Ph.D. Course Law
Academic Year
2017/2018
Civil Liability and Regulation in
The European Market of
Unauthorized Uses of Medicines
Author
Andrea Parziale
Supervisor
Prof. Giovanni Comandé
3 ABSTRACT
The thesis proposes a mixed institutional response to the uncertainties surrounding, in the EU, unauthorized uses of medicines, i.e., off-label and compassionate uses. It combines a reinterpretation of civil liability rules in light of the precautionary principle, complemented by a proportional liability model, with a no-fault plan, funded by general taxation and the industry. Both are integrated into a mandatory, non-binding ADR scheme.
The thesis develops in three parts.
First, the thesis explores EU pharmaceutical regulation, under which off-label uses are legal but represent a regulatory grey area between medical practice and research, where the levels of protection of patients’ health and legal certainty for health actors are low.
Secondly, the thesis considers the potential contribution of civil liability rules, i.e., courts, to the regulation of off-label uses in the EU, France, and Italy. It highlights that, through an incremental process of trial and error, EU and national courts are adapting civil liability rules and categories (e.g., fault, product defectiveness, and causation) to tackle uncertain pharmaceutical and vaccinal risks, using the language and the methodology of the precautionary principle. When fully and correctly developed, this approach can promote victims' compensation, incentivize correct practices on the part of health actors (i.e., physicians, manufacturers, and regulators), and educate these latter.
Thirdly, the role of a no-fault plan is appraised vis-à-vis those unknown risks that cannot and should not fall under the scope of civil liability. The thesis also considers how the French and the Italian legal systems are using and could use ADR systems to improve access to justice. A well-designed ADR mechanism would let civil liability realize its full potential and avoid distortionary distributive effects. This complex institutional arrangement can thus foster a fair and efficient allocation of uncertain and unknown pharmaceutical risks among the involved stakeholders.
The same analysis is conducted about compassionate use programs.
Conclusions sum up the outcome of the research and argue for its relevance in other regulatory grey areas. They also contend that such a proposal could contribute to reconciling science and democracy, i.e., experts’ accountability from below and rigorous scientific scrutiny over their decisions, thus overcoming the rigid contrast between scientific “populists” and “anti-populists” Western countries are currently experiencing.
5
Abbreviations………....10
Introduction………..13
Chapter I. EU Pharmaceutical Regulation and Unauthorized Uses of Medicines……….18
1. Pharmaceutical Product Safety………18
2. US Pharmaceutical Regulation………19 3. EU Pharmaceutical Regulation………...20 3.1 History………...20 3.2 Authorization Procedures………...21 3.3 Pharmacovigilance………...23 3.3.1 In The EU………23
3.3.2 New EU Pharmacovigilance Legislation (2010-2012)………24
3.3.3 Good Pharmacovigilance Practices (GVP)……….25
4. Unauthorized Yet Lawful Uses of Medicines……….29
4.1 Off-label Uses…….………...30
4.2 Drivers of Off-label Uses ………..31
5. EU Legislation………32
5.1 Pharmacovigilance and Off-label Uses ………34
5.2 Good Pharmacovigilance Practice and Off-label Uses………35
6. National Legislation on Off-label Uses………..36
6.1 Italy………...36
6.2 France………...37
7. Adaptive Licensing……….37
8. Advantages and Risks of Early Access to Non-validated Therapies………..38
9. Off-label Uses Between Experimentation and Clinical Practice………39
9.1 Research vs Practice: A Problematic Divide……….39
9.2 The Belmont Report Between Epistemological Hurdles and Political Compromise……40
9.3 The Declaration of Helsinki………..42
9.4 EU Clinical Trial Legislation………42
10. Clinical Trials on Off-label Uses in The Transition Towards Regulation 536/2014………43
10.1 International Ethics of Human Experimentations: from Nuremberg to Helsinki………43
10.2 Oviedo Convention………..44
10.3 Directive 2001/20………44
10.4 Regulation n. 536/2014 ………..46
10.5 National Implementing Legislation: the Italian Case……….47
11. Observational Studies on Off-label Uses Between Persistent and New Uncertainties………….47
11.1 Non-interventional Studies: A Definition………47
11.2 Directive 2001/20………47
11.3 Implementing Domestic Law………...48
11.4 A Difficult Transition to Regulation 536/2014………48
12. Off-label Prescriptions in Clinical Practice ………..49
12.1 Deontology and Disciplinary Responsibility of Medical Doctors………..49
12.2 (Supra)national Ethics of Off-label Prescriptions………..50
13. The Potential Role of Ethics Committees……….50
14. Potential Civil Liability of Ethics Committees in Clinical Practice……….52
Chapter II. Methodology………..54
1. Some Methodological Notes………...54
2. The Role of Civil Liability in The Grey Areas of Pharmaceutical Regulation………56
6
3.1 Fault-based Civil Liability………..57
3.2 Strict Liability……….58
4. Regulation………...59
4.1 Hetero-regulation ………...59
4.2 Self-regulation………60
5. The Precautionary Principle………61
5.1 Strong Precaution: ‘uncertainty justifies shifting the burden and standard of proof’……….63
5.2 Weak Precaution: ‘uncertainty does not justify inaction’………63
5.3 Moderate Precaution: ‘uncertainty justifies action’………...64
5.4 Criticisms………65
5.5 Precaution and Innovation………..66
5.6 Precaution and Pro-action………..66
5.7 The Precautionary Principle and Civil Liability……….67
6. Safety Regulation and Civil Liability in Regulatory Grey Areas………67
7. A Precautionary Reinterpretation of Civil Liability Rules………..69
8. Civil liability as a Watchdog - and an Educator………..72
9. The Institutional Alternatives and the Legal Systems Considered………..73
Chapter III. Medical Liability………..75
1. How Off-label Uses Originate……….75
2. The Legal Framework of Off-label Prescription……….76
3. The Ethical Framework of Off-label Uses………..77
4. Civil Liability of Prescribing Physicians for Off-label Uses of Drugs………78
4.1 Extracontractucal Liability of Physicians………..79
4.2 Contractual Liability of Physicians……….……83
4.3 Strict Liability of Physicians……….…85
5. Contractual Liability of Healthcare Facilities……….85
6. Civil Liability of Pharmacists………..………...86
Chapter IV. Civil Liability of Producers for Damages Arising from Off-label Uses of Medicines………...88
1. Defective Product Liability……….90
1.1 Product Defectiveness………...92
1.1.1 Manufacturing and Design Defect………..93
1.1.2 Warning/information Defect………...93
1.1.3 Rethinking Pharmaceutical Product Defectiveness: The Role of The EMA PV Guidelines and Cognitive Sciences………97
1.1.4 Proof of Product Defectiveness and Proof of Causation………....98
1.2 Causation………..99
1.2.1 The Sanofi case (2017)………99
1.2.2 Italian Case Law on Vaccine Indemnification………..102
1.2.3 Incoherence with Presumption Law and The Principle of Effectiveness………..104
1.2.4 Inconsistency with The Precautionary Principle………...105
1.2.5 Economic and Insurance Implications………..106
1.2.6 A Different Take on Uncertain Causation……….108
