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Vitamins: Research Shows No Benefit and Some Risks

Posted by medconsumers on December 1, 2008

Vitamins Don’t Work: Research Continues to Find No Benefit and Some Risks

Looking for ways to save money? Stop taking vitamins. The scientific case against them has been building over the last few years, starting with the report from the 2006 U.S. National Institutes of Health State-of-the Science Conference on Multivitamins/Mineral Supplements. The next year, a Cochrane review of all antioxidant trials caused an uproar because it found no preventive benefit to taking these supplements and a slight increase in mortality. And just in the last month alone, one new trial found no cancer preventive benefit to taking B vitamins; and another trial found no cardiovascular preventive effects for vitamins C and E. Both were published in the Journal of the American Medical Association.

B Vitamins
The B vitamins trial was led by Shumin M. Zhang, MD, and colleagues at Brigham and Women’s Hospital in Boston and Harvard Medical School. The impetus for this trial, explained the researchers, was the prevailing idea that folate, vitamin B6 and vitamin B12 might play an important role in cancer prevention. Yet the researchers also noted that information from earlier trials of folic acid alone or in combination with B vitamins have produced mixed results, and one trial “even raised concerns about deleterious effects.” What’s more, women were underrepresented in these trials.

Zhang and colleagues recruited 5,442 female health professionals, aged 42 years or older with cardiovascular disease or three or more risk factors for heart disease. All were randomly assigned to take a placebo or a daily supplement that combined 2.5 mg of folic acid, 50 mg of vitamin B6 and 1 mg of vitamin B12.

After seven years, the women taking the combination supplement had the same rate of cancer as those taking a placebo. This trial was funded by a grant from the U.S. National Institutes of Health.

Vitamins E and C
The other new trial found that vitamins E and C did not prevent cardiovascular disease in healthy men, aged 50 and older. The Physicians’ Health Study II involved 14,641 male physicians, 5% of whom had cardiovascular disease at the start of the trial. The men were randomly assigned to take 400 IU of vitamin E every other day and 500 mg of vitamin C daily or a placebo.

After a mean follow-up of eight years, the supplements had not reduced the risk for heart attack, stroke, death, heart failure, angina or the need for a coronary artery-opening procedure. Worse, vitamin E was associated with an increased risk for hemorrhagic stroke, or bleeding in brain (39 hemorrhagic strokes in the men taking vitamin E, compared with 23 in those taking a placebo). The negative results shown for vitamin E confirm those from earlier studies that involved men and women with preexisting cardiovascular disease.

This trial was led by Howard D. Sesso, ScD, Harvard School of Public Health, and funded by grants from the National Institutes of Health, the BASF Corporation, Wyeth Pharmaceuticals, and DSM Nutritional Products Inc (formerly Roche Vitamins).

Earlier Vitamin Research:
These two new trials are but a small part of the research that has found vitamins do not prevent illness or prolong life. Far more extensive is the following government report about multivitamins and the Cochrane review of antioxidant trials mentioned at the beginning of this article.

The report from the 2006 NIH State of the Science Conference on Multivitamins/Minerals for the Prevention of Chronic Conditions. A panel of experts was charged with the task of reviewing all placebo-controlled trials designed to see whether multivitamins and/or minerals can prevent cancer; age-related sensory loss; and cardiovascular, endocrine, neurologic, musculoskeletal, gastroenterologic, renal and pulmonary diseases. This is the report’s conclusion:

In systematically evaluating the effectiveness and safety of multivitamins and/or minerals in relation to chronic disease prevention, we found few rigorous studies on which to base clear conclusions and recommendations. Most of the studies we examined do not provide strong evidence for beneficial health-related effects of supplements taken singly, in pairs, or in combinations of 3 or more.

Within some studies or subgroups of the study populations, there is encouraging evidence of health benefits, such as increased bone mineral density and decreased fractures in postmenopausal women who use calcium and vitamin D supplements. However, several other studies also provide disturbing evidence of risk, such as increased lung cancer risk with beta-carotene use among smokers.”

The updated 2008 Cochrane review: “Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases.” The 68 placebo-controlled trials included in this review attempted to answer these questions: Can antioxidants prevent disease in healthy people? Can they prevent recurrences in people with cancer, heart disease or other illnesses?

This is the Cochrane review’s conclusion:

We found no evidence to support antioxidant supplements for primary or secondary prevention. Vitamin A, beta-carotene, and vitamin E may increase mortality. Future randomized trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.

