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Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology
  1. Peter Doshi1,
  2. Florence Bourgeois2,
  3. Kyungwan Hong1,
  4. Mark Jones3,
  5. Haeyoung Lee1,
  6. Larissa Shamseer1,4,
  7. O'Mareen Spence1,
  8. Tom Jefferson5,6
  1. 1Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
  2. 2Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Institute for Evidence-based Healthcare, Bond University, Gold Coast, Queensland, Australia
  4. 4University of Ottawa, Ottawa, Ontario, Canada
  5. 5Centre for Evidence-Based Medicine, University of Oxford, Oxford, UK
  6. 6Nordic Cochrane Centre, Copenhagen, Denmark
  1. Correspondence to Peter Doshi, Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA; pdoshi{at}rx.umaryland.edu

Abstract

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 control was 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 non-placebo control may have obscured an accurate assessment of safety and the participant consent process of some trials raises ethical concerns.

  • paediatric infectious disease & immunisation
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Footnotes

  • Contributors PD: conceptualisation; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; software; supervision; validation; visualisation; roles/writing: original draft; PD had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. LS: conceptualisation; data curation; methodology; data curation; writing: review and editing. TJ: conceptualisation; formal analysis; funding acquisition; investigation; methodology; roles/writing: original draft. KH: investigation; writing: review and editing. HL: investigation; writing: review and editing. FB: investigation; writing: review and editing. OS: data curation; writing: review and editing. MJ: investigation; writing: review and editing.

  • Funding Laura and John Arnold Foundation

  • Competing interests The Laura and John Arnold Foundation funds the RIAT Support Center which supports the salaries of Doshi, Bourgeois, Hong, Jefferson, Jones, Shamseer (until 2018) and Spence. In addition, PD has received travel funds from the European Respiratory Society (2012) and Uppsala Monitoring Center (2018); grants from the Laura and John Arnold Foundation (2017–2021), American Association of Colleges of Pharmacy (2015), Patient-Centered Outcomes Research Institute (2014–2016), Cochrane Methods Innovations Fund (2016–2018) and UK National Institute for Health Research (2011–2014); and is an editor at the BMJ and unpaid member of the Reagan-Udall Foundation for the FDA. TJ was a recipient of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza. In addition, TJ receives royalties from his books published by Il Pensiero Scientifico Editore, Rome and Blackwells. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011–2013, TJ acted as an expert witness in litigation related to the antiviral oseltamivir, in two litigation cases on potential vaccine-related damage (including the vaccine Pandemrix (2015–2017)) and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997–1999), GSK (2001–2002), Sanofi-Synthelabo (2003) and IMS Health (2013). In 2014, he was retained as a scientific adviser to a legal team acting on oseltamivir. TJ has a potential financial conflict of interest in the drug oseltamivir. In 2014–2016, TJ was a member of three advisory boards for Boehringer Ingelheim. TJ was holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. Between 1994 and 2013, TJ was the coordinator of the Cochrane Vaccines Field. TJ was a cosignatory of the Nordic Cochrane Centre Complaint to the European Medicines Agency (EMA) over maladministration at the EMA in relation to the investigation of alleged harms of HPV vaccines and consequent complaints to the European Ombudsman. TJ is coholder of a John and Laura Arnold Foundation grant for development of a RIAT Support Center (2017–2020) and Jean Monnet Network Grant, 2017–2020 for the Jean Monnet Health Law and Policy Network. TJ is an unpaid collaborator to the project Beyond Transparency in Pharmaceutical Research and Regulation led by Dalhousie University and funded by the Canadian Institutes of Health Research (2018–2022). TJ is a consultant to Illumina LLC (2019-current). MJ was a coinvestigator on a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza; was a corecipient of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews; and is a paid consultant on a John and Laura Arnold Foundation grant for development of an RIAT Support Center (2017–2020). LS, HL, FB and KH: no competing interests to declare. OS received the Maryland CERSI Scholar award from the Food and Drug Administration (grant #1U01FD005946) and the PhRMA Foundation’s Predoctoral Fellowship in Health Outcomes.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Our completed extraction sheets are publicly available on the Open Science Framework (http://doi.org/10.17605/OSF.IO/KPE2T) and CSRs are available upon request.

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