The Cochrane Review [on HPV vaccine clinical trial data] conducted trial searches up until June 2017 and included 26 randomised trials with 73428 women. [However, we] identified 46 completed and eligible trials. The number of randomised participants could be assessed for 42 of the 46 trials and was 121704.
[T]he Cochrane authors would… have identified more trials if they had searched ClinicalTrials.gov in more depth and searched additional trial registers.
The Cochrane authors stated that they ‘did not include the nine-valent vaccine [Gardasil 9] … since the randomised trials … did not incorporate an arm with a non-HPV vaccine control’.
This is not correct. The only saline placebo trial of approved HPV vaccines is a Gardasil 9 trial that was published in 2015.
Its participants had previously been vaccinated with four-valent Gardasil, but according to the Cochrane Review protocol, this was not an exclusion criterion. Since many countries are shifting to Gardasil 9, it is unfortunate that the Gardasil 9 trial was not included in the Cochrane Review.
All 26 trials included in the Cochrane Review used active comparators: adjuvants (aluminium hydroxide (Al(OH)3) or amorphous aluminium hydroxyphosphate sulphate) or hepatitis vaccines.
Adjuvants are not regulated separately from their vaccine antigens. According to the Food and Drug Administration, adjuvants are unreliable comparators.
One HPV vaccine manufacturer (GlaxoSmithKline that produces Cervarix) states that its aluminium-based comparator induces harms: ‘higher incidences of myalgia might namely be attributable to the higher content of aluminium in the HPV vaccine… than the content of aluminium in the HAV (hepatitis A) vaccine.
The Cochrane authors mistakenly used the term placebo to describe the active comparators.
They acknowledged that ‘The comparison of the risks of adverse events was compromised by the use of different products (adjuvants and hepatitis vaccines) administered to participants in the control group’. Nevertheless, this statement can easily be overlooked, as it comes after 7500 words about other issues in the discussion…
Active comparators was not a bias in the review process but a bias in the design of the HPV vaccine trials.
The use of active comparators probably increased the occurrence of harms in the comparator groups and thereby masked harms caused by the HPV vaccines.
It is noteworthy that many women were excluded from the trials if they had received the adjuvants before or had a history of immunological or nervous system disorders…
These exclusion criteria lowered the external validity of the trials and suggest that the vaccine manufacturers were worried about harms caused by the adjuvants.
The Cochrane authors did not describe any cervical cancers in the 26 trials, although cancers did occur in the trials; for example, in the ClinicalTrials.gov entry for the VIVIANE Trial, one case of ‘Adenocarcinoma of the cervix’ and one case of ‘Cervix cancer metastatic’ are listed in the HPV vaccine group.
The Cochrane authors concluded with ‘high certainty’ that the risk of serious adverse events was similar in the HPV vaccine groups and the comparator groups. However, the authors failed to mention that several of the included trials did not report serious adverse events for the whole trial period.
For example, [three clinical trials]—which in total included 21441 women with up to 4 years follow-up—only reported serious adverse events occurring within 14 days postvaccination.
Furthermore, the Cochrane authors did not explain what the serious adverse events consisted of or whether some of them were more common in the HPV vaccine groups.
The Cochrane authors found more deaths in the HPV vaccine groups than in the comparator groups. The death rate was significantly increased in women older than 25 years… the total numbers of deaths were 51 in the HPV vaccine groups and 39 in the comparator groups).
the authors cannot rule out that the increase could be caused by the HPV vaccines. A death may be coded in a way that does not raise suspicion that the vaccine caused it; for example, a ‘traumatic head injury’ or ‘drowning’ could have been caused by a ‘syncope,’ which is a recognised harm. As of May 2018, WHO’s pharmacovigilance database—VigiBase, managed by the Uppsala Monitoring Centre (UMC)—contained 499 deaths reported as related to HPV vaccination.
The Cochrane authors did not include all of their trials that were eligible for systemic events in [their analysis]…
The Cochrane authors referred to many observational studies in their discussion that found no safety signals of harms associated with the HPV vaccines.
The Cochrane authors did not mention a study from 2017 by the WHO UMC that found serious harms following HPV vaccination overlapping with two syndromes: postural orthostatic tachycardia syndrome (POTS) and complex regional pain syndrome (CRPS).
As of May 2018, the WHO UMC VigiBase contained 526 cases of POTS and 168 cases of CRPS reported related to HPV vaccination.
The Cochrane authors did not investigate whether the included trial data reported cases of POTS, CRPS or other safety signals.
Instead, the authors cited EMA, which concluded that ‘No causal relation could be established’ between POTS or CRPS and the HPV vaccines. The EMA’s conclusion was based on the HPV vaccine manufacturers’ own unverified assessments that only included half of the eligible trials.
Furthermore, the HPV vaccine manufacturers search strategies for POTS and CRPS were inadequate and led to cases being overlooked.
The Cochrane authors assessed the impact of industry funding… They stated that, ‘All but one of the trials was funded by the vaccine manufacturers’, which is not correct.
[T]his particular trial was sponsored by GlaxoSmithKline. Therefore, all included trials were funded by the HPV vaccine manufacturers and the meta-regression was meaningless.
The Cochrane Collaboration aims to be free from conflicts of interest related to the manufacturers of the reviewed products. Most of the 14 Cochrane authors on the first published protocol for the Cochrane Review had major conflicts of interest related to the HPV vaccine manufacturers.
The review’s first author currently leads EMA’s ‘post-marketing surveillance of HPV vaccination effects in non-Nordic member states of the European Union’, which is funded by Sanofi-Pasteur-MSD that was the co-manufacturer of Gardasil.
The announcement of the Cochrane Review on Cochrane.org under ‘News’ included a ‘Science Media Centre roundup of third-party expert reaction to this review’. Six experts were cited…
Two of the experts had financial conflicts of interest with the HPV vaccine manufactures.
A third expert was responsible for vaccinations in Public Health England that promotes the HPV vaccines.
The experts highlighted the ‘intensive and rigorous Cochrane analysis’, ‘that the HPV vaccine is the most effective way for young girls to protect themselves against cervical cancer’, and that, ‘the vaccine causes no serious side-effects’. No expert criticised the review.
In our view, this is not balanced and people with conflicts of interest in relation to the manufacturers should not be quoted in relation to a Cochrane review.
Richard Smith—the former editor of the British Medical Journal—described medical journals as an extension of the marketing arm of the drug industry. We are concerned that some observers may see Cochrane Reviews in the same light when Cochrane publishes such public relations messages.