• Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology

      Bourgeois, Florence; Hong, Kyungwan; Lee, Haeyoung; Shamseer, Larissa; Spence, O'Mareen; Jefferson, Tom; Doshi, Peter; Jones, Mark A., B.Sc., Ph.D. (BMJ, 2020-03-17)
      Purpose: Trustworthy reporting of quadrivalent human papillomavirus (HPV) vaccine trials is the foundation for assessing the vaccine’s risks and benefits. However, several pivotal trial publications incompletely reported important methodological details and inaccurately described the formulation that the control arms received. Under the Restoring Invisible and Abandoned Trials initiative (RIAT), we aim to restore the public record regarding the content and rationale of the controls used in the trials. Methods: We assembled a cohort (five randomised controlled trials) described as placebo-controlled using clinical study reports (CSRs) obtained from the European Medicines Agency. We extracted the content and rationale for the choice of control used in each trial across six data sources: trial publications, register records, CSR synopses, CSR main bodies, protocols and informed consent forms. Results: Across data sources, the controlwas inconsistently reported as ‘placebo’- containing aluminium adjuvant (sometimes with dose information). Amorphous aluminium hydroxyphosphate sulfate (AAHS) was not mentioned in any trial registry entry, but was mentioned in all publications and CSRs. In three of five trials, consent forms described the control as an ‘inactive’ substance. No rationale for the selection of the control was reported in any trial publication, register, consent form, CSR synopsis or protocol. Three trials reported the rationale for choice of control in CSRs: to preserve blinding and assess the safety of HPV virus-like particles as the ‘safety profile of (AAHS) is well characterised’. Conclusions: The stated rationale of using AAHS control—to characterise the safety of the HPV virus-like particles—lacks clinical relevance. A nonplacebo control may have obscured an accurate assessment of safety and the participant consent process of some trials raises ethical concerns. Trial registration numbers NCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.
    • Contradictory findings on efficacy of neuraminidase inhibitors not cited

      Doshi, Peter; Jefferson, Tom; Heneghan, Carl; Jones, Mark A., B.Sc., Ph.D. (Oxford University Press (OUP), 2020-04-24)
    • Does oseltamivir really reduce complications of influenza?

      Cochrane Neuraminidase Inhibitors Review Team; Del Mar, Chris; Doshi, Peter; Hama, Rokuro, M.D.; Heneghan, Carl; Jefferson, Tom; Jones, Mark A., B.Sc., Ph.D.; Thompson, Matthew J. (University of Chicago Press, 2011-12-15)
    • Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data

      Heneghan, Carl; Onakpoya, Igho; Jones, Mark A., B.Sc., Ph.D.; Doshi, Peter; Del Mar, Chris; Hama, Rokuro, M.D.; Thompson, Matthew J.; Spencer, Elizabeth A.; Mahtani, Kamal R.; Nunan, David, M.Sc., Ph.D.; et al. (NIHR Journals Library, 2016)
      Objectives: To investigate the practice of post-marketing studies in Germany during a three year period and to evaluate whether these trials meet the aims specified in the German Medicinal Products Act. Design: Survey of notifications submitted to German regulatory agencies before post-marketing studies were carried out, 2008-10. Setting: Notifications obtained through freedom of information requests to the three authorities responsible for registering post-marketing studies in Germany. Main outcome measures: Descriptive statistics of post-marketing studies, including the products under study, intended number of patients, intended number of participating physicians, proposed remunerations, study plan and protocol, and availability of associated scientific publications and reports on adverse drug reactions. Results: Information was obtained from 558 studies, with a median of 600 (mean 2331, range 2-75 000) patients and 63 (270, 0-7000) participating physicians per study. The median remuneration to physicians per patient was €200 (€441, €0-€7280) (£170, £0-£6200; $215, $0-$7820), with a total remuneration cost of more than €217m for 558 studies registered over the three year period. The median remuneration per participating physician per study was €2000 (mean €19 424), ranging from €0 to €2 080 000. There was a broad range of drugs and non-drug products, of which only a third represented recently approved drugs. In many notifications, data, information, and results were, by contract, strictly confidential and the sole property of the respective sponsor. No single adverse drug reaction report could be identified from any of the 558 post-marketing studies. Less than 1% of studies could be verified as published in scientific journals. Conclusions: Post-marketing studies are not improving drug safety surveillance. Sample sizes are generally too small to allow the detection of rare adverse drug reactions, and many participating physicians are strictly obliged to maintain confidentiality towards the sponsor. High remuneration and strict confidentiality clauses in these studies could influence the physicians’ reporting behaviours of adverse drug reactions.
    • Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

