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

2015; Elsevier BV; Volume: 150; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2015.11.017

1528-0012

Arun J. Sanyal, Brent A. Neuschwander‐Tetri, James Tonascia,

Liver Disease and Transplantation

Nonalcoholic fatty liver disease (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.1Adams L.A. Harmsen S. St Sauver J.L. et al.Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study.Am J Gastroenterol. 2010; 105: 1567-1573Crossref PubMed Scopus (202) Google Scholar, 2Dunn W. Xu R. Wingard D.L. et al.Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study.Am J Gastroenterol. 2008; 103: 2263-2271Crossref PubMed Scopus (243) Google Scholar, 3Adams L.A. Lymp J.F. St Sauver J. et al.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (2235) Google Scholar 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.4Charlton M.R. Burns J.M. Pedersen R.A. et al.Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.Gastroenterology. 2011; 141: 1249-1253Abstract Full Text Full Text PDF PubMed Scopus (836) Google Scholar, 5Wong R.J. Cheung R. Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.Hepatology. 2014; 59: 2188-2195Crossref PubMed Scopus (504) Google Scholar Although weight loss can be effective, it is difficult to achieve and sustain.6Vilar-Gomez E. Martinez-Perez Y. Calzadilla-Bertot L. et al.Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.Gastroenterology. 2015; 149 (quiz e314–365): 367-378 e365Abstract Full Text Full Text PDF PubMed Scopus (1062) Google Scholar, 7Stewart K. Haller D. Sargeant C. et al.Readiness for behavior change in non-alcoholic fatty liver disease: implications for multidisciplinary care models.Liver Int. 2015; 35: 936-943Crossref PubMed Scopus (39) Google Scholar Similarly, bariatric surgery can be effective,8Lassailly G. Caiazzo R. Buob D. et al.Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.Gastroenterology. 2015; 149 (quiz e315–376): 379-388Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar 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.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google ScholarUnfortunately, 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.10Younossi Z.M. Guyatt G. Kiwi M. et al.Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease.Gut. 1999; 45: 295-300Crossref PubMed Scopus (430) Google Scholar 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.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar 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 2013.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar 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.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar 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.12Kim D. Kim W.R. Kim H.J. et al.Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States.Hepatology. 2013; 57: 1357-1365Crossref PubMed Scopus (496) Google Scholar 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.13Ekstedt M. Hagstrom H. Nasr P. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; 61: 1547-1554Crossref PubMed Scopus (1239) Google Scholar, 14Ekstedt M. Franzen L.E. Mathiesen U.L. et al.Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression.Scand J Gastroenterol. 2012; 47: 108-115Crossref PubMed Scopus (32) Google ScholarIn 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.15Byrne C.D. Targher G. Time to replace assessment of liver histology with MR-based imaging tests to assess efficacy of interventions for nonalcoholic fatty liver disease.Gastroenterology. 2016; 150: 7-10Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar 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.16Pais R. Charlotte F. Fedchuk L. et al.A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.J Hepatol. 2013; 59: 550-556Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 17McPherson S. Hardy T. Henderson E. et al.Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.J Hepatol. 2015; 62: 1148-1155Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar 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 the FDA. Therefore, whether determined by MR or other means, improvement in steatosis alone does not meet regulatory standards as either a reasonably accepted or generally accepted surrogate for approval of drugs for NASH.There are also other aspects of the arguments put forward by Byrne and Targher that are not evidence based. The 10- to 15-year probability of a liver-related outcome in those with isolated hepatic steatosis is vanishingly small.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar, 13Ekstedt M. Hagstrom H. Nasr P. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; 61: 1547-1554Crossref PubMed Scopus (1239) Google Scholar Furthermore, the rates of fibrosis progression reported in retrospective analyses of limited subsets of subjects with fatty liver in individual centers suffer from ascertainment and selection bias, including studies reporting both high and low rates of progression. The ideal study would be to perform protocol biopsies in a large and diverse cohort of subjects at intervals fixed by protocol to ascertain the true rates of fibrosis progression in this population. This constitutes an essential first step before considering therapy to decrease liver-related outcomes in those with fatty liver alone. In addition to the relatively low gain in terms of liver-related outcomes, demonstration of safety will be critically important before potentially approving drugs with possible side effects that could be prescribed to almost one-third of the population.18Browning J.D. Szczepaniak L.S. Dobbins R. et al.