Incorporating patient preferences into drug development and regulatory decision making: Results from a quantitative pilot study with cancer patients, carers, and regulators.

Currently, patient preference studies are not required to be included in marketing authorization applications to regulatory authorities, and the role and methodology for such studies have not been agreed upon. The European Medicines Agency (EMA) conducted a pilot study to gain experience on how the collection of individual preferences can inform the regulatory review. Using a short online questionnaire, ordinal statements regarding the desirability of different outcomes in the treatment of advanced cancer were elicited from 139 participants (98 regulators, 29 patient or carers, and 12 healthcare professionals). This was followed by face-to-face meetings to gather feedback and validate the individual responses. In this article we summarize the EMA pilot study and discuss the role of patient preference studies within the regulatory review. Based on the results, we conclude that our preference elicitation instrument was easy to implement and sufficiently precise to learn about the distribution of the participants' individual preferences.

Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.

A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009-2010 Pandemrix vaccination programme in Sweden.

In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Accelerated access to innovative medicines for patients in need.

There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and this practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.

The Role of Modeling and Simulation in Development and Registration of Medicinal Products: Output From the EFPIA/EMA Modeling and Simulation Workshop.

The European Medicines Agency (EMA) and the Federation of Pharmaceutical Industries and Associations (EFPIA) hosted a workshop on modeling and simulation (M&S).(1) Representatives from industry, academia, and regulatory agencies from Europe and beyond discussed the role of M&S in the development and registration of medicinal products within plenary and breakout sessions (BOS). This manuscript summarizes the plenary discussion (Table 1) focusing on the European perspective. Deliverables from each BOS are included in separate papers.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e31; doi:10.1038/psp.2013.7; advance online publication 27 February 2013.

Gatekeepers and enablers: how drug regulators respond to a challenging and changing environment by moving toward a proactive attitude.

This article analyzes the role of regulatory authorities in facilitating innovation in the pharmaceutical sector. We describe how regulators are expanding their role to be not only gatekeepers but also enablers of development. They have already responded to the challenging and changing environment by moving toward a proactive attitude beyond evaluation of products, thereby more actively contributing to their development. Regulators have to continuously evolve their knowledge and standards alongside evolution in science. Creation of supportive regulatory frameworks and multistakeholder interaction will help address unmet regulatory needs.

The effect of amiloride on the in vivo effective permeability of amoxicillin in human jejunum: experience from a regional perfusion technique.

The purpose of this human intestinal perfusion study (in vivo) was twofold. Firstly, we aimed to determine the effective in vivo jejunal permeability (P(eff)) of amoxicillin and to classify it according to the Biopharmaceutics Classification System (BCS). Secondly, we investigated the acute effect of amiloride on the jejunal P(eff) of amoxicillin. Amoxicillin, a beta-lactam antibiotic, has been reported to be absorbed across the intestinal mucosa by both passive diffusion and active transport. A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut perfusion tube in 14 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The concentration of amoxicillin entering the jejunal segment was 300 mg/l in both periods, and amiloride, an inhibitor of the Na+/H+ exchanger, was added at 25 mg/l in period 2. The concentrations of amoxicillin and amiloride in the outlet jejunal perfusate were measured with two different HPLC-methods. Antipyrine and [14C]PEG 4000 were added as internal standards to the perfusion solution. Amiloride had no significant effect on the jejunal P(eff) of amoxicillin. The human in vivo jejunal P(eff) for amoxicillin was 0.34+/-0.11 x 10(-4) and 0.46+/-0.12 x 10(-4) cm/s in periods 1 and 2, respectively. The high jejunal P(eff) for amiloride was 1.63+/-0.51 x 10(-4) cm/s which predicts an intestinal absorption of more than 90%. Following the BCS amoxicillin was classified as a low P(eff) drug, and amiloride had no acute effect on the in vivo jejunal P(eff) of amoxicillin.

Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers.

