key: cord-0757967-93viq4ak
authors: Vogler, Sabine; Fischer, Stefan
title: How to address medicines shortages: Findings from a cross-sectional study of 24 countries
date: 2020-09-21
journal: Health Policy
DOI: 10.1016/j.healthpol.2020.09.001
sha: b05eb77ddb8df5b15b39b127971ce8aadb115fad
doc_id: 757967
cord_uid: 93viq4ak

Shortages of medicines have become a major public health challenge. The aim of this study was to survey national measures to manage and combat these shortages. A questionnaire survey was conducted with public authorities involved in the Pharmaceutical Pricing and Reimbursement Information (PPRI) network. Reponses relating to measures as of March / April 2020 were received from 24 countries (22 European countries, Canada and Israel). In 20 countries, manufacturers are requested to notify – usually on an obligatory basis – upcoming and existing shortages, which are recorded in a register. Further measures include a regular dialogue with relevant stakeholders (18 countries), financial sanctions for manufacturers in cases of non-supply and/or non-compliance with reporting or stocking requirements (15 countries) and simplified regulatory procedures (20 countries). For defined medicines, supply reserves have been established (14 countries), and legal provisions allow the issuing of export bans (10 countries). Some measures have been introduced since the end of 2019 and countries are planning and discussing further action. While governments reacted by taking national measures, the COVID-19 crisis might serve as an opportunity to join forces in cross-country collaboration and develop joint (e.g. European) solutions to address the shortage issue in a sustainable manner. A practical first step could be to work on a harmonisation of the national registers.

Medicines shortages have become a major issue globally [1] , as they affect numerous countries, including Canada [2, 3] and European countries [4] (e.g. Belgium [5, 6] , Finland [7] [8] [9] , France [10, 11] , Germany [12] , Italy [13, 14] , the Netherlands [15, 16] and Poland [17] ).

Shortages relate to temporary (and sometimes permanent) disruptions of the supply of medicines. The national definitions of a shortage of medicines differ, and some countries do not have an official definition at all ( [18, 19] , for examples see Supplementary Materials 1). A common feature of a shortage is that the supply of a medicinewhich has been brought onto the marketis discontinued. There are other circumstances when medicines are unavailable for patients but they are not called shortage: medicines are not launched if a pharmaceutical company does not perceive a country's market to be sufficiently attractive (e.g. in the case of small markets or lower-income countries with limited ability to pay [20, 21] ). Medicines may be launched with a delay of some months and even years; this delayed availability is frequently caused by the widespread use of the external price referencing policy (for instance, apart from Sweden and the UK, all European countries with price regulation use external price referencing, at least as supplementary pricing policy [22, 23] ). External price referencing incentivises pharmaceutical companies to bring medicines to market later in lower-priced countries so as not to reduce the benchmark price across countries (strategic launch of pharmaceutical industry) [24] [25] [26] .

Shortages limit patient access to medicines which likely results in increased negative health outcomes (e.g. no or delayed therapy, risks for patient safety due to switches and medication errors [12, 27] ), increased workload for health professionals (e.g. searching for therapeutic alternatives) [6, 7, 28] and economic consequences (e.g. need to procure higher-priced alternatives) [29, 30] .

To respond to the public health threat resulting from shortages, governments started taking action to improve the management of these disruptions and to reduce and ideally prevent them.

Measures reported in the literature include the obligation for industry to report shortages to authorities (e.g. France [10] ), the Netherlands [15] ) and the creation of national reporting systems (several countries [18, 31] ), supply reserve stocks (e.g. Finland [9] ), notification of parallel exports [17] and collaborative projects with stakeholders such as representatives of the pharmaceutical industry, wholesale and pharmacies (e.g. Italy [14] ). Most scientific articles related to single countries and reported measures as background information while the J o u r n a l P r e -p r o o f research question had a different focus (e.g. workload for pharmacists to manage shortages, types of medicines subject to shortages). Acosta et al. 2019 [18] presented some national approaches to manage shortages in their scoping study but their narrative review was limited to published articles. To the knowledge of the authors, no up-to-date overview of government policies to address shortages of medicines is available.

Therefore, this study aimed to present up-to-date information about the actions taken in different countries to manage, reduce and prevent shortages of medicines.

To ensure the collection of the most current information and inclusion of a high number of countries, including those that tend to be less covered in scientific research (e.g. smaller and/or less resourced countries), a primary survey (using a questionnaire) with public authorities was carried out.

