Table 1.

Comprehensive summary of case studies that enabled faster access to innovative medicines for patients (references to the case studies are included in the Supplemental Material)

Quantitative pharmacology (QP) application area	Compound and title of case study	Key question addressed in case study	Conclusion	Impact on decision making	Estimated time savings by case study owner	Enablers of successful QP application
Model‐informed dose selection for pivotal trials by integrated analysis of totality of data.	Secukinumab: Model‐based selection of the secukinumab doses and dosing regimens for psoriasis patients for the pivotal trials.	What is the optimal dosing regimen to be used in phase III?	Model‐based integration of phase I/II data allowed the selection of two dosing regimens for phase III which had not been tested previously. Phase III confirmed the positive benefit‐risk for those doses and dosing regimens, and these were subsequently approved (150 and 300 mg once weekly for 5 injections, followed by a dose every 4 weeks).	Without M&S, a suboptimal regimen would have been selected that would have led to an inferior benefit‐risk profile, or required further iterations of finding optimal dosing regimen.	> 1 y representing one phase III study duration. Note that the phase III program consisted of 6 studies. In the case of use of inferior dosing regimens, the program may not have delivered a successful outcome that could have been fixed with a single additional study.	Long‐term collaboration with team that created trust and understanding. Comprehensive and diverse phase II data combined with iterative modeling and prospectively predicting study readouts, leading to an iterative learning and confirming cycle.
	Naloxegol: Modeling and simulation to support Naloxegol dose selection for Phase 3 studies.	What is the optimal dose of Naloxegol and best trial design for clinical phase III trial to confirm efficacy and safety?	The exposure–response analysis at phase II demonstrated that 25 mg was an effective dose with updated primary endpoint. Model‐based simulations suggested that doses of 12.5 mg and higher would provide a promising clinical benefit over placebo. This was subsequently confirmed in the phase III studies, followed by approval.	Prediction of the dose with an optimal risk/benefit ratio.	∼0.5 year through not generating additional Phase 2 data on the 12.5 mg dose.	Early and active involvement was a key enabler. Continuous engagement with study clinician and statisticians was important to win their trust.
	Pembrolizumab: Modeling and simulation drove the selection of pembrolizumab efficacious dose of 2 mg/kg.	What is the efficacious dose and dosing regimen of pembrolizumab?	Translational, clinical pharmacokinetics and exposure–response analyses demonstrated that 2 mg/kg Q3W achieved a maximal response and that 10 mg/kg Q3W dose and regimen did not produce further improvement. The 2 mg/kg Q3W was subsequently approved for patients with advanced metastatic melanoma. This dose, however, was not studied in the pivotal trial (KEYNOTE‐006) but justified through integrated analysis of the totality of the data of other trials (KEYNOTE‐001,002 and 006).	M&S enabled approval at a lower dose (2 mg/kg Q3W) than studied in the pivotal trial (10 mg/kg Q3W) for ipilimumab naïve metastatic melanoma patients through integrated analysis of clinical data.	∼ 6 months to 1 year by avoiding addition of a dose arm of 2 mg/kg Q3W to the pivotal trial.	Studying a wide dose range in initial trials allowed bridging through understanding of the exposure response relationship.
Reducing trial burden for vulnerable populations by model‐informed trial design, dose selection and replacement.	Raltegravir: Adaptive trial design to define raltegravir dosing regimen to treat neonates from birth up to 6 weeks of age.	How should the dramatic increase of clearance due to UGT‐1A1 maturation be addressed in in a 6‐week dosing regimen for neonates?	The dramatic increase in raltegravir clearance as the result of UGT‐1A1 enzyme activity in neonates requires 2 dose changes over the first 6 weeks of life to meet efficacy and safety PK criteria.	Traditional paradigm of dose ranging followed by confirmatory study was changed into a single study in which M&S was used to integrate data to adapt dosing recommendations and update predictions.	∼3–4 y by removing 1 study in a vulnerable population that would be very slowly in recruitment.	Both company and regulator supported the use of modeling and simulation approaches, which resulted in shortened development time.
	Ivabradine: Modeling and simulation for clinical studies in pediatric populations.	How to determine the starting dose in children suffering from chronic heart failure?	This work emphasizes the importance of modeling and simulation for internal decision‐making such as the design of clinical studies in pediatric populations. With this work, it was possible to determine the starting dose in children and to define a lower weight‐normalized dose in younger children since they presented a higher exposure compared to adults and thus avoiding the risk of excessive bradycardia.	M&S supported to pick a higher weight‐normalized dose in children older than 1 year and thus quicker titration avoiding the risk of insufficient efficacy in children. Inclusion of dry‐blood spot sampling reduced additional trial burden.	∼ 1 y through reduced need for more extensive dose ranging.	Early interaction with the pediatric committee at the European Medical Agency. In addition, good examples needed to be shared to convince stakeholders.
	Eslicarbazepine acetate (ESL): Extrapolation strategy for ESL dosing in pediatric patients with partial‐onset seizures (POS).	Which doses of ESL provide exposures in 4‐17 y patients with POS that are similar to those determined to be safe and effective in adult patients for ESL adjunct therapy or monotherapy?	Extrapolation obviated the need to conduct a US‐based clinical trial in pediatric patients aged ≥4 y. Benefits of this strategy were to reduce the number of pediatric patients exposed to clinical trials and to allow for earlier availability of ESL for clinical use in pediatric patients.	Reduced number of patients exposed in clinical trial, earlier availability for children.	∼2–3 years by obviating a confirmatory efficacy trial in pediatric patients.	Early clear and transparent interaction with stakeholders. Inclusion of experts to discussions in project team. The collection of sufficient pharmacokinetic data in children in age range of interest.
Simplified dosing for patients and physicians by model‐informed bridging of weight‐based and flat dosing regimens.	Nivolumab: Quantitative clinical pharmacology analyses conducted in support of 240 mg nivolumab flat dose approval.	Can quantitative clinical pharmacology approaches be used to switch body weight based dosing (3 mg/kg Q2W) to simplified, flat dose (240 mg Q2W) of nivolumab?	The quantitative clinical pharmacology approach provided evidence for regulatory decision‐making on dose modification, obviating the need for an independent clinical study.	Demonstration of efficacy and safety was similar for flat dose as mg/kg dose for wide range of body weight.	>2 y through avoiding a flat dose trial and simplifying study design for expanding therapeutic use to other indications.	Thorough understanding of pharmacokinetics, pharmacodynamics, efficacy and covariates across multiple tumor types and multiple endpoints. Being proactive, demonstrating potential value through exploratory analysis in time.
	Ixazomib: Switch from body‐surface area (BSA)‐based to fixed dosing led to simplified dosing guidance and clinical development.	Can modeling guide switching from BSA‐based to fixed dosing without conducting a standalone study to compare fixed dosing vs BSA‐based dosing?	Clinical development switched posology from BSA‐based to fixed dosing, simplifying capsule strength manufacture and dosing in global clinical trials. Fixed dose of 4 mg was subsequently used in the phase III (TOURMALINE MM1) study that formed basis for approval of ixazomib by FDA and EMA.	Modeling helped challenge the established practice of weight based dosing in oncology. Simplified dosing for patients and physicians reducing pill burden and avoiding dosing errors.	∼1–2 years through avoiding a trial for fixed dose.	Early engagement with team, good understanding of intrinsic/extrinsic factors and consistent education of all stakeholders (including oncology key opinion leaders) was critical for success.