Overall, the time it takes to progress to needing a transplant can be decades. It is unrealistic to expect to design a research trial to test a new drug if we have to wait 20 years to see if it prevents the need for a liver transplant. For this reason, it is important that validated surrogate markers are developed to predict outcomes for people with PSC (and used as trial endpoints).
Surrogate markers were the subject of a joint FDA, AASLD, ACG, AGA workshop in 2016, which concluded there was insufficient evidence to recommend individual surrogate endpoints for PSC 44. The underlying complexity of PSC was recognised and it was suggested that surrogate endpoints that measure more than one aspect of the disease may be appropriate (such as measuring bile duct pathology and liver fibrosis) depending on the intervention being investigated 44.
The International PSC Study Group (IPSCSG), in a comprehensive review of the field, emphasised the importance of establishing and validating surrogate biomarkers in PSC. They concluded that until they exist, future clinical trials should use a range of potential surrogate biomarkers that can be evaluated individually and in combination 45.
However, this goal of finding the best surrogates does not mean patients like or trust surrogate biomarkers, nor do we think they are the best way to judge treatments. Some clinical trial design experts argue against the use of surrogates, saying they don’t definitively test the drugs and that hard endpoints such as death and liver transplant, taking many years to reach, are preferable. In December 2018, PSC Support spoke at the ‘European Medicines Agency stakeholder interaction on the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH)’ and supported the use of surrogates as endpoints in PSC because the unmet needs of PSC patients need to be addressed urgently.
PSC Support emphasised that people with PSC don’t have the luxury of time to wait for trials that last 20 years and their unmet needs must be resolved as a matter of urgency. Surrogates shorten trial duration, so patients accept them. However, we urged investigators to consider longer-term outcome observation when using surrogates - as long as possible to be confident these drugs really do demonstrate positive change.