ACCESSPOINT • VOLUME 5 • ISSUE 10 PAGE 27

Jacco Keja, PHD is Senior Principal, RWE Solutions, IMS HealthJKeja@nl.imshealth.com

The authors

birgit Ehlken, mSC is Director, RWE Solutions, IMS HealthBehlken@de.imshealth.com

Multi-country drug utilization studies in Europe

A major shift in regulatory requirements has placed RWD atthe heart of drug safety activities in Europe. most drugutilization studies (DUS) – a key tool in evaluating riskmanagement measures – are now underpinned by analysesleveraging vastly expanded datasets. As the role of RWDcontinues to broaden, we consider its particular value inpharmacovigilance and the challenges fuelled by a growingneed for multi-country DUS assessments.

INSIGHTS HEOR, PHARMACOEPIDEMIOLOGY & DRUG SAFETY

PAGE 28 IMS HEALTH REAL-WORLD EVIDENCE SOLUTIONS

Increasing importance of using RWD database analysisIn 2012, the European Medicines Agency (EMA)established a framework for Post-AuthorizationSafety Studies (PASS) in Europe. PASS are anystudies relating to an authorized medicinal product.These are conducted with the aim of:

• Identifying, characterizing or quantifying a safety hazard

• Confirming the safety profile of the medicinal product

• Assessing the effectiveness of risk managementmeasures

A PASS can be requested by the EMA whenever there areconcerns about the risks of an authorized medicinal product:

• As part of the initial marketing authorization application

• During a post-authorization regulatory procedure

• Due to an emerging safety concern

Drug utilization studies to meet regulatoryrequirementsThe PASS design should be appropriate to address the studyobjectives. Knowledge of the quantitative and qualitativepatterns of drug use is a key element for the rational use ofmedicines, the rational assessment of the risk-benefitratio, and for decision making on risk-minimizing actionsfor medicines. Drug utilization studies (DUS) provide simplemetrics for monitoring appropriate drug use and thus areoften a key element for assessing the effectiveness of riskminimization measures (RMMs).

The Pharmacoepidemiological Research on Outcomes ofTherapeutics by a European ConsorTium (PROTECT) study isa collaborative European project which aims to enhancemonitoring of the safety of medicinal products, firstly byaddressing the limitations of methods currently used inpharmacovigilance and pharmacoepidemiology, andsecondly by strengthening the monitoring of the benefit-risk assessment of medicines in Europe.

According to a search on nationwide administrativemedicines consumption databases in Europe, conducted in2010, PROTECT has identified 31 administrative nationwidemedicine consumption databases in 25 countries.1 Themajority of the databases provide information on theoutpatient sector, whereas inpatient drug utilization dataon a national level basis is rarely available.2

A recent analysis of 35 DUS requested by the EMA andregistered in the EU-PAS register found that about two-thirds of studies (63%) are based on already availabledata sources such as electronic medical records (EMR)databases, claims databases and registries.3 The majorityconsider multiple countries (Figure 1).

Most of the 35 DUS include France, Germany, Italy, Spainand the UK as target countries (Figure 2). The choice of thebig EU5 countries reflects the potentially high number ofexposed subjects but also the access of eligible databases.This data consideration explains why Scandinaviancountries are frequently included, despite the relativelysmaller number of patients. Specifically, they offer rich data(including potentially patient hard-level linkages ofdifferent registers on morbidity, drug use, etc) with nationalcoverage registry data.

*listed in the e-register of ENCePP

0

5

10

15

20

25

1 country 2-4 countries 5-7 countries 8-10 countries >10 countries

Num

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Figure 1: Number of target countries in DUS

INSIGHTS HEOR, PHARMACOEPIDEMIOLOGY & DRUG SAFETY

multi-country drug utilization studies in Europe

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• Better cost-effectiveness: typically lower resource andcost requirements

• Information that is closer to real prescriptions and thusless prone to observational bias (social desirability,information obtained through the study, etc) which caninfluence the answers of a healthcare professional in astudy using primary data collection

The eligibility of databases is highly dependent on theobjectives of the DUS requested by regulators as well as theparameters of interest. Whereas several databases allow thedescription of drug utilization on a cross-sectional basis,according to prescribed, dispensed or reimbursed medicines,they often lack the availability of longitudinal anonymouspatient-level information in order to describe, for example,pre-treatment or concomitant drug use. Two approaches fora multi-country PASS using a drug utilization of substancesindicated for mental and behavioral disorder are outlined inTable 1.

lessons learned The data integration working group of the EuropeanNetwork of Centres for Pharmacoepidemiology andPharmacovigilance (ENCePP) is working on guidelines formethods of using multiple data sources for studies withsafety endpoints. These guidelines are expected to bereleased for public consultation in 2015. Given theimportance of these data sources, a topic of the last plenarymeeting of ENCePP in November 2014 was dedicated to thelessons learnt from using different data sources, includingtheir advantages and limitations.4

Summary and outlook Increasingly demanding regulatory requirements on the onehand and technological advances on the other are driving aparadigm shift to RWD databases as the foundation forpharmacovigilance in Europe.

