Big Data - How to Realize the Promise.

The increasing volume and complexity of data now being captured across multiple settings and devices offers the opportunity to deliver a better characterization of diseases, treatments, and the performance of medicinal products in individual healthcare systems. Such data sources, commonly labeled as big data, are generally large, accumulating rapidly, and incorporate multiple data types and forms. Determining the acceptability of these data to support regulatory decisions demands an understanding of data provenance and quality in addition to confirming the validity of new approaches and methods for processing and analyzing these data. The Heads of Agencies and the European Medicines Agency Joint Big Data Taskforce was established to consider these issues from the regulatory perspective. This review reflects the thinking from its first phase and describes the big data landscape from a regulatory perspective and the challenges to be addressed in order that regulators can know when and how to have confidence in the evidence generated from big datasets.

Master protocols in clinical trials: a universal Swiss Army knife?

Master protocols combine several sub-trials, each with their own research objectives, which is usually presented as one single clinical trial application. Master protocols have become increasingly popular in oncology and haematology, as either basket, umbrella, or platform trials. Although master protocols are intended to accelerate drug development and to reduce futility, their use poses challenges to ethics committees, patients, study investigators, and competent authorities during the review and authorisation process of a clinical trial application. In this Personal View, we review the experiences of clinical trial applications from two European medical regulators-the Danish Medicines Agency and the German Federal Institute for Drugs and Medical Devices. We view master protocols as a good opportunity to identify new treatment options more quickly, particularly for patients with cancer. However, the complexity of trial documentation, the amount of information resulting from sub-trials, and the volume of changes and amendments made to clinical trial applications can cause issues during trial supervision, and during the analysis and review of a corresponding application for marketing authorisation. We draw attention to the potential issues arising from these trial concepts and propose possible solutions to avoid problems during clinical trial authorisation and trial conduct.

Data Rich, Information Poor: Can We Use Electronic Health Records to Create a Learning Healthcare System for Pharmaceuticals?

Judicious use of real-world data (RWD) is expected to make all steps in the development and use of pharmaceuticals more effective and efficient, including research and development, regulatory decision making, health technology assessment, pricing, and reimbursement decisions and treatment. A "learning healthcare system" based on electronic health records and other routinely collected data will be required to harness the full potential of RWD to complement evidence based on randomized controlled trials. We describe and illustrate with examples the growing demand for a learning healthcare system; we contrast the exigencies of an efficient pharmaceutical ecosystem in the future with current deficiencies highlighted in recently published Organisation for Economic Co-operation and Development (OECD) reports; and we reflect on the steps necessary to enable the transition from healthcare data to actionable information. A coordinated effort from all stakeholders and international cooperation will be required to increase the speed of implementation of the learning healthcare system, to everybody's benefit.

Clinical Pharmacology in Denmark in 2016 - 40 Years with the Danish Society of Clinical Pharmacology and 20 Years as a Medical Speciality.

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues.

AIMS: To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin and the GnRH receptor blocker degarelix. METHODS: Fifty-eight healthy subjects received single subcutaneous or intramuscular injections of 3.75 mg of triptorelin and 170 prostate cancer patients received multiple subcutaneous doses of degarelix of between 120 and 320 mg. All subjects were pooled for the population PK/PD data analysis. A systematic population PK/PD model-building framework using stochastic differential equations was applied to the data to identify nonlinear dynamic dependencies and to deconvolve the functional feedback interactions of the HPG axis. RESULTS: In our final PK/PD model of the HPG axis, the half-life of LH was estimated to be 1.3 h and that of testosterone 7.69 h, which corresponds well with literature values. The estimated potency of LH with respect to testosterone secretion was 5.18 IU l(-1), with a maximal stimulation of 77.5 times basal testosterone production. The estimated maximal triptorelin stimulation of the basal LH pool release was 1330 times above basal concentrations, with a potency of 0.047 ng ml(-1). The LH pool release was decreased by a maximum of 94.2% by degarelix with an estimated potency of 1.49 ng ml(-1). CONCLUSIONS: Our model of the HPG axis was able to account for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system.

Pharmacokinetic interaction studies of atosiban with labetalol or betamethasone in healthy female volunteers.

