Access to Non-Summary Clinical Trial Data for Research Purposes Under EU Law (Munich Studies on Innovation and Competition, 16)

This book draws a unique perspective on the regulation of access to clinical trial data as a case on research and knowledge externalities. Notwithstanding numerous potential benefits for medical research and public health, many jurisdictions have struggled to ensure access to clinical trial data, even at the level of the trial results. Pro-access policy initiatives have been strongly opposed by research-based drug companies arguing that mandatory data disclosure impedes their innovation incentives. Conventionally, access to test data has been approached from the perspective of transparency and research ethics. The book offers a complementary view and considers access to individual patient-level trial data for exploratory analysis as a matter of research and innovation policy. Such approach appears to be especially relevant in the data-driven economy where digital data constitutes a valuable economic resource. The study seeks to define how the rules of access to clinical trial data should be designed to reconcile the policy objectives of leveraging the research potential of data through secondary analysis, on the one hand, and protecting economic incentives of research-based drug companies, on the other hand. Overall, it is argued that the mainstream innovation-based justification for exclusive control over the outcomes of research and development can hardly rationalise trial sponsors’ control over primary data from trials. Instead, access to such data and its robust analysis should be prioritised. Preface Acknowledgements Contents Abbreviations Chapter 1: Introduction References Part I: Setting the Scene Chapter 2: The Context and the Problem 2.1 Clinical Trials: General Aspects 2.1.1 Basic Definitions 2.1.2 The Social Value of Clinical Trials 2.1.3 Clinical Trials in the Regulatory Context 2.1.3.1 Clinical Trial Approval 2.1.3.2 Drug Marketing Authorisation 2.1.4 Clinical Trials as a Part of Industry RandD 2.2 The Debate Over Access to Clinical Trial Data 2.2.1 Concerns Related to Restricted Access to Clinical Trial Data 2.2.2 Transparency Issues 2.2.3 Levels of Transparency in Clinical Trials 2.2.3.1 Trial Registration 2.2.3.2 Reporting and Publication of Trial Results 2.2.3.3 Accessibility of Non-Summary Data 2.2.4 International Norm-Setting Initiatives Promoting Transparency in Clinical Research 2.2.5 Institutional Developments 2.2.5.1 Editorial Campaign 2.2.5.2 Funding Institutions 2.2.6 Access to Data as a Digital Resource in the Context of Data-Driven Innovation 2.2.6.1 The Promises of `Big Data ́ 2.2.6.2 Legal and Policy Debate Concerning `Ownership ́ of Sensor-Generated Data 2.2.6.3 `Big Data ́ Analysis in Public Healthcare and Drug RandD 2.2.6.4 Data-Sharing Policies and Practices Adopted by the Pharmaceutical Industry 2.3 Diversity of Policy Approaches and Academic Views 2.3.1 The Controversy Over Disclosure of Non-Summary Clinical Trial Data in the EU 2.3.1.1 Investigations of the European Ombudsman 2.3.1.2 The EMA Transparency Policies 2.3.1.3 Evolving Case Law of the CJEU on Clinical Trial Data Disclosure 2.3.2 Policy Approaches in Other Jurisdictions 2.3.3 Academic Discourse 2.3.3.1 General Medical Literature 2.3.3.2 Legal Discourse on Access to Clinical Trial Data Removing Financial Ties with the Industry Disclosure as a quid pro quo for Data Exclusivity Protection Amending the Freedom of Information Legislation 2.3.3.3 Comparative and International Law Perspectives 2.4 The Present Study Against the Background of Policy and Legal Discourse References Chapter 3: