{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:42:39Z","timestamp":1789764159638,"version":"4.0.1"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15\u201320 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices.<\/jats:p>","DOI":"10.3389\/fmed.2020.608249","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T06:26:06Z","timestamp":1608704766000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Development and Use of Gene Therapy Orphan Drugs\u2014Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society"],"prefix":"10.3389","volume":"7","author":[{"given":"Sandor","family":"Kerpel-Fronius","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varvara","family":"Baroutsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Carlesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Collia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Franke-Bray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kleist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieko","family":"Kurihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Filipe","family":"Laranjeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotone","family":"Matsuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shehla","family":"Naseem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Schenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honorio","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"B1","unstructured":"Orphanet Website Luxemburg"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0140002","article-title":"Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries","volume":"10","author":"Gammie","year":"2015","journal-title":"PLoS ONE"},{"key":"B3","first-page":"86","article-title":"Orphan drug considerations in health technology assessment in eight European countries","volume":"1","author":"Tordrup","year":"2014","journal-title":"Rare Dis Orphan Drugs"},{"key":"B4","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.tips.2018.03.003","article-title":"Orphan drugs and their impact on pharmaceutical development","volume":"39","author":"Attwood","year":"2018","journal-title":"Trends Pharmacol Sci"},{"key":"B5","unstructured":"Orphan Drug Report2017"},{"key":"B6","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1177\/0018578719867665","article-title":"The orphan drug act: an appropriate approval pathway for treatments of rare diseases?","volume":"54","author":"Gabay","year":"2019","journal-title":"Hosp Pharm"},{"key":"B7","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1093\/shm\/hkx098","article-title":"Orphans in the market: the history of orphan drug policy","volume":"32","author":"Mikami","year":"2019","journal-title":"Soc Hist Med"},{"key":"B8","unstructured":"OllendorfDA\n            ChapmanRH\n            PearsonSD\n          Assessing the Effectiveness and Value of Drugs for Rare Conditions2017"},{"key":"B9","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.jval.2018.01.008","article-title":"Evaluating and valuing drugs for rare conditions: no easy answers","volume":"21","author":"Ollendorf","year":"2018","journal-title":"Value Heal"},{"key":"B10","unstructured":"KwonD\n          How Orphan Drugs Became a Highly Profitable Industry2018"},{"key":"B11","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1016\/j.jval.2015.05.008","article-title":"Rare disease terminology and definitions \u2013 a systematic global review: report of the ISPOR rare disease special interest group","volume":"18","author":"Richter","year":"2015","journal-title":"Value Heal"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-018-0762-1","article-title":"Characteristics of drugs for ultra-rare diseases versus drugs for other rare diseases in HTA submissions made to the CADTH CDR","volume":"13","author":"Richter","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1001\/jama.2019.0290","article-title":"The orphan drug act revisited","volume":"321","author":"Thomas","year":"2019","journal-title":"J Am Med Assoc"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e028634","DOI":"10.1136\/bmjopen-2018-028634","article-title":"Application of orphan drug designation to cancer treatments (2008-2017): a comprehensive and comparative analysis of the USA and EU","volume":"9","author":"Vokinger","year":"2019","journal-title":"BMJ Open"},{"key":"B15","unstructured":"BagleyN\n            ChandraDA\n            GarthwaiteC\n            SternAD\n          It's Time to Reform the Orphan Drug Act"},{"key":"B16","unstructured":"ShannonT\n          Making Orphan Drug Prices Work for Society"},{"key":"B17","doi-asserted-by":"publisher","first-page":"182","DOI":"10.3389\/fmed.2017.00182","article-title":"Regulatory and scientific advancements in gene therapy: state-of-the-art of clinical applications and of the supporting European Regulatory Framework","volume":"4","author":"Carvalho","year":"2017","journal-title":"Front Med"},{"key":"B18","first-page":"105","article-title":"Two decades of clinical gene therapy\u2014success is finally mounting","volume":"9","author":"Herzog","year":"2010","journal-title":"Discov Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMra1706910","article-title":"Gene therapy","volume":"381","author":"High","year":"2019","journal-title":"N Engl J Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1038\/s41587-019-0194-z","volume":"37","author":"Gene","year":"2019","journal-title":"Nat Biotechnol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1002\/ana.24864","article-title":"Emerging therapies and challenges in spinal muscular atrophy","volume":"81","author":"Farrar","year":"2017","journal-title":"Ann Neurol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-017-0671-8","article-title":"Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy\u2014a literature review","volume":"12","author":"Verhaart","year":"2017","journal-title":"Orphanet J Rare Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.18553\/jmcp.2018.24.12-a.s3","article-title":"Gene therapy for spinal