AHIP Coverage (Sept/October 2007)
Collaborative Improves Monitoring of Vaccine Safety
By Christopher J. Gearon
This past spring, U.S. Food and Drug Administration (FDA) officials wanted to determine whether any young children were being diagnosed with Kawasaki syndrome a month after receiving RotaTeq, a vaccine approved in February 2006 in the United States for potentially deadly rotavirus infection. Pre-licensure clinical study for RotaTeq—one of the largest clinical vaccine trials ever held—had found five infants diagnosed with Kawasaki shortly after receiving RotaTeq -- out of several thousands of children who had received the vaccine.
But this rate of Kawasaki was no higher among test subjects than in the general childhood population. And three additional reports of Kawasaki following RotaTeq vaccination since February 2006 via the Vaccine Adverse Events Reporting System (VAERS)—a monitoring tool available to anyone in the United States to lodge suspected problems with a vaccine—were not out of the ordinary.
However, considering that the FDA had pulled an earlier rotavirus vaccine, RotaShield, off the market in 1999 for separate adverse events associated with the vaccine, federal officials did not want to take any chances. FDA wanted to know the vaccine’s real world experience pertaining to Kawasaki, so it turned to vaccine safety experts at the Centers for Disease Control and Prevention (CDC) for answers.
Kawasaki syndrome, which occurs primarily in young children, affects some 4,000 kids annually in the United States. Symptoms include a fever that lasts more than five days, red eyes, body rash, and severely chapped lips. Untreated, it can lead to serious complications involving the heart. A prompt diagnosis of Kawasaki is crucial in treating the condition.
To get answers, CDC pressed into action a key component of the world’s most sophisticated post-marketing surveillance system in place for vaccines, a system far superior to post-marketing surveillance currently in place for prescription drugs and other biologicals. At the heart of this system is the Vaccine Safety Datalink (VSD)—a large linked data model that allows real-time analysis of vaccination and medical records of more than 5.5 million people for the purposes of conducting objective, population-based vaccine safety research. These data are de-identified to protect patient confidentiality.
VSD is a valued resource that allows researchers at CDC and eight health plans to conduct studies that provide information about the short and long-term effects of specific vaccines on various populations. “That doesn’t exist for drugs. VSD is a model,” says Paul Offit, chief of infectious diseases at Children’s Hospital of Philadelphia, a renowned vaccine researcher and author.
Developed by CDC, the VSD is a collaborative between the federal agency, leading vaccine researchers, and eight health plans—Group Health Cooperative; Harvard Pilgrim Health Care; HealthPartners Research Foundation; Kaiser Permanente plans in Colorado, Northern and Southern California, and the Northwest; and Marshfield Clinic Research Foundation. Rather than relying on reports from vaccine manufacturers themselves or solely on a passive reporting system like VAERS, the VSD offers a rich data resource that can be quickly accessed by CDC officials and top vaccine investigators employed by health plans to monitor continually vaccine safety. This is done via rapid analyses of specific vaccines and through large-scale, retrospective studies of individuals experiencing unusual or severe adverse reactions to vaccines.
Within days of the FDA’s request last spring, an extensive, updated post-market assessment conducted by CDC and its VSD health plan partners supported earlier evidence that no statistically significant association existed between RotaTeq and Kawasaki. Two weeks later, the FDA revised the label for the vaccine to include information on reports of Kawasaki occurring before and after the vaccine’s licensure, but did not make changes to its indications for use of RotaTeq and did not issue any warnings or precautions.
In another important surveillance, the CDC has asked the VSD to identify any cases of Guillain-Barre Syndrome (GBS) following administration of the Menactra meningococcal vaccine. (See Sidebar.)
Successes and Fears
Ever since Edward Jenner observed that milkmaids who had contact with cowpox did not get smallpox, the world, and in particular the United States, has been a much safer place when it comes to disease. A low-cost medical intervention, vaccines have saved millions of lives, unquantifiable suffering, and significant health care expenditures. While clean water, antibiotics, and other public health advances have done their part to prevent death and disease, Offit says vaccines are the chief reason why life expectancy in the United States has risen by 30 years over the last century. “The other part of the track record of vaccines is they save society money, as they’ve reduced morbidity and mortality [for the diseases the vaccines were used against] by 99 percent,” says John Iskander, acting director of CDC’s Immunization Safety Office.
