The Economic Impact of Innovative Therapies for Rare Diseases on Healthcare Providers and the Healthcare System in Germany – The Example of Spinal Muscular Atrophy

The Economic Impact of Innovative Therapies for Rare Diseases on Healthcare Providers and the Healthcare System in Germany – The Example of Spinal Muscular Atrophy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research The Economic Impact of Innovative Therapies for Rare Diseases on Healthcare Providers and the Healthcare System in Germany – The Example of Spinal Muscular Atrophy Heiko Brennenstuhl, Kim Green, Dominic Störzinger, Torsten Hoppe-Tichy, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-93955/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Despite a constant number of prescriptions, the expenditures of the statutory health insurance funds for pharmaceuticals are rising sharply. This is due to high prices for orphan drugs and advanced therapy medicinal products (ATMPs). Despite attempts by policymakers to intervene, such as the 2011 German Pharmaceutical Market Restructuring Act (Arzneimittelmarktneuordnungsgesetz, AMNOG), the use of these therapies poses numerous challenges for the healthcare system, especially insurance companies and healthcare providers. Results: Using data from the University Hospital Heidelberg, we found that the division of pediatric neurology is experiencing a disproportionate increase in drug costs, caused by two drugs for the treatment of spinal muscular atrophy (SMA), Nusinersen and Onasemnogen Abeparvovec. A survey of 41 German SMA treatment centers revealed a lack of human and infrastructural resources to manage therapy and follow-up care, which currently is insufficiently reimbursed. Disease-independent registers that comply with the rules of the European Union for medication surveillance and which are not tied to the pharmaceutical industry are necessary. Conclusion: Innovative forms of therapy require a critical discussion and regulation of application, aftercare and reimbursement as well as (inter)national industry independent registry work. Based on the model of evidence-based dynamic pricing by the Techniker Krankenkasse , we propose a concept which offers an internationally scalable solution to combat these challenges. Neurology ATMP orphan drugs modified dynamic evidence pricing registry work spinal muscular atrophy Figures Figure 1 Figure 2 Figure 3 Background The pharmaceutical market has seen rising expenditure on prescription drugs over the past years although the number of prescriptions has remained constant.(1, 2) This is mainly due to high prices and increased availability of patented drugs, including orphan drugs (OD) and advanced therapy medicinal products (ATMPs), a group which includes gene therapies, somatic cell therapies and tissue engineered products.(3) In 2019, expenses for drugs in the statutory health insurance system in Germany for the first time exceeded € 45 billion, and while OD accounted for only 0.05 % of all prescribed daily doses, they caused 10 % of the total expenditure.(1) The share of orphan drugs in the worldwide total drug market is expected to increase to 18 % by 2024, making it the most dynamic segment of innovation development in the field of pharmaceuticals.(4) First regulations were implemented by the European Union in the 1990s to provide targeted incentives for the development of drugs for rare diseases.(5, 6) The resulting increment in approved orphan drugs has raised the discussion of the mechanisms of research funding, pricing of drugs and means of reimbursement.(2, 6-8) Since then, national legislators are trying to find ways to better regulate drug prices at the national level. In Germany, the postmarket comparative benefit assessment stipulated in the 2011 German Pharmaceutical Market Restructuring Act (Arzneimittelmarktneuordnungsgesetz, or AMNOG) represents the linchpin of the Federal Joint Committee (the German main regulatory institution for legally binding decisions in healthcare) for price negotiations of the statutory health insurance companies with pharmaceutical firms.(9) However, during the first 12 months after approval of the drug, prices are freely chosen by the pharmaceutical manufacturers. Only afterwards price negotiation between the pharmaceutical company and the umbrella association of insurers is possible. Nevertheless, several years after its introduction it can be stated that the AMNOG has improved the ratio of negotiated prices and the clinical benefit of evaluated compounds.(10) The evaluation of an ODs efficacy and safety is proven in the context of the centralized approval for the European Economic Area.(5) However, an evaluation of the therapy’s benefit is missing at the time of approval and a valid statement on the benefit-risk assessment can, therefore, often not be made by the European Medicines Agency (EMA) at this early stage.(11) In this context, Onasemnogene Abeparvovec, a gene therapy product for the treatment of spinal muscular atrophy (SMA), is a very prominent example. Lately it received a conditional approval based on the results of a Phase 1/2A study with only 15 SMA-patients compared to historical control cases and preliminary non-published data of an international phase-3-study with 55 SMA-children.(12, 13) With costs of € 1.945 million per single application, Onasemnogen Abeparvovec is the world's most expensive drug to date. However, the high costs associated with such innovative therapies require standards in research and risk assessment of such orphan drugs that are at least equivalent to those of non-orphan drugs. This process of a sharp increase in medication expenditure was previously observed with the approval of Nusinersen, another drug for the treatment of SMA. Regardless of their therapeutic potential, ODs and ATMPs generate major challenges for national healthcare systems, healthcare providers and insurance companies as many issues regarding their use, associated (organizational and personnel) costs as well as the reimbursement of follow-up care remain to be addressed. In order to provide a solution for the dilemma between rising drug expenditures and the evidence gap regarding the efficacy and safety of innovative therapies, we have developed a model in collaboration with the Techniker Krankenkasse , Germany's largest health insurance company, which attempts to help regulate price-finding as well as the financing of patient registries and follow-up care independently of the disease. Results From 2010 to 2019, inpatient departments of the Heidelberg University Hospital incurred average annual costs of € 45.1 million (SD = ±7.6 million) for drugs and pharmaceutical products. In 2019, the highest costs ever of € 60.5 million were recorded. Figure 1 shows the annual expenditure on drugs in the five departments that generate the largest annual costs for pharmaceuticals at Heidelberg University Hospital. Since 2016, the strongest increase in drug expenditure took place in the Center for Child and Adolescent Medicine with annual progressions of up to 84 percent. In 2019, € 14.46 million were spent on pharmaceuticals in the field of pediatrics. Compared to 2010, this represents an increase in expenditure by a factor of 5.3, essentially generated by the Department of Pediatric Neurology (74 %) (Figure 1). A detailed investigation of the Department of Pediatric Neurology identified in particular two drugs for the treatment of SMA as the main cost drivers: Nusinersen and Onasemnogene Abeparvovec. In 2019, 92 doses of Nusinersen were applied at the Centre for Children and Adolescent Medicine Heidelberg with a total expenditure of € 8.44 million. The average drug cost of a single application was € 91,739.13. In the same year, a first patient was treated with Onasemnogene Abeparvovec, the net drug cost amounted to € 1.945 million.(14) The conditional marketing authorization of Onasemnogene Abeparvovec by the EMA was granted in May 2020. However, already in the first half of 2020, three more patients were treated with Onasemnogene Abeparvovec with total drug expenditures of € 5.835 million plus import VAT, more patients will follow in the course of the year. The incidence of SMA is estimated at 1:7,500 for Germany. It represents the most common genetic cause of infant and childhood mortality.