As noted in part one of this blog series, Worldwide Clinical Trials takes an uncommonly proactive approach to reducing screen failure in Alzheimer’s disease (AD) research. This strategy is especially useful as early-stage clinical studies make up a growing percentage of Alzheimer’s clinical trials.
Worldwide’s uncommonly proactive four-step strategy is initiated at the protocol development stage, carries through into prescreening and pre-randomization by targeting semi-predictable reasons for screen failure in Alzheimer’s clinical trials and improving decision making with a centralized eligibility review system.
Here is an outline of Worldwide’s strategy to improve Alzheimer’s disease research:
- Ensure clinical trial protocol will result in minimal patient burden.
- Understand which patients are more likely to qualify before formal screening begins.
- Positively influence semi-predictable reasons for screen failure.
- Introduce a centralized eligibility review system to improve enrollment decisions.
Screen Failure and Retention – Proactive Approach Aims to Increase Predictability
As shown in Figure 1 below, there are several causes of screen failure in Alzheimer’s disease clinical trials that can be predicted before consent. Predictable causes of screen failure include a patient’s medical history and status; dementia history and diagnosis; concurrent medications; scores on the Mini Mental State Examination (MMSE); the likelihood of study benefits; patient and caregiver ability to manage the study burden, including travel and logistics; and the desires and expectations of the patient and caregiver, as well their external pressures.
As the first step in this process, Worldwide works with study sponsors to develop effective protocols designed to achieve meaningful results while also limiting study burden caused by such factors as dosing frequency, lack of perceived benefit in symptom improvement and other variables.
The labor intensity and length of Alzheimer’s disease clinical trials are important considerations during protocol development because there remains a heavy examination burden, with practically every patient exam taking between two and three hours, making it difficult for patients to stay in the clinic comfortably.
Causes of screen failure segmented by stage of Alzheimer’s clinical trial enrollment
Figure 1: The goal of Worldwide’s proactive approach in Alzheimer’s disease research is to influence semi-predictable causes of screen failure so that they become more predictable.
Once an effective protocol is in place, Worldwide’s proactive approach to improving screen failure rates moves to the second step in which predictable reasons for screen failure are mitigated early in the enrollment process. Although good clinical practice (GCP) guidelines recommend no formal screening actions take place before patient consent, leading memory research centers in Alzheimer’s disease research are able to prequalify patients based on the predictable dimensions noted above. Given familiarity with a clinical trial protocol, a few highly sophisticated clinical sites in Europe can offer this data. Notably, screen failure rates in Alzheimer’s disease research at these clinical sites are much lower than average.
Influence semi-predictable reasons for screen failure in Alzheimer’s clinical trials
After consent, there are both non-predictable and semi-predictable reasons for screen failure. The non-predictable reasons include failure in structural and functional MRI, diagnostic lab results, PET scans or CSF results, safety lab and electrocardiogram (ECG) results, adverse events (AE) or new medications, and any paramedical reasons. Unfortunately, there is no way to reduce screen failures in this unpredictable group.
However, in the period immediately following consent there are several semi-predictable reasons for screen failure that can be influenced positively. In step three of Worldwide’s proactive approach to reducing screen failure in Alzheimer’s clinical trials, staff put a focus on these semi-predictable reasons. For example, they ensured that clinical staff had a process in place to adequately address patient and caregiver wishes and fully explained the study benefits and risks.
In studies targeting cognition, Worldwide’s proactive approach to improving screen failure in Alzheimer’s disease research has been seen to substantially reduce the number of patients who withdraw their consent.
Centralized eligibility review reduces diagnosis variability in Alzheimer’s diseases research
In step four of Worldwide’s proactive approach to reducing screen failure in Alzheimer’s disease research, Worldwide introduces a centralized eligibility review system to improve enrollment decisions. In some cases, patients who pass successfully through screening are later deemed to be ineligible for Alzheimer’s clinical trials. This is due in part to the subjective nature of evaluating Alzheimer’s disease, which places a heavy burden on clinical judgement. Although focused on ensuring a high-quality patient pool and protocol compliance, investigators often interpret inclusion criteria differently, enrolling patients who might not have otherwise qualified for an Alzheimer’s disease clinical trial. Different levels of risk tolerance cause variability across trial sites, which becomes more pronounced in global Alzheimer’s disease research due to country- or region-specific approaches to diagnosis.
To reduce this variability, Worldwide’s central eligibility review team of physicians and experienced clinical scientists collect key diagnostic and medical data just after patient screening and then review the data as a group. Eligibility concerns are discussed with the sites and investigators who make the final decisions, and subjects are withdrawn or randomized if additional clinical history is supplied to support eligibility. Because the centralized review system leaves the final randomization decision in the hands of the treating physicians, it has been an accepted and vital part of limiting variability across clinical sites and reducing screen failure in Alzheimer’s disease research.
A path forward for the tenacious researchers on the front lines of Alzheimer’s disease research
Currently affecting 47 million people worldwide, dementia is a growing, costly, global epidemic. Targeted at the most common form of dementia occurring late in life, Alzheimer’s disease research offers great promise, yet the lack of progress continues to frustrate stakeholders on all sides.
Worldwide’s proactive approach to reducing screen failure offers a viable path forward to Alzheimer’s clinical investigators who have the tenacity to take on this difficult, time consuming and vastly uncertain challenge.