Nevertheless, there is increased focus on vaccine safety today. “We have a history of known adverse events following immunizations,” says Eric France, chief of preventive medicine at Kaiser Permanente-Colorado. These include the Cutter vaccine incident in the 1950s when 200,000 people were inadvertently injected with live virulent polio virus, causing permanent paralysis in some, and, more recently, the instances of RotaShield causing gastrointestinal bleeding in young children. Considering that more than two dozen vaccines are recommended for children, and that schools mandate vaccinations, questions have been raised about the possible effects of vaccines on small, developing bodies.
Yet vaccines successfully wiped out smallpox and diphtheria, nearly eradicated polio, and significantly reduced the threat of whooping cough, measles, and meningitis. When we no longer have children in the neighborhood dying of measles and polio, “the risk-benefit equation changes in people’s minds [because] they don’t see the risks,” says Lisa Jackson, senior investigator at Group Health Cooperative’s Center for Health Studies.
Instead, the focus has been on adverse effects of some of the vaccines, both real and perceived. News headlines can frighten parents into not having their children vaccinated for measles, for example, which could lead to an outbreak of serious disease. The return of epidemic diseases has occurred with unfortunate results in Japan, Sweden, and the United Kingdom. “Life is full of risks and a child is much more likely to die next week from a car accident than from a result of a vaccine,” France says. “The chance of having an adverse event from a vaccine is higher than the [occurrence of the] disease itself,” he adds, so public attention tends to focus on those side effects.
Maintaining trust in the nation’s vaccine system is crucial, particularly as vaccines have allowed us to keep pace with emerging threats -- from seasonal influenza to bioterrorism -- and vaccines even hold the promise of curing cancer and other conditions. In the United States, the VSD is an effort to gather the facts, today in nearly real time, on vaccine safety, and monitor, analyze and put into perspective the risks of certain vaccines. The research performed as part of VSD directly influences the nation’s vaccination policies.
For example, VSD research led to RotaShield being pulled from the market when it was associated with intussusception, the prolapse of one portion of the bowel into an adjacent segment. Recent VSD studies also have quantified the extremely rare risk of potentially life-threatening anaphylactic reactions associated with vaccines administered to children and adolescents and found that hepatitis B immunization is not associated with neonatal death. Meanwhile, the first epidemiologic study evaluating and confirming the safety of trivalent inactivated influenza vaccine among infants and children was done by VSD researchers. (See sidebar for a sampling of other VSD research initiatives.)
“The fact of the matter is you can’t [completely] figure out the side effects (of a vaccine) until large numbers of it are in place,” says Offit, “and that’s what the VSD brings.” While this is also true of drugs, the surveillance system for drugs on the market lacks the rigor of vaccine monitoring.
Caution Is Foremost
The recent case of RotaTeq illustrates the work of the nation’s vaccine post-marketing surveillance system. The RotaTeq case also shows the commitment by federal officials and the vaccine community to err on the side of caution in order to ensure the safety of vaccines and maintain the public’s confidence in vaccines.
On the morning of May 30, the day after FDA’s alert, CDC’s Dr. Iskander met with vaccine safety officials to chart out a course of action. Since RotaTeq’s approval, CDC and health plan vaccine experts had been monitoring it for intussusception and other side effects, largely because of problems linked to its predecessor, RotaShield—although the properties of the two vaccines are very different.
The potential side effects being monitored for RotaTeq weren’t showing up -- a good thing since RotaTeq protects against the rotavirus, which is the leading cause of gastroenteritis in infants and children worldwide. The virus is responsible for more than 400,000 doctor visits, 200,000 emergency room visits, and as many as 60 deaths a year in the United States for kids under age 5. Worldwide rotavirus kills about 1,600 young kids a day.
Since RotaTeq’s approval, researchers at CDC, Marshfield Clinic, and Harvard Pilgrim Health Plan had led the monitoring of RotaTeq, and the vaccine had shown no signs of concerns. Just after Memorial Day, at the FDA’s request, Iskander directed researchers to run a rapid cycle analysis on RotaTeq immunizations to search for kids who were later diagnosed with Kawasaki.
Thanks to a recent advancement to the VSD, where de-identified patient data is updated on a weekly basis and available to each site at 4 a.m. every Tuesday—instead of the traditional yearly basis—CDC statistician Eric Weintraub was able to adjust the rapid cycle system specifications that were developed by Kaiser Permanente-Northern California statistician Ned Lewis. The ICD-9 code for Kawasaki syndrome was added for monitoring children following vaccination with RotaTeq.
By noon that day, VSD began rapidly scouring more than 5.5 million patient records from the eight health plans in order to detect patterns of children under age 1 who had received the oral vaccine. From that cohort, VSD would then identify how many went to the doctor and received a Kawasaki diagnosis within 30 days of getting RotaTeq. “It was pretty impressive,” Lewis says about the system’s ability to respond.
