Transparency and accountability are essential components at all stages of the trade negotiation process. This study evaluates the extent to which these principles were upheld in the United States’ public consultation process during the negotiation of the United States-Mexico-Canada Agreement (USMCA), with respect to public comments about the pharmaceutical sector and access to medicines.The public consultation process occurred before the start of official negotiations and was overseen by the Office of the United States Trade Representative (USTR). It included both written comments and oral testimony about US trade negotiation objectives. Of the written comments that specifically discussed issues relating to pharmaceuticals, the majority were submitted by private individuals, members of the pharmaceutical industry, and civil society organizations. Nearly all comments submitted by non-industry groups indicated that access to medicines was a priority issue in the renegotiated agreement, with specific reference to price affordability. By contrast, more than 50% of submissions received from members or affiliates of the pharmaceutical industry advocated for strengthened pharmaceutical intellectual property rights, greater regulatory data protections, or both.This study reveals mixed outcomes with respect to the level of transparency achieved in the US trade negotiation process. Though input from the public at-large was actively solicited, the extent to which these comments were considered in the content of the final agreement is unclear. A preliminary comparison of the analyzed comments with the USTR’s final negotiating objectives and the final text of the USMCA shows that several provisions that were advanced exclusively by the pharmaceutical industry and ultimately adopted in the final agreement were opposed by the majority of non-industry stakeholders.Negotiators could increase public transparency when choosing to advance one competing trade objective over another by actively providing the public with clear rationales for their negotiation positions, as well as details on how public comments are taken into account to form these rationales. Without greater clarity on these aspects, the public consultation process risks appearing to serve as a cursory government mechanism, lacking in accountability and undermining public trust in both the trade negotiation process and its outcomes.The online version contains supplementary material available at 10.1186/s12992-021-00740-1. In trade negotiations, governments are faced with managing the competing interests of different sectors and stakeholders within their domestic populations. This often includes balancing national economic imperatives with policies seeking to improve health outcomes, such as expanding access to essential medicines – a health systems component critical to upholding the human right to health . ConflicTransparency and accountability are integral to the trade negotiation process. Policies that embrace transparency ensure that information about the plans, processes, and actions of government negotiators are made publicly available, easily accessible, and understandable to citizens . IncreasMultilateral trade agreements under the World Trade Organization (WTO) include a number of transparency obligations. However, oversight of bilateral and regional trade agreements made by WTO member states is limited to the WTO Transparency Mechanism, which merely requires countries to “report trade measures to the relevant WTO body if the measures might have an effect on other members” . Beyond There is a lack of research that systematically explores the degree of transparency and accountability embedded in the trade negotiation process. While recent studies have analyzed the risks new bilateral and regional trade agreements pose to public health policy –13, 35, This paper aims to contribute to transparency and accountability in international trade negotiations by evaluating the United States’ public consultation process during the renegotiation of the North American Free Trade Agreement (NAFTA), now predominantly referred to as the United States-Mexico-Canada Agreement (USMCA). In this paper, we map the USMCA negotiation process and analyze the public comments relating to medicines and pharmaceuticals submitted during the United States’ (US) consultation period. In doing so, the policy priorities advanced by the various classes of USMCA stakeholders relating to health, access to medicines, and international trade are identified and evaluated.Since most aspects of trade negotiations are held under conditions of strict confidentiality, the public consultation process provides the primary window through which the public can actively engage with the development of trade policy. The US was selected as the country for analysis based on the immediate and robust availability of its public consultation documents. An analysis of Mexico’s public consultation process was excluded because its public consultation was limited to industry and commercial stakeholders rather than the public at large , 16. An A qualitative research study focussing on publicly available documents was completed to map the US negotiation rounds of the USMCA. Government and other administrative actors directly involved in the trade negotiation process were identified, with the mechanisms for filling their positions  recorded. Then, opportunities for the public to receive information about the trade negotiations and to provide feedback about the agreement’s proposed provisions were noted. While records of both written comments and oral testimonies made by stakeholders are publicly available, oral testimonies were delivered by a subset of stakeholders that also submitted written comments. Thus, only written comments were selected for analysis due to their more comprehensive representation of the total feedback submitted by members of the public. Finally, the written comments submitted by stakeholders during the public consultation process were systematically queried for language related to pharmaceuticals.Regulations.gov is the US government’s online platform that enables members of the public to find, read, and comment on officially issued federal regulations and related documents [Regulations.gov platform at Docket USTR-2017-0006 Requests for Comments: Negotiation Objectives Regarding Modernization of North American Free Trade Agreement with Canada and Mexico (“the Docket”). The search tool embedded in the ‘Comments’ tab of the Docket was used to query the set of publicly available comments submitted during the public consultation period with the search terms pharma, pharmaceutical, medicine, medical, drug, and health to identify an initial pool of comments for analysis. These search terms were developed based on the search engine’s functionality, which, for example, is not sensitive to wildcard (*) searches. The resulting comments were then downloaded from the Docket. Comments that were identified multiple times by different search terms  were only recorded once.ocuments . During To facilitate qualitative analysis, a hierarchical coding tree (‘node tree’) was constructed in two iterative rounds of review between the authors based on a sampling of 20 downloaded comments. The downloaded comments were annotated based on this tree see Fig.  using quThe following section outlines the process by which the US government negotiated the USMCA, including the timeline, involved stakeholders, and mechanisms through which the public was consulted. It also presents the major findings from the qualitative analysis of the comments submitted to the Docket, with respect to the number of submissions, submitter identities, and substantive policy themes.Trade negotiations for the USMCA formally began on 16 August 2016 and were concluded on 30 September 2018 after seven rounds of negotiations between the US, Mexico and Canada , 20. On Trade Promotion Authority Act, 2015 [The US trade negotiation process involves internal consultations between various groups and committees, including the USTR, the Advisory Committee for Trade Policy and Negotiations (ACTPN), Policy Advisory Committees, and Technical and Sectoral Advisory Committees Fig. . Politicct, 2015 , 22. Befct, 2015 , 20.FigRegulations.gov website to submit comments [Between 23 May – 14 June 2017, prior to the start of official negotiations with Canada and Mexico, the USTR solicited input from the US public about its negotiation objectives. Publications in the Federal Register, press releases from the USTR website, and tweets from the USTR official Twitter account (@USTradeRep) directed members of the public to the comments –28. At tcomments .The USTR also held three days of public hearings at the U.S. International Trade Commission in Washington, D.C. to solicit input from over 140 stakeholders . StakehoOn 17 July 2017, the USTR released its NAFTA Negotiation Objectives . These o12,460 comments were submitted by stakeholders during the USTR-hosted public consultation process for the negotiation of the USMCA. Of these submissions, 1458 (11.7%) were publicly available on the ‘Comments’ tab of the Docket Fig. A. Additipharma, pharmaceutical, medicine, medical, drug, and health. Following the exclusion of duplicative comments, comments not pertaining to pharmaceuticals for human use, and comments that exclusively mentioned the pharmaceutical sector to illustrate the size of a different industry, 75 comments were included for analysis , Biotechnology Innovation Organization (BIO), and the US Chamber of Commerce), 15 comments were received from civil society organizations , 5 comments were received from individuals affiliated with academic institutions or think tanks, 4 comments were received from members of government or civil servants writing on behalf of their employing government office , and 5 comments were received from professional associations Fig. C. All suOverall, issues of intellectual property and other pharmaceuticals-related exclusivities, access to medicines, and pharmaceutical sector transparency emerged as major stakeholder areas of interest Fig. .Fig. 4SNo stakeholders that were ascribed a civil society, government, individual, or professional association identity expressed the opinion that intellectual property rights (IPRs) for pharmaceuticals should increase, with 51% expressly advocating for trade policies that would weaken pharmaceutical IPRs or prevent them from expanding. These included submissions that advocated for the complete elimination of NAFTA’s existing IP protections, the expanded use of TRIPS flexibilities such as compulsory licensing and parallel importation, and the rejection of expanding