The pharmacokinetics of iron were investigated after intravenous administration to 12 healthy volunteers of iron(III)-hydroxide sucrose complex (Venofer) as a single i.v. dose containing 100 mg Fe. The average predose concentration was 35.7 +/- 12.5 mumol/l. There was no statistically significant difference between the serum iron level before injection (0 h) and the level at 24 h after the injection. The compartment model used includes a Michaelis-Menten term and is in excellent agreement with the observed exchange of iron to transferrin and with the daily iron turnover by transferrin. The intravenously injected iron(III)-hydroxide sucrose complex led rapidly to high serum iron levels. Maximum measured levels averaged 538 mumol/l (30.0 mg/l) at 10 min after the injection. The terminal half-life of the injected iron was calculated to be 5.3 h. Mean total area under the curve (AUC) was 1491 mumol/l h, the mean residence time (MRT) was 5.5 h. The total body clearance was 20.5 ml/min. The volume of distribution of the central compartment (Vc) was 3.21, hence close to the volume of the serum; the volume of distribution at steady state (Vdss) was 7.31; and the volume of distribution during elimination (Vdarea) was 9.21. The calculated amount of iron transported by transferrin was 31.0 +/- 6.6 mg Fe/ 24h. In summary, the data show that the injected iron(III)-hydroxide sucrose complex is quickly cleared from the serum with a terminal half-life of approximately 5-6 h. Renal elimination of iron contributed very little to the overall elimination (in average < 5%). Renal elimination of sucrose averaged about 68 +/- 10% and 75 +/- 11% of the administered dose after 4 h and 24 h, respectively.

Enantioselective assay of beta-receptor antagonists present in microdialysis and plasma samples of rats.

The enantiomers of alprenolol, metoprolol, and propranolol have been separated on an enantioselective cellulase column and analysed using a fully automated HPLC system involving coupled column chromatography and fluorescence detection. The assays had sufficient selectivity and sensitivity to investigate the disposition of these beta 2-receptor antagonists in blood and brain extracellular fluid of rats. A cellulase column was used as the first column to separate the enantiomers giving separation factors between 2.9 and 4.3. After the separation, the enantiomers were trapped on two small precolumns by the use of a switching valve and were then introduced on an achiral C18 analytical column by eluting the small columns backward. The enantiomers in blood and brain tissue dialysates were analysed by direct injection of 8 microliters samples. The limit of quantitation was 0.025-0.4 micrograms/ml of the different enantiomers. Plasma samples were analysed after a simple extraction procedure. The intraassay precision of the lowest quality control plasma samples (0.2-0.8 micrograms rac-drug/ml) was 4-8% for the different enantiomers.

Pharmacokinetics and pharmacodynamics of nitroglycerin and its dinitrate metabolites in conscious dogs: intravenous infusion studies.

Intravenous infusions of nitroglycerin (GTN), 1,2-glyceryl dinitrate (1,2-GDN), and 1,3-glyceryl dinitrate (1,3-GDN) were given to four conscious dogs at 10 micrograms/min, 30 micrograms/min, 50 micrograms/min, and 70 micrograms/min of GTN and 20 micrograms/min and 100 micrograms/min of GDNs. The steady state plasma concentrations (Css) of GTN were reached after about 60 min whereas for 1,2-GDN and 1,3-GDN the Css were reached at about 150 min after the infusion began. Except for one dog, the Css of GTN were not proportional to infusion rate, however, all dogs together showed a good linear relationship between Css of GTN and infusion rates with an average correlation coefficient of 0.917 +/- 0.102. Large variability in GTN clearance after various infusion rates was observed in all dogs. The Css ratios of 1,2-GDN/GTN and 1,3-GDN/GTN yield overall averages of 31.5 +/- 17.2 and 5.47 +/- 3.19, respectively. Average Css ratios of metabolites 1,2-GDN/1,3-GDN were 5.78 +/- 1.23. This ratio is different from those obtained after iv bolus and oral dosing indicating that the biotransformation of GTN to 1,2-GDN and 1,3-GDN differs for each dosing route. The clearances for 1,2-GDN and 1,3-GDN were not changed over the dose range of 20 micrograms/min to 100 micrograms/min. Terminal half-lives of 1,2-GDN and 1,3-GDN postinfusion were similar to those values obtained after a single bolus dose (45 min). It appears that all the GTN dose at steady state can be accounted for by the formation of measurable 1,2-GDN and 1,3-GDN. Large intra- and interdog variations in systolic blood pressure decrease (SPD) following infusions of GTN were observed, however, all dogs showed a clear systolic blood pressure decrease when the highest infusion rate (70 micrograms/min) was given. No significant systolic blood pressure drop was detected following 20 micrograms/min infusions of 1,2-GDN or 1,3-GDN. It was clear that systolic blood pressure in all dogs decreased following 100 microgram/min infusions of 1,2-GDN or 1,3-GDN. When SPD values were plotted vs. log GTN concentrations following the infusion of 70 micrograms/min of GTN in all four dogs, a counterclockwise hysteresis was observed indicating the significant contribution of the active dinitrate metabolites to GTN pharmacodynamics.

Pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its two dinitrate metabolites in conscious dogs.

The pharmacokinetics and pharmacodynamics of nitroglycerin (GTN) and its dinitrate metabolites, 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN), were examined in a seven-way crossover study in six conscious dogs. The mean apparent clearance after a low GTN i.v. dose (0.025 mg/kg) was 1440 ml/min/kg (S.D. = 630), which decreased to 686 ml/min/kg (S.D. = 317) after a high GTN i.v. dose (0.25 mg/kg), demonstrating dose-dependent pharmacokinetics. Bioavailability of oral GTN (0.25 mg/kg) was very low (0.015 +/- 0.019). The formation of dinitrate metabolites was rapid and extensive after i.v. and oral dosing of GTN. The pharmacokinetics of 1,2-GDN and 1,3-GDN were very similar. The dinitrates exhibited longer half-lives (approximately 45 min) and lower apparent clearances (approximately 16 ml/min/kg) than those found for GTN. The apparent fractional GTN clearances to 1,2-GDN (CLapp,m1) and 1,3-GDN (CLapp,m2) were also determined. The CLapp,m1 decreased significantly (P less than .05) in going from the low GTN dose (1030 +/- 620 ml/min/kg) to the high dose (425 +/- 145 ml/min/kg). In contrast, CLapp,m2 remained unchanged (low dose: 107 +/- 55 ml/min/kg; high dose: 115 +/- 37 ml/min/kg). The duration of systolic blood pressure decrease after low i.v. GTN doses was very short (approximately 15 min) and significantly longer (approximately 90 min) for high i.v. GTN doses. GTN is about 10 to 12 times more efficient than 1,2-GDN and 1,3-GDN in terms of the maximal systolic blood pressure decrease produced by a therapeutic dose. Oral GTN is pharmacodynamically active and this effect can be attributed to the formation of high levels of dinitrate metabolites.

Pharmacokinetics of intravenous imipenem/cilastatin during intermittent haemofiltration.

The pharmacokinetics of a single iv dose of imipenem/cilastatin (500/500 mg) were studied during and after intermittent haemofiltration (IHF) treatment in six patients with chronic renal failure. The elimination half-lives of imipenem and cilastatin during the IHF treatment were almost identical, 1.4 +/- 0.3 and 1.5 +/- 0.3 h, respectively. Accordingly, approximately 75% of the given dose was eliminated during a 3-h IHF session. However, there was a great difference between the elimination half-lives of the two drugs in the post-treatment period, 3.4 +/- 1.0 and 16 +/- 10 h for imipenem and cilastatin, respectively. The haemofiltration clearance of imipenem was 134 +/- 41 ml/min and that of cilastatin 109 +/- 8 ml/min. On the basis of our results, we suggest that a supplementary dose of imipenem/cilastatin (500/500 mg) should be given directly after the IHF treatment. This dose should be the starting dose for a period of 12-h dosing intervals until the next IHF procedure.

Pharmacokinetics of intravenous recombinant human erythropoietin in patients with chronic renal failure.

In order to improve our understanding of the dose-concentration and concentration-effect relationships, the pharmacokinetics of recombinant erythropoietin were studied after the initial dose (n = 6) and after repeated doses (n = 9) administered intravenously in patients with chronic renal failure. Several venous blood samples were collected before (to obtain the baseline concentration) and after an intravenous dose of erythropoietin. A radioimmunoassay was used to determine the erythropoietin concentration in the samples. The apparent volume of distribution at steady state was 4.2 +/- 0.91 (initial dose) and 3.7 +/- 0.61 (repeated dosing), which is close to the assumed plasma volume in these patients. The half-life was 5.3 +/- 1.3 h and 5.8 +/- 1.2 h in the two groups, respectively, and is therefore too short for any accumulation to be expected when dosing three times per week. Consequently, no difference in baseline values could be detected between the groups. The clearance of erythropoietin in the groups was estimated to be 11.4 +/- 7.0 ml min-1 and 7.8 +/- 3.8 ml min-1, respectively. Erythropoietin kinetics did not differ after repeated dosing compared to the single initial dose. Intravenous administration of erythropoietin will result in high peak concentrations followed by a rapid decline to basal values.

