ORIGINAL RESEARCH published: 16 June 2022 doi: 10.3389/fphar.2022.873556 Challenges and Opportunities With Routinely Collected Data on the Utilization of Cancer Medicines. Perspectives From Health Authority Personnel Across 18 European Countries Alice Pisana 1*, Björn Wettermark 2,3, Amanj Kurdi 4,5,6, Biljana Tubic 7, Caridad Pontes 8,9, Corinne Zara 8, Eric Van Ganse 10,11, Guenka Petrova 12, Ileana Mardare 13, Jurij Fürst 14, Edited by: Marta Roig-Izquierdo 8, Oyvind Melien 15,16, Patricia Vella Bonanno 17,18, Rita Banzi 19, Tais Freire Galvao, Vanda Marković-Peković 20, Zornitsa Mitkova 12 and Brian Godman 4,6,21* State University of Campinas, Brazil 1 Reviewed by: Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden, 2Department of Pharmacy, Faculty of Pharmacy, Janet Sultana, Disciplinary Domain of Medicine and Pharmacy, Uppsala University, Uppsala, Sweden, 3Faculty of Medicine, Vilnius University, Mater Dei Hospital, Malta Vilnius, Lithuania, 4Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, Zsombor Zrubka, United Kingdom, 5Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq, 6 Óbuda University, Hungary Division of Public Health Pharmacy and Management, School of Pharmacy, Sefako Makgatho Health Sciences University, Pretoria, South Africa, 7Department of Pharmacy, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and *Correspondence: Herzegovina, 8Catalan Health Service, Barcelona, Spain, 9Department of Pharmacology, Therapeutics and Toxicology, Alice Pisana Universitat Autònoma de Barcelona, Barcelona, Spain, 10RESHAPE, INSERM U1290 & Claude Bernard University Lyon 1, Lyon, alice.pisana@icloud.com France, 11Asthma Self Care Training Unit, Respiratory Medicine, Croix Rousse University Hospital, Lyon, France, 12PELyon, Brian Godman PharmacoEpidemiology Lyon, Lyon, France, 13Public Health and Management Department, Faculty of Medicine, “Carol Davila” Brian.Godman@smu.ac.za University of Medicine and Pharmacy, Bucharest, Romania, 14Health Insurance Institute, Ljubljana, Slovenia, 15Head of Section for Drug Therapeutics and Safety, Oslo University Hospital, Oslo, Norway, 16Head of National Center for Drug Shortage in Specialty section: Specialist Health Care, Department of Pharmacology, Oslo University Hospital, Oslo, Norway, 17Division of This article was submitted to Pharmacoepidemiology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Drugs Outcomes Research and United Kingdom, 18Department of Health Systems Management and Leadership, Faculty of Health Sciences, University of Malta, Policies, Msida, Malta, 19Center for Health Regulatory Policies, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy, 20 a section of the journal Department of Social Pharmacy, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina, 21Centre Frontiers in Pharmacology of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates Received: 10 February 2022 Accepted: 18 May 2022 Background: Rising expenditure for new cancer medicines is accelerating concerns that their Published: 16 June 2022 costs will become unsustainable for universal healthcare access. Moreover, early market Citation: Pisana A, Wettermark B, Kurdi A, access of new oncology medicines lacking appropriate clinical evaluation generates Tubic B, Pontes C, Zara C, uncertainty over their cost-effectiveness and increases expenditure for unknown health Van Ganse E, Petrova G, Mardare I, Fürst J, Roig-Izquierdo M, Melien O, gain. Patient-level data can complement clinical trials and generate better evidence on the Bonanno PV, Banzi R, effectiveness, safety and outcomes of these new medicines in routine care. This can support Marković-Peković V, Mitkova Z and policy decisions including funding. Consequently, there is a need for improving datasets for Godman B (2022) Challenges and Opportunities With Routinely Collected establishing real-world outcomes of newly launched oncology medicines. Data on the Utilization of Cancer Medicines. Perspectives From Health Aim: To outline the types of available datasets for collecting patient-level data for oncology Authority Personnel Across 18 among different European countries. Additionally, to highlight concerns regarding the use and European Countries. Front. Pharmacol. 13:873556. availability of such data from a health authority perspective as well as possibilities for cross- doi: 10.3389/fphar.2022.873556 national collaboration to improve data collection and inform decision-making. Frontiers in Pharmacology | www.frontiersin.org 1 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe Methods: A mixed methods approach was undertaken through a cross-sectional questionnaire followed-up by a focus group discussion. Participants were selected by purposive sampling to represent stakeholders across different European countries and healthcare settings. Descriptive statistics were used to analyze quantifiable questions, whilst content analysis was employed for open-ended questions. Results: 25 respondents across 18 European countries provided their insights on the types of datasets collecting oncology data, including hospital records, cancer, prescription and medicine registers. The most available is expenditure data whilst data concerning effectiveness, safety and outcomes is less available, and there are concerns with data validity. A major constraint to data collection is the lack of comprehensive registries and limited data on effectiveness, safety and outcomes of new medicines. Data ownership limits data accessibility as well as possibilities for linkage, and data collection is time- consuming, necessitating dedicated staff and better systems to facilitate the process. Cross-national collaboration is challenging but the engagement of multiple stakeholders is a key step to reach common goals through research. Conclusion: This study acts as a starting point for future research on patient-level databases for oncology across Europe. Future recommendations will require continued engagement in research, building on current initiatives and involving multiple stakeholders to establish guidelines and commitments for transparency and data sharing. Keywords: new cancer medicines, patient-level datasets, pricing and reimbursement, funding concerns, pharmaceutical policy, cross-national collaboration, european countries 1 INTRODUCTION Vogler et al., 2017; Godman et al., 2021a; Vogler, 2021), with the cost of cancer care accounting for up to 30% of total hospital Cancer is a major global health challenge, with currently almost expenditure across Europe and rising (Simoens et al., 2017). 