Friday, August 21, 2009

JAMA Nails the Problem with Gardasil — and Our Healthcare System

With all the debate about the state of American health care going on, it’s interesting that this month’s Journal of the American Medical Association (JAMA) has—perhaps unintentionally—presented the Gardasil vaccine against the HPV virus as a microcosm of what’s wrong with our current system. Over-prescribing, “skewed” information for doctors, “surrogate endpoint” approval that can lead to ineffective or harmful drugs, irrational risk/benefit scenarios that are influenced by financial interests, medication rather than intelligent living—sound familiar?

More health care for those who don’t need it.

American health care, for those who can afford it, is often as excessive as a Hardee’s Thickburger. The Congressional Budget Office estimates that 700 billion per year, or 5 percent of the US GDP, goes to tests and procedures that don’t improve health outcomes in the least.

Drs. Sheila and David Rothman note that in “creating a market out of thin air,” as PharmExec aptly put it when naming Gardasil 2007 Brand of the Year, Merck’s HPV vaccine was pushed to the entire population, rather than to those who really need it.

Cervical cancer kills around 4,000 people every year in the US. The death rate has dropped impressively since annual Pap smears were introduced in the 50s, and continues to drop by about four percent each year. Indeed, a large percentage of deaths from cervical cancer can be attributed to lack of access to, or inattention to, routine health care. Roughly 40 percent of women in the US are unwilling or unable to get regular Pap smears, and Kaiser Permanente found that more than half of its members with cervical cancer had not done so.

The Gardasil campaign, say the Rothmans, “bypassed public health officials who would have spear-headed a risk-sensitive vaccination campaign…this manufacturer understandably wanted as many adolescents as possible to be vaccinated. But the pursuit of this goal was neither cost-effective nor equitable. It meant rather than concentrating on populations in geographic areas with excess cervical cancer mortality, including African Americans in the south, Latinos along the Texas-Mexico border and whites in Appalachia, the marketing campaign posited that every girl was at equal risk.”

At least impoverished girls in the regions the Rothmans describe can sometimes get the shots at taxpayer expense. Women in the developing world, alas, are far more vulnerable to cervical cancer than the average American woman; it is the leading cause of cancer-related deaths among women there and kills some 215,475 women annually. Limited or non-existent access to routine health care means that an HPV vaccine would probably be well worth the small risk—but it’s currently unaffordable.

One of the more compelling arguments for the current private health care system in the US is that without being able to eye the highly lucrative American market, many lifesaving technologies and medications would never be developed and implemented around the world. It’s possible…maybe…that Merck has it in mind to pay for Gardasil development costs and huge profit margins by over-selling to the American market—at $360 plus administration costs per kid—and then offer the vaccine at a fractional cost to the market that actually needs it.

Oops. Maybe not. In India the series runs at about $173; far, far out of reach for the average woman in a country where 42 percent of the population lives below the international poverty level of $1.25/day. Absent a massively expensive and ill-afforded government program, only the rich, who already have access to preventive health care, are able to get it. And with a population of 1.2 billion, any government program will necessarily have limited coverage.

Then again, Americans have to ask ourselves about the morality of injecting substances into our children partly in order to defray the cost of overseas health care, if that’s what we’re looking at. There’s a big difference between subsidizing MRI technology with your money and subsidizing a vaccination with your child’s body.

Better living through chemistry.

We Americans (and increasingly other nations, too) have shown that we’re willing to be told that pills, potions, and now vaccinations are a convenient answer to epidemics like Type 2 diabetes, heart disease, ADD and now HPV. Way better, in fact, than taking responsibility for our own health and using medications only as a last resort. We’re apparently quite willing to transfer our dollars from the farmers’ market to the pharmaceutical market.

What the Rothmans didn’t say: A good deal of the potential physical trauma caused by persistent (not transient) HPV infection can be avoided by lifestyle changes, particularly if they’re made early. People who smoke, eat a lousy diet with a tiny or non-existent vegetable/fruit component, and/or have multiple sexual partners, are at a dramatically greater risk of getting a persistent HPV infection that might lead to abnormal cervical cells. A healthy immune system enables people to shrug off the vast majority of highly prevalent HPV infections. Your initially tiny risk of getting a persistent infection increases by as much as 15 percent with each sexual partner, by at least 50 percent with a bad diet, and by up to 2,600 percent with a smoking habit. But Merck is not inclined to tell you that, and neither are most doctors—or at least, not with the same force that they’ll put into the vaccination sales job.

Who cares about ultimate effectiveness? Just approve it already!

The FDA commonly accepts “surrogate endpoints” when approving drugs. Because it can take too long and cost too much to take drug trials to the ultimate outcome, and because doing so could deprive other patients from potentially life-saving treatments, the FDA often looks instead at interim markers. For instance, it might approve a drug because it lowers blood pressure rather than waiting to see how many people in the study die of a stroke instead of sheer old age.

That’s very reasonable—except that we are then often “surprised” by the ineffectiveness or negative side effects of drugs like Avandia, Vytorin, Zetia, Vioxx. Medications are effective for some 60 percent of treated patients at best.

The approval of Gardasil was an even bigger jump than usual. The assumption was that if we can defeat the two oncogenic strains of HPV that are responsible for 70 percent of cases of cervical cancer, then we can reduce the number of cases by 70 percent. That’s how it’s sold to parents, at least by implication.