The pharmacokinetics of recombinant human erythropoietin after intravenous and subcutaneous administration to healthy subjects.

1. The pharmacokinetics of recombinant erythropoietin, r-Epo, were evaluated after intravenous and subcutaneous administration of 50 u kg-1 to six healthy male volunteers. 2. The calculated mean values (+/- s.d.) for volume of distribution at steady state and clearance after an i.v. dose were 76 (+/- 33) ml kg-1 and 12 (+/- 3) ml h-1 kg-1, respectively. 3. Serum concentrations of r-Epo peaked at 13 (+/- 6) h after the s.c. dose and the bioavailability over 72 h was 36 (+/- 23)%. The mean residence time and half-life of erythropoietin were 6.2 (+/- 1.0) and 4.5 (+/- 0.9) h respectively after i.v. and 46 (+/- 18) and 25 (+/- 12) h after s.c. administration. 4. The results demonstrate the possibility of changing the profile of the concentration-time curve by changing the mode of administration of r-Epo, with implications for the time-course of clinical response.

Maternal kinetics of morphine during labour.

The disposition of parenterally administered morphine was investigated in 13 nulliparous parturients in comparison with six healthy non-pregnant women of child-bearing age. Morphine was administered intravenously or intramuscularly and repeated venous blood samples were taken up to 360 minutes after the dose, or until delivery. At delivery samples were taken from the umbilical artery and vein. The plasma concentrations of morphine and M3G (morphine-3-glucuronide) were determined. The elimination half-life of morphine was shorter (43 +/- 19 versus 84 +/- 40 min) and the plasma clearance larger (3.4 +/- 1.4 versus 2.0 +/- 0.5 l/min) in the parturients than in the non-pregnant women. There was no difference in the apparent volume of distribution of morphine between those two groups. The time to peak plasma concentration of M3G was shorter (11 +/- 3 versus 21 +/- 6 min) and the M3G/morphine concentration ratio at 10 minutes higher (6.4 +/- 1.0 versus 3.4 +/- 0.6) in parturients than in non-pregnant women. In all but one infant, three of whom were born within three hours after the dose, no morphine was detectable. The rapid elimination of morphine by the parturients, resulting in only a short period of intrauterine exposure of the fetus to this drug, may be of clinical importance in the choice of obstetric analgesic agent.

Pharmacokinetic and pharmacodynamic studies on recombinant human erythropoietin.

In order to optimize the treatment of anemia in uremic patients the pharmacokinetic and pharmacodynamic properties of recombinant erythropoietin (r-Epo) were studied after i.v., s.c. and i.p. administration. Both in healthy volunteers and in patient with chronic renal failure, the half-life of r-Epo after i.v. administration was short (about 6 h) in comparison with the commonly used dosing interval of 3 to 7 days. Hence, the minimum serum concentration during a dosing interval is expected to be less than 1% of the peak concentration. Absorption following a s.c. dose was slow, resulting in a markedly different concentration-time profile in comparison to i.v. dosing. The half-life was about 25 h and only approximately 25% of the given dose reached the systemic circulation. As a result of differences in concentration-time profiles, higher trough concentrations during s.c. dosing intervals may be expected in comparison to those occurring after i.v. dosing. When r-Epo was given i.p. (diluted in dialysate) the extent of systemic absorption depended on the dwell time in the peritoneal cavity. A long administration time was required to absorb an amount of r-Epo predicted from s.c. studies to be adequate to achieve the desired clinical effect. In spite of reduced bioavailability, s.c. treatment did not require higher r-Epo doses than i.v. treatment to maintain the desired hemoglobin concentration. On the contrary, a trend to a requirement for lower doses was detected. The pharmacodynamic and pharmacokinetic results strongly indicate a more efficacious concentration-time profile following s.c. administration. Since s.c. dosing also allows self-administration the use of this administration route is recommended. To simplify the treatment of anemic patients with r-Epo, a model was developed to predict the required weekly s.c. dose. To facilitate the use of this model a nomogram was constructed.