“When a new vaccine comes out (on the market) you want up-to-the-minute data,” says Tracy Lieu, a principal investigator with Harvard Pilgrim and Harvard Medical School. Along with CDC, the Boston-area plan leads rapid cycle analyses of vaccines run through the VSD. Rapid cycle analysis, a newer methodology developed by the VSD over the last several years, has helped today’s post-marketing surveillance to jump “light years ahead of how vaccine safety monitoring was conducted even five years ago,” Lieu says.
By the close of business the next day, May 31st, the program had identified about 65,000 kids under age 1 who had received RotaTeq at the participating health plans. No cases of Kawasaki were identified in the last week of May. Another rapid cycle analysis was run during the first week of June after the regular weekly data update. That new analysis yielded one possible case of an infant diagnosed with Kawasaki shortly after a RotaTeq vaccination.
Simon Hambidge, a principal investigator at Kaiser Permanente Colorado’s Clinical Research Unit, pulled the chart of the tiny Kaiser member that same day. Because the child’s situation was medically complicated, it could not be identified as a clear-cut instance of Kawasaki. Nevertheless, federal officials decided to consider it Kawasaki. “The folks at the CDC very appropriately tend to err on the side of not wanting to miss anything,” Hambidge says.
The best-known studies of Kawasaki suggest its incidence is approximately 1 to 1.9 cases per 10,000 in children 0 to 5 years old. That rate includes unvaccinated as well as vaccinated children. Looking at 65,000 kids in the VSD population, one case of Kawasaki within 30 days of RotaTeq vaccination is within expectation. “This is basically reassuring information,” Lieu says. “It’s clear the situation needs to be closely monitored, but there is no indication of risk at this time,” Weintraub says.
In the end, the FDA still revised RotaTeq’s packaging. In addition to Kawasaki now being monitored as part of the rapid cycle analysis of RotaTeq, VSD researchers are now gearing up for a “full-blown” study evaluating Kawasaki in children following all immunizations, says Weintraub.
What Health Plans Bring to Vaccine Safety
“The question is, do the benefits [of a vaccine] far outweigh the risks?” says Offit, who co-holds the patents with Merck for RotaTeq. “You have to have a high bar when you give something to healthy children,” Offit says.
“If you look at the track record of vaccines, almost all of them meet that bar,” says Iskander. Like prescription drugs, vaccines must prove themselves through a series of clinical trials before they are approved by the FDA for licensure, a process that can take more than a decade.
But, after approval, the post-marketing surveillance for vaccines and other medicines diverge. Unlike most drugs and biologicals, vaccines have a vast post-licensing infrastructure in place that monitors closely, in nearly real time, side effects of both established and newly approved vaccines. Other drugs and biologicals rely on a 10-year-old adverse events reporting system, which is based on volunteer reports from health care providers and pharmaceutical manufacturers and is widely viewed as limited in effectiveness. (See “New Drug Approvals: Shifting the Focus From Speed to Safety,” p. xx.) That was the problem with Vioxx, asserts Offit; adding a VSD system would have caught the problems associated with Vioxx much sooner.
The vaccine model has it roots two decades ago when Congress passed the National Childhood Vaccine Injury Act, spurred by legal damages awarded to claimants presumably sickened by the diphtheria, pertussi, tetanus (DPT) vaccine—even without scientific evidence to support the claims. Among other things, the law coordinated immunization-related activities within the federal government and mandated that all health care providers report to the VAERS certain events following vaccination. The VAERS system is used for answering many vaccine-related questions as they arise.
“That’s simply an early warning system,” says Marie McCormick, professor of maternal and child health at Harvard School of Public Health. “That certainly happened with the autism case.” McCormick chaired an IOM committee that examined the controversy surrounding claims that the mercury-based vaccine preservative thimerosal caused autism. Her committee found overwhelming evidence that childhood vaccines are not associated with autism. Recent VSD research continues to confirm that 2004 report.
Gaps in information of rarer vaccine side effects spurred the CDC to develop VSD in 1990, on the assumption that large pools of data were needed in order to do population-based studies and track rarer problems. Starting with four managed care organizations, the VSD today is a collaborative effort among Iskander’s office, AHIP and the eight plans, all of which have electronic medical record capacity and significant research centers involved in cutting-edge vaccine-related investigations. Pooling their data makes the information even more valuable to researchers.