OBJECTIVES: In two separate trials, we studied the concomitant administration of atosiban with labetalol and betamethasone to determine any possibility of a clinically relevant pharmacokinetic interaction. DESIGN: Study 1 was an open-label, single dose atosiban, multiple dose labetalol, interaction study. Study 2 was an open-label, randomised, three-period crossover pharmacokinetic study. SETTING: The studies were carried out at the Clinical Pharmacology Unit of AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany. POPULATION: The study population consisted of healthy female volunteers. METHODS: In Study 1, 14 healthy female volunteers participated. On study day 1, a 12-hour intravenous infusion of 114.75 mg atosiban was administered; on days 2-4, participants received labetalol orally (100 mg twice daily), and on study day 5 they received the combined treatment. In Study 2, a total of 18 healthy female volunteers received, on three separate occasions, a 12-hour intravenous infusion of 114.75 mg atosiban, a single intramuscular injection of 12 mg betamethasone or the two drugs in combination. MAIN OUTCOME MEASURE: For Study 1, the outcome parameter for atosiban was area under the plasma concentration-time curve (AUC); the study parameters for labetalol were AUC, maximum plasma concentration (C(max)) and time to C(max) (t(max)). In Study 2, AUC, C(max) and time to C(max) (t(max)) were assessed for atosiban and betamethasone. RESULTS: Labetalol had no clinically relevant influence on the bioavailability (AUC) of atosiban. For labetalol, the co-administration with atosiban did not affect the extent of bioavailability, however, C(max) decreased by 36% and t(max) increased by 45 minutes. The C(min) was not affected by atosiban. The betamethasone and atosiban combination led to similar mean plasma concentration-time curves as the administration of each substance alone. Pharmacokinetic parameters (AUC, C(max), t(max)) did not differ markedly between treatments and all 90% CIs for ratios between treatments were fully within limits (80-125%). The co-administration of atosiban with labetalol or betamethasone resulted in similar tolerability to each substance alone. CONCLUSION: The co-administration of atosiban with betamethasone or labetalol had no clinically relevant influence on their bioavailability or tolerability.

Pharmacokinetics and renal excretion of desmopressin after intravenous administration to healthy subjects and renally impaired patients.

OBJECTIVE: To evaluate the influence of renal impairment on the pharmacokinetics of desmopressin. METHODS: Twenty-four subjects were enrolled in the study, 18 with varying degrees of renal impairment and six healthy volunteers. Each subject received a single intravenous dose of 2 microg desmopressin. Blood and urine samples were collected for 24 h and assayed for desmopressin by radioimmunoassay. Plasma concentrations and the amounts of desmopressin excreted in the urine were analysed simultaneously by use of mixed effects modelling. RESULTS: Only mild adverse events were observed. Both the renal and the nonrenal clearance of desmopressin were found to vary with the creatinine clearance (CrCL). A decrease of 1.67% in the CrCL (corresponding to 1 ml min(-1) from 60 ml min(-1)) was found to cause a 1.74% decrease in the renal clearance and a 0.93% decrease in the nonrenal clearance. The fall in renal clearance caused the amount of desmopressin excreted in urine to decrease from 47% in healthy subjects to 21% in the patients with severe renal impairment. The mean systemic clearance of desmopressin was 10 litres h(-1) in healthy subjects and 2.9 litres h(-1) in patients with severe renal impairment (difference -7.5 litres h(-1), 95% CI [-11; -4.3] litres h(-1)). Correspondingly, the mean terminal half-life, was 3.7 h in healthy subjects and 10 h in patients with severe renal impairment (difference 6.7 h, 95% CI [4.0; 9.4] h). CONCLUSION: Although desmopressin appears to be safe and well-tolerated by patients with impaired renal function, great caution should be exercised when titrating towards an efficient dosage regimen if patients with moderately or severely impaired renal function are to be treated with desmopressin at all.

Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus intravenously at daytime versus night-time in healthy men aged 55-70 years.