10 million deaths annually and an estimated 19.3 million new There are similar concerns in the US where expenditures on cases occurring in 2020 (Sung et al., 2021). This burden is new oncology medicines approved in 2018 alone could be as high consistently growing, with a projected rise to 28.4 million new as US$39.5 billion per year if prescribed to all eligible patients cancer cases globally in 2040 (Sung et al., 2021). Cancer also has a (Demartino et al., 2020). Furthermore, there is a constant high and growing economic burden, with an estimated US$1.16 pressure to quickly fund and facilitate market access to new trillion spent on direct costs in 2010 and rising (McCormick, oncology treatments, even with only limited clinical trial data, in 2018). In Europe, between 1995 and 2018 direct costs due to order to try and address continued unmet medical need (Pontes cancer increased by 98% from €52 billion to €103 billion, et al., 2020). Consequently, current funding and reimbursement constituting 6.2% of total health expenditure in 2018 models especially for new cancer medicines often place a heavy (Hofmarcher et al., 2019). Much of this increase was strain on healthcare systems and will impact on the sustainability attributed to higher expenditure for cancer medicines of universal healthcare in Europe (Godman et al., 2021a; Vogler, (Hofmarcher et al., 2019). Overall, expenditure on oncology 2021). This has resulted in the development of new pricing medicines in Europe increased from €12.9 billion to €32.0 models including managed entry agreements (MEAs) and billion between 2009 and 2018 (Hofmarcher et al., 2019) and multiple criteria decision analysis as well as better systems for is expected to rise further. This is attributed to the increasing the introduction and follow-up of new medicines including prevalence of cancer, as well as the development and early launch horizon scanning and budget-forecast activities (Godman of new high-priced treatments, with over 500 companies et al., 2014a; Godman et al., 2021a). currently investing in new cancer medicines for more than Various regulatory mechanisms have also been introduced 600 indications (Pontes et al., 2020; Godman et al., 2021a), including adaptive licensing (Eichler et al., 2012; Eichler et al., exacerbated by the emotive nature of the disease (Haycox, 2015; Vella Bonanno et al., 2017), accelerated assessments and 2016; Cohen, 2017). New cancer medicines continue to conditional marketing approval, to facilitate authorization and dominate research and development activities among funding of promising candidate medicines early in their pharmaceutical companies (IQVIA, 2022). development (Hoekman et al., 2015; Martinalbo et al., 2016). This issue of affordability of new cancer medicines is an However, there are concerns with such proposals due to the lack increasing concern among European and other countries of robust evidence for improved outcomes of these new medicines (Hirsch et al., 2014; Vogler et al., 2016; Godman et al., 2017; when used in routine clinical practice (Godman et al., 2014a; Frontiers in Pharmacology | www.frontiersin.org 2 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe Beachler et al., 2021). In addition, currently new oncology hospitals (Ferrer et al., 2014; Sabaté et al., 2015). However, treatments are often evaluated based on Phase II and III trials oncology medicines, especially new medicines, are a specific using surrogate endpoints, which are easier to measure (Kim and challenge since these are neither completely covered among Prasad, 2015; Kemp and Prasad, 2017). For instance, in the US in prescription registries nor in the nationwide cancer registries 2017, 21% of new medicines for patients with cancer were (Siesling et al., 2015). Consequently, there is a need to document approved by the US Food and Drug Administration (FDA) the availability of such resources among health authorities across based on Phase I/II trials with 50% based on Phase II trials Europe, as well as the type of data they collect, their robustness and (IQVIA Institute for Human Data Science, 2018). This is a applicability to inform continued funding decisions. This builds on concern for health authorities, as surrogate markers do not ongoing European projects including the European Network of necessarily translate into improved survival rates in practice, Centres for Pharmacoepidemiology and Pharmacovigilance leaving considerable uncertainty in terms of the overall clinical (ENCePP) programe. ENCePP aims to strengthen research benefit and therapeutic value of new medicines (Cortazar et al., regarding the benefit-risk balance of medicines, including 2014; Prasad et al., 2015; Kemp and Prasad, 2017; Paoletti et al., oncology medicines, in Europe by facilitating multi-centre, 2020). Uncertainty over cost-effectiveness due to lack of independent post-authorisation studies based principally on appropriate evaluation data often leads to overestimating the observational research. Alongside this, bringing together resources clinical value of a new medicine, higher prices and concerns and expertise in pharmacovigilance and pharmacoepidemiology regarding who should fund the new medicine until more data providing a platform for cross-collaborations (ENCePP, 2015). becomes available (Fojo et al., 2014; Cohen, 2017; Pontes et al., This also builds on any post-authorisation efficacy studies as part 2020). Consequently, studies undertaken with data collected in of registration with the European Medicines Agency (European routine care are becoming increasingly important as part of post- Medicines Agency, 2022). marketing activities to evaluate if the new medicines achieve the As a result, this study aims to outline the types of datasets that are desired outcomes to support continued funding (Booth et al., available, especially among health authorities, regarding routinely 2019; Godman et al., 2021a). collected patient-level data for oncology among different European In this context, real-world data collected outside randomized countries. This includes what kind of patient-level data is routinely clinical trials (RCTs) is a powerful tool that can be used to generate collected and the extent of its use from a health authority perspective. robust real-world evidence to support future health authority The objective being to better inform decision-making, including decisions, including surrounding their funding and continued funding for new expensive oncology medicines. reimbursement (Cave et al., 2019; Martini et al., 2020). Real- Additionally, to explore and understand the challenges and world data collected in routine care can derive from a number of avenues for collaboration and data sharing across Europe sources including hospital and pharmacy registers, electronic health principally among health authority personnel. This is important records, administrative datasets, patient registers as well as given the recognized complexities with the sharing of government population and healthcare surveys (OECD Health Division, and health authority data within and among countries. Complexities 2019). Such data can complement RCTs to help assess the include issues surrounding security and privacy laws, technological effectiveness of new medicines in routine clinical care versus their challenges especially when combining different datasets (record documented efficacy in trials (Khor et al., 2014; Kibbelaar et al., 2017; linkage), organizational and financial concerns surrounding data Kilburn et al., 2017; Zanotti et al., 2017; Eriksson et al., 2018; Baillie entry, regulatory issues, limited government support and other et al., 2020; Lemanska et al., 2020; Beachler et al., 2021; Lester et al., political issues (Galetsi et al., 2019). However, we are aware there 2021; Nakayama et al., 2021). Real-world data has for instance been is a need to make patient-level data more available for research used in the evaluation of real-world outcomes of olaparib treatment purposes across Europe to improve future patient care. We believe for ovarian cancer in Sweden (Eriksson et al., 2018). Additionally, such discussions will contribute to improving accessibility, Frisk et al. (2018) in their follow-up studies using health authority affordability and appropriateness of potential life-saving cancer databases in patients with chronic hepatitis C demonstrated an therapies as more data becomes available. overall cure rate of 96% with second-generation direct-acting antivirals justifying continued funding (Frisk et al., 2018). Post- launch studies have also been undertaken confirming the 2 MATERIALS AND METHODS effectiveness and safety of novel oral anticoagulants given initial concerns (Malmström et al., 2013; Mueller et al., 2019; Komen et al., 2.1 Study Design 2021). We are also seeing generally an increase in the use of real- This study applied a mixed method approach consisting of a cross- world data to support reimbursement and funding decisions sectional survey (Creswell and Clark, 2006), with the qualitative data (IQVIA, 2022). collected simultaneously and integrated in the cross-sectional survey Cancer registries have existed since the mid-20th century to as open-ended questions (Figure 1). A follow-up discussion was monitor incidence, mortality and prevalence in populations and undertaken after the cross-sectional survey data was collected to are increasingly being expanded and linked to other sources of data complement and further explore responses gathered form open- on medicine utilization as well as outcomes and effectiveness of ended survey questions. Analogous mixed-method approaches have oncology treatments (Siesling et al., 2015; Forsea, 2016; Booth et al., been used before by the authors and collaborators when conducting 2019). The availability of registries to monitor overall drug utilization similar research on key topics across Europe (Wild et al., 2016; Vella in Europe has been investigated in both ambulatory care and Bonanno et al., 2017; Moorkens et al., 2017; Godman et al., 2019; Frontiers in Pharmacology | www.frontiersin.org 3 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe FIGURE 1 | Visual representation of the study design steps for data collection, analysis and interpretation. Vella Bonanno et al., 2019; Gad et al., 2020; Godman et al., 2021a), as Europe focusing on the rational use of medicines (Garattini well as by others in various research fields (Taylor and Abernathy, et al., 2008; Sabaté et al., 2014). Many of these senior-level 2014; Creswell and Hirose, 2019; Biermann et al., 2020). decision makers and academics, including some of the co- authors, have previously been involved through these 2.2 Setting and Participant Sampling networks in various cross-national studies on diverse areas The survey was conducted among key stakeholders across the of pharmaceutical policy, providing drug utilization and healthcare sector, especially health authority personnel and expenditure data, including on oncology medicines their advisers, from various European countries to represent (Godman et al., 2014b; Moon et al., 2014; Godman et al., different perspectives and experiences. Purposive sampling 2019; Pontes et al., 2020; Godman et al., 2021b). The was considered the most appropriate strategy for this study as stakeholders were invited by email to participate in the the main interest was to include key senior-level players that survey. The initial sample consisted of 56 participants could provide the most up-to-date and relevant information selected through purposive sampling and an additional 4 and insights on the topic from the standpoint of their were included through snowball sampling. In total 60 professional background. Consequently, key informants stakeholders across 28 countries were contacted and invited were purposefully selected to include clinicians, oncologists to take part in the study. and particularly health authorities personnel and their advisers responsible for pricing, funding and 2.3 Data Collection reimbursement decisions for cancer medicines including 2.3.1 Questionnaire new cancer medicines. They were also selected based on Data was collected through a structured questionnaire, with their country to include a wide range of geographical quantifiable questions including yes/no and a multiple choice locations, population sizes, economic powers and health format, as well as open-ended questions with a qualitative system organizations. Figure 2 and Table 1 illustrate the focus. A small pilot discussion was initially conducted with 6 countries which were involved in the study, broken down by key stakeholders, among the invited participants, from these different characteristics, which were considered different European countries and regions (including important for the survey outcomes. In addition, snowball Catalonia [Spain], Lithuania, Sweden, Poland and Scotland sampling was also used where appropriate to identify [the United Kingdom]) all of whom had a deep knowledge in additional senior-level stakeholders suggested through the the field. This resulted in an improved structuring of the survey initial contacts. as well as testing the feasibility and validity of the questions. A Participants were identified through known research complete version of the questionnaire was developed following networks, such as the European branch of the International the pilot discussion, and was pretested with key selected Society for Pharmacoepidemiology Special Interest Group for informants to further refine the questions in terms of their Drug Utilization Research (EuroDURG), as well as the clarity, focus and importance of the topics covered, to enhance Piperska group of policymakers and their advisers across the questionnaire validity and robustness. Frontiers in Pharmacology | www.frontiersin.org 4 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe The final survey was distributed in electronic format (through the authors (BG and BW) due to their knowledge in this area to Zoho Survey platform (Zoho Survey, 2021)) to the other identified facilitate a stimulating and natural flow of the dialogue. The stakeholders. The questionnaire was written in English and contained principal author (AP) was the assistant moderator and 20 questions, which were organized into four topics: 1) general mainly responsible for taking notes and observations availability of cancer medicines; 2) pricing and reimbursement during the discussion. The session was videotaped after systems; 3) types of databases collecting overall drug utilization obtaining informed consent and the conversation was and patient-level data in oncology; 4) future improvements and transcribed to use for analysis. developments in data collection and data sharing (Supplementary File S1). The first two topics were included to gain understanding of 2.4 Data Analysis the key issues surrounding the availability of cancer medicines and 2.4.1 Quantitative funding decisions, which will be followed-up in future research. The Using the questionnaire platform Zoho Survey and Microsoft third and fourth topic more strictly pertain to this study and the Excel (version 16.16.27), quantifiable questionnaire data was outlined research aims. The responses were collected over a period of analyzed with traditional descriptive statistics (frequencies, 2 weeks between March 29 and 14 April 2021. proportions, mean and median). When stakeholders from the same country provided contrasting answers, this was managed by 2.3.2 Focus Group Discussion checking back with the respondents for their interpretation of the A focus group discussion was additionally conducted after the questions and attempting to reach a consensus. However, this was questionnaire data was collected to complement and not always possible. In these instances, contrasting responses consolidate understanding of the qualitative responses within countries were maintained. obtained to the open-ended survey questions. Participants for the discussion were selected among the survey respondents based on the extent of and need to clarify 2.4.2 Qualitative some of the open-ended responses provided. 