Funding Questioned: When this Cochrane Review was first published in 2007, we reported its findings and addressed one of the strongest criticisms leveled against it. Many suspected that the review was funded by the pharmaceutical industry to counteract public enthusiasm for vitamins. In our 2007 article on this topic, one of the review’s co-authors was asked about the funding: Christian Gluud, MD, of the Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen University Hospital, responded, “The sole sponsor of this review is the Copenhagen University Trial Unit, a publicly funded, not-for-profit clinical research center, and about 90% of the trials in this review were funded by companies that make vitamins.”

Maryann Napoli, Center for Medical Consumers©

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Anemia Drugs For Cancer Patients

Posted by medconsumers on March 13, 2008

Testimony Submitted to FDA Oncologic Drugs Advisory Committee Meeting
March 13, 2008

Maryann Napoli, Associate Director, Center for Medical Consumers

As a consumer advocate who attended the May ODAC meeting, I came away wondering why these drugs remain on the market. They cause some patients to die sooner. They have many other risks that are severe and well documented, and any quality-of-life benefit has yet to be proven. The FDA approved the first ESA because it reduced the percentage of patients transfused. But the agency has since acknowledged that the infectious disease risks of a blood transfusion are far lower now than they were in 1993.

No doubt there are many cancer patients who see these drugs as an instant cure for chemotherapy-induced fatigue or as the means of allowing chemotherapy to continue. The former indication was fostered by Johnson & Johnson’s fraudulent ad campaign for Procrit, which continued for seven years in the mainstream TV and print media. I urge ODAC to discuss the misconceptions imparted by these ads and to consider recommending that the FDA require J&J to run a corrective ad campaign.

The ability of a cancer patient to make a truly informed decision with the help of her oncologist is seriously compromised by J&J’s and Amgen’s reprehensible practice of offering rebates—that is, kickbacks—to oncologists. Patients are always encouraged to discuss their treatment decisions with their doctors. Yet it’s hard for patients to believe oncologists’ recommendations are unbiased when they are “reaping millions” from the prescription of anemia drugs, as The N.Y. Times reported last May. (1) Companies that give kickbacks and other financial incentives intended to manipulate oncologists into using the most expensive drugs are poisoning the doctor/patient relationship.

Where can people turn for unbiased information? It should be the FDA, but it’s not clear to me that black box warnings are the way to go. The changes in the product labeling in 2004 did not change clinical practice. (2) And what do we know about the effects of black box warnings on the ones who need them the most—the cancer patients? The cancer patient should be given scientifically accurate, written information about ESA well before she needs it. The time to weigh the risks and benefits is not when she’s awaiting her next chemo treatment and just learned that her hemoglobin is too low for the next round.

Patients cannot make truly informed decisions unless they are given quantitative information to help them decide whether ESA is appropriate. They need to know, for example, the chances of…1) needing a transfusion; 2) suffering harm by foregoing a transfusion, 3) experiencing a serious adverse effect from the transfusion itself, and 4) having a severe adverse effect from the ESA. Patients need to know the magnitude of each of these four risks. Telling them that ESA will reduce their risk of having a blood transfusion is simply too vague. It gives them no way to compare this purported benefit with the other risks of taking ESA. If the FDA will not remove these drugs from the market, it must find the best ways to get clearly written, accurate quantitative ESA information to cancer patients.

(1) Berenson A, Pollack A. “Doctors Reap Millions for Anemia Drugs.” N.Y. Times, May 9, 2007

(2) Blau AC. “Erythropoietin in Cancer: Presumption of Innocence?” Stem Cells 2007; 25;2094-2097; originally published online Apr 26, 2007.

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Screening for Prostate Cancer: The More They Test, The More They Find

Posted by medconsumers on November 1, 2007

It’s a controversy that has been roiling among research physicians for two decades: Does the prostate-specific antigen, or PSA, blood test for prostate cancer cause more harm than good? Does the early detection of prostate cancer—that is, before symptoms appear—actually save lives? These questions still haven’t been answered, though many physicians automatically test their middle-aged and elderly male patients as if they have.

A new study conducted in Europe was initiated to see whether PSA screening symptom-free men every two years has any advantage over screening at four-year intervals. The short answer is no, but this study, published in the September 5 issue of the Journal of the National Cancer Institute, suggests that the PSA test is more likely to find non-life threatening cancers without reducing the number of advanced and potentially lethal cancers.

