|cartoon by Khalil Bendib|
In early January Marilyn Canavan and Andrea Boland, two legislators from wintry Maine, traveled to the tourist resort of Marco Island, Florida, for a conference organized by Women in Government (WIG), a non-profit organization.
The annual, bi-partisan event for elected women in state governments around the U.S. had a number of issues on its agenda from higher education to the state of women in politics.
One focus, preventing cervical cancer, included information on Gardasil a new vaccine manufactured by pharmaceutical giant Merck, that protects against the two human papilloma virus (HPV) strains that cause 70 percent of cervical cancers.
"The tenor of presentations - they were not discussions ... (they) seemed one-sided to me," said Canavan, a four-term legislator. "I remember thinking as I was leaving the meeting, 'I just don't want to do this ... we need to have public dialogue.'"
Boland also reported "a pull to get on board [promoting vaccination]... and when I raised questions, the response was 'Do you want your daughter to die of cancer?'"
Boland, a first-time legislator, joined Canavan, a WIG state director, at a small planning session, where she was taken aback by the extent to which corporations influenced WIG. "When discussing what the agenda for next year would be," participants were told to 'wait to see who's funding things.'" Similarly before fixing the program for next year, they "had to see what the sponsors want," said Boland.
Boland's suspicions were further raised by a casual conversation one evening over a glass of wine with one of the conference speakers, Boston pop singer Christine Baze. "She was a young attractive woman with a beautiful voice and a moving tale of surviving cervical cancer," said Canavan. Baze mentioned that a pharmaceutical company had paid for her appearance.
Both legislators believed that preventing cervical cancer was a worthy project, but it wasn't until a month later that Canavan and Boland learned that, more than making the vaccine available, Merck and WIG were campaigning to make Gardasil mandatory for all 11-12 year old girls.
Testing in the Third World
JayaJan Pharmaceutical Research in India was one of the companies
with which Merck had a contract to test Gardasil. Like most of the
industry, Merck increasingly outsources its clinical trials to Contract
Research Organizations (CROs) in areas of the world where trial
subjects are plentiful, operating costs are low, and regulations lax.
Some $285 million worth of clinical trials are outsourced to CROs in India,
according to biopeer.com. These CROs are a booming $15 billion
industry whose revenues are rising at 15 percent a year.
are known for their speed and efficiency; they can complete a clinical
trial in two-thirds the time a drug company can, shaving months off the
process and offering $120 million to $150 million in increased revenue
per drug." Sam Bidwell an executive with Quintiles a U.S.-based CRO
told Nature. "Of the top 30 best-selling drugs, we've touched every
Critics point out that CROs can come with built-in
problems. Conflicts of interest can arise when CROs are paid royalties
only after a drug is approved rather than being paid a set fee that is
independent of how safe or effective the drug turns out to be. Problems
can also arise because CROs know that favorable findings mean that
research into a test drug will continue, and they may also believe that
results that please the hiring corporation can lead to future
contracts. "[C]ompanies know that the farther the compound moves
through the research cycle, the more money they can raise," Nature
Merck spokesperson Amy Rose refused say how many
trials Merck contracted to CROs or what percentage of the Gardasil
subjects these contractors recruited in the Third World. She also
refused to specify how, or even if, the company oversees CROs.
consumers assume that the FDA carefully monitors CROs. But the agency
hobbled by under-funding, politicization, and dependence on industry
fees has few resources to assess foreign trials and relies on drug
Then, after the governor of Texas, Rick Perry, passed an executive order mandating vaccination for all girls entering sixth grade, Canavan learned something that shocked the former director of the State Ethics Commission: She discovered that WIG had taken funding from Merck.
On March 2nd, Canavan resigned from WIG. "An organization that stands to profit, like a pharmaceutical company, shouldn't be driving the health agenda in public realm," said Canavan. "You see so many front organizations, I'm not going to say Women in Government is one, but it matters who's funding them. My early training emphasized doing the right thing and being guided by conscience."
What Boland and Canavan had come to realize was that the Florida conference presentations had been part of a state-by-state lobbying campaign spearheaded by WIG to support Merck's efforts to make Gardasil mandatory. WIG members were well placed to promote bills in state legislatures or help convince governors to promote that agenda. But revelations of money trails and the rush to make a new vaccine mandatory created a backlash and forced Merck, on February 20th, to publicly abort its lobbying campaign for mandatory vaccination of school girls.