19 Open-ended answers and the focus discussion transcript were respondents were invited via email, and six eventually took analyzed with content analysis (Erlingsson and Brysiewicz, 2017), part in the focus group discussion, which was held through focusing on the manifest content. The content analysis focused on zoom. The discussion was moderated by two of the principal generating the meaning units, codes and categories that emerged FIGURE 2 | Map of countries included in the survey according to geographical region as defined by EU Vocabularies (European Commission, 2021). Map generated through MapChart (MapChart, 2021). It is important to note that Scotland and Catalonia are included in the study as independent entities from the respective countries (United Kingdom and Spain), with autonomous decision-making power including in the healthcare sector. Frontiers in Pharmacology | www.frontiersin.org 5 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe from the open-ended questions and from the additional information et al., 2017; Godman et al., 2018; Godman et al., 2019; Vella obtained through the focus discussion. Bonanno et al., 2019; Gad et al., 2020; Godman et al., 2021a). 2.5 Ethical Considerations No ethical approval was sought for this project as the study did 3 RESULTS not involve handling of sensitive or confidential data and the issues discussed were not likely to bring any personal risk to the 3.1 Response Rate and Respondent participants. In addition, the topic covered strictly pertained to Characteristics the stakeholders’ professional competence and knowledge. Out of the initial sample of 60 stakeholders that were invited to take Ethical considerations were made regarding completion of the part in the questionnaire, a total of 25 stakeholders from 18 questionnaire. This was addressed by providing comprehensive European countries (Figure 2) responded, resulting in a 42% information to the stakeholders concerning the context and aim response rate. The respondents represented a varied mix of of the study. Participation was entirely voluntary, and different professional backgrounds across the healthcare settings participants indicated their consent to take part in the (Table 2). In addition, a number of respondents were classified as questionnaire form before providing their answers, with the “multiple affiliations” due to their involvements between health option to decline to answer to any question or exit the authorities, healthcare services, and academia. The results from questionnaire at any time. Furthermore, the voluntary option the quantifiable survey responses are described in the following to include their name and contact details was included and sections in terms of the proportion of participants who answered the participants were informed that this would be used only if questions as not all questions were answered by all 25 respondents. they agreed to be further contacted for potential interviews. When conducting the focus group discussion, the participants’ informed consent was ascertained orally prior to recording the 3.2 Overview of Oncology Datasets Across session. This is in accordance with national regulations and Countries institutional guidelines and is in line with previous projects 3.2.1 Availability and Use of Databases undertaken by the co-authors across a number of topics According to the responses from most stakeholders (n = 21/25), (Godman et al., 2014a; Vella Bonanno et al., 2017; Ferrario there are different types of organizations collecting drug utilization TABLE 1 | Country information broken down by population, economic power and type of health system. Country Population in 2020 GDP per Capita Health System (European (Millions) Eurostat, (2021a), in 2020 (€) Health Observatory on Scottish Government (2021), Eurostat, (2021b), Statistical Health Systems and Statistical Institute of Institute of Catalonia, Policies, 2021) Catalonia (2021a) (2021b), Office for National Statistics (2021), The World Bank Data (2021) Austria 8.9 42,300 Social health insurance Germany 83.2 40,490 Social health insurance Scotland (United Kingdom) 5.5 33,744a National health service France 67.3 33,960 Social health insurance Norway 5.4 59,180 National health service Sweden 10.3 45,910 National health service Lithuania 2.8 17,510 Social health insurance Italy 59.6 27,780 National health service Catalonia (Spain) 7.7 32,577b National health service Malta 0.5 25,310 National health service Slovenia 2.1 22,310 Social health insurance Slovakia 5.4 16,770 Social health insurance Poland 39 13,640 Social health insurance Hungary 9.8 13,940 Social health insurance Croatia 4.1 12,170 Social health insurance Romania 19.3 11,290 Social health insurance Bulgaria 6.9 8,750 Social health insurance Bosnia and Herzegovina 3.5c 5,031d Social health insurance a NB: GDP, for Scotland is from 2019 and was taken in GBP., It was converted to euros through the European Central Bank currency converter (European Central Bank, 2021) with the exchange rate for 2019. b NB: GDP, for Catalonia is from 2019. c NB: Population for Bosnia and Herzegovina is from 2019. d NB: GDP, for Bosnia and Herzegovina was in US, dollars. It was converted to euros through the European Central Bank currency converter (European Central Bank, 2021) with the exchange rate for 2020. Frontiers in Pharmacology | www.frontiersin.org 6 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe TABLE 2 | Respondent breakdown by professional setting. Respondent Profession Total n Total % Academic (research institute, university) 12 48 Healthcare professional (pharmacist, health services) 3 12 Health Authority (health insurance, social security, HTAa, medicine agency) 5 20 Multiple affiliations (university hospitals, academic institutions and health services or authorities) 5 20 Total 25 100 a HTA = Health Technology Assessment. FIGURE 3 | Types of databases for oncology ((A), n = 24) and entities that may use the collected data ((B), n = 25), according to the participants. data across the countries, as displayed in Figure 3A. A summary of Hungary, Italy, Lithuania, Malta, Norway, Poland, Romania, the situation concerning datasets in each country is also available in Catalonia and Sweden (Supplementary File S2). the Appendix (Supplementary File S2). Concerning hospital “Other” types of databases also exist as specified by 29% (n = 6/ records, 76% (n = 16/21) of respondents said these are used to 21) of respondents. Examples include the Scottish Prescribing collect data for hospital medicines (inpatient care within their Information Systems that records information for prescription healthcare system), while this is less of a case for ambulatory care medicines from community pharmacies as well as electronic medicines (outpatient care) (24%, n = 5/21). In contrast, prescription prescribing for some hospital medicines; the National Health registers were predominantly indicated for collecting ambulatory Insurance Fund and National Council on Pricing and medicine data (71%, n = 15/21). Many respondents also documented Reimbursement in Bulgaria, which collect data and maintain the availability of national cancer registries that collect data for registers for reimbursed and used medicines; and the French ambulatory (52%, n = 11/21) and inpatient care (57%, n = 12/21). national claims data collected through the National Health Data This pertains to Bulgaria, France, Hungary, Malta, Norway, Poland, System. In Sweden, register