Clinical Pharmacology Applications of Real-World Data and Real-World Evidence in Drug Development and Approval-An Industry Perspective.

Since the 21st Century Cures Act was signed into law in 2016, real-world data (RWD) and real-world evidence (RWE) have attracted great interest from the healthcare ecosystem globally. The potential and capability of RWD/RWE to inform regulatory decisions and clinical drug development have been extensively reviewed and discussed in the literature. However, a comprehensive review of current applications of RWD/RWE in clinical pharmacology, particularly from an industry perspective, is needed to inspire new insights and identify potential future opportunities for clinical pharmacologists to utilize RWD/RWE to address key drug development questions. In this paper, we review the RWD/RWE applications relevant to clinical pharmacology based on recent publications from member companies in the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) RWD Working Group, and discuss the future direction of RWE utilization from a clinical pharmacology perspective. A comprehensive review of RWD/RWE use cases is provided and discussed in the following categories of application: drug-drug interaction assessments, dose recommendation for patients with organ impairment, pediatric plan development and study design, model-informed drug development (e.g., disease progression modeling), prognostic and predictive biomarkers/factors identification, regulatory decisions support (e.g., label expansion), and synthetic/external control generation for rare diseases. Additionally, we describe and discuss common sources of RWD to help guide appropriate data selection to address questions pertaining to clinical pharmacology in drug development and regulatory decision making.

Effect of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intravenous Rivipansel.

Two studies evaluated the effects of renal and hepatic impairment on pharmacokinetics and safety of rivipansel (NCT02813798, NCT02871570). A single intravenous 840-mg rivipansel dose was administered to subjects with renal impairment or normal renal function in study 1005 and subjects with moderate hepatic impairment or normal hepatic function in study 1006. Plasma (both studies) and urine (study 1005) samples were collected for 96 hours postdose. All subjects in studies 1005 (n = 28) and 1006 (n = 16) completed all study procedures. Rivipansel exposure (AUCinf ) was 47%, 124%, and 437% higher and total clearance 30%, 57%, and 82% lower in the mild, moderate, and severe renal impairment groups, respectively, than in the normal renal function group. Overall rivipansel exposure was 20% lower and total clearance 31% higher in the moderate hepatic impairment group than in the normal hepatic function group. Ten treatment-emergent adverse events occurred in studies 1005 and 1006; no event was considered treatment related. As expected, clearance of rivipansel decreased with increasing renal impairment. The difference observed between rivipansel pharmacokinetics in subjects with moderate hepatic impairment and subjects with normal hepatic function was not considered clinically significant. Single doses of rivipansel were well tolerated in subjects with either renal or hepatic impairment.

Dose Selection Based on Modeling and Simulation for Rivipansel in Pediatric Patients Aged 6 to 11 Years With Sickle Cell Disease.

This modeling and simulation exercise aimed to provide dosing recommendations for rivipansel phase III studies in children aged 6-11 years with sickle cell disease (SCD). Pharmacokinetic data from 109 patients aged 12-51 years who received rivipansel (2-40 mg/kg) in previous studies (three phase I and one phase II) were integrated to build a three-compartmental simulation model. Renal clearance simulations across the age range accounted for renal function development and postulated hyperfiltration in SCD. Simulated demographic distributions for the pediatric SCD population were used to predict concentration-time profiles from three dosing regimens, which were then compared against efficacious average steady-state concentrations observed in phase II. A dosing regimen comprising a 40-mg/kg loading dose followed by a 20-mg/kg maintenance dose every 12 hours was selected, as it will likely provide an efficacious concentration range. Its validity will be confirmed in the ongoing phase III study.

Lack of Effect of Rivipansel on QTc Interval in Healthy Adult African American Male Subjects.