The authors benefited from an existing collaboration with the Pharmaceutical Pricing and Reimbursement Information (PPRI) network. This network comprises public authorities for pharmaceutical policy, with a focus on pricing and reimbursement, in 47 countries (at the time of the study). Most PPRI member countries are from the WHO European region [32] . Given an ongoing exchange of information to update each other, PPRI network members are used to receiving and responding to requests, and involving further colleagues and institutions in their country if needed [33] .

A questionnaire was developed based on a taxonomy of possible measures to manage, reduce and/or prevent shortages of medicines (implemented as well as under discussion), which were known from the literature [6, 9, 10, 14, 18, 31] and policy debate [34, 35] . The authors tested the questionnaire by pre-filling information for five pilot countries (Austria, Finland, Italy, the Netherlands and Sweden). The information for these countries was sought in an unsystematic literature review that considered peer-reviewed articles and grey literature (e.g. media reports, websites of the public authorities and private actors in the medicines supply chain) in national J o u r n a l P r e -p r o o f languages as well as in English. Additionally, the authors contacted national stakeholders (usually the medicines agency and the community pharmacy association) in the pilot countries (except Austria) and asked them in a telephone interview to identify further measures, including those already implemented or under discussion. The research for the pilot countries was conducted in January 2020. countries were asked to validate the pre-filled information.

The questionnaire was sent to the members of the PPRI network on 5 March 2020, with the request to respond within two weeks. The invitation to participate in the survey was accompanied by information on the authors' intention to publish the findings. In March and April 2020 two rounds of reminders were sent to those network members that had not yet responded. In addition, during the compilation of answers in April 2020 some PPRI network members were contacted on an individual basis to clarify some ambiguous answers and ask for missing information. A summary table of the synthesised results was shared with all PPRI network members that participated in this study, thus allowing them to comment on possible errors.

In August 2020, as part of the revision of the paper, the authors analysed publicly accessible registers for notification of shortages with regard to the type of information provided (e.g. cause of shortage, information on alternative medicine for substitution). 

A frequently used measure to manage shortages was a national register to which suppliers report current and upcoming shortages: In 20 of the 24 responding countries, regulatory authorities (usually the medicines agency or the ministry of health) ran a shortages register. In all countries with such a register, with the exception of Malta, suppliers were obliged to report to the register, while Austria and Germany had made their voluntary registers obligatory only on 1 April 2020 ( Table 1 ). The majority of these registers were publicly accessible. The outlines of the registers and the kinds of information collected differed from country to country. While several registers provided for the possibility to include relevant dates (expected and/or actual start and end dates of the shortage), only few registers published information on causes and solutions (e.g., existence of alternative medicines) for managing the shortage situation (Supplementary Materials 3).

To cover shortages, 20 countries had simplified regulatory procedures, in particular related to the import, marketing authorisation and also dispensing of medicines procured on the world market. Usually, exceptions were granted with regard to labelling requirements of the packages and product information leaflets in other languages were permitted.

Banning exports of medicines that are critically needed for the supply in a national market was a less frequent measure, but it was increasingly being used at the time of the survey. Of the 24 responding countries, five countries provided for the possibility to impose export bans on defined medicines by the end of 2019, seven countries by the end of Q1/2020 and ten countries by mid-April 2020. Medicines eligible for an export ban were usually listed (e.g. the "ex-ante notification list" in Portugal). Three further EU Member States considered introducing export bans, and Israel discussed an extension to further medicines. In addition to export bans for some medicines, four countries asked for export notification of further selected medicines (Czech Republic, Norway, Portugal) or all medicines (Latvia), respectively. Romania, which requested distributors to notify the export of reimbursed medicines, had planned to introduce an export ban in 2019, however, it had withdrawn this measure due to changes in the political environment.

Insert Table 2 around here In 14 countries (including the Netherlands which planned to implement this measure in the course of 2020) marketing authorisation holders and/or wholesalers have the obligation to keep a stock of defined medicines for a certain period (usually at least three months). Such stocking requirements were also built into tender contracts (e.g. Albania, Denmark).

Most of the surveyed countries (18 countries) reported regular meetings with relevant stakeholders, in particular marketing authorisation holders, wholesalers and community pharmacists and, but less frequently, patients and the public (e.g. in Finland). This exchange usually took place in a rather formal setting of a working group or task force. In Germany, the stakeholder dialogue was officialised as an advisory board to the medicines agency ("Jour Fixe") in a law that came into effect on 1 April 2020 (Table 2) .