The lower number of executed studies in Eastern Europeancountries likely reflects the limited availability of eligibledatabases, especially when longitudinal information atpatient level is required, for example pre-treatment, co-morbid conditions as well as treatment duration.

Indications of high public-health relevance like infection,cancer, contraception, mental health, cardiovascularconditions and metabolic disorders are in the focus of DUSrequested by the EMA (24 of 35 studies; 69%).

Varied information requirementsInformation requested by the EMA varies by indication. Inareas like contraception and infections it included basicdrug utilization patterns such as number of users,distribution of indications associated with the prescriptionand off-label use. In the case of drugs for metabolic diseases(eg, diabetes) impacts on drug utilization patterns by label-change were sought, as well as trends over time in drugswitches and laboratory parameters. For indications that areprone to off-label use, abuse and diversion, such as painmedication and psychoactive drugs, pharmaceuticalcompanies were requested to show the effectiveness of RMMs.

benefits of databases for DUSSince the majority of DUS are conducted through databases,it is reasonable to conclude that this timely and efficientmethod of data collection has become a standard approachfor such studies. But what are the advantages of workingwith databases in DUS instead of more bespoke, non-interventional observational approaches?

• Wide geographic coverage

• Good representativeness

• Larger patient sample sizes

• More time efficient for study set-up and conduct

Source: EU-PAS register, October 2014

4

Figure 2: Countries included in 35 DUS requested by the EMA

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INSIGHTS HEOR, PHARMACOEPIDEMIOLOGY & DRUG SAFETY

Table 1: Approaches for a multi-country PASS using a drug utilization of substances indicated for mental and behavioral disorder

Situation

Approach

DUS as part of Risk Management Plan (RMP)for upcoming launch in EU countries

• Client – Pharma HQ

• Upcoming product launch in 15 EU countries

• Wish to include 5-year DUS in Europe aspart of RMP

• Goal of providing drug utilization dataannually for up to 5 years following launchto allow evaluation of off-label use

DUS to provide annual data on establishedproduct for Periodic Safety Update Report(PSUR)

• Client – Consortium of Pharma HQ

• Wish to include annual updates of drugutilization data in 20 EU countries in PSUR

• Goal of providing drug utilization dataannually for up to 5 years to allowevaluation of compliance of prescriptionbehavior with labeling information.

FOCUS OF ANALYSIS

• Patient profile (age, gender)

• Prescriber specialty

• Indication

• Prescription (dosage, switches, duration,first-time user, repeat user)

• Pre-treatment

DATABASES USED

Longitudinal databases

• IMS RWD EMR (IMS Disease Analyzer) data(Germany) and CPRD (UK)

• National disease plus prescriptionregistries (Denmark, Finland, Norway,Sweden)

• IMS RWD LRx pharmacy prescription data(Belgium, Italy, Spain, Netherlands,Switzerland)

Cross-sectional databases

• IMS Health Prescribing Insights databases

FOCUS OF ANALYSIS

• Patient profile (age, gender)

• Prescriber specialty

• Indication

• Average daily dosage

DATABASES USED

Cross-sectional databases

• IMS Health Prescribing Insights databases

The next task is clear: since most DUS involve multiplecountries, the shift to RWD poses the new challenge ofharmonizing and finding the right electronic data sources toaddress the required objectives. Currently, this can be onlyhandled by groups with the right level of expertise to ensurethat the advantages of working with RWD are upheld.

DUS are increasingly being used as part of a broader PASSpackage and RWD is becoming a more effective, efficient andcost-effective way to conduct them. Already, the majority ofthese studies that are requested and registered by the EMAare based on established data sources. These massivedatasets provide larger patient pools and geographiccoverage, good representativeness and faster results.Historic limitations, such as lack of longitudinality andsufficient detail on endpoints, along with the siloed systemview, are evaporating with technological advancements andthe development of validated advanced methods of linkage.

1 Ferrer P, Ballarín E, Sabaté M, Laporte JR, Schoonen M, Rottenkolber M, Fortuny J, Hasford J, Tatt I, Ibáñez L. Sources of European drugconsumption data at a country level. Int J Public Health, 2014; 59(5): 877-87

2 Sabaté M, Ferrer P, Ballarín E, Rottenkolber M, Amelio J, Schmiedl S, Reynolds R, Klungel O, Ibáñez L; PROTECT Work Package 2. InpatientDrug Utilization in Europe: Nationwide Data Sources and a Review of Publications on a Selected Group of Medicines (PROTECT Project). BasicClin Pharmacol Toxicol, 2015; 116(3) 201-11

3 Schroeder C, Keja J, Hughes B, Ehlken B, Toussi M. Understanding patterns of drug utilization studies (DUS) requested by the EuropeanMedicines Agency (EMA). Presentation. 30th ICPE Conference, Taipei, Taiwan, 24-27 October 2014

4 Use of routinely collected electronic healthcare data: Lessons learned. ENCePP Plenary, 25 November 2014, European Medicines Agency.Available at: http://www.encepp.eu/publications/documents/3.1_MToussi_electronic_healthcare_data.pdf