Clinical N-of-1 strategies with off-label precision treatments for monogenic epilepsies

Background

Precision treatments for monogenic epilepsies—therapies that target the biochemical consequences of pathogenic gene variants—are increasingly emerging. However, evidence for their efficacy is still largely limited to case reports and retrospective studies. As a result, the clinical use of these treatments often lacks consistency and structured outcome monitoring.

N-of-1 strategies in clinical care are predefined, individually tailored, multiple crossover therapeutic trials designed to assess the value of a treatment for a single individual (Figure 1). Despite their potential to improve clinical decision-making, their implementation remains limited due to challenges such as limited methodological guidance and lack of consensus on oversight procedures.

Members of EpiCARE have recently published a guidance document outlining principles for designing N-of-1 strategies using off-label precision treatments in monogenic epilepsies. The guidance can be applied:

On a case-by-case basis to design an N-of-1 strategy for an individual patient
Adapted as a local Master Protocol to support N-of-1 strategies across a range of monogenic epilepsies when clinical equipoise exists (Figure 2)

Multidisciplinary Expert Panel (MEP)

To support clinicians, EpiCARE and the European Consortium for Trials (ECET) have established a Multidisciplinary Expert Panel (MEP).

The panel includes:

(Paediatric) neurologists
Clinical pharmacologists
Methodological experts
(Clinical) geneticists

The MEP does not replace local quality assurance processes or ethics committees. Instead, it serves as an external advisory body that can assist with:

Independent risk–benefit assessment
Methodological guidance for N-of-1 trial design
Support for responsible use of off-label precision treatments
Opportunities for collaboration across centers

Project Objectives

Improve the evaluation of off-label precision treatments in monogenic epilepsies through structured, methodologically sound N-of-1 strategies.
Promote safe and responsible implementation of N-of-1 strategies with international expert oversight.

Workflow

Physicians who wish to submit a proposed N-of-1 strategy to the MEP should:

Obtain patient consent to discuss the patient’s medical information with experts within the European network.
Complete the submission form available via the link below.
Send the completed form to: [email protected]
If additional support is needed for the pharmacological section of the benefit–risk assessment:
- consult a local clinical pharmacist, or
- request assistance from the MEP clinical pharmacology expert
Expected response time:
- Urgent requests: within 2 weeks
- Non-urgent requests: within 1 month

Possible MEP Feedback:

Positive benefit–risk assessment
Conditional advice, suggesting adjustments to the proposed plan (e.g., phenotype considerations, dosing, or trial design)
Negative advice based on an unfavorable benefit–risk balance
Connection with other clinicians conducting similar N-of-1 strategies to enable collaboration or shared protocols

N-of-1 strategy

An N-of-1 strategy involves one or more cycles composed of paired periods, e.g. (A) active treatment of interest, in this case a precision treatment and (B) a comparator which could be placebo, another active treatment or standard clinical care. Each cycle also includes a (W) washout interval between interventions. The dotted line at the end and start of each period represent titration and tapering phases. At the end of each cycle an interim assessment takes place to decide whether an additional cycle would be required. Throughout the N-of-1 therapy plan the underlying treatment with antiseizure medication remains unchanged. Created in https://BioRender.com

Key stakeholders involved in developing a local Master Protocol for clinical N-of-1 strategies

Proposed workflow for implementing a Master Protocol for clinical N-of-1 strategies with off-label precision treatments in monogenic epilepsies based on published guiding principles (blueprint). Healthcare professionals and patient representatives identify situations of clinical equipoise, adapt the blueprint into a Master Protocol with local quality-of-care teams, appoint a multidisciplinary expert panel (MEP), and obtain local approval. Implementation may vary according to local regulations.

Schematic representation of steps to be followed by clinicians to conduct N-of-1 strategy in individual cases of equipoise

Workflow for implementing a clinical N-of-1 strategy with off-label precision treatment in cases of clinical equipoise. After approval to conduct N-of-1 strategies, clinicians assess feasibility, discuss a preliminary plan with the patient, submit documentation for review by the Multidisciplinary Expert Panel (MEP), and finalise and conduct the N-of-1 therapy plan based on the panel’s advice.