By Gilad Rosenberg, MD, MSc, Executive Medical Director, Therapeutic Area Medical Lead (Neuroscience) at Allucent
Introduction
Challenges in neuropsychiatric clinical trials are numerous, including gaps in understanding disease pathophysiology, the distinctive cognitive, motor, and psychiatric characteristics of study participants, and various design and operational challenges unique to these conditions. Recognizing these challenges is crucial for improving clinical trial design, facilitating participant recruitment, and ultimately delivering effective new therapies to patients.
1. Limited Understanding of the Underlying Biology of Most Neuropsychiatric Diseases
The most significant hurdle in developing therapeutics for neurological and psychiatric disorders is the limited understanding of their pathophysiology at the cellular, tissue, and organ levels, in a system that is remarkably complex, where even normal function is often not fully understood. This applies not only to neurodegenerative disorders – often brought as the most complex examples of brain disorders – but also to non-progressive conditions like epilepsy. To date, no preventive (“anti-epileptogenic”) or disease-modifying therapy exists for epilepsy. Moreover, about a quarter of epilepsy patients are drug-resistant, yet the physiological causes of this resistance remain largely unknown.
Without a clear understanding of both the root causes of neuropsychiatric disorders and the significance of their downstream consequences like inflammation, protein clearance disruptions, and intercellular communication disturbances, it is difficult to determine which drug candidates should be prioritized, which biomarkers should be used (discussed further below), and which endpoints should be selected.
2. Lack of Validated, Objective, Quantitative, and Regulatory-Accepted Biomarkers
The U.S. FDA defines a biomarker as a “characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention.” The FDA categorizes biomarkers into seven types: diagnostic, monitoring, predictive, prognostic, pharmacodynamic, safety, and susceptibility/risk biomarkers.
In neuropsychiatric clinical research, pharmacodynamic biomarkers are particularly critical, serving both as criteria for patient selection and as trial endpoints. In early-phase trials, fluid- or imaging-based biomarkers primarily demonstrate target engagement. However, in Phase 2 studies, pharmacodynamic biomarkers are expected to indicate drug effects likely to translate into meaningful clinical benefits in larger confirmatory Phase 3 trials. A biomarker may also lead to accelerated regulatory approval if regulators deem it a “surrogate endpoint” – a substitute for direct measurements of how a patient feels, functions, or survives. In Phase 3 trials, pharmacodynamic biomarkers can serve as secondary endpoints, validating the results of the primary endpoint.
Unfortunately, validated biomarkers in neurological and psychiatric disorders remain scarce, particularly those accepted as surrogate endpoints by regulators. Exceptions include beta-amyloid PET for cognitive decline in Alzheimer’s disease, gadolinium-enhanced lesion counts on MRI for disease activity in relapsing-remitting multiple sclerosis, and plasma neurofilament light chain levels in ALS.
Validating biomarkers is a lengthy and expensive process, but it is essential for making neuropsychiatric trials more efficient and potentially shorter.
3. Clinical Endpoints in Neuroscience Clinical Trials are Often Subjective and Rater-Dependent
As said, biomarkers primarily serve as exploratory endpoints in neuropsychiatric clinical trials, while clinician-administered rating scales, which assess signs, symptoms, and/or function, are typically the main endpoints. Insufficient emphasis on rater training can compromise the reliability and validity of the data derived from such scales.
Common challenges in rater training include variability in raters’ qualifications and experience (rater may range from expert clinicians to novices in allied health professions), limitations of traditional training methods (which are often passive, such as reading or watching videos), and the lack of real-time monitoring of rater performance during the study. These issues increase inter- and intra-rater variability.
Effective rater training programs should cover interviewing techniques, including the use of structured interviews, and expert-supervised practical rating exercises using test cases of varying severities. This should be coupled with an ongoing in-trial monitoring to prevent “rater drift” (declining rater consistency over time). Centralized adjudication of video- or audio-recorded rating sessions, as well as rater re-training during the study, can both reduce scoring variability. These measures should be documented in a study-specific training manual, and completion of training should be verified through a certification process.
4. Standard of Care Differs Across Regions, Affecting Outcomes and Limiting Site Selection
Even with standardized training and monitoring, differences in healthcare quality across regions can profoundly influence trial outcomes. For instance, in acute ischemic stroke studies , the likelihood of admission to a specialized stroke unit – rather than to a general neurology ward – varies widely between countries, as does the quality of post-stroke rehabilitation.
Variability in care quality can obscure the true effects of an experimental intervention, even when study-specific procedures are meticulously followed. Site selection should minimize country-to-country discrepancies in care standards, and patient follow-up should go beyond measuring the investigational treatment’s direct effects. Rather, factors such as rehabilitation, pain and mood management, as well as secondary prevention measures, should be standardized as much as reasonably feasible, and monitored throughout the study.
5. Neuropsychiatric Clinical Trial Duration and Design May Lead to Subject Retention Issues
In the absence of validated surrogate endpoints, most neuroscience clinical trials rely on changes in clinical status as the primary endpoint, necessitating long follow-up periods of months or even years. This can create challenges in retaining participants. Additional burden, such as repeated lumbar punctures, lengthy cognitive assessments, and long-distance travel to specialized sites, can further contribute to participant attrition. In neurodegenerative research these problems are further compounded by the mere nature of the disorders under study: the relentless motor, psychiatric, and/or cognitive decline over the course of a lengthy trial can reduce the participants’ ability to continue the study.
