Higher persistence with valsartan compared with enalapril in daily practice

Satu J Siiskonen1, Nancy S Breekveldt-Postma1, Gábor Vincze2, Zeba M Khan3, Joëlle A Erkens1, Ron MC Herings11PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands; 2Novartis Pharma AG, Basel, Switzerland; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USAObjective: To compare persistence with valsartan and enalapril in daily practice.Methods: The PHARMO Record Linkage System includes various data registries including drug dispensing and hospitalizations for ≥2 million subjects in the Netherlands. Patients newly treated with valsartan or enalapril in the period of 1999–2002 were selected. Persistence was calculated by summing up the number of days of continuous treatment. Patients who remained on therapy with valsartan or enalapril for 12 or 24 months were defined as persistent at 1 or 2 years, respectively.Results: 3364 patients received valsartan and 9103 patients received enalapril. About 62% of patients treated with valsartan and 55% of patients treated with enalapril remained on therapy at 12 months after the initial dispensing, while 48% of patients treated with valsartan and 43% of patients treated with enalapril were persistent at 24 months. Patients treated with valsartan were about 20% more likely to stay on treatment than patients treated with enalapril (1 year RRadj: 1.23, 95% CI: 1.16–1.32; 2 years RRadj: 1.16, 95% CI: 1.11–1.23).Conclusions: Real-life persistence is higher with valsartan than with enalapril. The results of this and other studies on persistence in daily practice should be taken into account when deciding upon drug treatment for hypertension.Keywords: persistence, antihypertensive, valsartan, enalapril, angiotensin-converting enzyme inhibitors, angiotensin-2-receptor blocker

Higher persistence with valsartan compared with enalapril in daily practice

Objective: To compare persistence with valsartan and enalapril in daily practice. Methods: The PHARMO Record Linkage System includes various data registries including drug dispensing and hospitalizations for ≥2 million subjects in the Netherlands. Patients newly treated with valsartan or enalapril in the period of 1999-2002 were selected. Persistence was calculated by summing up the number of days of continuous treatment. Patients who remained on therapy with valsartan or enalapril for 12 or 24 months were defined as persistent at 1 or 2 years, respectively. Results: 3364 patients received valsartan and 9103 patients received enalapril. About 62% of patients treated with valsartan and 55% of patients treated with enalapril remained on therapy at 12 months after the initial dispensing, while 48% of patients treated with valsartan and 43% of patients treated with enalapril were persistent at 24 months. Patients treated with valsartan were about 20% more likely to stay on treatment than patients treated with enalapril (1 year RRadj: 1.23, 95% CI: 1.16-1.32; 2 years RRadj: 1.16, 95% CI: 1.11-1.23). Conclusions: Real-life persistence is higher with valsartan than with enalapril. The results of this and other studies on persistence in daily practice should be taken into account when deciding upon drug treatment for hypertension

Regulatory sanctions for ethically relevant GCP violations

Although EU inspectors and clinical assessors are mandated to identify and act upon ethical issues, regulators lack guidance on how this can be done. Hence, we propose a four-step regulatory approach on ethically relevant GCP violation findings. The first step is identification of the ethical issue. Next is analysis [i.e., identifying the gravity (intensity or severity) and the magnitude (amount and duration) of the ethics violation as well as the responsible person(s) or entity or entities]. The third step is evaluation, (i.e., the process of deliberating to determine the significance of the ethics violation, with the intention of identifying the most reasonable sanction and/or corrective or reparative action). Last is decision-making or the process of choosing and implementing a regulatory course of action

Ethics and the marketing authorization of pharmaceuticals: what happens to ethical issues discovered post-trial and pre-marketing authorization?

