The central nervous system (CNS), consisting of the brain and spinal cord, is the command center of the human body. It assures cognitive, sensory, and motor functions through a dense network of billions of neurons. Disorders affecting the CNS have no age or geographic boundaries, resulting in heavy economic and societal burdens. In 2016, neurological disorders ranked as the leading cause of disability and the second leading cause of death. Nearly one in three individuals worldwide experiences a neurological disorder at some point in their lives.

CNS disorders are a growing burden as the population ages. For instance, the prevalence of dementia is projected to increase from 57.4 million cases globally in 2019 to 152.8 million cases in 2050. When considering direct medical and non-medical costs, and family care expenses, the economic burden of CNS diseases in the United States and European Union surpasses US$2 trillion, a figure anticipated to triple by 2030.

This article explores the need for innovative therapies in the treatment of CNS disorders, the particularities of CNS protocols, and the challenges in Cns Drug Development, as well as strategies to overcome these challenges. Additionally, it discusses current trends in CNS clinical research and emphasizes the significance of collaborations and the evolving regulatory landscape in the context of CNS clinical trials.

CNS Disorders Urge Novel Therapies

CNS research has a spotlight in current Drug Development. In 2010, the CNS therapeutic market was valued at US$78 billion, making it the second largest therapeutic category after cardiovascular. The global central nervous system treatment market is expected to grow from US$89.02 billion in 2021 to US$166.53 billion in 2028 at a CAGR of 9.4%3.

Despite the efforts, many CNS disorders, such as Alzheimer’s disease and Parkinson’s disease, still lack effective treatments, and many available treatments are palliative. The need for novel drugs capable of modifying or slowing down disease progression, ultimately leading to improved outcomes for patients, is urgent. However, the complexity of the CNS, as well as safety, efficacy, and ethical considerations, hamper CNS drug development.

The failure rate for new drugs targeting CNS diseases is high compared to most other areas of drug discovery, both preclinically and clinically. This has led to business decisions by some large pharmaceutical companies, such as Pfizer and Glaxo Smith Kline, as well as companies that specialized in psychiatry, such as Eli Lilly, to discontinue some drug development programs.

However, the paradigm is changing as CNS research advances, with big pharma’s renewed interest in CNS drug development giving new hope for patients suffering from CNS disorders.

Understanding CNS Protocols

The uniqueness and complexity of the CNS make it essential to have specialized protocols for drug development and research in CNS diseases.

What Are CNS Protocols?

CNS protocols are structured frameworks that provide a roadmap for researchers, clinicians, and healthcare professionals involved in studies and trials focused on the central nervous system. These protocols encompass a range of crucial elements, including the rationale behind the study, its primary objectives, the specific methodologies employed, data management and analysis strategies, ethical considerations, and approaches for addressing gender-related factors. Additionally, it should emphasize the integration of ethical considerations and, if applicable, the strategies for addressing gender-related concerns. These protocols ensure that drugs effectively reach their target site while minimizing off-target effects. Researchers must provide a thoroughly written protocol for each study.

Key Components of CNS Protocols

1. Study Rationale: CNS Protocols begin by outlining the fundamental reasons for conducting a particular study or clinical trial within the realm of the central nervous system. This section elucidates the significance of the research and its potential impact on our understanding of neurological disorders or therapies.
   
2. Study Objectives: Clearly defined objectives are essential in CNS Protocols. They provide a precise roadmap of what the research aims to achieve, whether it’s exploring the efficacy of a new treatment, understanding the progression of a neurological disease, or assessing the impact of interventions.
   
3. Methodology: The methodology section outlines how the research will be conducted. It encompasses details about data collection methods, patient recruitment, experimental procedures, and any specialized tools or assessments used.
   
4. Data Management and Analysis: Effective data management and analysis are critical in CNS research. This section of the protocol delineates how data will be collected, stored, and analyzed, ensuring the accuracy and reliability of study results.
   
