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Reporting the details of consent procedures in clinical trials

  • Rafael Dal−Ré
    Correspondence
    Corresponding author. Unidad de Epidemiología, Instituto de Investigación Sanitaria-Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avda. Reyes Católicos 2, E-28040 Madrid, Spain. Tel.: +34-649410221; fax: +34-914974083.
    Affiliations
    Epidemiology Unit, Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain
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  • Berge Solberg
    Affiliations
    Bioethics Group, Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway
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  • Uwe Fuhr
    Affiliations
    University of Cologne Faculty of Medicine and University Hospital Cologne Centre of Pharmacology, Department I of Pharmacology, Clinical Pharmacology Unit, Cologne, Germany
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  • Stefan Eriksson
    Affiliations
    Centre for Research Ethics & Bioethics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
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Published:September 19, 2019DOI:https://doi.org/10.1016/j.jclinepi.2019.09.014
      We read with interest the report by Kotz et al. [
      • Kotz D.
      • Viechtbauer W.
      • Spigt M.
      • Crutzen
      Details about informed consent procedures of randomized controlled trials should be reported transparently.
      ] calling for transparent and full reporting of participants' information sheets (PISs)—ideally including an English translation—used in randomized controlled trials (RCTs), published as supplementary material or otherwise. They suggest that this requirement should be included in future versions of CONSORT and other guidelines. Kotz et al. worry that participants are insufficiently informed, which may cause bias. Publishing PISs would make it possible for readers to judge whether the information might have affected participants’ decision to participate. We believe this suggestion misses the mark.
      First, it is possible that Kotz et al. overstated the risk of being insufficiently informed. The examples of “very brief” information mentioned came from three articles of RCTs conducted in Brazil [
      • Vitolo M.R.
      • Bortolini G.A.
      • Dal Bo Campagnolo P.
      • Feldens C.A.
      Effectiveness of a nutrition program in reducing symptoms of respiratory morbidity in children: a randomized field trial.
      ], Spain [
      • Duran-Cantolla J.
      • Aizpuru F.
      • Montserrat J.M.
      • Ballester E.
      • Teran-Santos J.
      • Aguirregomoscorta J.I.
      • et al.
      Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial.
      ], and the United States [
      • Davidson K.W.
      • Rieckmann N.
      • Clemow L.
      • Schwartz J.E.
      • Shimbo D.
      • Medina V.
      • et al.
      Enhanced depression care for patients with acute coronary syndrome and persistent depressive symptoms: coronary psychosocial evaluation studies randomized controlled trial.
      ]. But all three articles stated that their RCT was approved by the relevant research ethics committee (REC). One of the main responsibilities of RECs is to review the informed consent process and PIS and, in fact, many question the appropriateness of the included information [
      • Dal-Ré R.
      • Espada J.
      • Ortega R.
      Performance of research ethics committees in Spain. A prospective study of 100 applications for clinical trial protocols on medicines.
      ]. RECs are better equipped to judge the information provided by the PIS than are most readers. With an REC approval, we have to reasonably trust the appropriateness of that PIS.
      Second, the applicable guidelines and laws often depend on the types of intervention assessed in the trial and can heavily affect the content of the PIS. In the examples mentioned by Kotz et al., there were regulated (medicine, device) [
      • Duran-Cantolla J.
      • Aizpuru F.
      • Montserrat J.M.
      • Ballester E.
      • Teran-Santos J.
      • Aguirregomoscorta J.I.
      • et al.
      Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial.
      ,
      • Davidson K.W.
      • Rieckmann N.
      • Clemow L.
      • Schwartz J.E.
      • Shimbo D.
      • Medina V.
      • et al.
      Enhanced depression care for patients with acute coronary syndrome and persistent depressive symptoms: coronary psychosocial evaluation studies randomized controlled trial.
      ] and nonregulated (nutrition) [
      • Vitolo M.R.
      • Bortolini G.A.
      • Dal Bo Campagnolo P.
      • Feldens C.A.
      Effectiveness of a nutrition program in reducing symptoms of respiratory morbidity in children: a randomized field trial.
      ] interventions that could be subject to ethical assessments based on different regulations or guidelines. To assess the information included in the PIS, RECs generally use the ICH's GCP Guidelines [
      ] and the Declaration of Helsinki [
      WMA Declaration of Helsinki – Ethical principles for medical research involving human subjects.
