Author information

¹Faculty of Medical Sciences, Newcastle University, UK.

²Department of Gastroenterology and Hepatology, Academisch Medisch Centrum Universiteit van Amsterdam, Netherlands.

³Division of Gastreonterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA.

⁴Division of Gastroenterology and Centre for Autoimmune Liver Disease, University of Milano-Bicocca, Milan, Italy and Liver Unit, ASST Grande Ospedale, Metropolitano Niguarda, Milan, Italy.

⁵John Radcliffe Hospital, Oxford, UK and University of Oxford, UK.

⁶Liver Unit, Freeman Hospital, Freeman Road, Newcastle upon Tyne, UK.

⁷Hepatitis B Foundation, San Diego, California, USA and Division of Gastroenterology and Hepatology, Stanford Medicine, Stanford, USA.

⁸Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, Netherlands and University of Toronto, Toronto, Canada and Toronto Center for Liver Disease & Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.

⁹Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada.

¹⁰Leeds Liver Unit, St James's University Hospital, Leeds, UK.

¹¹Liver Institute Northwest, Elson S. Floyd College of Medicine, Washington State University, USA and Velocity Clinical Research, Seattle, USA.

¹²Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.

¹³College of Health Solutions, Arizona State University, USA.

¹⁴Department of Internal Medicine, University of Texas Southwestern Medical Center, Texas, USA.

¹⁵The Cambridge Liver Unit, Addenbrooke's Hospital, Cambridge, UK.

¹⁶Liver and Hepato-Pancreato-Biliary Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

¹⁷Central Manchester University Hospitals NHS Foundation Trust, Department of Gastroenterology (Manchester Royal Infirmary), Manchester, UK.

¹⁸University of Calgary, Calgary, Alberta, Canada.

¹⁹Department of Medicine, Teikyo University School of Medicine, Japan.

²⁰Liver Unit, Royal Free Hospital, London UK.

²¹Division of Gastroenterology and Hepatology, Department of Medicine III Medical University of Vienna, Austria.

²²National Institute for Health and Care Research, Birmingham Biomedical Research Centre, Birmingham, UK and Liver Unit, University Hospitals Birmingham, UK.

²³Gastroenterology and Hepatology, Nepean Hospital, New South Wales, Australia.

²⁴Aneurin Bevan University Health Board, Gwent Liver unit, Newport, Wales, UK.

²⁵Division of Digestive Health and Liver Diseases and Schiff Center for Liver Diseases, Miami, USA.

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of Ursodeoxycholic Acid (UDCA). Up to 40% of patients do not, however, respond adequately to UDCA and therefore still remain at risk of disease progression to cirrhosis. The introduction of Obeticholic acid (OCA) as second-line therapy for patients failing UDCA has improved outcomes for PBC patients. There remains, however, a need for better treatments for higher risk patients. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorisation for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcomes trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with OCA, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcomes trials when a licensed drug is commercially available. New PBC therapies in development such as the PPAR agonists, face even greater challenges in demonstrating outcomes benefit through randomized placebo-controlled studies once following conditional marketing authorisation, 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 recognise the importance of Real-World Data in providing evidence of outcomes 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.