End Points Must Be Clinically Meaningful for Drug Development in Nonalcoholic Fatty Liver Disease.

onalcoholic fatty liver disease N(NAFLD) has emerged as a major cause of chronic liver disease in many parts of the world. It is associated with increased mortality owing to cardiovascular and liver disease and is also associated with an increased risk of several types of cancer including hepatocellular cancer, which can develop even in the absence of cirrhosis. It is projected to surpass hepatitis C virus infection as an etiology for end-stage liver disease as well as hepatocellular cancer requiring liver transplantation. Although weight loss can be effective, it is difficult to achieve and sustain. Similarly, bariatric surgery can be effective, but is not risk free and is unlikely to be the solution for the majority of afflicted individuals. These data underscore the urgent need for drug development for this condition. The process of drug development is, however, a multistep process beginning with target identification and preclinical assessment followed by safety and dosing studies and then clinical trials to demonstrate efficacy and safety, which can lead to approval by regulatory agencies. The majority of published phase 2B efficacy-based trials of drugs for nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, to date have been performed by academic groups without the primary objective to take a compound to approval for marketing. These trials, based on short and intermediate time frames, have used a reduction in disease activity as assessed by histologic features as the primary end point. In recent months, there has also been a surge in interest in NASH from the pharmaceutical sector with >100 registered clinical trials on clinicaltrials.gov. It is, therefore, timely to bring the principles of drug development to center stage in this field and to integrate these with efforts to develop therapies for NAFLD. The fundamental principle guiding drug development is the demonstration of safety, tolerability, and “clinically meaningful benefit. ” Clinically meaningful benefit is broadly defined in terms of improvement in how patients “feel,” “function,” or “survive. ” This has been outlined by the US Food and Drug Administration (FDA) and recent discussed in a combined workshop of the FDA and the American Association for Study of Liver Diseases. Unfortunately, a properly validated patient-reported outcomes instrument for NAFLD that can be used to document improvement in how patients feel does not exist currently. General measures of quality of life such as the Short Form (SF)-32 are not specific enough to capture NAFLD-related symptoms, whereas the chronic liver disease questionnaire is most relevant for those with established cirrhosis. Similarly, the impact of NAFLD, independent of underlying obesity, hypertension, and diabetes, on the functional status of individuals and their days of work lost directly attributable to fatty liver disease is not known. Thus, development efforts have focused on demonstrating improvement in “how a patient survives. ” The concept of “how a patient survives” captures a broad array of outcomes from all-cause mortality to liver-related mortality and hard clinical outcomes such as decompensation of cirrhosis, which is well-established to be related to increased use of health care resource and mortality. Because NASH can lead to liver transplantation or death from cirrhosis or hepatocellular carcinoma, each of these 3—transplantation, death or liver cancer—would serve as the most definitive end points for clinical trials. Any intervention that prevented all of these “hard” outcomes would be a clear winner. The problem of course is that NASH is often identified decades before these hard outcomes emerge and drugs simply cannot be developed using end points that take decades to occur. The only alternative for trial design is to identify surrogate end points that reliably predict the development of the hard end points. The challenges of doing clinical trials in NASH were the subject of extensive discussions at a meeting of representatives from academics, the pharmaceutical, and diagnostic testing industries and regulatory bodies organized by the American Association for the Study of Liver Diseases in 2013. The case was clearly made by representatives of the FDA that, in accordance with current statutes, drugs cannot be approved in the United States based on surrogate end points unless there is compelling evidence that such end points are reliable predictors of meaningful, hard outcomes. There are currently only limited data correlating surrogate markers with hard outcomes in patients with NAFLD or NASH. The surrogate most consistently reported to be linked to outcomes is the fibrosis stage. Furthermore, biomarkers reflective of fibrosis stage such as the NAFLD fibrosis score and the Fibrosis-4 score have also been shown to be related to mortality. Importantly, none of the other features of NASH such as steatosis, severity of inflammation or cytological ballooning have been consistently shown to be related to outcomes. In this issue of Gastroenterology, Byrne and Targher attempt to make a case for demonstration of improved steatosis using MR-based methods as an acceptable endpoint for approval for drugs developed for NAFLD. They further propose that everyone with fatty liver should be targeted for treatment. They support these recommendations based on recent data that subjects with fatty liver can progress to steatohepatitis and fibrosis. Although there is no question that the drug development process needs to be accelerated, there is no compelling evidence at this point to demonstrate that improvement of steatosis will translate in to “clinically meaningful benefit,” as intended by