Norway was the sole country to offer financial support to economic operators. In a COVID-19 related voluntary agreement of March 2020 between the authorities and wholesalers, the latter were asked to extend their stock to a wider range of medicines (this request added to a previously defined supply reserve obligation). The additional costs for wholesalers would be J o u r n a l P r e -p r o o f covered by the state. In several countries, financial sanctions were in place to penalise noncompliance (in cases of non-supply -6 countries, of non-compliance with reporting requirements -12 countries and of non-compliance with stocking requirements -4 countries plus the Netherlands in the planning phase). Nine countries did not report the use of financial sanctions (Table 3) .

Insert Table 3 [37] ). In addition, the COVID-19 pandemic that hit European countries in the course of March 2020, prompted further measures (e.g., the "COVID-19 ad-hoc agreement" as of 6 March 2020 in Norway, which asked wholesalers to stock more, and export bans imposed in Israel and Russia in March 2020 and in Latvia in April 2020, respectively). However, the legal changes in Austria and Germany, which made reporting to registers mandatory in April 2020, had been decided at earlier times, and it was a coincidence that they entered in force in COVID-19 times.

Third, in addition to obligations and regulatory measures, supplemented by sanctions in some countries, public authorities tend to seek collaborative action with stakeholders. Canada started its stakeholder dialogue already in 2012. Italy opted for a large stakeholder platform that involved law enforcement institutions besides national and local authorities and associations (industry, wholesale, pharmacy). In a joint project ("inspection campaign"), first done as a pilot in one region and later repeated at national level, economic operators responsible for illegal transactions and breaches of the Good Distribution Practice were identified and penalised (over 20 withdrawals of licences, financial sanctions of nearly € 800,000) [14] . It is interesting to note that in most countries marketing authorisation holders are the sole economic operators that have to report to the register (in 18 of 20 countries with a register). In this respect, the introduction of the notification obligation in Germany that is also targeted at wholesalers may serve as a good practice example. Despite obligatory notification to the register in all countries except Malta, not all countries impose financial sanctions in case of non-compliance (e.g. Norway: obligatory, but no sanctions). However, a few countries (e.g.

Cyprus and Finland) were discussing the introduction of sanctions at the time of the survey.

Fourth, access to information related to the shortage situation plays a major role, not only for public authorities, but also for health professionals such as pharmacists who are involved in the management of shortages [29, 30] . In several countries, public authorities responded to this need for information for health professionals by offering publicly accessible registers. For health professionals it is particularly important to learn about the expected duration of the shortages and possible approaches on how to ensure access to (similar) treatment. However, J o u r n a l P r e -p r o o f in only few countries do the regulatory authorities publish on alternative medicines or other solutions. In some countries (e.g. Italy, the Netherlands), pharmacists have established their own registers to cover for missing data of the authorities' registers [38] .

Fifth, differences exist with regard to the medicines that are subject to shortages-related measures. Most countries apply a rather broad approach for the registers (12 of the 20 countries with a register report shortages on any authorised medicine; 3 countries on prescription-only medicines or prescription-only and selected non-prescription medicines, respectively, and 2 countries on reimbursed medicines), while three countries (Denmark, Germany and Switzerland) limit the reporting requirements to medicines that are considered critical to ensure supply and treatment of patients. Medicines supply reserves and particularly export bans are usually more focused and often concern considerably fewer medicines compared to the medicines requiring notification.

Sixth, the measures comprise different types of action, with different purposes. Registers and stakeholder dialogues are, in principle, measures to generate information before and during the shortages management. But they are not necessarily policies to prevent or combat shortages. Preventive measures and those to fight the shortages include export bans and reserve stocks, which aim to protect the supply of the national markets, as well as imports from other countries, with the intention to cover gaps in national supplies. Having a focus on the national markets, these preventive measures compete with similar initiatives of other countries that struggle with the same challenges. Anecdotal evidence on trucks and airplanes with COVID-related medical supply goods being stopped at borders or being redirected to other countries that were willing to pay higher prices as reported in the media [39, 40] confirm conflicting national interests.

