Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology

Randomised, placebo-controlled clinical trials are considered the gold standard for evaluating new vaccines. To assess its efficacy and safety, the manufacturer of quadrivalent human papillomavirus (qHPV) vaccine conducted multiple clinical trials involving approximately 30,000 volunteers. The trials of the qHPV vaccine are reported as ‘placebo-controlled.’ However, participants in the ‘placebo’ arms received an injection-containing amorphous aluminium hydroxyphosphate sulfate (AAHS), a proprietary adjuvant. AAHS is used in the qHPV vaccine to boost immune response, but the rationale for adding it to the ‘placebo’ is not reported in publications of these trials and is contrary to the advice of the public health bodies and regulators. Standard recommendations for control recipients in trials testing an unlicensed, experimental vaccine include using either an inert substance or an approved efficacious vaccine. 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), the primary objective of this study was to characterize the reporting of the methodology with respect to the rationale for the choice of standalone aluminum-containing adjuvanted controls. Clinical study reports (CSRs) from five randomized controlled trials described as placebo-controlled were obtained from the European Medicines Agency (EMA). Content and rationale for the choice of control used in each trial was extracted across six data sources: trial publications, register records, CSR synopses, CSR main bodies, protocols and informed consent forms. For each source within each trial, the following was recorded: (1) the phrases used to describe the comparator to qHPV vaccine; (2) the rationale for using aluminum-containing adjuvant as a control, if present and (3) all listed contents (ingredients) of formulation received by intervention and control arms. This dataset includes data extraction sheets and RIAT protocol documentation publicly accessible via the Open Science Framework with the CSRs available upon request.

随机对照、安慰剂对照的临床试验被视为评估新型疫苗的黄金标准。为了评估四价人乳头瘤病毒（qHPV）疫苗的有效性和安全性，疫苗制造商开展了多项临床试验，涉及约30,000名志愿者。qHPV疫苗的试验报告为‘安慰剂对照’。然而，在‘安慰剂’组中接受注射的受试者接收了一种含有无定形铝羟磷酸硫酸盐（AAHS）的注射剂，这是一种专有佐剂。AAHS在qHPV疫苗中用于增强免疫反应，但将该佐剂添加到‘安慰剂’组的理由并未在试验的出版物中报告，且与公共卫生机构和监管机构的建议相悖。在测试未经许可的实验性疫苗的试验中，对对照组受试者的标准推荐包括使用惰性物质或已批准的有效疫苗。然而，在几个关键性试验的出版物中，对重要的方法学细节的报道不完整，且对对照组接受制剂的描述不准确。在恢复不可见和废弃试验倡议（RIAT）下，本研究的首要目标是描述关于选择独立铝佐剂对照组的理由的方法学报告。从欧洲药品管理局（EMA）获得了五项描述为安慰剂对照的随机对照临床试验的临床研究报告（CSR）。从六个数据来源中提取了每个试验中使用的控制方法的描述及其理由：试验出版物、登记记录、CSR摘要、CSR正文、方案和知情同意书。在每个试验的每个来源中，记录了以下内容：（1）描述与qHPV疫苗比较的短语；（2）如果存在，使用含铝佐剂作为对照组的理由；（3）干预组和对照组接受的制剂的所有列出的成分。本数据集包括数据提取表和RIAT方案文件，可通过开放科学框架公开访问，CSR可在请求后提供。