Study Weighs Risks of Vaccine for Cervical Cancer
By RONI CARYN RABIN
Published: August 18, 2009
The new vaccine designed to protect girls and young women from cervical cancer has a safety record that appears to be in line with that of other vaccines, a government report has found. Some serious complications occurred, including at least 20 deaths and two cases of Lou Gehrig’s disease, but they were not necessarily caused by the vaccine, the study said.
The most common serious complications after vaccination with Gardasil were fainting episodes and an increased risk for potentially fatal blood clots, possibly related to oral contraceptive use and obesity, the study found.
The vaccine has been given to more than seven million girls and young women nationwide and there is no way to prove that complications came from the vaccine.
But while the tone of the study, published in The Journal of the American Medical Association, was reassuring, the authors noted that the analysis was based on imperfect data drawn from reports made to a voluntary government surveillance database. The majority of adverse event reports were filed by Merck & Company, the vaccine’s manufacturer, and most failed to provide enough information for further investigation.
“We feel confident recommending people get the vaccine; the benefits still outweigh the risks,” said Dr. Barbara A. Slade, the study’s first author and medical officer with the Centers for Disease Control and Prevention, which did the study together with the Food and Drug Administration. She added, “This is the most complete picture we have.”
Nevertheless, an accompanying editorial questioned whether any level of risk is acceptable when inoculating a healthy population against a disease that can be prevented through screening.
“There are not a huge number of side effects here, that’s fairly certain,” said the editorial writer, Dr. Charlotte Haug, an infectious disease expert from Norway, about the vaccine. “But you are giving this to perfectly healthy young girls, so even a rare thing may be too much of a risk.
“I wouldn’t accept much risk of side effects at all in an 11-year-old girl, because if she gets screened when she’s older, she’ll never get cervical cancer,” Dr. Haug said in an interview. “You don’t have to die from cervical cancer if you have access to health care.”
The vaccine was approved for girls and young women ages 9 to 26 and is recommended for routine vaccination of girls 11 and 12.
Merck officials said they were pleased with the findings of the new report.
“This confirms the very favorable safety profile we’ve seen in our extensive clinical trials,” said Dr. Richard M. Haupt, executive director of clinical research for Merck Research Laboratories, adding that while screening is important, the vaccine can reduce the number of abnormal results and procedures, because it prevents infection with four strains of HPV, including two implicated in most cases of cervical cancer today.
“Pap screening alone is not the answer,” Dr. Haupt said.
Another paper in JAMA described how Merck, whose sales of Gardasil totaled $1.4 billion last year, provided professional medical societies with grant money the organizations used to develop educational programs promoting the product. The lectures glossed over questions about the vaccine’s effectiveness and whether booster shots would be needed, said Sheila M. Rothman, the paper’s author.
“The message they were giving was really the drug company message,” said Dr. Rothman, professor of sociomedical sciences at Mailman School of Public Health at Columbia. The marketing strategy overstated the risks of cervical cancer for American women, she said. “It was being marketed as if every girl were at equal risk for this disease and needed this vaccine, even though cervical cancer is not a disease of all women in the U.S. ― it particularly affects girls who don’t have access to health care and Pap tests,” Dr. Rothman said.
The study on adverse events analyzed 12,424 reports of adverse events that occurred after immunization with the HPV vaccine from June 1, 2006, to Dec. 31, 2008, when more than 23 million doses of vaccine were distributed, enough to vaccinate more than seven million girls with all three required doses.
That was calculated as a rate of 53.9 adverse event reports to the Vaccine Adverse Event Reporting System for every 100,000 doses of vaccine distributed. Syncope, or fainting, occurred most frequently, with a rate of 8.2 reports per 100,000 vaccine doses, followed by 7.5 per 100,000 for local site reactions and 6.8 per 100,000 for dizziness.
Report rates were then compared with those of other vaccines given in similar populations of girls the same age, Dr. Slade explained.
Of the total number of reports, 6.2 percent, or 772 reports, were considered serious events, including 32 reports of death. Only 20 of the deaths could be verified; the others included four that were provided by the manufacturer without further information, and eight secondhand reports that could not be verified.
Of the 20, 14 of the deceased had only received the HPV vaccine, while others had received multiple vaccines. The average age of the girls who died was 18, and causes of death varied widely ― including two cases of diabetic ketoacidosis, one case related to prescription drug abuse, one case of juvenile amyotrophic lateral sclerosis or Lou Gehrig’s disease, one case of meningoencephalitis, three pulmonary embolisms or blood clots to the lung, six cardiac-related deaths, one case of sepsis related to influenza B and two because of seizure disorders. Four deaths were unexplained.
Dr. Slade said the disparate causes of death made it difficult to determine an underlying cause, or to determine if the vaccine played a causal role.
“We didn’t see any patterns in the causes of death, any pattern in the time between vaccination and death, or the age of the people who died ― there just didn’t seem to be any real pattern that would cause us to have heightened concern,” Dr. Slade said, adding that the number of deaths was “actually very similar to what we see after other vaccines in similar age groups.” She said the A.L.S. cases were being investigated further.
Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine
Barbara A. Slade, MD, MS; Laura Leidel, RN, FNP-C, MPH; Claudia Vellozzi, MD, MPH; Emily Jane Woo, MD, MPH; Wei Hua, MD, PhD; Andrea Sutherland, MD, MSc, MPH; Hector S. Izurieta, MD, MPH; Robert Ball, MD, MPH; Nancy Miller, MD; M. Miles Braun, MD, MPH; Lauri E. Markowitz, MD; John Iskander, MD
Context In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years.
Objective To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV.
Design, Setting, and Participants Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting.
Main Outcome Measures Numbers of reported AEFIs, reporting rates (reports per 100 000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates.
Results VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100 000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, 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-Barre' 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.
Conclusions Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.
Author Affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Slade, Vellozzi, Markowitz, and Iskander and Ms Leidel); US Food and Drug Administration,Washington, DC (Drs Woo, Hua, Sutherland, Izurieta, Ball, Miller, and Braun).
The Risks and Benefits of HPV Vaccination
Charlotte Haug, MD, PhD, MSc
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-Barre' 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.
Marketing HPV Vaccine
Implications for Adolescent Health and Medical Professionalism
Sheila M. Rothman, PhD; David J. Rothman, PhD
The new vaccine against 4 types of human papillomavirus (HPV), Gardasil, like other immunizations appears to be a cost-effective intervention with the potential to enhance both adolescent health and the quality of their adult lives. However, the messages and the methods by which the vaccine was marketed present important challenges to physician practice and medical professionalism. By making the vaccine's target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to adolescents was maximized, and the subpopulations most at risk practically ignored. The vaccine manufacturer also provided educational grants to professional medical associations (PMAs) concerned with adolescent and women's health and oncology. The funding encouraged many PMAs to create educational programs and product-specific speakers' bureaus to promote vaccine use. However, much of the material did not address the full complexity of the issues surrounding the vaccine and did not provide balanced recommendations on risks and benefits. As important and appropriate as it is for PMAs to advocate for vaccination as a public good, their recommendations must be consistent with appropriate and cost-effective use.
Author Affiliations: Sociomedical Sciences, Mailman School of Public Health (Dr S. Rothman), and Social Medicine, Columbia College of Physicians and Surgeons (Dr D. Rothman), New York, New York.
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