1 I Vrancken, “Off-Label Prescription of Medication” (2015) 22 European Journal of Health Law 165; MA Rodwin, “Rooting Out Institutional Corruption to Manage Inappropriate Off-Label Drug Use” (2013) 41 Journal of Law, Medicine & Ethics 654.

2 M Weda et al, “Study on Off-Label Use of Medicinal Products in the European Union” (European Commission, 2017) <https://ec.europa.eu/health/sites/health/files/files/documents/2017_02_28_final_study_report_on_off-label_use_.pdf> (last accessed 3 November 2020).

3 ibid.

4 Riou, S et al, “Unlicensed and Off-Label Drug Use: A Prospective Study in French NICU” (2015) 104 Acta Paediatrica, International Journal of Paediatrics e228CrossRefGoogle Scholar.

5 In the EU, a disease is rare if the prevalence is equal to or lower than five in ten thousand persons (Council Recommendation No. 2009/C 151/02). Moreover, Regulation (EC) No. 141/2000 established a set of incentives (eg ten years of market exclusivity) to encourage the research, development and marketing of orphan drugs.

6 V Plate, The Impact of Off-Label, Compassionate and Unlicensed Use on Health Care Laws in Preselected Countries (New York, Columbia University Press 2009).

7 The limitations of clinical trials and the reasons for the exclusion of children and pregnant women encompass multiple factors. They involve cost reduction by increasing the speed of approval for the marketing of the product. For instance, children, pregnant women and the elderly are more vulnerable to adverse effects, and the industry deliberately chooses to narrow the patient population and the therapeutic indications. By doing so, the industry not only makes the process quicker, but also expects a broader range of use of medicinal products. Ultimately, this works as a cost-saving regulatory strategy (Plate, supra, note 6). As a result, the research protocol of clinical trials deliberately excludes significant segments of the population, aiming at specifically supporting an application to market a new drug, and it does not provide information about the drug’s effect on a significant share of potential consumers (Rodwin, supra, note 1). Additionally, research and development has other opportunity costs due to the limited patient pool available for clinical trials involving some orphan or paediatric diseases. Eichler et al (infra, note 59) highlight that “the need for large clinical trials of one product may hinder the enrolment of patients into other trials, thus affecting opportunities to study another product for the same condition, even when financial resources might not be the limiting factor”.

8 G Wyatt and KM Black, “Reimbursing a Drug ‘Off-Label’: It’s What You Don’t Know …” (Policy Options, 2011) 69 <https://policyoptions.irpp.org/magazines/from-climate-change-to-clean-energy/reimbursing-a-drug-off-label-its-what-you-dont-know/> (last accessed 11 August 2020).

9 LS Hauck, “Off-Label Marketing and Its Dangerous Side Effects: How Pharmaceutical Companies Sell Drugs for Unauthorized Purposes” (Corporate Crime Stories, 2019) <http://heigos.hypotheses.org/11024> (last accessed 18 February 2020).

10 R Abbott and I Ayres, “Evidence and Extrapolation: Mechanisms for Regulating Off-Label Uses of Drugs and Devices” (2014) 64 Duke Law Journal 377.

11 Another example of a drug whose revenue consisted of a great extent of off-label use was Neurontin®. There was a time when Pfizer had total revenue of $2.27 billion from sales of Neurontin®, of which $2.12 billion (approximately 94%) came from off-label use. See F Khan and J Holloway, “Verify, Then Trust: How to Legalize Off-Label Drug Marketing” (2012) 117 Penn State Law Review 407.

12 S Haughey, “Impact of the Avastin Case on Prescribing Medicines Off-Label” (2019) 30 Prescriber 28.

13 EFPIA, “European Federation of Pharmaceutical Industries and Associations. Promotion of off-Label Use of Medicines by European Healthcare Bodies in Indications Where Authorised Medicines Are Available” (2014) <https://docplayer.net/20816552-Position-paper-promotion-of-off-label-use-of-medicines-by-european-healthcare-bodies-in-indications-where-authorised-medicines-are-available.html> (last accessed 3 November 2020).

14 A Degrassat-Théas et al, “The ‘Temporary Recommendations for Use’: A Dual-Purpose Regulatory Framework for off-Label Drug Use in France” (2015) 119 Health Policy 1399.

