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Working towards harmonised access to clinical trial data across European drug regulatory agencies

On 31 May 2021, a group of researchers and NGOs (see list of signatories in the acknowledgement section below) submitted an open letter to the Heads of Medicines Agencies, a European umbrella organisation consisting of the heads of the national drug regulatory agencies, proposing them to harmonise access to clinical trial data across European drug regulatory agencies. [1]

During 2018 and 2019, independent researchers (two of the signatories) approached several European national drug regulatory agencies and requested access to documents related to clinical trials of ADHD medications and statins for use in systematic reviews. [2-4] The documents, known as Clinical Study Reports, are submitted by pharmaceutical companies to drug regulators as part of marketing authorisation applications. Some regulators granted access to this data, whereas the German and Finnish regulators did not, arguing the data are confidential and thus could not be shared. [2] The rejections are described in more detail in our letter. [1] The rejections revealed important differences in Clinical Study Reports’ legal status in Europe, which may prevent access to important data. This can have detrimental consequences for independent drug assessments. 

The European legislative framework for clinical trials, the EU Trial Regulation 536/2014, stipulates that Clinical Study Reports are not considered confidential. [5] However, despite being passed in 2014, the regulation only comes into force in January 2022 due to problems with key IT infrastructure. [6] For that reason, the old EU Trial Directive 2001/20/EC7 is still applicable. The directive does not mention Clinical Study Reports and is therefore not helpful in ensuring access to data. 

On a regulatory level, the European Medicines Agency (EMA) practices a high level of transparency related to drugs centrally approved by the Agency. EMA has instated two “transparency policies”: Policy 0043 guarantees the right to access Clinical Study Reports of already centrally authorised drugs, and Policy 0070 ensures prospective release of newly centrally authorised drugs. [8,9]

Pharmaceutical companies have challenged these policies in court twice, arguing that the release of Clinical Study Reports is harmful to their business. [10-12] The European Court of Justice dismissed the arguments and ruled in favour of EMA’s transparency policies, stating that Clinical Study Reports do not constitute commercially confidential information in their entirety. [12]

The European pharmaceutical market is not governed solely by EMA, but also by national regulators. National drug regulatory agencies may authorise a drug for use in their own country (“national route”), or a group of countries may authorise a drug for use in those countries (“decentralised procedure”/”mutual recognition procedure”). [13] Importantly, because the old EU Trial Directive 20/2001/EC7 is still applicable, national European regulators are not obliged to adhere to European transparency policies. Therefore, national regulators authorise drugs according to local legislation, which may conflict with European transparency policies as we experienced. [1] 

Why we need access to Clinical Study Reports 

This discrepancy has created a loophole where centrally approved drugs are applicable to a high level of transparency, while drugs authorised through national routes are applicable to various degrees of transparency. This has three consequences: Clinical Study Reports from a drug authorised by national regulators may be inaccessible; independent researchers, guideline developers, and health technology assessment agencies may not be able to include important clinical data in systematic reviews and other research projects with potential detrimental impacts; and pharmaceutical companies may choose national or decentralised authorisations instead of EMA’s central approval.

Empirical studies have demonstrated that Clinical Study Reports contain more complete and exhaustive data compared to journal publications and clinical trial registries, especially with regards to patient-reported outcomes and harms. [14-18] Researchers therefore need Clinical Study Reports to make the most reliable drug assessments.

The Heads of Medicines Agencies is a European umbrella organisation consisting of the heads of the national drug regulatory agencies. [19] The HMA has previously, together with EMA, published a guideline on the confidentiality status of marketing authorisation applications. [20] Clinical Study Reports were classified as “can be released”, i.e. not confidential.

We, the signatories of the letter, have proposed the HMA introduce two concrete actions points. [1] First, the HMA should compile a list of the Clinical Study Report’s legal status in each EU Member State and flag conflicting national laws and practices that prevent sharing of Clinical Study Reports. Secondly, we propose the HMA should publish this list accompanied with a statement setting out its position on the issue of access to Clinical Study Reports. 

The HMA has no legal power to compel national regulators to adhere to European transparency policies. However, HMA’s engagement may draw attention to this issue within Member States, which is required to resolve the issue. In this context, it is important to highlight that the EU Trial Regulation 536/20145 will seemingly not apply retroactively. The regulation applies to new trials only and to trials not completed within three years after its application (see section 3.4). [21] Immediate national political action is therefore needed; otherwise clinical trial data from a large number of nationally authorised drugs may be lost.

