Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

European Society for Organ Transplantation (ESOT) Consensus Statement on Outcome Measures in Liver Transplantation According to Value-Based Health Care.

Liver transplantation is a highly complex, life-saving, treatment for many patients with advanced liver disease. Liver transplantation requires multidisciplinary teams, system-wide adaptations and significant investment, as well as being an expensive treatment. Several metrics have been proposed to monitor processes and outcomes, however these lack patient focus and do not capture all aspects of the process. Most of the reported outcomes do not capture those outcomes that matter to the patients. Adopting the principles of Value-Based Health Care (VBHC), may provide an opportunity to develop those metrics that matter to patients. In this article, we present a Consensus Statement on Outcome Measures in Liver Transplantation following the principles of VBHC, developed by a dedicated panel of experts under the auspices of the European Society of Organ Transplantation (ESOT) Guidelines' Taskforce. The overarching goal is to provide a framework to facilitate the development of outcome measures as an initial step to apply the VMC paradigm to liver transplantation.

The evolution of the liver transplant candidate.

The first successful human liver transplant (LT) was done over 60 years ago; since the early pioneering days, this procedure has become a routine treatment with excellent outcomes for the great majority of recipients. Over the last six decades, indications have evolved. Use of LT for hepatic malignancy is becoming less common as factors that define a successful outcome are being increasingly defined, and alternative therapeutic options become available. Both Hepatitis B and C virus associated liver disease are becoming less common indications as medical treatments become more effective in preventing end-stage disease. Currently, the most common indications are alcohol-related liver disease and metabolic associated liver disease. The developing (and controversial) indications include acute on chronic liver failure, alcoholic hepatitis and some rarer malignancies such as non-resectable colorectal cancer liver metastases, neuroendocrine tumours and cholangiocarcinoma. Candidates are becoming older and with greater comorbidities, A relative shortage of donor organs remains the greatest cause for reducing access to LT; therefore, various countries have developed transparent approaches to allocation of this life saving and life enhancing resource. Reliance on prognostic models has gone some way to improve transparency and increase equity of access but these approaches have their limitations.