Pieter Stolk

Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder☆

OBJECTIVES Administration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms. METHODS Medication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA(2) and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone. RESULTS Low-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed for > or =180 or > or =90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0. CONCLUSIONS Low-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials.

Between-country variation in the utilization of antihypertensive agents: guidelines and clinical practice

Variation in antihypertensive drug utilization and guideline preferences between six European countries (Denmark, Finland, Germany, Norway, Sweden, the Netherlands) was investigated. Our objectives were to compare between-country variability in utilization per class of antihypertensive agents and to assess guideline preferences in relation to actual use. Antihypertensive consumption data (2003) was retrieved. We classified antihypertensive agents using ATC-codes: C02CA – alpha-blockers (AB), C03A – thiazide diuretics (TD), C07AB – beta-blockers (BB), C08CA – dihydropyridine calcium antagonists (CA), C09A/C09BA/C09BB – ACE-inhibitors+combinations (AI) and C09C/C09D – angiotensin II receptor blockers+combinations (AT2). For each class, DDDs/1000 persons/day and share (%) of total antihypertensive utilization was calculated. Per class, relative standard deviations (RSD) across countries were computed. Current hypertension guidelines were requested from national medical associations. Total antihypertensive utilization varied considerably, ranging from 152.4 (Netherlands) to 246.9 (Germany) DDDs/1000 persons/day. RSD was highest for TD (106.2%) and AB (93.6%). Where guidelines advocated TDs (Norway and Netherlands), TD utilization was below (Norway) or just above (Netherlands) median TD use. Guidelines recommended TD (Norway and Netherlands), TD/BB/AI (Finland, German Physicians Association) or TD/BB/CA/AI/AT2 (Denmark, German Hypertension Society), Sweden had no recent national guideline. In conclusion, antihypertensive utilization patterns varied largely across these six countries, in absolute and relative terms. Furthermore, guidelines seem disconnected from clinical practice in some countries, and none of the guidelines discuss current utilization. Whether this reflects a need for change in prescribing or re-evaluation of guidelines warrants further research.

The use of driving impairing medicines: a European survey

AimTo analyse the consumption of a number of medicines with a known potential for increasing the risk of road traffic accidents in the general population of Europe.MethodsQuestionnaires were distributed through the European Drug Utilization Research Group (EuroDURG) and Post-Innovation Learning through Life-events of drugs (PILLS) networks. A total of 30 countries (the current EU Member States, Iceland, Norway and Switzerland) were asked to supply data on the use of driving impairing medicines for the period 2000–2005, aggregated at the level of the active substance and presented in Defined Daily Doses (DDDs) per 1000 inhabitants per day.ResultsNational utilization data were provided by 12 of the 30 countries. Based on these data, a considerable increase in consumption was only seen for the antidepressants and the selective serotonin reuptake inhibitors. A slight increase, decrease or no increase was seen for the rest of the drugs studied (i.e. opioids, antipsychotics, anxiolytics, hypnotics and sedatives, drugs that are used in addictive disorders and antihistamines). Limitations were encountered when data on driving impairing medicines were compared between countries (e.g. variation in the data sources and providers, population coverage, inclusion of hospital data, use of divergent ATC/DDD versions) and, therefore, a cross-national comparison could not be performed.ConclusionsDuring the study period, trends within countries showed slight to no increase in the consumption of selected medicinal drug groups, with the exception of the antidepressants and the selective serotonin reuptake inhibitors: they showed a remarkable increased use during the study time-frame. Our results illustrate that it is still difficult to perform a valid and comprehensive collection of drug utilization data on driving impairing medicines. Therefore, efforts to harmonize data collection techniques are required and recommended.