1.2.7 Compatibility with Presumption Law, The Principle of Effectiveness, and The Precautionary Principle………..111
1.2.8 Economic and Insurance Implications: The Case for Compulsory Liability Insurance for Manufacturers………112
1.3 Damages: Making The Case for Proportional Liability……….113
1.4 Development Risk Defense………..115
7
2.1 Article 2050 ICC vs Product Liability Directive………..118
2.2 Impact of AI Innovations on Pharmacovigilance and Civil Liability (and Vice Versa).120 Chapter V. Civil Liability of Regulators………...122
1. EU Member States’ Pharmacovigilance Obligations………122
2. The Role of Civil Liability in Regulating The Regulators……….124
2.1 State Civil Liability Under EU Law……….124
2.2 State Civil Liability Under The Italian and French Law………..126
2.2.1 The Schmitt Case: Implications for Pharmaceutical Regulators’ Civil Liability……...127
2.2.2 The Italian “Infected Blood” Scandal: State Liability for “Generic” Risks and The Precautionary Principle………..130
2.2.3 The “Affaire Du Mediator”: The Relationship Between State and Product Liability in France………132
3. Civil Liability of EU Pharmaceutical Regulators………..135
4. Some Comments………...138
Chapter VI. The Role of No-Fault Plans, Class Actions, and ADR………141
1. Civil Liability and Insurance……….141
2. External Limit and Internal Limitation of The Tort System……….…141
2.1 External Limit: Civil Liability and Unknown Risks……….142
2.1.1 No-Fault Plans: Institutional Functions and Characteristics……….143
2.1.2 Comparative Advantages and Disadvantages of No-Fault Plans Over Civil Liability……….144
2.1.3 History (and Politics) of No-Fault Systems………..145
2.1.4 The Case for A Pharmaceutical No-Fault Plan……….…146
2.2 Internal Limitation: Litigation Costs Drive Aggregate Compensation and Under-Deterrence………147
2.2.1 The Role of Class Actions: Advantages and Disadvantages………....149
2.2.2 Alternative Dispute Resolution (ADR) Systems: Main Features……….150
2.2.3 Advantages and Disadvantages of ADR Systems Over Litigation………...150
2.2.4 The Case for A Mandatory, Non-Binding ADR and Pharmaceutical Disputes and Related Incentives………...151
3. Italian Indemnification Funds: The Vaccine Sector……….…153
3.1 Nudging Claimants’ Preferences for No-Fault and Civil Litigation………156
3.2 The Role of Subrogation……….….157
3.3 The Failed Promises of The Class Action à l’italienne………159
3.4 The Role of ADR Systems: Law n. 24/2017……….…161
4. Aléa Thérapeutique and National Solidarity: The French ONIAM System………...…163
4.1 The Mediator (Benfluorex) and Dépakine (Sodium Valproate) Funds………165
4.2 The Role of Health-Related Class Actions………...167
5. Learning The French Lesson To Avoid Under-Compensation and Under-Deterrence…………..168
6. Cost Transfer Issues and Institutional Constraints……….170
6.1 Administrative Price Controls and Demand Centralization………171
6.2 The Role of Competition Law………..173
7. Summary………...174
Chapter VII. The Role of Civil Liability in Compassionate Use Programs………176
1. The Rationale for Compassionate Uses (or Expanded Access Programs)………176
2. US Expanded Access Programs Regulations………178
3. Compassionate Uses in The EU………179
3.1 EU Legislation of Compassionate Uses ………..179
8
3.2.1 Italy………...181
3.2.2 Temporary Authorizations for Use in France………184
4. Benefits and Risks of Compassionate Uses………..….185
5. Medical Liability………...186
5.1 Medical Ethics of Prescribing Unapproved Medicines………...187
5.2 The Role of Medical Liability………..…192
5.2.1 Extracontractual Fault-Based Civil Liability Of The Treating Physician……….192
5.2.2 Contractual Liability of Healthcare Facilities………...194
6. Civil Liability of Pharmaceutical Manufacturers………..194
6.1 Product Liability and Civil Liability for Dangerous Activities………194
6.2 Civil Liability for Omission……….195
7. The Role of Administrative Law………...197
8. Civil Liability of Regulators………..…198
8.1 In Compassionate Use Programs………198
8.2 Outside Compassionate Use Programs………..…198
9. The Role of No-Fault Plans………...199
Conclusions……….200
1. Main Findings………...200
1.1 Health Actors’ Civil Liability for Damages Arising from Non-Validated Uses of Medicines………..200
1.2 No-Fault, Class Actions, ADR………202
1.3 Compassionate Uses………...203
2. Filling The Gaps of Modern-Day Pharmaceutical Regulation In Europe With A Precautionary Reinterpretation of Civil Liability Rules……….…..203
3. Beyond Unauthorized Uses of Medicines and Unapproved Pharmaceuticals: Tackling Scientific Uncertainty from Medicinal To Borderline Products………205
4. Bridging Science and Democracy After The End of Modernity………...……...…205
10
Abbreviations
Courts
App. Corte d’Appello
CA Cour d’Appel
Cass. civ. Corte di Cassazione civile
Cass 1ère civ. Cour de Cassation, première chambre civile
CE Conseil d’État
CFI Court of First Instance
Corte cost. Corte costituzionale
ECJ EU Court of Justice
TAR Tribunale amministrativo regionale
Trib. Tribunale, Tribunal
Journals and databases
AJDA Actualité juridique Droit administratif
Ann Intern Med. Annals of Internal Medicine
Calif. L. Rev. California Law Review
CED Centro Elettronico di Documentazione (Corte di
Cassazione)
Chi.-Kent. L. Rev. Chicago-Kent Law Review
Clin Med Clinical Medicine
Danno e resp. Danno e responsbailità
Dir. economia assicur. Diritto economia e assicurazione
Dr. Adm. Droit Administratif
Duke Jou. Compar. & Int. Law Duke Journal of Comparative & International Law
Eur J Hosp Pharm European Journal of Hospital Pharmacy
Eur J Law Econ European Journal of Law and Economics
Expert Rev Mol Diagn Expert Review of Molecular Diagnostics
Foro it. Foro italiano
Gaz. Pal. Gazette du Palais
Ger Med Sci German Medical Science
Giust. civ. Giustizia civile
Giust. civ. Mass. Giustizia civile Massimario
JAMA Intern Med. JAMA Internal Medicine
J. Am. Med. Ass’n. Journal of the American Medical Association
JCP Adm. Juris-classeur périodique édition
administrations et collectivités territoriales
J Young Pharm Journal of Young Pharmacists
L.Q.R. Law Quarterly Review
Mass. Foro it. Massimario del Foro italiano
Nat Rev Drug Disco. Nature Reviews Drug Discovery
N Engl J Med. The New England Journal of Medicine
11
Notre Dame L. Rev. Notre Dame Law Review
Nuova Giur. Civ. Nuova giurisprudenza civile
Perspect Clin Res Perspectives on Clinical Research
Ragiusan. Rassegna giuridica della sanità
Rass. dir farmaceutico Rassegna di diritto farmaceutico
RDSS. Revue de Droit Sanitaire et Social
Rec. Lebon. Recueil Lebon
Resp. civ. prev. Responsabilità civile e previdenza
Riv. dir. civ. Rivista di diritto civile
Riv. dir. nav. Rivista di diritto della navigazione
Riv. it. medicina legale Rivista italiana di medicina legale
13
Introduction
The thesis deals with the role of civil liability, i.e., courts, and other institutional alternatives, in integrating the regulatory grey area of unauthorized prescriptions and uses of medicinal products. It makes the case for a complex institutional framework, where a "precautionary" reinterpretation of civil liability rules, combined with a proportional liability model, cooperates with a no-fault fund, and both are integrated into a mandatory, non-binding ADR system.