(15, 16) Most patients suffer from subtype 1 (Werdnig-Hoffmann) and are diagnosed in infancy. In our survey 1,097 patients were included. Of these patients, 646 (59 %) were younger than 18 years of age at the time of the survey. Based on our survey, in Germany, 92 patients are expected to qualify for start of treatment with Onasemnogen Abeparvovec during the next 12 months, confronting payors with total drug costs of € 178.94 million (corresponding to € 212.94 million gross). According to the survey results, the number of patients with Nusinersen therapy will decrease from 867 during the last 12 months to 761 in the coming 12 months (Supplementary Table 1). All 41 respondents state that the application of innovative SMA therapies in standard care create new challenges, 28 (68.3%) expect challenges half medical and half non-medical in character. A total of 82.9 % (n = 34) of those responsible for the organization in their centers report an additional workload of more than 5 hours per week. New tasks will primarily arise in the areas of case management, pre- and post-clinical care, and administration of reimbursement or invoicing. The need for additional human resources (even more so than infrastructural or financial resources) is thus perceived as the biggest challenge in the overall process of applying innovative therapies (Figure 2). Those responsible for the SMA treatment centers see the need for standardization of processes. While both, the indication process as well as the pharmacy process were reported to be well regulated, there is a strong need for improvement and more precise standardization of follow-up care, by 39 (95.1 %) respondents. At the time of investigation only 25 (61 %) of the centers reported to have standard operating procedures (SOPs) related to SMA treatment. While reporting an increase of workload, 80.5 % (n = 33) of the respondents do not consider the reimbursement for the healthcare providers of innovative therapies to be appropriate. With regard to follow-up care, 87.8 % (n = 36) even stated that compensation was insufficient, and 95.2 % (n = 39) saw the reason for this in the existing outpatient remuneration systems. When respondents were given the opportunity to prioritize different areas of optimization, the compensation for aftercare was ranked highest. All respondents indicated that structured documentation and analysis of the outcomes of innovative therapies should be carried out in international registries, 94.4% (n = 39) also support that this should be done independently of the pharmaceutical industry. There was also broad consensus concerning financing of clinical trial registers, where 80.5 % (n = 33) of the respondents were in favor of a fund to be administered in trust by the Federal Joint Committee, into which the pharmaceutical company would have to pay an amount based on the price of the drug after approval. Only a small proportion of those surveyed saw responsibility for structured documentation with the insurance companies (12.2 %, n = 5) or with the health-care providers (7.3 %, n = 3). Since international recommendations for the implementation of registry work are missing so far, a modified model of quality management and price-finding based on the dynamic evidence price will be presented in the discussion. Discussion The present analysis using the example of Heidelberg University Hospital reveals a considerable annual increase in drug expenditure over the last few years, which is largely attributable to orphan drugs and ATMPs, predominantly in the field of pediatric and adolescent neurology. An increasing number of gene therapy products, which will soon reach market maturity, are not yet matched by adequate standards of organization and structured pre- and post-treatment pathways for patients and caregivers. In view of rising prices and rapidly increasing application of innovative therapies, the current billing models expose treatment centers to a potential but threatening liquidity problem. In general, the medication is ordered through the hospital's in-house pharmacy. In a first step, the costs for the drug are, therefore, pre-financed by the treatment center. Only after the therapy has been completed the costs of drugs can be claimed against the responsible insurance company. This corresponds to the granting of an interest-free loan to a pharmaceutical company by the public authorities. What initially was manageable for a large academic center with a low number of cases will become more difficult or even impossible in the coming years. Alternative billing models, which allow linear direct billing are being discussed. For Zynteglo ® , a gene therapy drug for the therapy of Beta-Thalassemia, direct billing between pharmaceutical companies and the insurance company in a pay-for-performance model is being considered, but this is a case-by-case arrangement between the insurance company and the manufacturer and cannot be automatically transferred to other preparations and areas of application.(17) Models spanning diseases and medications are therefore urgently needed.(18) The survey of 41 SMA treatment centers revealed that the implementation of innovative forms of therapy lacks personnel resources for case management and administrative processes in particular. Transparent linear direct billing between the payer and the pharmaceutical company would make it possible to allocate processes that are not directly related to the patient to the primarily responsible actors, thus relieving the burden on service providers. Costs for organizational, personnel and infrastructural resources that arise for the service provider through the application of innovative forms of therapy must be refinanced. A fund to be financed by the pharmaceutical companies and administered in trust by the Federal Joint Committee could be used for centers that fulfill quality requirements (e.g., defined by the Federal Joint Committee) for the implementation of innovative therapies. A structured medical treatment pathway developed by the professional associations and the treatment centers on behalf of the Federal Joint Committee at the time of approval (comparable to the recommendations for action for SMA gene therapy published by the treatment centers at the time of approval, see (19)) would be a milestone for quality assurance. The thorough documentation of therapy process would have to be refinanced on the basis of corresponding cost models by the cost units or via the above-mentioned trust fund (Figure 3). (14). Due to the low prevalence of rare diseases, ODs cannot be tested extensively for efficacy and safety in clinical trials.(20) Nevertheless, patients are entitled to comparable standards in research, approval and testing. Registers collecting agreed minimum of data to monitor diagnostic and therapeutic processes in combination with valid patient outcomes are therefore necessary.(21) The European legislator has formulated clear requirements for the marketing of drugs in Regulation (EC) 726/2004; Regulation (EC) 141/2000 provides a similar framework for orphan drugs.(5, 22) The implementation of patient registries of orphan medicinal products available in Europe is an integral part of this regulation. The establishment and operation of such a patient register by scientific consortia of academic centers independent of industry should be aimed at in order to avoid data fragmentation and duplication at national and European levels, to adapt the data model of the Registry to the requirements of a patient-centered disease registry instead of a drug-centered therapy registry and to ensure the interoperability of the registry through compliance with the FAIR principles (F = findable, A = accessible, I = interoperable, R = reusable).(23, 24) For SMA, the SMArtCARE Registry fulfills parts of these requirements.(25) For the future, a cross-entity, modularly expandable registry that complies with European registry standards is reasonable and necessary to avoid a multitude of disease-specific individual registries. We propose a modified model of the dynamic evidence price of the Techniker Krankenkasse , extended by an obligatory, fiduciary and industry independent register for the application centers (Figure 3).