Complaint Filed Over EMA's Handling of HPV Vaccine Safety Issues

Zosia Chustecka

July 05, 2016

An official complaint has been filed by the Nordic Cochrane Center against the European Medicines Agency (EMA) over its handling of safety issues concerning human papillomavirus (HPV) vaccines.

The EMA looked at the safety issue last year after a request from Denmark, where physicians had documented in the medical literature case reports of chronic symptoms in girls who had received HPV vaccines.

After conducting a review of HPV vaccine safety, the EMA concluded that "evidence does not support that vaccines cause" the chronic symptoms.

At the time, several European researchers questioned the review process.

Now, the Nordic Cochrane group, headed by Peter Gøtzsche, DrMedSci, from the University of Copenhagen, Denmark, has lodged an official complaint. Dr Gøtzsche and colleagues have recently been vocal about the negative effects of mammography, and they have campaigned for more information about potential harms to be included in patient leaflets.

In the complaint, which runs to 19 pages, the Nordic group says that the official EMA report is flawed. It points out several issues with the way the safety review was conducted, including the fact that the manufacturers were asked to search their own databases and that they compared the vaccine to an aluminimum adjuvant instead of a saline placebo.

The group also highlights the "extreme levels of secrecy" that surround the EMA review process, in which experts who are involved in the process are not named and are bound by lifelong secrecy about what was discussed. This contrasts with the workings of other groups, for example, the advisory committees of the US Food and Drug Adminstration (FDA). Advisory committee meetings are open to the public and streamed live online, and documents relating to the case are posted online ahead of the meetings.

The Nordic group argues that in this case involving HPV vaccination safety, the internal report and all other documents related to the case should be made publicly available. "We did not find any commercially confidential information anywhere in the documents we reviewed," it adds.

All available material about suspected harms of a public health intervention directed towards healthy children should be accessible to anyone. Nordic Cochrane Center

"All available material about suspected harms of a public health intervention directed towards healthy children should be accessible to anyone," it asserts.

The Nordic group also questions whether the EMA has behaved fairly. In particular, it questions the EMA's behavior toward the Danish whistle-blower Louise Brinth, PhD, MD, from Danish Syncope Unit, Frederiksberg Hospital, in Copenhagen, who reported cases in the medical literature.

Dr Brinth has published her own lengthy response (63 pages) to the EMA review and is a cosignatory on the Nordic group complaint. She declined an interview with Medscape Medical News, adding that all she was concluding was "we need to look into this."

The EMA told Medscape Medical News that it has received the complaint by the Nordic Cochrane Center and that, as with all correspondence, it will carefully consider the issues raised in the complaint and reply directly to the sender. The agency added that it is "taking the safety of HPV vaccines extremely seriously."

In the United States, the FDA and the Centers for Disease Control and Prevention have both said that there is no evidence to support a causal link between chronic symptoms and HPV vaccination and have emphasized the fact that HPV vaccines have an "excellent safety record."

Many American medical organizations actively encourage HPV vaccination. The latest to join in has been the American Society of Clinical Oncology (ASCO), which in April 2016 published a statement that urged that aggressive efforts be made to increase uptake of the HPV vaccine in order to "protect young people from life-threatening cancers."

In an interview with Medscape Medical News, the lead author of the ASCO statement, Howard H. Bailey, MD, from the University of Wisconsin Carbone Cancer Center, Madison, said that the concerns over safety should not be dismissed and should be studied further.

These issues need continued study, even if the authorities say that the vaccines are safe, he emphasized. These reports of girls becoming very ill and experiencing pain syndromes and weakness should not be diminished, he said, adding: "We can't just ignore these reports.... If there is risk involved, then that needs to be sorted out better."

However, there is always a possibility that the syndromes and the adverse effects that have been reported "have nothing to do with the vaccine," Dr Bailey commented, citing the case of a now- discredited theory linking autism to the pediatric vaccine for measles, mumps, and rubella.

Manufacturers Searched Their Own Databases

At the heart of the issue is whether the chronic symptoms that have been reported after HPV vaccination are causally related to the vaccine.

"The prominent symptoms, which are suspected of being caused by the vaccine, are similar to those seen in so-called functional disorders such as chronic fatigue syndrome (CFS) and include postural orthostatic tachycardia syndrome (POTS) and chronic regional pain syndrome (CRPS)," the Nordic group explains. "These syndromes are difficult to diagnose; their causes are poorly understood; and they are likely to be underreported. This complicates studies of a causal link," it adds.

The EMA has concluded that there is no causal link, but the Nordic Cochrane group questions the way that the agency arrived at this conclusion.

"The EMA's official report gives the impression of a unanimous rejection of the suspected harms," the group comments.

"However, the EMA's internal report of 256 pages (EMA/666938/2015), which provided the draft for its 40-page official report, tells a very different story," the groups asserts.

This "internal report is confidential but has been leaked," the group notes in its complaint, and it "reveals that several experts had the opinion that the vaccine might not be safe and called for further research, but there was nothing about this in the official report."

The Nordic group also takes issue with how the EMA review was conducted.

It asserts in its complaint that the review was based on data from clinical trials, postmarketing surveillance, and the literature review, all collected by the marketing authorization holders (GlaxoSmithKline Biologicals, Merck Sharp & Dohme Limited, and Sanofi Pasteur MSD).

"The EMA asked the companies to search for side effects of the vaccine in their own databases and did not check the companies' work for accuracy," the group notes.

It adds that at this point, there is "a huge amount of money at stake: the global expenditure so far on HPV vaccines can be roughly estimated at €25 billion [US$27.85]."

One issue is that some of the reported cases of POTS were dismissed, the group states.