The impact of suboptimal subject retention on data quality can be very significant, and manifest in reduced statistical power due to diminished sample size (while an attempt to compensate for that through the recruitment of replacement subjects results in increased trial duration and cost) and in selection bias: dropouts can skew results if those who remain differ significantly from those who leave, affecting generalizability (it has been suggested that a loss to follow-up of > 20% of study participants should cast doubt on a trial’s validity).
Successful patient retention can be aided by minimizing invasive procedures, enabling virtual visits through remote monitoring (as far as this is acceptable to regulators), providing travel support and reimbursement, fostering empathetic interactions with study staff (without amplifying placebo effect, if applicable; see below), and collaborating with patient advocacy groups to highlight the trial’s importance the participants and to the patient community at large.
6. Placebo Effect Can Jeopardize Neuropsychiatric Clinical Trials in Certain Indications
In neuropsychiatric conditions such as depression, anxiety or pain – where subjective symptom reporting is often the primary endpoint – double-blind placebo-controlled trials are highly susceptible to ‘placebo effect,’ a phenomenon in which participants receiving an inactive intervention report improvement due to their expectations rather than a genuine biological change in the condition under study.
A strong placebo effect reduces the observable difference between treatment and placebo, increasing the risk of underestimating the investigational treatment’s efficacy (possibly leading to its premature abandonment). The reduced ability to differentiate between the effects of the intervention and the placebo often necessitates larger sample sizes to achieve adequate statistical power, increasing the trial’s costs and logistical complexity.
Several statistical and design strategies can mitigate the placebo effect, e.g., the employment of a single-blind placebo run-in, where all participants receive placebo before randomization and those who show significant improvement (‘placebo responders’) are excluded from further participation. However, these approaches are often logistically complex and pose ethical challenges.
Another approach involves educating both participants and study staff: study personnel are trained to interact with participants in a neutral, unbiased manner, distinct from the typical caring approach employed in routine clinical practice, and participants are informed that the double-blind nature of placebo-controlled trials implies that neither the staff nor the participants should have expectations regarding improvement or worsening, and participants are encouraged to candidly report their experiences without concern for pleasing or disappointing the staff. This educational approach has been demonstrated to reduce the magnitude of the response to placebo.
7. Clinical Trials in Rare Neuropsychiatric Disorders Face Unique Challenges
There is growing momentum in the development of experimental disease-modifying interventions for rare neuropsychiatric conditions, and several effective treatments for such diseases have reached the market in the past decade.
However, such investigational therapies face several obstacles entering clinical research. A significant challenge in rare disorders is the limited understanding of their natural history. Without comprehensive understanding of a rare disease’s progression, it is difficult to identify critical stages, determine the appropriate study duration, establish inclusion criteria, or define clinically meaningful endpoints (which themselves often require the development and validation of de-novo disorder-specific rating scales, an additional challenge). The small patient population, broad geographical dispersion, and the lack of researchers with an interest in a specific rare disorder often make gathering data on the natural history particularly challenging. To address this, collaborative initiatives should focus on compiling high-quality patient data through international registries, which can later inform trial design.
Another significant challenge is the prompt recruitment of sufficient participants into rare neuropsychiatric trials given the small and scattered patient populations. Additional dilemma is that often trials require patients at specific disease stages, while the scarcity of candidates makes it highly problematic to limit eligibility criteria. Collaborating with patient advocacy groups and utilizing the patient registries can improve recruitment and streamline the identification of potential subjects. When multiple studies compete for the same limited pool of rare participants recruitment becomes understandably even more challenging.
8. Obtaining Informed Consent in Neuropsychiatric Clinical Trials Can Be Difficult
Obtaining informed consent in neuropsychiatric clinical trials presents unique challenges when participants have cognitive impairments or psychiatric conditions that affect decision-making, and especially when the time window for administering the experimental intervention is limited, e.g., in acute stroke trials. Such individuals may struggle to fully understand the risks, benefits, and procedures involved, leading to ethical concerns whether the consent is truly informed. Additionally, lengthy consent forms occasionally required by institutional review boards can deter or confuse participants despite an attempt to keep the language simple. In borderline cases it may be difficult to determine whether a participant can or cannot understand the information in the consent form: in Parkinson’s disease it has been shown that patients who score 22 or less on the Montreal Cognitive Assessment are likely incapable of providing their own consent, but in many other conditions similar guidance is lacking.
The legal avenues for obtaining consent in these situations are limited and vary from country to country. For example, deferred consent – when consent is obtained after enrollment – is increasingly used in emergency settings – such as acute stroke trials – in many countries in Europe as well as in Canada, but in the United States deferred consent is not permitted. The US federal regulations allow, however, waiving informed consent by IRBs in specific minimal-risk or emergency research circumstances: this applies when patients are unable to provide consent due to life-threatening conditions and obtaining consent from a legally authorized representative is impractical within the therapeutic window. However, such waivers require strict safeguards, including community consultation and public disclosure. In Europe, the Clinical Trials Regulation (CTR) allows for consent waivers in emergency situations, however, implementation varies across member states, with some countries’ regulations accepting family or health professional representatives while others require a court-appointed representative for incapacitated patients.
Conclusion
This review touched only on some of the challenges clinical trials in neuropsychiatric indications face. Additional hurdles not discussed here include, for example, the need for an invasive administration of certain interventions (devices or therapeutics that cannot cross the blood brain barrier). However, there are effective ways to cope with these challenges and perform a clinical study proficiently, even when trial subjects are handicapped, suffering from a rare disorder or require complex assessments. As a Neuroscience CRO , Allucent has the experts that can help you design your neuroscience clinical trial optimally and find the relevant patients effectively. For more details about how the A-Team can support your drug development programs and neuroscience clinical trials, contact us today.
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