Laying at the core of significant trends in contemporary pharmaceutical market and regulation, unapproved pharmaceutical uses simultaneously offer significant advantages and pose critical challenges for risk management and consumer safety in the EU.
In order to catch fully their impact, it is appropriate to situate them into the general trends occurring within the global pharmaceutical market.
At the outset, the immense importance of the pharmaceutical sector is indisputable from both the economic and social points of view.
The financial figures of the global pharmaceutical industry are impressive.1 In 2014, total global
pharmaceutical earnings surpassed one trillion US dollars. With the most substantial portion of these revenues, the U.S. pharmaceutical industry plays the leading role. Indeed, although the Chinese pharmaceutical market is the fastest-growing one in the world, the main pharmaceutical companies remain North American and European. In 2016, the EU pharmaceutical sector's total market value at ex-factory prices surpassed 200 billion euros, with a substantial trade surplus of about 100 billion euros. The three biggest pharmaceutical producers in Europe are Italy, Germany, and France.2 Italy
recently secured the European leadership in pharmaceutical production thanks to a high rate of investment and innovation, along with high-quality human resources.3
The pharmaceutical industry plays a vital social role as well by delivering to the market ever more sophisticated and innovative products aimed at treating diseases.
Such immense benefits, however, do not come without risks. As the ambivalent meaning of the Ancient Greek and Latin words phàrmakon and pharmacum well depicted (which simultaneously meant medicine and poison), pharmaceuticals have a positive impact on human health but might also entail severe negative side-effects. Given the broad risks associated with modern mass-scale pharmaceutical production, regulations require manufacturers to properly test products before marketing; then, based on such experimental results, public regulators authorize their commercialization, if the overall benefit-risk ratio is favorable. Regulations also require post-marketing monitoring since pre-authorizations experiments cannot catch all possible situations. From this point of view, pharmacovigilance aims to remedy the discrepancy between the standardized pre-marketing testing approach and the wild variety of individual situations.
On their side, physicians have the mission to give their patients the best individual treatment option based on available medical knowledge and individual appraisal of the risk-benefit ratio, rather than on the content of marketing authorizations. Considering the peculiar characteristics of individual patients, medicine has always been, in a sense, a personalized discipline.
An essential source of appropriate care, medical innovations, and commercial revenues, unauthorized prescriptions of approved medicines (off-label uses), are particularly widespread in areas where alternative products authorized explicitly for an indication are not available, such as oncology, pediatrics, and rare diseases. Not only are off-label uses a driver of medicinal personalization, but also one of early access to treatment. By definition, off-label uses do not require prior testing and
1 STATISTA, Global Pharmaceutical Industry, available at: https://www.statista.com/topics/1764/global-pharmaceutic al-industry/; P. Biecheler, M. Hosseini, and H. Nyctelius, Pharma's fight for profitability, RolandBerger, 2013.
2 L. Cavestri, I farmaci made in Italy battono Francia e Germania, in Il Sole 24 Ore, 7th October 2017, available at: https://www.ilsole24ore.com/art/impresa-e-territori/2017-10-06/i-farmaci-made-italy-battono-francia-e-germania-132315.shtml?uuid=AEWU9OgC.
14 regulatory authorization. Their ambition is to provide patients with the best therapy available at the fastest speed possible. With a similar logic, investigational products can be prescribed in exceptional circumstances under so-called compassionate use or expanded access programs.
Both off-label and compassionate uses lie at the core of two significant trends in contemporary pharmaceutical industry and regulation.
The first one is a shift occurring from a one-size-fits-all approach to a tailored and personalized one.4
Biotechnological innovations are driving these changes, the aim of which is to market products better at meet individual patients’ medical needs than standardized blockbusters.5 For centuries, traditional
pharmaceutical production used to deliver medicines that are the same for everyone. While this approach benefited humanity greatly, it could not consider adequately the personal characteristics of patients, which might vary significantly across individuals, so that the same drug can have different effects on different individuals. Knowledge gained from genomics, proteomics, systems biology, and even genetic engineering allows for a personalized medicine instead, where products are tailored to the characteristics of ever-narrower patient subpopulations. Investigating how genes influence a patient’s response to medicines, pharmacogenomics is one of most advanced fronts of medicinal personalization.6 This discipline integrates pharmacology and genomics to develop drugs tailored to
a patient’s genetic characteristics.
Personalized medicine has significant implications for the healthcare.7 By giving patients the best care according to their peculiar characteristics, personalized medicine promises to improve healthcare services and lower related costs.8 Indeed, pharmaceuticals do not work the same way for everyone:
someone might benefit from a medicine, someone else might not respond to it, and yet some other might suffer from adverse reactions. Thanks to pharmacogenomics, as well as the increasing availability of behavioral information, personalized medicine aims to predict the effectiveness of a medicine for an individual patient so to help prevent adverse reactions.
In a sense, personalized medicine is also about reconciling mass-scale pharmaceutical commercial strategies with the individual-based approach of physicians.
Turning to the second significant trend in the contemporary pharmaceutical market, not only are off-label and compassionate uses drivers of medicinal personalization; they are also among the vehicles
4 F.R. Vogenberg, C. Isaacson Barash, and M. Pursel, Personalized Medicine: Part 1: Evolution and Development into Theranostics, in Pharmacy and Therapeutics, 2010, 35, 10, pp. 560-576.
5 One-size-fits-all drugs are suboptimal because they do not consider patients’ unique bioly (J.T. Jørgensen, Are we approaching the post-blockbuster era? – Pharmacodiagnostics and rational drug development, in Expert Rev Mol Diagn, 2008, 8, pp. 689-695).
6 E. Mini - S. Nobili, Pharmacogenetics: implementing personalized medicine, in Clinical Cases in Mineral and Bone Metabolism, 2009, 6, 1, pp. 17-24.
7 Personalized medicine also has implications for the commercial sphere. While the thesis will not touch upon this aspect, this is nonetheless worth mentioning. the ongoing trend to medicinal personalization or stratification implies a shift from blockbuster products to the search of niche markets (S.G. Gibson – T. Lemmens, Niche Markets and Evidence Assessment in Transition: A Critical Review of Proposed Drug Reforms, in Medical Law Review, 2014, 22, 2, pp. 200-220, https://d oi.org/10.1093/medlaw/fwu005). According to the blockbuster philosophy, medicines should be developed for the largest possible number of people to reach sales for 1 billion US dollars (R. Collier, Bye, bye blockbusters, hello niche busters, in Canadian Medical Association Journal, 2011, 183, 11, pp. E697-E698. doi:10.1503/cmaj.109-3874) However, the number of products that succeed in doing so has been shrinking in recent years. This was mainly due to drying drug pipelines and staggering generic competition, which both threaten profitability (ibid.). In response to that, many pharmaceutical manufacturers carried out mergers and acquisitions not only to increase productivity but also to escalate research investments to offer treatments targeted at the patients that are most likely to benefit from them (ibid.) Although niche markets are smaller than mass ones, pharmaceutical manufacturers find the former more and more attractive because they suffer from lower competitive pressure than the latter (S.G. Gibson – T. Lemmens, Niche Markets and Evidence Assessment in Transition: A Critical Review of Proposed Drug Reforms, in Medical Law Review, 2014, 22, 2, pp. 200-2 20, https://doi.org/10.1093/medlaw/fwu005). Indeed, first comers in niches can often secure a position of dominance or even de facto monopoly on them.
8 R. Collier, Bye, bye blockbusters, hello niche busters, in Canadian Medical Association Journal, 2011, 183, 11, pp. E697-E698. doi:10.1503/cmaj.109-3874.