      Jefferson, Tom; Jones, Mark A., B.Sc., Ph.D.; Doshi, Peter; Spencer, Elizabeth A.; Onakpoya, Igho; Heneghan, Carl (BMJ Publishing Group, 2014-04-09)
    • Restoring biomedical literature with RIAT

      Doshi, Peter; Shamseer, Larissa; Jones, Mark A., B.Sc., Ph.D.; Jefferson, Tom (BMJ Publishing Group, 2018-04-26)
    • Rethinking credible evidence synthesis

      Doshi, Peter; Jones, Mark A., B.Sc., Ph.D.; Jefferson, Tom (BMJ Publishing Group, 2012-01-17)
    • Risk of bias in industry-funded oseltamivir trials: comparison of core reports versus full clinical study reports

      Jefferson, Tom; Jones, Mark A., B.Sc., Ph.D.; Doshi, Peter; Del Mar, Chris; Hama, Rokuro, M.D.; Thompson, Matthew J.; Onakpoya, Igho; Heneghan, Carl (BMJ Publishing Group, 2014-09)
    • The use of clinical study reports to enhance the quality of systematic reviews: a survey of systematic review authors

      Hodkinson, Alex; Dietz, Kristina Charlotte; Lefebvre, Carol; Golder, Su; Jones, Mark A., B.Sc., Ph.D.; Doshi, Peter; Heneghan, Carl; Jefferson, Tom; Boutron, Isabelle; Stewart, Lesley (London: BioMed Central, 2018-08-08)
      Background: Clinical study reports (CSRs) are produced for marketing authorisation applications. They often contain considerably more information about, and data from, clinical trials than corresponding journal publications. Use of data from CSRs might help circumvent reporting bias, but many researchers appear to be unaware of their existence or potential value. Our survey aimed to gain insight into the level of familiarity, understanding and use of CSRs, and to raise awareness of their potential within the systematic review community. We also aimed to explore the potential barriers faced when obtaining and using CSRs in systematic reviews. Methods: Online survey of systematic reviewers who (i) had requested or used CSRs, (ii) had considered but not used CSRs and (iii) had not considered using CSRs was conducted. Cochrane reviewers were contacted twice via the Cochrane monthly digest. Non-Cochrane reviewers were reached via journal and other website postings. Results: One hundred sixty respondents answered an open invitation and completed the questionnaire; 20/160 (13%) had previously requested or used CSRs and other regulatory documents, 7/160 (4%) had considered but not used CSRs and 133/160 (83%) had never considered this data source. Survey respondents mainly sought data from the European Medicines Agency (EMA) and/or the Food and Drug Administration (FDA). Motivation for using CSRs stemmed mainly from concerns about reporting bias 11/20 (55%), specifically outcome reporting bias 11/20 (55%) and publication bias 5/20 (25%). The barriers to using CSRs noted by all types of respondents included current limited access to these documents (43 respondents), the time and resources needed to obtain and include these data in evidence syntheses (n = 25) and lack of guidance about how to use these sources in systematic reviews (n = 26). Conclusions: Most respondents (irrespective of whether they had previously used them) agreed that access to CSRs is important, and suggest that further guidance on how to use and include these data would help to promote their use in future systematic reviews. Most respondents who received CSRs considered them to be valuable in their systematic review and/or meta-analysis.