5. Ethical Considerations: Ethical issues are of paramount importance in any research involving human subjects. CNS Protocols address these concerns by detailing how participant rights and privacy will be safeguarded throughout the study.
   
6. Gender Considerations: In some cases, gender-related factors can influence the outcomes of CNS studies. Protocols may specify how these factors will be taken into account, ensuring that research results are comprehensive and applicable to diverse populations.

Understanding CNS Drug Development

CNS drug development starts with the identification and validation of biological targets, a process that demands a deep understanding of the underlying biology of the disorder. Once a target is identified and validated, various strategies, including high-throughput screening and rigorous in vitro assays, are employed for hit identification and validation—a critical step in the drug discovery and development process.

Data generated is used to establish a structure-activity relationship profile and define the chemical structure of a lead compound, which is further optimized to understand biodistribution, efficacy, safety, and pharmacokinetic properties. Recent progress has been made in the hit-to-lead and lead optimization phase, including novel strategies to pass through the blood-brain barrier (BBB), which restricts the entry of compounds into the CNS. The ultimate goal of these stages is to develop a drug with a highly favorable profile for preclinical testing in animals.

Animal studies and human clinical trials are detrimental to translating into a promising lead to market. In CNS clinical trials, thorough CNS protocols, appropriate patient selection, and recruitment are key aspects for the success of the trial. Moreover, long-term follow-up studies are often necessary to assess the sustained efficacy and safety of treatments due to the chronic and progressive nature of many CNS diseases.

Challenges in CNS Drug Development

CNS drug development presents unique challenges that contribute to the high failure rate of new drugs. For Patrizia Cavazzoni, MD, director of the Center for Drug Evaluation and Research, one of the main reasons is the lack of knowledge.

“We – the scientific and medical community broadly – simply do not have a sufficient understanding of the pathophysiology of many of these diseases, their direct causes, and why or how these diseases can present differently in different patients, among other factors. We simply do not know enough about the basic underlying causes of these terrible diseases or how to predict and monitor their progression, to have all of the tools we need to develop treatments to fight, or better yet, cure them.”

Apart from the limited understanding of relevant pathophysiology, CNS drug development faces several other prominent challenges, some of which may be specific to certain CNS disorders:

• Disease complexity and heterogeneity
• The need for drugs to cross the BBB
• Lack of relevant preclinical models with predictive validity
• Inadequate clinical trial designs
• Patient/phenotype heterogeneity
• Difficulties in patient recruitment and high dropout rates
• Efficacy and safety concerns
• Lack of accurate biomarkers and clinical scales (effective clinical trial outcomes)
• High placebo effects
• Insufficient CNS protocols
• Ethical Considerations
• Regulatory challenges
• Long development timelines
• High costs
• High failure rates

Blood-brain barrier considerations

The BBB, while serving as a protective structure, is also the bottleneck in CNS drug development, limiting the number of drugs that make it into clinical trials. It is estimated that approximately 100% of large molecule pharmaceuticals (i.e., peptides, recombinant proteins, monoclonal antibodies, RNA interference (RNAi)-based drugs, and gene therapies) and more than 98% of small molecule drugs do not cross the BBB.

Safety and efficacy concerns

Balancing safety and efficacy is particularly challenging in CNS drug development due to the CNS’s significant role in controlling behavior and personality. Even if side effects don’t reflect typical toxicity, they can impact drug development if they lead to significant neurologic or behavioral dysfunction or if patients refuse to take the medication. Thus, rigorous preclinical and clinical research, adequate trial design, careful participant monitoring, and adherence to ethical standards are imperative in this field.

Approaches to Address CNS Drug Development Challenges

Researchers and pharmaceutical companies are continually exploring innovative approaches and strategies to overcome the challenges in CNS drug development.