15 P von Czettritz and A Meier, “Off-Label Use Reimbursement: A Review of the Status Quo in the Context of the Recent Novartis/AIFA Case” (2019) 3 European Pharmaceutical Law Review 73.

16 W Farnsworth, The Legal Analyst: A Toolkit for Thinking about the Law (Chicago, IL, University of Chicago Press 2007); RA Posner, Economic Analysis of Law (8th edn, New York, Aspen Publishers 2011).

17 D Cavalla, Off-Label Prescribing: Justifying Unapproved Medicine (Hoboken, NJ, Wiley-Blackwell 2015).

18 AMD consists of abnormal angiogenesis at the back of the eye, causing visual distortion and loss.

19 Thepharmaletter, “Novartis/Genentech Deal for Lucentis” (2003) <www.thepharmaletter.com/article/novartis-genentech-deal-for-lucentis> (last accessed 21 April 2020).

20 E Low and F Yusof, “The Controversies Surrounding Bevacizumab and Ranibizumab” (2015) 3 Advances in Research 334.

21 R Boscheck, “Off-Label Drugs vs. the Merits of Centralised Regulatory Control” (2008) 43 Intereconomics 277; D Cohen, “Why Have UK Doctors Been Deterred from Prescribing Avastin?” (2015) 350 British Medical Journal h1654.

22 Weda et al, supra note 2.

23 Haughey, supra, note 12.

24 Cavalla, supra, note 17.

25 T Klimenta and W Sauter, “An Eye for an Eye? Off-Label Use and Misleading Information: Hoffmann-La Roche v ALCM” (2018) 2 European Pharmaceutical Law Review 100.

26 EC, “Italy: The Italian Competition Authority Fines Roche and Novartis for Cartelizing Sales of Two Major Ophthalmic Medicines” (European Commission, 2014) <https://ec.europa.eu/competition/ecn/brief/02_2014/it_roche.pdf> (last accessed 3 November 2020).

27 L Šimas and G Tzifa, “F. Hoffmann-La Roche v AGCM: Misleading Information Fits Into the ‘Object Box’” (2018) 2 European Competition and Regulatory Law Review 138; M Todino and N Colombo, “Case C-179/16 Hoffmann-La Roche: By Object Restrictions Still Bitter Pills to Swallow? A Close Watch on the Pharmaceutical Sector” (2018) 9 Journal of European Competition Law & Practice 376.

28 M Lo Bue, “A Substantial Approach to Competition Law Issues in the Pharmaceutical Sector. The Ruling of the CJEU in Hoffman-La Roche vs. AGCM” (2018) <https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3229738> (last accessed 3 November 2020).

29 M Kane, “Off-Label Drug Use: Pros and Cons” (2009) 19 Albany Law Journal of Science and Technology 577; E Von Hippel, H DeMonaco and JPJ de Jong, “Market Failure in the Diffusion of Clinician Developed Innovations: The Case of off-Label Drug Discoveries” (2017) 44 Science and Public Policy 121; M Ratner and T Gura, “Off-Label or Off-Limits?” (2008) 26 Nature Biotechnology 867; Khan and Holloway, supra, note 11.

30 S Felder and A Olbrich, “Dealing with Excessive Off-Label Drug Use: Liability vs. Patent Prolongation” (Ruhr Economic Papers, No. 114, 2009) <https://papers.ssrn.com/sol3/papers.cfm?abstract_id=1491481> (last accessed 3 November 2020).

31 Boscheck, supra, note 21; DB Klein and A Tabarrok, “Do Off-Label Drug Practices Argue against FDA Efficacy Requirements? A Critical Analysis of Physicians’ Argumentation for Initial Efficacy Requirements” (2008) 67 American Journal of Economics and Sociology 743.

32 RS Stafford, “Off-Label Use of Drugs and Medical Devices: A Review of Policy Implications” (2012) 91 Clinical Pharmacology and Therapeutics 920.

33 R Sila, “Incentivizing Pharmaceutical Testing in an Age of Off-Label Promotion” (2018) 93 New York University Law Review 941.