“No data were available to establish the duration of efficacy, possible adverse effects on natural immunity, whether vaccinated women will forgo Papanicolaou tests, and whether after suppressing HPV-16 and HPV-18 ‘other strains may emerge as significant oncogenic serotypes,’” note the Rothmans.

The last trial data showed Gardasil to be 17-45 percent effective in preventing pre-cancerous cells, with the most dangerous types at the lower end of the range. It is too early to tell much about potential replacement diseases and longevity. When a healthy system shrugs off a particular HPV strain, it virtually always retains a life-long immunity to infection with that type; we’re many years from knowing that about Gardasil and from understanding the implications of an infection in later years. Plus, the many oncogenic HPV strains not covered by Gardasil may move into the post-vaccination void. We just don’t know yet.

The FDA has also been curiously incurious about the growing burden of vaccines on developing bodies. At 50, I’ve had few vaccines in my life, and those mostly later; today’s average child will have had 26 by the time he’s just two years old. And they just keep coming. Spurred by the blockbuster success of Gardasil, there’s wild speculation in the vaccine industry and several new vaccines are well along in development.

Although the FDA requires “concomitant use” studies to prove that a new vaccine doesn’t affect the safety or effectiveness of existing vaccines given at the same time, little or no attention is given to the total lifetime burden of adjuvants like aluminum injected directly into the circulatory and lymphatic system. Some girls who have been hit with post-Gardasil autoimmune issues have been given lumbar punctures, which have revealed “high” levels of aluminum.

It’s all about the marketing/money, baby.

An even bigger jump was Merck’s saturation of the airwaves and doctors’ offices with the message that, as consumers inevitably inferred, not getting Gardasil equals cervical cancer. And here’s where the Rothmans really got going.

Their article lashed the professional medical associations (PMAs) that took Merck’s money to promote Gardasil to other health professionals—notably the American Society for Colposcopy and Cervical Pathology, the Society of Gynecologic Oncologists, and the American College Health Association.

The campaign was a shocking piece of marketing, and “that these arguments were delivered by PMAs is cause for concern,” wrote the Rothmans. “(PMAs) are obligated to provide members with evidence-based data so they can present relevant risks and benefits to their patients. To this end, PMAs must become more transparent about their relationship with industry, disclosing both the precise funding and technical assistance they have received to develop the promotional products. Under no circumstances should PMAs administer product-specific speakers’ bureaus, nor should they accept funding that requires them to report activity to the donor” (as actually happened).

Well, color me surprised. Pharma’s aggressive marketing techniques and slanted information have long permeated the entire medical profession.

A UCSF study found that doctors frequently make decisions about which drugs to prescribe based on “skewed” reports that are essentially written by the drug companies and then published in medical journals, typically emphasizing the positive reports of the trials and selectively reporting data. Trials with favorable outcomes were about five times more likely than those with unfavorable outcomes to be published. There were often many discrepancies between the results the FDA received and the published data; and one-fourth of the results of trials testing the effectiveness of new drugs were not published at all within five years after FDA approval.

Then there was the revelation that Merck had published an entire medical fake journal to push its products as well as keeping a list of researchers and doctors to be ‘discredited’ or ‘neutralized.’

Next, a UM study that found that researchers often didn’t properly disclose potential conflicts of interest in cancer studies. Where a potential conflict existed, randomized trials were more likely to link patient survival to a particular treatment.

Frankly, it’s a wonder that anyone trusts the medical industry at all. And that’s a shame. Good doctors, good researchers, imaginative and disciplined scientists, and effective, life-saving medications and treatments abound, but they’re drowned out by the shrill clamor of—shills.

Risk/benefit assessment

We all resent doctors who think they’re God, but we let them take on that role when we are not given, or do not search out, sufficient information. We should be able to trust them, but sometimes we can’t. Sometimes they themselves get skewed info.

Here’s how Dr. Charlotte Haug sums up Gardasil in JAMA. “If the potential benefits are substantial, most individuals would be willing to accept the risks. But the net benefit of the HPV vaccine to a woman is uncertain. Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened. So rationally, she should be willing to accept only a small risk of harmful effects from the vaccine.

“When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit. Patients and the public logically expect that only medical and scientific evidence is put in the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed. The balance will also tilt if the adverse events are not calculated correctly.”

And they’re not. As Deborah Kotz reported in the US News and World Report yesterday, 68 percent of reports of adverse events were filed in the VAERS system by Merck itself, and 89 percent didn't include "sufficient identifying information to allow medical review of the individual cases." The VAERS passive reporting system is notoriously fallible.

Kotz goes on to say that the results of the autopsy of Jenny Tetlock, who died of a mystery progressive paralysis after getting her Gardasil shots, showed that Jenny died from a “neurological disease that was ‘mediated by immune responses,’ leading to extensive damage in her spinal cord.” Her tissue samples will now be compared with those of Whitney Baird, who died of similar problems, but whose illness was never noted in the VAERS data base until Jenny’s case hit the internet.

It gave me great joy to read Dr. Haug’s words about rationally looking at the risk/reward ratio of Gardasil. I’ve been trying to look at the vaccine rationally since 2006, but maybe now that Dr. Haug,the Rothmans and JAMA have weighed in, our pediatrician will stop saying I’m an idiot for doing so.

Now if we can only apply the lessons to our healthcare system.

1 comment:

Anonymous said...

Excellent analysis.