      ] or the CIOMS guidelines [
      Council for International Organizations of Medical Sciences (CIOMS)
      International Ethical Guidelines for Health-related Research involving Humans. Geneva.
      ]. In some countries, additional research regulation [
      Spain. Ley 14/2007, de 3 de julio, de investigación biomédica
      BOE nº 159, de 4 de julio de 2007.
      ,
      US Code of Federal Regulations
      21CFR50.25 Protection of human subjects.
      ,
      ,
      Norway. ACT 2008-06-20 no. 44: Act on medical and health research (the Health Research Act).
      ] or guidance documents [
      UK. NHS Health Research Authority Informing participants and seeking consent 11 Mar 2019.
      ,
      Germany. Arbeitskreis Medizinischer Ethik-Kommissionen in der Bundesrepublik Deutschland e.V..
      , ,
      Norway. REK
      Regional committees for medical and health research ethics. Templates for participation information and consent.
      ] and legislation on data protection are considered. When informing participants, these various regulations/guidelines will play a part in forming the understanding of what is said and its implications. Just reading the PIS will not convey this framework. Thus, much more is required beyond publishing the PIS to assess its appropriateness. To make matters worse, both PISs and regulations might only be accessible in national languages, thereby creating an obvious barrier to appraisals.
      Third, it is questionable whether the cost is defendable. As we have shown, a call for translating PISs into English is insufficient. By itself, that would not make possible an effective and fair assessment of its appropriateness. PISs would have to be both professionally translated and checked for accurateness to have the required precision needed for enabling a thorough assessment.
      Fourth, PISs have traditionally been regarded as an ethical issue and not a “quality” issue. Details about informed consent procedures have not been seen as relevant for the interpretation of findings from a trial. Despite the attempt of Kotz et al. to show such a relevance, it is not easy to become convinced how reporting of PIS actually may change the interpretation of the findings in a trial because any deficiency on the quality of a PIS would have affected all trial participants—regardless of the treatment received. We believe that a PIS belongs to the domain of research ethics.
      Fifth, and most importantly, the suggestion of Kotz et al. assumes that PIS actually show the content of the informed consent. By contrast, informed consent should involve both verbal and written information and might involve different members of the investigating team in discussion, where potential participants raise questions. In other words, informed consent is a process that might also continue all through the trial. This process is not captured by the content of PIS alone, regardless that many investigators—as stated by Kotz et al.—behave as if seeking informed consent merely is the action concluded by signing a form. Requesting researchers to publish PISs will convey the message that this is the only relevant part of the whole consent process.
      Still, to publish PISs with the trial results might be useful if fulfilling a few requirements and is applicable to all types of trial, RCTs and nonRCTs. PISs should be published in the original language, investigators should report which regulations/guidelines were applicable when the trial was assessed by the REC, and describe how informed consent was collected (e.g., which members of the investigating team were involved, the time elapsed between the discussion of the PIS and the signing of the consent form, any additional information provided when the trial was ongoing). In most cases, we should be content with the review of PIS conducted by RECs in each country. Because RECs approved the three RCTs mentioned previously [
      • Vitolo M.R.
      • Bortolini G.A.
      • Dal Bo Campagnolo P.
      • Feldens C.A.
      Effectiveness of a nutrition program in reducing symptoms of respiratory morbidity in children: a randomized field trial.
      ,
      • Duran-Cantolla J.
      • Aizpuru F.
      • Montserrat J.M.
      • Ballester E.
      • Teran-Santos J.
      • Aguirregomoscorta J.I.
      • et al.
      Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial.
      ,
      • Davidson K.W.
      • Rieckmann N.
      • Clemow L.
      • Schwartz J.E.
      • Shimbo D.
      • Medina V.
      • et al.
      Enhanced depression care for patients with acute coronary syndrome and persistent depressive symptoms: coronary psychosocial evaluation studies randomized controlled trial.
      ], there is no reason why readers should assume that the PISs used did not fulfill the national regulations and that the “very brief” information reported in the articles was the only information actually provided to participants.
      Finally, the informed consent process information is only a small part of the trial documentation, and if full transparency for the public should be achieved to allow unrestricted assessment, other documents such as the protocol, the (core) clinical trial report, the statistical analysis plan, and any raw data might be more relevant. But again, investigators should publish all these documents in the original language.

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      1. Conference on Harmonisation (ICH): ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6(R1), Step 4 version. ICH, Geneva1996 (Available at:)
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