Call to action: RIAT restoration of a previously unpublished methodology in Gardasil vaccine trials
We write to issue a call to action to restore the reporting of multiple trials in Merck’s clinical development program for quadrivalent human papillomavirus (HPV) vaccine (Gardasil) vaccine. These trials include:
FUTURE II (NCT00092534), published as FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007 May 10;356(19):1915–27.
FUTURE III (NCT00090220), published as Muñoz N, Manalastas R Jr, Pitisuttithum P, Tresukosol D, Monsonego J, Ault K, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-blind trial. Lancet. 2009 Jun 6;373(9679):1949–57.
These highly influential publications (totalling over 1300 citations together, according to publishers’ websites) report the results of two pre-marketing clinical trials of Gardasil that involved over 15,000 women between the ages of 15 and 45.[1,2] These were pivotal trials that underpin the approval of the vaccine.
However these trial publications have incompletely reported important methodological details and inaccurately describe the formulation that the control arm received, necessitating correction of the record.
We intend to restore the written record for these trials in accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative, of which we are founders.
Our rationale for correcting the record
Both trial publications state that they are reports of “placebo-controlled” trials.[1,2] However participants in the control arm of these trials did not receive an inert substance, such as saline injection. Instead, they received an injection containing amorphous aluminium hydroxyphosphate (AAHS), a proprietary adjuvant system that is used in Gardasil to boost immune response.
The use of a comparator that was neither an inert substance nor an efficacious vaccine against another disease demands explanation. The clinical rationale for such a decision is unclear, as the trial arms do not mimic the real life choice of deciding whether or not to receive HPV vaccine, and it is incompatible with established ethical principles regarding the use of placebo in vaccine trials. However, in at least two key trial publications, of the FUTURE II and FUTURE III trials, the rationale for the use of AAHS-containing control is unstated. Trial registration entries for these trials also lack a rationale on the selection of this control.
Furthermore, because AAHS is not inert, the choice of AAHS-containing control complicates the interpretation of efficacy and safety results in trials. While there is no evidence or reason to believe that AAHS adjuvant can induce efficacy on its own without the HPV virus like participles (VLPs) present in the approved vaccine, AAHS is understood to have a harms profile. For example, in a phase 2 study testing multiple doses of potential Gardasil formulations (V501-007), the manufacturer included two active AAHS-containing adjuvant dose arms, “for appropriate safety comparisons.” Concerns about the safety profile of AAHS-containing control and the impact on interpretation of results is also evidenced by the fact that the FDA directed Merck to conduct a 6 month safety study comparing 3 doses of Gardasil against a non-aluminum containing placebo, according to the company’s submission to Japanese regulators. At the time of Gardasil’s 2006 approval in the US, trial V501-018 was the only study to compare Gardasil with a non-aluminum containing placebo, and the FDA medical officer referred to the control used in this trial as “true placebo,” in contrast to the control used in other trials.
The FUTURE II and FUTURE III trial publications however do not discuss how AAHS-containing control could affect the interpretation of results.
We consider the omission in journal articles, of any rationale for the selection of AAHS-containing control, to be a form of incomplete reporting (of important methodological details), and believe the rationale must be reported. We also consider that use of the term “placebo” to describe an active comparator like AAHS inaccurately describes the formulation that the control arm received, and constitutes an important error that requires correction. If trial participants were told they could receive “placebo” (widely defined as referring to an “inactive”[10,11] or “inert” substance) without being informed of all non-inert contents of the control arm injection, this raises ethical questions about trial conduct as well.
Scope of our restoration
After documenting that these deficiencies in reporting were not confined to a single study, but at least applied to two Phase 3 trials in the Gardasil evidence development program, we have decided to systematically correct the record for all Gardasil and Gardasil 9 trials with standalone aluminum-containing control arms. We may therefore discover additional trials in need of restoration for the same reason, and we will include this as part of our work….