Silent plight – PharmaTimes
Despite ever increasing funding, clinical trials in primary biliary cholangitis (PBC) continue to struggle.
PBC is an often silent, rare disease which means recruitment can be slow, impeding enrolment timelines and reducing the ability of researchers to develop new treatments.
What is PBC?
PBC is an autoimmune condition affecting a person’s bile ducts and liver. If left untreated it can lead to scarring of the liver (fibrosis), cirrhosis and eventually liver failure.
The condition classifies as a rare disease, however it is one of the most common ones, it is estimated that there are at least 22,000 people with PBC in the UK alone. It disproportionately impacts women, affecting 9 women to every 1 man.
Blood tests are the primary method for diagnosing PBC, with the combination of cholestatic serum liver tests and PBC-specific serological markers having a diagnostic accuracy of >95% for sensitivity and specificity
Although diagnostic tests are relatively simple, PBC is often symptomless in its early stages. As a result, many sufferers do not know they have it until it becomes advanced.
This lack of a systematic identification process can have a significant impact on people living with PBC, as it affects their opportunity to access treatment early when it is at its most effective.
More generally, research is hindered by being unable to find enough people who might be eligible to participate in clinical trials aimed at developing better treatments for the disease.
Current treatment options are not always effective for everyone and come with side-effects, leaving many patients with limited options.
As a result, there is a pressing need for new treatment options that can help to alleviate the symptoms and improve the quality of life for those suffering from the disease or treatment side-effects.
There is an increasing amount of research into PBC, and the recent $4.3bn acquisition of Cymabay Therapeutics by Gilead shows that the outlook for new PBC treatments is positive, and there are more than 40 active PBC trials.
Anecdotally, we know that recruitment for these trials is notoriously hard, with most sponsors only aiming to recruit around four patients (or fewer) per site each year. This means that the cost of trials is high, and time to market is longer than it needs to be.
Recruitment dive
The recruitment process for PBC clinical trials encounters significant hurdles.
The availability of existing, approved treatments, such as ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), means that while these treatments offer relief for patients, immediate prescription upon diagnosis creates a scarcity of participants for clinical trials.
This scarcity demands that research sites remain on standby, incurring substantial costs for sponsors, while awaiting a drip feed of newly diagnosed and untreated individuals. To further illustrate this issue, it is estimated that the global incidence of PBC is around 1.76 per 100,000.
Compounding the issue is the inherent challenge of diagnosing PBC at its earlier stages. As with many silent liver diseases, most individuals remain asymptomatic and, consequently, undiagnosed unless the disease becomes symptomatic.
This difficulty in early-stage identification results in exceedingly slow recruitment rates, and biases data to those with symptoms from advanced disease, forcing sponsors to establish numerous sites across many countries.
The financial implications of this are significant, with each site activation adding tens of thousands of dollars to the study cost.
Moreover, the limited pool of experienced and capable research sites exacerbates the recruitment issues. These sites are pivotal for the efficient and accurate identification of eligible participants, a task made difficult by the complex recruitment criteria characteristic of PBC trials.
While expanding the network of sites may seem like a plausible solution to slow recruitment rates, a reluctance to engage newer sites stems from a justified concern over their lack of expertise.
Inexperienced sites might not only struggle to identify suitable candidates but also risk making expensive errors that could compromise the trial’s integrity.
Strategy shift
As we’ve seen, those recruiting for PBC clinical trials face significant challenges, however, these could potentially be addressed with a targeted, data-driven approach.
Considering the high volume of blood tests conducted annually across various healthcare settings, there’s a valuable opportunity to improve the identification of PBC among patients.
Our own research suggests that a significant number of individuals with abnormal liver test results may not be receiving follow-up in line with current medical guidelines.
This indicates a gap in the healthcare system that, if bridged, could benefit both patient care and clinical research – as well as an opportunity for the health care providers to save considerable costs.
The “case-finding” strategy proposes the use of historical blood test data to identify individuals who may have PBC. This approach does not require additional testing but rather enables a more efficient use of existing available data.
In the UK, where PBC diagnosis is primarily based on blood tests, there is an abundance of data that could be utilised more effectively. By identifying individuals with undiagnosed PBC, we can potentially prevent disease progression and simultaneously create a larger, more viable pool of candidates for clinical trials.
Another potential benefit of a case-finding approach is that centralised protocols for recruitment could be established.
This would enable a uniform set of criteria to be applied across different sites, reducing the administrative burden, and making it feasible for more sites to participate in recruitment, without the constraint of extensive prior experience.
Such an approach would not only streamline the recruitment process but also ensure a broader representation of the population in clinical trials, avoiding the biases associated with more limited recruitment strategies.
In essence, by adopting a case-finding approach, we could make more efficient use of historic blood test results to enhance both the management of PBC and the recruitment process for clinical trials.
Dr Tim Jobson is Consultant Gastroenterologist in the NHS & Medical Director of Predictive Health Intelligence