TRIPS-plus measures that had previously been advanced by the United States during negotiations of the Trans-Pacific Partnership Agreement. In contrast, over half of the submissions in the industry category advocated for either increased IPRs or greater regulatory data protection provisions for pharmaceuticals. In particular, industry submissions predominantly advocated for the harmonization of Canada and Mexico’s IPR and regulatory data policies with that of the United States, including the adoption of strengthened patent linkage provisions to prevent the market entry of allegedly infringing generics and 12-year regulatory data protection periods.Almost all stakeholders that were ascribed an academic, civil society, government, individual, or professional association identity indicated that access to and/or the affordability of medicines was a priority issue area for pharmaceuticals-related provisions in the renegotiated agreement. Most expressed broad concern about this topic, however some suggested specific policy solutions, such as incorporating trade clauses permitting pharmaceutical price regulation or the importation of medicines from Canada. Of note, only submissions from government stakeholders specifically emphasised the need for a renegotiated agreement to include provisions that enable the US public health system to actively negotiate for lower drug prices. The majority of industry stakeholders indicated that incentivizing pharmaceutical innovation was their priority trade issue. However, some submissions from industry stakeholders also appealed to a rationale of increased access to medicines or lower medicines prices to advocate for stronger of IPRs and/or regulatory data protection terms. For example:“National laws, regulations or judicial decisions that prohibit patents on certain types of biopharmaceutical inventions or impose additional or heightened patentability criteria restrict patient access to valuable new medicines and undermine investment in future treatments and cures” .“providing data protection for Rx-to-OTC switches in Canada will lower the cost of medicines, lower health care costs more generally, increase access to medicines, increase market access for health care companies, and bring Canadian intellectual property law up to the standard in United States law.” .Of the submissions that discussed agreement provisions related to transparency, more than half were submitted by industry stakeholders. Of these, all but two submissions emphasised the importance of predictability and transparency in the pharmaceutical IP, regulatory, pricing, and reimbursement spaces to facilitate greater innovation, with some explicitly advocating for the inclusion of provisions that would enable greater stakeholder participation in the development of rules and regulations for the biopharmaceutical sector. The remaining two submissions advocated for the inclusion of provisions that would improve pharmaceutical patent transparency to better facilitate the development of generic medicines. These were submitted by the generic industry group Association for Accessible Medicines and the broad multi-industry group United States Council for International Business. Only two comments advocated for increased transparency in the negotiation process itself, and both were submitted by non-industry actors.For a detailed analysis of comments by submitter identity, see supplemental materials.The process employed by the US during the USMCA negotiations shows some evidence of including transparency mechanisms: opportunities for public input were clearly described in publicly available documents, the public could contribute through both written submissions or oral testimony, and the contents of all submissions were entered into the public record. Furthermore, as many of the government actors involved in the agenda-setting process were elected officials or political appointees, there exists a built-in democratic incentive for accountability to members of the voting public. However, a robust understanding of the extent to which the public’s interest was truly taken into consideration remains incomplete despite these measures.aware of and understood how to navigate the consultation process. For example, if those who submitted comments to the Docket were drawn from a limited pool of the public that already engages frequently with the federal US public consultation process, this would lead submitted comments to only represent a subset of the perspectives represented by the public at large with respect to trade and health.First, while public stakeholders were notified about the consultation period through several channels, it is difficult to gauge the extent to which the public at large was generally Second, while anyone could submit a comment to the Docket, the process by which stakeholders were selected to testify in-person after requesting to participate in the public hearings is unclear. This lack of transparency risks undermining public trust in the consultation process itself, potentially rendering it vulnerable to criticism that the views ultimately adopted by trade negotiators disproportionately reflected those advanced by the individuals and groups with the specialized knowledge and resources required to secure participation in the public hearings.Finally, since the public consultation period uniquely took place before the trade negotiations officially began, there were no opportunities for the public to provide feedback on the iterative draft agreements made between each round of negotiations. Without such an opportunity, the value of the public consultation process in ensuring that the views and interests of the public-at large are actually brought to the negotiation table is limited; stakeholders are unable to discern whether negotiators advanced their particular positions but yielded as a compromise to make gains in other areas of the agreement, or whether negotiators did not advance their particular positions at all. Even if opportunities for the public to provide further input between draft texts of an agreement are not established, the US government can improve its accountability to the public by actively reporting how stakeholder feedback is taken into account during negotiation rounds.Excluding duplicates, a relatively small proportion  of stakeholder comments were related to pharmaceuticals for human use. This may reflect a low level of public interest or knowledge in these topics relative to other sectoral trade issues. Of the comments included for analysis, the high number of comments submitted by individuals and the pharmaceutical sector indicates a proportionately higher level of interest in pharmaceuticals and access to medicines by these groups compared to the others.Overall, the comments submitted by the pharmaceutical industry tended to advocate for policies most likely to be commercially beneficial to them, including improved market access and greater IP protections. In select cases where access to medicines was mentioned by members of the pharmaceutical industry, it was used as a rationale to promote trade provisions that were also presented as commercially beneficial. In contrast, non-industry stakeholder groups were primarily interested in promoting access to medicines as an end in itself, framed in the context of personal health outcomes, the integrity of the health system as a whole, and/or the affordability of medicines.Of the comments submitted by industry stakeholders that discussed provisions within the USMCA related to transparency, most focused on reducing the costs associated with market uncertainty by advocating for improved predictability in pharmaceutical regulation, IP, pricing, and reimbursement in Canada and Mexico. An emphasis on promoting Canadian and Mexican harmonization with the existing US system of IP law and pharmaceutical regulatory affairs suggests a perception by US industry members that legal and regulatory differences between these countries serve as a significant cross-border market barrier. Equally, the industry comments that advocated for increasing transparency in the development of the biopharmaceutical sector’s rules and regulations indicate an industry interest in asserting greater influence over the pharmaceutical regulatory system through participation and consultation in the rule-making process.A preliminary comparison of the analyzed comments and the final text of the USMCA shows that several provisions that were advanced exclusively by the pharmaceutical industry – and opposed by the majority of comments submitted by non-industry stakeholders – were included in the final agreement. These include provisions for patent term restoration mechanisms, 5-year regulatory data protection minimums for new pharmaceutical products, and 10-year regulatory exclusivities for biologics . NotablySupport for stronger intellectual property provisions in trade agreements has been historically presented as a dichotomy, with proponents stemming from the pharmaceutical industry and opponents from civil society public health advocates. Though nearly three decades has passed since the original implementation of Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), the results of this study provide empirical evidence indicating that this dichotomy continues to characterize the trade and health landscape.The impact of trade agreements on access to medicines remains a pressing area of global health policy. Incorporating mechanisms that advance transparency and accountability in the negotiation of trade agreements is critical to ensuring that trade policies do not undermine the public good, including improving populations’ access to medicines. The examination of the US public consultation process during the USMCA negotiations, through the lens of pharmaceuticals and access to medicines, reveals mixed outcomes with respect to the level of transparency achieved in the US trade negotiation process. Though input from the public at-large was actively solicited, the extent to which these comments were considered in the content of the final agreement is unclear, particularly given that industry and non-industry stakeholders advocated for largely incompatible pharmaceuticals-related trade policies. Negotiators could increase public transparency when choosing to advance one competing trade objective over another by actively providing the public with clear negotiating position rationales. Without greater clarity on these aspects, the public consultation process risks appearing to serve as a cursory government mechanism, lacking in accountability and undermining public trust in both the trade negotiation process and its outcomes.Additional file 1.


