Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology

Abstract

PurposeTrustworthy 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.MethodsWe 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.ResultsAcross 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’.ConclusionsThe 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 numbersNCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.

Was amorphous aluminium hydroxyphosphate sulfate adequately evaluated before authorisation in Europe?

“…Doshi et al also came to the same conclusion that the comparator was AAHS. 23 In the section for the clinical material description in the Future II protocol, the placebo is described as 'Merck standard aluminium diluent (225 µg alum) in normal saline, unique selling proposition (NaCl 0.9%)', which does not correspond to the description of AAHS. In other sections of the protocol, the placebo is described as 'Merck aluminium adjuvant placebo', but as aluminium hydroxide was used in Merck vaccines in 2002, and as AAHS according to the EMA was unknown by the authorities before 2004, we can speculate that the Committee on Health Research Ethics may have interpreted the placebo as being aluminium hydroxide.…”

“…17 18 Criticisms have been raised of the prelicensure randomised clinical trials, that forms the body of evidence for the approval of Gardasil, a Merck Sharp & Dohme Corp manufactured human papilloma virus (HPV) vaccine made of recombinant HPV types 6, 11, 16 and 18 L1 virus-like particles. [19][20][21][22][23] One criticism is the use of amorphous aluminium hydroxyphosphate sulfate (AAHS) as a comparator in the prelicensure trials. 20 23 However, the European Medicines Agency (EMA) and the WHO conclude high vaccine safety and efficacy.…”

Incompletely Reported Important Methodological Details and Inaccurate Description of the Formulation That the Control Arms Received in a Gardasil Vaccine Trial

“…However, control arm participants did not receive a “placebo” or an “inactive solution,” the descriptions provided in the informed consent forms for this trial. Instead, they received an injection containing amorphous aluminum hydroxyphosphate sulfate (AAHS), a proprietary adjuvant added to enhance immune response ( 3 ). The use of the term “placebo” to describe an active and reactogenic comparator like AAHS inaccurately describes the formulation that the control arm received and may also have obscured an accurate assessment of vaccine safety.…”

“…On the other hand, the safety profile of the HPV 6, 11, 16 and 18 L1 VLPs required further evaluation in humans. By using placebo that contained a dose of aluminum adjuvant that was identical to the dose included in the qHPV vaccine, it was possible to assess the safety profile attributable to the HPV 6, 11, 16 and 18 L1 VLP component of the vaccine” ( 3 ).…”

“…Thus, the manufacturer’s stated rationale for selecting AAHS as a control (to characterize the safety of human papillomavirus [HPV]-like particles) lacks clinical relevance, and a nonplacebo control may have obscured an accurate assessment of quadrivalent HPV vaccine safety ( 3 ). We have documented all of these issues elsewhere ( 3 ).…”