Anouk Donners

170 Chapter 9 6. Clinical evaluation Cost-efficient dosing is often off-label. Efficacy and safety must be demonstrated in a clinical evaluation with well-designed, prospective clinical studies. Designs with blinding, randomisation and a (placebo-)control are favoured to exclude bias. However, to evaluate the cost-efficient dosing of biopharmaceuticals, blinding is impractical due to self-injections, randomising requires a large sample size, and using a placebo is unethical because of the drug’s proven effectivity. Therefore, I recommend a crossover, noninferiority design with intensive monitoring for the clinical evaluation of cost-efficient dosing for biopharmaceuticals (Chapter 8). A crossover approach has the advantage of comparing treatment effects on one person, which increases study power and lowers the required sample size [67]. In addition, noninferiority tests whether cost-efficient dosing is not unacceptably less efficacious than conventional dosing [68]. However, testing for noninferiority makes the design and interpretation less straightforward than testing for superiority [69]. Therefore, choosing the noninferiority margin is crucial and should be based on both statistical reasoning and clinical judgement. Consulting a statistical expert and achieving a broad clinical consensus when setting noninferiority margins are highly recommended [68]. Conducting a clinical trial to evaluate cost-efficient dosing is labour intensive. Increasing technical innovations mean big data analytics and common data models herald a new era in the generation of evidence for clinical evaluations [70, 71]. A common data model is a standardised model that allows data exchange between multiple healthcare data sources and applications, such as different hospital systems, electronic healthcare records, clinical registries, databases and healthcare apps [72]. These models standardise the observational, real-world data to provide reliable, real-world evidence rapidly [73]. This process is especially beneficial for the clinical evaluation of rare indications that require multi-center or multinational studies. 7. Clinical-practice implementation Cost-efficient dosing, combined with monitoring, can be implemented in clinical practice following a successful clinical evaluation. Funding parties generally require extensive implementation plans before funding is granted. Such plans often include commitment of the support base, set-up of measurement methods in laboratories, upscaling requirements, and revising protocols and guidelines. This plan should be executed in Step 7 of the cost-efficient dosing strategy in Figure 3. Another important effort to make, is a drug label change by including the new cost-efficient dosing strategy in the Summary of Product Characteristics (i.e., the drug label). A drug label change is the highest achievable goal for the research team because the drug label reaches clinicians and patients globally,