Background

Primary Sclerosing Cholangitis (PSC) is an immune-mediated disease of the liver characterized by chronic inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts [1, 2]. This inflammation may result in multifocal biliary strictures and can affect the entire biliary tree [2, 3]. Over time PSC leads to cholestasis, progressive hepatic fibrosis and eventually decompensated cirrhosis in a substantial number of patients over the course of 10- 15 years. Patients with PSC also have an increase in hepatobiliary cancers, such as cholangiocarcinoma and hepatocellular carcinoma; cancer is the leading cause of mortality in PSC [1].

The incidence of PSC in the United States is 0.9 per 100,000 population and the prevalence is estimated at 13.6 per 100,000 [1]. PSC appears to have a similar incidence in North America and Northern Europe, and has increased over time [3]. Additionally, since PSC may present in asymptomatic patients with normal liver tests, it has been suggested that the incidence and prevalence are underestimated [4].

Yet, there are no effective medical treatments for halting the progression of PSC [1].  In eligible patients with advanced stage PSC, intractable pruritus, or recurrent cholangitis, liver transplantation is the only therapeutic modality available [1, 2]. Liver transplant free survival varies from 13-21 years in patients with PSC and it is the fifth most frequent indication for liver transplantation in the United States [3, 5].  However, even after liver transplantation the PSC recurrence rate is 20-25% within five to ten years [6].  

During the 2011 International Liver Congress, the European Association for the Study of the Liver (EASL), stated that PSC is one of the greatest unmet needs in hepatology [5].  There are a number of challenges in establishing an effective medical therapy for PSC.  First, it is a rare disease, which complicates executing a study design with sufficient logistical power.  Second, since the pathogenesis of PSC is not well understood, identifying targeted molecular therapies is challenging. Third, it is difficult to establish clinical endpoints, aside from death or the need for liver transplantation in therapeutic trials [7].

Interest in the development of therapeutic options to treat PSC and prevent liver failure is high, with more than 35 clinical trials identified through the U.S. National Institutes of Health website.Therapeutic agents that have been tested include immunosuppressants, ursodeoxycholic acid and other bile acids, antifibrotics, anti-tumor necrosis factors, and antibiotics. However, the drug development field is challenged by the unknown etiology and pathophysiology of the disease, variable natural course of the disease, and the resulting divergent strategies for therapeutic approaches, which further complicates the regulatory pathway.

Read more about The Forum for Collaborative Research's history, achievements, operating procedures and working process.

The PSC Forum

The PSC Forum, which is part of the Liver Forum, aims to advance the regulatory sciences for the treatment of PSC and its associated morbidities by providing an independent and neutral venue for ongoing multi-stakeholder dialogue. Our work is designed to promote improving research and treatment by facilitating science-based decision making on how to study efficacy and safety in real time, as our collective knowledge and experience with therapies for PSC advances

Once new drug candidates and therapeutic strategies are identified, their rapid, safe development is in the best interest of all stakeholders, most of all, the patient. Careful deliberation on issues of common interest and concern by an independent body whose neutrality and objectivity is ensured through representation and active engagement of scientific experts from all stakeholder groups, including academia, industry, professional societies, patient community, and regulatory agencies in a non-competitive and safe environment, breaks down inefficiencies by increasing clarity and standardization and decreasing uncertainty, and allows the whole field to benefit from valuable lessons learned. The PSC Forum will provide a platform for such a process.

Context

Traditional FDA approval mechanisms require demonstration of benefit based on hard clinical endpoints. For conditions, such as PSC, studies of medical treatment are complicated by asymptomatic presentation, poorly understood natural history and a lengthy time to reach hard endpoints, such as liver transplantation or death. The potential for accelerated approval, requiring identification and validation of surrogate markers, is hampered by the low incidence of the disease, numerous phenotypes, variable disease progression, and multiple clinical outcomes. The field lacks ideal standards, suitable for point of care use, and for assessing and identifying patients at the highest risk of developing liver failure and other PSC related complications, such as cancer. 

These issues also affect clinical trial design and patient selection. Effective therapeutic strategies may require combination therapies, personalized according to patient phenotypes and confounding factors. The regulatory pathway for combination therapies can be complex, full of uncertainties and burdensome for patients, clinical researchers, regulators and industry. 

These issues and concerns were highlighted at the Trial Design and Endpoints for Clinical Trials in Adults and Children with PSC meeting sponsored by the U.S. Food and Drug Administration (FDA) and the American Association for the Study of Liver Diseases (AASLD), which took place on the March 3-4, 2016. The field of rare liver diseases will benefit from continuing the multi-stakeholder dialogue initiated at that meeting. This rapidly moving and dynamic field will require collaborative bridges and coordinated efforts between many parties. 

Action Plan

The PSC Forum is led by a Steering Committee and managed by Forum staff. The project agenda is set by the Steering Committee and is designed to focus on accelerating drug development by identifying gaps in research and synergizing ongoing work in PSC across various groups of experts.  

Working groups have been developed to carry on the work of the PSC Forum by addressing priority areas identified by both the steering committee and PSC Forum members. Expected outcomes of the working groups include recommendations, position papers, reports, manuscripts for submission to peer-reviewed journals, and presentations at conferences. Throughout the year, working groups communicate and collaborate by conference calls, email, in-person meetings, and workshops as needed. There is no time requirement for participation; however, working group members are expected to be active participants and participate in as many calls and activities as possible. 

References

1. Singh S, Talwalkar JA. Primary sclerosing cholangitis: diagnosis, prognosis, and management. Clin Gastroenterol Hepatol 2013,11:898-907.
2. Nayagam JS, Pereira SP, Devlin J, Harrison PM, Joshi D. Controversies in the management of primary sclerosing cholangitis. World J Hepatol 2016,8:265-272
3. Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013,145:521-536.
4. Kumar A, Wheatley D, Puttanna A. Primary Sclerosing Cholangitis: Therapeutic Options and Surveillance Management. Clin Med Insights Gastroenterol 2016,9:25-29.
5. Ponsioen CY, Chapman RW, Chazouilleres O, Hirschfield GM, Karlsen TH, Lohse AW, et al. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process. Hepatology 2016,63:1357-1367.
6. Saadi M, Yu C, Othman MO. A Review of the Challenges Associated with the Diagnosis and Therapy of Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2014,2:45-52.
7. Eaton JE, Talwalkar JA. Primary Sclerosing Cholangitis: Current and Future Management Strategies. Curr Hepat Rep 2013,12:28-36.