Secondary Analysis of Individual Patient-Level Clinical Trial Data: A Primer 3.1 Clinical Trial Data 3.1.1 Definitions and General Aspects 3.1.2 The Types of Clinical Trial Data 3.1.3 The `Life-Cycle ́ of Clinical Trial Data 3.2 Clinical Trial Data as a Source of Medical Knowledge 3.2.1 Clinical Trial Data as a Source of Scientific Knowledge 3.2.2 The Types of Data Analyses 3.2.2.1 Primary and Secondary Data Analyses 3.2.2.2 Confirmatory Secondary Data Analysis 3.2.2.3 Exploratory Secondary Analysis 3.2.2.4 Subgroup Data Analysis 3.2.2.5 Interaction Analysis 3.2.2.6 Predictive Models and Prognostic Variables 3.2.2.7 Meta-analysis and Systematic Reviews 3.2.3 Fields of Research 3.2.3.1 Pharmacology 3.2.3.2 Epidemiology, Clinical Epidemiology and Pharmacoepidemiology 3.2.3.3 Aetiology, Pathology and Pathophysiology 3.2.3.4 Research on Biomarkers 3.3 Exploratory Analysis of Clinical Trial Data in Drug RandD 3.3.1 `Data-Driven ́ Drug RandD 3.3.2 The Application of Data Analytics in Drug Discovery 3.3.3 Secondary IPD Analysis in Planning and Design of New Trials 3.3.4 Secondary Analysis of Data from Unsuccessful Trials 3.4 Secondary Data Analysis by Drug Regulators 3.4.1 Advancing Regulatory Science 3.4.2 Extrapolation 3.5 Conclusion on Chapter 3 References Part II: Analysis De Lege Lata Chapter 4: Legal Sources of Control Over and Access to Clinical Trial Data Under the EU Applicable Framework 4.1 The EU Legal and Regulatory Framework Applicable to Clinical Trial Data 4.1.1 Relevant Provisions Under Primary Law 4.1.2 Relevant Sources of Secondary Law 4.1.2.1 The EU Regulation on Clinical Trials General Aspects Data Reliability and Robustness The EU Database for Clinical Trial Data 4.1.2.2 The EU Drug Authorisation Regulation 4.1.2.3 The EMA ́s Guidance on the Implementation of the Publication Policy 4.2 Legal Sources of Control of Trial Sponsors Over Individual Patient-Level Clinical Trial Data 4.2.1 Do Drug Sponsors `Own ́ Clinical Trial Data? 4.2.1.1 Competing Claims of Data Ownership 4.2.1.2 De facto Control But Not de jure Ownership of IPD The Obligation to Protect Data Against Unauthorised Access as the Source of de facto Exclusive Control No Property Rights in IPD as Personal Data No in rem Rights in Sensor-Generated Data Data Fixed and Stored in a Material Medium 4.2.2 The Applicability of the EU Trade Secrets Directive to Non-summary Clinical Trial Data 4.2.2.1 The Legal Definition of a Trade Secret 4.2.2.2 The Applicability of Trade Secret Protection to CSRs 4.2.2.3 The Applicability of Trade Secret Protection to IPD The Secrecy Requirement The Requirement of Commercial Value Due to Secrecy The Requirement of Protection Measures to Preserve Secrecy 4.2.3 The Applicability of the EU Database Directive to IPD 4.2.3.1 IPD from an Individual Trial 4.2.3.2 The Applicability of the Copyright Type of Database Protection 4.2.3.3 The Applicability of the sui generis Database Right 4.2.4 Data Exclusivity Protection 4.2.4.1 The Abridged Procedure for Drug Marketing Authorisation 4.2.4.2 Data Exclusivity as a Temporary Derogation from the Abridged Procedure 4.2.4.3 The Nature and Scope of Test Data Exclusivity Protection 4.2.5 Contractually Obtained Exclusive Control 4.2.5.1 Contractual Practice Related to Obtaining Clinical Trial Data 4.2.5.2 Implications of Contractually Defined `Exclusive Property ́ in Trial Data 4.3 Access Regimes Applicable to Clinical Trial Data 4.3.1 Regulatory Requirements for Clinical Trial Data Disclosure 4.3.1.1 What Data Is (Supposed to Be) in the Public Domain? 