Off-label prescription of medicines: what do we know about the legislation in EU member states?

Aim: Off-label prescription is not regulated on the European Union (EU) level and therefore not harmonised in the EU Member States (MS). Despite this, the use of medicines outside of the drug label occurs in clinical practice, and it can be included in treatment guidelines and/or reimbursed in some cases. It is, however, currently not clear to what extent off-label use national questionnaire EMACOLEX. Case The identified categorical elements and prerequisites in national categorised. a comparison made to the five Good Off-Label Use Practice (GOLUP) principles. Conclusion: The main contribution of this work is to flag that off-label prescription actually needs to be well defined and understood before it can be appropriately taken into consideration in regulatory discussions. There is a heterogeneity in legislation regarding off-label prescription in the investigated MS, which may lead to different perspectives. A common understanding of the concept and more alignment in off-label prescription practices and their regulation at MS level may contribute to further regulatory discussions.


INTRODUCTION
Off-label use and prescription are often referred to in the context of different discussions related to medicine development, approval and use. Prescription is part of European health policies, but it falls within the responsibility of the Member States (MS) [1] . Hence, how individual MS regulate off-label prescription is an internal matter of the MS [2] . Additionally, based on different sources, the prevalence of off-label prescription is reported as being extremely variable.
Recent judgements of the Court of Justice of the European Union have triggered a discussion about off-label use of medicinal products and the extent to which these practices and data generated may be considered in the context of assessment of dossiers for approval of medicinal products [3] . Several categories of medicines, including orphan medicinal products, medicines for paediatric use and medicines in oncology and the central nervous system, should be approved via the centralised procedure. This centralised authorisation procedure is covered by European Union (EU) legislation [4] . The clinical experience with off-label prescription in the discussions related to approval of medicinal products can be different. For instance, according to the Orphan regulation, one criterion that needs to be fulfilled (if applicable) is "significant benefit". That means that, in cases where other satisfactory methods exist for the same indication, the medicinal product applied should be shown to be of significant benefit for the patients affected by the same condition. When defining which medicinal products to include as a comparator for assessing significant benefit, off-label prescribed medicinal products should not be considered a satisfactory method of treatment [5] . On the other hand, off-label use is widely considered when discussing medicinal products for paediatric patients [6][7][8] . Moreover, off-label use can be the basis for well-established use procedures [9] . Such a procedure can be started when an active substance of a medicinal product has been used for more than 10 years and its efficacy and safety have been well established, often based on results from the scientific literature [9] .
Related to the above, the aim of this research was to provide an overview of the current legislation concerning off-label prescription and use of medicinal products in the distinct MS of the EU. In our study, we used the following definition for off-label prescription: "prescription of medicinal products not in accordance with the Summary of Product Characteristics (SmPC) for which the medicinal product is authorised". Since this study focused on the EU, only medicinal products that have been authorised for at least one indication by the European Commission or by a National Competent Authority were included. Consequently, the term (marketing) authorisation in this study refers to approval in the EU. This definition was also used in the study of Weda et al. [10] (2017). Off-label prescription occurs when an authorised medicinal product is prescribed for a different patient group, another indication, via a different administration route or with a different frequency or altered dose than included in the SmPC of that authorised medicinal product [11,12] . First, we identified the elements present in national legislations associated with off-label prescription. Subsequently, we made a classification based on the legislation in the MS, as well as assessed the content of the legislation in relation to the principles from the Declaration on Good Off-Label Use in Practice (GOLUP) [13] .

SOURCES AND METHODS
We prepared a questionnaire consisting of four open questions about national legislation regarding off-label prescription [Supplementary Material 1]. This questionnaire was distributed among legal experts of the European Medicines Agencies Cooperation on Legal Issues (EMACOLEX). EMACOLEX is mandated to enhance trust, knowledge and confidence between legal staff in order to legally assist the European Medicines Regulatory Network and the national medicines agencies [14] . At least three email reminders were sent. Based on the EMACOLEX questionnaire, the national legislation references of the primary sources of national legislation -the laws in their original language -for each MS were identified. Subsequently, the acts and regulations that were indirectly or directly associated with off-label prescription were examined in English with the use of a translation tool, with exception of the Dutch legislation which was studied in the original language. Case law was excluded, because the legal status varies between the countries and in most MS it is published in the original language only. Despite the existing possibility for translation from the original language, we decided not to follow this approach as it is known that certain nuances can be lost in translation and hence lead to incorrect interpretation.

Identification of categorical elements in law from national legislation
The method for comparative legal research, as executed by Elkins et al. [15] in 2009 and applied by Voermans [16] in 2019, was used for the identification of elements in law that were associated with off-label prescription. The identified regulated subjects from the national legislation of MS were categorised into categorical elements in law and the frequency of each of these elements was counted [ Figure 1].