The amount of literature reporting “aging-in-place” studies has increased sharply in recent decades. However, the studies have taken a global view of the range and scope of the research that has taken place. This study presents a bibliometric analysis of the current status of the aging in place research themes published as scientific articles between 1970 and 2021, using the Web of Science database. VOSviewer software was employed to map and visualize the 1331 items of bibliographic data retrieved. The findings reveal a continuous growing trend in the publication of aging in place research. Most productive institutions derive from the USA. The International Journal of Environmental Research and Public Health is the most preferred Journal. The most popular research hotspots or areas include; older adults, aging, housing, dementia, long-term care, and technology, and their associations with the field of “aging in place” field were elucidated. This study offers several valuable insights to scholars, research institutions, and policymakers, enabling a better understanding of the developments in the aging in place research domain. There is evidence of a rapid increase in population aging across the globe ,2. CountThis rapid increase in population aging necessitates a reevaluation of conventional economic, political, and social policies to mitigate the potential problems associated with population aging ,19. It hThus, aging in place has received, and is receiving, great attention from policymakers and scholars, with a surge in quantity and substance in the literature . This suAs aging is a prevalent phenomenon, the question is, how has the development of the research literature on this topic fared over the year? More precisely, the following research questions are addressed: (1) Who are the geographic contributors to aging in place research, and how have contributions evolved over the past years? (2) Which countries and organizations attract the most citation activity and by whom? (3) What form do international collaborations take based on publication co-authorship relationships? (4) How have research fronts changed over time based on the prevalence and co-occurrence of author keywords? (5) What are the related and relevant sources for the publication of aging in place research? Thus, this study aims to provide a systematic overview and identify future aging in place research trends. Because of the vast increase in literature on aging in place, bibliometric methods were employed to provide a quantitative analysis of the output (measured by the number of publications) and impact (measured by the number of citations). Although there are ongoing discussions about the reliability of specific bibliometric indices, the importance of evaluating the productivity of scientific research through the analysis of the quality of the publication and the corresponding citation data cannot be undermined . HoweverThe essence of the literature review study is to map and appraise the body of literature to identify potential research gaps and the frontiers of knowledge . StructuThe Web of Science (Core Collection) was searched to collect bibliographic data used for the bibliometric analysis in this study because the Web of Science core collection contains comprehensive literature databases with high quality and influential articles . LikewisTraditionally, bibliometric analyses have been categorized into two types; whether the analyses yield activity or relationship indicators . ActivitThe 1331 published research articles were analysed, and the results were presented. The “co-authorship” identification is one of the main options provided by the Create Map wizard in VOSviewer. Co-authorship network analysis includes reliable algorithms that can track almost every aspect of scientific collaboration . HosseinA total number of 3901 researchers participated in the 1331 bibliographic documents. However, in VOSviewer, the minimum number of documents for any author was set at five publications for clarity, which produced 40 authors meeting the threshold. This is to avoid the overlapping of many authors with fewer publications in the subsequent analysis of network visualization. The threshold was decided after several iterations, with five documents producing sufficient clarity. Moreover, articles with multiple authors were counted in full rather than proportionately to avoid confusion in their link strength. For each of the 40 authors, the corresponding number of citations and the total strength of their citation links with other authors were calculated as shown in With such knowledge of the contemporary scientific collaboration networks, access to specialities, funds, expertise, and research productivity can be enhanced in this research domain . Such knMany institutions from all over the world publish aging-in-place-related research papers. A network visualization map showing collaboration among those research institutions that have produced a productivity minimum of five documents is shown in Fifty-five countries contributed to the publication of the retrieved documents, but only 30 met the threshold of five publications. The 10 most prolific countries are listed in Occurrences attributed in VOSviewer indicate the number of documents in which a specified keyword occurs . Co-occuVOSviewer technique was used to map the keywords, using author keywords rather than all keywords to achieve a reproducible and readable map ,68. WithThe strongest links are among the following pairs of keywords: aging in place–older adults (link strength = 88); aging in place and aging (link strength = 30); aging in place–housing (link strength = 27); aging in place–dementia (link strength = 21); aging in place–technology (link strength = 18); aging in place–independent living (link strength = 16). Therefore, older adults, aging, housing, dementia, technology, and independent living are the research hotspots on aging in place studies. This reveals multiple issues surrounding aging in place among diverse populations, thus creating various research directions for scholars in this field. Vasunilashorn et al.  put it tOlder people will continue to live in their familiar surroundings for as long as they are able. To increase the age-friendliness of communities, housing activists and older citizens can address individual and community-wide challenges such as loneliness, dementia, long-term care, and disability. The growing population of older persons and their desire to age in place pose considerable healthcare and housing issues . PreviouCo-citation analysis entails tracking pairs of publications that are referenced together in the source articles. The data gathered in the co-citation study were counts of the number of times two journal titles were jointly cited in later works. It is considered that the more two journals are referenced together, the more closely they are related. The co-citation analysis of sources enables the identification of the most cited and highly influential research documents and author journals responsible for aging in place studies. Academic journals play an important role in disseminating research findings . Thus, iSources are referred to as journals in the VOSviewer platform. From the data analysis, it has been found that all the bibliographic references obtained from the Web of Science were included in 473 journals. Of these, only 24 meet the threshold of 10 publications. The minimum threshold was decided after five attempted iterations, with 10 producing a clear network visualization. As shown in This study aimed at presenting a bibliometric analysis of the current status of the aging in place research themes. A global view of the publications produced in the research field of aging in place between 1970 and 2021 is presented in this paper. A total of 1331 original and review articles, published in 473 different peer-reviewed journals by a total of 3901 authors, were identified. The study focused on the Web of Science since it was deemed the most reliable and influential database for bibliometric research. The keywords selected for the bibliometric study was identified by the prominent research themes under aging in place.The concept of aging in place was not common during the 1970s and 1980s, hence, the low number of publications. However, there has been a significant increase in publications from the 1990s upwards, with the most significant number of publications in recent years, in line with Vasunilashorn et al. . The UniThe study can be viewed as the first step towards an objective analysis of the literature existing in the aging in place research field. The study identified housing, dementia, long-term care, and technology as emerging research focuses within the subject area. Noticeable contributions from the authors listed were prominent in underpinning future research focuses in the subject area. As bibliometric analysis is not static, for instance, concepts may gain or lose attention over time as more publications are released, relationships between authors, documents, and countries can be altered, and new research directions may emerge. Therefore, similar studies should be performed in the future to keep tracks of changes in the field. Nonetheless, the data analysed offer useful insights for guiding interested researchers and prioritizing future research efforts in aging in place studies. The analysis offers several insights that may aid aging in place researchers, educational institutions, and policymakers in their perception of the development of the field. Thus, this study has successfully achieved the primary objectives in recognizing the current context and future research trends in improving aging in place subject area.The study further identified the degree of international collaborations and identified that most of the collaborations were carried out with the USA. Very limited collaborations were identified within Asian and Asian-pacific regions with the European regions. However, the study does not underpin the research carried out from developed and developing regions as the regional focus was not the scope of this study. Further research might be beneficial if more collaborations were carried out to identify the research emphasis from regional focus and weigh in the prominence of collaboration between Asian/Asian-pacific and European regions. Future research may also make data sources, such as Scopus, because Web of Science is not all-encompassing, and some critical articles might have been omitted. More so, the findings should be interpreted in line with the definition of aging in place given in this study. It is difficult to relate if all the included papers have anything to do with aging in place—some papers might be using the term as a buzzword in the title/abstract, while the inclusion of some papers published in languages other than the English language could alter the results.


