New drug modalities and treatments are revolutionizing central nervous system (CNS) therapies, bringing hope to patients suffering from some of the most devastating diseases. Yet, drugs targeting the CNS are subjected to particularly stringent regulations in terms of safety assessment. This is due to the irreversibility of damage to the CNS, the difficulties of detecting neurotoxicity, and the complexity of the systems targeted.
As sponsors invest time, effort, and resources into developing novel therapeutics in this area, they must pay special attention to evolving regulatory requirements for safety assessment.
A constantly evolving regulatory framework can be a lengthy, expensive, and complex process to navigate. Developers working with CNS therapies must master global guidelines for safety assessment, methodology evaluation, and the special considerations for novel therapeutic modalities.
1. Stay on Top of Current Regulatory Frameworks
CNS toxicity often causes issues during clinical trials, making it an issue of particular concern for regulatory bodies. As their rules changes with scientific advancements, it is essential to develop compliant strategies for early assessment of neurotoxicity in the preclinical phase.
Existing regulatory frameworks include:
- FDA’s Red Book: A broad set of guidelines for neurotoxicity that are not typically used in non-clinical routine studies.
- ICH S7A: A mandatory safety guideline issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guideline should be conducted before the Investigational New Drug (IND) application.
- OECD guidelines: The Organisation for Economic Co-operation and Development (OECD) guidelines primarily apply to Developmental and Reproductive Toxicity (DART) and are often required post-IND but before the submission of a New Drug Application (NDA).
Testing methodologies and practices have evolved in tandem with CNS drugs, but regulation has failed to keep pace. For example, since the development of oligonucleotides has accelerated, the number of CNS drugs requiring testing has increased significantly. Developers will likely face a long wait for regulations to catch up, and as such should ensure they enforce their own safety frameworks as stringently as possible until standardized protocols are established.
2. Balance Tried and True Evaluation Methods with Innovative Ones
Several new techniques for evaluating nonclinical neurotoxicity are slowly emerging but aren’t yet ready for deployment. In the meantime, several established methods are still in use. Sponsors should prepare to adopt new, more efficient techniques emerging in the future, while continuing to rely on established methods today. This approach ensures developers are making the most of tried and trusted means without risking falling behind the latest scientific innovation.
The functional observational battery (FOB), a neurobehavioral change assessment, is mandated in ICH S7A. It is typically conducted with rodents, but other species can be used. The FOB is an established test, but it relies on the technician’s observations, which can introduce subjectivity issues. To combat this, it’s a common approach to conduct blind assessments where the observer is unaware of what the subject has been administered.
Motor activity assessments are also a standard aspect of CNS toxicity assessment and are outlined in ICH S7A. They are an automated measure of locomotor activity and track sedation, stimulation, motor coordination, and hyperactivity.
In addition, methodologies on the horizon include patient-derived cells, where human-induced pluripotent stem cells (hiPSCs) are used in early-stage screening and research. However, they are not at the stage where they can replace in vivo neurotoxicity testing. Organoids, 3D mini-brains grown from stem cells, are even further away, and other future methods, such as an in silico approach, are still being explored.
3. Establish the Special Considerations Required for New Modalities
Novel treatments that address the previously unmet CNS needs are a source of great excitement for developers, but due to a lack of historical data, they are challenging for regulators to evaluate and establish criteria for. As a result, there is little specific regulatory guidance on the use of new modalities targeting CNS diseases, and regulators typically give their feedback on a case-by-case basis.
For example, the characteristics of oligonucleotides fall somewhere between those of small and large molecule drugs, from a regulatory standpoint. There are few specific regulations for this drug type, so developers must ensure that they assess efficacy data from disease models, target specificity, and anticipated pharmacological and safety concerns.
Early input from experienced test partners helps developers navigate this complex pathway, as does ongoing dialogue with regulatory agencies.
4. Make the Most of Expedited Regulatory Pathways
Expedited pathways offer developers the chance to receive extra regulatory support, increase efficiency and potentially bring drugs to market faster. There are three major pathways to expedite a submission.
Breakthrough Therapy designation. This program fast-tracks the development and review of drugs that are a substantial improvement over existing therapies for treating serious or life-threatening conditions. Benefits include more frequent interaction with regulatory bodies, clinical trial design guidance, rolling reviews, and potentially priority review. To receive the designation, developers must demonstrate, through preliminary clinical evidence, that the drug candidate offers a substantial improvement over existing therapies and achieves one or more clinically significant endpoints.
RMAT designation. Regenerative Medicine Advanced Therapy (RMAT) designation requires a drug candidate to be a regenerative medicine of some kind, and intended to treat, modify, reverse, or cure a serious or life-threatening disease. Developers must demonstrate their product can address an unmet medical need. RMAT designation enables increased interaction with regulators and makes drug candidates eligible for flexible trial designs, accelerated approval, and priority review.
Orphan Drug designation: This designation is available in the E.U. and the U.S., but eligibility rules differ. Orphan drugs treat rare diseases. To qualify for this designation in the U.S., the condition must affect fewer than 200,000 people annually. If more people are affected, the sponsor must demonstrate that there is no reasonable expectation of recovering development costs from U.S. sales. In the E.U., the condition must affect fewer than 5 in 10,000 people, and the candidate must offer a significant benefit over existing treatments. The benefits of this designation include seven-year market exclusivity, tax credits, and eligibility for grants in the U.S. In the E.U., developers receive 10 years of exclusivity and are eligible for fee waivers and cost reductions.
A Final Word
Drugs targeting the CNS can bring relief to some of the most devastating conditions, but navigating the regulatory landscape that has yet to catch up with these scientific advancements is difficult. Compounding the challenges, the CNS division of most regulatory agencies is often the most stringent, and developers frequently face delays. As such, the failure rate for candidates targeting CNS diseases is high compared to other areas of drug development.
Developers need to strike a balance between innovation and the appropriate safety protocols needed to move development forward. Leaning heavily on lab partners with the experience to navigate a shifting and complex regulatory landscape provides the input and scientific rigor needed to achieve success.
