Multi-country drug utilization studies in Europe

INSIGHTS HEOR, PHARMACOEPIDEMIOLOGY & DRUG SAFETY

Multi-country drug utilization studies in Europe A major shift in regulatory requirements has placed RWD at the heart of drug safety activities in Europe. most drug utilization studies (DUS) – a key tool in evaluating risk management measures – are now underpinned by analyses leveraging vastly expanded datasets. As the role of RWD continues to broaden, we consider its particular value in pharmacovigilance and the challenges fuelled by a growing need for multi-country DUS assessments.

The authors

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

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

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INSIGHTS HEOR, PHARMACOEPIDEMIOLOGY & DRUG SAFETY

multi-country drug utilization studies in Europe Increasing importance of using RWD database analysis In 2012, the European Medicines Agency (EMA) established a framework for Post-Authorization Safety Studies (PASS) in Europe. PASS are any studies 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 management measures

A PASS can be requested by the EMA whenever there are concerns 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 regulatory requirements

The PASS design should be appropriate to address the study objectives. Knowledge of the quantitative and qualitative patterns of drug use is a key element for the rational use of medicines, the rational assessment of the risk-benefit ratio, and for decision making on risk-minimizing actions for medicines. Drug utilization studies (DUS) provide simple metrics for monitoring appropriate drug use and thus are often a key element for assessing the effectiveness of risk minimization measures (RMMs).

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) study is a collaborative European project which aims to enhance monitoring of the safety of medicinal products, firstly by addressing the limitations of methods currently used in pharmacovigilance and pharmacoepidemiology, and secondly by strengthening the monitoring of the benefitrisk assessment of medicines in Europe.

According to a search on nationwide administrative medicines consumption databases in Europe, conducted in 2010, PROTECT has identified 31 administrative nationwide medicine consumption databases in 25 countries.1 The majority of the databases provide information on the outpatient sector, whereas inpatient drug utilization data on a national level basis is rarely available.2 A recent analysis of 35 DUS requested by the EMA and registered in the EU-PAS register found that about two-thirds of studies (63%) are based on already available data sources such as electronic medical records (EMR) databases, claims databases and registries.3 The majority consider multiple countries (Figure 1).

Most of the 35 DUS include France, Germany, Italy, Spain and the UK as target countries (Figure 2). The choice of the big EU5 countries reflects the potentially high number of exposed subjects but also the access of eligible databases.

This data consideration explains why Scandinavian countries are frequently included, despite the relatively smaller number of patients. Specifically, they offer rich data (including potentially patient hard-level linkages of different registers on morbidity, drug use, etc) with national coverage registry data.

Figure 1: Number of target countries in DUS

25

Number of studies*

20

15

10

5

0 1 country

2-4 countries

5-7 countries

8-10 countries

>10 countries

*listed in the e-register of ENCePP

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

Source: EU-PAS register, October 2014

The lower number of executed studies in Eastern European countries likely reflects the limited availability of eligible databases, especially when longitudinal information at patient level is required, for example pre-treatment, comorbid conditions as well as treatment duration.

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

Varied information requirements

Information requested by the EMA varies by indication. In areas like contraception and infections it included basic drug utilization patterns such as number of users, distribution of indications associated with the prescription and off-label use. In the case of drugs for metabolic diseases (eg, diabetes) impacts on drug utilization patterns by labelchange were sought, as well as trends over time in drug switches and laboratory parameters. For indications that are prone to off-label use, abuse and diversion, such as pain medication and psychoactive drugs, pharmaceutical companies were requested to show the effectiveness of RMMs.

benefits of databases for DUS

Since the majority of DUS are conducted through databases, it is reasonable to conclude that this timely and efficient method of data collection has become a standard approach for such studies. But what are the advantages of working with databases in DUS instead of more bespoke, noninterventional observational approaches?

• • • •

Wide geographic coverage Good representativeness

Larger patient sample sizes

More time efficient for study set-up and conduct

• •

Better cost-effectiveness: typically lower resource and cost requirements

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

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

lessons learned

The data integration working group of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) is working on guidelines for methods of using multiple data sources for studies with safety endpoints. These guidelines are expected to be released for public consultation in 2015. Given the importance of these data sources, a topic of the last plenary meeting of ENCePP in November 2014 was dedicated to the lessons learnt from using different data sources, including their advantages and limitations.4

Summary and outlook

Increasingly demanding regulatory requirements on the one hand and technological advances on the other are driving a paradigm shift to RWD databases as the foundation for pharmacovigilance in Europe.

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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

DUS as part of Risk Management Plan (RMP) for upcoming launch in EU countries • Client – Pharma HQ

• Upcoming product launch in 15 EU countries

Situation

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

• Goal of providing drug utilization data

annually for up to 5 years following launch to allow evaluation of off-label use

DUS to provide annual data on established product for Periodic Safety Update Report (PSUR) • Client – Consortium of Pharma HQ

• Wish to include annual updates of drug

utilization data in 20 EU countries in PSUR

• Goal of providing drug utilization data

annually for up to 5 years to allow evaluation of compliance of prescription behavior with labeling information.

FOCUS OF ANALYSIS

FOCUS OF ANALYSIS

• Prescriber specialty

• Prescriber specialty

• Patient profile (age, gender)

• Patient profile (age, gender)

• Indication

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

• Indication

• Average daily dosage

• Pre-treatment

Approach

DATABASES USED

DATABASES USED

• IMS RWD EMR (IMS Disease Analyzer) data

• IMS Health Prescribing Insights databases

Longitudinal databases

(Germany) and CPRD (UK)

Cross-sectional databases

• National disease plus prescription

registries (Denmark, Finland, Norway, Sweden)

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

Cross-sectional databases

• IMS Health Prescribing Insights databases DUS are increasingly being used as part of a broader PASS package and RWD is becoming a more effective, efficient and cost-effective way to conduct them. Already, the majority of these studies that are requested and registered by the EMA are based on established data sources. These massive datasets provide larger patient pools and geographic coverage, good representativeness and faster results.

Historic limitations, such as lack of longitudinality and sufficient detail on endpoints, along with the siloed system view, are evaporating with technological advancements and the development of validated advanced methods of linkage.

1 2

3 4

The next task is clear: since most DUS involve multiple countries, the shift to RWD poses the new challenge of harmonizing and finding the right electronic data sources to address the required objectives. Currently, this can be only handled by groups with the right level of expertise to ensure that the advantages of working with RWD are upheld.

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

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

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

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

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