... attack by Nordic Cochrane calls Cochrane review of HPV vaccines into question but has wider implications

An astonishing attack by three members of the Nordic Cochrane group in BMJ Evidenced Based Medicine on the recent Cochrane review of HPV vaccines, Arbyn et al Propylactactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors  calls not only the integrity and competence of the review into question, but poses by implication the most serious questions about how the products themselves were designed, trialed, licensed and marketed. The authors of the present of review of the review have been associated with a series of complaints against the European Medicines Agency concerning the vaccines and their safety. The Arbyn paper concludes:

There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate-certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status.

We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long-term of follow-up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.

The key findings new paper by Jørgensen, Gøtzsche and Jefferson are:

-The Cochrane human papillomavirus (HPV)
vaccine review missed nearly half of the eligible
trials.
-The review was influenced by reporting bias
and biased trial designs.
-Authors of Cochrane reviews should make
every effort to identify all trials and the trials’
limitations

They found that the authors had included in the review only 26 of 46 eligible trials and state for this reason alone the conclusion "'that the risk of reporting bias may be small' was inappropriate" and they warn that none of the trials included were anyway for the new product Gardasil 9 which many countries are switching to. They further castigate the Cochrane review for using misleading language, referring to trials against placebo when all those included in the review were against "active comparators: adjuvants (aluminium hydroxide (Al[OH]3) or amorphous aluminium hydroxyphosphate sulfate [AAHS]) or hepatitis vaccines". They identify this as a bias in the original design of the trials masking the harm of the vaccines, and they note that women were excluded from trials if they had received adjuvants before or a history of immunological or nervous disorders. They say that this lowered the validity of trials and suggested that the manufacturers were concerned about the harms of the product in these groups, although no packet warnings are included.

They further complain that Arbyn failed to mention cases of cervical cancer in the trial groups but also that the relationship CIN2 lesions and cancer was uncertain since they regressed spontaneously in women under 30 who were mostly the subjects of the trial. They also say that the review misreported trials. In the so called PATRICIA trial where Cochrane reported 701 vs 699 from the trial publication, and 835 vs 829 in its "Clinical trial.gov" entry the Nordic Cochrane group found 1046 vs 982. Some trials recorded no adverse events at all and had very short follow up periods. While the original review could detect no pattern to the greater risk of death in the vaccinate vs comparator groups (51 vs 39) the Nordic Cochrane point out:

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.

A meta-analysis which sought determine funding bias was flawed because the one trial which was deemed to be not funded by manufacturers was in fact funded by GSK by a circuitous route, and they failed to mention a report by the WHO Uppsala Monitoring Centre which found:

that found serious harms following HPV vaccination overlapping with two syndromes: postural orthostatic tachycardia syndrome (POTS) and complex regional pain syndrome (CRPS).

Instead they had relied on assurances from the European Medicines Agency handed down from the manufacturers. They note that in contravention of Cochrane guidelines 14 of the authors on the original protocol for the review had significant conflicts, as did three of the four authors of the final paper. While the main thrust of the paper is that Cochrane - to which the authors are affiliated -  needs to clean up its act, we all may wonder at how the governments of the world have allowed pharmaceutical companies to subject young women to these ill-tested and dangerous products for the last dozen years, and even at how the pre-marketing trials in the format described were ever allowed. We shudder over the fact that in the last week the recommendation for Gardasil 9 has extended to boys and young men in the United Kingdom, and that in France the vaccine is about to be made compulsory. We know we cannot trust the pharmaceutical industry but how can we ever trust our governments?