Dealing with agencies like the FDA can make you a little crazy. Lawyers and laws have turned life and death decision making into our version of the wailing wall. We come as supplicants to leave our prayers and we are told to stand silently while our fates are debated in secret. Sorry, this is long but important.

People who suffer with advanced fatty liver disease, nonalcoholic steatohepatitis (NASH), find ourselves in that situation. About 100 million Americans have fatty liver disease (NAFLD) and about 20 million have its more dangerous advanced stages of NASH and there are no therapies. Most of the people who have the disease don’t know it yet as it is a very silent killer with few symptoms. The first drug to offer a useful therapy recently applied for a conditional approval. The FDA is supposed to consider the patient’s viewpoints but to date has not and recently cancelled the only public forum where patients would be able to be heard.

As fatty liver disease patients we care deeply about the research being done to bring us therapies. Recent action by FDA regarding the Intercept drug candidate obeticholic acid (OCA) may signal a shifting strategy with regard to breakthrough drugs and the accelerated approval process. If that is the meaning of recent actions, as patients, we are concerned about the impact it may have on the drug pipeline and research being done for NASH. If agency guidelines are fuzzy or unreliable the effect on us is ultimately more disease and death.

The Intercept Pharmaceutical phase 3 trial, REGENERATE, for OCA as a therapy for NASH reported out last year that it had met the surrogate endpoint of a one stage reduction of fibrosis without a worsening of NASH. The key term is surrogate histopathologic endpoints.

OK, no ordinary person understands surrogate histopathologic endpoints. In simple terms it means that the FDA has told researchers what level of effectiveness they must meet to be approved. Simply put, the OCA trial met the agreed upon goal and it would seem reasonable to assume that we could move to the next step which is to hold a public meeting, or AdCom, where patients could comment on the drug. Instead of holding that meeting the agency declined to act based upon some unstated benefit analysis without consideration from the people who might benefit. We view that as unacceptable and we want our AdCom meeting back. We want to be able to participate in development of our drug treatments.

The Fatty Liver Foundation (FLF) is a leading, non-profit, grassroots patient advocacy organization dedicated to improving the identification, diagnosis, treatment, and support of Americans with NAFLD or NASH. We are very concerned about the FDA’s process with regard to OCA as a designated breakthrough therapy but more importantly we are concerned about what appears to be a changing policy regarding surrogate endpoints.

We applaud recent actions taken by the Agency in granting an accelerated approval pathway for the review of drugs that are intended to treat patients with NASH. Our patient community is very aware of the fact that there are no therapies or treatments for NASH. We are grateful for the efforts made by the Agency to issue guidance to assist industry sponsors in the clinical development of drugs for the treatment of liver fibrosis. NASH patients and our advocate community praised FDA’s initial announcement on convening this much-anticipated AdCom meeting.

We were anxious to have an opportunity add our voice to the record and we were dismayed when the Agency issued a notice called a Complete Response Letter (CRL), without holding the Adcom. A CRL notice essentially tells a company that their application is rejected. We understand that the Agency suggested that Intercept could submit additional post-interim analysis of efficacy and safety in order to address uncertainty related to the predicted benefit of OCA.

We are anxious to understand what risk factors prompted the CRL, but it is important that FDA weigh benefits appropriately. Absent new data, the results of the Phase III trial demonstrated that OCA met the design endpoint. As patients, we wish to be on record as stating that a reduction in NASH staging is of great value to us. It is well documented that a reduction in fibrosis reduces mortality so the OCA results are of great interest. Fibrosis stage improvement is crucial to our health and we seek to have our voices be considered in the deliberations about drugs under consideration.

To put that argument into perspective, a stage 4 NASH diagnosis means a patient is almost 11 times as likely to die as someone who is healthy. A one stage reduction to a stage 3 means that the risk is reduced to about 4 times as likely that you will die. That is a big deal to us so dismissing this first potential therapy for the disease is a big deal.

Drug regulation is more than minimizing risks. Given the high prevalence of NASH, the associated co-morbidities, and the growing burden of end-stage liver disease, we believe that it is important to focus on maximizing public health gains by licensing therapies that will slow the progress of, halt, or reverse NASH. OCA is the first of what we hope will be a variety of alternatives for our treatment, but we are concerned that this action on OCA will discourage other research since it appears to be unclear whether reaching agreed endpoints is being given sufficient valuation in this very complex drug development field.

An inference can be made from the FDA actions that the agency is changing course in the way it manages surrogate endpoints in trials. The agreed upon endpoint for OCA was met and yet the process was terminated without any opportunity for the patient voice to be heard. We find that unacceptable but there is a larger issue here.

Research on NASH is dealing with very complex chemistries and there is no single test of merit, like blood pressure or cholesterol that can define progress unambiguously. The result is that we are dealing with these surrogate endpoints which are not easy to determine but are the agreed upon target. We expect at a minimum that all trials receive even handed treatment.

If what we are witnessing here is a move by the agency to step away from a one stage measure of fibrosis we anticipate that the entire research community and its investors will find themselves untethered as to their goals. That will certainly dissuade researchers and investors from choosing to work on NASH and likely greatly harms our community by delaying development of treatments.

As patients we have asked the agency for clarification of this decision and to take note of the patient voice in decisions of this kind. The agency response has been to tell us that the draft document on file, which allows for the agreed upon surrogate endpoints, is still available to researchers. We don’t feel that that answer is responsive to our question and we are concerned that this action has already harmed us by injecting uncertainty into what is already a very uncertain and difficult field of research. More patients will die as a result of having no therapies for what is a tsunami of liver disease building in our society.