34 D Holley, “Balancing on the Edge: The Implications and Acceptability of Off-Label Drug Use” (2009) 19 Albany Law Journal of Science & Technology 633; T Lemmens and S Gibson, “Decreasing the Data Deficit: Improving Post-Market Surveillance in Pharmaceutical Regulation” (2014) 59 McGill Law Journal 943.

35 Plate, supra, note 6.

36 Vrancken, supra, note 1.

37 VLC Raposo, “Off-Label Prescription and How It Is (Not) Regulated in China” (2017) 10 Asia Pacific Journal of Health Law & Ethics 1.

38 RA Tabora, “Litigation Aspects of Off-Label Use: Quality of Care, Generally Accepted Medical Practices & Emergence of Cost Containment” (2009) 19(3) Albany Law Journal of Science & Technology 619; D Kwok, “Controlling Excessive Off-Label Medicare Drug Costs through the False Claims Act” (2017) 27 Health Matrix 185.

39 Holley, supra, note 34; Stafford, supra, note 32.

40 AE Todd, “No Need for More Regulation: Payors and Their Role in Balancing the Cost and Safety Considerations of Off-Label Prescriptions” (2011) 37 American Journal of Law and Medicine 422.

41 Plate, supra, note 6.

42 SF Halabi, “Off-Label Marketing’s Audiences: The 21st Century Cures Act and the Relaxation of Standards for Evidence-Based Therapeutic and Cost-Comparative Claims” (2018) 44 American Journal of Law and Medicine 181.

43 Lemmens and Gibson, supra, note 34.

44 Plate, supra, note 6.

45 Stafford, supra, note 32.

46 CJJ Mulder, DP van Asseldonk and NK de Boer, “Drug Rediscovery to Prevent Off-Label Prescription Reduces Health Care Costs: The Case of Tioguanine in The Netherlands” (2014) 23 Journal of Gastrointestinal and Liver Diseases 123.

47 Halabi, supra, note 42.

48 Rodwin, supra, note 1.

49 Stafford, supra, note 32.

50 Rodwin, supra, note 1.

51 R Abbott and I Ayres, “Evidence and Extrapolation: Mechanisms for Regulating Off-Label Uses of Drugs and Devices” (2014) 64 Duke Law Journal 377.

52 Stafford, supra, note 32.

53 Holley, supra, note 34.

54 Lemmens and Gibson, supra, note 34.

55 Plate, supra, note 6.

56 WK Viscusi and RJ Zeckhauser, “Regulating Ambiguous Risks: The Less than Rational Regulation of Pharmaceuticals” (2015) 44 Journal of Legal Studies S387.

57 K Mulryne and M Davar, “Off-Label Use: Current Position in the EU and U.S.” in ICLG – The International Comparative Legal Guide to Pharmaceutical Advertising 2017 (14th edn, London, Global Legal Group Ltd 2017) <https://iclg.com/practice-areas/pharmaceutical-advertising-laws-and-regulations/singapore> (last accessed 11 August 2020).

58 C Wolfgram, “The Case for Banning Off-Label Use” (Washington University Law Review Online Essays, 2018) <https://wustllawreview.org/essays/the-case-for-banning-off-label-use/> (last accessed 15 February 2020).

59 HG Eichler et al, “The Risks of Risk Aversion in Drug Regulation” (2013) 12 Nature Reviews Drug Discovery 907; Rodwin, supra, note 1.

60 P Craig and G de Búrca, EU Law: Texts, Cases and Materials (5th edn, Oxford, Oxford University Press 2011).

61 DZ Paget, N Renshaw and M Droogers, “What Role Can Civil Society Organizations Have in European Health Policy?” (2017) 27 European Journal of Public Health 52.

62 T Walley, MF Mrazek and E Mossialos, Regulating Pharmaceuticals in Europe: Striving for Efficiency, Equity, and Quality (New York, McGraw-Hill Education 2004).

63 HTAs originated from the diffusion of costly medical equipment and concerns regarding resource constraints. Thus, they aim to inform policymakers in their decisions regarding the social, economic, organisational and ethical implications of the development, adoption and use of technologies in health systems and help them to avoid the uptake of those that are of doubtful value for health governance; see World Health Organization, “Health Technology Assessment of Medical Devices” 39 <https://www.who.int/medical_devices/assessment/en/> (last accessed 11 August 2020). The economic dimension may include budget impacts, cost–benefit analyses, cost–utility analyses (measured in quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs)), cost minimisation and cost-effectiveness. Similarly to the Hauté Autorité de Santé (HAS) in France, other formal organisations in many other countries deploy HTAs, such as the Institut Für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) in Germany and the National Institute for Health and Care Excellence (NICE) in the UK.