Internet gaming disorder (IGD) has become an important health concern in a significant proportion of adolescents. Intervention studies in this age group are scarce, mostly follow quantitative designs, and rarely consider adolescents’ experiences. This study aimed to evaluate the requirements for a group therapy program for adolescents with IGD. A qualitative interview study was conducted in a German clinic for addictive disorders in childhood and adolescence with nine participants  and two psychotherapists). The semi-structured interviews addressed helpful contents, general conditions, and suggestions for alterations for an effective group intervention. Data were analyzed using content structuring qualitative analysis. Patient interview data resulted in 234 codings with eight main categories. Expert interview data yielded 151 codings with six main categories. The following treatment components were described as effective by the participants and experts: psychoeducation, emotion management, behavior analysis and modification, social skills training, parent participation, and relapse prevention. Additionally, adolescents emphasized the importance of group functionality for coherence, feedback and rewards, content presentation, physical activity and fun. The results are a valuable addition to findings from quantitative studies on IGD interventions and an interesting starting point for further representative studies. In the last two decades, the availability and the use of digital games has increased immensely ,2. EspecIGD in adolescence is often accompanied by dysfunctional emotion regulation strategies , as wellWith regard to the clinical relevance of this new diagnosis, health care professionals call for effective treatment strategies. However, the number of systematically evaluated programs for children and adolescents in clinical settings is still limited.Among all approaches for the treatment of IGD in adolescents, programs based on cognitive behavioral therapy (CBT) are the most common and best investigated ones ,20,21. TSome programs are complemented with other interventions, such as a psychoeducation group for parents ,26 or thGiven the early state of research on this complex and novel disorder, individual experiences of patients and experienced practitioners are of high relevance for the development and the evaluation of treatment programs. To the best of our knowledge, until today only one qualitative study has been published that investigated adolescents’ perspectives on useful components and mechanisms in the treatment of problematic gaming behavior by semi-structured interviews . The samWe are aware of only one study that has addressed clinical professionals’ perspectives on the treatment of adolescents with IGD. Lo et al.  conducteTo date, no qualitative study has been available on treatment needs for adolescents diagnosed with IGD in full or partial inpatient care in a group therapy setting. Moreover, no interview study has been conducted in Europe to examine experiences, specific demands, and needs for IGD interventions in adolescents. The current study aimed to fill these gaps by conducting a qualitative investigation of young IGD patients and clinical experts to contribute to a better understanding of treatment requirements for this new disorder.The IGD group intervention applied in this study was an adaption of a manualized German CBT-based program (Lust for Life instead of Online Escape (ger. Lebenslust statt Onlineflucht)), designed to meet the requirements of the local  inpatient setting including heterogeneous and changing group constellations, a high severity of individual symptoms, comorbidities, and an average therapy duration of 12 weeks.“Program start and motivation of participants”.“Development of a disturbance model”.“Role of own feelings and individual goal setting”.“Development of control behavior and compensation mechanisms”.“Importance and development of relationships”.“Interim review of achievements”.“Relapse prevention and dealing with social pressure”.“Conclusion and farewell”.The original weekly program comprises eight modules of 90 min each for four to eight patients and was developed at the German Center for Addiction Research in Childhood and Adolescence (DZSKJ) at the University Medical Center Hamburg-Eppendorf (UKE) . ProgramA first evaluation study in a quasi-experimental pre-post design with 18 adolescents found a significant reduction of problematic Internet use patterns and reduced average hours of use after program completion .The adaption for the inpatient setting was realized by specialists of the DZSKJ and in cooperation with creators of the original program. This included, e.g., a reduction of the duration of one group therapy session to a maximum of 60 min, group sizes of no more than five patients, a focus on IGD, a simplified and age-appropriate presentation of contents, and a higher number of repetitions of theoretical information. Moreover, patients are asked to keep a diary of their digital media use, non-digital leisure activities, and their mood. The patients were professionally introduced to the IGD group (setting and content) before and in more detail within the first session they attended. The IGD program was integrated in the regular local inpatient and day-clinic  treatment for adolescents with substance-related and behavioral addictions and mental comorbidities. This included individual psychotherapy sessions (once to twice a week), psychopharmacological medication if indicated, weekly cross-disorder group psychotherapies , occupational and sports therapy, adjacent experiential and individual pedagogical offers, clinical school classes, family support by IGD-specific parental therapeutic groups, individual family therapy sessions, and social counselling. The day clinic offers 8 and the ward 13 treatment places and is part of the Department of Child and Adolescent Psychiatry and Psychotherapy at the UKE.N = 9). Thus, the sample size was in line with the recommendations for qualitative studies [The study sample included seven patients and two clinical experts . In line with the gender-dependent IGD prevalence [N = 6) than girls (N = 1). All patients had comorbid mental disorders, with ADHD and affective disorders being the most common ones. Of the seven patients, two had been discharged from the day clinic 14 and 28 months before the interview and were contacted via telephone. The other five patients had been in ongoing treatment for 4.8 weeks  at the time of the interview . For more information on the sample, please refer to The patients’ age at the time of the treatment ranged from 12 to 18 years . The interviewer was a psychologist and not part of the treatment team of the patients. Before the interviews began, the interviewer gave a brief introduction explaining the general conditions of the study. This included the voluntary participation, content and aim of the study, the permission to record the interview for the transcript, and the anonymity of stored data. The interview guidelines were followed chronologically. In-depth questions were added if appropriate.All interviews were carried out in German. Since the interviews took place during the coronavirus SARS-CoV-2 (COVID-19) pandemic, they were held face-to-face in compliance with the hygiene guidelines or by telephone (with four patients). On average, an interview lasted 22 min . The data were analyzed separately for the interviews with patients and experts using qualitative content analysis (QCA) with a category-based method developed by Kuckartz .First, main categories were developed directly from the interview guidelines in the form of deductive category generation. After testing the applicability of the deductively developed categories, the category system was further developed and differentiated directly from the material after inductive category formation . The catThe analysis of the patient interviews resulted in 234 codings, which could be classified into eight main categories. Escape;Neglect;Loss of control.The first main category on the characteristics of problematic gaming behavior contained 27 codings and could be divided into three subcategories from the data material:All patients reported that they use gaming mainly to escape from stress, and/or to cope with negative emotions, and/or problems at school or within the family. Five patients described the neglect of school or family obligations as well as non-digital leisure activities as a negative effect of their gaming patterns. In addition, two patients emphasized regulation of gaming time as particularly difficult.Besides problem behavior, two patients also stated positive and functional effects of gaming. These are summarized in the second main category with four codings. They described the digital gaming world as a safe and comfortable place to try out different roles and to undertake positive, interpersonal experiences that would not be available in real life.The third main category included 54 codings that were classified into three subcategories with minor categories. Patients emphasized the role of the group therapy setting as comparably important to the therapy content.Respectful interaction between group members;Mutual support of group members;Difficulty with unstable group constellation;No difficulty with unstable group constellation;Positive group atmosphere;Stable group constellations;Requirements for a functional group settingWorking on tasks;Presentation of contents.Four patients said that they had difficulty with changing group constellations. They found it more difficult to be open to new group members. Other patients described problems with the composition of the group mixing patients of the day clinic and inpatients. This contrasted with the statements of two patients who had no difficulties with an inconstant group constellation.Four patients stated that getting to know new patients and having fun in the group were important for a confident group atmosphere.Moreover, it became apparent that in a group setting it can be challenging to meet the individual preferences of the patients when it comes to the accomplishment of tasks and the presentation of therapy contents. Five of the seven patients describe themselves as visual learners and would have preferred a thoroughly visual presentation of the content.Problem identification and discussion;Structure of everyday life;Group cohesion.The patients’ statements on effective or helpful factors in treatment could be classified into three subcategories with a total of 15 codings:In the three subcategories, six patients reported that they