthermore, there are additional uncertainties regarding the methods that can be utilised to better characterise and quantify lifestyle variables - which can influence disease activity and alter trial endpoints - to allow for comparisons of trial outcomes across different phases of research and/or within drug-classes. This summary by the Liver Forum's Standard of Care Working Group reviews currently available clinical data, identifies the barriers and challenges associated with the standard of care in NAFLD/NASH clinical trials, defines available assessments of lifestyle changes, and proposes approaches to better understand and define the influence of diet and exercise on NASH treatment in the context of different pharmacologic interventions. The ultimate objective is to propose tangible solutions which enable investigators, sponsors, and regulatory authorities to meaningfully interpret clinical trial outcomes and the impact of lifestyle modification on such outcomes as they pertain to phase I-IV clinical trials. (C) 2020 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Nonalcoholic steatohepatitis (NASH) is an important cause of liver-related morbidity and mortality. There are no approved therapies, and the results of clinical trials have been difficult to compare due to inconsistent definitions of relevant disease parameters in patients with NASH. The natural course of the disease has not been rigorously characterized, particularly with respect to the contributions of underlying obesity, type 2 diabetes, and other comorbidities and the treatments provided for these comorbidities. Efforts to perform analyses of pooled data are limited by heterogeneous case definitions used across studies to define disease states. There remains a major unmet need in the field to develop standardized definitions for populations for interventional trials. Such definitions are expected to impact how endpoints for clinical trials are constructed. The Liver Forum is a multistakeholder effort including US and European regulatory agencies, academic investigators, professional and patient representative organizations, and industry to catalyze therapeutic development for NASH by developing potential solutions to barriers to development. The Case Definitions Working Group was established by The Liver Forum to evaluate the validity of case definitions for populations to be included in clinical trials for NASH from a regulatory science perspective. Based on such analyses, specific recommendations are provided noting the strengths and weaknesses of the case definitions along with knowledge gaps that require additional study. (Hepatology 2018;67:2001-2012).

Increased understanding of the immunopathology of inflammatory bowel disease (IBD) has resulted in the development of novel therapies such as vedolizumab or ustekinumab, and the investigation of new agents including Janus kinase inhibitors, anti-mucosal vascular addressin cell adhesion molecule-1 agents, anti-interleukin-12/23 monoclonal antibody and sphingosine-1-phosphate receptor-1 selective agonists.1 Over the last years, new approaches to mentoring drug research and testing have been developed. Among these methods, the fast-track drug designation and subsequent approval of safe regimens represent an emerging drug development approach in IBD treatment.2 Since 2001, the European Commission has started a fast-track approval programme for the European Medicines Agency (EMA). The Committee for Human Medicinal Products, established under the EMA, is responsible for such an accelerated review process.2 The requirements and time frames for approval of a drug under the accelerated review process are similar to those used by the United States Food and Drug Administration authorities (FDA). Eligibility for fast-track (in the USA) or accelerated approval (EMA) is based on whether a product will be of major public health interest, particularly from the point of view of therapeutic innovation3 and on endpoints that predict substantial clinical improved outcomes.2 In IBD, this can be difficult to define and the gold standard would probably be complete mucosal or histological healing.2 The cost of IBD care is rising worldwide as IBD incidence and prevalence are rapidly increasing.4 One key reason for the rising cost of IBD treatment is the significant costs of new therapeutic molecules brought into the market, particularly biologics.2 4 Indeed, evidence suggests that the cost of biologic agents now accounts for the main expenditure in treating patients with IBD.5 6 To reduce the cost of IBD drugs, efforts must be made to optimise the drug development process and …

The role of placebo in clinical trials for drug development in inflammatory bowel disease [IBD] was the topic of a panel discussion held during the 10th Congress of the European Crohn's and Colitis Organisation [ECCO], in Barcelona, Spain, in 2015. Panellists discussed a number of issues around placebo-controlled trials in IBD, noting issues such as difficulties with recruitment, leading to less then representative patient populations in clinical studies. It was noted that, whereas the easiest answer may be to drop placebo, it is much more complicated than that. The relevance of placebo is affected by a number of factors, including the phase of the trial, as well as the nature of the drug. In most cases where placebo has been left out in drug development, it has been for trials involving a new formulation, a new dosing schedule, or a biosimilar, for example. The panel agreed that placebo-controlled trials are of particular importance early in the development programme, perhaps not so much in phase III, although placebo is important for monitoring safety. The current trial paradigm, in which patients remain on a plethora of, likely ineffective and toxic, background medication, was also questioned. The applicability of placebo in the paediatric population was also discussed. The overall consensus from this panel discussion was that placebo is still necessary in clinical trials in inflammatory bowel disease, but there remain questions as to how and when placebo should be used.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease worldwide and is an increasing cause of liver-related morbidity and mortality. Nonalcoholic steatohepatitis (NASH), the progressive histological subtype of the disease, is a growing target for drug design and development. Currently, no effective drug therapies exist for the management of NASH and multiple challenges exist for NASH-related clinical trials, stressing the need for a focused deliberative approach to facilitate drug development. One such challenge includes the inconsistent measurement of baseline parameters across clinical trials, which makes interpretation and comparison of trial data difficult and impedes drug development effort.

Irritable bowel syndrome (IBS) is a chronic functional gastroinestinal disorder characterised by intestinal pain or discomfort ogether with alteration of bowel habit, abdominal distension, loating, constipation or diarrhoea [1–4]. Symptoms usually wax nd wane for many years, often resulting in reduced quality of life nd work productivity. The pathophysiology of IBS is incompletely nderstood. Despite affecting 5–20% of the Western population, no medicine as authorised in the European Union specifically for the treatent of IBS until recently. Patients and prescribers were limited o general symptomatic treatments such as laxatives, antidiarhoeals and antispasmodics, which are recommended in current uidelines but on the basis of weak evidence [1,5,6]. Alternatively, hey may use unapproved treatments such as antidepressants and on-absorbable antibiotics when lifestyle modifications such as educing stress, altering diet or psychological interventions have hown to be ineffective. On 26 November 2012, the European-wide marketing authoriation of Constella (linaclotide) was issued for adults with moderate o severe IBS with constipation (IBS-C), a common subtype of the isease. This authorisation is based on a positive recommendaion from the European Medicines Agency’s (EMA’s) Committee for edicinal Products for Human Use (CHMP) [7]. The recommended ose is one capsule (290 g) once daily, to be taken at least 30 min efore a meal. Linaclotide, a synthetic 14-amino-acid peptide, is new oral compound that works by increasing intestinal fluid ecretion and accelerated transit. It stimulates guanylate-cyclaseubtype-C (GC-C) receptors on the luminal surface of the intestinal pithelium, leading to increased intraand extracellular levels of yclic guanosine monophosphate (cGMP). The increase in intraellular cGMP in turn activates the cystic fibrosis transmembrane onductance regulator (CFTR), leading to secretion of chloride and icarbonate into the intestinal lumen [7–10].