OBJECTIVE: To investigate (1) the pharmacokinetic and pharmacodynamic profiles of desmopressin in men from an age group with a high incidence of nocturia; and (2) circadian variation in the pharmacokinetic parameters. METHODS: The study had an open, randomised, four-way cross-over design. Desmopressin was administered orally (0.2 mg) and intravenously (2 microg), daytime and night-time, yielding four in-hospital sessions, separated by at least 2 days. Blood samples were taken before and at predetermined time points up to 12 h after dosing. Pharmacokinetic parameters were derived using a two-compartmental model except for AUC(0-->t), which was derived using non-compartmental analysis. Bioavailability was estimated using AUC(0-->t) for the oral and the intravenous periods. Urine, for measurements of volume and osmolality, was collected in predetermined intervals before and until 12 h after dosing. RESULTS: Fifteen healthy men aged 55-70 years were included in the analysis. The concentration-time curve after 2 microg intravenous desmopressin was best described using a biexponential term. The mean (95% CI) AUC at night was 302 (272-335) pg x h/ml and in the day was 281 (253-312) pg x h/ml. No statistically significant differences were detected between night and day except for terminal half-life, which was 3.1 h at night and 2.8 h in the daytime (P=0.02). After oral desmopressin, concentrations above the limit of quantification (2.5 pg/ml) were only detected in 51% of the samples. Peak plasma concentration (Cmax) was 6.2 (5.1-7.5) pg/ml at night and 6.6 (5.5-7.9) pg/ml in the daytime. Median time to reach Cmax (tmax) was 1.5 (range 1.0-4.1) h at night and 1.5 (range 0.5-3.0) h in the day. The bioavailability was 0.08%. The pharmacodynamic effects of oral and intravenous desmopressin given in the daytime were similar during the first 6 h after dosing. The night-time dosing and daytime intravenous dose resulted in antidiuresis throughout the measuring period, while the effect of the daytime peroral dose receded after 6 h. CONCLUSION: The pharmacokinetic profile of desmopressin is biexponential. Terminal half-life was longer at night than in the daytime, but the difference is considered too small to be of clinical importance. The plasma levels given by the intravenous dose resulted in a duration of action of 12 h or more. Despite low bioavailability, the pharmacodynamic effects of oral desmopressin were similar in magnitude to those after intravenous dose at night and during the first 6 h after daytime administration.

Pharmacokinetics and pharmacodynamics of a new formulation of recombinant human growth hormone administered by ZomaJet 2 Vision, a new needle-free device, compared to subcutaneous administration using a conventional syringe.

The objective of the present study was to investigate the applicability of a new human growth hormone (Zomacton) formulation, administered both by a conventional syringe and by a new needle-free device (ZomaJet 2 Vision). The study was performed according to a randomized, controlled, three-period crossover design. On 3 separate days, all subjects received in a random order a single subcutaneous injection of 1.67 mg hGH as follows: Zomacton 4 mg/ml conventional syringe administration (Treatment A), Zomacton 10 mg/ml conventional syringe administration (Treatment B), or Zomacton 10 mg/ml ZomaJet 2 Vision administration (Treatment C). The pharmacokinetic parameters were assessed for the individual subjects in each group by noncompartmental methods. Bioequivalence was assessed based on log-transformed AUC and C(max) values. To investigate the effectiveness of two formulations and the different administration methods, the pharmacodynamic parameters (insulin-like growth factor-1 [IGF-1] and free fatty acids [FFA]) were also evaluated. No subjects were withdrawn due to adverse events. The local tolerance assessment (assessed by inspection)revealed no differences between ZomaJet2 Vision application and conventional injections by syringe. Administration of the new hGH formulation by syringe was found to be bioequivalent with the reference treatment, both based on AUC and C(max) values; the new formulation administered by use of ZomaJet 2 Vision was found to be bioequivalent based on AUC values only. When using the ZomaJet 2 Vision, the absorption of hGH was faster, resulting in higher C(max) values. The maximum hGH serum concentration of around 20 ng/ml was observed 3.5 to 4 hours after drug administration. The terminal half-life was found to be around 2.5 hours. Comparison of the pharmacodynamic profiles (both IGF-1 and FFA) demonstrated bioequieffectiveness. These results support the use of jet injectors as a viable alternative to the traditional injection pens.