Was vaccine rushed to market?
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Dr. Diane Harper, a professor of medicine at Dartmouth Medical School in Hanover, N.H., is critical of the rush to provide a cervical cancer vaccine. ''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,'' she said. CALEB KENNA / THE NEW YORK TIMES |
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By ELISABETH ROSENTHAL The New York Times - Published: September 3, 2008
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 Europe in the two years since two vaccines were given government approval in many countries and, often, recommended for universal use among females ages 11 to 26.
One of the vaccines, Gardasil, from Merck, is made available to the poorest girls in the country, up to age 18, at a potential cost to the U.S. government of more 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 normally 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, which offer some protection against infection from sexually transmitted viruses, 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 with markup and office visits (and often only partially covered by health insurance).
Award-winning advertising has promoted the vaccines. Before the film "Sex and the City," some moviegoers in the U.S. saw ads for Gardasil. On YouTube and in advertisements on popular shows like "Law and Order," a multiethnic cast of young professionals urges girls to become "one less statistic" by getting 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.
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 money. When it occurs, cervical cancer is a dreadful disease; genital warts, partly 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, 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. Legislative efforts to require girls to have the vaccine only add to the pressure.
In the U.S., 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 have been lobbied and invited to receptions urging them to legislate against a global killer. And former state officials have been recruited to lobby their former colleagues.
"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 Centers for Disease Control and Prevention that recommended the vaccine for all girls once they reached 11 or 12.
"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. Canada will spend $300 million on a cervical cancer vaccine program.
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. If a 12-year-old is vaccinated, will she still be protected in college, when her risk of infection is higher? Or will a booster vaccine be necessary?
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 classified as very rare in the West because it is almost always preventable through regular Pap smears, which detect precancerous cells early enough for effective treatment. 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. Dr. Harper was a principal investigator on the clinical trials of both Gardasil and Cervarix, and she spent 2006-07 on sabbatical at the World Health Organization developing plans for cervical cancer vaccine programs around the world.
"Because Merck was so aggressive, it went too fast," Harper said. "I would have liked to see it go much slower."
In receiving expedited consideration from the Food and Drug Administration, Gardasil took six months from application to approval and was recommended by the CDC weeks later for universal use among girls. Most vaccines take three years to get that sort of endorsement, Harper said, and then five to 10 more for universal acceptance.
Dr. Richard Haupt, medical director at Merck, said the vaccine had not been rushed into use, saying that five years in clinical trails was normal 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. A Glaxo spokeswoman, Sarah Alspach, said 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 saved it, in contrast to less expensive shots, against measles and tetanus, for example, that pay for themselves by preventing costly diseases.
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 treating people already suffering from deadly cancers. That number will be far higher if a booster is needed.
Looked at another way, countries that pay for the vaccines will have less money available for other health needs. "This kind of money could be better used to solve so many other problems in women's health," said Lippman at McGill. "Some of our provinces are running out of money to provide primary care. 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, particularly Africa, 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 that are caused by other strains of the virus.
In Britain, "this initiative was seen as a good use of resources that fits with the government's health priorities and political priorities," said Professor David Salisbury, who heads the Department of Health's Vaccine and Immunization Committee.
But critics urge restraint. "There is no need to rush," said Angela Raffle, a specialist in cervical cancer screening with the National Health Service in Britain, where 400 people die of the cancer each year. "If we do this quickly and badly, we could cause more deaths," from side effects, for example, or from giving girls false security that they are protected for life and no longer need to be screened, Raffle said.
Many questions about the vaccines remain unanswered, including how long immunity will last. Even commercials for Gardasil say — in small print — that "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 said she believed that at least one booster shot, and probably more, would be needed over a lifetime. Haupt of Merck said that the "durability of immunity" would ultimately be defined through widespread use of the vaccine, but that the company's research strongly suggested that immunity would be long lasting — far more than five years.
Other independent experts worry that eliminating the two cancer-causing HPV strains covered by Gardasil and Cervarix might allow the other cancer-causing strains of HPV to increase in frequency, reducing the vaccine's effect.
The question of side effects, however, has nagged the vaccine.
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 patients experiencing adverse events after receiving the vaccine, 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 at least 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 and CDC said.
The agencies 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 observe patients for 15 minutes after receiving a shot.
Countries and consumers must decide whether it is worth preventing cervical cancer with a costly vaccine.
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 of them are in developing countries, according to the World Health Organization; 274,000 women died of this cancer in 2006, nearly 95 percent in developing countries.
Where there are Pap smear programs, few women die of cervical cancer. In the United States, it is responsible for 12,000 new cases a year and 3,600 deaths, most in women who did not get Pap smears, said Laurie Markowitz, head of the HPV working group at the CDC (Women with HIV are predisposed to the cancer.)
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