64 O Löblová et al, “Alternative Access Schemes for Pharmaceuticals in Europe: Towards an Emerging Typology” (2019) 123 Health Policy 630; C Verbaanderd et al, “On-Label or Off-Label? Overcoming Regulatory and Financial Barriers to Bring Repurposed Medicines to Cancer Patients” (2020) 10 Frontiers in Pharmacology 1.

65 See Directive No. 2001/83/EC, Directive No. 2005/28/EC, and Regulation No. 726/2004/EC.

66 Weda et al, supra note 2; M Dooms and J Killick, “Off-Label Use of Medicines: The Need for Good Practice Guidelines” (2017) 29 International Journal of Risk & Safety in Medicine 17.

67 “Article 5(1). A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorized health-care professional and for use by an individual patient under his direct personal responsibility”.

68 “Article 6(1). No medicinal product may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State in accordance with this Directive or an authorization has been granted in accordance with Regulation (EC) No 726/2004 …”.

69 L Busatta, “Farmaci Off-Label Ed Equilibrio Interno Dei Sistemi Sanitari: La Parola Della Corte Di Giustizia” (2019) 38 DPCE Online 3.

70 J Emmerich, N Dumarcet and L Annie, “France’s New Framework for Regulating Off-Label Drug Use” (2012) 367 New England Journal of Medicine 1279.

71 G Bouvenot et al, “Les Prescriptions Médicamenteuses Hors AMM (Autorisation de Mise Sur Le Marché) en France. Une Clarification est Indispensable” (2018) <http://www.academie-medecine.fr/les-prescriptions-medicamenteuses-hors-amm-autorisation-de-mise-sur-le-marche-en-france-une-clarification-est-indispensable/> (last accessed 3 November 2020); Weda et al, supra, note 2.

72 Different exceptional procedures in France work as exemptions from the requirement for a MA. In this context, Article L. 5121-12-1 of the French Public Health Code also alludes to the Autorisations Temporaires d’Utilisation (ATUs), which is the French compassionate-use programme and is beyond the scope of the present paper.

73 F Drogou et al, “Off-Label Drug Prescriptions in French General Practice: A Cross-Sectional Study” (2019) 9 BMJ Open 1; M Auffret et al, “On-the-Ground Application of the ‘Temporary Recommendation for Use’ Regulatory Measure on Off-Label Use of Baclofen for Alcohol Dependence in France: A Regional Survey of Community Pharmacies” (2018) 32 Fundamental and Clinical Pharmacology 234; Cavalla, supra, note 17; C Rémuzat, M Toumi and B Falissard, “New Drug Regulations in France: What Are the Impacts on Market Access? Part 2 – Impacts on Market Access and Impacts for the Pharmaceutical Industry” (2013) 1 Journal of Market Access & Health Policy 20892.

74 Degrassat-Théas et al, supra, note 14.

75 ibid.

76 Weda et al, supra note 2.

77 B Guidi and L Nocco, “The Debate Concerning the Off-Label Prescriptions of Drugs: A Comparison between Italian and U.S. Law” (2011) 1 Opinio Juris in Comparatione 1.

78 P Zuccheri, “La Normativa Vigente in Italia in Tema Di Gestione Del Dolore” (2015) 3 QUADERNI – Italian Journal of Medicine 139.

79 E Jackson, Law and the Regulation of Medicines (Oxford, Hart Publishing 2012).

80 AP Caputi and MR Luppino, “Normative Nazionali Di Riferimento” in Prescrizione off-label: normative e applicazioni (1st edn, Turin, SEEd Edizioni Scientifiche 2011).

81 AIFA, “Home > Accesso Al Farmaco > Accesso Precoce e Uso Off-Label > Legge 648/1996” <https://www.aifa.gov.it/legge-648-96> (last accessed 13 April 2020).

82 Weda et al, supra note 2.

83 von Czettritz and Meier, supra, note 15.