4.3.1.2 Uncertainty Regarding the Definition of CCI 4.3.2 The Relevance of the Right of Access to Personal Data 4.3.3 Access to IPD Under the Right of Access to Documents 4.3.3.1 The Right of Access to Documents Held by Public Authorities 4.3.3.2 The Exception for Protection of Commercial Interests in the Case of Clinical Trial Data The Exception for Protection of Commercial Interests The Existence of the General Presumption of Confidentiality for CSRs 4.3.3.3 Implications for the Publication of Clinical Trial Data in the EU Database 4.3.3.4 Limitations of the Right of Access to Documents as an Instrument of Access to IPD for Research Purposes 4.3.4 Competition Law as an (Unsuitable) Instrument of Access to IPD 4.3.4.1 Access to IPD as a Hypothetical Case on a Refusal to Deal 4.3.4.2 The Assessment of a Refusal to Grant Access to IPD for Exploratory Analysis Under Article 102 of the TFEU The Standard of Intervention Where Access to Information or Data Is Refused The Dominance of the IPD Holder IPD Indispensability for Exercising an Activity on a Neighbouring Market The Exclusion of Effective Competition in a Neighbouring Market The Appearance of a New Product for Which There Is Potential Consumer Demand The Objective Justification of a Refusal 4.3.4.3 Conclusion on the Application of Competition Law 4.4 Conclusion on Chapter 4 References Chapter 5: Implications of IPD Disclosure for Statutory Innovation Incentives 5.1 The Impediment-to-Innovation-Incentives Claim 5.1.1 Arguments Submitted During the EMA Public Consultation 5.1.2 Arguments Raised Before the CJEU 5.1.3 Restrictive Provisions Under the Industry Data-Sharing Policies 5.2 Dissecting the Claim 5.2.1 Innovation 5.2.2 Innovation Incentives 5.2.3 The Problem of Appropriability in Drug Innovation 5.2.4 Innovation Incentives 5.2.4.1 Patents and SPCs 5.2.4.2 Incentive Instruments Under the Sector Legislation 5.3 Implications of IPD Disclosure for Patent Protection 5.3.1 Concerns of Drug Companies 5.3.2 Implications of Non-summary Clinical Trial Data Disclosure for Patentability 5.3.2.1 Novelty 5.3.2.2 Inventive Step 5.3.2.3 Summary of Implications of Data Disclosure for Patentability 5.3.2.4 Implications of Disclosure for SPC Protection 5.4 Implications of IPD Disclosure for Sector-Specific Incentives 5.4.1 Implications of Data Disclosure for Data Exclusivity Protection in the EU 5.4.1.1 Concerns Regarding the Circumvention of Data Exclusivity Protection 5.4.1.2 Implications of Data Disclosure for Test Data Exclusivity Protection in the EU 5.4.1.3 The Risk of Misusing Disclosed Data Outside of the EU 5.4.2 Implications of Data Disclosure for Orphan Drug Exclusivity 5.5 Conclusion on Chapter 5 References Part III: Analysis De Lege Ferenda: Exclusively Controlled or Readily Accessible? Chapter 6: Defining the Intervention Logic of Access-To-Data Measures: A Problem Analysis 6.1 General Principles of Regulatory Intervention 6.1.1 Regulatory Intervention as an Exception 6.1.2 The Grounds for Policy Intervention 6.1.3 Social Welfare as a Normative Benchmark 6.1.4 Necessity and Proportionality as the Guiding Principles 6.2 The European Commission ́s Methodology for Problem Analysis 6.2.1 The `Intervention Logic ́ 6.2.1.1 The Components of the Intervention Logic 6.2.1.2 Causality 6.2.1.3 The Choice of a Policy Measure 6.2.2 The Framework for the Problem Analysis 6.3 Defining the Status Quo of Access to Non-Summary Clinical Trial Data 6.3.1 Summarising the Legal Status Quo of Access to Clinical Trial Data 6.3.2 Evidence on Industry Data-Sharing Practice 6.4 Dissecting the Problem of Access 6.4.1 The `Problem Tree ́ 6.4.2 The Issue of Reproducibility of Clinical Trials 6.4.2.1 The Concept of Research Reproducibility 6.4.2.2 Systematic Errors (Research `Biases ́) 6.4.2.3 The `Industry Bias ́ 6.4.2.4 Empirical Studies on the `Industry Bias ́ 6.4.2.5 The Role of Access to Non-summary Data in Improving Research Quality 6.4.2.6 Implications for Clinical Practice 6.4.3 The Issue of the Under-Realised Research Potential of Clinical Trial Data 6.4.3.1 Concerns 6.4.3.2 The Scope of the Problem 6.4.4 The `Objectives Tree ́ 6.5 The Regulatory Status Quo 6.5.1 The Issue of Research Quality Under the Current Framework 6.5.1.1 Relevant Regulatory Provisions 6.5.1.2 Does the EMA Collect and Hold IPD? 6.5.2 Provisions Related to Exploratory Data Analysis 6.5.2.1 Derogations from Personal Data Protection for Scientific Research 6.5.2.2 Reservations for the Protection of Economic Interests of Trial Sponsors 6.6 The Summary and Conclusion References Chapter 7: Access to Clinical Trial Data as a Case on RandD Externalities: A Theoretical Framework 7.1 Framing the Dilemma 7.1.1 Clinical Trial Data as a Non-rivalrous Research Tool 7.1.1.1 Clinical Trial Data as an Inherently Public Good 7.1.1.2 Digital Data as an Intermediate Good and a Research Infrastructure 7.1.1.3 Data as a Dual-Purpose Research Tool 7.1.2 The `Access-Incentives Paradox ́ 7.1.3 Limitations of the Welfare Cost-Benefit Analysis 7.1.4 The Notion of RandD Externalities as the Common Denominator 7.2 RandD Externalities in Innovation Law: A Theoretical Framework 7.2.1 The Concept of RandD Externalities 7.2.2 Imitation Externalities v Research Externalities 7.2.3 Multiple Implications of Knowledge Externalities for Innovation 7.2.3.1 The Efficiency-Enhancing Effect of RandD Externalities 7.2.3.2 The Efficiency-Reducing Effect of RandD Externalities The Disincentive Effect of RandD Externalities A Trade-off Between Knowledge Diffusion and Innovation Incentives Patent Rights as a Means to Prevent the Disincentive Effect of Knowledge `Spillovers ́ 7.2.3.3 The Issue of Excessive Incentives Due to Knowledge Spillovers The `Exhaustion ́ Externality or the `Stepping-on-Toes ́ Effect Duplicative Research v Multiplicity and Diversity of Experimentation The (Controversial) Role of Patents as a Means to Coordinate Research Efforts 7.3 The Summary of Theoretical Propositions and Implications for Further Analysis 7.3.1 A Systematic View on RandD Externalities 7.3.2 General Caveats 7.3.3 The `Access-Incentives Dilemma ́ Revisited References Chapter 8: IPD as a Research Resource: Exclusively Controlled or Readily Accessible? 8.1 Examining a Potential Disincentive Effect of Clinical Trial Data Disclosure 8.1.1 The Relationship Between Clinical Trial Data and the Problem of Incentives in Drug Innovation 8.1.2 Protection of the Competitive Advantage as an Innovation Incentive 8.1.2.1 The Structure of the Pharmaceutical Market 8.1.2.2 New Medicinal Products: First-in-Class v Follow-on Drugs 8.1.2.3 Competitive Strategies of Drug Companies 8.1.2.4 Innovation as the Main Parameter of Competition in the Pharmaceutical Sector 8.1.2.5 The Hypothesis Regarding the Effects of Data Disclosure on Innovation Incentives 8.1.3 Implications of Non-summary Clinical Trial Data Disclosure for Competition by Imitation 8.1.3.1 The Relevance of Access to IPD for Generic and Biosimilar Drug Development and Manufacturing 8.1.3.2 Relevance of IPD Disclosure for the Protection Against the Competition by Imitation 8.1.4 Implications of IPD Disclosure for Competition in Innovation 8.1.4.1 New Research Hypothesis as a Technological Opportunity 8.1.4.2 Concerns About the Impact of Data Disclosure on Competitive Advantage in Drug RandD 8.1.4.3 Potential Scenarios Follow-on Improvements of the Investigational Product New Medical Use of the Initial Investigational Product A