Health - Shots are popular ,but fail to clear doubts (V.G.Read)

In two years, cervical cancer has gone from obscure killer confined mostly to poor nations to the West's disease of the moment.
Tens of millions of girls and young women have been vaccinated against the disease in the United States and in Europe in the two years since two vaccines were given government approval in many countries and, often, recommended for universal use among females from 11 to 26.
One of the vaccines, Gardasil, from Merck, is paid for by the government for the poorest girls to age 18 in the United States, at a potential cost of greater than $1 billion; proposals to mandate the vaccine for girls in middle schools have been offered in 24 states, and one will take effect in Virginia this fall. Even the often stingy British National Health Service will start giving the other vaccine - Cervarix, from GlaxoSmithKline - to all 12-year-old girls at school this September.
The lightning-fast transition from newly minted vaccine to must-have injection in the United States and Europe represents a triumph of what the manufacturers call education and their critics call marketing. The vaccines are far more expensive than earlier vaccines against other diseases - Gardasil's list price is $360 for the three-dose series, and the total cost is typically $400 to nearly $1,000 when including markup and office visits.
Award-winning advertising has promoted the vaccines. Before the film "Sex and the City," some American moviegoers saw ads for Gardasil. On YouTube and in advertisements during popular shows like "Law and Order," a multi-ethnic cast of young professionals urges girls to get vaccinated.
The vaccine makers have also brought attention to cervical cancer by providing money for activities by patients' and women's groups, doctors and medical experts, lobbyists and political organizations interested in the disease, sometimes in ways that skirt disclosure requirements or obscure the companies' involvement.
In the United States, hundreds of doctors have been recruited and trained to give talks about Gardasil - $4,500 for a lecture - and some have made hundreds of thousands of dollars. Politicians in Britain have been invited to receptions catered with drug company money.
Legislators in dozens of countries willingly rallied behind a vaccine that combined two popular, hot button issues: cancer prevention and women's health.
"There was incredible pressure from industry and politics," said Dr. Jon Abramson, a professor of pediatrics at Wake Forest University who was chairman of the committee of the U.S. Centers for Disease Control and Prevention that recommended the vaccine for all girls from age 11 or 12 through 26, though he later opposed state proposals to require it.
Although cervical cancer kills close to 300,000 women a year globally, pap smears and follow-up treatment limit the death toll in countries with good medical care: 3,600 in the U.S., 1,000 in France and 400 in Britain annually.
Even critics of the marketing efforts recognize the benefits of the vaccines. Girls who get the shots are less likely to have Pap tests with worrisome results that would lead to further treatment, saving themselves anxiety and discomfort and, in those cases, saving health budgets. When it occurs, cervical cancer is a dreadful disease; genital warts, partially prevented by the Merck vaccine, can be a painful nuisance.
But some experts worry about the consequences of the rapid rollout of the new vaccines without more medical evidence about how best to deploy them. They say that because of the aggressive marketing and lobbying campaigns, even parents of girls who are far from being sexually active may feel pressured into giving them a vaccine that is not yet needed and whose long-term impact is still unclear.
"This big push is making people crazy - thinking they're bad moms if they don't get their kids vaccinated," said Dr. Abby Lippman, a professor at McGill University in Montreal and policy director of the Canadian Women's Health Network.
Merck's vaccine was studied in clinical trials for five years, and Glaxo's for nearly six and a half, so it is not clear how long the protection will last. Some data from the clinical trials indicate immune molecules may wane after three to five years.
Some experts are concerned about possible side effects that become apparent only after a vaccine has been more widely tested over longer periods.
And why the sudden alarm in developed countries about cervical cancer? some experts ask. A major killer in the developing world, particularly Africa, where the vaccines are too expensive for use, cervical cancer is almost always preventable through regular Pap smears that detect precancerous cells effectively. Indeed, because the vaccines prevent only 70 percent of cervical cancers, Pap smear screening must continue anyway
"Merck lobbied every opinion leader, women's group, medical society, politicians, and went directly to the people - it created a sense of panic that says you have to have this vaccine now," said Dr. Diane Harper, a professor of medicine at Dartmouth Medical School. Harper was a principal investigator on the clinical trials of both Gardasil and Cervarix, and she spent 2006-7 at the World Health Organization developing plans for vaccine programs around the world.
"Because Merck was so aggressive, it went too fast," Harper said.
In receiving expedited consideration from the Food and Drug Administration in the United States, Gardasil took six months from application to approval. Most vaccines take 3 years, Harper said, and then 5 to 10 more for universal acceptance.
"In that time, you learn a lot about safety and side effects and how to use it," Harper said. "Those getting it early should be the ones who really want it and willing to accept the risk."
