Merck’s HPV Gardasil Vaccine: Risks, Benefits, Marketing_JAMA

Two reports in the Journal of the American Medical Association (JAMA) [1][2] and an editorial written by Dr. Charlotte Haug, the editor-in-chief of the Journal of the Norwegian Medical Association, have re-ignited a debate about the rationale of encouraging–in some instances mandating–mass inoculation of women and girls (as young as 11) with the human papillomavirus (HPV) vaccine.
 
Below, Dr. Haug raises fundamental medical questions that need to be considered before adopting an invasive medical treatment whose documented risks–including 32 post-vaccination deaths–outweigh the evidence of potential benefits for the populations being targeted for "preventive treatment." 

"Whether a risk is worth taking depends not only on the absolute risk, but on the relationship between the potential risk and the potential benefit. If the potential benefits are substantial, most individuals would be willing to accept the risks. But the net benefit of the HPV vaccine to a woman is uncertain.  Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened. So rationally she should be willing to accept only a small risk of harmful effects from the vaccine."

Why then is the target population for Merck’s Gardasil HPV vaccine, girls and young women in the US and other industrialized countries who are LEAST at risk of dying from cervical cancer? They are least at risk because they are protected by regular PAP screens that identify early signs which are effectively treatable.

Below, CBS reporter, Sharyl Attkisson, interviewed Dr. Diane Harper, the principle investigator who helped design and carry out the Phase II and Phase III safety and effectiveness studies to get Gardasil approved, and authored many of the published, scholarly papers about it. She has been a paid speaker and consultant to Merck.

However, Merck’s aggressive marketing of the vaccine for populations least at risk, and its dissemination of disinformation about the vaccine’s benefits, have led Dr. Harper to publicly criticize the vaccine that she helped get approved. Indeed, Dr. Harper joins a number of consumer watchdogs, vaccine safety advocates, and parents who question the vaccine’s risk-versus-benefit profile. She says data available for Gardasil shows that it lasts five years; THERE IS NO DATA SHOWING THAT THE GARDASIL VACCINE REMAINS EFFECTIVE BEYOND FIVE YEARS.

She also questions the wisdom of the Centers for Disease Control and Prevention (CDC) recommendation encouraging girls as young as 11-years old to be given a series of shots:

“If we vaccinate 11 year olds and the protection doesn’t last… we’ve put them at harm from side effects, small but real, for no benefit. The benefit to public health is nothing, there is no reduction in cervical cancers, they are just postponed, unless the protection lasts for at least 15 years, and over 70% of all sexually active females of all ages are vaccinated.”

Dr. Harper also says that enough serious side effects have been reported after Gardasil use that the vaccine could prove riskier than the cervical cancer it purports to prevent. Cervical cancer is usually entirely curable when detected early through normal Pap screenings.

FACTS about HPV:

There are more than 100 different types of HPV and at least 15 of them are oncogenic (potentially cancerous).
The current vaccines target only 2 oncogenic strains: HPV-16 and HPV-18.
The relationship between infection at a young age and development of cancer 20 to 40 years later is not known.
HPV is the most prevalent sexually transmitted infection, with an estimated 79% infection rate over a lifetime.
The virus does not appear to be very harmful because almost all HPV infections are cleared by the immune system.
In a few women, infection persists and some women may develop precancerous cervical lesions and eventually cervical cancer.
It is currently impossible to predict in which women this will occur and why.
Likewise, it is impossible to predict exactly what effect vaccination of young girls and women will have on the incidence of cervical cancer 20 to 40 years from now.
The vaccine’s effectiveness is confirmed for only five years.
The true risk /benefit of the vaccine can be determined only through clinical trials and long-term follow-up.

In other words, every girl being vaccinated with the HPV vaccine is a human guinea pig in an uncontrolled medical experiment.

The JAMA editorial notes: "When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit." Gardasil’s risks are borne by the girls and women vaccinated: its benefit clearly goes to Merck.
 
A report by Drs. Sheila Rothman and David Rothman in the same issue of JAMA, documents how Merck resorted to corrupt practices in the promotion of Gardasil, much as it had done in the marketing of Vioxx. [1]

The authors expose Merck’s covert payments to professional medical associations who sponsored marketing events at which commercial propaganda masqueraded as "educational" material. Merck not only bankrolled professional medical associations, the company provided ready-made presentations, slide sets, e-mails, and letters endorsing the vaccine–which were disseminated under the auspices of influential medical associations.

Among the influential professional medical associations who helped Merck promote Gardasil–having essentially sold their integrity for cash:

The Society of Gynecologic Oncology, the American Society for Colposcopy and Cervical Pathology, and American College Health Association.

All of these organizations helped Merck sell the vaccine with unsubstantiated claims, and helped Merck influence decisions about vaccine policy. None mentioned Merck funding.