15 of the so-called early access movement.9 The movement for early access calls for delivering
promising treatments to patients in particular medical need rapidly. Unauthorized uses of approved medicine and the use of unauthorized, investigational medicinal products let patients access encouraging therapies without waiting for the long experimental and approval process traditional regulations require.
Both the pharmaceutical industry and certain patients’ organizations strongly support early access.10
While the former benefits from it because early access reduces approval times and costs, the latter have an interest in accessing new treatments in the fastest way possible.
As an original early access regulatory concept, adaptive licensing has the ambition to overcome the rigid, bi-phasic traditional approval process, allowing for a staggered one instead, where approval is initially restricted to narrow patients’ subpopulations and then expanded according to the real-world effects of off-label uses on broader populations. In other terms, the adaptive licensing concept uses off-label prescriptions to extend the scope of the initial approval.
Recent medical scandals and technological innovations triggered further regulatory innovations. Although off-label prescriptions typically occur at the initiative of physicians, the digitalization of healthcare and the consequent increasing availability of health information11 also let manufacturers
and regulators monitor such unauthorized uses at sustainable costs. Considering these developments, it is ever less justifiable for private producers and public authorities not to intervene when risks emerge associated with unauthorized medicinal uses (which happened in the French Mediator scandal in 2010 with devastating consequences). It is not by chance that the 2010-2012 European pharmacovigilance reforms expanded post-marketing surveillance obligations of companies and agencies as to include uses not covered by marketing authorizations too.
This points to the other side of unauthorized pharmaceutical uses, i.e., the risks and uncertainties they might entail for patients. By definition, unapproved prescriptions are not validated through clinical trials. Therefore, they tend to expose patients to higher uncertainties than tested and approved ones, with their sources of scientific legitimacy lying outside clinical trials. The relationship between decision-making and alternative sources of medical and scientific knowledge is inherently problematic. This is especially true in a context where the increasingly specialization of decision-making processes allocates decisional powers on distant experts that are hardly subject to public control and get exposed to lobbying pressures from special interest groups. This feeds widespread mistrust among the public, with rising forms of "scientific populism" gain ground, calling for forms of electoral control over "science." As a reaction to these tensions, many experts content themselves with claiming that science is not democratic, thus escalating tensions and exacerbating mutual alienation between them and ordinary citizens.
Under this complex and multi-faceted framework, unauthorized uses of medicines are beneficial and lawful, but health actors, i.e., physicians, producers, and regulators, do not know what they can, cannot, or must do about them due to both scientific and legal uncertainty. In other terms, such uses constitute a regulatory grey area, the uncertainties of which hinder the pursuit of risk management and consumer protection goals under the European pharmaceutical regulation.
With the ambition to establish a continuous interaction between the development of scientific knowledge and human decision-making, the precautionary principle requires agents to act before an uncertain risk becomes a formally validated one. In contrast to the traditional preventive approach, which manages established risks only, the precautionary principle aims to tackle uncertain, yet scientifically plausible risks of severe and irreversible harm. In a sense, it changes the content of
9 S. Patil, Early access programs: Benefits, challenges, and key considerations for successful implementation, in Perspectives in Clinical Research, 2016, 7(1), pp. 4-8. doi:10.4103/2229-3485.173779.
10 Ibid.
11 Not to mention the impact AI (big) data-driven technologies can have on pharmacovigilance activities (V.G. Koutkias – M.-C. Jaulent, Computational Approaches for Pharmacovigilance Signal Detection: Toward Integrated and Semantically-Enriched Frameworks, in Drug Safety, 2015, 38(3), pp. 219-232, doi:10.1007/s40264-015-0278-8).
16 relevant scientific knowledge for decision-making. Such a principle is crucial to manage the uncertainties associated with unauthorized, i.e., non-validated, pharmaceutical uses.
In theory, civil liability can provide decision-makers with incentives to and guidance on how to enforce such a principle, thus favoring a fair and efficient allocation of scientific uncertainties among the stakeholders involved. As a matter of fact, by compensating injured parties, civil liability rules can also have a deterrent and regulatory effect on agents' behaviors, which can be held accountable for their decisions and receive guidance on how to behave correctly, so to avoid future claims. In other terms, civil liability aims not only to protect victims' rights but can also contribute to higher legal certainty for all the actors involved in this market.
The pharmaceutical sector is one of the domains where the traditional rules of civil liability display their limitations. Civil liability rules and categories, such as fault and causation, were created to resolve more straightforward cases typical of pre-industrial societies, where identified agents caused injuries, which were clearly and immediately linked to their conducts. The expansion of mass-scale production and technological innovations triggered a shift towards rules of anonymous and strict liability, as well as new, probabilistic causal conceptions. The precautionary principle reflected a change in the public's attitude towards scientific uncertainty. The thesis will assess if and how such a principle is helping to reshape traditional civil liability categories, anchored to a preventive approach to (actual) risks. In other terms, it will be assessed how the scientific knowledge relevant for civil liability can be aligned to that relevant for a precautionary decision-making. Given the uncertain and even unknown risks they might entail, non-validated pharmaceutical uses make a good case study to analyze such changes in European civil liability law.
The first research question of this thesis is, therefore, if and how civil liability rules, i.e., courts, can increase the protection of the rights of patients and incentivize health actors to perform correct practices in the grey area of the European regulation of off-label uses of medicines.
To this end, the European pharmaceutical regulation of unauthorized pharmaceutical uses and the methodology applied in this research will first be analyzed in detail (Chapters I and II). While the standard marketing authorization process presupposes a neat distinction between pre-approval experimental phases and the post-marketing commercial and medical practice, unauthorized uses of medicines inhabit a grey area between research and treatment that challenge traditional distinctions. The thesis will then consider the civil liability of physicians, manufacturers, and regulators for damages arising from off-label uses in the EU, French, and Italian legal systems (Chapters III, IV, and V). Following a bottom-up approach, the main case law trends at both EU and national level will be analyzed and critically considered. It will be appraised how, through an incremental trial and error process, courts are updating legal concepts and doctrines, such as fault, product defectiveness, and causation, to the realm of scientific uncertainty unauthorized medicinal prescriptions belong to. Since civil liability (and insurance) cannot be expected to manage all the uncertainties associated with non-validated treatments, our second research question is if and how no-fault plans can efficiently integrate its scope of application without producing distortionary distributive effects (Chapter VI). Here, national legislative changes will be reviewed. Also, it will be assessed how the said legal systems use and could use alternative dispute resolution systems and class actions to ease the difficulties victims face in access to justice in scientifically uncertain personal injury cases. Here again, the analysis will focus on national legislations for a critical appraisal thereof.
A chapter will then deal with the role of civil liability and the other institutional devices considered in compassionate uses, given the scientific and regulatory peculiarities of these latter (Chapter VII). Finally, conclusions will first be devoted to summing up the results and proposals of our inquiry and appraising their full potential in areas other than non-validated treatments. Secondly, conclusions will display how our proposal might help to reconcile conflicting views about the relationship between science and democracy, as well as rediscovering the substantive meaning of democracy in such a technically complex and politically sensitive sector as the pharmaceutical one.