Dr. Richard Haupt, medical director at Merck, said it was crucial to get a groundbreaking vaccine into use as quickly as possible. "You can only study a vaccine for so long before you license and use it in a population where it has enormous value," Haupt said. "Our hope and belief is that this is a remarkable vaccine that will have huge impact on women."
Haupt said the vaccine had not been rushed into use, saying that five years in clinical trials was a normal period before applying for licensing. He said Merck educated physicians, politicians and the public about the new vaccine to "accelerate and facilitate access."
Spokesmen for Merck and Glaxo say all indications are that their vaccines are safe and effective, and there is no evidence that a booster shot will be needed. Sarah Alspach, a spokeswoman for Glaxo, said that its formulation produces a "stronger and longer-lasting immune response" than conventional vaccines.
But with their high price, the vaccines are straining national and state health budgets as well as family pocketbooks. These were the first vaccines approved for universal use in any age group that clearly cost the health system money rather than save it.
Health economists estimate that depending on how they are used, the two cervical cancer vaccines will cost society $30,000 to $70,000, or higher, for each year of life they save in developed countries - a cost commonly seen in treatments for people already suffering from deadly cancers. That number will be far higher still if a booster is needed.
"This kind of money could be better used to solve so many other problems in women's health," said Lippman at McGill. "I'm not against vaccines, but in Canada and the U.S., women are not dying in the streets of cervical cancer."
By contrast, if the vaccine were to become cheap enough to be used in the developing world, it would revolutionize women's health. Charities like the Global Alliance for Vaccine and Immunizations, backed by the Bill & Melinda Gates Foundation, are trying to devise a solution.
The vaccines offer partial protection against infection from human papillomavirus, or HPV, a common and generally benign sexually transmitted virus that can in rare cases cause cancer after years of silent infection. The Merck vaccine also prevents some genital warts.
Dr. David Salisbury, head of the British Department of Health's Vaccine and Immunization Committee said the government decided to vaccinate school girls because "this initiative was seen as a good use of resources that fits with the government's health priorities and political priorities."
But critics urge restraint. Angela Raffle, a specialist in cervical cancer screening with the National Health Service in Britain said, "If we do this quickly and badly we could cause more deaths," for example, from side effects or from giving girls false security that they no longer need to be screened.
Stephanie Levi decided to give her two daughters the vaccine in late 2006 in New York, after receiving a newsletter from their physician.
That same week, she noticed articles and ads for the vaccine, "I remember thinking I had better do this quickly."
It is not hard to hear about Gardasil.
In ads like the "Law and Order" ones, a cast of hip 20-somethings describe why they got the shots, in the language of liberation. "I chose to get vaccinated because my dreams don't include cervical cancer," a bespectacled artist claims. The ads direct viewers to gardasil.com, which includes patients' stories, buddy icons and downloads for holding an event at a college sorority.
The marketing has helped make Gardasil one of Merck's best sellers, with a projected $1.4 to $1.6 billion outside Europe this year, and more from sales in Europe, where Merck sells the vaccine through a joint venture with Sanofi Aventis
Aggressive pharmaceutical advertising is nothing new, but the campaign was a revolution for a vaccine cheap and not particularly profitable.
In 2006, hundreds of doctors and nurses in the United States were signed up as unofficial spokesmen for Gardasil, trained by Merck, provided with a multimedia presentation and paid $4,500 for each 50-minute talk, presented over Merck-sponsored meals. Many were paid for attending Merck "advisory board" meetings to discuss the shots.
Merck said it provided assistance to speakers "to make sure they are providing accurate information in accordance with FDA-approved labeling and to make sure dissemination of information is always appropriate," said Amy Rose, a spokeswoman.
Promotion and marketing for Cervarix, the Glaxo version of the vaccine, has been far less visible, in part because it is not yet approved for use in the United States, and consumer advertising of medicines is prohibited in much of Europe.
But on both continents, there has been a proliferation of cervical cancer awareness campaigns, sponsored by new or newly energized scientific and patient groups financed with the assistance of Merck and Glaxo.
In some cases, the financial support has often been indirect, so that patients are unaware that expert advice has been at last partly financed by the vaccine makers.
Dr. Gregory Poland, a vaccine expert at the Mayo Clinic, was a nonvoting member on the CDC panel that recommended Gardasil in 2006 and has been a frequent defender in the media. Records show that Poland received at least $27,420 in expenses and consulting fees from Merck between 1999 and 2007.
To encourage vaccination on campuses, Merck provided the American College Health Association with an unrestricted grant to train its officers to speak about the new vaccine and to create kits to for college health services. "You, the female students sitting in your class, your sorority sisters, your teammates and your best girlfriends could all be at risk," a sample message reads.