No difference in between-country variability in use of newly approved orphan and non- orphan medicinal products - a pilot study

BackgroundRegulators and payers have to strike a balance between the needs of the patient and the optimal allocation of resources. Drugs indicated for rare diseases (orphan medicines) are a special group in this context because of their often high per unit costs. Our objective in this pilot study was to determine, for drugs used in an outpatient setting, how utilisation of centrally authorised drugs varies between countries across a selection of EU member states.MethodsWe randomly selected five orphan medicines and nine other drugs that were centrally authorised in the European Union between January 2000 and November 2006. We compared utilisation of these drugs in six European Union member states: Austria, Denmark, Finland, Portugal, The Netherlands, and Sweden. Utilisation data were expressed as Defined Daily Doses per 1000 persons per year. Variability in use across countries was determined by calculating the relative standard deviation for the utilisation rates of individual drugs across countries.ResultsNo association between orphan medicine status and variability in use across countries was found (P = 0.52). Drugs with an orphan medicine status were more expensive and had a higher innovation score than drugs without an orphan medicine status.ConclusionsThe results show that the variability in use of orphan medicines in the different health care systems of the European Union appears to be comparable to the other newly authorised drugs that were included in the analysis. This means that, although strong heterogeneity in access may exist, this heterogeneity is not specific for drugs with an orphan status.

Pharmaceutical sciences in 2020

By 2020, current scientific, business and social challenges and developments — such as R&D productivity, increased regulatory stringency and ageing populations — are likely to substantially affect many aspects of the pharmaceutical sciences. Here, we present four potential future scenarios based on discussions with experts in the pharmaceutical sciences, industry, regulation and society to identify the most crucial driving forces that might affect the evolution of the pharmaceutical sciences (see Supplementary information S1 (box) for details of the methodology).

Variable Access to Clopidogrel in a Harmonized EU Market

OBJECTIVES This study focuses on the different national coverage and reimbursement strategies and their consequences for access to clopidogrel, a drug with a central European Union (EU) registration. Our objectives are 1) to assess whether changes in reimbursement policies in EU member states influenced clopidogrel prescribing; and 2) to determine whether clopidogrel-specific policy characteristics, general characteristics of the health system, or indicators for the amount of cardiovascular care delivered were associated with the level of clopidogrel prescribing. METHODS Data were collected in Austria, Belgium, Denmark, Germany, Hungary, Portugal, Slovenia, The Netherlands, and the United Kingdom (England). Utilization rates were expressed as defined daily doses (DDDs)/1000 persons/day. To determine whether changes in reimbursement policies influenced clopidogrel utilization, a segmented linear regression approach was used. RESULTS Clopidogrel prescribing varied widely in the studied countries, from 2.76 (The Netherlands) to 6.83 (Belgium) DDDs/1000 persons/day (March 2005). Six countries had therapeutic indication restrictions to clopidogrel use. Health system characteristics did not explain variation in clopidogrel prescribing. CONCLUSION A disconnect will be indicated in this study between the concept of a harmonized EU pharmaceuticals market and the reality in an individual member state. Although clopidogrel was centrally registered in the EU, policy measures at the national level result in different roles in clinical practice for this drug.

Adaptive licensing and facilitated regulatory pathways: A survey of stakeholder perceptions.

Timely access to safe and effective new medicines of societal value is a goal of medicine developers, regulators, and payers. However, medicine development remains a costly and timeconsuming activity, with median development times in 2013 of 9.9 years for new molecular entities. Flexible approaches have been formalized in several mature jurisdictions, providing options to accelerate the regulatory review process, particularly in response to unmet medical needs. Baird et al. described 13 accelerated access pathways being adopted or investigated by key agencies. We characterize these approaches as Facilitated Regulatory Pathways (FRPs): regulatory pathways designed to accelerate submission, review, and approval of medicines where there is an unmet medical need by providing alternatives to standard regulatory review routes. FRPs may increase the communication and level of commitment between the developer and agency, can give a larger role to effects on surrogate endpoints, and may move the burden of evidence generation to the postauthorization phase. In general, FRPs emphasize particular approaches to accelerate the process: regulators working (early) with applicants to improve trial designs, surrogate and endpoint selection; facilitating the ability of regulators to make a decision based on an expedited assessment of preliminary clinical data or surrogate endpoints; improving the processes that speed the review on a comprehensive phase III dataset. In 2010, the Athenaeum Group proposed a simple, flexible blueprint that could deliver the evidence for both regulatory review and value assessment. Since then, attention has focused on transformative access pathways that address diverse stakeholder input from the earliest stages of development, align regulatory and health technology assessment (HTA)/reimbursement requirements, and ensure appropriate use of innovative medicines, thus explicitly connecting all components and stakeholders in the development chain. A term used for this approach is adaptive licensing (AL), described as a prospectively planned, flexible approach to regulation. Through iterative phases of evidence gathering to reduce uncertainties following initial regulatory evaluation and licensing, AL seeks to balance timely access with the need to provide adequate evolving information on benefits and harms so that better informed patient-care decisions can be made. By comparison, current FRPs have not been designed to strategically address aligned stakeholder needs, nor do they typically require periodic postauthorization reapprovals. Although there is diversity in terminology—adaptive licensing, medicines adaptive pathways to patients (MAPPs), staggered approval, etc.—these share certain commonalities. The explicit involvement of all stakeholders and the iterative nature of the licensing process are, together, hallmarks of AL compared with current FRPs. However, as FRPs evolve to incorporate elements of AL (e.g., multistakeholder involvement, periodic reassessment, risk management strategies, postauthorization assessments), FRPs may evolve into de facto AL pathways. Despite this growing interest, no research has assessed stakeholder perception of currently available FRPs and potential AL pathways. Therefore, this study was undertaken to characterize stakeholder impressions of these pathways, to understand opinions about the key elements of AL pathways, to recognize the barriers to implementing these pathways, and to seek recommendations for overcoming these challenges.