More than five years ago, researchers called for collaboration among countries to tackle the shortages challenge: "Currently, the Member States of the European Union are striving to resolve the problem very much on their own, although a far more focused and dedicated J o u r n a l P r e -p r o o f collaboration may well prove instrumental in coping with drug shortages throughout Europe more effectively" [11] .

The situation appears not to have changed considerably though some initiatives were launched and the topic has meanwhile become high on the political agenda [41, 42] . In [44] . But the JPA framework was not intended to be extended to medicines in general [45] .

In recent years, cross-country collaborations (such as the Beneluxa Initiative or the "Valletta Declaration") were established between European countries. Their key aim is to ensure sustainable patient access to new innovative medicines [46] . Shortage management appears to be of lower importance for these collaborations, except for the Baltic Procurement Initiative of Estonia, Latvia and Lithuania. For the latter, managing shortages based on a "lending agreement" is a major collaborative action. In case of a shortage in one of the countries, another country lends the needed medicines or medical devices and does not charge any fees for this service. Once the beneficiary country receives its supply, it will return the products it borrowed to the lending country [47] .

Major causes of shortages are production and quality problems [11, [48] [49] [50] . In our research, two responding countries mentioned national production to overcome medicine shortages (Switzerland reported a discussion on strengthening the domestic production base, and Italy J o u r n a l P r e -p r o o f mitigates some shortages by using military sites for production). Bringing the pharmaceutical production back to Europe has been proposed and discussed in the political debate, including discussions initiated by the German Presidency of European Council in the second half of 2020 [42] . This longer-term endeavour would require joint efforts of several European countries, based on strong political will. It is beyond the scope of this paper to assess the feasibility and effectiveness of this measure. However, the COVID-19 crisis could offer an opportunity to use the momentum for change.

In the meantime, European countries could start collaborating in the more technical area of information sharing. Despite the above-mentioned agreement on a definition of a shortage between EMA and national regulatory agencies, the national legal specifications continue to differ among European countries ( [14, 18] , see also Supplementary Materials 1). These differences are also reflected in the variation in the deadlines for the shortage notification. As shown in this study (Table 1) , deadlines range from "immediately" to "at least six months in advance". In addition, the structure and the contents of the national registers (e.g. frequency of updates, information on start and end of the shortages, causes) also vary among the countries ( [18, 31, 38, 50] 

Governments have increasingly been using a mix of measures to address and combat medicines shortages. In the months and even weeks preceding and even during this survey, some countries implemented additional measures. Regarding the design of policies, voluntary tools tend to have been substituted by obligatory mechanisms linked to sanctions. High-income countries were found to apply a higher number of measures, but the introduction of new policies in this field was also observed in some lower-income countries in Europe. The measures appear to be rather reactive with a focus on managing existing or upcoming shortages and not addressing the causes of shortages.

For the time being, measures to manage and combat shortages of medicines were predominantly taken at national level, though the need for a multi-country approach to identify global or at least European answers has been repeatedly voiced. The COVID-19 crisis that will likely aggravate the shortage situation could give new momentum to jointly search for solutions that go beyond national measures and could also address the causes of shortages.

The authors declare that they have no conflict of interest.

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. However, the authors acknowledge to have drawn from knowledge that they have gained in a previous research. That project investigated medicines shortages in Finland, Italy, the Netherlands and Sweden and was funded by the National Association of Statutory Health Insurance Funds ("GKV-Spitzenverband") in Germany.

Furthermore, the Pharmaceutical Pricing and Reimbursement Information (PPRI) Secretariat that maintains and coordinates the PPRI network of competent authorities, whose delegates

were key respondents in this study, has been financially supported by the Austrian Federal Ministry of Social Affairs, Health, Care and Consumer Protection.

No funding was received for designing the survey, analysing and compiling the data and writing the manuscript. Further information on the accessibility of the shortages registers maintained by public authorities and their contents is provided in Supplementary Materials 3.

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The authors are highly grateful to the representatives of public authorities for pharmaceutical pricing and reimbursement involved in the Pharmaceutical Pricing and Reimbursement Information (PPRI) network who responded to the survey of this study. In line with the PPRI policy, their names and affiliations are not mentioned. Further thanks go to Nina Zimmermann, PPRI coordinator, for keeping this network active, and to Manuel Alexander Haasis, member of the PPRI Secretariat, for his support in the data collection.

Since a legal change on 1 April 2020, which introduced the obligation to notify the register c In addition, financial sanctions for the export of medicines which are prohibited to be exported