E-DRUG: Controversy around HPV vaccine
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News in Depth: Viral marketing: A cancer vaccine faces questions about
its efficacy --- Merck predicts big fall in cervical lesions, but data
are complex
By John Carreyrou
17 April 2007
The Wall Street Journal Europe
WHEN MERCK & Co. introduced its new vaccine against cervical cancer last
June, it gave it one of the biggest pushes any new medicine has
received. The company lobbied dozens of U.S. states to make the vaccine
mandatory for 11- and 12-year-old girls. It aired TV ads featuring young
girls skipping rope while reciting the slogan, "I want to be one less"
woman to battle the disease.
The campaign scored some big victories. The U.S. Centers for Disease
Control and Prevention declared all women age 11 to 26 should get the
vaccine, called Gardasil. Texas and Virginia passed
mandatory-vaccination laws for girls entering the sixth grade. Even
after Merck halted its lobbying in February amid criticism, an
organization backed by the company continues to push for similar laws,
and about 20 states are considering them. The vaccine costs $360 for a
three-shot regimen.
But behind the scenes, Gardasil has been dogged by uncertainty about how
effective it really is. Merck won approval for the vaccine based on
research that showed it protected against two strains of the human
papillomavirus, known as HPV 16 and 18, that are thought to cause 70% of
cervical-cancer cases. The U.S. Food and Drug Administration didn't ask
its panel of experts advising on Gardasil to rule on whether the vaccine
specifically prevented the cancer itself. In clinical trials, 361 of
8,817 women who received at least one shot of Gardasil went on to
develop precancerous lesions on their cervixes within three years of
vaccination, just 14% fewer than in a placebo control group.
Scott Emerson, a professor of biostatistics at the University of
Washington who sat on the FDA advisory committee, says he isn't
persuaded the vaccine is worth the billions of dollars likely to be
spent on it in coming years. "I do believe that Gardasil protects
against HPV 16 and 18, but the effect it will have on cervical-cancer
rates in this country is another question entirely," says Dr. Emerson.
"There is a leap of faith involved."
Merck says the 14% figure is misleading because more than a quarter of
the women in the study were already infected with HPV before receiving
the vaccine, blunting its effect. Gardasil isn't designed to treat those
with pre-existing infection. The company prefers to point to a subset of
4,616 trial participants who were mostly free of HPV when they were
vaccinated. Only 52 of these women went on to develop precancerous
lesions on their cervixes over the next three years, 46% fewer than
among the placebo group. Merck says this smaller group of women is the
one most representative of the 11- and 12-year-old girls for whom Texas
and Virginia have required vaccination.
Safety is another issue. Merck tested the vaccine in only a few hundred
11- and 12-year-old girls. Some doctors consider that number too small
to declare the vaccine safe for preteen girls, given the big changes
their bodies undergo.
In its approval letter, the FDA ordered Merck to follow "a sufficient
number of children 11-12 years of age" in a large postmarketing study to
further establish the vaccine's safety. That study won't be completed
until 2009. Norman Baylor, the director of the Office of Vaccines
Research and Review at the FDA, says it is common for the agency to
recommend postmarketing studies for vaccines, and the FDA considers
Gardasil safe.
The company says it complied with the FDA's request that the clinical
trials include more than 3,000 9- to 17-year-olds. It adds that it
didn't test Gardasil more widely on girls because it wanted to focus on
sexually active women to demonstrate the vaccine's efficacy. So far,
Merck has distributed more than four million doses of the vaccine in the
U.S., and the CDC says adverse events have been mostly minor and within
the normal range.
Eliav Barr, the head of Merck's HPV-vaccine program, says Gardasil is a
"lifesaving" vaccine and its widespread adoption will result in "a
substantial decline in the rate of cervical cancer." Dr. Barr says Merck
provided "an extremely strong dossier" on Gardasil that both the FDA and
the CDC have deemed satisfactory.
Merck has a lot riding on Gardasil. It faces patent expirations on other
best sellers and legal costs related to Vioxx, the withdrawn painkiller
linked to heart attacks and strokes. Some analysts believe Gardasil's
annual sales could reach $2 billion or more by 2010.