and clinical data can also be available Scotland, Slovakia and Sweden (Supplementary File S2). A smaller through the Information Network for Cancer Care, a common proportion of respondents also indicated that regional cancer platform to pool together different cancer registries registries are employed to collect data in ambulatory (19%, n = (Supplementary File S2). Overall, 74% (n = 17/24) of 4/21) and hospital (24%, n = 5/21) care. Furthermore, some stakeholders considered that databases that collect drug utilization countries have specific drug programs or dedicated registers that data for oncology do not differ from structures that collect drug collect data for oncology medicines both from hospital (48%, n = 10/ utilization data in general, with the exception of specific drug 21) and ambulatory care (43%, n = 9/21). This is the case for registries. Frontiers in Pharmacology | www.frontiersin.org 7 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe FIGURE 4 | Types of oncology data recorded ((A), n = 24), perceived data robustness and validity ((B), n = 23), frequency of data update and analysis ((C), n = 22) and possibilities for data linkage ((D), n = 22), according to the participants. PROMs = Patient Reported Outcome Measures. Concerning data access and use, 63% (n = 24/25) of respondents As specified by 43% (n = 9/21) of the respondents, data on answered that there are specific regulations that limit data access and medicines safety such as adverse events is also recorded, as well as sharing, usually limited to data owners. According to the data on effectiveness measures such as survival, progression-free stakeholders’ responses (n = 25) (Figure 3B), databases or survival and quality of life (ambulatory care: 43%, n = 9/21; hospital registries can be accessed or used by reimbursement agencies care: 48%, n = 10/21). According to the responses, some countries (84%, n = 21/25), hospitals (56%, n = 14/25), health professionals only appear to collect safety data, such as Romania, Scotland and (52%, n = 13/25), and Ministries of Health (48%, n = 12/25). In Sweden, or effectiveness data, as seen in Bulgaria and Lithuania. In contrast, data is less available for public access (12%, n = 3/25) and contrast, both types of evidence were collected in Hungary, Italy, for pharmaceutical companies (4%, n = 1/25) (Figure 3B). 68% (n = Norway, France, Poland, and Catalonia. Information on medicine 17/25) of participants also specified “other”, referring to possibilities dispensing is available in fewer countries for ambulatory (19%, n = 4/ of data availability for public use, research and academia, usually 21) and hospital (14%, n = 3/21) care, as was stated by respondents upon request and permission. This is the case for Germany, Austria, from France, Hungary, Italy and Catalonia. Limited data on Patient Sweden, France, Slovakia, Scotland, Catalonia and Hungary Reported Outcome Measures is currently being collected among the (Supplementary File S2). involved countries, and this was indicated as available only by Scotland. The option “Other” was chosen when referring to 3.2.2 Characteristics of the Data Collected instances where no precise schemes for data collection are 67% of respondents (n = 16/24) agreed that both individual- established and the type of data recorded depends on individual level and aggregated data is collected in their country. As registries or facilities collecting the data. shown in Figure 4A, the most widely available data in the With regards to data robustness and validity, Figure 4B shows majority of countries is medicine expenditure data, which is 35% (n = 8/23) of respondents answered that there are limitations recorded both for medicines prescribed in ambulatory (90%, with data robustness, and 26% (n = 6/23) that there are problems of n = 19/21) and hospital care (86%, n = 18/21). A number of poor validity. In contrast, 22% (n = 5/23) believed the data gathered stakeholders also mentioned that data on diagnosis is robust and well validated, whilst 17% (n = 4/23) had no knowledge (ambulatory care: 67%, n = 14/21; hospital care: 71%, n = or experience regarding this. 15/21), indication (ambulatory care: 52%, n = 11/21; hospital Another aspect of interest regarding the type of drug utilization care: 67%, n = 14/21) and treatment duration (71%, n = 15/21) data is how up to date the information collected is (Figure 4C). is collected for both ambulatory and hospital settings. Concerning database update, 33% (n = 5/15) of respondents agreed Frontiers in Pharmacology | www.frontiersin.org 8 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe this can occur annually, 20% (n = 3/15) weekly and 13% (n = 2/15) 3.3.1 Advantages and Disadvantages of Current Data answered on a monthly basis. In terms of analyzing the data stored, Collection Systems 36% (n = 5.14) of respondents suggested the data is analyzed The established database systems. The state of currently established annually and 29% (n = 4/14) monthly, versus 7% (n = 1/14) databases was represented both as an advantage and disadvantage saying this is undertaken on a weekly basis. Over 40% of (Figure 5). In countries where comprehensive registries to collect respondents picked “other” as an option, referring to uncertainty drug utilization data across both ambulatory and hospital care of the answer, lack of knowledge or difficulty in providing a defined settings are in place, this is seen as an advantage of current data answer due to variation in how the data is collected and analyzed collection systems, i.e. one that allows for the collection of ample across databases. information on medicine consumption, often with quite large Finally, the possibility of linking databases and registries across population coverage. Nonetheless, in many countries there is a ambulatory and hospital settings within countries was also addressed lack of registries and databases for patient-level and drug in the questionnaire (Figure 4D). 45% (n = 9/20) of the stakeholders utilization data. In addition, even where available within one answered that linking datasets is possible in ambulatory care and country, data collection systems are not always consistent in 60% (n = 12/20) said so for databases in hospital settings. This collecting data across regions, healthcare settings or pertains to Germany, Lithuania, Malta, Romania, Sweden, France, therapeutic areas. Catalonia, Hungary and Scotland. On the other hand, participants Availability and extent of data collected. A key drawback from Bosnia and Herzegovina, Slovenia, Croatia, Bulgaria, Italy and with the current data collection systems is that there is often Slovakia answered linking datasets is not possible in their country limited data, mainly focusing on aggregated data for volumes neither in ambulatory care (55%; n = 11/20) nor hospital care (40%; and expenditure, compared to limited reporting of actual n = 8/20). patient-level data on effectiveness, safety and patient outcomes measures (Figure 5). In line with this, the quality and detail of the evidence collected represents a 3.3 Challenges and Opportunities for concern as there are often gaps in the measures and Collaboration and Improving Data variables that are recorded, which makes it difficult to Collection accurately monitor and analyze treatment regimens, The following key themes that were investigated through a outcomes and adverse events (Figure 5). Most participants qualitative analysis of open-ended questions and follow-up felt that a major hurdle to the efficient use and