New evidence emerges that Merck downplayed the harms caused by Gardasil

New evidence has emerged that the pharmaceutical company Merck seriously underreported harms caused by its HPV vaccines.

The evidence is revealed in a 350-page report by Danish physician and researcher Peter Gøtzsche.

Gøtzsche’s expert review of Merck’s HPV vaccine studies was submitted as a pre-trial document (in the Motion for Summary Judgement) in the Robi v. Merck & Co. lawsuit, in which proceedings were adjourned in February this year and are due to resume with a new jury in Los Angeles in September.

Jennifer Robi alleges that Gardasil caused her severe health problems, including a heart condition and nerve pain. In the lawsuit, it is alleged that Merck wrongfully marketed Gardasil, downplaying its risks and overstating its benefits.

Robi, a former athlete who has been confined to a wheelchair since receiving her third Gardasil vaccine at the age of 16, suffers from uncontrolled neuro/muscular contractions (jerking), postural orthostatic tachycardia syndrome (POTS), and numerous other symptoms of systemic autoimmune dysregulation.

Gøtzsche studied the preclinical (animal) and clinical (human) reports about the Merck-sponsored studies of monovalent and quadrivalent Gardasil, and Gardasil 9, and other related reports about Merck’s HPV vaccines.

He says he found numerous flaws in Merck’s clinical trials of its HPV vaccines “in its study reports, in the published clinical trial reports, and in its package inserts for Gardasil”.

After ploughing through tens of thousands of pages of documents, Gøtzsche concluded: “The issues I found ... are so pervasive that Merck’s clinical trials cannot be used to fully assess Gardasil’s risks because of the design and conduct of the studies, and because Merck seriously underreported the potential harms of its vaccines ...”.

Merck split the data in so many ways that it would be difficult if not impossible for any scientist, including regulators, to assemble them in a way that would allow a full evaluation of the risks, Gøtzsche writes.

He says the primary flaws included Merck’s failure to use a true placebo in comparison to Gardasil in the clinical trials – with the exception of one small study, which, Gøtzsche says, was flawed in its own right.

In another study, Merck misleadingly called a highly immunogenic aluminium adjuvant a placebo, “thus obscuring the vaccine’s harms”, Gøtzsche says.

“Participants in Merck’s trials were lied to,” he says. “They were told they were receiving a placebo when they were injected with an aluminium adjuvant.”

It is indefensible that Merck avoided comparing Gardasil with a placebo, Gøtzsche says.

“Merck’s clinical study reports, its informed consent forms, corresponding journal publications, and the package inserts all used the term placebo even though it contained the adjuvant,” he writes.

There was just one small placebo-controlled trial (P006) in the testing of Gardasil 9.

Merck’s justification for using an adjuvant instead of placebo is unfounded, Gøtzsche says.

The adjuvant was not needed to preserve the blinding, he says, and the safety of Merck’s adjuvant was never tested in comparison with an inert substance in humans.

“Merck’s claim that, ‘The safety profile of Merck’s aluminum adjuvant is well characterised’ is false because the adjuvant varies from batch to batch,” Gøtzsche writes.

Adjuvants, he says, are not perfectly safe as they are strongly immunogenic substances, which is the reason for using them to bolster the immune response to a non-live vaccine.

The World Health Organisation has stated that using an adjuvant or another vaccine as a comparator instead of a placebo makes it difficult to assess the harms of a vaccine, and that a placebo can be used in trials of vaccines against diseases for which there are no existing vaccines, which was the case with Gardasil.

Merck also counted adverse events only if they were deemed by a “study coordinator” to be vaccine-related¸ Gøtzsche states.

In addition, he says, Merck only counted adverse events if they occurred within 14 days, thus excluding (by as much as 90%) adverse events that took longer to manifest.

The company called adverse events that occurred after 14 days “new medical conditions”, Gøtzsche says.

Merck also failed to delineate whether adverse events were mild, moderate, or severe, which was contrary to the study protocols, he adds.

Gøtzsche says the company “squandered the opportunity to legitimately study the safety of Gardasil in the multiple studies conducted involving tens of thousands of study participants (mostly young girls)”.

He says the “significant and elevated risks” identified in his meta-analyses would almost certainly be higher than he calculated because vaccine harms were not adequately collected by Merck.

“Because of the studies’ numerous flaws, Merck’s clinical trials also cannot be used to claim that Gardasil is generally safe or that specific risks do not exist,” Gøtzsche writes.

“Notwithstanding the flaws, I found a clear signal of serious harms, including neurological harms, from Merck’s HPV vaccines, which almost certainly would have been even larger than what I found had Merck’s studies been properly conducted and reported.”

Gøtzsche notes that Merck’s emphasis was on “prespecified adverse experiences: vaccine-related adverse experiences …”.