Since the thesis oscillates continuously and deliberately between the description of legal rules and operational solutions and their critical appraisal, it seems appropriate, before letting the reader into
17 the first Chapter, to clarify the relationship between the descriptive and the normative dimensions of this work. As will be seen, both judges and lawmakers are gradually adapting civil liability rules and pharmaceutical legislations to the challenges arising from scientific uncertainty in the pharmaceutical sector. Feeling the inadequacy of traditional rules and categories, they often do so without a general plan and sometimes even unconsciously, under the pressure of a growing workload and in reaction to isolated affaires. In a nutshell, the thesis aims to identify such trends to make them evident and offer proposals to facilitate their development. The idea is that legal scholars and practitioners complement each other: while the former “see” but do not, the latter do but “see” not. By identifying and systematizing the trends practitioners often foster without a clear, overall vision, scholars can indirectly contribute to a more rapid and consistent transformation of the law with their analysis and proposals.
The relationship between description and prescription, therefore, presupposes a specific vision of the relationship between legal research and practice. This somehow translates the metaphor of the owl and the mole Hegel used for philosophy and history12 in the admittedly more prosaic domain of the
law.
It was with this spirit that this research was conducted.
12 The owl of Minerva spreads its wings at sunset to examine an epoch approaching its end and push the "mole" of history to keep digging beneath the ground. Leaving metaphors aside, Hegel meant that philosophy must analyze the contradictions of reality to accelerate the end of a declining world, while history creates a new one - which new philosophies will interpret (R. Bodei, La civetta e la talpa, Il Mulino, 2014).
18
Chapter I.
EU Pharmaceutical Regulation and Unauthorized Uses of Medicines
Pharmaceutical regulation is conceived to make sure that only safe and effective products reach patients. The amount of data needed to warrant a marketing authorization is not a datum but is the function of policy and regulatory decision.
In a sense, regulators always make decisions under conditions of scientific uncertainty. However, regulations do not set the "adequate" level of information required to prove a drug's safety and efficacy arbitrarily. Indeed, pre-marketing experimental phases aim to reduce uncertainty to an acceptable level. The movement for earlier access to medicines claims that, at least under certain conditions, regulations should lower this level, so that new products can address patients' needs timely. This is already a reality in the case of off-label uses, that is, uses of already authorized medicines for unauthorized indications, which are widespread in clinical practice.
Another example is that of compassionate use programs, under which, in exceptional circumstances , patients use an unapproved product. Besides their advantages, non-validated treatments are ethically challenging, as they put patients in a situation of greater scientific uncertainty on the safety and efficacy profiles of medicinal uses. What is more, recent regulatory experiments at the EU level seem to institutionalize these "shortcuts" to standard authorization, at least in specific instances.
The following paragraphs describe the standard pharmaceutical marketing authorization procedure and the phenomenon of off-label uses. First, this comparison highlights the differences between validated and non-validated uses of medicines both regarding regulatory requirements and entailed scientific uncertainty. Secondly, it gives a comprehensive overview of the regulatory regime applica ble to off-label uses, as several regulations and institutional recommendations require companies and health authorities to monitor the effects of marketed medicines used outside the marketing authoriza tion. Subsequently, the relation of non-validated treatments with the medical research-practice divide is addressed. Thus, this chapter will set the ground for the following analysis, by showing that off-label uses constitute a regulatory weak spot, which bypasses the standard marketing authorization procedure, as well as the protections and guarantees applicable to clinical trials.
1. Pharmaceutical Product safety
Safety and quality problems affect medicines across many countries in the world due to many different reasons.13 Sometimes these problems result in significant emergencies involving vast
amounts of patients. Pharmaceutical regulation aims to ensure the safety, efficacy, and quality of medicinal products.14 Over time, legislators and regulators have tackled such a complex scientific and
technological field with increasing sophistication to protect patients and not to discourage socially beneficial economic activities. The historical evolution of these efforts has shaped the contemporary institutional design of Western pharmaceutical regulation.
13 M.A. Hamburg, Pathway to Global Product Safety and Quality, FDA, 2012, pp. 1-4; G.V. Reklaitis, C. Seymour, S. Garcìa-Munoz (ed.), Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture, Wiley, 2017, pp. 4-6; K. Purnhagen, The Politics of Systematization in EU Product Safety Regulation: Market, State, Collectivity, and Integration, Springer, 2013, p. 24; V.B. Patravale, J.I. Disouza, and M. Rustomjee (eds.), Pharmaceuti cal Product Development: Insights into Pharmaceutical Processes, Management, and Regulatory Affairs, CRC, 2016, pp. 17 et seq. and 31 et seq.; M.K. Olson, Pharmaceutical Policy Change and the Safety of New Drugs, in Journal of Law and Economics, 2002, 45, n. 2, Part II, pp. 615-642.
14 G. Permanand, EU Pharmaceutical Regulation: The Politics of Policy-Making, Manchester University Press, 2006, pp. 19 et seq.; N. Chowdhury, European Regulation of Medical Devices and Pharmaceuticals, Springer, 2014, pp. 85 et seq.; S. Shorthose, Guide to EU Pharmaceutical Regulatory Law, Kluwer, 2011, pp. 3 et seq.
19 While early legislative interventions in pharmaceutical production mainly aimed to set basic quality standards and prevent product adulteration,15 it is with modern pharmaceutical mass production that
the public demand for higher safeguards for health led to the enactment of a comprehensive set of laws governing medicinal products along with their entire life cycle. The 19th-century breakthrough progresses in chemistry, medicine, and pharmacology, coupled with the expansion of industrial production, dramatically increased the availability of medicines but also the possibilities that defective goods could reach patients.16
The US introduced the first kind of modern pharmaceutical regulation in response to severe pharmaceutical scandals that shocked the public opinion. In 1906, Congress passed, and President Theodore Roosevelt signed the original Food and Drug Act, establishing the Food, Drug, and Insecticide Administration (later shortened as Food and Drug Administration, FDA).17 In 1938, FDA
recommendations and the tragic Sulfanilamide scandal led to the enactment of the Federal Food, Drug, and Cosmetic Act (FDCA), under the Administration of Franklin D. Roosevelt.18 The Act was
extensively amended following the European Thalidomide scandal in the 1960s, although only a few cases concerned American patients.19
2. US Pharmaceutical Regulation
The FDCA sets the essential features of any following pharmaceutical regulatory, institutional design, including the European ones.20 The FDCA has materially changed over time,21 but the basic
idea remains that new drugs must show safety and efficacy before and (after) selling. In essence, companies must apply to the FDA for the marketing authorization of new products, providing the Agency with data showing a favorable risk-benefit ratio.22 Companies and regulators should also
closely monitor the effects of the use of the product after the latter is put into circulation. In particular, a standard four-stage process produces relevant data.
Phase I provides early evidence on the safety and tolerability of the product by testing increasing dosages in 20-80 volunteers.23
15 L. Rägo – B. Santoso, Drug Regulation: History, Present and Future, in C.J. van Boxtel, B. Santoso and I.R. Edwards (ed.), Drug Benefits and Risks: International Textbook of Clinical Pharmacology, IOS Press and Uppsala Monitoring Centre, 2008, pp. 65 et seq.