availability of discussion are presented: 1) advantages and disadvantages of data is that it is often not possible or very difficult to link data current data collection systems, 2) suggestions to improve data between datasets and healthcare settings within countries systems, 3) barriers and opportunities to cross-national let alone across countries. collaboration. Regulations for data access and use. Closely linked to the availability and extent of data collected, many stakeholders suggested that strict regulations for data access and use represent further limitations in the data collection systems (Figure 5). The legal barriers in terms of data ownership and data protection exacerbate issues in accessibility of the data. Consequently, even when data is collected, it is often not available for analysis and use outside of the scope of hospitals, reimbursement agencies or other institutions responsible for gathering evidence and information for specific purposes. Resources for data collection. A final issue that emerged as a drawback of current data systems is the resources - or lack thereof - needed for data collection (Figure 5). Many current information systems require oncologists, clinicians and physicians to enter the data manually, which represents a high additional workload and is time-consuming. In addition, the lack of dedicated staff, financial resources and IT infrastructure to speed and facilitate data recording can result in data not being accurately recorded and in low reporting rates, further exacerbating issues with data quality, validity and robustness. 3.3.2 Suggestions to Improve Data Systems Improving policies and guidelines for data collection. Participants FIGURE 5 | Main advantages and disadvantages of data collection systems for oncology identified by the participants. suggested the establishment of better guidelines and regulations for data access as a step towards improving data systems. Namely, there Frontiers in Pharmacology | www.frontiersin.org 9 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe the availability and structures of health authority and other databases across countries as well as how health systems are organized in the provision of care. Consensus is that much has to be achieved first within individual countries to improve their data collection before potentially strengthening collaborations cross-nationally. On this front, the engagement of multiple stakeholders from different professional and healthcare settings is considered a key opportunity to share knowledge and to obtain meaningful patient-level data for oncology. Nevertheless, this can also represent a barrier to collaboration as it can be difficult to reach consensus especially with important organizational issues as well as potential involvement with commercial organizations. Moreover, issues with legal frameworks to data access and sharing can also FIGURE 6 | Key opportunities and barriers outlined by the participants for cross-country collaborations to improve data collection systems for hinder the establishment of cross-national cooperation for common oncology across Europe. datasets to improve availability of individual-level data across Europe. Recommendations and legislations. To facilitate engagement at is pressing need for more transparency in publishing data and the European level, stakeholders consider the most feasible way strengthening opportunities to use the available evidence for forward involves maintaining and promoting further engagement in analysis and observational studies. However, mindful of existing cross country research projects and networks. This could foster a security and privacy regulations within countries in terms of data better understanding of the situation concerning the availability of collection and analysis. The promotion of further incentives for patient level-datasets for oncology across Europe, and identify healthcare professionals to collect and provide detailed routine common visions and targets to encourage smoother cooperation clinical data to health authority and other key stakeholder groups between health authorities and others across countries through the is also a potential step to improve the current datasets. Building on establishment of guidelines and common models for data collection, comparisons and successful examples from different countries analysis and data-sharing. through health authority cooperation is also a key step for future improvements in the prompting of real-world evidence, as well as developing common data models to pool and analyze data from 3.4 Cancer Medicine Availability, Pricing different sources both within and among countries. and Reimbursement Investing in databases. Stakeholders discussed how addressing Various key cancer medicines were mentioned to be the guidelines for data collection and access should be accompanied by current focus across countries in terms of their prices, further investment in current and future databases, with many expenditure and patient use. As this was an open question countries requiring the introduction of registries and information and not answered by all respondents, it is difficult to quantify systems where they are not available at present. Moreover, previously the medicines. However, an overview of the different established databases necessitate expanded coverage at national and oncology medicines mentioned is available in regional levels, and encompassing different healthcare settings Supplementary File S3 and will be the subject of future including hospital and ambulatory care, as well as promote research projects. systems and common data models that allow information to be Overall, a wide variety of medicines was specified for individual more easily linked across databases and healthcare settings. countries. The following medicines were mentioned by multiple Allocating resources for data collection. A further area that was countries: Ibrutinib, Nivolumab, Paclitaxel, Palbociclib, highlighted by the participants was the importance of allocating Pembrolizumab, Trastuzumab which suggests these oncology more resources to data collection in terms of having dedicated people medicines could be of common interest in terms of priority and competent staff other than medical professionals involved in therapeutic indications, consumption and budget concerns. We reporting data to alleviate workloads. In addition, enhanced will be following this up in future research projects. resources and infrastructure for automatization in data capture Among most countries, funding of oncology medicines is and entering would also simplify and improve the data collection regulated at the national level both for ambulatory (88%, n = 22/ process. 25) and hospital (64%, n = 16/25) medicines. In fewer instances, funding is managed at the regional level (for hospital medicines) or 3.3.3 Barriers and Opportunities for Cross-National at both levels (Supplementary File S4A). MEAs or other risk- Collaboration sharing arrangements are commonly used mechanisms to establish Challenges of promoting collaborations in the short term. Whilst pricing agreements, with 82% (n = 18/22) respondents indicating there is agreement that cross-country collaboration is an important there are 5 or more operating nationally, and 56% (n = 5/9) factor to promote the collection of meaningful data especially in the regionally (Supplementary File S4B). MEAs and other similar cancer field, the general opinion reflects current barriers and schemes involve confidential discounts (67%, n = 16/24), price: challenges that often hinder efficient cooperation and volume agreements (63%, n = 15/24) and price: cap agreements improvements (Figure 6). These include the many differences in (58%, n = 14/24), and to a lesser extent outcome schemes (46%, n = Frontiers in Pharmacology | www.frontiersin.org 10 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe 11/24). 