Background: In the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes. To this date, we know very little about the manner that these regulators put this obligation into action. In this paper, we intend to look into the manner and the extent that ethical issues discovered during inspection have reached the deliberation processes. Methods: To gather data, we used the Dutch Medicines Evaluation Board database and first searched for the inspections, and their accompanying site inspection reports and integrated inspection reports, related to central marketing authorization applications (henceforth, application/s) of drugs submitted to the European Medicines Agency (EMA) from 2011 to 2015. We then extracted inspection findings that were purely of ethical nature, i.e., those that did not affect the benefit/risk balance of the study (issues related to informed consent, research ethics committees, and respect for persons). Only findings graded at least major by the inspectorate were included. Lastly, to identify how many of the ethically relevant findings (ERFs) reach the application deliberation processes, we extracted the relevant joint response assessment reports and reviewed the sections that discussed inspection findings. Results: From 2011 to 2015, there were 390 processed applications, of which 65 had inspection reports and integrated inspection reports accessible via the database of the Dutch Medicines Evaluation Board. Of the 65, we found ERFs in 37 (56.9%). The majority of the ERFs were graded as major and half of the time it was informed-consent related. A third of these findings were related to research ethics committee processes and requirements. Of the 37 inspections with ERFs, 30 were endorsed in the integrated inspection reports as generally GCP compliant. Day 150 joint response assessment reports and Day 180 list of outstanding issues were reviewed for all 37 inspections, and none of the ERFs were carried over in any of the assessment reports or list of outstanding issues. Conclusion: None of the ethically relevant findings, all of which were graded as major or critical in integrated inspection reports, were explicitly carried over to the joint assessment reports. This calls for more transparency in EMA application deliberations on how ERFs are considered, if at all, in the decision-making processes

Drug regulators and ethics : which GCP issues are also ethical issues?

Within the European Union (EU), good clinical practice (GCP) provides an ethical mandate to regulators; however, it is unclear what the content of that mandate is. By looking at the correspondence between GCP and ethical imperatives, we identify that the mandate is within the following: principles; benefit:risk ratio; scientific validity; results publication; informed consent; respect for participants; and special populations. There are also cases when regulations were ethical but were not pairable to an imperative, and when the former were stricter than latter. Hence, we suggest closer cooperation between ethics committees and regulators to ensure that future versions of ethics guidelines cover the ethically relevant regulations that were not directly pairable to any imperative, and cooperation between GCP legislative bodies and ethics guideline-making bodies to resolve the discordant areas

Treatment patterns and health care costs of mebeverine-treated IBS patients: a case-control study

BACKGROUND: Irritable bowel syndrome (IBS) is a functional disorder affecting the quality of life of patients. In the Netherlands, mebeverine is currently the only medical treatment registered for IBS, although its efficacy is considered disputable. OBJECTIVE: To assess treatment patterns and associated health care cost in mebeverine users relative to matched controls. METHODS: A matched case-control study was performed using pharmacy data. Cases were mebeverine users as proxy for IBS patients. Controls were non-mebeverine users and matched to cases by age, gender and pharmacy. Prevalence and incidence of mebeverine use, concomitant drug use and hospitalizations were assessed in 3431 cases and 3431 controls. Concomitant drug use and hospitalizations was also assessed in a subgroup of 1222 users of mebeverine and laxatives (proxy for constipation-IBS) and their controls. RESULTS: Twelve per 1000 residents were ever-dispensed mebeverine in 1998. One-third of these mebeverine users used laxatives concomitantly. Concomitant drug use and hospitalizations were increased in mebeverine users. The odds ratio for hospitalizations for gastrointestinal reasons was increased predominantly in mebeverine users with concomitant laxative use (OR:8.7; 95%CI [4.3-17.3]). Excess yearly costs for all concomitant medications were 94 Euros [95%CI 79 Euros-109 Euros] and for hospital admissions 120 Euros [74 Euros-166 Euros] per mebeverine user. In mebeverine users with concomitant laxative use these costs were 136 Euros and 251 Euros respectively. CONCLUSIONS: In treated IBS patients, concomitant drug use and hospitalizations are increased relative to matched controls. Medical resource use and associated health care costs are particularly increased in mebeverine users using laxatives. The total mean excess cost per patient per year is 482 Euro