Rivipansel is a pan-selectin inhibitor in phase 3 development for the treatment of vaso-occlusive crises in patients with sickle cell disease. This single-dose, randomized, 3-period, 3-treatment (400 mg moxifloxacin open-label, 4 g rivipansel-blinded, and placebo-blinded) crossover study evaluated the effect of rivipansel on the QT/QTc interval in 48 healthy male African American subjects (age, 21-53 years; weight, 60-115 kg). Time-matched, placebo-adjusted change from baseline QT interval using Fridericia's correction method (QTcF) was determined using a repeated-measures mixed-effects model. The highest upper bound of the 2-sided 90% confidence interval (CI) for QTcF change was 3.22 milliseconds 3 hours postdose. Moxifloxacin showed the anticipated QTcF effect, indicating that the study had adequate sensitivity to detect changes in the QTcF interval. The study concluded that no QTcF effect was demonstrated with rivipansel compared with placebo, as the upper bound of the 2-sided 90%CI was less than 10 milliseconds at all times. Exposure-response modeling for rivipansel concentrations and change from baseline in QTcF data corroborated a lack of effect with rivipansel compared with placebo. Single doses of rivipansel 4 g by intravenous infusion over 20 minutes were well tolerated in this study.

Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.

PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.

Randomized, open-label, multicentre pharmacokinetic studies of two dose levels of pantoprazole granules in infants and children aged 1 month through <6 years with gastro-oesophageal reflux disease.

BACKGROUND AND OBJECTIVE: The primary objective of this study was to characterize the pharmacokinetic profile of pantoprazole delayed-release granules in infants and children aged 1 month to <6 years with gastro-oesophageal reflux disease (GORD). The studies described in this manuscript were conducted to fulfil the requirements of the paediatric written request for pantoprazole by the US FDA. METHODS: Two randomized, open-label, multicentre studies were conducted in infants aged 1 month to <12 months (study 1) and children aged 1 year through <6 years (study 2) with GORD. Patients were randomly assigned to either the low-dose pantoprazole group (0.6 mg/kg equivalent) or the high-dose pantoprazole group (1.2 mg/kg equivalent) in a 1 : 1 fashion. Pantoprazole granules were administered approximately 30 minutes before breakfast for at least five consecutive doses. Blood samples were obtained at prespecified intervals. Plasma pantoprazole concentration-time data were analysed by non-compartmental methods. Descriptive statistics were calculated for pharmacokinetic parameters. Patients in study 2 additionally received pantoprazole for 28 days. Safety was monitored throughout. RESULTS: In study 1, 43 patients were randomized; 42 were included in the single-dose pharmacokinetic evaluation (15 females, 27 males; mean postnatal age 6.3 months). In study 2, 17 patients were randomized, and all were included in the single-dose pharmacokinetic evaluation (6 females, 11 males; mean age 3.2 years). In both studies, exposure increased with dose. Mean (standard deviation) maximum (peak) plasma concentration values for the low and high doses were 503 (506) ng/mL and 1318 (1307) ng/mL, respectively, in study 1, and 229 (196) ng/mL and 653 (645) ng/mL, respectively, in study 2. Area under the plasma concentration-time curve values for the low and high doses were 1046 (1043) ng · h/mL and 3602 (3269) ng · h/mL, respectively, in study 1, and 293 (146) ng · h/mL and 2448 (2170) ng · h/mL, respectively, in study 2. There was a trend for increasing clearance with increasing age across the ages 1 month through <6 years. There was no evidence of drug accumulation after multiple doses. On-treatment adverse events (AEs) occurred in 19 of 43 patients in study 1 and in 11 of 17 patients in study 2. Serious AEs occurred in two patients in study 1 (gastroenteritis in one patient and acute gastroenteritis from rotavirus infection resulting in discontinuation of one patient); the serious AEs resolved and were not considered by the investigators to be drug related. No other safety-related discontinuations occurred in either study. CONCLUSIONS: Exposure increased with increasing doses of pantoprazole granules, even though wide interindividual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar in study 1 and slightly lower in study 2. Pantoprazole was generally well tolerated in infants and children aged 1 month through <6 years with GORD. Trial registration numbers (ClinicalTrials.gov): NCT00259012 (study 1) and NCT00141817 (study 2).