As Rothman and Rothman point out:

"Marketing this HPV vaccine as an anticancer vaccine appears to have enabled its manufacturer to circumvent possible parental and public unease with an antidote to sexually transmitted diseases. But in doing so, the company bypassed public health officials who would have spearheaded a risk-sensitive vaccination campaign…. So too, this manufacturer understandably wanted as many adolescents as possible to be vaccinated. But the pursuit of this goal was neither cost-effective nor equitable."

"It meant rather than concentrating on populations in geographic areas with excess cervical cancer mortality, including African Americans in the South, Latinos along the Texas-Mexico border, and whites in Appalachia–i.e., populations that cannot afford the $300 price tag of the vaccine–Merck’s marketing campaign targeted those least likely to die from cervical cancer, thanks to regular PAP tests. Merck’s aggressive propaganda FALSELY claimed that every girl was at equal risk: 

“Your daughter could become 1 less life affected by cervical cancer.”

"By making this vaccine’s target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to all adolescents maximized, and the subpopulations most at risk practically ignored."  

That is a consequential disservice to girls and young women.

The fact that professional medical associations participated in this charade validates critics who charge that professional American medical associations are not to be trusted–they have betrayed the public trust by selling their integrity to industry.

The second report in the same issue of JAMA, by Barbara Slade and colleagues from the U.S. Centers for Disease Control, addresses Gardasil-linked adverse events reported to the US national database, AERS, which comprise only an estimated 1% to 10% of actual adverse events. [2]

Between June 1, 2006, through December 31, 2008 VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100 000 doses distributed.
772 reports (6.2% of all reports) described serious AE following inocularion, including 32 reports of death.
The reporting rates per 100 000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache;
3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease.
Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods.

The authors acknowledge:  "there was disproportional reporting of syncope and venous thromboembolic events," but they soft-peddle the significance of these (admittedly) underreported findings:
"the significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system."

What possible risk/benefit standard can justify giving an inadequately studied vaccine whose risks include serious, permanent adverse effects–including death– to millions of girls and women–who will likely never get cervical cancer?

References:
1. Marketing HPV Vaccine: Implications for Adolescent Health and Medical Professionalism. Sheila M. Rothman, PhD; David J. Rothman, PhD
JAMA. 2009;302(7):781-786.

2. Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine. Barbara A. Slade, Laura Leidel, Claudia Vellozzi, Emily Jane Woo, Wei Hua, Andrea Sutherland, Hector S. Izurieta, Robert Ball, Nancy Miller, M. Miles Braun, Lauri E. Markowitz, and John Iskander
JAMA. 2009;302(7):750-757.

Posted by Vera Hassner Sharav

The Risks and Benefits of HPV Vaccination
Charlotte Haug, MD, PhD, MSc
JAMA. 2009;302(7):795-796.

When do physicians know enough about the beneficial effects of a new medical intervention to start recommending or using it? When is the available information about harmful adverse effects sufficient to conclude that the risks outweigh the potential benefits? If in doubt, should physicians err on the side of caution or on the side of hope? These questions are at the core of all medical decision making. It is a complicated process because medical knowledge is typically incomplete and ambiguous. It is especially complex to make decisions about whether to use drugs that may prevent disease in the future, particularly when these drugs are given to otherwise healthy individuals. Vaccines are examples of such drugs, and the human papillomavirus (HPV) vaccine is a case in point.

zur Hausen, winner of the Nobel Prize in Physiology or Medicine in 2008, discovered that oncogenic HPV causes cervical cancer.1-4 His discovery led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis, and eventually to the development of prophylactic vaccines against HPV infection.

The theory behind the vaccine is sound: If HPV infection can be prevented, cancer will not occur. But in practice the issue is more complex. First, there are more than 100 different types of HPV and at least 15 of them are oncogenic. The current vaccines target only 2 oncogenic strains: HPV-16 and HPV-18. Second, the relationship between infection at a young age and development of cancer 20 to 40 years later is not known. HPV is the most prevalent sexually transmitted infection, with an estimated 79% infection rate over a lifetime5-6 The virus does not appear to be very harmful because almost all HPV infections are cleared by the immune system.7-8 In a few women, infection persists and some women may develop precancerous cervical lesions and eventually cervical cancer. It is currently impossible to predict in which women this will occur and why. Likewise, it is impossible to predict exactly what effect vaccination of young girls and women will have on the incidence of cervical cancer 20 to 40 years from now. The true effect of the vaccine can be determined only through clinical trials and long-term follow-up.