found it helpful to identify and discuss their individual problems in therapy, to structure their daily lives, to share experiences with other affected people, and to make progress together with the group.Level of knowledge about psychoeducative contents;Psychoeducation;Addressing individual problematic behavior;Fun;Competent group leaders;Helpful group content;Mechanisms of IGD and regaining control over gaming;Conception and mechanisms of games;Interesting group content;Contents without personal reference;Content without gaming reference;Redundant content (with regard to other attended therapy groups);Less helpful group content;Challenging group content.The fifth main category comprised 53 codings and included the patients’ experiences with the contents of the group therapy. These could be classified into five subcategories with a total of eleven further subcategories:All of the seven patients reported that they feel well educated in terms of IGD after having attended the group program. Thus, the psychoeducational content of the applied program seems to satisfactorily provide knowledge about the disorder.However, four patients reported that they already had some IGD-specific knowledge before having started the program. Five patients named different aspects to be helpful in IGD psychoeducation. These included knowledge about causes and triggers of problematic gaming patterns, awareness of negative effects of gaming and learning how to individually deal with IGD. Three patients reported that it had been helpful for them to reflect on their individual problems and to be supported by finding alternatives to gaming. Moreover, having fun in therapy and believing the group leaders to be competent were mentioned as helpful by many patients.Three interviewees named the exchange about mechanisms of IGD as particularly interesting as a tool to regain better control over gaming. Furthermore, understanding professional conception and mechanisms of games to create strong user attachment was reported as particularly fascinating.According to the interviewed adolescents, contents would not be experienced as helpful if they seemed redundant to other therapy groups the patients attended, did not obviously relate to gaming, or could not be connected to the individual situation.The first sessions of the group program were described as especially demanding. Two adolescents reported that they had difficulties in adapting to the requirements of the clinical setting at the beginning of their  inpatient therapy in general.Feedback on individual progress;Motivation through meaningful others;Positive reinforcement;Structuring of group therapy sessions.The sixth main category included four subcategories with a total of 14 codings:The first three subcategories reflected that motivation was most enhanced and sustained by feedback on individual progress, rewards for progress, and through meaningful interactions with others, especially peers. Five patients described how their motivation could be maintained by the structure of the group therapy sessions. Above all, fun and sufficient physical activity in the sessions were claimed to be important motivational factors by several patients.Self-responsibility;Professional support;Diary structure;Motivational aspects for regular filling in of the therapeutic diary;Volume of homework;Optional homework.Statements related to patients’ experiences with homework were categorized into six subcategories with a total of 24 codings in the seventh main category:A diary on daily gaming times has a key role in supporting self-monitoring and reflection in the group program the patients attended. The first subcategory contained statements on three subcategories on factors to increase motivation for regular diary completion. Three patients emphasized self-responsibility for the accomplishment of this recurring task. In addition, three patients argued for a need of support by therapeutic staff. In the third subcategory, two patients mentioned that they would be more motivated to keep the diary if it was easier and more appealing to fill it out.Five of the patients expressed that extensive homework  had been demotivating to them. In contrast, one patient said that optional homework would help him to fight boredom.General conditions;Guidance by the group leader;Content details;Creation of tension.Conduction of group therapy;The statements of the last main category were divided into two subcategories, one without and one with three further subcategories. A total of 43 codings could be assigned to the upper category including the patients’ views on reasonable group therapy modifications:In the first subcategory, three patients suggested additional individual therapy sessions, less content overlap with other therapy groups, and a closed group setting.In the second subcategory, three patients proposed modifications related to consistent enforcement of group rules, well-structured preparation of sessions, and sufficient attention to all group participants. In addition, two patients indicated that they would generally like to work on the content in more detail by completing more tasks. Another patient wished topics to be more closely aligned with the needs of individual patients. To make the group more exciting, patients suggested the inclusion of more creative tasks, self-directed work, games, and discussions.The analysis of the expert interviews resulted in 151 codings that could be classified into six main categories. These are listed together with their subcategories and selected anchor examples in Indication;Individual group ability.The first main category included two subcategories with eight codings on patient requirements for the group therapy:In the first subcategory, the experts emphasize the importance of an appropriate indication for therapy before the start of the group. This includes a thorough diagnosis and the clarification of potential exclusion criteria. The group ability of the patient needs to be checked and a certain degree of motivation must be present. The content and structure of the group therapy should be explained to each patient in advance.Nine codings were made in the second major category of requirements the professional group leader should fulfill. First, the therapist should be experienced and competent enough to respond to the group dynamics and to pay attention to all participants. Second, IGD-specific knowledge was considered mandatory and experience with/knowledge about computer games was considered as helpful.Group structure;Group composition;Task setting;Requirements of a functional group setting;Transparency;Social competence;Feedback and positive reinforcement;Long-term consequences;Therapy motivation;Presentation of contents.The third main category included a total of 58 codings in three subcategories with zero to four sub-subcategories:Both experts said that structure was very important in group therapy. As many patients were lacking structure in daily life, structured therapy was helpful for a good, often first therapy experience. Each therapy session should consist of an opening phase, a main part, and a closing phase. Regarding group size, both experts agreed that a group of eight participants would be optimal. Furthermore, the experts argued that adolescents of different age groups were intentionally included in one group. Thereby older patients could be a role model for younger ones and take responsibility for them. This could lead to contrasting experiences to their everyday lives. However, different age groups would also create difficulties due to different levels of life experiences and maturity. This makes group rules even more important, and balanced age groups are desirable. Moreover, this subcategory contained statements about setting, dealing with different age groups and individual needs. The first expert would give the same tasks to all adolescents and add individual explanations. This is contrasted with the opinion of the second expert. She thinks that different, age-appropriate worksheets could be useful.In the second subcategory, aspects for maintaining and increasing motivation to participate were subsumed in four further subcategories. The experts stated that motivational work started before the group program with the transparent presentation of the group concept, processes, and contents. Furthermore, motivation could be encouraged through social competence, feedback, and individual rewards for behavioral successes. One expert pointed out that an over- or under-challenging process would decrease motivation. Motivation can be increased by discussing long-term negative consequences of problematic gaming together. To illustrate these, pro and con arguments to maintaining the status quo could be collected.The third subcategory summarized experts’ statements regarding the presentation of contents so that they could be integrated into the patients’ everyday lives in the best possible way. Both experts agreed that visualizing the content on a flipchart was sufficient. Moreover, a higher learning effect for the patients was assumed if they wrote down the discussed contents themselves.Psychoeducation;Therapeutic diary;Social competence training;Emotion management;Control mechanisms;Building up alternative activities;Reflection on the group participation and saying goodbye;Important/effective contents;Individual disorder model;Situational control;Challenging content;Scope for structuring the sessions.In the fourth main category, 51 codings could be classified from the data material into three subcategories and nine sub-subcategories:Important and effective contents of the group therapy, as mentioned by the psychotherapists, were listed in the first subcategory and seven sub-subcategories. At the beginning of the group therapy, psychoeducation should take place. Problem awareness could be supported by helping patients to familiarize themselves with the diagnostic criteria of IGD and to consider which criterion applies to them. The vicious circle of IGD should help the participants to reflect on how the disorder emerged and persisted in their individual case. Regarding the most important psychoeducative contents, the experts mentioned the provision of information about long-term negative consequences of IGD and the explanation of gaming mechanisms that promote addiction. In addition, a therapeutic diary should be kept by the patients to encourage reflection on their usage times. The development of social competence was seen as especially important therapy content. According to the second expert, this could be practiced within the group