(26) In the proposed model, the Federal Joint Committee would delegate the coordination of registry work to specialized treatment centers, usually academic institutions. The documentation obligation of the pharmaceutical manufacturer would be taken care of in such an approach, while the data sovereignty would not remain in industry-dependent registries, but in the hands of the regulatory authorities at the level of the European Union. A royalty payment for the use of data from such registers would be conceivable. The determination of a maximum drug price based on European average prices and methods of health technology assessment is an integral part of the dynamic evidence price model and has the potential to counteract a cost explosion and impeding liquidity problems of health care providers and insurance companies.(26) The dynamic adjustment of the medication costs is based on the evidence created by the registry work regarding the efficacy and safety of the drugs. This will ultimately ensure long-term availability of high-quality patient care with innovative therapies and secure the profitability of health care providers. Conclusions The application example of SMA is suitable as a blueprint for the rapidly increasing number of ATMPs and innovative orphan drugs expected in the coming years. First experiences show that existing structures are not sufficiently prepared for the associated economic challenges. However, health care systems, the insurance payers and the health care providers must be prepared for such (cost-)relevant treatments by creating appropriate structures and regulations. Last but not least, the responsibilities of the pharmaceutical company, especially with regard to high-priced drugs, must be more clearly defined and proper quality assurance guidelines must be formulated within the framework of national and European legislation. The model of the modified dynamic evidence price presented here offers a possibility to address the rising costs of innovative drugs and can serve as a blueprint for the development of national guidelines and laws in other (European) countries. Methods Data sources Total quantities and expenditures for prescriptions and ready-to-use drugs of the University Pharmacy of the Heidelberg University Hospital were analyzed for the time period of 2009 – 2019. Data from the Center for Pediatric and Adolescent Medicine were assigned to individual departments and the main driving forces behind pharmaceutical expenditures were identified. Using a structured questionnaire survey distributed to all German SMA treatment centers, the following dimensions were investigated: 1) workload before and after the introduction of innovative forms of therapies, 2) standardization of procedures, and 3) availability of registries. Questionnaire items were designed as 5 point Likert scales, implemented into the Limesurvey tool as an anonymous survey and then sent via e-mail to the participating centers of the SMArtCARE registry (25) (URL https://www.smartcare.de/ , n = 49) and the list of "Neuromuscular Centers" of the German Society for Muscular Diseases (DGM). A total of 41 questionnaires were completed, covering 1,097 SMA patients (see Supplementary Table 1) corresponding approximately to the SMA prevalence of 1:100,000 expected for Germany.(27) Limitations The National Center for Tumor Diseases (NCT) is located at Heidelberg University Hospital, where patients receive highly specific and individualized oncological therapy. These treatments generate extremely high costs totaling € 36.46 million per year (corresponding to 37.6 % of total expenditure on drugs at the University Hospital Heidelberg). Due to the lack of comparability to other sites, NCT data were excluded from the analysis. The true cost of medicines in Germany is partly subject to individually negotiated discount rates between the health care provider and the health insurance company, which are highly confidential. In our assessment we only consider the costs directly caused by drugs. Costs for the implementation of the therapy, such as personnel costs and costs for the maintenance of the infrastructure could not be considered due to their complexity. Our cost analysis can therefore only provide an approximation of the true costs, but it nevertheless expresses a clearly discernible trend in the application of innovative therapies. Abbreviations AMNOG: Arzneimittelmarktneuordnungsgesetz / German Pharmaceutical Market Restructuring Act, ATMP: Advanced therapy medicinal products, EMA: European Medicines Agency, DGM: German Society for Muscular Diseases, NCT: National Center for Tumor Diseases, OD: Orphan drugs, SMA: Spinal muscular atrophy, SOP: Standard operating procedure, VAT: Value added tax Declarations Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval Not applicable. Consent for publication Not applicable. Competing interests H.B., K.G., D.S., T.H.-T., P.B., U.K., S.K., S.N., G.S., T.S., J.B., G.F.H., I.A. do not declare to have any conflict of interest as defined in the Uniform Requirements for Manuscripts Submitted to Biomedicinal Journals of the ICMJE. A.Z. declares to have received fees for consulting services related to the subject of the publication from the companies Biogen, Avexis, Roche and PTC. A.Z. declares to have received fees from Biogen to a third-party account for conducting clinical trials related to the subject of the publication. A.Z. declares to have received funds from Biogen into a third-party account for a research project it initiated related to the subject of the publication. Funding H.B. receives support by the Physician Scientist Program at Ruprecht Karls University Heidelberg, Faculty of Medicine. Authors' contributions Conceptualization, H.B., A.Z.; methodology, H.B., K.G., D.S., T.H.-T., P.B.; validation, H.B., P.B., K.G., D.S., S.K.; formal analysis, H.B., A.Z.; writing—original draft preparation, H.B.; writing—review and editing, K.G., D.S., T.H.-T., P.B., U.K., S.K., S.N., G.S., T.S., J.B., G.F.H., I.A., A.Z.; visualization, H.B.; supervision, A.Z.; all authors have read and agreed to the published version of the manuscript. Acknowledgements We would like to thank the Management Board of Heidelberg University Hospital and the University Pharmacy of Heidelberg University Hospital for providing the data for analyzing cost dynamics at the Heidelberg University Hospital. We would also like to thank the SMArtCARE Steering Committee, in particular Prof. Dr. Jan Kirschner and Dr. Astrid Pechmann, for their help with the distribution, and all organizational representatives of the neuromuscular centers for answering the questionnaire. 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Drug-Future-Report: Techniker Krankenkasse; 2019 [Available from: https://www.tk.de/resource/blob/2058676/4b8da4a8174e5000910441dfd3c4b320/drug-future-report-2019-data.pdf . Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis. 2017;12(1). Tables Table 1: Annual costs for drugs (in € million) and the percentage change compared to the previous year for the five most cost-intensive centers at Heidelberg University Hospital. Child and Adolescent Medicine Internal Medicine Surgery Anesthesiology Neurology Year Costs (Mio. €) % Costs (Mio. €) % Costs (Mio. €) % Costs (Mio. €) % Costs (Mio. €) % 2010 2,72 -6,04 19,51 -2,91 6,77 16,89 4,53 3,9 2,24 -15,37 2011 2,79 2,6 15,25 -21,8 5,76 -14,82 4,88 7,6 3,02 34,84 2012 3,48 24,77 16,3 6,9 5,85 1,55 4,57 -6,24 2,86 -5,27 2013 2,97 -14,6 18,49 13,39 4,6 -21,35 4,14 -9,54 3,04 6,25 2014 3,05 2,69 17,82 -3,63 4,33 -5,92 4,33 4,66 3,28 7,83 2015 3,13 2,66 17,94 0,72 4,15 -4,12 5,11 17,99 4,08 24,5 2016 3,64 16,36 20,35 13,41 4,23 1,92 4,35 -14,84 3,74 -8,32 2017 6,73 84,94 23,61 15,99 3,96 -6,54 3,46 -20,54 3,48 -7,08 2018 11,04 63,96 23,18 -1,79 4,27 7,9 3,42 -0,98 8,85 154,51 2019 14,46 31,01 23,14 -0,17 4,52 5,83 4,44 29,59 7,76 -12,35 Supplementary Files OJRD20201009SupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-93955","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":3605715,"identity":"f3c356eb-0f80-4f28-9c8c-e52b32589d3a","order_by":0,"name":"Heiko Brennenstuhl","email":"","orcid":"https://orcid.org/0000-0002-6909-0003","institution":"University Hospital Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Heiko","middleName":"","lastName":"Brennenstuhl","suffix":""},{"id":3605716,"identity":"383e129e-1c45-48ed-9b62-583e75986ffe","order_by":1,"name":"Kim Green","email":"","orcid":"","institution":"University Hospital Heidelberg Pharmacy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kim","middleName":"","lastName":"Green","suffix":""},{"id":3605717,"identity":"85511a22-a979-46e7-bf47-9ee5fe75bfe9","order_by":2,"name":"Dominic Störzinger","email":"","orcid":"","institution":"University Hospital Heidelberg Pharmacy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dominic","middleName":"","lastName":"Störzinger","suffix":""},{"id":3605718,"identity":"c12ee9dd-b334-470e-a1c0-ca322911d3c3","order_by":3,"name":"Torsten Hoppe-Tichy","email":"","orcid":"","institution":"University Hospital Heidelberg Pharmacy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Torsten","middleName":"","lastName":"Hoppe-Tichy","suffix":""},{"id":3605719,"identity":"d1b96d37-f500-4720-941e-68dc96d4f382","order_by":4,"name":"Peter Burgard","email":"","orcid":"","institution":"University Hospital Heidelberg Center of Paediatric and Adolescent Medicine: Universitatsklinikum Heidelberg Zentrum fur Kinder und Jugendmedizin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Burgard","suffix":""},{"id":3605720,"identity":"df0a454b-44ba-45a5-b468-66f4b5458936","order_by":5,"name":"Ulrike Klein","email":"","orcid":"","institution":"University Hospital Heidelberg: UniversitatsKlinikum Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ulrike","middleName":"","lastName":"Klein","suffix":""},{"id":3605721,"identity":"14b13ca3-bc39-4677-91f7-a08e3410ac41","order_by":6,"name":"Stefan Kölker","email":"","orcid":"","institution":"University Hospital Heidelberg Center of Paediatric and Adolescent Medicine: Universitatsklinikum Heidelberg Zentrum fur Kinder und Jugendmedizin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stefan","middleName":"","lastName":"Kölker","suffix":""},{"id":3605722,"identity":"26010a4d-f8c2-4493-979f-06b95e5e10fd","order_by":7,"name":"Sandra Neitemeier","email":"","orcid":"","institution":"Techniker Krankenkasse","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sandra","middleName":"","lastName":"Neitemeier","suffix":""},{"id":3605723,"identity":"0443e8c6-ee3a-4fce-908f-d034cd9dbd4d","order_by":8,"name":"Goentje-Gesine Schoch","email":"","orcid":"","institution":"Techniker Krankenkasse","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Goentje-Gesine","middleName":"","lastName":"Schoch","suffix":""},{"id":3605724,"identity":"b8f9425f-072f-421a-90bb-0bb3c80e68a0","order_by":9,"name":"Tim Steimle","email":"","orcid":"","institution":"Techniker Krankenkasse","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tim","middleName":"","lastName":"Steimle","suffix":""},{"id":3605725,"identity":"5b599a9f-ccec-463e-a302-38431d88aa74","order_by":10,"name":"Jens Baas","email":"","orcid":"","institution":"Techniker Krankenkasse","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jens","middleName":"","lastName":"Baas","suffix":""},{"id":3605726,"identity":"6dacbd63-0546-4e7a-8936-be3aaefcd5f0","order_by":11,"name":"Georg F. Hoffmann","email":"","orcid":"","institution":"University Hospital Heidelberg Center of Paediatric and Adolescent Medicine: Universitatsklinikum Heidelberg Zentrum fur Kinder und Jugendmedizin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Georg","middleName":"F.","lastName":"Hoffmann","suffix":""},{"id":3605727,"identity":"dac41c45-51bb-49bb-8072-7df780436ae9","order_by":12,"name":"Ingo B. Autenrieth","email":"","orcid":"","institution":"University Hospital Heidelberg: UniversitatsKlinikum Heidelberg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ingo","middleName":"B.","lastName":"Autenrieth","suffix":""},{"id":3605728,"identity":"48280aae-de93-4447-8b9b-5a72d153ee3f","order_by":13,"name":"Andreas Ziegler","email":"data:image/png;base64,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","orcid":"","institution":"Zentrum für Kinder- und Jugendmedizin Heidelberg, Sektion Neuropädiatrie und Stoffwechselmedizin, Universitätsklinikum Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Ziegler","suffix":""}],"badges":[],"createdAt":"2020-10-16 20:19:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-93955/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-93955/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":3118629,"identity":"47f79537-c41e-4365-bccb-f229b341b6d2","added_by":"auto","created_at":"2020-10-21 21:49:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":242812,"visible":true,"origin":"","legend":"Total drug costs at the Center for Child and Adolescent Medicine Heidelberg from 2009 – 2019.\nA) Drug costs (bars) and order quantities (dots and lines) at the Center for Child and Adolescent Medicine Heidelberg. B) Distribution of drug costs across the departments of the Center for Child and Adolescent in 2019.\n","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-93955/v1/a1e05cc6d43faf3f363b8f0a.jpg"},{"id":3118630,"identity":"64f5cd01-f23f-4432-b74e-c5680243db6c","added_by":"auto","created_at":"2020-10-21 21:49:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":480677,"visible":true,"origin":"","legend":"Newly emerged tasks and challenges in the application of innovative forms of therapy.\nAbbreviations: IOT = Innovative Orphan (or ATMP) - Therapeutics, SOP = Standard Operating Procedure Development of total drug costs at the Center for Child and Adolescent Medicine Heidelberg in the years 2009 – 2019.\n","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-93955/v1/6008459904deb7125c362c06.jpg"},{"id":3118631,"identity":"76d9d806-5ded-49b7-a539-785d1044194d","added_by":"auto","created_at":"2020-10-21 21:49:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":218135,"visible":true,"origin":"","legend":"Modified dynamic evidence price.\nAbbreviations: AMNOG = German Drug Market Restructuring Act, EMA = European Medicines Agency, G-BA = Joint Federal Committee, PC = pharmaceutical company.\n","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-93955/v1/e8c93a1a80055cc27411220c.jpg"},{"id":13604751,"identity":"021eabae-d884-4f29-a068-35893e3033fd","added_by":"auto","created_at":"2021-09-17 06:01:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":617091,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-93955/v1/b21b9cfd-851d-4a1d-ad9e-4bf7cce87a81.pdf"},{"id":3118632,"identity":"d9e35513-8e4b-429e-835f-b700438c6d43","added_by":"auto","created_at":"2020-10-21 21:49:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17731,"visible":true,"origin":"","legend":"","description":"","filename":"OJRD20201009SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-93955/v1/8cca31886a0e813e994a5dfb.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe Economic Impact of Innovative Therapies for Rare Diseases on Healthcare Providers and the Healthcare System in Germany – The Example of Spinal Muscular Atrophy\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe pharmaceutical market has seen rising expenditure on prescription drugs over the past years although the number of prescriptions has remained constant.(1, 2) This is mainly due to high prices and increased availability of patented drugs, including orphan drugs (OD) and advanced therapy medicinal products (ATMPs), a group which includes gene therapies, somatic cell therapies and tissue engineered products.(3) In 2019, expenses for drugs in the statutory health insurance system in Germany for the first time exceeded \u0026euro; 45 billion, and while OD accounted for only 0.05\u0026nbsp;% of all prescribed daily doses, they caused 10\u0026nbsp;% of the total expenditure.(1) The share of orphan drugs in the worldwide total drug market is expected to increase to 18 % by 2024, making it the most dynamic segment of innovation development in the field of pharmaceuticals.