muscular atrophy: an emerging treatment option for a devastating disease","volume":"24","author":"Rao","year":"2018","journal-title":"J Manag Care Spec Pharm"},{"key":"B24","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/nbt.1610","article-title":"Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN","volume":"28","author":"Foust","year":"2010","journal-title":"Nat Biotechnol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/scitranslmed.3000830","article-title":"Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy","volume":"2","author":"Valori","year":"2010","journal-title":"Sci Transl Med"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-dose gene-replacement therapy for spinal muscular atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N Engl J Med"},{"key":"B27","unstructured":"SingerM\n          FDAZolgensma, BLA Clinical Review Memorandum2019"},{"key":"B28","unstructured":"ByrnesA\n          FDAZolgensma, Summary Basis for Regulatory Action2019"},{"key":"B29","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1056\/NEJMoa1908490","article-title":"Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for Hemophilia A","volume":"382","author":"Pasi","year":"2020","journal-title":"N Engl J Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/nbt0715-678","article-title":"Gene therapy \u201ccure\u201d for blindness wanes","volume":"33","author":"Azvolinsky","year":"2015","journal-title":"Nat Biotechnol"},{"key":"B31","unstructured":"FDAGuidance for Industry2014"},{"key":"B32","unstructured":"Draft Guidance FDARare Diseases: Common Issues in Drug Development Guidance for Industry2019"},{"key":"B33","unstructured":""},{"key":"B34","unstructured":"2019"},{"key":"B35","unstructured":"EMA2015"},{"key":"B36","unstructured":"European Medicines Agency"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/S0092-8674(00)80367-0","article-title":"The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins","volume":"90","author":"Liu","year":"1997","journal-title":"Cell"},{"key":"B38","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.1016\/S0140-6736(16)31408-8","article-title":"Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study","volume":"388","author":"Finkel","year":"2016","journal-title":"Lancet"},{"key":"B39","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1056\/NEJMoa1710504","article-title":"Nusinersen versus sham control in later-onset spinal muscular atrophy","volume":"378","author":"Finkel","year":"2018","journal-title":"N Engl J Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e2492","DOI":"10.1212\/WNL.0000000000007527","article-title":"Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1\/2 studies","volume":"92","author":"Darras","year":"2019","journal-title":"Neurology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/j.nmd.2019.09.007","article-title":"Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 NURTURE study","volume":"29","author":"De Vivo","year":"2019","journal-title":"Neuromuscul Disord"},{"key":"B42","unstructured":"Spinraza\u00ae and Zolgensma\u00ae for spinal muscular atrophy: effectiveness and value122332434404Inst Clin Econ Rev2019"},{"key":"B43","unstructured":"15ICERICER Issues. Final Report on Spinraza and Zolgensma, Provides Policy Recommendations Related to Pricing and Coverage of Treatments for Spinal Muscular Atrophy\u2014ICER2019"},{"key":"B44","unstructured":"110Novartis newsAveXis Announces Innovative Zolgensma2019"},{"key":"B45","unstructured":"ICER2017"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.18553\/jmcp.2019.25.12.1300","article-title":"The effectiveness and value of treatments for spinal muscular atrophy","volume":"25","author":"Pearson","year":"2019","journal-title":"J Manag Care Spec Pharm"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12962-020-00234-8","article-title":"Cost effectiveness of Nusinersen for patients with infantile-onset spinal muscular atrophy in US","volume":"18","author":"Thokala","year":"2020","journal-title":"Cost Eff Resour Alloc"},{"key":"B48","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1007\/s40273-019-00769-6","article-title":"Cost effectiveness of nusinersen in the treatment of patients with infantile-onset and later-onset spinal muscular atrophy in Sweden","volume":"37","author":"Zuluaga-Sanchez","year":"2019","journal-title":"Pharmacoeconomics"},{"key":"B49","unstructured":"SteinesR\n          PharmaphorumGermany first in EU to get Novartis' SMA gene therapy, costing almost 2m euros"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1001\/jamanetworkopen.2020.3284","article-title":"Assessment of clinical trials supporting US Food and Drug Administration approval of novel therapeutic agents, 1995-2017","volume":"3","author":"Zhang","year":"2020","journal-title":"JAMA Netw Open"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2083","article-title":"Randomised controlled trials versus real world evidence: neither magic nor myth","author":"Eichler","year":"2020","journal-title":"Clin Pharmacol Ther"},{"key":"B52","unstructured":"LoveJ\n          STATWhy Didn't Nonprofits and the NIH Require \u2018Reasonable' Pricing for Zolgensma? That may Happen in France2019"},{"key":"B53","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1111\/j.1468-0009.2011.00636.x","article-title":"An empirical review of major legislation affecting drug development: past experiences, effects, and unintended consequences","volume":"89","author":"Kesselheim","year":"2011","journal-title":"Milbank Q"},{"key":"B54","doi-asserted-by":"publisher","first-page":"4627","DOI":"10.1136\/bmj.l4627","article-title":"Pricing of pharmaceuticals is becoming a major challenge for health system","volume":"368","author":"Morgan","year":"2020","journal-title":"BMJ."