Analysis of classification
First, based on the nature of the legislation, a classification was made between explicit and implicit regulation regarding off-label prescription. MS that make in their national legislation a distinction between non-authorised medicinal products ("use or prescription without marketing authorisation") and authorised off-label medicinal products ("use or prescription outside the terms of the marketing authorisation") were categorised to have explicit regulation. MS that did not make such distinction were classified as having implicit regulation. Since this study focused on the EU, "marketing authorisation" refers to authorisation by the EC or any of the national competent authorities.
Second, MS were classified based on the extent of regulation, based on two parameters: the number of regulations and the number of prerequisites. The number of regulations was defined by the number of distinct sections -an article of law in a certain act or code -that have a direct or indirect association with off-label prescription of medicinal products. The number of distinct subsections or sub-articles of regulations was not counted. The number of regulations which are related to off-label prescription shows to what extent a MS has made regulations about the topic. The number of prerequisites was defined by the number (between 0 and 14) of prerequisites for off-label prescription. Prior to the analysis of classification, prerequisites were identified from the categorical elements in legislation. The number of prerequisites is an indication of the level of granularity in which the topic of "off-label prescription" is addressed in a certain MS. The complete list of these prerequisites can be found in Supplementary Material 2.

Analysis of content of legislation
To assess the content of legislation, the prerequisites for off-label prescription identified in the national legislation of MS were related to the five GOLUP principles [Supplementary Material 3] [13] . The frequency of each prerequisite was counted. GOLUP aims to create a harmonised approach on how and when off-label prescription might take place in the EU [13] . The five GOLUP principles are as follows: 1. "Presence of a medical therapeutic need based on a current examination of the patient by a suitably qualified health care professional".
2. "Absence of authorised treatment and licensed alternatives tolerated by the patient or repeated treatment failure".
3. "A documented review and critical appraisal of available scientific evidence favours off-label use to respond to the unmet medical need of the individual patient". 4. "Patients (or their legal representative) must be given sufficient information about the medicines that are prescribed to allow them to make an informed decision". 5. "Presence of established reporting routes for outcomes and adverse events linked to off-label use" [13] .

RESULTS
Responses were received from 10 EU MS and 3 EEA countries [ Figure 2]. Since this research was initiated to inform EU regulatory discussions, the information from the EEA countries was appreciated but not included in the final analysis. In total, 24 categorical elements in legislation were identified. The full list of categorical elements can be found in Supplementary Material 4. Figure 3 displays the elements that were found in the legislation of two or more MS. In five out of 10 MS, there was no definition or reference to offlabel prescription in the national legislation, whereas, in the other five MS, a definition or reference to offlabel prescription was present. In five MS, "informed patient consent" was found. Categorical elements such as the "professional standards of physicians", "responsibility in case of off-label prescription" and "notification of a policy organ" were found in the lowest number of MS. In addition, "Distinction" (five MS) and "No distinction" (five MS), respectively, refer to whether there is a distinction in legislation between non-authorised medicinal products and off-label prescribed medicinal products or not. This in fact categorises a MS as having implicit or explicit legislation.   Table 1 provides an overview of the extent to which off-label prescription is regulated. It includes the number of regulations, the number of prerequisites and the nature of regulation (explicit or implicit). The number of regulations that are associated to off-label prescription varies between one (Bulgaria, Czech Republic and Estonia) and five (Germany). Despite these differences in the extent of regulation, all MS have more general regulations, such as ethical or professional standards of the physician in general. Seven out of 10 MS have prerequisites for off-label prescription. Such prerequisites concern, e.g., "informed patient consent" or "notification of a policy organ". Bulgaria has the most prerequisites for off-label prescription (8) and Ireland, Romania and Slovenia the fewest (0). However, the MS without prerequisites (Romania, Ireland and Slovenia) do have regulations that are related to the topic.

Classification of legislation associated with off-label prescription
Lastly, five out of 10 MS were classified as having explicit regulation: Bulgaria, Czech Republic, Germany, The Netherlands and Slovenia. The other five MS were classified as having implicit regulation: Estonia, Finland, Ireland, Romania and Sweden. The legislation text of the MS with explicit regulation can be found in Supplementary Material 5, and the number of regulations and national legislation references per Member State is presented in Supplementary Material 6. Table 2 shows the 14 prerequisites for an off-label prescription of a medicinal product that have been identified in the law of the 10 MS. For each prerequisite, the relation to the GOLUP principles, the frequency and the MS in which the prerequisite has been identified are included. Except for "no payment of off-label treatment with public funds", all identified prerequisites are related to the five principles stated in GOLUP Declaration [13] . In fact, the prerequisite "no payment of off-label treatment with public funds" is related to the general aim of the GOLUP declaration.