(4)\u003c/p\u003e\n\u003cp\u003eFirst regulations were implemented by the European Union in the 1990s to provide targeted incentives for the development of drugs for rare diseases.(5, 6) The resulting increment in approved orphan drugs has raised the discussion of the mechanisms of research funding, pricing of drugs and means of reimbursement.(2, 6-8) Since then, national legislators are trying to find ways to better regulate drug prices at the national level. In Germany, the postmarket comparative benefit assessment stipulated in the 2011 \u003cem\u003eGerman Pharmaceutical Market Restructuring Act\u003c/em\u003e (Arzneimittelmarktneuordnungsgesetz, or AMNOG) represents the linchpin of the Federal Joint Committee (the German main regulatory institution for legally binding decisions in healthcare) for price negotiations of the statutory health insurance companies with pharmaceutical firms.(9) However, during the first 12 months after approval of the drug, prices are freely chosen by the pharmaceutical manufacturers. Only afterwards price negotiation between the pharmaceutical company and the umbrella association of insurers is possible. Nevertheless, several years after its introduction it can be stated that the AMNOG has improved the ratio of negotiated prices and the clinical benefit of evaluated compounds.(10)\u003c/p\u003e\n\u003cp\u003eThe evaluation of an ODs efficacy and safety is proven in the context of the centralized approval for the European Economic Area.(5) However, an evaluation of the therapy\u0026rsquo;s benefit is missing at the time of approval and a valid statement on the benefit-risk assessment can, therefore, often not be made by the European Medicines Agency (EMA) at this early stage.(11) In this context, Onasemnogene Abeparvovec, a gene therapy product for the treatment of spinal muscular atrophy (SMA), is a very prominent example. Lately it received a conditional approval based on the results of a Phase 1/2A study with only 15 SMA-patients compared to historical control cases and preliminary non-published data of an international phase-3-study with 55 SMA-children.(12, 13) With costs of \u0026euro; 1.945 million per single application, Onasemnogen Abeparvovec is the world's most expensive drug to date. However, the high costs associated with such innovative therapies require standards in research and risk assessment of such orphan drugs that are at least equivalent to those of non-orphan drugs.\u003c/p\u003e\n\u003cp\u003eThis process of a sharp increase in medication expenditure was previously observed with the approval of Nusinersen, another drug for the treatment of SMA. Regardless of their therapeutic potential, ODs and ATMPs generate major challenges for national healthcare systems, healthcare providers and insurance companies as many issues regarding their use, associated (organizational and personnel) costs as well as the reimbursement of follow-up care remain to be addressed.\u003c/p\u003e\n\u003cp\u003eIn order to provide a solution for the dilemma between rising drug expenditures and the evidence gap regarding the efficacy and safety of innovative therapies, we have developed a model in collaboration with the \u003cem\u003eTechniker Krankenkasse\u003c/em\u003e, Germany's largest health insurance company, which attempts to help regulate price-finding as well as the financing of patient registries and follow-up care independently of the disease.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom 2010 to 2019, inpatient departments of the Heidelberg University Hospital incurred average annual costs of \u0026euro; 45.1 million (SD = \u0026plusmn;7.6 million) for drugs and pharmaceutical products. In 2019, the highest costs ever of \u0026euro; 60.5 million were recorded. Figure 1 shows the annual expenditure on drugs in the five departments that generate the largest annual costs for pharmaceuticals at Heidelberg University Hospital.\u003c/p\u003e\n\u003cp\u003eSince 2016, the strongest increase in drug expenditure took place in the Center for Child and Adolescent Medicine with annual progressions of up to 84 percent. In 2019, \u0026euro; 14.46 million were spent on pharmaceuticals in the field of pediatrics. Compared to 2010, this represents an increase in expenditure by a factor of 5.3, essentially generated by the Department of Pediatric Neurology (74 %) (Figure 1).\u003c/p\u003e\n\u003cp\u003eA detailed investigation of the Department of Pediatric Neurology identified in particular two drugs for the treatment of SMA as the main cost drivers: Nusinersen and Onasemnogene Abeparvovec. In 2019, 92 doses of Nusinersen were applied at the Centre for Children and Adolescent Medicine Heidelberg with a total expenditure of \u0026euro; 8.44 million. The average drug cost of a single application was \u0026euro; 91,739.13. In the same year, a first patient was treated with Onasemnogene Abeparvovec, the net drug cost amounted to \u0026euro; 1.945 million.(14) The conditional marketing authorization of Onasemnogene Abeparvovec by the EMA was granted in May 2020. However, already in the first half of 2020, three more patients were treated with Onasemnogene Abeparvovec with total drug expenditures of \u0026euro; 5.835 million plus import VAT, more patients will follow in the course of the year.\u003c/p\u003e\n\u003cp\u003eThe incidence of SMA is estimated at 1:7,500 for Germany. It represents the most common genetic cause of infant and childhood mortality.(15, 16) Most patients suffer from subtype 1 (Werdnig-Hoffmann) and are diagnosed in infancy. In our survey 1,097 patients were included. Of these patients, 646 (59 %) were younger than 18 years of age at the time of the survey. Based on our survey, in Germany, 92 patients are expected to qualify for start of treatment with Onasemnogen Abeparvovec during the next 12 months, confronting payors with total drug costs of \u0026euro; 178.94 million (corresponding to \u0026euro; 212.94 million gross). According to the survey results, the number of patients with Nusinersen therapy will decrease from 867 during the last 12 months to 761 in the coming 12 months (Supplementary Table 1).\u003c/p\u003e\n\u003cp\u003eAll 41 respondents state that the application of innovative SMA therapies in standard care create new challenges, 28 (68.3%) expect challenges half medical and half non-medical in character. A total of 82.9 % (n = 34) of those responsible for the organization in their centers report an additional workload of more than 5 hours per week. New tasks will primarily arise in the areas of case management, pre- and post-clinical care, and administration of reimbursement or invoicing. The need for additional human resources (even more so than infrastructural or financial resources) is thus perceived as the biggest challenge in the overall process of applying innovative therapies (Figure 2).\u003c/p\u003e\n\u003cp\u003eThose responsible for the SMA treatment centers see the need for standardization of processes. While both, the indication process as well as the pharmacy process were reported to be well regulated, there is a strong need for improvement and more precise standardization of follow-up care, by 39 (95.1 %) respondents. At the time of investigation only 25 (61 %) of the centers reported to have standard operating procedures (SOPs) related to SMA treatment. While reporting an increase of workload, 80.5 % (n = 33) of the respondents do not consider the reimbursement for the healthcare providers of innovative therapies to be appropriate. With regard to follow-up care, 87.8 % (n = 36) even stated that compensation was insufficient, and 95.2 % (n = 39) saw the reason for this in the existing outpatient remuneration systems. When respondents were given the opportunity to prioritize different areas of optimization, the compensation for aftercare was ranked highest.