We hope that our letter can help catalyse the necessary efforts towards harmonised access to Clinical Study Reports across European drug regulatory agencies.

Kim Boesen, Meta-Research Innovation Center Berlin (METRIC-B), Berlin Institute of Health at Charité, QUEST Center for Transforming Biomedical Research, Germany

Competing interests: None declared.

Acknowledgements:

Kim Boesen first-authored the open letter to the HMA. Co-signatories of the letter (in alphabetic order): Till Bruckner (TranspariMED), Ulrich Dirnagl (QUEST Center for Transforming Biomedical Research), Peter C Gøtzsche (Institute for Scientific Freedom), John PA Ioannidis (Meta-Research Innovation Center Berlin), Tom Jefferson (Department for Continuing Education, University of Oxford), and Jaume Vidal (Health Action International). Please refer to our letter for more details on the rejections and other background material.

References:

  1. Boesen K, et al. Open letter. Proposal to the Heads of Medicines Agencies to improve harmonisation of access to Clinical Study Reports across National Competent Authorities. 31 May 2021. Available from: https://www.bihealth.org/fileadmin/QUEST/Dokumente/Boesen_HMA_letter.pdf    (accessed June 2021).
  2. Boesen K, Danborg PB, Gøtzsche PC, Jørgensen KJ. Extended-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults (protocol). Cochrane Database Syst Rev 2017; 11: CD012857.
  3. Statins – a call for transparent data. Available from: https://www.bmj.com/campaign/statins-open-data (accessed June 2021).
  4. Jefferson T, Demasi M, Doshi P. Statins for primary prevention: what is the regulator’s role? BMJ Evid Based Med 2020; 26 Feb.
  5. Regulation No. 536/2014 of the European Parliament and of the council. Official Journal of the European Union 2014; L 158/1. Available from: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf (accessed June 2021).
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  8. European Medicines Agency. European Medicines Agency policy on access to documents. POLICY/0043. EMA/729522/2016. 4 October 2018. Available from: https://www.ema.europa.eu/en/documents/other/policy/0043-european-medicines-agency-policy-access-documents_en.pdf (accessed June 2021).
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  12. Court of Justice of the European Union. Press release No 6/20. The Court confirms the right of access to documents contained in the file of a marketing authorisation application for a medicinal product. 22 Jan 2020. Available from: https://curia.europa.eu/jcms/upload/docs/application/pdf/2020-01/cp200006en.pdf (accessed June 2021).
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  15. Maund E, Tendal B, Hrobjartsson A, et al. Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications. BMJ 2014;348:g3510.
  16. Jørgensen L, Gøtzsche PC, Jefferson T. Benefits and harms of the human papillomavirus (HPV) vaccines: comparison of trial data from clinical study reports with corresponding trial register entries and journal publications. Syst Rev 2020;9:42
  17. Paludan-Müller AS; Créquit P, Boutron I. Reporting of harms in oncological clinical study reports submitted to the European Medicines Agency compared to trial registries and publications—a methodological review. BMC Medicine 2021;19:88.
  18. Tamiflu campaign. Not dated. Available from: https://www.bmj.com/tamiflu (accessed June 2021).
  19. Heads of Medicines Agencies. Website. Front page. https://www.hma.eu/ (accessed June 2021).
  20. Heads of Medicines Agencies/European Medicines Agency. Principles to be applied for the implementation of the HMA/EMA Guidance on the identification of CCI and PPD in MA Applications. Edited 14 March 2012. Available from: https://www.hma.eu/fileadmin/dateien/HMA_joint/02-_HMA_Strategy_Annual_Reports/07-Transparency/2012_03_HMA_EMA_Principles_to_be_applied_20120309.pdf (accessed June 2021).
  21. European Medicines Agency. Appendix, on disclosure rules, to the “Functional specifications for the EU portal and EU database to be audited – EMA/42176/2014”. 2 Oct 2015. Available from: https://www.ema.europa.eu/en/documents/other/appendix-disclosure-rules-functional-specifications-eu-portal-eu-database-be-audited_en.pdf (accessed June 2021).