Re-Check’s Catherine Riva and Dr. Jean-Pierre Spinosa released an article that analyzes unpublished documents from the Food and Drug Administration (US FDA). This original research, published on December 2, 2020 in the open access Journal of Scientific Practice and Integrity, highlights the cascade of problematic decisions that led to the approval of Gardasil®, Merck’s quadrivalent HPV vaccine. It is part of a long-term investigative effort that began in 2008. The article shows that, under the pressure of an unjustified fast-track procedure, U.S. regulatory authorities failed to comply with the methodological guidelines supposed to be applied during drugs and vaccines approval (ICH guidelines). As a result, almost 15 years later it is still impossible to know what the true benefit-risk ratio of HPV vaccination is. Furthermore, in industrialized countries Gardasil® approval has generated a constellation of “over-prevention” that allows Merck to be freed by the burden of proof while generating huge profits. Meanwhile, health authorities promote the product, and the society bears the costs of vaccination campaigns, and its potential health risks.

At the end of 2020, HPV vaccination has been once more in the spotlight. On one hand, the World Health Organization has launched its strategy to eliminate cervical cancer by 2050, which plans to rely primarily on vaccination to achieve its goal; on the other hand, the results of a study based on health registries in Sweden have been published. Its authors concluded that among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level.

From there to the conclusion that HPV vaccination is winning its bet, there is only one step that many enthusiastic commentators have not hesitated to take.

But things are much less clear than these announcements suggest.

Both the Swedish study and the publications on which WHO relies are so-called observational studies, whose results should be considered with the utmost caution. Firstly, because causality cannot be assessed from observational studies. Evidence-based medicine (EBM) teaches that the results of such studies cannot be considered evidence, since they are prone to many biases, and since their design does not allow to control the so-called confounding factors. For further developments on these issues, interested readers may refer to Chapter 2 of the GIJN Guide Investigating Health & Medicine recently published by Catherine Riva and Serena Tinari of Re-Check.

In the case of cervical cancer prevention through HPV vaccination, the confounding factors are the variables that can influence precancerous lesions’ and cervical cancer’s incidence: socio-economic status, tobacco smoking, early sexual activity, number of partners, oral contraceptives, vaginal microbiota composition, and especially participation to cervical cancer screening (with Pap smear), as well the screening’s modalities. And although adjustments can be made when analyzing observational data, there are just too many unknowns to be able to say with certainty that the observed effect is due to HPV vaccination.

Last but not least, numerous authors of these observational studies on HPV vaccination effectiveness have disclosed conflicts of interest with companies that market these vaccines. Conflicts of interest can also be a major source of bias (in the aforementioned GIJN Guide, this topic is extensively covered in Chapter 3).

The only solid evidence available on HPV vaccination efficacy shows that it can prevent precancerous cervical lesions linked to high-risk HPVs 16 and 18 (in the case of Gardasil® and Cervarix®), as well as high-grade cervical lesions linked to high-risk HPVs 31, 33, 45, 52 and 58 (in the case of Gardasil9®). This effect has been demonstrated in randomized controlled trials, a study design that allows establishing causal relationship between the intervention and its effect.

But no randomized controlled trials have assessed the vaccination’s effect on the overall incidence of cervical precancerous lesions and cervical cancer – related to any HPV type. This is critical, because other high-risk HPVs than those targeted by the vaccines can cause cervical cancer. And it can’t be excluded that other strains might take the place of the strains held in check by the vaccination – a scenario known as viral replacement. In other words, the only way to be sure that viral replacement does not occur, and that with a high degree of certainty HPV vaccination will probably reduce the incidence of cervical cancer, is to test in randomized controlled trials if a global reduction of precancerous lesions related to all high-risk HPVs is achieved in the vaccinated group.

Unfortunately, no randomized controlled trial has been conducted to date to assess this effect. Given the importance of the issue from a public health perspective, one might ask: why there is no better data available than observational studies?