\u003c/p\u003e\n\u003cp\u003eAll respondents indicated that structured documentation and analysis of the outcomes of innovative therapies should be carried out in international registries, 94.4% (n = 39) also support that this should be done independently of the pharmaceutical industry. There was also broad consensus concerning financing of clinical trial registers, where 80.5 % (n = 33) of the respondents were in favor of a fund to be administered in trust by the Federal Joint Committee, into which the pharmaceutical company would have to pay an amount based on the price of the drug after approval. Only a small proportion of those surveyed saw responsibility for structured documentation with the insurance companies (12.2 %, n = 5) or with the health-care providers (7.3 %, n = 3). Since international recommendations for the implementation of registry work are missing so far, a modified model of quality management and price-finding based on the \u003cem\u003edynamic evidence price\u003c/em\u003e will be presented in the discussion.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present analysis using the example of Heidelberg University Hospital reveals a considerable annual increase in drug expenditure over the last few years, which is largely attributable to orphan drugs and ATMPs, predominantly in the field of pediatric and adolescent neurology. An increasing number of gene therapy products, which will soon reach market maturity, are not yet matched by adequate standards of organization and structured pre- and post-treatment pathways for patients and caregivers.\u003c/p\u003e\n\u003cp\u003eIn view of rising prices and rapidly increasing application of innovative therapies, the current billing models expose treatment centers to a potential but threatening liquidity problem. In general, the medication is ordered through the hospital's in-house pharmacy. In a first step, the costs for the drug are, therefore, pre-financed by the treatment center. Only after the therapy has been completed the costs of drugs can be claimed against the responsible insurance company. This corresponds to the granting of an interest-free loan to a pharmaceutical company by the public authorities. What initially was manageable for a large academic center with a low number of cases will become more difficult or even impossible in the coming years. Alternative billing models, which allow linear direct billing are being discussed. For Zynteglo\u003csup\u003e\u0026reg;\u003c/sup\u003e, a gene therapy drug for the therapy of Beta-Thalassemia, direct billing between pharmaceutical companies and the insurance company in a pay-for-performance model is being considered, but this is a case-by-case arrangement between the insurance company and the manufacturer and cannot be automatically transferred to other preparations and areas of application.(17) Models spanning diseases and medications are therefore urgently needed.(18) The survey of 41 SMA treatment centers revealed that the implementation of innovative forms of therapy lacks personnel resources for case management and administrative processes in particular. Transparent linear direct billing between the payer and the pharmaceutical company would make it possible to allocate processes that are not directly related to the patient to the primarily responsible actors, thus relieving the burden on service providers.\u003c/p\u003e\n\u003cp\u003eCosts for organizational, personnel and infrastructural resources that arise for the service provider through the application of innovative forms of therapy must be refinanced. A fund to be financed by the pharmaceutical companies and administered in trust by the Federal Joint Committee could be used for centers that fulfill quality requirements (e.g., defined by the Federal Joint Committee) for the implementation of innovative therapies. A structured medical treatment pathway developed by the professional associations and the treatment centers on behalf of the Federal Joint Committee at the time of approval (comparable to the recommendations for action for SMA gene therapy published by the treatment centers at the time of approval, see (19)) would be a milestone for quality assurance. The thorough documentation of therapy process would have to be refinanced on the basis of corresponding cost models by the cost units or via the above-mentioned trust fund (Figure 3). (14).\u003c/p\u003e\n\u003cp\u003eDue to the low prevalence of rare diseases, ODs cannot be tested extensively for efficacy and safety in clinical trials.(20) Nevertheless, patients are entitled to comparable standards in research, approval and testing. Registers collecting agreed minimum of data to monitor diagnostic and therapeutic processes in combination with valid patient outcomes are therefore necessary.(21) The European legislator has formulated clear requirements for the marketing of drugs in Regulation (EC) 726/2004; Regulation (EC) 141/2000 provides a similar framework for orphan drugs.(5, 22) The implementation of patient registries of orphan medicinal products available in Europe is an integral part of this regulation. The establishment and operation of such a patient register by scientific consortia of academic centers independent of industry should be aimed at in order to avoid data fragmentation and duplication at national and European levels, to adapt the data model of the Registry to the requirements of a patient-centered disease registry instead of a drug-centered therapy registry and to ensure the interoperability of the registry through compliance with the FAIR principles (F = findable, A = accessible, I = interoperable, R = reusable).(23, 24) For SMA, the SMArtCARE Registry fulfills parts of these requirements.(25) For the future, a cross-entity, modularly expandable registry that complies with European registry standards is reasonable and necessary to avoid a multitude of disease-specific individual registries. We propose a modified model of the \u003cem\u003edynamic evidence price\u003c/em\u003e of the \u003cem\u003eTechniker Krankenkasse\u003c/em\u003e, extended by an obligatory, fiduciary and industry independent register for the application centers (Figure 3).(26)\u003c/p\u003e\n\u003cp\u003eIn the proposed model, the Federal Joint Committee would delegate the coordination of registry work to specialized treatment centers, usually academic institutions. The documentation obligation of the pharmaceutical manufacturer would be taken care of in such an approach, while the data sovereignty would not remain in industry-dependent registries, but in the hands of the regulatory authorities at the level of the European Union. A royalty payment for the use of data from such registers would be conceivable.\u003c/p\u003e\n\u003cp\u003eThe determination of a maximum drug price based on European average prices and methods of health technology assessment is an integral part of the dynamic evidence price model and has the potential to counteract a cost explosion and impeding liquidity problems of health care providers and insurance companies.(26) The dynamic adjustment of the medication costs is based on the evidence created by the registry work regarding the efficacy and safety of the drugs. This will ultimately ensure long-term availability of high-quality patient care with innovative therapies and secure the profitability of health care providers.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe application example of SMA is suitable as a blueprint for the rapidly increasing number of ATMPs and innovative orphan drugs expected in the coming years. First experiences show that existing structures are not sufficiently prepared for the associated economic challenges. However, health care systems, the insurance payers and the health care providers must be prepared for such (cost-)relevant treatments by creating appropriate structures and regulations. Last but not least, the responsibilities of the pharmaceutical company, especially with regard to high-priced drugs, must be more clearly defined and proper quality assurance guidelines must be formulated within the framework of national and European legislation. The model of the modified dynamic evidence price presented here offers a possibility to address the rising costs of innovative drugs and can serve as a blueprint for the development of national guidelines and laws in other (European) countries.