GLOBAL: Drug Makers' Push Leads to Cancer Vaccines' Fast Rise

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The New York Times

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 United States 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 United States 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 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 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 2006-7 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," Dr. 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 C.D.C. weeks later for universal use among girls.
Most vaccines take three years to get that sort of endorsement, Dr.
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," Dr. 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 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.

"You can only study a vaccine for so long before you license and use it
in a population where it has enormous value," said Dr. Haupt at Merck.
"Our hope and belief is that this is a remarkable vaccine that will
have huge impact on women."

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
Dr. 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, Ms. Raffle said.

The Campaigns

Stephanie
Levi decided to give her two daughters the vaccine in late 2006 after
receiving a newsletter from their physician. "When you get a letter
saying this is what you need to do to protect your girls, of course you
do it," she said, adding that she was curious because she had not
realized cervical cancer was a problem.

That week, she noticed
articles and advertisements for the vaccine. "I remember thinking I had
better do this quickly," said Ms. Levi who lived in New York then and
now lives in Rome.

It is not hard to hear about Gardasil.

In
television advertisements, a cast of hip people in their 20s - artists,
writers and professionals - describe why they got the shots, in the
language of liberation, such as, "I chose to get vaccinated because my
dreams don't include cervical cancer." The advertisements direct
viewers to gardasil.com, which includes patients' stories, buddy icons and downloads for holding an event at sororities.

Girls of any age who have had one dose of the vaccine can ask for
text-message "reminders" from Merck to get the next two shots. The
offers come with another reminder: "I understand that the information I
provide will be used by Merck or those working on behalf of Merck for
market research purposes."

For such efforts, Merck last May
swept the 2008 Pharmaceutical Advertising and Marketing Excellence
awards, and Gardasil was named Brand of the Year by Pharma Executive
Magazine.

The marketing helped make Gardasil one of Merck's best
sellers, with a projected sales of $1.4 billion 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. Vaccines were traditionally the orphans of
the pharmaceutical world because they were cheap and not particularly
profitable. But the two for cervical cancer are the latest in a wave of
high-priced vaccines that have come to market since 2001, opening a
lucrative new field.

Co-opting Doctors and Nurses

Girls and their families are by no means the only marketing target.

In
2006, hundreds of doctors and nurses 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, delivered 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 F.D.A.-approved labeling and to make
sure dissemination of information is always appropriate," said Amy
Rose, a company spokeswoman.

Promotion and marketing for
Cervarix, Glaxo's version of the vaccine, has been far less visible, in
part because it has not been approved yet for use in the United States,
and because consumer advertising of medicines is prohibited in much of
Europe. Outstanding data from final clinical trials will probably be
submitted to American drug regulators early next year, the company
said.

There has also been a proliferation of cervical cancer
awareness conferences and campaigns, sponsored by a host of new or
newly energized scientific and patient groups financed with the help of
Merck and Glaxo. In some cases the financial support has been indirect,
so patients are unaware that expert advice has been at last partly paid
for by the vaccine makers.

Gregory A. Poland, a vaccine expert at the Mayo Clinic,
was a nonvoting member on the C.D.C. panel that recommended Gardasil in
2006 and has publicly defended the panel's decision. Records show he
received at least $27,420 in expenses and consulting fees from Merck
from 1999 to 2007. Both the C.D.C. and Dr. Michael Camilleri, chairman
of the Mayo Clinic Conflict of Interest Review Board, speaking on Dr.
Poland's behalf, said the payments complied with institutional
requirements.

To encourage vaccination on campus, 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 discuss cervical cancer and promote the vaccine for
college health services. The association now recommends the shot for
all female college-age students, even though many in that group already
have HPV, rendering the vaccine less useful.

Dr. James Turner,
president-elect of the association, said it accepted Merck's grant to
undertake the campaign because "HPV is a very important health issue
for college students," adding that his group was "a very small
organization, and we don't have funds."

Small charities have also benefited from Merck's contributions.

At the second annual patient conference of the National Cervical Cancer
Coalition, planned for Los Angeles this October, four of the seven
scheduled speakers have received money for research or consulting from
Merck, Glaxo or other companies involved in HPV screening or detection,
though the conference organizers do not mention that. The coalition,
which supports widespread use of the cervical cancer vaccines, is
headed by a businessman, Alan Kaye, who owns a pathology lab that
performs Pap smears and HPV tests, among other services. "We are a poor
nonprofit, and I've been working on this issue for years," said Mr.
Kaye, who hopes to receive grants from the drug makers to help pay for
the conference.

Persuading the Governments

In country after country, Merck and Glaxo also appealed to politicians. Vaccines, unlike antibiotics, tend to be recommended or mandated by governments. "We support policy leaders and try to educate legislators," Dr. 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.

Many bills, like
ones passed in Colorado, New Jersey and New York, allocate more money
for HPV and cervical cancer education or to promote the vaccine.
Others, like proposals in Iowa and Louisiana, require insurers to cover
it.

The only state to pass a bill requiring the vaccine for
school entry is Virginia; it takes effect in October, after school
begins, so will first apply in 2009.

Merck has a growing
economic interest in Virginia. In December 2006, Merck announced it
would invest $57 million to expand its Elkton, Va., plant to make
Gardasil, helped by a $700,000 grant from a state economic development
agency that is part of the executive branch. Two months later, Gov. Tim Kaine,
who has been mentioned as a possible Democratic vice presidential
candidate, signed legislation requiring Gardasil for schoolgirls. Four
months after that, Merck pledged to invest $193 million more in the
plant to make drugs and vaccines, helped by a state grant of $1.5
million.