Launching the Vaccine
Cervical cancer affects 10,000 women in the United States every year, and kills 3,700. The toll is far greater in the developing world, where most women lack the diagnostic Pap tests that catch signs of cancer when it is still treatable.
New Jersey-based Merck, one of the world's largest pharmaceutical companies had been hoping to reap billions of dollars from Gardasil. Most of the world's sexually active men and woman and every child over 9 years of age are potential customers for the expensive course of injections.
A quick and successful launch was crucial, both for Merck's failing financial health and because rival GlaxoSmithKline was developing a similar HPV vaccine. Things looked good for Merck when the U.S. Food and Drug Administration (FDA) agreed to fast-track Gardasil in February 2006 and approved it in June, pronouncing the vaccine effective and safe for girls as young as nine. Soon after the FDA approved Gardasil, WIG was helping introduce bills in some 20 states, with Merck actually writing the legislation in at least one state: Florida.
Merck also launched a subtly frightening advertising campaign featuring quick images of vital young girls: a young drummer, a child with a skateboard, two playing basketball, and three skipping rope. The drummer says: "I want to be one less woman who will battle cervical cancer," as she starts tosses her drumsticks and starts to play, the others spell out a chant: : "O-N-E-L-E-S-S. I want to be one less. One less."
Merck's targeting of young girls and eventually boys who are carriers and on rare occasions develop HPV-caused cancers is based in rational public health principles. Since the vaccine is only effective in preventing, not treating HPV infection, it needs to be dispensed before exposure to the viruses. And while 11-12 year old girls are unlikely to be sexually active, policy makers could make their entry into middle school contingent on vaccination in the same way that 5-6 year olds are required to be vaccinated for polio and measles before entering elementary school. If officials waited until the more common age of sexual initiation, around 16, public health officials would not have the leverage to compel vaccination.
As with any new drug, concerned parents and public health officials had to balance Gardasil's obvious promise against potential problems. They understood that Merck's contention that its HPV vaccine is safe and effective was only as sound as its data and only as solid as the independence and rigor of the FDA review process that approved the drug. But while most people applauded the new protection Gardasil offered, both experts and consumers found good reasons for waiting before making the vaccine mandatory. (They did not include fears that all vaccines are dangerous, or that protecting against a sexually transmitted disease encourages girls to have sex.)
Is mandatory vaccination cost effective?By promoting vaccination as a public health imperative mandated by
government, rather than as a private choice, Merck has opened the door
to the inherently uncomfortable discussion of whether mandatory
vaccination is cost effective. Since Gardasil protects against the two
strains of HPV that cause 70 percent of cancers, women will still need but may be less likely to get Pap smear tests to catch the signs of
cancers caused by the other 30 percent of dangerous strains.
the cost of vaccinating American girls with Gardasil will amount to
some $800 million a year," New Scientist reported in an analysis that,
while overly simplistic, raises fundamental questions about public
health priorities and drug company influence over them.
Scientist estimates that Gardasil will save "around 1,200 lives. This
is an unequivocally desirable outcome, but at $800 million per year,
the cost of saving each life will be over $650,000. If the goal is to
save lives, there are more cost-effective ways of doing so." They
include spreading public health measures including low-cost, readily
available Pap testing to the non-white, poorer populations that now die
in disproportionate numbers of cervical cancer.
health equation adds up differently in the developing world, which
accounts for 80 percent of the world's 275,000 cervical cancer deaths,
with 30 percent in India alone. Because very few of these women have
access to Pap tests, or indeed any regular health care, vaccination has
proportionately greater benefits - if the program is publicly funded
and the protection proves lasting.
The data Merck presented to the FDA were based on some 21,000 test subjects between ages 16 and 26, half of whom received Gardasil and half a placebo. All subjects, followed for up to five years, were found free of pre-cancerous changes from the targeted strains.
Some critics pointed out that the test period was too short to assess long-term effects and efficacy. In fact, the studies on children, who often react differently to drugs, were shorter yet, and smaller. Only 1,184 subjects in the nine to 15 year-old age test group got Gardasil, and they were followed for 18 months, according to New Scientist magazine. A Merck spokesperson refused to break down the data further to reveal how many of that small sample were below the age of puberty.