This predicament has led Re-Check’s Catherine Riva and Dr. Jean-Pierre Spinosa to track back the approval history of Merck quadrivalent HPV vaccine Gardasil®, that is interesting for several reasons, as Gardasil® is the first vaccine in history to have been granted the FDA’s accelerated approval and fast track. This research is part of a long-term investigative effort, which since 2008 has resulted in articles in mainstream media (by Catherine Riva), rapid responses in biomedical journals (by Catherine Riva, Jean-Pierre Spinosa and Jérôme Biollaz), a book by Riva and Spinosa (La piqûre de trop? – An injection too many?), TV documentaries (by Serena Tinari), a poster (by Riva and Tinari), and a letter to the editor published by BMJ-Evidence-Based Medicine (by Riva, Tinari and Spinosa). For details, interested readers can refer to the dedicated page on Re-Check website.

In their new article published in December 2020 in the Journal of Scientific Practice and Integrity, Riva and Spinosa sought to understand how the evaluation criteria were selected during the approval and the impact of the FDA experts’ choices on the quality of the available evidence about the vaccine’s efficacy in preventing cervical precancerous lesions. Using unpublished documents they obtained from the FDA, they assessed FDA experts’ methodological choices in order to see if they complied with the ICH guidelines, which set methodological standards that shall be applied during approval procedures.

Their analysis shows that as early as 2001, FDA experts made problematic methodological choices (endpoints, primary and exploratory analysis criteria, etc.), which in many respects do not comply with ICH guidelines. These choices resulted in a cascade of bad decisions that could only lead to inconclusive results and have far-reaching consequences, since medical community, health authorities, and the public have been deprived of the possibility to gain unbiased insights about Gardasil®’s efficacy in preventing precancerous cervical lesions.

The article also elaborates on unpublished analyses, whose results strongly suggest that HPV vaccination will probably not lead to the expected reduction of the incidence of cervical precancerous lesions, nor of the incidence of cervical cancer. Still, like any other biological product Gardasil® has side effects and therefore exposes to risks the vaccinated population. Consequently, its risk/benefit ratio could actually be unfavorable.

Furthermore, not only Gardasil® approval brought to the market a product with an uncertain risk/benefit ratio. It also paved the way for the marketing of other HPV vaccines and created a new situation in industrialized countries where, prior to the introduction of this vaccination, cervical cancer was already prevented by cervical cancer screening with Pap smear. As a matter of fact, cervical cancer screening must be maintained because the available vaccines do not target all high-risk HPV strains. The marketing of Gardasil® has thus inaugurated a new form of medical overuse in the field of prevention: the introduction of a low-value primary prevention measure (vaccination) whose effectiveness can’t be fully assessed, since the secondary prevention measure (screening) cannot be removed. This inextricable “over-prevention” situation has allowed Merck to escape the burden of proof while generating huge profits. Meanwhile, health authorities promote the product and the society bears the costs of both vaccination campaigns and health risks.

The authors conclude: “In view of the many regulatory oversights in the approval of Gardasil, an independent, non-industry funded reassessment of the clinical study reports of all available HPV vaccines (including anonymized individual patient data) is urgently required.”

More broadly, the problems generated by Gardasil® accelerated approval should serve as a warning: good methodological practices are not dispensable and regulatory authorities should be committed to not deviating from these principles, as any shortcut will come with consequences. Once some decisions have been taken, there is no turning back. These lessons should be urgently considered in the context of the current hyper-accelerated licensing of COVID-19 vaccines.

Riva C. and Spinosa JP. 2020. Journal of Scientific Practice and Integrity. 2(1). DOI: 10.35122/001c.18180

“Has the HPV vaccine approval ushered in an era of over-prevention?” was published online on December 2, 2020 in the open access Journal of Scientific Practice and Integrity following a peer review process. It can be downloaded for free as PDF here.