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Published online by Cambridge University Press: 02 December 2020
Many governments have implemented a controlled off-label use of medicines as a tool combined with reimbursement decisions, among other policies, to avoid pharmaceutical firms gaming regulatory systems based on the requirement for marketing authorisation. This article aims to compare the drug regulations in selected European Union countries (France, Italy and Germany) in order to identify specific provisions and concrete solutions implemented by them regarding that matter. The employment of an economic analysis of the law as a theoretical framework allows for the identification of the incentives created in the long run by the referred regulations. The scholarly literature identifies a myriad of drawbacks and advantages associated with off-label practices, and a welfare analysis is ambiguous. Off-label practices are a reality; thus, it is advisable to elaborate policy measures in order to address these practices and condition them on some requirements, taking into account that off-label practices imply trade-offs among access to healthcare, protection of public health, competitiveness and innovation in the industry.
The views expressed in this article are the personal views of the author and may not be understood or quoted as being made on behalf of or reflecting the position of the organisation that the author works for.
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).
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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.
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18 AMD consists of abnormal angiogenesis at the back of the eye, causing visual distortion and loss.
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22 Weda et al, supra note 2.
23 Haughey, supra, note 12.
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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.
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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.
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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.
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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.
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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.
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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.
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75 ibid.
76 Weda et al, supra note 2.
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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.
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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.
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96 Weda et al, supra note 2.
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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).
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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).