The first HPV vaccine was licensed for use in the United States in June 2006,9 and the Advisory Committee on Immunization Practices recommended routine vaccination of girls aged 11 to 12 years later that same month.10 However, the first phase 3 trials of the HPV vaccine with clinically relevant end points—cervical intraepithelial neoplasias grades 2 and 3 (CIN 2/3)—were not reported until May 2007.11 Previously only reduction in the prevalence of persistent infection and CIN from the 2 virus strains included in the vaccine had been reported. The results were promising, but serious questions regarding the overall effectiveness of the vaccine for protection against cervical cancer remained to be answered, and more long-term studies were called for.12 However, no longer-term results from such studies have been published since then.

So how should a parent, physician, politician, or anyone else decide whether it is a good thing to give young girls a vaccine that partly prevents infection caused by a sexually transmitted disease (HPV infection), an infection that in a few cases will cause cancer 20 to 40 years from now? Two articles in this issue of JAMA13-14 present important data that may influence, and probably already have influenced, such decisions about HPV vaccination.

The report by Rothman and Rothman13 demonstrates how the vaccine manufacturer funded educational programs sponsored by professional medical associations in the United States. The article illustrates how the Society of Gynecologic Oncology, the American Society for Colposcopy and Cervical Pathology, and American College Health Association helped market the vaccine and influenced decisions about vaccine policy with the help of ready-made presentations, slide sets, e-mails, and letters. It is of course reasonable for professional medical associations to promote medical interventions they believe in. But did these associations provide members with unbiased educational material and balanced recommendations? Did they ensure that marketing strategies did not compromise clinical recommendations? These educational programs strongly promoting HPV vaccination began in 2006, more than a year before the trials with clinically important end points were published. How could anyone be so certain about the effect of the vaccine? This matters because the voices of experts such as the professional medical associations are especially important with a complex issue such as this.

In another article, Slade and colleagues14 from the US Centers for Disease Control and Prevention and the US Food and Drug Administration describe the adverse events that occurred 2.5 years following the receipt of quadrivalent HPV vaccine that were reported through the US Vaccine Adverse Events Reporting System (VAERS). Even though most of the reported adverse events were not serious, there were some reports of hypersensitivity reactions including anaphylaxis, Guillain-Barré syndrome, transverse myelitis, pancreatitis, and venous thromboembolic events. VAERS is a passive, voluntary reporting system, and the authors call attention to its limitations. They point out that only systematic, prospective, controlled studies will be able to distinguish the true harmful effects of the HPV vaccine. These limitations work both ways: it is also difficult to conclude that a serious event is not caused by the vaccine.

Whether a risk is worth taking depends not only on the absolute risk, but on the relationship between the potential risk and the potential benefit. If the potential benefits are substantial, most individuals would be willing to accept the risks. But the net benefit of the HPV vaccine to a woman is uncertain. Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened.15 So rationally she should be willing to accept only a small risk of harmful effects from the vaccine.

When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit. Patients and the public logically expect that only medical and scientific evidence is put on the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed. The balance will also tilt if the adverse events are not calculated correctly.

AUTHOR INFORMATION
Corresponding Author: Charlotte Haug, MD, PhD, MSc, The Journal of the Norwegian Medical Association, Akersgata 2, Oslo 0107, Norway (charlotte.haug@legeforeningen.no).

Financial Disclosures: None reported.
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Author Affiliation: The Journal of the Norwegian Medical Association, Oslo, Norway.

 
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WASHINGTON, August 19, 2009
Gardasil Researcher Speaks Out
"Public Should Receive More Complete Warnings"
By Sharyl Attkisson

(CBS)  Amid questions about the safety of the HPV vaccine  Gardasil  one of the lead researchers for the Merck drug is speaking out about its risks, benefits and aggressive marketing.

Dr. Diane Harper says young girls and their parents should receive more complete warnings before receiving the vaccine to prevent cervical cancer. Dr. Harper helped design and carry out the Phase II and Phase III safety and effectiveness studies to get Gardasil approved, and authored many of the published, scholarly papers about it. She has been a paid speaker and consultant to Merck. It’s highly unusual for a researcher to publicly criticize a medicine or vaccine she helped get approved.

Dr. Harper joins a number of consumer watchdogs, vaccine safety advocates, and parents who question the vaccine’s risk-versus-benefit profile. She says data available for Gardasil shows that it lasts five years; there is no data showing that it remains effective beyond five years.

Read also:
Judicial Watch reports on Gardasil  http://www.judicialwatch.org/gardasil
Dr. LaPook’s Story on HPV  http://www.cbsnews.com/stories/2009/08/18/eveningnews/main5250640.shtml
Attkisson’s Exclusive Report on Gardasil http://www.cbsnews.com/stories/2009/02/06/eveningnews/main4781658.shtml

This raises questions about the CDC’s recommendation that the series of shots be given to girls as young as 11-years old. “If we vaccinate 11 year olds and the protection doesn’t last… we’ve put them at harm from side effects, small but real, for no benefit,” says Dr. Harper. “The benefit to public health is nothing, there is no reduction in cervical cancers, they are just postponed, unless the protection lasts for at least 15 years, and over 70% of all sexually active females of all ages are vaccinated.” She also says that enough serious side effects have been reported after Gardasil use that the vaccine could prove riskier than the cervical cancer it purports to prevent. Cervical cancer is usually entirely curable when detected early through normal Pap screenings.