setting. Moreover, patients’ deficits in perceiving and dealing with negative emotions should be addressed. Control mechanisms, especially in dealing with craving, should also be focused on. Furthermore, building up alternative, non-digital activities to gaming were indicated as essential. In the last group therapy session, patients should be guided to reflect on the past therapy weeks to appreciate the progress they had achieved. Prevention strategies for possible relapses were also named as a relevant aspect to be considered within the last group session. Finally, a farewell ritual should complete the group therapy, as many digital games have no end and saying goodbye is a rare topic in patients’ everyday life.In the second subcategory, the experts referred to challenging therapy contents. Accordingly, the patients’ confrontation with personal stress factors and efforts to reduce habituated gaming behavior was described as demanding. Consequently, creating an individual disorder model including potential personal and social difficulties could lead to new psychological stress within the therapy group. Moreover, regaining control over gaming behavior was seen as difficult for the patients.In the third subcategory one psychotherapist described the group content as comprehensive because sessions could be flexibly adapted and arranged with reference to the current group constellation and the clinical picture of IGD.Relevance;Motivation;Therapeutic diaries.The experts’ statements on homework in group therapy could be classified into three subcategories:One expert said that homework is particularly relevant for repetition and consolidation of therapy content.How to maintain and increase motivation for homework among patients was listed in the second subcategory. One expert experienced that her patients did their homework regularly and responsibly if they felt that they identified with the group. In contrast to the first expert, the second expert found homework to be a difficult topic but considered using reminders as helpful. In addition, the motivation for homework could be increased by offering support and rewards.The therapeutic diary was regarded as important in helping patients gain self-control through self-observation. One expert indicated that the diary should include information about the patient’s usage times, digital devices used, sleep times, alternative activities, and mood. It should be completed every day.The last main category included statements about the role of parents in the therapy of their affected children.According to the experts, involving the parents in therapy was difficult in clinical practice due to limited time and conditions. A parental group training on IGD parallel to their children’s group therapy was seen as highly valuable. Regardless of whether parents participate in parent training, they should definitely be present at a joint pre- and post-treatment consultation. In addition, one psychotherapist suggested that it might be helpful to talk to the parents about their child’s progress after half of the group therapy sessions were completed.Overall, a positive effect on the therapy of the adolescents by actively involving their parents in the therapeutic process was emphasized by the experts.The aim of this qualitative interview study was to evaluate components of a group therapy program for adolescents with IGD and to identify requirements for potentially effective treatment approaches in clinical settings. The patients’ perspective was taken into account, as this is usually not the case in published studies of the field but of high information value. Additionally, professionals’ opinions complemented affected adolescents’ views by expert knowledge and profound clinical experiences.According to a meta-analytic review, group therapy in general is an effective tool for children and adolescents, with no difference in effectiveness compared to individual psychotherapy . At the Patients’ characteristics have been discussed repeatedly as a possible factor influencing the effectiveness of group therapy . Among aThe following therapy contents were defined as important and effective by patients and professionals and are supported by published studies on the treatment of IGD: psychoeducation ,26,27,44Besides the specific contents of an intervention program, both patients and experts of this study emphasized the importance of general conditions for a functional group setting. In current treatment studies, specifics for the setting of an IGD intervention program were usually not paid attention to .The patients reported social skills and a sense of community to have an important role in a functional group setting. The latter  was also identified as one out of three effective treatment factors by the patients. This is in line with findings from a review that used a systematic PubMed search to discuss factors for effective group CBT in depressive adolescents . AccordiPatients argued for the importance of a competent therapist leading the group intervention. Competent and well-trained therapists under effective supervision are considered significant in group interventions with addicted adolescents . AccordiInterviewed patients suggested the inclusion of more active elements in the group therapy, such as physical exercises and games to increase activity, excitement, and fun. Furthermore, patients and experts mentioned feedback and rewards for success as desired factors to increase motivation. This reflects elements of classic CBT and might be realized by, e.g., verbal reinforcers and token programs for accomplished tasks including therapeutic homework and conscientious keeping of gaming or mood diaries. Homework was considered to be important for the repetition and consolidation of therapy content by the interviewed experts and previous therapy studies ,50. By kPhysical and psychological safety;Appropriate structure;Supportive relationships;Opportunities for belonging;Positive social norms;Support for efficacy and mattering;Opportunities for skill building.Kaminer  listed sThese factors support major findings of the current study on the structural requirements for group therapy settings in adolescents with IGD and should be implemented regularly.The results of the study cannot be generalized and reflect individual opinions due to the qualitative study design with a small sample. The patient sample was heterogeneous regarding treatment duration and the overall treatment setting (day clinic or inpatient) at the time of the interview. It can be assumed that participants who had been in the treatment for at least eight weeks were more experienced with the program, which might have led to a more elaborate reflection on it. Although inpatients and patients at the day clinic attended the same IGD program and comparable therapies in general, the biggest difference between both groups was the time spent at home during treatment. Consequently, the possibility to transfer therapy contents to the home environment varied significantly. Thus, day-clinic patients had to take more personal responsibility for their gaming behaviors, which might have led to different views on the relevance of program topics. The minimum patient’s age was 12 and the majority of patients were 16 to 17 years old at the time of the treatment. Future studies should include a higher proportion of younger adolescents for a larger emphasis of their needs. As only one female patient was interviewed, the results were dominated by the experiences of male patients. The gender ratio for IGD patients is in line with the literature , but futAccording to Mayring , high leThe data were collected during the COVID-19 pandemic. Thus, mandatory contact restrictions had to be taken into account for the interview setting. Accordingly, a sitting distance of at least 1.5 m was maintained, and mouth-nose protection was worn by the interviewer and the interviewees at all times. Four interviews had to be conducted via telephone. These measurements might have created a personal distance between the interview partners. To preserve the highest possible naturalness of interaction, special care was taken to use encouraging and empathic communication techniques.For reasons of economy and comparability a semi-structured interview guide was chosen. It was developed by clinical and scientific experts on IGD but, considering the novelty of this research field, had not been validated before. It can be assumed that different results would have been obtained by a higher proportion of inductive category-based evaluation of data material if the interview had been less structured and the interviewees had been encouraged to tell their stories more freely by asking more open questions. Further research comparing these different approaches should be encouraged.Moreover, as this is a retrospective study, cognitive biases such as recall errors or memory bias must always be taken into account , especiaFuture studies on adolescent IGD programs are warranted that integrate and further evaluate aspects for effective outcomes based on individual, content- and structure-related aspects.The present qualitative interview study is the first that has addressed patients’ and experts’ views on requirements of an effective IGD group therapy program in a clinical setting. Based on the participants’ responses, the following can be concluded:IGD group therapy can serve as an effective tool to help affected adolescents in an efficient and useful way. On the one hand, relevant therapeutic content can be transmitted to more than one patient at a time, given that limited resources are a common problem. On the other hand, an environment can be built in which peers act as guided feedback providers, role models, and practice partners in dealing with symptoms, trying new functional behavior, and improving social skills. Potentially effective group intervention programs for adolescents with IGD should not only address up-to-date CBT-based therapy content  and parental involvement. They also need to consider patient characteristics  as well as a functional group setting to create a motivating atmosphere in a safe, structured, appreciative, adaptable, and supportive environment.The presented findings need to be viewed with caution, taking into account the small sample size and the non-representative sample structure. Future studies should, therefore, investigate the results in more detail and with larger sample sizes. The experiences of patients and psychotherapists could be of added value for the development and testing of effective IGD group programs in clinical care and research.