},{"key":"B55","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.jval.2017.12.026","article-title":"Societal preferences for funding orphan drugs in the United Kingdom: an application of person trade-off and discrete choice experiment methods","volume":"21","author":"Bourke","year":"2018","journal-title":"Value Heal"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-018-0927-y","article-title":"The European challenges of funding orphan medicinal products","volume":"13","author":"Szegedi","year":"2018","journal-title":"Orphanet J Rare Dis"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.3389\/fphar.2018.01263","article-title":"Reimbursement of orphan drugs in Europe in relation to the type of authorization by the European Medicines Agency and the decision making based on health technology assessment","volume":"9","author":"Malinowski","year":"2018","journal-title":"Front Pharmacol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1186\/1472-6963-10-153","article-title":"Risk sharing arrangements for pharmaceuticals: potential considerations and recommendations for European payers","volume":"10","author":"Adamski","year":"2010","journal-title":"BMC Health Serv Res"},{"key":"B59","doi-asserted-by":"publisher","first-page":"15","DOI":"10.2217\/cer-2017-0068","article-title":"Gene therapy: evidence, value and affordability in the US health care system","volume":"7","author":"Hampson","year":"2018","journal-title":"J Comp Eff Res"},{"key":"B60","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.1016\/j.ymthe.2018.10.017","article-title":"Addressing the value of gene therapy and enhancing patient access to transformative treatments","volume":"26","author":"Salzman","year":"2018","journal-title":"Mol Ther"},{"key":"B61","unstructured":"PestiH\u00edrlap\n          Most Treatments with Zolgensma were Performed in the Bethesda Hospital in Budapest"},{"key":"B62","unstructured":"FreulerR\n            VoigtB\n          The Lottery with Medicines is not Fair Says Tanja Krones2020"},{"key":"B63","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/1472-6939-14-36","article-title":"Benefit sharing: an exploration on the contextual discourse of a changing concept","volume":"14","author":"Dauda","year":"2013","journal-title":"BMC Med Ethics"},{"key":"B64","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1080\/15265161.2010.482629","article-title":"How to do research fairly in an unjust world","volume":"10","author":"Ballantyne","year":"2010","journal-title":"Am J Bioeth"},{"key":"B65","unstructured":"Access to COVID-19tools (ACT) Accelerator"},{"key":"B66","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s41669-017-0044-1","article-title":"Risk-sharing agreements in the EU: a systematic review of major trends","volume":"2","author":"Piatkiewicz","year":"2018","journal-title":"PharmacoEconomics Open"},{"key":"B67","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1377\/hlthaff.2010.1147","article-title":"Risk-sharing arrangements that link payment for drugs to health outcomes are proving hard to implement","volume":"30","author":"Neumann","year":"2011","journal-title":"Health Aff"},{"key":"B68","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.jval.2018.03.004","article-title":"Challenges in research and health technology assessment of rare disease technologies: report of the ISPOR rare disease special interest group","volume":"21","author":"Nestler-Parr","year":"2018","journal-title":"Value Heal"},{"key":"B69","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1017\/S0266462314000671","article-title":"Revealing and acknowledging value judgments in health technology assessment","volume":"30","author":"Hofmann","year":"2014","journal-title":"Int J Technol Assess Health Care"},{"key":"B70","unstructured":"GenevaCIOMS2016"},{"key":"B71","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40900-016-0029-8","article-title":"A patient and public involvement (PPI) toolkit for meaningful and flexible involvement in clinical trials\u2014a work in progress","volume":"2","author":"Bagley","year":"2016","journal-title":"Res Involv Engagem"},{"key":"B72","doi-asserted-by":"publisher","first-page":"k4738","DOI":"10.1136\/bmj.k4738","article-title":"Impact of patient and public involvement on enrolment and retention in clinical trials: systematic review and meta-analysis","volume":"363","author":"Crocker","year":"2018","journal-title":"BMJ."},{"key":"B73","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s40900-019-0145-3","article-title":"Patient involvement in clinical trials: motivation and expectations differ between patients and researchers involved in a trial on urinary tract infections","volume":"5","author":"Schilling","year":"2019","journal-title":"Res Involv Engagem"},{"key":"B74","unstructured":""},{"key":"B75","doi-asserted-by":"publisher","first-page":"793","DOI":"10.18553\/jmcp.2019.18378","article-title":"Value-based pricing for emerging gene therapies: the economic case for a higher cost-effectiveness threshold","volume":"25","author":"Garrison","year":"2019","journal-title":"J Manag Care Spec Pharm"},{"key":"B76","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s10198-019-01147-x","article-title":"Advanced therapy medicinal products: value judgement and ethical evaluation in health technology assessment","volume":"21","author":"Gon\u00e7alves","year":"2020","journal-title":"Eur J Heal Econ"},{"key":"B77","unstructured":""},{"key":"B78","doi-asserted-by":"publisher","first-page":"l6925","DOI":"10.1136\/bmj.l6925","article-title":"Industry funding of patient and health consumer organisations: systematic review with meta-analysis","volume":"368","author":"Fabbri","year":"2020","journal-title":"BMJ"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2020.608249\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T06:26:23Z","timestamp":1608704783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2020.608249\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,23]]},"references-count":78,"alternative-id":["10.3389\/fmed.2020.608249"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2020.608249","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,23]]},"article-number":"608249"}}