Work on a cervical-cancer vaccine goes back nearly two decades, after
scientists discovered that HPV infection can trigger lesions of the
cervix that eventually turn into cancer. In the early-to-mid-1990s,
Merck licensed patents held by the National Cancer Institute and CSL
Ltd. of Australia, and began work on commercializing the vaccine.
From the start, Merck faced a challenge in winning acceptance of the
vaccine as a universal necessity for American women. Though common in
developing nations, cervical cancer is a relatively rare disease in the
U.S., accounting for about 0.7% of cancer diagnoses and deaths each
year. Women already have a highly effective method of prevention:
visiting a gynecologist for regular Pap tests. The low-tech exam has
contributed to an 80% reduction in cervical-cancer deaths in the U.S.
over the past 50 years.
Human studies of the present version of the vaccine, which also targets
two HPV strains that cause genital warts, began in 2000. The vaccine was
administered to more than 20,000 women. It is delivered in three
injections over six months. Merck submitted Gardasil to the FDA for
approval in 2005.
A meeting of the FDA advisory panel that reviewed Gardasil in May 2006
gave the first hint of Merck's troubles in persuading doctors of
Gardasil's real-world efficacy. In its presentation, Merck stressed the
vaccine's nearly 100% effectiveness in blocking infection by HPV 16 and
18 and in preventing precancerous lesions caused by those two strains.
But a document prepared for the committee by an FDA reviewer noted the
vaccine's limited overall efficacy against precancerous lesions in the
broader group of nearly 9,000 trial participants.
Dr. Emerson, the University of Washington professor, expressed concern
that Merck wasn't putting enough emphasis on the question of whether the
vaccine prevented cervical cancer. "It's almost the treating the symptom
but not the disease sort of idea," he said, according to a transcript of
the meeting.
Merck pointed to the confounding factors behind the lower efficacy
rates, including the problem of women who came into the trial already
infected. In an interview, Merck's Dr. Barr says Gardasil's true
efficacy will become more apparent with time, particularly in the group
that includes women with a pre-existing infection.
While Merck often states that Gardasil prevents infection with viruses
that account for 70% of cervical-cancer cases, Dr. Barr concedes that
the vaccine is less than 70% effective against precancerous lesions.
Merck says this is because the HPV strains not covered by Gardasil cause
disproportionately more precancerous lesions that don't end up turning
into cancer.
Efficacy against lesions is a significant issue because after a Pap
test, doctors generally remove any lesions that reach a certain grade of
seriousness, even though some might not turn into cancer. The surgery
involves cutting out part of the cervix and can cost several hundred to
several thousand dollars. Dr. Barr predicts Gardasil will eventually be
shown to prevent nearly 60% of precancerous lesions that doctors would
want to remove among women who were free of HPV infection when they were
vaccinated.
Ultimately Gardasil received the panel's unanimous approval, and the FDA
approved the vaccine in June 2006. The agency reasoned that waiting for
more data would prevent some women who needed the vaccine from getting
it.
With the FDA's approval, Merck faced a new challenge: persuading the
public to take its vaccine. It got a quick boost from the CDC, which
issued guidance in late June recommending that all girls receive the
vaccine at age 11 or 12. The CDC said women age 13 to 26 should also get
the vaccine. Gardasil was also endorsed by the American Academy of
Pediatrics.
Merck crafted its advertising and public relations to avoid some of the
less-favorable numbers surrounding Gardasil. The TV commercial says the
vaccine "may help protect you" from HPV strains "that may cause 70% of
cervical cancer." The company doesn't often discuss the lower efficacy
against precancerous lesions or in populations where some women are
already infected. The "one less" slogan avoids the question of how many
lives will be saved.
Some Gardasil supporters funded by Merck are less careful about
qualifying their claims. At the FDA advisory committee hearing, Martha
Nolan, vice president of a women's health group that receives funds from
Merck, said that by approving Gardasil, the agency had "the opportunity
to eradicate this terrible disease."
After the FDA approval, a group of female state legislators called Women
in Government started a campaign to get states to mandate vaccinations.
The group receives money from Merck but won't say how much. Many of the
pending bills would allow parents to keep their children out of the
vaccination program, but only after submitting proof that they have
received information about cervical cancer and the vaccine.