16 Ibid.
17 M.T. Law - G.D. Libecap, The Determinants of Progressive Era Reform The Pure Food and Drugs Act of 1906, in E.L. Glaeser – C. Goldin (ed.), Corruption and Reform: Lessons from America's Economic History, Chicago University Press, 2006, available at: DOI:10.7208/chicago/9780226299594.003.0011; M.T. Law, History of Food and Drug Regulation i n the United States, in R. Whaples (ed.), Economic History Encyclopedia, available at: http://eh.net/encyclopedia/histor y-of-food-and-drug-regulation-in-the-united-states/; B. Randall, Drug Regulation: Historical Review and Current Refor m Proposals, in E.N. Parvis (ed.), The Pharmaceutical Industry: Access and Outlook, Nova Science, 2002, pp. 2 et seq. 18 M.T. Law - G.D. Libecap The Determinants of Progressive Era Reform. The Pure Food and Drugs Act of 1906, in E.L. Glaeser – C. Goldin (ed.), Corruption and Reform: Lessons from America's Economic History, Chicago University Press, 2006, available at: DOI:10.7208/chicago/9780226299594.003.0011.
19 Ibid.
20 R.S. Tancer - C. Mosseri Marlio, Evolution of Pharmaceutical Regulations and Their Consequences in the European Union and the United States, in Thunderbird International Business Review, 2002, pp. 263–281.
21 H. Rahalkar, Historical Overview of Pharmaceutical Industry and Drug Regulatory Affairs, in Pharmaceut Reg Affairs, 2012, S11:002, doi:10.4172/2167-7689.S11-002
22 FDA - U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health, Factors to Consider Regarding Benefit Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions – Guidance for Industry and Food and Drug Administration Staff, 27th December 2016, pp. 5 et seq., available at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments /ucm506679.pdf.
23 FDA, From Test Tube to Patient: The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective, 4th Ed., 2006, available at http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html.
20 Phase II measures the effectiveness of the medicine by administering it to several hundreds of patients suffering from the condition the drug is intended to treat.24
Phase III trials test the efficacy of the product against a placebo in around 600 to a few thousand patients, depending on the size of the interested population.25
On average it can take two to ten years for a drug to be thoroughly tested.26
Marketing authorization applications contain data collected throughout these three experimental phases. The regulator reviews pre-market test data on a case-by-case basis and with a certain degree of discretion.
Phase IV is dedicated to post-marketing surveillance (also known as pharmacovigilance).27 Phase IV
studies aim to monitor products’ safety and efficacy based on data developed by the use of the drug in the real world. Regulators can require post-marketing trials and producers can perform them voluntarily to discover new possible uses that could increase the market of the medicine.28 Detection
of unknown side effects might trigger regulatory measures to protect the public.29
From a procedural point of view, the standard pharmaceutical regulatory model consists in two main phases, i.e., the pre-marketing one, aimed to collect data to support marketing authorization applications, and the post-marketing one, devoted to the surveillance of products' effects.
From a substantive point of view, regulators assess the safety and efficacy of a new product against the scientific knowledge available at the time of the authorization, as mediated by the role of experts. However, the existence of pharmacovigilance obligations makes it clear that subsequent developments in scientific consensus might have regulatory relevance. Pharmaceutical regulation has the ambition to establish a permanent and dynamic link between the evolutions of scientific knowledge and the regulatory status of medicinal products.
3. EU Pharmaceutical Regulation 3.1 History
EU pharmaceutical regulation fundamentally follows the US model. However, while the North-American regulatory framework is purely domestic, the European one has a supra-national dimension.30
The Thalidomide scandal triggered the enactment of the first Directive of 1965/65, requiring producers to obtain a marketing authorization based on a safety and efficacy assessment.31
24 CDER, FDA, DHHS, The CDER Handbook, 1998 (as amended in 2007), available at http://www.fda.gov/cder/handb ook/handbook.pdf.
25 Ibid.
26 R. Chin - M. Bairu, Global Clinical Trials, Elsevier, 2012; PhRMA (Pharmaceutical Research and Manufacturers of America), Pharmaceutical Industry Profile, Report given in Washington D.C., 2006; IOM (Institute of Medicine), Regulatory Authorities for Drug Safety, in The Future of Drug Safety –Promoting and Protecting the Health of the Public, The National Academies Press, 2007.
27 G. Jeetu - G. Anusha, Pharmacovigilance: A Worldwide Master Key for Drug Safety Monitoring, in J Young Pharm., 2010, 2(3), pp. 315-320. doi: 10.4103/0975-1483.66802; WHO, The Importance of Pharmacovigilance Safety Monitori ng of Medicinal Products, 2002, pp. 4 et seq.; J.C.C. Talbot – B.S. Nilsson, Pharmacovigilance in the pharmaceutical i ndustry, in British Journal of Pharmacology, 1998, 45, pp. 427-31; P.I. Folb - P. Olliaro, Pharmaceutical policies and regulatory control, in WHO Drug Information 2000, 14(2), pp. 82-84.
28 M. Kashoki et alii, FDA Oversight of Postmarketing Studies, in N Engl J Med, 2017, 377, pp. 1201-1202, DOI: 10.1056/NEJMc1709185.
29 V. Suvarna, Phase IV of Drug Development, in Perspect Clin Res., 2010, 1(2), pp. 57–60.
30 F.G. Jacobs, Foreword, in R. Goldberg – J. Lonbay (eds), Pharmaceutical Medicine, Biotechnology and European Law, Cambridge University Press, 2001, p. xiii; C. Hodges, European Regulation of Consumer Product Safety, Oxford University Press, 2005, p. 38.
31 H. Teff - C.R. Munro, Thalidomide: The Legal Aftermath, Westmead Hants, 1976; J.P. Griffin – R.R. Shah, The Development of the Control of Human Medicines in Europe from Classical Times to the Year 2000, in J.P. Griffin – J.
21 In 1975, two Directives harmonized the rules governing clinical trials [Directive 1975/319] and introduced a mutual recognition procedure to facilitate the movement of medicinal products across Member States [Directive 1975/318]. Under this new regulatory regime, the Committee for Proprietary Medicinal Products (CPMP, now CHMP) had the mandate to provide the first EU forum for experts from Member States, which resulted in harmonized guidelines on clinical testing being d eveloped.32 However, Member State authorities retained the responsibility to decide on marketing
authorization, so divergent assessments were still possible.
After the Single European Act (1986), Directive n. 1987/22 established a concerted authorization procedure for high-technology medicinal products, involving the CPMP, national authorities, and applicants.33
Finally, Regulation n. 2309/1993 introduced the first form of a proper European marketing authorization procedure, under the supervision of the European Medicines Evaluation Agency (EMEA, now EMA).34 The EMA is an advisory institution for the Commission, which makes the
final decisions concerning medicines subject to centralized procedure.35 Regulatory decisions on
medicines for human use, however, heavily rely on the opinion of the EMA Committee for Medicinal Products for human use (CHMP).36 This is why EMA is sometimes referred to as a "quasi-regulatory"
institution.37
3.2 Authorization procedures
EU legislation on medicinal products serves the two-fold purpose of protecting public health [Art. 168 TFEU] and ensuring the free movement of medicinal products in the EU [Art. 114 TFEU]. Its primary legal sources are Regulation 726/2004 and Directive 2001/83, as amended.38
Regulation n. 726/2004 governs the centralized marketing authorization procedure. The latter is mandatory for some categories of medicinal products and voluntary for other. Over time, the scope of mandatory centralized procedure has been expanding significantly.39 In the beginning, it only
concerned biotechnological products.40 Nowadays, it is compulsory for high-technology medicinal
products indicated by the Annex, particularly those resulting from biotechnical processes, orphan drugs and any medicinal product containing an entirely new active ingredient aimed "to treat acquired immune deficiency syndrome, cancer, neurodegenerative disorder" or diabetes [Art. 3, Annex to Regulation 726/2004].
O'Grady, The Textbook of Pharmaceutical Medicine, Routledge, 2002; J. Abraham – G. Lewis, Regulating Medicines in Europe, Routledge, 2000.