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2878) Google Scholar The assumption that steatosis invariably precedes and is causally linked to the development of steatohepatitis is also not established.On the other hand, subjects with fatty liver are at risk of adverse cardiovascular outcomes.19Targher G. Day C.P. Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.N Engl J Med. 2010; 363: 1341-1350Crossref PubMed Scopus (1375) Google Scholar Here again, proving that NAFL directly contributes to other outcomes such as cardiovascular mortality has been remarkably difficult and most of the literature is based on demonstration of association, not causality. One perspective is that the inflammatory state in the liver contributes to adverse extrahepatic effects, whereas others argue that triglyceride in the liver is but an epiphenomenon and serves as a marker of a dysmetabolic state but does not contribute directly the extrahepatic manifestations of this complex disorder. To date, there is no evidence that an isolated decrease in liver triglycerides translates in to clinically meaningful benefits as defined by regulatory science and demanded by law for drug approval. In fact, the existing literature suggests that it does not affect outcomes.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar Regardless of the nature of the relationship, the development of cardiovascular outcomes and type 2 diabetes do represent clinically meaningful outcomes in this population and thus it may be reasonable to reduce such outcomes in this population. It is, however, worth noting that there are no validated data that reduction of triglycerides in the liver by itself improves either liver or cardiovascular outcomes in this population.These considerations have led the hepatology field to focus on those at greater risk for developing liver-related outcomes as the target population for clinical trials to decrease liver-related outcomes. Given the long natural course of the disease before outcomes occur and the logistic difficulties associated with trials in such a population, the FDA has provided a pathway for accelerated approval using generally accepted surrogate end points or reasonably accepted surrogate end points.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar Unfortunately, we do not yet have the data to fulfill the requirements for an endpoint to be accepted as a generally accepted endpoint other than progression to cirrhosis, which clearly represents a clinically significant change in liver status in those who have precirrhotic stages of NASH. Identification of such an endpoint that is easy to demonstrate remains a major unmet need in the field. In the absence of a generally accepted surrogate, a reasonably accepted surrogate may provide a legal mechanism using the subpart H pathway, which permits conditional approval based on reasonably accepted surrogates with the caveat that long-term post approval studies be performed to demonstrate that the surrogate translates in to clinically meaningful benefit.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar Such end points must be related to disease biology and sensitive to change. Liver histology is the basis for disease definition and staging, and steatohepatitis and hepatic fibrosis stage have been linked to clinical outcomes.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar, 13Ekstedt M. Hagstrom H. Nasr P. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; 61: 1547-1554Crossref PubMed Scopus (1239) Google Scholar Furthermore, steatohepatitis progresses to cirrhosis far more commonly than a fatty liver alone. Thus, resolution of steatohepatitis or a decrease in both the NAFLD activity score and fibrosis has been suggested as a reasonably accepted surrogate for approval under subpart H.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google ScholarIt is also important to consider drug safety in the context of drug development for NASH. An ideal drug should not only prevent clinically meaningful liver outcomes, but at the very least must be safe in terms of cardiovascular, diabetes, and cancer-related outcomes. Given the logistical challenges of studies to demonstrate noninferiority to placebo arms with respect to these outcomes, the minimum requirement in phase III trials is to demonstrate a lack of signal suggesting a increased risk for a safety event followed by phase IV studies to confirm cardiovascular safety and lack of any unexpected adverse events.There is no question that there is a need for a noninvasive profile of subjects with NAFLD at risk of progression to liver-related outcomes and ways to assess response to treatment without subjecting individuals to multiple invasive liver biopsies. This will not only accelerate drug development, but enhance access to care for all patients with the disease in the community. However, this requires a major investment of effort to develop and validate such biomarkers as has been done for low-density lipoprotein cholesterol and hemoglobin A1C for heart disease and diabetes, respectively. Until then, liver histology based end points rather than MR-based fat quantification will remain the standard for approval as a reasonably accepted surrogate endpoint under subpart H for approval. Nonalcoholic fatty liver disease (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.1Adams L.A. Harmsen S. St Sauver J.L. et al.Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study.Am J Gastroenterol. 2010; 105: 1567-1573Crossref PubMed Scopus (202) Google Scholar, 2Dunn W. Xu R. Wingard D.L. et al.Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study.Am J Gastroenterol. 2008; 103: 2263-2271Crossref PubMed Scopus (243) Google Scholar, 3Adams L.A. Lymp J.F. St Sauver J. et al.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology. 2005; 129: 113-121Abstract Full Text Full Text PDF PubMed Scopus (2235) Google Scholar 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.4Charlton M.R. Burns J.M. Pedersen R.A. et al.Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States.Gastroenterology. 2011; 141: 1249-1253Abstract Full Text Full Text PDF PubMed Scopus (836) Google Scholar, 5Wong R.J. Cheung R. Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.Hepatology. 2014; 59: 2188-2195Crossref PubMed Scopus (504) Google Scholar Although weight loss can be effective, it is difficult to achieve and sustain.6Vilar-Gomez E. Martinez-Perez Y. Calzadilla-Bertot L. et al.Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.Gastroenterology. 2015; 149 (quiz e314–365): 367-378 e365Abstract Full Text Full Text PDF PubMed Scopus (1062) Google Scholar, 7Stewart K. Haller D. Sargeant C. et al.Readiness for behavior change in non-alcoholic fatty liver disease: implications for multidisciplinary care models.Liver Int. 2015; 35: 936-943Crossref PubMed Scopus (39) Google Scholar Similarly, bariatric surgery can be effective,8Lassailly G. Caiazzo R. Buob D. et al.Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.Gastroenterology. 2015; 149 (quiz e315–376): 379-388Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar 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.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar 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.10Younossi Z.M. Guyatt G. Kiwi M. et al.Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease.Gut. 1999; 45: 295-300Crossref PubMed Scopus (430) Google Scholar 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.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar 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 2013.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar 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.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar 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.12Kim D. Kim W.R. Kim H.J. et al.Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States.Hepatology. 2013; 57: 1357-1365Crossref PubMed Scopus (496) Google Scholar 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.13Ekstedt M. Hagstrom H. Nasr P. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; 61: 1547-1554Crossref PubMed Scopus (1239) Google Scholar, 14Ekstedt M. Franzen L.E. Mathiesen U.L. et al.Low clinical relevance of the nonalcoholic fatty liver disease activity score (NAS) in predicting fibrosis progression.Scand J Gastroenterol. 2012; 47: 108-115Crossref PubMed Scopus (32) Google Scholar 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.15Byrne C.D. Targher G. Time to replace assessment of liver histology with MR-based imaging tests to assess efficacy of interventions for nonalcoholic fatty liver disease.Gastroenterology. 2016; 150: 7-10Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar 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.16Pais R. Charlotte F. Fedchuk L. et al.A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.J Hepatol. 2013; 59: 550-556Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 17McPherson S. Hardy T. Henderson E. et al.Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.J Hepatol. 2015; 62: 1148-1155Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar 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 the FDA. Therefore, whether determined by MR or other means, improvement in steatosis alone does not meet regulatory standards as either a reasonably accepted or generally accepted surrogate for approval of drugs for NASH. There are also other aspects of the arguments put forward by Byrne and Targher that are not evidence based. The 10- to 15-year probability of a liver-related outcome in those with isolated hepatic steatosis is vanishingly small.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar, 13Ekstedt M. Hagstrom H. Nasr P. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; 61: 1547-1554Crossref PubMed Scopus (1239) Google Scholar Furthermore, the rates of fibrosis progression reported in retrospective analyses of limited subsets of subjects with fatty liver in individual centers suffer from ascertainment and selection bias, including studies reporting both high and low rates of progression. The ideal study would be to perform protocol biopsies in a large and diverse cohort of subjects at intervals fixed by protocol to ascertain the true rates of fibrosis progression in this population. This constitutes an essential first step before considering therapy to decrease liver-related outcomes in those with fatty liver alone. In addition to the relatively low gain in terms of liver-related outcomes, demonstration of safety will be critically important before potentially approving drugs with possible side effects that could be prescribed to almost one-third of the population.18Browning J.D. Szczepaniak L.S. Dobbins R. et al.