Operational Challenges of Neuroscience Clinical Trials, Part 4: Assessment Subjectivity

In this blog series, we’ve been discussing some of the challenges of conducting clinical trials in neuroscience. In our final post of the series, we turn to another major one: ensuring that assessments are conducted with high quality whilst also minimizing subjectivity.

Rating subjectivity can make signal detection substantially more difficult, if not impossible. This is especially true in central nervous system (CNS) trials, where endpoints in some indications can rely exclusively on human judgment. Strategies to improve assessment subjectivity include:

  • standardization of raters
  • standardization of enrolled patients
  • the use of biomarkers to decrease subjective outcomes

Standardize raters at clinical trial sites

The most meticulous method to improve assessment subjectivity is to employ rater surveillance programs, a strategy that is increasingly being utilized by sponsors and CROs. Traditionally, individual raters at a given trial site have been responsible for maintaining their own integrity and quality. A key component of surveillance programs involves structured rater training at the start and throughout the study.

Second, assessments of inter- and intra-rater reliability at the beginning and throughout a trial help guard against rater “drift” over time. It’s important that these assessments, and any subsequent needed re-training, occur contemporaneously to both the assessment being administered to the subject and to the need for re-training on the part of the rater.

One advantage of a centralized rater program is very high inter-rater reliability. In addition, due to the rigorous training methodology, and because the ratings are often performed remotely via phone or video-conferencing, the raters are subject to fewer biases related to patient history and trial details. The use of structured interviews – ensuring all raters ask the same questions in the same manner across sites and at every study visit – also helps to guard against rater drift. Finally, the use of remote raters in a centralized rater program may also allow access to additional sites such as those in rural locations that might not otherwise have raters available and would therefore be unable to participate in clinical research.

Standardize clinical trial patients

Another important strategy to reduce assessment subjectivity is to ensure that each and every patient qualifies for the study and meets enrollment eligibility. Incorrectly classified patients can be very detrimental to signal detection. Many sponsors utilize a pre-enrollment form that ensures that ratings of medications, medical history, illness severity, demographics, and other patient variables are standardized.

It is also important to ensure that clinical trial patients understand the scale being administered, and that their own responses to scale questions do not drift over time. This can be accomplished via training as well, not only via that discussed above for the rater administering the scale, but also via training of the patients themselves. Ensuring the patient’s “anchors” on the scale remain consistent throughout the trial will help with signal detection and to minimize placebo response (as discussed in another blog in this series).

Moving towards biomarkers

Finally, an obvious solution towards improving assessment subjectivity is to move away from subjective assessments entirely. For example, biomarkers of diabetes and high cholesterol provide empirical evidence of disease changes. Biomarker development is underway for a number of CNS indications, including in predicting evolution to AD in patients with clinically ambiguous dementia, though to date there are few that have been validated sufficiently for clinical trial use. As more and more biomarkers are discovered and validated, the goal is that rater subjectivity will become less of a challenge to neuroscience trials.

CNS disorders represent a major medical challenge and a significant opportunity for therapeutic innovation, and Premier Research has been helping pioneers make their vision a reality for years. To learn more, download our white paper Measuring How Well Subjects Know and Do in CNS Trials or contact us today.

Read more:

Operational Challenges of Neuroscience Clinical Trials, Part 3: Patient Recruitment

Operational Challenges of Neuroscience Clinical Trials, Part 2: High Placebo Responses

Operational Challenges of Neuroscience Clinical Trials, Part 1: Overview 

Author Details

Krista Armstrong
Krista Armstrong, Ph.D. oversees the overall execution of Premier’s Strategic Development Strategies, and is also responsible for oversight of the Executive Director Leadership Team for the company’s neuroscience, oncology, general medicine, pediatric, and rare disease portfolios. Her primary therapeutic and operational expertise is within neuroscience, with a specific emphasis in psychiatric indications and neurological conditions, such as ADHD, bipolar disorder, autism, addiction, Alzheimer’s disease, Parkinson’s disease, and stroke.
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