Highlighting the real Achilles Heel of rare disease trials
Retention is the Achilles heel of rare disease trials. How could early detection of dropouts help outcomes and where does this fit ICH E6(R3)?
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Every successful clinical trial must balance a complex range of risk factors, but there are arguably some trials where this balance is more finely poised than others; rare diseases being a clear example.
By definition, these conditions affect a relatively small proportion of the population, a threshold of fewer than 1 in 2,000 people in Europe (1), meaning trials often involve participants who are widely dispersed across geographic regions. In addition, trial co-ordinators must accommodate the probability of a high or fluctuating disease burden, which will vary from individual to individual, and continually wrestle with the broader context of comparatively poor understanding of the disease’s pathophysiology.
Add into this mix the pragmatic real-world challenges that underlie trial management more generally, from ethics and safety, to logistics and protocol design, and the risks associated with rare disease trials are elevated to if not unmanageable levels, certainly uncomfortable ones.
Success in such conditions will be dependent on several crucial factors, one of which is undoubtedly patient recruitment. Finding, engaging and enrolling suitable candidates can be problematic with any trial, indeed, it is estimated to account for 32% of the total budget (2).
But in the case of rare diseases this problem is multiplied many times over. Here, participant populations are smaller in scale and therefore co-ordinators are fishing from inherently smaller pools across global territories, struggling in the face of low levels of diagnosis for rare conditions.
This not only compounds the geographical and logistical challenges associated with recruitment, but it can also add a costly time variable to the already lengthy process of bringing a drug to market. These factors all serve to amplify the overall recruitment cost per patient in rare disease trials.
Overcoming the hurdle of recruitment introduces a related and arguably more acute issue: retention. Having invested in attracting the right patients, co-ordinators must work to ensure those individuals remainengaged with the trial. If, however, they slip through the net or disconnect from the process then there is either renewed pressure on recruitment or there is a risk that the data generated is weakened to the point where potentially the trial fails.
At its core, retention is a people problem. Human behaviour can be unpredictable and inconsistent, meaning patients can decide to act in certain ways that have the potential to compromise the overall integrity of a trial. Whether they are driven by conscious or subconscious thought, these actions can be damaging nevertheless. Moreover, they can be difficult for unprepared trial co-ordinators to manage.
Adherence is a case in point. How well a patient complies with the dosing regimen specified by the protocol correlates directly with their level of engagement with the trial. Patterns of reduced behaviours therefore send a clear signal of heightened disengagement and elevated risk of dropout. And in the focused arena of rare disease trials, each of those resulting dropouts will represent a larger proportion of the population as a whole.
Of course, it shouldn’t be this way as trial protocols are designed to be faithfully followed. Indeed, the quality of the output data and power of the analysis depends on it; only then can robust judgements be made on efficacy and safety. But it is highly unlikely that perfect compliance will be achieved and highly likely that human fallibility will be flagged through suboptimal adherence.
Adherence signals are therefore valuable currency for clinical teams, but protocols are not always designed in a way that ensures these signals are relayed effectively. When in progress, the many moving parts of a trial create a ‘fog’ of activity that can obscure the variable behaviours of participants on the ground. Co-ordinators do not see non-adherence in real time, allowing it to go unchecked; indeed their first indication that a patient is disengaged from the trial comes with notification of their decision to leave.
In the fragile context of rare disease trials, where recruited patients are precious rarities, these losses are felt keenly. It only adds to an already pressured environment, where success rates in Phase 2 trials for rare diseases stand at 48.8% and just 6.2% of rare drug development projects reach the market (3).
Improving these odds depends on close and careful in-trial management of participants, which should be planned in from the beginning. Understandably, much emphasis is placed on the difficult task of recruitment, but in reality, overcoming this challenge only brings companies to the foothills of a rare disease trial. It is only through continued patient engagement and retention that you can even stand achance of successfully reaching the summit.
In Chapter 2 we will discuss how and why the regulators didn’t change the ICH guidance by accident; they changed it because trials are failing. We will then go on to review how we can close the gap between the ICH guidance and the successful implementation of the trial.
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