84 C Agnello, “Regulation and Control of Drugs: Between Prescriptive Appropriateness and Limitation of Public Spending towards the Goal of Deregulating the Pharmaceutical Market” (2015) 17 Pharmaceuticals Policy and Law 373.

85 F Ferre et al, “Italy: Health System Review” (2014) <https://apps.who.int/iris/handle/10665/141626> (last accessed 3 November 2020).

86 AIFA, “Provvedimento Della Commissione Unica Del Farmaco – CUF, Del 20 Luglio 2000” <https://www.aifa.gov.it/documents/20142/0/tipo_file861e.pdf/b8a69467-8a64-bbf1-7ef8-9b681631e3f9> (last accessed 13 April 2020).

87 von Czettritz and Meier, supra, note 15.

88 There are peculiarities regarding private health insurers that are beyond the scope of the ongoing research and therefore this paper does not address.

89 C Vannieuwenhuysen et al, “Towards a Better Managed Off-Label Use of Drugs” (2015) <https://kce.fgov.be/sites/default/files/page_documents/KCE_252_Off-labeldrugs_Report.pdf> (last accessed 21 August 2016).

90 H-J Kretschmer, “Aktuelle Rechtsprechung Zum Off-Label-Use” in Im Zweifel auf Privatrezept? Sozial- und haftungsrechtliche Aspekte des Off-Label-Use (Baden-Baden, Nomos Verlagsgesellschaft mbH 2012).

91 S Ettelt, “Access to Treatment and the Constitutional Right to Health in Germany: A Triumph of Hope over Evidence?” (2020) 15 Health Economics, Policy and Law 30.

92 The BverfG delivered the “Nikolaus” decision in a lawsuit filed by an insured person suffering from Duchenne’s muscular dystrophy (DMD), who sought reimbursement for his medical treatment costs. Following a physician’s recommendation, he had received as treatment a combination of thymus peptides, cytoplasm and homeopathic remedies together with high-frequency vibrations (“bioresonance therapy”), for which the public health insurance (GKV) denied any payment, arguing the lack of scientific evidence of any therapeutic efficacy concerning the referred disease; see BverfG, Beschluss des Ersten Senats vom 06. Dezember 2005 – 1 BvR 347/98, Rn. 1-69 <https://www.bundesverfassungsgericht.de/e/rs20051206_1bvr034798.html> (last accessed 11 August 2020).

93 J Wicke, “Der Off-Label-Use – Probleme Bei Der Rechtsanwendung” in Im Zweifel auf Privatrezept? Sozial- und haftungsrechtliche Aspekte des Off-Label-Use (Baden-Baden, Nomos Verlagsgesellschaft mbH 2012).

94 Ettelt, supra, note 91.

95 S Greß and S Heinemann, “Germany: The Increasing Centralization of the Health Care Sector” in T Bossert and G Marchildon (eds), Federalism and Decentralization in Health Care: A Decision Space Approach (Toronto, University of Toronto Press 2018).

96 Weda et al, supra note 2.

97 B Sickmüller and C Lietz, “Der Off-Label-Use Aus Sicht Der Pharmaindustrie”, Im Zweifel auf Privatrezept? Sozial- und haftungsrechtliche Aspekte des Off-Label-Use (Baden-Baden, Nomos Verlagsgesellschaft mbH 2012).

98 T Bro et al, “Off-Label Use of Bevacizumab for Wet Age-Related Macular Degeneration in Europe” (2020) 258 Graefe’s Archive for Clinical and Experimental Ophthalmology 503.

99 RS Pindyck and DL Rubinfeld, Microeconomics (8th edn, London, Pearson 2013).

100 FA Sloan and C-R Hsieh, Health Economics (Cambridge, MA, MIT Press 2012).

101 Pindyck and Rubinfeld, supra, note 99.

102 DN Lakdawalla, “Economics of the Pharmaceutical Industry” (2018) 56 Journal of Economic Literature 397.

103 J Bhattacharya, T Hyde and P Tu, Health Economics (1st edn, London, Palgrave Macmillan 2014).

104 ibid.

105 A type I error means the agency wrongly rejects a safe and effective medicinal product, while a type II error means the opposite.

106 BN Roin, “Solving the Problem of New Uses” (2014) <https://ssrn.com/abstract=2337821> (last accessed 3 November 2020).