64% of respondents also specified “other” arrangements, many sources of patient-level data observed across Europe, as including pay-back schemes, budget caps, procurement by well as the scope and quality of data gathered, may also reflect tendering, conditional reimbursement among others the incentives there are for its collection and how the data is (Supplementary File S4C). subsequently used. For instance, in countries where health data is owned by health insurances and reimbursement agencies, the type of data available might focus on expenditure and 4 DISCUSSION consumption and be limited for the region covered by that service; consequently, it is more difficult to collect data on a Our findings show that there is appreciable variation and national scale (OECD Health Division, 2019). In contrast, fragmentation in the availability of registries and databases, some countries with nationally or regionally organized including health authority/health insurance company databases, to health systems are more advanced in terms of registries and collect patient-level data in oncology across Europe. This includes electronic health records with large population coverage, cancer registries, prescription registers and hospital records, as well as allowing for information to be linked and integrated across registries for specific drug programs, which is typically collected data care settings (OECD Health Division, 2019). for use in the context of health authorities such as reimbursement Our findings concerning the challenges and opportunities to agencies, Ministries of Health, as well as hospitals. There are also improve data collection accentuate the many concerns associated differences in the type of data collected, where aggregate expenditure with the current availability of oncology datasets among health data is the most widely available. However, patient-level data authorities and others, and the type and quality of clinical data being concerning diagnosis, treatment and indication, as well as collected. They also underline how, despite the availability of effectiveness and safety of medicines, is collected to a lesser extent, technology and information systems, practice and reality are particularly concerning outcome measures. quite different from expectations that establishing comprehensive Our study also highlights the main concerns associated with cross-country patient-level datasets are easily feasible. As current patient-level datasets for oncology. These include the highlighted, fragmentation of registries and databases is an issue lack of comprehensive registries across countries and across and within countries, and reflects the different capacities, healthcare settings, and the limited evidence available on financial and technological resources available to establish detailed effectiveness, safety and patient outcomes of new cancer and accurate data networks (Montouchet et al., 2018). Electronic medicines, especially with regards to medicines prescribed health records and registries might be specific to certain healthcare for inpatients in hospitals. Major hurdles with data settings but not available in others, and there are little guidelines, ownership limit data accessibility and use, as well as criteria and lack of common data models to ensure uniform possibilities for linking datasets, and the data collection collection of data within countries, let alone across borders. process is time-consuming for health professionals who Furthermore, there are still significant hurdles restricting access need to compile registries. This requires more financial and secondary use of patient data for research and healthcare resources to invest in dedicated staff and better information purposes (Galetsi et al., 2019), even for researchers working with systems to facilitate the recording of data. Fostering cross- health authority data to address key health policy issues. These national collaboration among health authorities and include barriers due to ownership and lack of transparency in data establishing better guidelines for transparency, publishing use, as well as data privacy and protection laws, hindering the and strengthening data sharing are an important aspect possibility to extensively link datasets to obtain and harness routine moving forward. data to inform policy decisions (Montouchet et al., 2018; OECD The variation and fragmentation in the availability of Health Division, 2019). databases and type of data collected is in part influenced by Nevertheless, there are examples of positive changes moving the different types of healthcare financing systems such as forward, reflected by a number of initiatives across Europe. The national health services or insurance-based models (Table 1), Scottish Cancer Medicines Outcome Program (CMOP) is a how different countries manage funding and reimbursement at noteworthy example in pooling together different datasets the national or regional level, and how this can vary for available to make better use of data for safety, effectiveness and medicines dispensed in ambulatory or inpatient care treatment outcomes for the different oncology medicines (CMOP, (Wilking and Jönsson, 2005). These differences are also 2020). The program has demonstrated success in linking registries reflected in the varying patterns in uptake and availability and electronic records, as well as collecting more patient-level data of new oncology medicines that have been observed across on quality of life and Patient Reported Outcome Measures (Baillie Europe (Wilking and Jönsson, 2005; Mayor, 2016; Hofmarcher et al., 2020; CMOP, 2020). In addition to CMOP in Scotland, et al., 2019). Furthermore, different funding mechanisms are another interesting initiative is the Systemic Anti-Cancer Therapy increasingly being adopted across Europe, including MEAs datasets in the United Kingdom, which routinely collects and reports and risk-sharing schemes, to address the affordability issue of data on cancer patients, regimens and treatments outcomes through new cancer medicines, which will likely influence their uptake the National Health Service (Bright et al., 2020). Its wide population and the type of data collected to support these schemes coverage and ability to link across different routine care databases (Pauwels et al., 2017; Godman et al., 2021a). Consequently, within the National Health Service are key strengths that allow for funding policies and health financing structures may impact collection of comprehensive evidence to support decision-making on the different types of data reporting systems available. The delivery of care and complement RCT evidence for medicines with Frontiers in Pharmacology | www.frontiersin.org 11 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe uncertainty over their clinical value, to better inform funding understanding regarding the main issues and opportunities to decisions (Bright et al., 2020). Along the same lines, the Catalan improve datasets in the future. In view of this, the open-ended Health Services experience with registries allowed for the questions and discussion was potentially limited in terms of depth consolidation of