Delacey Skinner, a spokeswoman for the governor, said
the state's vaccination program included an unusually broad freedom to
decline the shot. To exempt children from other vaccines, parents must
provide a medical reason; for Gardasil, they do not. "It is a very easy
step that we can take to prevent a sometimes deadly but certainly
serious form of cancer," Ms. Skinner said.

"Without hesitation
or question," she added, the decisions about the plant and about the
mandate legislation "were completely separate."

But, as in many
states where cervical cancer legislation has been considered, there
have been ties between drug makers and members of government. In 2006,
one of Merck's newly hired Virginia lobbyists was Sandra D. Bowen, who
had spent years as Virginia's secretary of administration. And Bill
Bolling, the state's lieutenant governor, became an outspoken
participant in the "Ending Cervical Cancer in Our Lifetime" campaign, a
program started in 2006 by the National Lieutenant Governors
Association and financed largely by Merck and Glaxo.

"This is an important public health issue," said Randy Marcus, Mr. Bolling's spokesman.

In Texas, Merck hired Gov. Rick Perry's
former chief of staff as a lobbyist, and contributed $6,000 to the
governor and $38,000 to other legislators. Last February, Mr. Perry
ordered that all schoolgirls be inoculated with Gardasil, a
pronouncement that was overturned by the Texas Legislature, 181 to 3, a
few months after the financial conflicts were revealed.

Early
last year, Merck announced that it would no longer actively lobby for
state mandates. But Dr. Haupt defended the initial impulse, saying that
historically such school requirements had been a successful way to
increase access to and financing for vaccines.

Other forms of
lobbying continue: Merck and Glaxo have both paid into a program run by
Cornerstone Government Affairs, a Washington firm, to lobby the C.D.C.
and Congress for more federal money for vaccines.

In Britain,
drug makers paid for breakfast meetings with politicians and visited
the nurses and family practitioners who are the backbone of the
National Health Service, urging them to offer the vaccine.

In
Belgium, the health minister approved the vaccine before the country's
health technology evaluation committee had finished deliberating.

Unanswered Questions

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."

Dr. 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. Dr. 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.
But Dr. Haupt said such "theoretical possibilities" should not deter
rapid distribution of an important vaccine. "We'll worry about whether
boosters are needed down the road," he said.

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 F.D.A. and C.D.C.
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.

For
some couples, the vaccine has raised agonizing questions over how to
safeguard their children's health. Phillip and Barbara Tetlock, both
professors at the University of California at Berkeley, are asking
whether Gardasil shots that their daughter, Jenny, received last year
contributed to her illness, an extremely rare form of progressive
paralysis that has left her bed bound and needing assistance to breathe
at age 14.

The Tetlocks, who are not pursuing legal action, are
appealing to the C.D.C. and Merck for more data and searching for other
girls with similar conditions through their blog (www.jenjensfamily.blogspot.com).
"Her parents are scientists - they know better than to assume Gardasil
caused her disease," said Terry Murray, a close friend speaking for the
family. "But you have to explore the possibility."

Dr. Harper
said she believed the vaccine was generally safe. She vaccinated her
own children. But with Gardasil's use having grown so fast, she added,
"you inevitably find adverse events that you wouldn't have suspected."

"The Tetlocks are right to ask these questions," she added.

Dr. Haupt of Merck said that the company knew of the case but saw no "causal association."

Worth the Cost?

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 C.D.C. (Women with H.I.V. are predisposed to the cancer.)

Pap smears work by detecting abnormal cells that are cancer precursors
and that can be destroyed using techniques like lasers and cryotherapy
or, rarely, surgery. As with any screening test, and most vaccines, the
process is not 100 percent effective, and a small number of women with
precancerous cells escape detection with false negative tests, for
example. But because the transformation from abnormal cell to cancer
normally takes a decade, and frequent Pap smears are recommended, it
has been a successful strategy - though the vaccine, used properly,
might well prove a useful adjunct.

Indeed, cervical cancer does not even make the American Cancer Society's
list of 10 deadliest cancers. Among American women, it causes well
under a 10th of the number of deaths caused by lung cancer or breast cancer.

Though classified as a sexually transmitted disease,
HPV is nearly universal and generally benign. Eighty percent of people
will contract it in their lifetime and most will clear it on their own.

Dr.
Haupt of Merck said the vaccines' price was worth it for the deaths
prevented and the tests avoided. "Most of the old vaccines are
undervalued," he said.

Dr. Abramson said he thought his C.D.C.
advisory committee did the right thing in recommending Gardasil.
"Cervical cancer is a worthwhile disease to prevent in a country that
has the resources," he said. He believes it should be available to
those who want it.

Still, he said he was shocked to hear of
proposals to mandate the vaccine for students. "Are you really going to
say a girl can't start school because she hasn't had this vaccine?" he
said.

Meanwhile, the vaccines' proponents are moving to the next
frontier: older women and boys. Merck recently applied for approval to
market the vaccine to women 26 to 45 and is conducting studies on
vaccinating boys, who can get genital warts from HPV.

One
rationale for inoculating boys is that entire populations should be
vaccinated to achieve what is called herd immunity. But critics ask
whether it is worth conducting a campaign on the scale of the one used
against polio to eliminate a generally harmless virus.

Said Dr. 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."

Andrew Lehren contributed reporting.

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