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (2878) Google Scholar The assumption that steatosis invariably precedes and is causally linked to the development of steatohepatitis is also not established. On the other hand, subjects with fatty liver are at risk of adverse cardiovascular outcomes.19Targher G. Day C.P. Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.N Engl J Med. 2010; 363: 1341-1350Crossref PubMed Scopus (1375) Google Scholar Here again, proving that NAFL directly contributes to other outcomes such as cardiovascular mortality has been remarkably difficult and most of the literature is based on demonstration of association, not causality. One perspective is that the inflammatory state in the liver contributes to adverse extrahepatic effects, whereas others argue that triglyceride in the liver is but an epiphenomenon and serves as a marker of a dysmetabolic state but does not contribute directly the extrahepatic manifestations of this complex disorder. To date, there is no evidence that an isolated decrease in liver triglycerides translates in to clinically meaningful benefits as defined by regulatory science and demanded by law for drug approval. In fact, the existing literature suggests that it does not affect outcomes.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar Regardless of the nature of the relationship, the development of cardiovascular outcomes and type 2 diabetes do represent clinically meaningful outcomes in this population and thus it may be reasonable to reduce such outcomes in this population. It is, however, worth noting that there are no validated data that reduction of triglycerides in the liver by itself improves either liver or cardiovascular outcomes in this population. These considerations have led the hepatology field to focus on those at greater risk for developing liver-related outcomes as the target population for clinical trials to decrease liver-related outcomes. Given the long natural course of the disease before outcomes occur and the logistic difficulties associated with trials in such a population, the FDA has provided a pathway for accelerated approval using generally accepted surrogate end points or reasonably accepted surrogate end points.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar Unfortunately, we do not yet have the data to fulfill the requirements for an endpoint to be accepted as a generally accepted endpoint other than progression to cirrhosis, which clearly represents a clinically significant change in liver status in those who have precirrhotic stages of NASH. Identification of such an endpoint that is easy to demonstrate remains a major unmet need in the field. In the absence of a generally accepted surrogate, a reasonably accepted surrogate may provide a legal mechanism using the subpart H pathway, which permits conditional approval based on reasonably accepted surrogates with the caveat that long-term post approval studies be performed to demonstrate that the surrogate translates in to clinically meaningful benefit.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar Such end points must be related to disease biology and sensitive to change. Liver histology is the basis for disease definition and staging, and steatohepatitis and hepatic fibrosis stage have been linked to clinical outcomes.11Angulo P. Kleiner D.E. Dam-Larsen S. et al.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology. 2015; 149: 389-397 e310Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar, 13Ekstedt M. Hagstrom H. Nasr P. et al.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology. 2015; 61: 1547-1554Crossref PubMed Scopus (1239) Google Scholar Furthermore, steatohepatitis progresses to cirrhosis far more commonly than a fatty liver alone. Thus, resolution of steatohepatitis or a decrease in both the NAFLD activity score and fibrosis has been suggested as a reasonably accepted surrogate for approval under subpart H.9Sanyal A.J. Friedman S.L. McCullough A.J. et al.Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop.Hepatology. 2015; 61: 1392-1405Crossref PubMed Scopus (243) Google Scholar It is also important to consider drug safety in the context of drug development for NASH. An ideal drug should not only prevent clinically meaningful liver outcomes, but at the very least must be safe in terms of cardiovascular, diabetes, and cancer-related outcomes. Given the logistical challenges of studies to demonstrate noninferiority to placebo arms with respect to these outcomes, the minimum requirement in phase III trials is to demonstrate a lack of signal suggesting a increased risk for a safety event followed by phase IV studies to confirm cardiovascular safety and lack of any unexpected adverse events. There is no question that there is a need for a noninvasive profile of subjects with NAFLD at risk of progression to liver-related outcomes and ways to assess response to treatment without subjecting individuals to multiple invasive liver biopsies. This will not only accelerate drug development, but enhance access to care for all patients with the disease in the community. However, this requires a major investment of effort to develop and validate such biomarkers as has been done for low-density lipoprotein cholesterol and hemoglobin A1C for heart disease and diabetes, respectively. Until then, liver histology based end points rather than MR-based fat quantification will remain the standard for approval as a reasonably accepted surrogate endpoint under subpart H for approval.