And then there is the possibility that, given time and real-world conditions, side effects will emerge. FDA briefing papers noted a small increase in birth defects in the babies of women given the vaccine within 30 days of becoming pregnant over those who took a placebo. The number, while not establishing causality, triggered an FDA recommendation that pregnant women not be vaccinated. The background documents also raised questions about whether selectively targeting a few HPV viruses (there are more than 100) would "advantage others." Another concern "was the potential for Gardasil to enhance disease among" subjects already infected "with vaccine-relevant HPV."
These kinds of concerns are not necessarily alarming or unusual for a new drug, According to a 2002 study in the Journal of the American Medical Association, "The safety of new agents cannot be known with certainty until a drug has been on the market for years. Serious ADRs [adverse drug reactions] commonly emerge after Food and Drug Administration approval."
"The published data look great, but at the very least, I would like to see efficacy data among 11 and 12 years old, which won't emerge until they are sexually active," says Karen Smith-McCune, a University of California associate professor of obstetrics and gynecology.
And so too, would many medical experts, public health officials and consumers. The American Academy of Pediatrics had urged the company to go slow and focus first on raising public awareness of HPV and monitoring the vaccine's safety. The U.S. Centers for Disease Control panel that recommended routine HPV vaccination told Merck that it opposed making Gardasil mandatory, the Washington Times reported.
In addition to questions about the data, was the FDA approval process itself. The drug was recommended for approval by the FDA's advisory committee comprised of "qualified experts with minimal conflicts of interest ... [who] provide FDA with independent advice," according to agency guidelines. While the committee's recommendations are not binding, the FDA almost always accepts them.
But at least two members of the advisory panel that found Gardasil safe had the appearance of a conflict of interest: They were former Merck employees connected with development of the vaccine. Vaccine expert Dr. John Boslego was executive director of Biologics, Clinical Research at Merck for ten years, and had left the company just two months before the committee ruled on Gardasil in February 2006. Another panel member, Alan Shaw, was part of Merck's Vaccine & Biologics Research and had represented the company as late as May 2005 at a conference on cervical cancer where he presented a paper on HPV Vaccines. The FDA granted waivers to both men, finding them free of any conflicts of interest.
The integrity of the FDA review process is also vulnerable to charges of conflict of interest over the fees the cash-strapped agency accepts from the drug companies. Under a law sponsored by U.S. Senator Richard Burr a decade ago, the FDA charges from nearly $50,000 to nearly $900,000 to fast track a drug, according to the Winston-Salem Journal. Since 1992, drug companies have paid the FDA $1.7 billion to speed up the approval process for particular drugs.
Of course, none of this means that Gardasil is unsafe. Few things in medicine are guaranteed, and many believe that the odds are that Gardasil is exactly what Merck says it is: a life-saving breakthrough with no significant side effects.
A Controversy in Texas
But new drugs, and vaccines in particular, raise not only promise but fear. And touching as it did on issues of teenage sexuality, Gardasil was particularly controversial.
Religious conservatives, already concerned that vaccination would encourage sexual activity, opposed making vaccination mandatory. "My main reason is that it is parents that have the right to decide when is the appropriate time to discuss sexuality," said Debi Vinnedge, the head of Children of God for Life. "One of my young grandchildren is more mature, but there is nothing that I can say to these kids" that won't send the wrong message.
It was perhaps the potential controversy in mind that Texas governor Rick Perry took the bull by the horns and circumvented abstinence junkies, public discussion, and the legislature to issue an executive order requiring vaccination for all girls entering the sixth grade, unless parents opted out.
Perry's February unilateral decision sparked a public relations disaster that Merck's orchestrated ad campaigns, lobbying efforts through WIG, and courting of the religious right had failed to anticipate.
Perry's February order also raised suspicions over his politics (the governor has previously shown little interest in health policies), his speed (just months after the FDA approved the vaccine and before all the data had been published), the financial arrangements (Merck got a statewide monopoly without concessions and without negotiating a discount for clinics and poorer Texans) and the stealth timing (Perry issued the order late on Friday before Super Bowl Sunday, the nation's biggest sporting event).
Questions about cronyism soon led to Perry insiders connected to Merck and to WIG: The WIG state director is the mother-in-law of Perry's current chief of staff, and his former chief of staff is now one of Merck's three Texas lobbyists. A Merck executive served on WIG's Business Council in 2006.
And then there was the money trail. In September, greasing the skids for Gardasil's November public relations blitz, "Merck's PAC spent $74,250 in a single day to influence elections in five states. It directed 60 percent of that money to 82 candidates in Texas," according to Lobby Watch, a newsletter put out by Texans for Public Justice. (A Public Action Committee or PAC is an advocacy group that buys political advertisements to support elections or legislation).