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eData sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal quantities and expenditures for prescriptions and ready-to-use drugs of the University Pharmacy of the Heidelberg University Hospital were analyzed for the time period of 2009 \u0026ndash; 2019. Data from the Center for Pediatric and Adolescent Medicine were assigned to individual departments and the main driving forces behind pharmaceutical expenditures were identified. Using a structured questionnaire survey distributed to all German SMA treatment centers, the following dimensions were investigated: 1) workload before and after the introduction of innovative forms of therapies, 2) standardization of procedures, and 3) availability of registries. Questionnaire items were designed as 5 point Likert scales, implemented into the Limesurvey tool as an anonymous survey and then sent via e-mail to the participating centers of the SMArtCARE registry (25) (URL \u003ca href=\"https://www.smartcare.de/\"\u003ehttps://www.smartcare.de/\u003c/a\u003e, n = 49) and the list of \"Neuromuscular Centers\" of the German Society for Muscular Diseases (DGM). A total of 41 questionnaires were completed, covering 1,097 SMA patients (see Supplementary Table 1) corresponding approximately to the SMA prevalence of 1:100,000 expected for Germany.(27)\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eThe National Center for Tumor Diseases (NCT) is located at Heidelberg University Hospital, where patients receive highly specific and individualized oncological therapy. These treatments generate extremely high costs totaling \u0026euro; 36.46 million per year (corresponding to 37.6\u0026nbsp;% of total expenditure on drugs at the University Hospital Heidelberg). Due to the lack of comparability to other sites, NCT data were excluded from the analysis. The true cost of medicines in Germany is partly subject to individually negotiated discount rates between the health care provider and the health insurance company, which are highly confidential. In our assessment we only consider the costs directly caused by drugs. Costs for the implementation of the therapy, such as personnel costs and costs for the maintenance of the infrastructure could not be considered due to their complexity. Our cost analysis can therefore only provide an approximation of the true costs, but it nevertheless expresses a clearly discernible trend in the application of innovative therapies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAMNOG: Arzneimittelmarktneuordnungsgesetz / German Pharmaceutical Market Restructuring Act, ATMP: Advanced therapy medicinal products, EMA: European Medicines Agency, DGM: German Society for Muscular Diseases, NCT: National Center for Tumor Diseases, OD: Orphan drugs, SMA: Spinal muscular atrophy, SOP: Standard operating procedure, VAT: Value added tax\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.B., K.G., D.S., T.H.-T., P.B., U.K., S.K., S.N., G.S., T.S., J.B., G.F.H., I.A. do not declare to have any conflict of interest as defined in the Uniform Requirements for Manuscripts Submitted to Biomedicinal Journals of the ICMJE. A.Z. declares to have received fees for consulting services related to the subject of the publication from the companies Biogen, Avexis, Roche and PTC. A.Z. declares to have received fees from Biogen to a third-party account for conducting clinical trials related to the subject of the publication. A.Z. declares to have received funds from Biogen into a third-party account for a research project it initiated related to the subject of the publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.B. receives support by the Physician Scientist Program at Ruprecht Karls University Heidelberg, Faculty of Medicine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, H.B., A.Z.; methodology, H.B., K.G., D.S., T.H.-T., P.B.; validation, H.B., P.B., K.G., D.S., S.K.; formal analysis, H.B., A.Z.; writing\u0026mdash;original draft preparation, H.B.; writing\u0026mdash;review and editing, K.G., D.S., T.H.-T., P.B., U.K., S.K., S.N., G.S., T.S., J.B., G.F.H., I.A., A.Z.; visualization, H.B.; supervision, A.Z.; all authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the Management Board of Heidelberg University Hospital and the University Pharmacy of Heidelberg University Hospital for providing the data for analyzing cost dynamics at the Heidelberg University Hospital. We would also like to thank the SMArtCARE Steering Committee, in particular Prof. Dr. Jan Kirschner and Dr. Astrid Pechmann, for their help with the distribution, and all organizational representatives of the neuromuscular centers for answering the questionnaire.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSchwabe U, Paffrath D, Ludwig W, Klauber J. In: Schwabe U, Paffrath D, Ludwig W, Klauber J, editors. Arzneimittelverordnungs-Report 2019. Berlin, Heidelberg: Springer; 2019.\u003c/li\u003e\n\u003cli\u003eHughes-Wilson W, Palma A, Schuurman A, Simoens S. Paying for the Orphan Drug System: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments? Orphanet J Rare Dis. 2012;7:74.\u003c/li\u003e\n\u003cli\u003eEuropean Commission. 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Pharmacoeconomics. 2011;29(9):771-80.\u003c/li\u003e\n\u003cli\u003eBundesministerium f\u0026uuml;r Gesundheit. Arzneimittelmarktneuordnungsgesetz (AMNOG): Bundesministerium f\u0026uuml;r Gesundheit; 2016 [Available from: \u003ca href=\"https://www.bundesgesundheitsministerium.de/service/begriffe-von-a-z/a/arzneimittelmarktneuordnungsgesetz-amnog.html\"\u003ehttps://www.bundesgesundheitsministerium.de/service/begriffe-von-a-z/a/arzneimittelmarktneuordnungsgesetz-amnog.html\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eLauenroth VD, Kesselheim AS, Sarpatwari A, Stern AD. Lessons From The Impact Of Price Regulation On The Pricing Of Anticancer Drugs In Germany. Health Aff (Millwood). 2020;39(7):1185-93.\u003c/li\u003e\n\u003cli\u003eFishman MC. Power of rare diseases: found in translation. Sci Transl Med. 2013;5(201):201ps11.\u003c/li\u003e\n\u003cli\u003eAl-Zaidy SA, Kolb SJ, Lowes L, Alfano LN, Shell R, Church KR, et al. AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort. J Neuromuscul Dis. 2019;6(3):307-17.\u003c/li\u003e\n\u003cli\u003eAveXis. Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1. ClinicalTrials.gov Identifier: NCT02122952. . Bethesda (MD): National Library of Medicine (US): \u003ca href=\"https://ClinicalTrials.gov/show/NCT02122952\"\u003ehttps://ClinicalTrials.gov/show/NCT02122952\u003c/a\u003e; 2019.\u003c/li\u003e\n\u003cli\u003eZiegler A, M\u0026uuml;ller-Felber W, Hahn A, von Moers A, Schara U, Kirschner J. Spinale Muskelatrophie: Gentherapie ohne Zulassung. Dtsch Arztebl. 2019;116(48).\u003c/li\u003e\n\u003cli\u003eVill K, Kolbel H, Schwartz O, Blaschek A, Olgemoller B, Harms E, et al. One Year of Newborn Screening for SMA - Results of a German Pilot Project. J Neuromuscul Dis. 2019;6(4):503-15.\u003c/li\u003e\n\u003cli\u003eKonig K, Pechmann A, Thiele S, Walter MC, Schorling D, Tassoni A, et al. 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[Recommendations for gene therapy of spinal muscular atrophy with onasemnogene abeparvovec-AVXS-101 : Consensus paper of the German representatives of the Society for Pediatric Neurology (GNP) and the German treatment centers with collaboration of the medical scientific advisory board of the German Society for Muscular Diseases (DGM)]. Nervenarzt. 2020;91(6):518-29.\u003c/li\u003e\n\u003cli\u003eJoppi R, Bertele V, Garattini S. Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU. Eur J Clin Pharmacol. 2013;69(4):1009-24.\u003c/li\u003e\n\u003cli\u003eJoppi R, Gerardi C, Bertele V, Garattini S. Letting post-marketing bridge the evidence gap: the case of orphan drugs. BMJ. 2016;353:i2978.\u003c/li\u003e\n\u003cli\u003eEurop\u0026auml;ische Union. Verordnung (EG) Nr. 1394/2007 des europ\u0026auml;ischen Parlaments und Rates vom 13. November 2007 \u0026uuml;ber Arzneimittel f\u0026uuml;r neuartige Therapien und zur \u0026Auml;nderung der Richtlinie 2001/83/EG und der Verordnung (EG) Nr. 726/2004: European Commission; 2007 [updated 10.12.200727.07.2020]. Available from: \u003ca href=\"https://eur-lex.europa.eu/legal-content/de/TXT/?uri=CELEX%3A32007R1394\"\u003ehttps://eur-lex.europa.eu/legal-content/de/TXT/?uri=CELEX%3A32007R1394\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eWilkinson MD, Dumontier M, Aalbersberg IJ, Appleton G, Axton M, Baak A, et al. The FAIR Guiding Principles for scientific data management and stewardship. Sci Data. 2016;3:160018.