RT Journal Article
SR Electronic
T1 Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology
JF BMJ Evidence-Based Medicine
JO BMJ EBM
FD BMJ Publishing Group Ltd
SP bmjebm-2019-111331
DO 10.1136/bmjebm-2019-111331
A1 Peter Doshi
A1 Florence Bourgeois
A1 Kyungwan Hong
A1 Mark Jones
A1 Haeyoung Lee
A1 Larissa Shamseer
A1 O'Mareen Spence
A1 Tom Jefferson
YR 2020
UL http://ebm.bmj.com/content/early/2020/03/17/bmjebm-2019-111331.abstract
AB 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.Trial registration numbers NCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.