32 F. Sauer, New Drugs in the Global Economy: Risk Assessment and Risk Management in the European Union and Co-operation with the USA, speech delivered to the Graduate School of Public Health, University of Pittsburgh, 13th November 2000, as cited by G. Permanand – E. Mossialos, Regulating the pharmaceutical sector, in M. Steffen (ed.), Health Governance in Europe: Issues, Challenges, and Theories, Routledge, 2005, pp. 49 et seq.
33 “[I]t is consequently important to provide for a Community mechanism for concertation, prior to any national decision relating to a high-technology medicinal product, with a view to arriving at uniform decisions throughout the Community” [Recital n. 7, Directive n. 1987/22].
34 G. Permanand, E. Mossialos, and M. McKee, Regulating medicines in Europe: the European Medicines Agency, marketing authorisation, transparency and pharmacovigilance, in Clin Med, 2006, 6(1), pp. 87-90.
35 P. Craig, EU Administrative Law, Oxford University Press, 2012, p. 151. 36 Ibid.
37 Ibid.
38 N. Chowdury, European Regulation of Medical Devices and Pharmaceuticals, Springer, 2014; S. Shorthose, Guide to EU Pharmaceutical Regulatory Law, Kluwer, 2014.
39 Council Regulation 726/2004/EC laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, OJ 2004, L 136/1. 40 Annex to Council Regulation 2309/93/EEC, OJ 1993, L214/1.
22 Instead, access to the centralized procedure is optional for therapeutically innovative medicinal products and for medicinal products which, although not innovative, may benefit society or patients if they are authorized at EU level [Art. 3(2) a-b, Regulation 726/2004].
Under the centralized authorization procedure, companies have to submit to the EMA CHMP a long series of data gathered from phase I to III clinical trials [Art. 6]. After the scientific committee gives its opinion on the application [Arts. 7-9], the Commission issues the formal marketing authorization [Art. 10(2)]. The approval is valid all across the EU [Art. 13(1)]. Although the CHMP's opinion is not binding, never has the Commission disagreed with it. Therefore, the EMA is claimed to be, in fact, a quasi-regulatory body more than a purely advisory one.41
Together with the marketing authorization, the competent authority issues the Summary of the product Characteristics (SmPC), which lists, among other things, the authorized indications and known adverse reactions [Art. 9(4)a]. In particular, under Article 11 of Directive 2001/83, the SmPC must specify: the “dosage” and the “pharmaceutical form” of the medicinal product; the “qualitative and quantitative composition” of all of its constituents; the “therapeutic indications”; the “posology and method of administration”; the “contra-indications”; “special warnings and precautions for use”; and the adverse reactions and the special precautions for storage and the duration thereof. Healthcare professionals decide how to use the medicinal product based on this information.42
Under the decentralized procedure, companies can apply for authorization of a product in a different of Member States, provided that the product is authorized in any EU country and the mandatory centralized procedure does not apply.43 A reference Member State leads the assessment procedure
[Arts. 28 ff. Directive 2001/83]. Under the mutual recognition procedure, other EU countries can approve a medicinal product already authorized in a EU Member State by mutual recognition of its first authorization based on an assessment report. The subsequent steps are identical to the decentralized procedure.
Finally, medicinal products that do not fit in the categories dictated by Regulation n. 726/2004 fall under the scope of the authorization procedure of the Member State where the manufacturers will market the product. Directive 2001/83 have harmonized national procedures, which fundamentally reproduce the pattern Regulation n. 726/2004 sets at the supranational level.
The Commission’s Guideline on Summary of Product Characteristics (2009) sets principles of presenting information in the SmPC.
First, the SmPC should be worded clearly and concisely.
Secondly, the SmPC should include: all adverse reactions from clinical trials; post-authorization safety studies; and "spontaneous reporting for which, after thorough assessment, a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility, based, for example, on their comparative incidence in clinical trials, or on findings from epidemiological studies" or on an assessment of causation from individual reports.44 The SmPC should not list adverse
events in if they do not imply at least a suspected causal relationship.
The marketing authorization holders and regulators should regularly review the SmPC section concerning undesirable effects to update the product' s safety profile. This section should not include claims regarding the absence of specific adverse reactions or general good tolerability statements, such as "well tolerated" and "adverse reactions are normally rare." Likewise, the SmPC should not include statements on lack of proof of causal association between product use and an adverse reaction. 3.3 Pharmacovigilance
41 P. Craig, EU Administrative Law, Oxford 2012, p. 151.
42 EU Commission, A Guideline on Summary of Product Characteristics (Smpc), September 2009, p. 2.
43 EMA, Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), available at http://www.ema.europa.eu/ema/, under ‘Committees’.
44 EU Commission, A Guideline on Summary of Product Characteristics (SmPC) , September 2009, p. 15, available at: https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-2/c/smpc_guideline_rev2_en.pdf.
23 3.3.1 In the EU
Pre-marketing trials should assess the efficacy and safety of any medicinal product before it is put into circulation. However, information produced during the pre-approval phases cannot capture all possible adverse reactions to the use of the product.45 This is due to a number of different reasons.
First, experimental subjects are limited in number, and the duration of the test is relatively short. Second, clinical trials might not represent certain special groups of patients and information about drug interaction might not be available.
Third, clinical trials cannot reproduce all possible conditions that can be found in clinical practice. These factors and many others prevent companies and authorities from discovering all adverse reactions a drug can produce before it is put into the shelves. This is the main reason pharmacovigilance is needed.46
The World Health Organization (WHO) defines pharmacovigilance as "the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine-related problem.47 Accordingly, EU pharmacovigilance legislation aims to prevent harm
from adverse reactions in humans deriving from the use of authorized medicinal products within or outside the terms of marketing authorization and to promote the safe and effective use of pharmaceuticals, by providing patients, healthcare professionals and the public with timely information about the safety of medicines. Therefore, pharmacovigilance contributes to the protection of public health.
In the EU, Member States and the Commission supervise pharmacovigilance under the coordination of the EMA. Also, marketing authorization holders (MAHs) are responsible for pharmacovigilance and have specific obligations. Over time, the role of patients and physicians in pharmacovigilance has been increasing significantly both at national and European level. Many Member States have established schemes letting patients report suspected adverse reactions by themselves. The new pharmacovigilance legislation has introduced an EU legal framework for patient reporting in all Member States. Under the new legislation, the Pharmacovigilance and Risk Assessment Committee (PRAC) and public hearings include patient and healthcare professional representatives to foster public participation.
Regulation n. 726/2004 and Directive 2001/83 provide for the legal framework for pharmacovigilance of medicinal products for humans in the EU. Regulation n. 1235/2010, Directives 2010/84 and 2012/26, and the Commission Implementing Regulation n. 520/2012 on Pharmacovigilance Activities have profoundly reformed this pharmacovigilance legislation with the aim to strengthen and rationalize pharmacovigilance and increase patient safety.
3.3.2 New EU Pharmacovigilance Legislation (2010-2012)
It is noteworthy that Directive 2010/84, which amended pharmacovigilance rules set by Directive 2001/83, expanded the notion of "adverse reaction" to include "noxious and unintended effects
45 WHO, Safety Monitoring of Medicinal Products: Guidelines for Setting Up and Running a Pharmacovigilance Centre, 2000, available at http://apps.who.int/medicinedocs/en/d/Jh2934e/2.html#Jh2934e.2.