\u003c/li\u003e\n\u003cli\u003eSummar ML, Endo F, Kolker S. On the Creation, Utility and Sustaining of Rare Diseases Research Networks: Lessons learned from the Urea Cycle Disorders Consortium, the Japanese Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases. Mol Genet Metab. 2014;113(1-2):105-8.\u003c/li\u003e\n\u003cli\u003ePechmann A, Konig K, Bernert G, Schachtrup K, Schara U, Schorling D, et al. SMArtCARE - A platform to collect real-life outcome data of patients with spinal muscular atrophy. Orphanet J Rare Dis. 2019;14(1):18.\u003c/li\u003e\n\u003cli\u003eArndt LK, Chytrek D, Fühner C, Ihly M, Neitemeier S, Schulz T, et al. Drug-Future-Report: Techniker Krankenkasse; 2019 [Available from: \u003ca href=\"https://www.tk.de/resource/blob/2058676/4b8da4a8174e5000910441dfd3c4b320/drug-future-report-2019-data.pdf\"\u003ehttps://www.tk.de/resource/blob/2058676/4b8da4a8174e5000910441dfd3c4b320/drug-future-report-2019-data.pdf\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eVerhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis. 2017;12(1).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Annual costs for drugs (in \u0026euro; million) and the percentage change compared to the previous year for the five most cost-intensive centers at Heidelberg University Hospital.\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003eChild and Adolescent Medicine\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003eInternal Medicine\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"109\"\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"111\"\u003e\n\u003cp\u003e\u003cstrong\u003eAnesthesiology\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"110\"\u003e\n\u003cp\u003e\u003cstrong\u003eNeurology\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e\u003cstrong\u003eCosts (Mio. \u0026euro;)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e\u003cstrong\u003eCosts (Mio. \u0026euro;)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e\u003cstrong\u003eCosts (Mio. \u0026euro;)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"56\"\u003e\n\u003cp\u003e\u003cstrong\u003eCosts (Mio. \u0026euro;)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e\u003cstrong\u003eCosts (Mio. \u0026euro;)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e2010\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e2,72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e-6,04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e19,51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e-2,91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e6,77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e16,89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"56\"\u003e\n\u003cp\u003e4,53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e3,9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e2,24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e-15,37\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e2011\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e2,79\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e2,6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e15,25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e-21,8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e5,76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e-14,82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"56\"\u003e\n\u003cp\u003e4,88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e7,6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e3,02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e34,84\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e2012\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e3,48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e24,77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e16,3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e6,9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e5,85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e1,55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"56\"\u003e\n\u003cp\u003e4,57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e-6,24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e2,86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e-5,27\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e2013\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e2,97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e-14,6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e18,49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e13,39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e4,6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e-21,35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"56\"\u003e\n\u003cp\u003e4,14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e-9,54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e3,04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e6,25\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e2014\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e3,05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e2,69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd 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width=\"55\"\u003e\n\u003cp\u003e-12,35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ATMP, orphan drugs, modified dynamic evidence pricing, registry work, spinal muscular atrophy","lastPublishedDoi":"10.21203/rs.3.rs-93955/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-93955/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Despite a constant number of prescriptions, the expenditures of the statutory health insurance funds for pharmaceuticals are rising sharply. This is due to high prices for orphan drugs and advanced therapy medicinal products (ATMPs). Despite attempts by policymakers to intervene, such as the 2011 \u003cem\u003eGerman Pharmaceutical Market Restructuring Act\u003c/em\u003e (Arzneimittelmarktneuordnungsgesetz, AMNOG), the use of these therapies poses numerous challenges for the healthcare system, especially insurance companies and healthcare providers.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Using data from the University Hospital Heidelberg, we found that the division of pediatric neurology is experiencing a disproportionate increase in drug costs, caused by two drugs for the treatment of spinal muscular atrophy (SMA), Nusinersen and Onasemnogen Abeparvovec. A survey of 41 German SMA treatment centers revealed a lack of human and infrastructural resources to manage therapy and follow-up care, which currently is insufficiently reimbursed. Disease-independent registers that comply with the rules of the European Union for medication surveillance and which are not tied to the pharmaceutical industry are necessary.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Innovative forms of therapy require a critical discussion and regulation of application, aftercare and reimbursement as well as (inter)national industry independent registry work. Based on the model of evidence-based dynamic pricing by the \u003cem\u003eTechniker Krankenkasse\u003c/em\u003e, we propose a concept which offers an internationally scalable solution to combat these challenges.\u003c/p\u003e","manuscriptTitle":"The Economic Impact of Innovative Therapies for Rare Diseases on Healthcare Providers and the Healthcare System in Germany – The Example of Spinal Muscular Atrophy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-21 21:47:52","doi":"10.21203/rs.3.rs-93955/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"15e4728a-fd13-427f-aaf4-02a42bce85df","owner":[],"postedDate":"October 21st, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":844114,"name":"Neurology"}],"tags":[],"updatedAt":"2020-11-15T20:07:40+00:00","versionOfRecord":[],"versionCreatedAt":"2020-10-21 21:47:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-93955","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-93955","identity":"rs-93955","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}