Content of legislation regarding off-label prescription
The three most frequently applied GOLUP principles were: Principle 4 about informing the patient about the consequences of off-label prescription (nine times), Principle 5 regarding reporting outcomes and adverse events associated with off-label use (seven times) and Principle 3 concerning the scientific evidence for off-label use (five times). GOLUP Principle 2 about absence of alternative authorised treatments or repeated treatment failure was found only once. Bulgaria is the only MS that has included all five principles in their national legislation. However, all MS that have prerequisites for off-label prescription in their law (seven out of 10) have at least two prerequisites which are related to at least two different GOLUP principles, except for Germany that has two prerequisites that are related to the same GOLUP principle.
A comparison of the prerequisites in the different countries has shown different levels of similarities. For instance, Bulgaria and Sweden share three similar prerequisites (the highest "n" of similarities): "informed patient consent", "scientific evidence" and "notification of a policy organ". The last two are also found in the Czech Republic. Germany, Estonia and the Netherlands have two similar prerequisites: requirement for "informed patient consent" and "informing the patient about the consequences of the treatment".

DISCUSSION
We studied the current legislation concerning off-label prescription and use of medicinal products in the distinct MS of the EU, which is of interest, as there is no EU legislation for off-label prescription. Hence, it is important to identify the exact nature of the national legislation in the different MS of the EU. Especially for marketing authorisation applications for medicinal products, it is currently not clear to what extent off-label use can be included in regulatory discussions at a European level at the different committees at the European Medicines Agency.
Our study is the first to investigate in detail the legislation of off-label prescription in the EU. We found that the national regulation for off-label prescription is heterogeneous in the different MS of the EU. Seven out of the 10 MS that responded to the EMACOLEX questionnaire have prerequisites for off-label prescription in their national legislation, and the number of regulations related to off-label prescription varied between one and five. Furthermore, five MS had explicit and five MS had implicit regulation for off-label prescription. It is noteworthy that several countries (Finland, Estonia and Sweden) did not define or refer to off-label prescription in their national legislation, but nevertheless they all had prerequisites for off-label prescription. However, the opposite was also observed. Germany refers to off-label prescription in national legislation, while the legislation only contains general prerequisites (i.e., informed patient consent) that do not apply exclusively to prescription of off-label products but to all medicinal products.
The lack of EU legislation and the current diversity of legislation regarding off-label prescription in the different MS leads to uncertainties. This issue was also flagged by Weda et al. [10] in their study from 2017. They investigated 24 MS and found that 10 MS have regulations concerning off-label prescription of medicinal products, while 14 MS do not have such regulations [10] .
In our study, we further analysed to what extent national legislations reflect the principles formulated in the GOLUP document. This document was signed in December 2017 by various European associations to summarise the main principles and ensure high standards of patient care [13] . We identified that, in seven MS, the legislation and all 14 identified prerequisites are related to the GOLUP principles. The other three MS from the 10 responding countries do not have prerequisites at all and only in one MS (Bulgaria) the legislation contains all GOLUP principles. It seems that the GOLUP principles have been formulated based on the experience and elements from the legislation as reflected in the various MS.
This study has some limitations. The first is that the analysis is based on 10 of the 27 MS which responded to the questionnaire. Consequently, it is unclear whether the regulation in these MS is representative for the whole EU. However, based on these 10 countries, it can already be concluded that off-label prescription is very heterogeneously regulated. The second limitation is that only the legislation of MS was taken into account. Case law was excluded, for reasons already explained. It could however contribute to a more complete picture of the off-label prescription regulation throughout MS in the EU.
In conclusion, this review provides an overview of the current legislation regarding off-label prescription of medicinal products on MS level in the EU. The aim was to determine whether off-label prescription can be taken into consideration in regulatory discussions at EU level. We conclude that several steps are necessary before fully addressing this question. First, it is important to have one common understanding (a clear definition) of the concept of off-label prescription of medicinal products. Additionally, we checked to what extent national legislations' prerequisites have been reflected in the GOLUP principles of 2017. Despite the limitations of this study, we found that there is heterogeneity in legislation regarding off-label prescription in the investigated MS. Due to this, it may be expected that representatives of MS may have a different perspective regarding this concept.
Hence, the main contribution of this work is to flag that off-label prescription actually needs to be well defined and understood before taken into consideration in regulatory discussions. A common understanding of the concept and more alignment in off-label prescription practices and their regulation at MS level may contribute to further regulatory discussions.