Dr. Scott Ratner and his wife, who’s also a physician, expressed similar concerns as Dr. Harper in an interview with CBS News last year. One of their teenage daughters became severely ill after her first dose of Gardasil. Dr. Ratner says she’d have been better off getting cervical cancer than the vaccination. “My daughter went from a varsity lacrosse player at Choate to a chronically ill, steroid-dependent patient with autoimmune myofasciitis. I’ve had to ask myself why I let my eldest of three daughters get an unproven vaccine against a few strains of a nonlethal virus that can be dealt with in more effective ways.”

Merck and the Centers for Disease Control and Prevention maintain Gardasil is safe and effective, and that adequate warnings are provided, cautioning about soreness at the injection site and risk of fainting after vaccination. A new study in the Journal of the American Medical Association found while the overall risk of side effects appears to be comparable to other vaccines, Gardasil has a higher incidence of blood clots reported. Merck says it continues to have confidence in Gardasil’s safety profile. Merck also says it’s looking into cases of ALS, commonly known as Lou Gehrig’s Disease, reported after vaccination. ALS is a progressive neurodegenerative disease that attacks motor neurons in the brain and spinal cord. Merck and the CDC say there is currently no evidence that Gardasil caused ALS in the cases reported. Merck is also monitoring the number of deaths reported after Gardasil: at least 32. Merck and CDC says it’s unclear whether the deaths were related to the vaccine, and that just because patients died after the shots doesn’t mean the shots were necessarily to blame.

According to Dr. Harper, assessing the true adverse event risk of Gardasil, and comparing it to the risk of cervical cancer can be tricky and complex. "The number of women who die from cervical cancer in the US every year is small but real. It is small because of the success of the Pap screening program."

"The risks of serious adverse events including death reported after Gardasil use in (the JAMA article by CDC’s Dr. Barbara Slade) were 3.4/100,000 doses distributed. The rate of serious adverse events on par with the death rate of cervical cancer. Gardasil has been associated with at least as many serious adverse events as there are deaths from cervical cancer developing each year. Indeed, the risks of vaccination are underreported in Slade’s article, as they are based on a denominator of doses distributed from Merck’s warehouse. Up to a third of those doses may be in refrigerators waiting to be dispensed as the autumn onslaught of vaccine messages is sent home to parents the first day of school. Should the denominator in Dr. Slade’s work be adjusted to account for this, and then divided by three for the number of women who would receive all three doses, the incidence rate of serious adverse events increases up to five fold. How does a parent value that information," said Harper.

Dr. Harper agrees with Merck and the CDC that Gardasil is safe for most girls and women. But she says the side effects reported so far call for more complete disclosure to patients. She says they should be told that protection from the vaccination might not last long enough to provide a cancer protection benefit, and that its risks – “small but real” – could occur more often than the cervical cancer itself would.

"Parents and women must know that deaths occurred. Not all deaths that have been reported were represented in Dr. Slade’s work, one-third of the death reports were unavailable to the CDC, leaving the parents of the deceased teenagers in despair that the CDC is ignoring the very rare but real occurrences that need not have happened if parents were given information stating that there are real, but small risks of death surrounding the administration of Gardasil."

She also worries that Merck’s aggressive marketing of the vaccine may have given women a false sense of security. "The future expectations women hold because they have received free doses of Gardasil purchased by philanthropic foundations, by public health agencies or covered by insurance is the true threat to cervical cancer in the future. Should women stop Pap screening after vaccination, the cervical cancer rate will actually increase per year. Should women believe this is preventive for all cancers – something never stated, but often inferred by many in the population– a reduction in all health care will compound our current health crisis. Should Gardasil not be effective for more than 15 years, the most costly public health experiment in cancer control will have failed miserably."

CDC continues to recommend Gardasil for girls and young women. The agency says the vaccine’s benefits outweigh its risks and that it is an important tool in fighting a serious cancer.

Dr. Harper says the risk-benefit analysis for Gardasil in other countries may shape up differently than what she believes is true in the US. “Of course, in developing countries where there is no safety Pap screening for women repeatedly over their lifetimes, the risks of serious adverse events may be acceptable as the incidence rate of cervical cancer is five to 12 times higher than in the US, dwarfing the risk of death reported after Gardasil.”

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