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http://www.nytimes.com/2008/08/20/health/policy/20vaccine.html

August 20, 2008

The Evidence Gap

Drug Makers' Push Leads to Cancer Vaccines' Rise

By ELISABETH ROSENTHAL

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.