With VSD, investigators have access to millions of de-identified patient records pertaining to vaccines, health care utilization, and outcomes, allowing researchers, for the first time, to link data on patient characteristics, health outcomes, and vaccination history. The health plans also bring tremendous resources and brain power to vaccine safety research. The participating “HMOs are well known for their capacity to conduct research,” McCormick notes. Since 1990, the VSD efforts have produced more than 65 scientific articles in premium medical and scientific journals.
“Without all this infrastructure in place, the intussusception would not have been noticed [in RotaShield]. We may still not have found it,” says Lewis.
VSD works in conjunction with other components in the vaccine safety system, including CDC’s Clinical Immunization Safety Assessment Network (CISA), a program managed by AHIP that provides for research on immunization-associated health risks on an individual level by experts at six medical research centers. The network’s mission: design scientifically sound research to clarify vaccine-associated risks, while supplying providers and the public with evidence-based guidelines when considering vaccination for adverse event-prone individuals. In working to respond to emerging technologies like DNA analysis, CISA, for example, collects and stores genetic specimens in a newly establish centralized registry and repository.
The value of the vaccine post-marketing surveillance can be measured in many ways. For example, even amid concerns of possible side effects -- much of which are limited to isolated injection-site soreness and fever -- immunization rates in the United States are as high as they have ever been, and the nation has among the lowest vaccine preventable disease rate. Without the current system, “it would be much longer to get a quick answer to a safety issue,” France says.
Optimism Amid the Challenges Ahead
With rapid advances in medical science and DNA technology, the potential for saving lives with more and better vaccines is greater than ever before. As the science of genomics matures, researchers can study whether certain people are at increased risk for adverse effects from vaccination because of an underlying health condition or because of individual genetic make-up. CISA has been studying what role genetics plays in adverse effects.
To maintain the public’s trust going forward, CDC and vaccine researchers realize public concern and other factors need to be addressed. For example, a 2005 IOM report recommended that the VSD be opened to outside researchers and be made more transparent. Changes are underway that will allow non-affiliated researchers access to VSD data while protecting patients’ identities.
Vaccine safety also requires more personnel and funding, McCormick says. Also, there is lag time between preliminary results of an investigation that are of “less value” and publication of the reports, she says. Also, VSD is built upon ICD-9 codes, and to get accurate vaccine safety results codes need to be accurate, she adds. Problematic coding is particularly evident in the area of developmental disabilities. Moreover, experts say determined investigators with a thorough knowledge of genetics and immunology are needed to meet the complex vaccine challenges ahead.
The role genomics will play in vaccine development and adverse events potentially is huge, as is the role of health plans in post-marketing surveillance of vaccines and other drugs, France says. Because of the importance of their datasets to vaccine and drug safety, “HMOs will be playing a bigger role in the future when it comes to drug safety,” France says.
SIDEBAR
The CDC and vaccine safety researchers at eight health plans undertake projects both on their own and in conjunction with other VSD partner sites. The following offers a slice of the health plans’ research.
Group Health Cooperative’ s Center for Health Studies is researching the risk of autoimmune thyroid disease following hepatitis B vaccine, the safety of a third dose of PPV (pneumococcal vaccine) in adults, and the safety and effectiveness of one dose of influenza vaccine versus two in first-time flu vaccine recipients ages 5 to 8.
Harvard Pilgrim Health Care, Harvard Medical School, and Harvard Vanguard Department of Ambulatory Care and Prevention is evaluating the temporary suspension of the birth dose of hepatitis B vaccine on certain 2-year-olds and conducting a case-control study of the association between thimerosal exposure and autism-type disorders, as well as doing rapid cycle analysis studies on meningococcal conjugate vaccine and influenza vaccine.
HealthPartners Research Foundation is examining rotavirus vaccine and intussusception, the health consequences that result from kids not getting immunizations, and the safety of Yellow Fever vaccine in children and adults.
Kaiser Permanente Colorado’s Clinical Research Unit is investigating the potential association of excessive bruising and bleeding with the measles, mumps, and rubella vaccination, evaluating the possible benefit to infants of influenza vaccination during pregnancy, and assessing the safety of the trivalent influenza vaccine for infants and toddlers.
Kaiser Permanente Northwest’s Center for Health Research is studying cardiac events after live viral vaccination in adults, immune hemolytic anemia in children after vaccination, and adverse events following pediatric flu vaccination.
Marshfield Clinic Research Foundation is studying the safety of a new rotavirus vaccine for infants, assessing the safety of the rabies vaccine and the varicella vaccine, and conducting a case-control study of risk factors for herpes zoster (shingles) and a rapid assessment of influenza vaccine effectiveness for preventing laboratory-confirmed influenza illness.