1. Novel drug delivery systems

Novel drug delivery systems for CNS diseases are designed to improve the permeation of CNS-active drugs through the BBB, thus enhancing drug delivery efficiency and bioavailability within the CNS. Several strategies have emerged to address this challenge, including:

·       Nanomedicines

·       Exosomes

·       Prodrugs

·       Bi-specific antibodies

·       Intranasal drug delivery

·       Device-enabled drug delivery (e.g., intracerebroventricular, intra-cisterna magna, or intrathecal injection, and focused ultrasound with microbubbles)

·       Convection-enhanced delivery

2. Biomarkers for CNS diseases

The identification of reliable biomarkers can aid in several aspects of CNS drug development. According to projections of the America’s State of Mind Report, the global CNS biomarkers market should reach US$9.5 billion by 2027 from US$5.7 billion in 2022.

Biomarkers have a crucial role in early disease diagnosis, patient stratification, treatment selection and monitoring, and safety assessment. By providing quantifiable measures, biomarkers can serve as objective endpoints in clinical trials, providing evidence of treatment safety and effectiveness. This, in turn, can facilitate regulatory approval and improve the chances of drug approvals. Additionally, biomarkers can help reduce the necessary sample size and trial duration by providing sensitive and early indicators of treatment outcomes. This leads to more efficient and cost-effective clinical trials.

Despite the advantages of using biomarkers as drug development tools, no regulatory-accepted biomarkers have been approved by the FDA for use as a clinical outcome measure in clinical trials for neurological diseases. Emerging solutions in the field of CNS biomarkers include digital biomarkers, derived from artificial intelligence, and imaging biomarkers.

Current Trends in CNS Clinical Research

These are exciting times for CNS clinical research. Our understanding of CNS pathophysiology is evolving at an unprecedented pace, as are areas of digital health technologies and artificial intelligence (AI). These trends are driving cutting-edge innovation in CNS disorders.

Wearable devices, smartphone applications, and remote monitoring tools have opened new avenues for real-time data collection, offering opportunities for more personalized and patient-centric approaches to treatment. Machine learning algorithms are being used to analyze comprehensive datasets, catalyzing our understanding of CNS disorders. Furthermore, AI is streamlining CNS drug development processes by identifying potential biomarkers, drug candidates, and optimizing clinical trial designs. The potential of these approaches is immense, but so are the challenges of their integration into clinical practice.

CNS clinical research is undoubtedly changing. Innovative, patient-centered clinical trials have become a primary focus. A survey conducted by Science 37 in late 2021 revealed that 63% of biopharma executives anticipate conducting hybrid or fully decentralized clinical trials in the following 12 months (11% increase compared to the previous year), while only 58% had plans for traditional site-based clinical trials (14% decrease).

Furthermore, data sharing and public-private partnership projects are paving the way of CNS clinical research.

1. Neurodegenerative disorders

Other trends in clinical research for neurodegenerative diseases, such as Alzheimer’s disease and Parkison’s disease, include:

·       Disease-modifying therapies (the first disease-modifying therapy for Alzheimer’s disease, Aduhelm [aducanumab], was approved by the FDA in 2021)

·       Drug repurposing

·       Precision medicine

·       Novel therapeutic targets (e.g., protein aggregates, neuroinflammatory pathways, mitochondria, and autophagy)

·       Immunotherapy

·       Gene therapy

·       Stem cell therapy

·       Degradomers

·       Multimodality imaging

2. Psychiatric disorders

The study of mental health conditions, such as depression, anxiety, schizophrenia, and bipolar disorder, is a priority. Research in psychiatry is challenging but has many opportunities for clinical researchers, particularly in the post-pandemic era. Current trends in clinical research for psychiatric disorders include:

·       Precision psychiatry

·       Psychiatric genomics

·       Novel therapeutic targets (e.g., neuroinflammation, immune system, and specific neurotransmitter systems)

·       Drug repurposing

·       Psychedelics-derived treatments

·       Digital psychiatry

·       Gut-microbiota-brain research

·       Innovative psychotherapy

·       Combined pharmacological and psychological interventions

Collaborations and Regulatory Landscape for CNS Clinical Trials

Regulatory guidelines for CNS clinical trials

Regulatory approval for CNS drugs remains a significant challenge. According to a 2018 report by the Tufts Center for the Study of Drug Development, the development and approval of drugs to treat CNS disorders required, on average, 20% more time than non-CNS drugs that won marketing approval in the United States.