In early January, Women in Government held a conference for some 60
state legislators in Marco Island, Florida, paying for their airfare and
hotel rooms. One of the speakers was Christine Baze, a pop singer and
cervical-cancer survivor. As she performed songs on the piano, Ms. Baze
told the story of her battle with the disease and said she wished a
vaccine had been available to her. Ms. Baze says Women in Government
paid her a $2,500 fee and covered her travel and lodging. She says she
didn't receive any money from Merck for the appearance, but the company
has paid her $7,500 to speak at three other events.
Marilyn Canavan, a representative in the Maine assembly who attended the
conference, says she was bothered by the large number of drug-industry
lobbyists she saw. A list of conference participants shows that 30
pharmaceutical-industry representatives were present -- one for every
two state legislators. Merck had two representatives there. Ms. Canavan
has since resigned her post as Women in Government's director in Maine
over concerns that the group's agenda is being dictated by drug
companies. Susan Crosby, Women in Government's president, says those
concerns are unfounded.
Other state lawmakers came away from the conference inspired. Upon
returning home, Jessica Sibley Upshaw, a representative in the
Mississippi assembly, drafted a bill that would make vaccination a
school requirement. "For me, it's a common-sense thing to do if we can
eradicate a disease," she says. Ms. Upshaw's bill has since died, but
she plans to reintroduce it.
In February, Texas Gov. Rick Perry bypassed the state legislature and
issued an executive order mandating that all girls entering the sixth
grade be vaccinated as of September 2008. One of Merck's lobbyists in
Texas is Mike Toomey, Gov. Perry's former chief of staff, and Merck
contributed $6,000 to the governor's re-election campaign. Mr. Toomey
didn't return calls and emails seeking comment. A spokeswoman for the
governor says he acted to protect the public's health, not because of
the contribution or the lobbying of his former aide.
Gov. Perry's order sparked an uproar. Among the opponents are religious
conservatives who say receiving the vaccine conflicts with their message
of abstinence. Other opponents say Gardasil isn't worth the cost, which
includes $360 for the vaccine and up to several hundred dollars more for
three doctors' appointments to get the shots. The money would be better
spent, these people say, in pushing Pap tests for women who aren't
getting them now.
John Schiller, one of the National Cancer Institute scientists whose
vaccine work was licensed by Merck, believes Gardasil is an important
advance that should receive wide use, but he has mixed feelings about
the way the company has promoted it. He hopes it won't divert
public-health dollars away from regular Pap screening, which he says
remains the most important weapon against cervical cancer. Merck "is a
heavy-handed company," Dr. Schiller says. "When they do something, they
spare no energy. It's the Merck way or the highway."
Merck says cost-effectiveness studies suggest the vaccine could deliver
its life-saving benefits at a reasonable cost, in part by reducing the
need for frequent Pap tests. Most of these studies have been funded by
Merck and GlaxoSmithKline PLC, maker of another HPV vaccine, Cervarix.
Glaxo applied for FDA approval of Cervarix last month.
One skeptic is Diane Harper, a longtime HPV researcher and professor at
Dartmouth Medical School, who was involved in Gardasil's clinical trials
and has received speaking and consulting fees from Merck and Glaxo. She
says as many as 10% of 11- and 12-year-old girls may already have HPV,
either from sexual activity, sexual abuse or transmission through
nonsexual skin-to-skin contact. That could reduce the vaccine's
efficacy, she says.
Dr. Harper also suspects the vaccine may require booster shots after 10
years. Merck says it isn't sure how long the vaccine's protection will
last and is monitoring women over the long term to find out.
The American Cancer Society, while agreeing with the CDC that girls
should be vaccinated, said in January there is "insufficient evidence"
that women age 19 to 26 will benefit from the vaccine because many have
already been exposed to HPV.
Worried about the backlash that emerged in February in Texas and other
states, Merck shifted into damage control. Richard Haupt, Merck's
executive director of medical affairs, placed calls to respected figures
in the vaccine field, including Jon Abramson, the chairman of the CDC's
advisory committee on immunization practices, and Joseph Bocchini,
chairman of the committee on infectious diseases at the American Academy
of Pediatrics. Both men and others told Dr. Haupt they supported the
vaccine, but it was too early and counterproductive to push for school
requirements.
On Feb. 20, Merck announced that it was suspending its lobbying push,
but Women in Government continues to lobby for school requirements.
Virginia's mandate became law two weeks ago.