In late February, less than three weeks after Perry's executive order to make the vaccine mandatory for all Texas schoolgirls entering sixth grade, Merck abandoned the lobbying campaign.
"Our goal is to prevent cervical cancer," Dr. Richard M. Haupt, executive director for medical affairs in Merck's vaccine division told the Associated Press. "Our goal is to reach as many females as possible. Right now, school requirements and Merck's involvement in that are being viewed as a distraction to that goal."
A Financial Shot in the Arm
Facing the storm of controversy that threatened to overwhelm news about preventing cancer, Merck's president for vaccines, Margaret McGlynn, defended her company. "Each and every day that a female delays getting the vaccine there is a chance she is exposed to human papilloma virus," she told the New York Times.
But Merck, like any corporation, is motivated by more than altruism. If Gardasil becomes routine, the $360-$400 course will generate annual sales of $3.2 billion by 2010.
Merck needs this financial shot in the arm to offset liabilities caused by Vioxx, its arthritis drug that may have caused almost 28,000 deaths, according to FDA estimates. Merck now faces some 4,000 lawsuits and potentially billions in payouts. In one Texas liability trial, lawyers produced documents and e-mails from Merck scientists discussing Vioxx's potential heart risks as early as 1997, more than two years before it went on the market.
This history of hiding data has done little to reassure Gardasil skeptics. "It used to be that funding for research was provided by government," says Canavan, the Maine legislator. "But now it comes from private corporations that stand to gain and the information can be - I won't say skewed - but made to work for the company."
What is clearly not working for Merck are the controversies around Gardasil that have derailed corporate plan to make vaccination mandatory and to capture the market before Glaxo releases its own vaccine.
The last few years have not gone smoothly for one of the world's biggest drug companies. On September 30, 2004, after it became known that Vioxx was doubling the rate of heart attacks and strokes, Merck withdrew the painkiller and saw its stock plummet nearly 27 percent. Taking the drug off the market wiped out $2.5 billion in annual sales.
In 2005, Merck's new chief executive officer Richard Clark announced a plan to cut the company's world-wide work force by 11 percent or 7,000 jobs and to close or sell five of its manufacturing facilities. The company's 2005 sales were down four percent and its net income had fallen by 20 percent. The company's financial woes will not be eased by the fact that its patent for cholesterol drug Zocor, with $5 billion in sales, expired in 2006, while patents on other best selling drugs, including, Folsom and Cozaar, are nearing expiration.
Merck's also announced on February 14 that it had signed an agreement that essentially brings to a close the U.S. Internal Revenue Service's (IRS) examination of the company for the period 1993-2001. Under the agreement, the final net cash cost to Merck is expected to be approximately $2.3 billion which covers federal tax, net interest after federal tax deductions and penalties." Merck, noted the "reasonableness" of the IRS settlement and said that it had reserved the funds so the payment would not impact 2007 earnings.
"As CEO, my priorities are clear," says Clark, "meeting the needs of patients and building shareholder value."
Those priorities are particularly hard to juggle given America's love-hate relationship with pharmaceuticals. In 2004, 82 percent of the U.S. population reported that they had taken at least one prescription drug, over-the-counter medication, or dietary supplement in the previous week; 30 percent of respondents reported using five or more, according to a study by the Sloan Epidemiology Center at Boston University. Even kids are consuming drugs in great quantities. In 2005, according to an analysis performed by Medco Health Solutions for the New York Times, "approximately 1.6 million U.S. teenagers and children (almost 300,000 of whom were under 10) were given at least two psychiatric drugs in combination."
At the same time as they are popping pills, Americans are widely distrustful of a pharmaceutical industry that has a long record of marketing wonder drugs with misleading advertising and dangerous side-effects. A 2007 health poll by the Kaiser Family Foundation found that fewer than 18 percent of Americans "say they can trust what pharmaceutical companies say in their ads most of the time." Some 70 percent "agree that drug companies put profits ahead of people."
By choosing to promote making Gardasil mandatory, Merck fell deep into the chasm between the public's desire to see drugs as the cure for all ills and its profound skepticism that pharmaceutical companies put the public's interests before profits.
"When we lose trust in company like pharmaceuticals or a group like Women in Government," said Canavan from her home in Maine, "we start to become suspicious about everything. We need to have public dialogue. The point is not that the vaccine is bad, but that the public agenda has all been company-driven."