Northern California Kaiser Permanente-Kaiser Permanente Vaccine Study Center is conducting a risk assessment of adverse events following vaccination, evaluating the possible association of alopecia with hepatitis B vaccination, and looking at genetic factors to predict possibility of arthritis following hepatitis B vaccination.
Southern California Kaiser Permanente Health Care Plan/ UCLA Center for Vaccine Research is studying hepatitis A vaccine (coverage?) among at-risk children and adults, influenza vaccine safety in young children, and thimerosal-containing vaccines and infant neurodevelopment.
Christopher J. Gearon is a health and financial freelance writer based in Silver Spring, Maryland.
Sidebar: Monitoring the Safety of an Important Vaccine
The Vaccine Safety Datalink, a surveillance collaboration of the Centers for Disease Control and Prevention (CDC) and eight U.S. managed care organizations, is currently monitoring to identify cases of Guillain-Barré Syndrome (GBS) following vaccination with Menactra, a vaccine licensed to Sanofi Pasteur in early 2005 that protects against meningococcal disease.
Meningococcal disease is a severe bacterial infection that can cause meningitis, bloodstream infection, and other localized infections. Although the disease is not common in the United States, in those who get it, symptoms develop and progress rapidly and can lead to death within 24-48 hours. Meningitis can lead to loss of a limb, permanent neurologic impairment, or death. Meningococcal bacteremia, a bloodstream infection, can result in joint infection, pneumonia, organ system failure, shock, and death.
The meningococcal conjugate vaccine (MCV4 or Menactra), is one of two meningococcal vaccines available in the United States and the only conjugate-type vaccine against the disease.
Although Menactra is considered safe, a possible association between Guillain-Barré Syndrome (GBS) and vaccination with Menactra was first reported by the CDC in October 2005. GBS causes muscle weakness, progressive paralysis, and in some cases, death.
Monitoring the safety of Menactra is particularly important in light of the new recommendations issued in July by the Advisory Committee on Immunization Practices (ACIP) that call for meningococcal immunization with conjugate vaccine of all adolescents 11 to 18 years of age. Originally, vaccination was limited to specific groups of adolescents and adults at high risk, based on concerns about vaccination supply. As the increased supply permitted, the recommendations have been expanded to include all adolescents and additional age groups.
Surveillance History
Following the October 2005 reports of a possible association between GBS and vaccination with Menactra, in December 2005, the Global Advisory Committee on Vaccine Safety recommended no change in Menactra vaccination policies. While a total of eight cases of GBS following vaccination with Menactra were reported through February 2006, a causal relationship between Menactra and GBS was never proven, and the CDC recommended continuing use of Menactra for persons for whom vaccination is recommended.
However, CDC recommended that information concerning the GBS investigation be shared with adolescents and caregivers before vaccinating with Menactra. Also, Sanofi Pasteur and the U.S. Food and Drug Administration (FDA) updated the Menactra vaccine package insert to list previous GBS as a contraindication and to provide a warning of the temporal relationship between GBS and Menactra.
The CDC also queried the VSD about the association of GBS with Menactra vaccination. The regularly updated dynamic data files of the VSD did not identify any other GBS cases in Menactra recipients. The addition of several million records from other health plans identified only one case. While the CDC acknowledged that the ability of VSD to detect rare health events such as GBS is limited, the VSD permits queries of almost real-time data and thus provides immediate answers to questions of the seriousness of a perceived problem with a vaccine.
The FDA and CDC have asked the public and health care providers to inform them about any links between GBS and Menactra. Sanofi Pasteur has pledged to work with the FDA and CDC to investigate any connection between Menactra and GBS. FDA and CDC continue to monitor reports to the Vaccine Adverse Event Reporting System (VAERS) and encourage reporting of any cases of GBS after Menactra to VAERS.
CDC and FDA will continue to closely monitor the situation. There is not a specific number of cases that would have to be reported before CDC or FDA take further action. The reason is that GBS can occur in the absence of vaccination, thus every case needs to be evaluated carefully for possible causes. The timing of GBS following vaccination, clinical factors, and the total number of people vaccinated are important to consider as well.
Pull Quotes:
Rapid cycle analysis, a newer methodology developed by the VSD over the last several years, has helped today’s post-marketing surveillance to jump “light years ahead of how vaccine safety monitoring was conducted even five years ago.”
“You have to have a high bar when you give something to healthy children.”
Vaccines are the chief reason why life expectancy in the United States has risen by 30 years over the last century.