Preclinical and clinical studies with CNS-active drugs are typically more detailed and rigorous than those conducted for non-CNS drugs due to their potential to affect cognitive abilities and motor function. Moreover, abuse potential, physical dependency, withdrawal, rebound, and additive effects are major concerns in CNS drug development.

Therefore, in addition to adhering to general regulatory guidance for clinical trials involving investigational new drugs (INDs), submissions for CNS-active drugs may require additional considerations and assessments.

To assist sponsors with CNS drug development, the FDA created the Office of Neuroscience in 2012. Furthermore, the European Medicines Agency (EMA) has published a set of scientific guidelines for the evaluation of medicinal products for CNS disorders. Sponsors should regularly consult the latest guidance documents from relevant regulatory agencies to ensure compliance with current requirements as they may evolve over time. For instance, the FDA has recently issued its first draft guidance on clinical research for psychedelic drugs, which have emerged as potential treatments for psychiatric disorders, such as depression.

Industry-CRO partnerships

Partnering with a contract research organization (CRO) in CNS clinical research has the potential to halt delays and expedite progress in addressing the high unmet needs of neurological disorders. CROs offer expertise and experience in managing CNS clinical trials, ensuring meticulous study design and execution. Their optimized workflows, efficient resources, and deep understanding of regulatory requirements minimize the risk of delays or complications. In addition, CROs excel in patient recruitment strategies, as well as data management and analysis.

Future Directions and Innovations

There is no place for a ‘one size fits all’ response in the complexity of CNS clinical research. There is an urgent need to recognize the individual variability among patients and the need for customized approaches to diagnosis and treatment—a personalized approach. Consequently, CNS drug development plans should adapt accordingly.

Several initiatives are emerging on this front. For example, the European regulatory network actively promotes the advancement of personalized medicine strategies within CNS disorders [46]. Additionally, strategic collaborations are forming to drive progress, as seen in the recently announced partnership between PrecisionLife, a leading techbio company specializing in precision medicine, and Nanopharmaceutics, Inc, a clinical-stage pharmaceutical development company.

Emerging technologies in CNS research are driving innovation and providing new tools to better understand, diagnose, and treat CNS disorders—a cornerstone of personalized medicine. For instance, advances in neuroimaging, neuroinformatics, brain-computer interfaces, digital biomarkers, gene therapy, and 3D bioprinting and organoids are reshaping the landscape of CNS drug development and clinical research.

Conclusion

The back-and-forth in CNS clinical research has provided important lessons, ultimately shaping the evolution of approaches and methodologies in CNS drug development and clinical research. Recognizing the unique challenges of CNS disorders and the need for more personalized and targeted treatments is encouraging researchers and pharmaceutical companies to explore innovative paths.

One thing is certain: time is of the essence when it comes to improving patients’ lives. The lack of effective treatments for CNS disorders, which represent a growing burden, demands change. The need for properly designed CNS protocols and clinical trials to enhance the prospects of success for new drugs is critical. Innovative CROs, like Vial, can help.

Vial: Your Full-Service CRO Partner for CNS Clinical Trials

Vial is a next-generation, technology-first CRO reimagining clinical trials to deliver faster, better, and cheaper results for biotech and biopharma sponsors. Vial’s Nervous Systems CRO executive team has extensive therapeutic expertise to help you push the boundaries of your next CNS clinical trial.

Discover what Vial’s CRO can do for your next study. Visit our website or contact a Vial representative today!