We estimate the budget impact of biosimilars in Spain from the perspective of the National Health System (NHS) over the period between 2009 and 2019. Drug acquisition costs considering commercial discounts at public procurement procedures  and uptake data for both originator and biosimilar as actual units consumed by the NHS were the two variables considered. Two scenarios were compared: a scenario where no biosimilars are available and the biosimilar scenario where biosimilars are effectively marketed. All molecules exposed to biosimilar competition during this period were included in the analysis. The robustness of the model was tested by conducting multiple sensitivity analyses. From the payer perspective, it is estimated that the savings produced by the adoption of biosimilars would reach EUR 2306 million over 11 years corresponding to the cumulative savings from all biosimilars. Three molecules  account for 60% of the savings. This study provides the first estimation of the financial impact of biosimilars in Spain, considering both the effect of discounts that manufacturers give to hospitals and the growing market share of biosimilars. We estimate that in our last year of data, 2019, the savings derived from the use of biosimilars relative total pharmaceutical spending in Spain is 3.92%. Although more research is needed, our evidence supports the case that biosimilars represent a great opportunity to the sustainability of the NHS through rationalizing pharmaceutical spending and that the full potential of biosimilar-savings has not been achieved yet, as there is a high variability in biosimilar uptake across autonomous regions.Since the first biosimilar medicine, Omnitrope Drug research and development has led to market access for many important therapeutic innovations, and undoubtedly is one of the multiple factors that influence population aging . Powrie-Trends in pharmaceutical markets have raised some concerns about the sustainability of pharmaceutical expenditure . Thus, tAs in the case of generics with chemical medicines, the loss of exclusivity and the expiry of a patent on innovative biological products, hereinafter referred to as the originator, allows the entry into the market of biosimilar products. The major difference between a generic and a biosimilar is that the natural variability and more complex manufacturing of biological medicines do not allow an exact replication, as is the case with generics. Consequently, biosimilars are subjected to a more comprehensive regulatory pathway to ensure that minor differences do not affect safety or efficacy .As stated by the European Medicines Agency, “a biosimilar is a biological medicine highly similar to another already approved biological medicine” and “biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines” . The EurBiosimilars are lower cost alternatives of originator biologicals and are expected to bring meaningful budgetary savings to health systems. However, the spending on biosimilars is still very low, at around 1.5% of pharmaceutical expenditure in Europe in 2018 . UnfortuIn order to understand the role of commercial discounts in price competition, it is convenient to first look at the regulation of prices for medicines in Spain .After marketing authorization has been granted, the price for a biosimilar medicine is set by the Interministerial Committee on Pricing of Medicines (ICPM). In general, the ex-factory price (EFP) for the first biosimilar of a given molecule is set at around 20–30% less than the originator price . The samEFP, or RP where applicable, is a fixed price in retail pharmacies (to which pharmacy and distributor margins and VAT are added). However, in Spain most originators and their biosimilars are dispensed at hospital pharmacies (11 of the 16 molecules with biosimilars on the Spanish market). In fact, the percentage of pharmaceutical spending on biosimilars within hospital pharmacy spending has grown continuously, from 1% in 2014 to 3% in 2018 . This faThis paper provides a new estimate of the budget impact generated by biosimilars in the National Health System for the years 2009 to 2019. It differs from a previous study in Spain  because According to our results, the budget impact derived from the introduction of biosimilar medicines in the Spanish NHS would reach more than EUR 2306.48 million of cumulative savings in the 11-year period from 2009 to 2019 . SomatroThe results from the analysis of alternative scenarios see a show thFinally, probabilistic sensitivity analysis provides 11-year (2009–2019) cumulative savings with an average of EUR 2310 million (95% IC: EUR 2170–EUR 2461 million) for the NHS. Overall, these results are in line with those obtained for the base case as shown in To our knowledge, ours is the first study that uses a BIA to estimate the retrospective savings in a European health system for the total of biosimilar molecules marketed and taking into account the real net price . The only precedent for Spain is González-Domínguez et al. . They esFew studies have calculated the real retrospective savings derived from the introduction of biosimilars in the European context. Simoens et al.  reviewedSince then, additional BIAs of biosimilar medicines in Europe have been published. They mainly aimed to analyze the budget impact of one molecule  in a time horizon between 3 and 5 years. For instance, in Italy, Rognoni et al.  estimateOf note, most studies cited used ex-factory prices excluding discounts as cost-input. This does not reflect reality, as hospitals usually negotiate individual discounts through public tenders. By contrast, our study uses purchase prices paid by hospitals. We believe this allows for a more accurate estimation of savings due to biosimilar competition in Spain since 2009. At the same time, the large period of time we analyze, from 2009 to 2019, allows us to observe how, in general and per molecule, savings are increasing in time.In any case, our results are broadly consistent with the observed financial impacts from other countries in that biosimilar uptake translates into significant savings and that when longer periods are considered, higher savings are realized, as expected.It is important to note that the estimated savings are affected by the variation and level of both quantities and prices. Consequently, a higher consumption of DDD does not always translate into higher savings, as observed with enoxaparin, chondroitin sulfate and insulin glargine, due to a lower price with respect to complex biosimilar molecules such as antiTNF or monoclonal antibodies. For the same reason, rituximab achieves considerable savings without reaching high consumption values.It is worthwhile to highlight that adalimumab (the first biosimilar launched at the end of 2018) accounts for almost 8% of the 11-year (2009–2019) cumulative savings. This figure corresponds to realized savings of EUR 187 million in scarcely one year. It is not surprising as adalimumab is responsible for the highest drug spending in Spain . This suAn additional finding of this work is that potential savings in Spain due to biosimilars are not yet fully exploited, as the biosimilar uptake is still lower than that in other countries, at least for some active substances. For example, antiTNF biosimilar uptake in Spain was 49% in 2019 vs. Denmark (96%), Germany (61%), Italy (64%) or Norway (74%). The same pattern is observed for biosimilar monoclonal antibodies in oncology. The penetration in Spanish market barely exceeds 35% vs. Denmark (74%), Germany (49%), Italy (52%) or Norway (70%). This lower utilization proves that there is a room for improvement in the Spanish NHS .In any case, it is important to note that different molecules behave differently and not all contribute equally to savings in each country, or in different countries, because of the different price and reimbursement policies, procurement procedures, and other pharmaceutical policies, which vary greatly among European countries.In the case of Spain, a comprehensive report by the Independent Authority for Fiscal Responsibility  confirmeAs in any other study, this retrospective BIA has certain limitations, mainly due to the non-availability of data, specifically among the first three biosimilar classes on the market . Additional sources ,43,44 weRegarding the estimation of commercial discounts, as mentioned, a sample of 143 public procurement tenders (the most recent in each autonomous community) was used. Although the sample was considered to be representative, it does not include all the public procurement procedures in the country for the entire period of analysis. This is because sharing transparent information on purchase prices (tenders) is a very recent trend motivated by the EU directives on public procurement. In addition, we acknowledge that an unequal distribution of tender procedures per region might influence the estimation of actual savings in Spain. The degree of variability in the level of discounts awarded via public tenders for the same molecule within the regions is out of the scope of this research and merits itself further exploration. In addition, to overcome the lack of data on the public tenders prior to 2016, a linear regression was performed with 0% as the lower limit of discount matching the time of biosimilar launch. This would represent the evolution of price discounts derived from competition between an originator and biosimilars over the years.The results of this BIA should be interpreted with these limitations in mind.We perform a retrospective BIA of the introduction of biosimilars from the Spanish Health System perspective covering the period from 2009 to 2019. All the molecules exposed to biosimilar competition in this period were included in the analysis . We adopTo estimate the budget impact, two scenarios are compared. First, the hypothetical scenario in which biosimilar drugs are not available on the market and therefore, an originator’s price would keep constant throughout the period examined. This assumption is based on a review of the price evolution of originators . We found that these originator medicines did not undergo major price changes before biosimilar entry. This could be interpreted to mean that even if other molecules generate competition in the same indication, the originator’s price is rarely modified. Second, the actual scenario with biosimilars available on the market after an originator’s patent expiration is examined. In this scenario, competition leads to a price reduction for originator medicines. The difference in terms of costs between the two scenarios provides the savings generated by the introduction of biosimilars.The two main variables of the analysis are uptake (consumption data) and price for each molecule, both originator and biosimilar. To