Treatment with inhaled corticosteroids in asthma is too often discontinued

Purpose To study persistence with inhaled corticosteroids (ICS) and its determinants in asthma-patients. Methods From the PHARMO database, asthma-patients (age <35 years) with a first dispensing for ICS in 1999-2002 and >= 2 dispensings in the first year were included. Persistence during the first year was defined as the number of days from start to time of first failure to continue renewal of the initial ICS. Potential determinants of persistence were assessed at ICS-start and I year before. Results The study-cohort included 5563 new users of single ICS and 297 of fixed-combined ICS. Less than 10% of patients using single ICS and 15% of patients using fixed-combined ICS were persistent at I year. Similar persistence-rates were observed when stratified forage (children/adolescents: 0-18 years and adults: 19-34 years). Increased persistence with single ICS was observed with the type of ICS (budesonide), prescriber (specialist), prior use of long-acting beta-agonists, previous hospitalization for asthma, metered-dose inhaler, low starting-dose and once-daily dosing regimen at start. Persistence with fixed combined ICS-treatment increased with younger age and was decreased in patients having high starting-dose of ICS and prior use of antibiotics. Conclusion New users of both single and fixed combined ICS have alarming low persistence rates with ICS-treatment in the first year of follow-up. Persistence was mainly related to patient factors, such as severity of disease, and to treatment-related factors, such as once-daily dosing frequency. Copyright (c) 2008 John Wiley & Sons, Ltd

Regulatory sanctions for ethically relevant GCP violations

Although EU inspectors and clinical assessors are mandated to identify and act upon ethical issues, regulators lack guidance on how this can be done. Hence, we propose a four-step regulatory approach on ethically relevant GCP violation findings. The first step is identification of the ethical issue. Next is analysis [i.e., identifying the gravity (intensity or severity) and the magnitude (amount and duration) of the ethics violation as well as the responsible person(s) or entity or entities]. The third step is evaluation, (i.e., the process of deliberating to determine the significance of the ethics violation, with the intention of identifying the most reasonable sanction and/or corrective or reparative action). Last is decision-making or the process of choosing and implementing a regulatory course of action

Ethics and the marketing authorization of pharmaceuticals: what happens to ethical issues discovered post-trial and pre-marketing authorization?

Background In the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes. To this date, we know very little about the manner that these regulators put this obligation into action. In this paper, we intend to look into the manner and the extent that ethical issues discovered during inspection have reached the deliberation processes. Methods To gather data, we used the Dutch Medicines Evaluation Board database and first searched for the inspections, and their accompanying site inspection reports and integrated inspection reports, related to central marketing authorization applications (henceforth, application/s) of drugs submitted to the European Medicines Agency (EMA) from 2011 to 2015. We then extracted inspection findings that were purely of ethical nature, i.e., those that did not affect the benefit/risk balance of the study (issues related to informed consent, research ethics committees, and respect for persons). Only findings graded at least major by the inspectorate were included. Lastly, to identify how many of the ethically relevant findings (ERFs) reach the application deliberation processes, we extracted the relevant joint response assessment reports and reviewed the sections that discussed inspection findings. Results From 2011 to 2015, there were 390 processed applications, of which 65 had inspection reports and integrated inspection reports accessible via the database of the Dutch Medicines Evaluation Board. Of the 65, we found ERFs in 37 (56.9%). The majority of the ERFs were graded as major and half of the time it was informed-consent related. A third of these findings were related to research ethics committee processes and requirements. Of the 37 inspections with ERFs, 30 were endorsed in the integrated inspection reports as generally GCP compliant. Day 150 joint response assessment reports and Day 180 list of outstanding issues were reviewed for all 37 inspections, and none of the ERFs were carried over in any of the assessment reports or list of outstanding issues. Conclusion None of the ethically relevant findings, all of which were graded as major or critical in integrated inspection reports, were explicitly carried over to the joint assessment reports. This calls for more transparency in EMA application deliberations on how ERFs are considered, if at all, in the decision-making processes