The association now recommends the shot for all female college students, even though many in that age group will already have HPV, rendering the vaccine less effective or even useless.
Dr. James Turner, incoming president of the association, said it undertook the campaign because "HPV is a very important issue for college students" and the association "is a very small organization and we don't have funds."
In Britain, Jo's Trust, a longstanding cervical cancer charity with a staff of one held a series of breakfasts that introduced cervical cancer and the vaccine to parliamentarians. The food bills went to Merck's European Joint Venture. Pamela Morton, executive director said: "I'm a one man band, so I was grateful for their support and to be able to do this for women."
Haupt, said that Merck did its best to "respond" to requests.
In country after country, Merck and Glaxo also appealed to politicians. "We support policy leaders and try to educate legislators," Haupt said
In the United States, 41 states have passed or begun considering legislation on cervical cancer, according to the National Conference of State Legislatures, and 24 have considered proposals to mandate the vaccine for girls, generally in middle school.
In Italy, parents of 10-year-olds have received letters from the Ministry of Health encouraging them to get the vaccine.
One bill to require the vaccine for school entry has been passed, in Virginia; it will first apply in 2009.
In December 2006, Merck announced it would invest $57 million to expand its Elkton, Virginia, plant to make Gardasil, helped by a $700,000 grant from a state economic development agency.
Two months later, Governor Tim Kaine signed legislation requiring Gardasil for schoolgirls. Four months after that, Merck pledged to invest $193 million more in the plant.
Delacey Skinner, spokeswoman for the governor, said the Virginia vaccination program includes an unusually broad freedom to decline the shot.
"Without hesitation or question," the decisions about the plant and about the mandate legislation "were completely separate," she added.
However, as in many American states where cervical cancer legislation has been considered, there were ties between drug makers and members of government.
In Britain, drug makers visited the nurses and family practitioners who are the backbone of the National Health Service urging them to offer the vaccine privately, if the NHS turned it down, Dr. Raffle said. "The people who understood the issues, with black belt cancer screening experience, were left out. "
In Belgium, the health minister approved the vaccine before the country's health technology evaluation committee had finished deliberating. "We have a case that's about cancer, so its very emotional. And we talk about prevention, which is also seen as good," said Ralph Crott, a economist who was on the committee. "In my opinion it was oversold."
Many questions about the vaccines remain unanswered, including how long immunity will last. Even commercials for Gardasil say - in small print -- "The duration of protection has not been established."
Harper said that in the data from Merck's clinical trials, which she helped conduct, the vaccine was no longer protective after just three years in some girls. "The immunity of Gardasil will not last - that is dangerous to assume," she said.
She believes that at least one booster shot, and probably more, will be needed over the course of a lifetime.
Other independent experts have worried that eliminating the two cancer-causing HPV strains covered by Gardasil and Cervarix might actually allow the other cancer-causing strains of HPV to increase in frequency, reducing the vaccine's effect.
But Haupt said these were "theoretical possibilities" that should not deter rapid distribution of an important vaccine. "We'll worry about whether boosters are needed down the road," he said.
The Centers for Disease Control asks health care centers to report side effects through its Vaccine Adverse Events Reporting System; reporting is voluntary. There have been 9,749 reports, almost all from doctors and nurses, of post-vaccine adverse effects, the agency announced in a joint report with the food and Drug Administration at the end of June. Ninety-four percent of them were not serious, ranging from arm pain to fainting, and 6 percent were classified as serious, including blood clots, paralysis and deaths. There have been 20 deaths.
But 16 million doses of the drug have been distributed by Merck in the United States, and in a population so large, "by chance alone some serious adverse effects and deaths" will occur, the FDA said.
It said there was no indication that the deaths or serious side effects were caused by the shot, concluding that "Gardasil continues to be safe and effective and its benefits continue to outweigh its risks."
Both the agencies and Merck acknowledge that there does appear to be a high rate of fainting, so doctors are now advised to have patients stay in the office for 15 minutes after receiving a shot.
Cervical cancer is the second-leading cause of cancer death in women, with 500,000 new cases worldwide each year. But more than 90 percent are in developing countries, according to the World Health Organization; 274,000 women died of this cancer in 2006, nearly 95 percent of them in developing countries. Where there are Pap smear programs, few women die of cervical cancer.
Meanwhile, the vaccine's proponents are moving to the next frontier: older women and boys.
One rationale for inoculating boys is that entire populations should be vaccinated to achieve what is called herd immunity.
Said Raffle, the British Cervical Cancer specialist: "Oh dear. If we give it to boys, then all pretense of scientific worth and cost analysis goes out the window."
"This big push is making people crazy - thinking they're bad moms if they don't get their kids vaccinated,"