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Increasing the impact of Post Authorisation Safety Studies: transparency is key

Published:December 01, 2020DOI:https://doi.org/10.1016/j.ejim.2020.11.019

      Keywords

      In ETNA VTA Europe: A contemporary snapshot of patients treated with edoxaban in clinical practice across eight European countries, Cohen et al. report the results of a non-interventional drug utilisation study of edoxaban and conclude that these data reinforce the largely appropriate use of edoxaban in clinical practice [

      Cohen AT, Hoffmann U, Hainaut P et al. EtNA VTA Europe: A comtenporary snapshot of patients treated with edoxaban in clinical practice across eight European countries. Eur J Intern Med. https://doi.org/10.1016/j.ejim.2020.08.014.

      ]. This report is part of the ETNA-VTA Europe post-authorisation safety study (PASS) included by the pharmaceutical company in the Risk Management Plan (RMP) of the product at the time of its marketing authorisation application [

      European Medicines Agency. Lixiana: EPAR- Public Assessment Report. http://www.ema.europa.eu.

      ]. The authors point out the limitations of the clinical trials to genuinely reflect real-world settings and concerns [
      • Buffel du Vaure C
      • Dechartres A
      • Battin C
      et al. Exclusion of patients with concomitant chronic conditions in ongoing randomised controlled trials targeting 10 common chronic conditions and registered at ClinicalTrials.gov: a systematic review of registration details.
      ,
      • Heneghan C
      • Goldacre B
      • Mahtani K
      Why clinical trial outcomes fail to translate into benefits for patients.
      , and post-authorisation safety studies are particularly important for regulatory authorities to further evaluate the safety of medicines as used in clinical practice (of note in the case of edoxaban, the summary of product characteristics recommends a reduced dose of 30mg in patients with renal impairment, with a bodyweight ≤ 60 kg and those receiving specific P-glycoprotein inhibitors).
      In the European Union, a PASS can be conducted voluntarily by a pharmaceutical company or it can imposed as a legal obligation by the European Medicines Agency (EMA) or a national competent authority whenever its results would significantly impact on the risk-benefit profile of the medicinal product. Results of a PASS may inform regulators in taking measures for the protection of patients and the safe use of the medicine. Examples of (risk minimisation) measures that may be taken include an amendment of the product information or a restriction of the use of the product to some indications or some categories of patients. The regulatory oversight of PASSs by the EMA Pharmacovigilance Risk Assessment Committee (PRAC) includes an in-depth review of the study protocol and its results in order to assess the possible impact of the outcomes [
      • Santoro A
      • Genov G
      • Spooner A
      • et al.
      Promoting and Protecting Public Health: How the European Union Pharmacovigilance System Works.
      ,

      European Medicines Agency. The Good Pharmacovigilance Practice Module VIII (rev. 3) – Post-authorisation safety studies. http://www.ema.europa.eu.

      . The ETNA VTA study is a good illustration of a PASS conducted voluntarily. It aimed to gain further insight into the use of edoxaban in routine clinical practice, including compliance to the summary of product characteristics (SmPC), the use of a heparin lead-in, dosing patterns and the consideration of concomitant diseases.
      The high level of scrutiny applied by regulators to PASS protocols and results is also justified by the potential conflicts of interests that may exist where pharmaceutical companies are requested to conduct PASS that may, at the end of the process, negatively affect their commercial interests. For this reason, the EMA strongly recommends in the Good Pharmacovigilance Practices [

      European Medicines Agency. The Good Pharmacovigilance Practice Module VIII (rev. 3) – Post-authorisation safety studies. http://www.ema.europa.eu.

      ] that the companies conducting a PASS adhere to the Code of Conduct published by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [
      • Gini R
      • Fournie X
      • Dolk H
      • Kurz X
      • Verpillat P
      • Simondon F
      • Strassmann V
      • Apostolidis K
      • Goedecke T
      The ENCePP Code of Conduct: A best practise for scientific independence and transparency in noninterventional postauthorisation studies.
      ,. The ENCePP Code of Conduct aims to promote scientific independence and transparency in the relationship between investigators and funders throughout the research process and, consequently, to strengthen the confidence of the general public and the scientific community in the integrity and value of the research. The ENCePP Code of Conduct also applies to post-authorisation safety studies requested by regulators and addresses many aspects including the rights and obligations of the researchers and the funder, declarations of interest, the research contract, the ownership and reporting of results and the publications. In the current environment where doubts are expressed on the value of real-world evidence on medicinal products [
      • Ioannidis J.
      Why most published research findings are false.
      ,
      • Collins R
      • Bowman L
      • Landray M
      • Peto R
      The Magic of Randomization versus the Myth of Real-World Evidence.
      , adherence to the ENCePP Code of Conduct, with a corresponding statement in publications, is an important element that may increase the credibility of the results of funded studies. In this study by Cohen et al., the registration of the study in the European Union Post-Authorisation Studies (EU PAS) register (number EUPAS15504) [

      The European Union electronic Register of Post-Authorisation Studies (EU PAS Register). http://www.encepp.eu/encepp/studiesDatabase.jsp.

      ] and the pre-publication of the study protocol [
      • At Cohen
      • C Ay
      • Hainaut P
      • et al.
      Design and rationale of the noninterventional, edoxaban treatment in routiNe clinical prActice in patients with venous ThromboEmbolism in Europe (ETNA-VTE-Europe) study.
      ] are much appreciated transparency actions. In line with the recommendations of the EMA Good Pharmacovigilance Practices [

      European Medicines Agency. The Good Pharmacovigilance Practice Module VIII (rev. 3) – Post-authorisation safety studies. http://www.ema.europa.eu.

      ], it would have been also desirable to upload the study protocol in the register before the start of data collection and provide the EU PAS registration number in the publication.
      Journals’ editors have also an important role to play to increase the impact of published PASS if the results may have public health consequences. Following the retraction of a publication based on data of uncertain provenance and quality, the Lancet journals will now require all research papers, irrespective of method, to include data-sharing statements about which data will become available and when and how they will become available. These data-sharing statements will be taken into account when making editorial decisions [
      The Editors of the Lancet Group
      Learning from a retraction.
      ]. This requirement might be followed by other journals. For real-world post-authorisation studies, statements about the registration of the study in the EU PAS register (with the registration number), the date of the posting of the protocol (before or after the start of data collection) and the adherence to the ENCePP Code of Conduct could support statements about transparency and data sharing and the editorial decision to publish. This process can not only increase the quality of protocols that will become public and subject to peer-review [
      • Schneeweiss S
      • Avorn J.
      Post-marketing studies of drug safety.
      ], it will also increase the dissemination and use of the results, and finally make best use of time and money for both investigators and pharmaceutical companies.

      Disclaimer

      The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agencies or organisations with which the authors are employed/affiliated.

      Conflict of Interest statement

      All authors declared no competing interests for this work.

      Funding

      No funding was received.

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