provide clarity on some specific terminology a glossary table see  with EngWe use two sources of data on the uptake of biosimilars. For the period between 2009 and 2015, we use data provided by all manufacturers, representing the number of units effectively consumed by the NHS  and for the period between 2016 and 2019, we use data provided by the Ministry of Health . In both scenarios (with and without biosimilars) the volumes have been converted to daily doses using the published World Health Organization (WHO) defined daily doses (DDD)  as previFor each molecule, drug acquisition costs (EFP) for the year 2019 have been obtained from BotPlus, the Health Information database of the General Council of the Association of Official Pharmacists that provides harmonized information on medicines . For thehttps://www.acobur.es, accessed on 15 April 2020). This reduced price was weighted by the total volume (in units) of each award (of originator and biosimilars) to obtain the commercial discount for each molecule and year. In the case of somatropin, epoetin, filgrastim and pegfilgrastim, internal BioSim data for years 2018 and 2019 were used and a linear regression was conducted assuming a discount of 0% the year before the marketing of the first biosimilar. No discount is considered for follitropin alfa, insulin glargine, chondroitin sulfate and enoxaparin, as they are mostly dispensed by retail pharmacies, where commercial discounts do not apply. Purchase prices in hospital tenders were used to calculate discounted prices per DDD compared to the EFP for infliximab, etanercept, adalimumab, trastuzumab and rituximab  . The newOne-way sensitivity analysis was performed by changing, one by one, some parameters of the model: the price of some biosimilars prior the application of the RPO, the month of application of the RPO, and the market share of biosimilar epoetin in 2011–2015 (data from ) Table .We also performed a probabilistic sensitivity analysis using the Monte Carlo method with 1000 simulations, simultaneously modifying all parameters from base-case values following a normal distribution, in line with the recommendations of the literature .The increase of health expenditures, and in particular, of pharmaceutical expenditures in Spain highlights the need for effective strategies to contain and rationalize pharmaceutical spending.This is the first study carried out which jointly analyzes the savings for the Spanish NHS in terms of pharmaceutical expenditure derived from both the uptake of biosimilar products and the downward effect on prices resulting from competition .Our results show how the introduction of biosimilar drugs in the Spanish pharmaceutical market has brought competition in the market of biological products, and unquestionable, increasing and significant savings, especially at the hospital level, where the majority prescriptions for the molecules herein analyzed are issued. Thus, biosimilar medicines represent a great opportunity to promote the sustainability of the NHS through rationalization and efficiency in pharmaceutical expenditure. Our study also shows that the full potential of biosimilar savings has not been achieved yet, as there is a high variability in biosimilar uptake across autonomous regions.This is a first approach to the impact of biosimilar medicines on the pharmaceutical market in terms of price competition, uptake and savings. However, a further research might address other issues such as level of competition, variability across molecules and within regions, relationships, if any, between market size and number of competitors or price discounts.In any case, any pharmaceutical policy to be adopted should not only analyze its expected impact in the short-term, but also in the medium- and long-term, to promote healthy competition in the market for biological pharmaceutical products, whether originator or biosimilar. After all, the ultimate goal is the sustainability of the healthcare system with rapid access to innovative products, but also a healthy competition from biosimilars when the patent from the originators expires, resulting in better access for patients to obtain the clinical benefits derived from the treatments.


One of the major problems facing healthcare systems in countries with poor socio-economic conditions is the need to strengthen the system through the training of physicians, nurses and other healthcare operators. Partnering with more affluent countries is the key for hospitals in these areas, but such alliances are often based on limited educational exchanges. We present a retrospective study of our experience in building a collaborative relationship between our cancer institute in Italy and a Medical Center in sub-Saharan Africa (Tanzania). The main purpose is to see the changes in the clinical practice after educational interventions on health personnel in a Tanzanian cancer center. In Africa, the current estimated annual number of new cancer cases is 1,109,209, for a crude incidence rate of 82.7 per 100,000 persons and an age-standardised (world) rate of 132 23, compreh6The poor awareness about cancer in both the general population and healthcare personnel prompted us to create a project that would provide medical and nursing staff with essential information to facilitate the the management of the disease. In view of the fact that few literature data are available on educational programs in oncology in sub-Saharan Africa, we felt that it would be important to report our experience of the impact of our educational program on the staff of hospital based in a low-income country. We performed a retrospective study to verify the changes that occurred in clinical practice following educational interventions in a Tanzanian cancer center.In 2000, a cancer institute and a cancer volunteer association (Associazione Vittorio Tison) based in northeast Italy, working in collaboration with Tanzanian political and health authorities, opened a Pathology Laboratory (considered to be a core element of a cancer care and control programme) and subsequently a Medical Oncology Unit at the Bugando Medical Center (BMC) in Mwanza, the largest referral hospital in the Lake zone of North-West Tanzania 9. The paFrom an educational point of view, the main intervention took the form of a five-year period of training in oncology (2004–2008) in Italy offered to a Tanzanian physician and was completely funded by Associazione Vittorio Tison. Thanks to their economic support, the physician was able to gain valuable, practical experience in the routine activities of the Department of Medical Oncology of our institute (IRST IRCCS), whilst also studying for a Specialization in Medical Oncology at Ferrara University. Thanks to a Memorandum of Understanding established in 2008 between BMC and the Italian partnership, an Oncology Day Hospital and Inpatient Ward were subsequently opened at BMC in Mwanza under the responsibility of the same oncologist.IRST provides drugs, normally paid for by patients, free of charge to BMC. A team of rotating volunteers from IRST, comprising of physicians, pharmacists, nurses, data managers, began to visit BMC. They brought their own expertise to the courses organized on medical oncology, biology, technical aspects and correct preparation of cytotoxic agents, and data management for clinical trials. The visiting teams went to the hospital every 3–4 months, as agreed by Dr. Nestory Masalu, Director of the BMC Oncology Unit. Together, they decided on how to best structure the time spent at the center. The visitors also documented their stay by collecting data and information on the impact of the medical education program.The principal milestones of the education program are reported in Given the level of our clinical healthcare and automated procedures in terms of technical know-how, the impact of our personnel on the quality of medical care at BMC has been substantial. At the beginning of the project, Italian medical volunteers visiting Mwanza were surprised to see that patients tended to choose their beds at random each night and that more than one patient often shared the same bed. This obviously increased the risk of error in drug administration. Moreover, beds were sometimes used as a table for nurses to prepare chemotherapy. Like hospitals in Italy 30 years ago, chemotherapy at BMC was prepared by unskilled personnel who did not have the protection of a laminar flow hood. On one occasion at BMC, a volunteer recalls seeing two nurses, one with her baby on her back, preparing chemotherapy in the Hospital Nursery which, fortunately, was closed at the time  for specific types of cancer, importance of maintaining sterility during the entire process. Other key aspects of drug preparation have also been focused on cleaning and disinfecting of the handling area, the use of protective equipment, and proper hand washing . A further important issue that has not been neglected is the importance of adherence to international guidelines for cancer therapies to ensure treatment standardization.st Century: a Multidisciplinary Approach, 2018  are available. Since 2013, trastuzumab has been the only monoclonal antibody accessible for use as targeted therapy, while immunotherapies are still not available. However, the drugs provided by the government are not always obtainable in a sufficient quantity. Furthermore, their cost is covered by the government because the majority of Tanzanian patients do not have sufficient funds to pay for treatments.The Mwanza Cancer Project has exerted a positive influence on the government’s decisions relating to the reimbursement policy for cancer drugs. The key to this change lies in the creation of a dedicated cancer centre at BMC with diagnosis and treatment services, an infrastructure for drug delivery, oncology-trained personnel, and a system for continuing professional health education. These are prerequisites for ensuring that universal accessibility of medicines may have a significant impact on the disease. The lack of trained personnel is a particularly important barrier to remove in order to expand cancer care services in developing countries. In terms of educational programs and technical support, as a result of the contribution of the Associazione Tison at BMC, Tanzanian operators are now able to teach the acquired processes to local personnel, representing an important step towards achieving that goal.We plan to carry out a follow-up study to determine whether the improvements made in clinical practice, specifically when it comes to patient management and chemotherapy preparation, have positively impacted the survival and quality of life of Tanzanian cancer patients attending BMC, and also whether, and in what way, the training process has continued independently without our support.