Given that a placebo-controlled trial of Gardasil had never been carried out before, no one could know which adverse events the vaccine might cause, and it was therefore inappropriate to prespecify these, Gøtzsche says.

“Both the 1% limit and the prespecifications mean that unanticipated harms, e.g. symptoms suggesting the occurrence of POTS, CRPS [complex regional pain syndrome] or autoimmune diseases, would very likely be missed,” he writes.

Merck had specified that “… risk differences and associated 95% confidence intervals were computed comparing the vaccine and placebo groups across all vaccination visits with respect to adverse experiences with ≥ 1% incidence in either vaccination group and elevated temperatures”.

Gøtzsche says it is inadequate for a study with a primary focus on safety that a drug regulator requested be carried out using a genuine placebo control to only collect and test possible harms in a 14-day period after each vaccination.

He writes that, in the 2011 package insert, the number of patients with serious adverse reactions had increased by only three, which, he says, is a mathematical impossibility, “as the Future 3 trial had 32 such reactions”.

Merck’s reporting of deaths was also unreliable, Gøtzsche adds. “In the 2011 package insert, the number of deaths had increased by only three, even though there were eight deaths in the Future 3 trial: another mathematical impossibility,” he writes.

In Study P001, 14,215 participants were enrolled to compare the original Gardasil vaccine with its newer version, Gardasil 9, which contains twice the amount of adjuvant and five more disease antigens than Gardasil.

Gøtzsche says that the study report of more than 8,000 pages was written in such a way that it “obfuscated and downplayed the harms of Gardasil”.

Merck claimed that the proportion of subjects with serious adverse experiences was “low and comparable” between the two groups, but this was not accurate, Gøtzsche says.

“The incidence of serious adverse events was not low; and the difference, 283 (3.3%) vs 183 (2.6%), was statistically significant ...,” he writes.

This was alarming for a vaccine that was not even compared with a placebo but with another vaccine, “because serious adverse events include deaths, life-threatening events, persistent or significant disability, and hospitalisation,” he adds.

Merck violated its own protocol, Gøtzsche says.

“The statistical analysis plan, and the three updates of this plan, all showed that a p-value would be computed for vaccine-related serious adverse events for the whole trial period,” he writes. “Merck provided no such p-value.”

Merck’s statistical analysis plan had glaring inconsistencies, Gøtzsche adds, pointing out that serious adverse events were only analysed if they occurred within the three two-week periods after each vaccination.

Serious adverse events considered to be vaccine related by investigators were not analysed for this restricted period, but for the whole trial period.

“Whether considered vaccine related or not, serious adverse events must be analysed the same way, but Merck failed to analyse ALL events for the WHOLE trial period,” Gøtzsche writes.

He says that Merck’s presentation of its trial data was disorganised.

“It is well known that regulatory agencies are understaffed, which means it is unlikely they would be able to undertake a thorough review of Merck’s data as presented,” he writes.

“The 388 tables in the main body of the report take up 895 pages, but suddenly yet another set of tables appear by the end, including the 1576 pages of ‘CIOMS [the Council for International Organisations of Medical Sciences] adverse experience reports’ … These CIOMS have no allocation numbers and therefore they cannot be compared with the narratives of adverse events or with other tables of adverse events.”

Gøtzsche concludes: “It is deeply concerning that Gardasil 9 was ever approved for marketing in any country based on this and other deficient reports, but it confirms observations made by many researchers that drug regulation is insufficient.”

It is remarkable, he says, that drug regulators “accepted Merck’s contradictory, biased and misleading reports based on trials that were already flawed by design (using adjuvant as ‘placebo’ and using many manoeuvres that avoided reporting possible harms of the vaccine)”.

When Denmark raised concerns in 2015 about possible harms caused by the HPV vaccines, the European Medicines Agency (EMA) asked the manufacturers to evaluate whether their vaccines were safe, review cases of CRPS and POTS in their trials, go through their post-marketing surveillance data, use these data to produce “observed versus expected” analyses of adverse events, and review and assess the published scientific literature.

Weaknesses in the scientific strategy employed by Merck and GlaxoSmithKline (the manufacturer of the Cervarix HPV vaccine) were obvious, Gøtzsche says.

He notes that the official report by the EMA didn’t mention that the search strategies the manufacturers used to search their databases were inadequate and must have overlooked many cases.

“Merck’s methods for collecting, analysing and reporting adverse events were highly problematic. Even after I had examined a total of 43,211 pages describing the three pivotal Future trials, corresponding to about 200 medium-sized books, I still did not know in sufficient detail how Merck collected data on clinical adverse events and reported on them, not even when they were serious or deadly,” Gøtzsche writes.

“The various messages were often contradictory or unclear and the ambiguity left the door wide open to biased reporting, as there were many ways in which possible harms could have been hidden, ignored, suppressed, or left out.”

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