Different Chemical Structure and a Different Therapeutic Indication 8.1.4.4 Analysis Theoretical Assumptions The Case of Drug Improvements Protection of Exploratory Endpoints as Intermediate Research Results 8.1.4.5 The Interim Conclusion 8.2 The Issue of the Underutilised Research Potential of Data 8.2.1 Concerns Regarding Lost Research Opportunities 8.2.2 A `Tragedy of Anticommons ́ Due to Exclusive Control Over IPD? 8.2.2.1 The Notion of Anticommons 8.2.2.2 `Anticommons ́ as the Problem of Unrealised Value Due to the Failure to Cooperate 8.2.2.3 The Analogy Between Exclusive Control Over IPD and Patents for Biotechnological Research Tools 8.2.2.4 The Relevance of the Concept of Anticommons for Clinical Trial Data 8.2.3 Foregone Efficiencies in Drug Development as a Distinct Social Cost 8.2.3.1 Duplicative v Cumulative Research 8.2.3.2 The Role of Secondary Analysis of Clinical Trial Data in Fostering Cumulativeness of Drug RandD 8.2.3.3 Reducing Uncertainty 8.3 The Issue of Wasteful Duplication of Research Efforts Due to Data Disclosure 8.3.1 The Hypothesis Regarding Wasteful Duplication of Research Efforts 8.3.2 Factors Contributing to Duplicative RandD 8.3.3 The Rivalry of RandD Benefits 8.3.4 Clinical Trial Data as a Rivalrous and Non-rivalrous Good 8.3.5 Evidence on Secondary Analysis of Clinical Trial Data in the Industry RandD 8.4 On Balance 8.4.1 The Summary of Implications of IPD Disclosure for the Allocation of Resources to RandD 8.4.2 Conclusion on Policy Implications References Chapter 9: Evaluating Legislative Options 9.1 General Aspects of the Access Regime 9.1.1 Policy Objectives 9.1.2 Data-Sharing as a Matter of Regulation at EU Level 9.1.3 The Overarching Principles 9.1.4 Main Parameters of the Access Regime 9.2 Policy Options 9.2.1 Arguments for the State Provision of Clinical Trials 9.2.2 More Feasible Policy Approaches 9.3 `Doing Nothing ́ 9.3.1 Factors of Efficient Allocation of Rights Through Negotiations 9.3.2 Factor Analysis 9.3.2.1 Parties ́ Motivation for Negotiations Personal Data Protection The Lack of the Established Practice Loss Aversion 9.3.2.2 Uncertainty About the Prospective Benefits 9.3.2.3 Transaction Costs 9.3.2.4 Concerns Regarding `Stacking Licenses ́ 9.3.2.5 A Reverse `Information Paradox ́ 9.3.2.6 On Balance 9.4 IPD Disclosure as an Instrument of Access 9.4.1 Can Erga Omnes Disclosure of IPD Improve Research Reproducibility? 9.4.2 Can IPD Public Disclosure Maximise the Research Potential of Data? 9.5 Creating a Statutory Right to Access and Use IPD for Research Purposes 9.5.1 The Analogy with the Right of Access to Test Data Under the REACH Regulation 9.5.1.1 The REACH Model of Mandatory Data-Sharing 9.5.1.2 Applying the REACH Model to Clinical Trial Data 9.5.2 The Pros and Cons of the Right of Access to IPD 9.6 A Centralised Clinical Trial Data Repository 9.6.1 The Data Repository Model 9.6.2 The Pros and Cons of a Centralised Repository for IPD 9.6.3 The Legislative Implementation 9.6.3.1 Mandatory Data Transfer as a Default Rule 9.6.3.2 Safeguards and Reservations Personal Data Protection Economic Interests of Trial Sponsors Public Interest in Transparency 9.6.4 Conclusion on Chapter 9 References Chapter 10: Final Conclusions and the Outlook 10.1 Conclusions de lege lata 10.2 Conclusions de lege ferenda 10.3 The Outlook 10.3.1 Shifting the Focus from Access to Data Analysis 10.3.2 Access to IPD as a Case Study on Data-Driven Innovation 10.3.3 Access to IPD as a Case on RandD Externalities Annex A Statistics on Requests for Access to Documents Held by the EMA (2012-2020) Annex B Glossary of Terms Related to the Design and Methodology of Randomised Clinical Trials