FDA Facilitated Regulatory Pathways : Visualizing Their Characteristics, Development, and Authorization Timelines

The US Food and Drug Administration (FDA) has four facilitated regulatory pathways (FRPs): Fast Track (FT), Breakthrough Therapy (BTD), Priority Review (PR), and Accelerated Approval (AA). Only PR specifies an expedited review timeline (6 months). We sought to determine to what extent the combination of two or more FRPs influenced development and approval times. We developed a “metro map” to illustrate FRP elements and their influence on review times. We assessed 125 new active substances (approved January 2013 to December 2015) 74 of which used one or more FRPs. For these 74, development times ranged from 1,458 (BTD + PR + AA) to 3,515 days (PR). PR alone had a median approval time of 242 days. The most common combination was FT + PR (median approval 292 days, n = 21). The fastest approval times were for PR + FT + BTD + AA (145 days) and PR + BTD + AA (166 days). Our findings support the combination of FRPs for shortening development and review times beyond that provided by PR alone.

The pharmaceutical sciences in 2020: report of a conference organized by the board of pharmaceutical sciences of the International Pharmaceutical Federation (FIP).

The Board of Pharmaceutical Sciences (BPS) of the International Pharmaceutical Federation (FIP) has developed a view on the future of pharmaceutical sciences in 2020. This followed an international conference with invited participants from various fields (academicians, scientists, regulators, industrialists, venture capitalists) who shared their views on the forces that might determine how the pharmaceutical sciences will look in 2020. The commentary here provides a summary of major research activities that will drive drug discovery and development, enabling technologies for pharmaceutical sciences, paradigm shifts in drug discovery, development and regulations, and changes in education to meet the demands of academia, industry and regulatory institutions for pharmaceutical sciences in 2020.

Impact analysis of the discontinuation of reimbursement: the case of oral contraceptives.

BACKGROUND We studied the impact of suspending oral contraceptive (OC) reimbursement in the Netherlands for women >21 years starting 1 January 2004. Discontinuation and switching patterns and the time course of the policy interventions effects were determined. STUDY DESIGN The intervention cohort contained OC users on 1 January 2004; the control cohort users on 1 January 2003. Follow-up duration was 1 year. Discontinuation and switching patterns were assessed using relative risks (RR). Weekly refill fractions were calculated to determine the time course of the policy effects. RESULTS Our intervention cohort contained 434,917 OC users; the control cohort 489,904 users. When we excluded patients not affected by the policy intervention (i.e., all patients younger than 20 years), discontinuation rates were 15.3% (intervention cohort) and 12.3% (control cohort) (RR=1.24; 95% CI=1.23-1.26) and increased with age. Switching to cheaper OCs was greatest in the intervention cohort, particularly in the 40- to 44-year age group. Differences in cumulative refill fractions showed large variation over time. CONCLUSION The OC reimbursement intervention led to an increase in the discontinuation rate of 24%. The effect increased with older age groups. Considering the time course of effects of policy interventions is of critical importance.