a Patient and Treatment Registry across all of understanding and reaching saturation, and perhaps further group public hospitals in Catalonia, collecting exhaustive information discussions or interviews with additional stakeholders could have on treatments, indications and clinical variables and can be yielded additional knowledge. Consequently, the objective and scope linked to other registries (Roig Izquierdo et al., 2020). The did not allow for an extensive exploration of this topic nor an in-depth information collected is analysed and integrated in decision- review of all databases available in each country. Despite these making concerning MEAs, re-assessment of medicines and limitations, the findings are believed to be valid given the seniority indicators based on effectiveness to assess quality and rational use and range of different stakeholders approached across Europe. of medicines. This also allows health authorities to discuss the results with hospitals and clinicians with respect to their practices and to 4.2 Conclusion and Future Implications review and follow-up on the Catalan Health Services We believe the data presented here are the most recent and recommendations (Reyes-Travé et al., 2021). Real-world data updated knowledge at present as provided among European initiatives have also taken shape in the Scandinavian countries. countries involving key stakeholder groups, but this could For instance, in Sweden studies concerning ovarian and prostate quickly change in the near future. Nevertheless, this study has cancers have demonstrated the value of harnessing real-world data important implications for the future of real-world data from registries and health records to investigate and understand the collection for oncology, particularly as this area will likely longer-term outcomes of cancer treatments (Eriksson et al., 2018; develop as a high priority for policy agendas. With the Beckmann et al., 2021). Nonetheless, it is interesting to note that increasing number of high-priced medicines that are despite the long history of Nordic countries with establishing cancer launched with immature data, expenditure and opportunity registries (Pukkala et al., 2018), there seems to be no clear lead in costs need to be accounted for by payers to balance finite real-world data initiatives compared to other countries mentioned. healthcare budgets with the necessity to provide access to safe In contrast, promising activities are arising across European regions, and cost-effective cancer medicines. These concerns can be creating opportunities for comparisons and a shared learning addressed by collecting more data on the performance of a environment. new medicine in routine care, to re-define funding decisions and better allocate resources for healthcare (Barrett et al., 4.1 Strengths and Limitations 2006; Godman et al., 2021a; Malmström et al., 2013). The involvement of key senior-level players representing Consequently, through this study we highlight the various professional backgrounds in different healthcare imperative need to move forward in collecting standardized settings across European countries is a major strength of datasets for oncology. the study alongside the wide range of countries included in To achieve this, a key step will be to continue involving this study. Nevertheless, this study has several limitations. multiple health authority and other stakeholders across the Since the intention was to select specific stakeholders in healthcare sectors and build a more common understanding individual countries no sample size calculation was of the value of real-world data on a European level in order to conducted as this was not considered appropriate. establish the necessary technology, infrastructure and Nonetheless, this, along with the relatively small sample of resources to incentivize data collection for oncology and 25 stakeholders, limits the generalizability of the quantitative improve its quality and availability across countries. In line findings. Additionally, as the survey contained different with this, building on current initiatives and promoting questions spanning medical practice, funding and policy, European-wide cooperation and research engagements will respondents’ background may have limited the extent of lay the ground for defining clear and common guidelines for responses for some questions over the others. Furthermore, implementing data use and develop information platforms for it is important to consider that the responses provided are data sharing and linkage (Montouchet et al., 2018; OECD based on the stakeholders’ knowledge and experience in the Health Division, 2019). Overall, this study has important field, which may have biased the interpretation of survey relevance in terms of pharmaceutical policy, as the questions. For instance, participants from a health collection of more robust and comprehensive data on authority perspective are usually more informed regarding patient outcomes, drug performance, effectiveness and issues of policy and funding, and may have more knowledge safety can help re-shape pricing, reimbursement and regarding datasets collecting information on expenditure, funding policies, regulatory processes, drug utilization consumption and volume rather than looking at patient policies as well as promote accessibility, affordability and outcomes. On the other hand, oncologists, clinicians, appropriateness of new cancer medicines. pharmacists and other healthcare professionals might be more knowledgeable with issues concerning the effectiveness and safety of different oncology medicines and DATA AVAILABILITY STATEMENT the situation concerning data collected at the patient-level. Concerning the qualitative aspect of the methodology, this The raw data supporting the conclusions of this article will be principally allowed an opportunity to gain a general overview and made available by the authors, without undue reservation. Frontiers in Pharmacology | www.frontiersin.org 12 June 2022 | Volume 13 | Article 873556 Pisana et al. Datasets for Cancer Across Europe ETHICS STATEMENT ACKNOWLEDGMENTS Ethical review and approval was not required for the study on We would like to acknowledge Gisbert W. Selke, Kristina human participants in accordance with the local legislation and Garuoliené, Vera Vlahovic-Palcevski, Nicole Grössmann, institutional requirements. The patients/participants provided Sarah Mörtenhuber, Magdalena Władysiuk, Gustaf Befrits, their written informed consent to participate in this study. Dominik Tomek, Gyongyver Soos, Roberta Joppi, Julie Clarke, Fanni Ispán, and Nils Wilking for taking part in our study and providing valuable experience and insights AUTHOR CONTRIBUTIONS on the subject. AP conducted the research, wrote the manuscript text and prepared figures. BG and BW supervised the work of AP and SUPPLEMENTARY MATERIAL provided guidance throughout the research process as well as in drafting and reviewing the manuscript. All other authors were The Supplementary Material for this article can be found online at: involved in data collection and contributed to the revision of the https://www.frontiersin.org/articles/10.3389/fphar.2022.873556/ final manuscript. full#supplementary-material and-conducting-mixed-methods-research/book241842 (cited May 8, REFERENCES 2021). Creswell, J. W., and Hirose, M. (2019). Mixed Methods and Survey Research in Baillie, K., Mueller, T., Pan, J., Laskey, J., Bennie, M., Crearie, C., et al. (2020). 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