Anouk Donners

168 Chapter 9 The secondary stakeholders for clinical support are the hospitals, universities, institutions, clinics or pharmacies of external colleagues and the patient and caregiver organisations. It is important to engage these stakeholders to use existing infrastructures, such as the SYMPHONY consortium, or to promote study inclusion [62]. Lower dosing can be difficult from a patient’s perspective, so a national standpoint from patient and caregiver organisations can help when explaining the risk–benefit ratio during informed consent as part of study enrolment. The secondary stakeholders for financial support are healthcare insurance companies, drug regulators and governments. Research on cost-efficient dosing and personalised medicine are pertinent topics for these organisations’ research agendas. For instance, in the Netherlands, the ZonMW and the NFU have programmes such as GoedGebruikGeneesmiddelen and Transformatiegelden Dure Geneesmiddelen, respectively. Funding research is highly attractive for these parties because successful research results in a high return on investment (e.g., one million euros invested in a study could result in hundreds of millions of euros of savings per year), generating additional savings for healthcare and new research projects. A manufacturer may even be interested in a funding role under specific agreements and conditions, such as the optimisation of user-friendly administrations to obtain a better product with increased sales and commercial value. 4. PKPD-relation investigation The next step to developing a cost-efficient dosing strategy is to investigate the clinical pharmacology of the biopharmaceutical to set the therapeutic window. A descriptive study can be conducted on the pre-approval studies in the literature, although PKPDmodelling these data is usually more insightful. In this step, both the dose–concentration (PK) and concentration–response (PD) relationships should be investigated (Chapter 6). The PK can be linear (dose proportional) for saturated targets or nonlinear for targetmediated distributions, each requiring a different dosing strategy. The PD should be investigated to determine the concentration in which all target receptors are occupied (i.e., Emax) and also to determine the potency of the drug, which is the required concentration for a given response (i.e., concentration at half of response [EC50]). The response can be a disease outcome, such as a clinical event, or a surrogate outcome parameter, such as a biomarker. The variability of the PK and PD parameters should also be evaluated to determine whether dose adjustments are required for the specific characteristics of an individual (Chapter 6). Beyond the data from the literature, real-world data from a clinic can also be evaluated to investigate the PKPD relations (Chapter 7). Such data better reflect a real-world setting than data from the literature because a Phase IV setting is different and less