Most products being developed today for CNS diseases and disorders are under development for a specific indication like depression, Parkinson’s disease, or schizophrenia. This approach focuses on obtaining approval to treat patients with a specific diagnosis and impacts drug development from selecting assessments and outcome measures to the recruitment of patients to the label claims presented to regulators and payers.
A new approach, however, is emerging. A transdiagnostic approach focuses on the notion that a single biological mechanism of action may be present across multiple disorders. With this approach, clinical trial protocols, including inclusion/exclusion criteria and endpoints, are designed to target a biological dimension and associated symptoms and signs rather than targeting a diagnostic category. For example, an investigational product could target apathy via the dopaminergic pathway. This would broaden the potential for an approval covering any disorder with apathy as a symptom to be treated using this product and more so if the mechanism of action (MoA) could be linked to increase dopaminergic transmission.
Transdiagnostic approaches are already being used in therapeutic areas outside of CNS. For example, they have been used with immune checkpoint inhibitors in the field of oncology. Programmed Death-1 (PD-1) inhibitors such as nivolumab have been approved to treat various cancers where blocking the PD-1/PD-L1 pathway promotes immune control over cancerous cells. The underlying mechanism of action is the same regardless of the original type of tissue for the cancer.
The transdiagnostic approach in CNS disorders has some challenges that need to be addressed. Generally speaking, less is known about the underlying biological cause of many CNS disorders compared to non-CNS medical disorders. If the mechanism of action of a disease or treatment is not established, even if a product is shown to work on a particular symptom across multiple diagnoses, it may be more prudent to follow a more traditional development pathway. As scientific discovery about the underlying biological cause and mechanism of action of a treatment become established, given the transdiagnostic approach’s relative newness, early and frequent interaction with regulatory authorities is strongly recommended.
When implementing a transdiagnostic approach, questions may emerge regarding outcome measures and endpoints. In the example of immune checkpoint inhibitors given previously, there were already some generally accepted, well-defined endpoints such as disease-free survival and time to progression that were used across numerous indications in oncology. Many validated and accepted endpoints in CNS are disease-specific, such as the Montgomery-Åsberg Depression Rating Scale (MADRS) in depression or the Expanded Disability Status Scale (EDSS) in multiple sclerosis. Consideration must be given to selecting endpoints and assessments that can be used appropriately across the spectrum of conditions that could be addressed by a transdiagnostic label claim.
Recruitment and selection of trial participants will also change. In order to take a transdiagnostic approach, it will be important to select trial participants who accurately reflect the intended patient population. If the proposed drug could treat a wide range of psychiatric disorders in adults of all ages, it would not be appropriate to select only patients in the 20–40-year-old range diagnosed with depression. For sponsors used to relying on sites to identify their own patients, it may mean reassessing their recruitment plans to ensure a representative population.
Transdiagnostic approaches represent a promising path for new therapeutics targeting CNS disorders. Yet there are many challenges that need to be addressed when implementing this new scientifically-grounded approach. Several of the VeraSci scientific and regulatory experts have been central members of the development of these approaches for the National Institue of Health, National and European regulatory agencies. We are available to help you take full advantage of the emerging science in this area and tailor your program for success.