46 M. Kaeding, J. Schmälter, and C. Klika, Pharmacovigilance in the European Union: Practical Implementation across Member States, Springer, 2017, pp. 11-17;
47 WHO, Pharmacovigilance: ensuring the safe use of medicines, available at: http://apps.who.int/medicinedocs/pdf/s61 64e/s6164e.pdf. See also G. Jeetu - G. Anusha, Pharmacovigilance: A Worldwide Master Key for Drug Safety Monitoring, in J Young Pharm., 2010, 2(3), pp. 315-320. doi: 10.4103/0975-1483.66802; WHO, The Importance of Pha rmacovigilance Safety Monitoring of Medicinal Products, 2002, pp. 4 et seq.; J.C.C. Talbot – B.S. Nilsson, Pharmacovi gilance in the pharmaceutical industry, in British Journal of Pharmacology, 1998, 45, pp. 427-31; P.I. Folb - P. Olliaro, Pharmaceutical policies and regulatory control, in WHO Drug Information 2000, 14(2), pp. 82-84.
24 resulting not only from the on-label use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorization, including the misuse and abuse of the medicinal product" [Recital 5, Directive 2010/84]. Accordingly, Article 1(11), Directive 2001/83 defines an adverse reaction as a "response to a medicinal product which is noxious and unintended". Consequently, MAH should report adverse reactions from misuse and off-label use too. Under the centralized procedure, the MAH must report adverse reactions to EMA. The manufacturer should inform both EMA and the Commission about new information that could influence the benefit-risk ratio of the medicinal product at issue, including "both positive and negative results of clinical trials or other studies in all indications and populations," including those not mentioned in the MA [Art. 28 Regulation 726/2004]. Under the national procedure, companies must inform national authorities, instead [Art. 23(2), par. 2, Directive 2001/83]. National and supranational databases, such as Eudravigilance, collect data [107(3), 107a(4) Directive 2001/83].
In turn, competent authorities can suspend, withdraw, or modify an authorization if data shows, e.g., that a product's risk-benefit ratio is not favorable anymore [Arts. 14a, 20(4), 28(4), par. 2 Regulation 726/2004].
Finally, Directive 2012/26 has profoundly reformed post-marketing surveillance to make sure that all Member States where the medicinal product is approved address related issues.
Under Article 23a(2) of the Directive, “if the product ceases to be placed on the market of a Member State, either temporarily or permanently, the marketing authorization holder shall notify the competent authority of that Member State. The marketing authorization holder shall inform the competent authority of the reasons for such action.”
In case urgent action is needed to protect public health, Member States and the Commission may suspend the marketing authorization and prohibit the use of a medicinal product until a definitive decision is made. The intervening authority should immediately inform the other stakeholders (i.e., the Commission, the Agency, and the other Member States) about the reasons for this action [Art. 31(3)(4), Directive 2001/83].
If concerns result from pharmacovigilance assessments, a Member State or the Commission must inform the other Member States, the Agency, and the Commission if: "(a) it considers suspending or revoking a marketing authorization; (b) it considers prohibiting the supply of a medicinal product; (c) it considers refusing the renewal of a marketing authorization; or (d) it is informed by the marketing authorization holder that, on the basis of safety concerns, the holder has interrupted the placing on the market of a medicinal product or has taken action to have a marketing authorization withdrawn, or intends to take such action or has not applied for the renewal of a marketing authorization” [Art. 107i(1) Directive 2001/83].
Likewise, MAHs shall immediately notify the Member States concerned of any action taken “to suspend the marketing of a medicinal product, to withdraw a medicinal product from the market, to request the withdrawal of a marketing authorization or not to apply for the renewal of a marketing authorization, together with the reasons for such action” [Art. 123 Directive 2001/83].
During pharmacovigilance, MAHs can perform post-authorization safety studies (PASS) voluntarily. The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) can impose PASS as a specific obligation for an MA granted under exceptional circumstances.
An online electronic register of post-authorization studies (EU PAS) contains public information on non-interventional post-authorization studies with the aim to increase transparency and reduce publication bias. EMA publish the protocols and abstracts of imposed non-interventional PASS in this register. MAHs should submit information on any PASS they initiated voluntarily or as required in a risk management plan (GVP Module VIII, see below) as well as on post-authorization efficacy studies that are not clinical trials and any other PAS.
25 EMA’s Good Pharmacovigilance Practices (GVP) detail the pharmacovigilance tasks and responsi bilities of MAHs, Member States, the Commission, and the EMA. The main pharmacovigilance acti vities relate to risk management, adverse reaction reporting, signal management, safety communicat ion, and risk minimization measures. This subparagraph describes the main GVP, which specify what manufacturers and regulators must and should do as they perform their post-marketing surveillance activities. As will be seen in the following chapters, the violation of such pharmacovigilance duties and responsibilities of MAHs and public authorities might warrant their civil liability.
Module V: Risk management. Risk management ensures that the benefits of a medicine exceed the risks by the highest possible margin. The risk management system must be proportionate both to the identified and the potential risks of the product.
MAHs should monitor pharmacovigilance data to determine if there are new risks or whether risks have changed or if there are alterations to the risk-benefit balance of medicinal products [Art 104(3)(e) Directive 2001/&83], and update the risk management system and the Risk Management Plan (RMP) accordingly. Some safety topics are of particular interest. The MAH should consider including potential risks of off-label use of the product in the safety specifications.
The RMP must describe both routine and additional pharmacovigilance activities, such as signal management and clinical studies, respectively. The MAH should perform additional activities ed to characterize risks and collect missing information.
Routine risk minimization activities apply to every medicinal product.
First, the SmPC and the package leaflet inform healthcare professionals and patients about the risks of the medicinal product and how to reduce them.
Secondly, setting the number of dosages can reduce risks by forcing patients to see a healthcare professional regularly. Likewise, a small pack size can make overdose less likely to occur.
Thirdly, controlling the conditions under which patients can access to a medicinal product (e.g., requiring a medical prescription) can reduce risks.
Module VI: Adverse reaction reporting. Reporting unexpected adverse reactions is the core activity of any pharmaceutical post-marketing surveillance system.
An adverse reaction is a response to a medicinal product which is noxious and unintended, which may arise from the use of the product within or outside the terms of the marketing authorization. However, there must be a reasonable possibility of a causal relationship between a suspected medicinal product and an adverse event. Otherwise, an adverse event is not an adverse reaction for the purposes of pharmacovigilance.
Competent authorities and MAHs should collect all suspected adverse reaction reports concerning medicinal products. Reports are either spontaneous or solicited.
Solicited reports derive, inter alia, from clinical trials, non-interventional studies, registries, post-approval patient programs, surveys, compassionate use, or named patient use.
The events healthcare professionals or patients report spontaneously are considered as adverse reactions, unless the reporters exclude a causal relationship. The same applies to reports arising from class action lawsuits and to those originating from media outlets or the internet.
The medical literature is an essential source of information about the safety profile of medicinal products.48 Therefore, MAHs should continuously review widely used databases as well as local
journals in countries where medicinal products are marketed. MAHs should also regularly look through the internet for suspected adverse reaction reports.
Reports are validated if they meet the following requirements: the reporter and the patient concerned are identifiable; there is a suspected medicinal product; there is a suspected adverse reaction.
48 O. Lapid – C.M. van der Horst, Does Pubmed accurately reflect the content of major plastic surgery journals?, in Journal of Plastic, Reconstructive & Aesthetic Surgery, Volume 61, Issue 10 , p. 1138.