The leaked internal document quotes one of the experts, who was unnamed, as saying: "In the search for cases coded as POTS in the database the manufacturers make a further selection by case definition criteria that appears too limiting.... 83 reports are identified as medically confirmed but out of these almost half (40 cases) are then dismissed for not meeting the case definition for POTS. It appears that they have been dismissed mainly due to lack of information in the reports. This does not appear to be in accordance with good practice, since spontaneous reports cannot be expected to describe all details for a diagnosis given to a patient."

Another issue is that the manufacturers were asked to search their databases "for reports specifically containing the terms POTS and CRPS" and were also asked to use "common search identify possible cases of undiagnosed CRPS and POTS," but these strategies were not described.

"This is extraordinary, as the companies have a huge vested interest in not finding these possible harms in their databases," the Nordic group comments.

It illustrates the point with a case from the not-distant past. In 2014, the Danish Health and Medicines Authorities asked Sanofi Pasteur MSD to review its database for potential adverse effects of its HPV vaccine. The company searched it in such a way that very few of the known cases showed up ― only 3 of 26 Danish reports of POTS came up in the company's search.

Then there is the question of the placebo that was used in the clinical trials of HPV vaccines. "In all the vaccine trials apart from a small one, the control group was given a placebo that contained an aluminium adjuvant, which is suspected of being neurotoxic," the Nordic groups notes.

The group quotes concerns from the leaked internal documents, in which two of the experts involved in the review noted, "Initially, the vaccine was compared with a placebo group being vaccinated with physiological serum, whereby the number of adverse reactions was much higher and much more serious than in the control group. After comparing 320 patients in the saline placebo group, a quick move was made to an aluminium-containing placebo, in order to be able to only evaluate the effects of the active substance. However, this distorted the comparison, because no one voluntarily wants to be vaccinated with toxic aluminium, as this is not really necessary, when inoculation with a harmless saline solution can be done."

The Nordic group says that it is clear from the leaked EMA internal report that the manufacturers "simply lumped the results from trials with a genuine placebo with those that had a potentially neurotoxic 'placebo.' "

The manufacturers were requested to provide an in-depth review of the CRPS and POTS cases observed within all clinical studies, the group notes. To respond to this request, the manufacturers pooled the safety data from 18 completed and unblinded studies designed with an active comparator group (either placebo or another vaccine other than an HPV vaccine, eg, hepatitis B, hepatitis A). These trials included a total of 42,047 vaccinees (21,268 in the HPV group and 20,779 in comparator groups).

"We believe this constitutes scientific misconduct," the Nordic group says.

"But the EMA accepted it nonetheless, without reservations," they continue, noting that the official report concluded, "The few cases reported from RCTs [randomized clinical trials] are evenly distributed between the HPV and placebo groups which does not suggest an association."

The Nordic group also highlights an unrelated vaccine case from a few years ago. "When doctors first alerted the scientific community to the possibility that Pandemrix [GlaxoSmithKline], one of the pandemic influenza vaccines used in 2009-2010, could be related to the occurrence of narcolepsy in people with a specific tissue type, the reaction was to ridicule these doctors. It has now been firmly established that Pandemrix can cause narcolepsy, a very serious condition, up to several years after vaccination of children and adolescents, and that this disease is immune- mediated."

The group adds that in this case of chronic symptoms after HPV vaccination, "the hypothetical mechanism is an autoimmune reaction triggered by either the active component of the vaccine or the adjuvant in the vaccine."

Chronic symptoms following HPV vaccination have been reported in many countries, often in lay press reports but also in case reports in the medical literature; the countries include the United States, the United Kingdom, New Zealand, Mexico, Columbia, and Israel. In Japan, a national program of HPV vaccination was halted and a national scheme for treating chronic symptoms after HPV vaccination was set up last year.

Physicians Scared to Report Symptoms

In her own response to the EMA, Dr Brinth, the Danish physician who reported the chronic symptoms after HPV vaccination, notes that she has been contacted by fellow physicians and researchers. "Many of them tell me that they have the same suspicion ― they see the same pattern ― but most of them tell me that they are afraid to speak up. I find that we have established a culture where it is not acceptable to have a critical approach towards vaccines.

"I am afraid that we do not take this seriously enough. No matter to what degree we are dealing with side effects or not, I think we need to act much more progressively than we do now," Dr Brinth writes.

"If the symptoms experienced in these many girls and women around the world are not related to the HPV vaccines, we owe it to all of us to find good evidence for this ― and then we need to elucidate what else could be the trigger, the common denominator in these patients," she writes.

"And if the symptoms in these patients are at all related to the HPV vaccines, I do not think that we are acting proactively and innovatively enough in order to establish what actions could be taken to prevent more vaccinees from getting side effects and how we should treat the patients already afflicted," she adds.

Dr Bailey, lead author of the ASCO statement, was more measured. There may be other explanations for the symptoms that are reported, or it could be that the symptoms/syndrome would have developed in the individual anyway but that the vaccination precipitated it sooner, he suggested.

"When a person's life has been devastated by an illness, that is very important, but if it turns out that the illness is not related to the vaccine, and in the meantime, the concerns over safety have stopped thousands of young people from being vaccinated.... Well, eventually this will mean that there are more people who die from cancer," he said.

"I would be very reluctant right now to shut down the goals of vaccination over what has been reported, because the bottom line is that we have a tremendous problem with the rising incidence of HPV-related cancers, including in men as well as women when it comes to oropharyngeal cancers here in the States," he added.

"The data, at least in my opinion, are so strong that HPV vaccination, if it's done in a [systematic] way, will reduce the incidence of these cancers.... I don't want to stop whatever progress we are making when there is at best disagreement over whether these things are associated," he said, but added, "Maybe if it was my daughter, I would feel differently."


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