Monique J. Roobol, PhD, and colleagues at medical centers in Holland and Sweden based their findings on data from a large trial called the European Randomized Study of Screening for Prostate Cancer. Initiated in 1993, this trial will answer the question of whether early detection of prostate cancer reduces mortality from this disease.

The reason that this trial and its American equivalent, the Prostate, Lung, Colorectal and Ovarian Cancer trial ongoing since 1992, will take so long to provide answers is the fact that most prostate cancers found on the basis of PSA screening are either non-progressive or so slow-growing that they will never become life threatening or symptomatic. A minority of the prostate cancers diagnosed during the course of this trial will be the deadly aggressive version, and it is unclear whether early detection and prompt treatment of these fast-growing cancers will result in prolonged lives. About 17% of U.S. men contract prostate cancer and 3% of them will die of the disease.

Context Needed

Any discussion of the new study about screening intervals requires some background information on prostate cancer itself. Pathologists have long known that many of the cancers that show up in the prostate will never become lethal had they remained undetected for a lifetime. Autopsy studies of men who died in accidents show that the older they are, the more likely they will have cancer in the prostate.

That’s why the measure of a screening test’s value is not how many cancers it can find; instead it is a reduction in prostate cancer deaths. But that’s not all. Harm must also be taken into account. The detection of prostate cancers that would never progress or become lethal clearly results in a high rate of biopsies and unnecessary treatment. The latter—irradiation or surgical removal of the prostate—is associated with an increased risk of urinary incontinence, bowel dysfunction and impotence.

The diagnosis of new cases of prostate cancer increased substantially in all countries after PSA screening was introduced. In the U.S., for example, PSA screening began in the late 1980s. But contrary to expectations, the prostate cancer death rate has decreased only modestly. And it is not known whether the drop in prostate cancer mortality is due to early detection or improvements in treatment, or both. Such uncertainties can be resolved by a long-term clinical trial that randomly assigns men to be screened (with a PSA test and a digital rectal examination) or not. This describes the European and the American ongoing trials.

“Interval Cancers” Studied

The new study by Roobol and colleagues takes on yet-another unanswered question about prostate cancer screening: What is the appropriate interval for screening? In the U.S. trial, men are usually screened annually.

Not so in Europe. Some medical centers participating in the European trial screen participants every four years, and others screen every two years. This difference in intervals provided the opportunity for Roobol and colleagues to see whether one has any advantage over the other. Of particular interest was the number of prostate cancers detected in men between screening tests. These are what researchers call “interval cancers.” And they are worrisome because they are likely to be the potentially fatal, advanced cancers. A reduction in their detection would be a good sign that screening might eventually reduce the number of prostate cancer deaths.

Roobol and colleagues found that, after 10 years, more cancers were diagnosed in the men (12%) screened at the shorter (two-year) intervals than in the men (8%) screened at longer (four-year) intervals. Contrary to expectations, the number of potentially life-threatening prostate cancers was the same in both groups. The downside of too frequent screening is overdiagnosis, i.e., the increased detection of cancers that do not progress, resulting in more unnecessary biopsies and treatments.

Asked by e-mail for the bottom line message from her study, Dr. Roobol wrote, “Screening should not be done at fixed intervals but through a more personal approach. Men with very low PSA levels (<1.0 ng/ml) can, depending on their age, be screened at much longer intervals. Screening every year for me looks [like] too much for the majority of men in the age group 55 or higher.”

E. David Crawford, MD, University of Colorado Health Sciences Center, author of the editorial that accompanied this study, had this observation: “Although many of us believe that early detection is saving lives, definitive evidence is lacking.”

This uncertainty is reflected in the treatment options listed for all stages of prostate cancer on the National Cancer Institute Web site (www.cancer.gov). Whether prostate cancer is diagnosed at stage I (early) or stage IV (advanced)—no treatment is as reasonable a choice as having the prostate surgically removed or irradiated.

That raises the obvious question: Why test symptomless men when—once cancer is found—no treatment is a valid option? We still don’t know whether the man whose cancer was detected after symptoms appeared is any worse off than the symptom-less man whose cancer was detected with a screening PSA test.

More Needle Biopsies, More Prostate Cancers Detected

“Despite the considerable attention given to the prostate-specific antigen (PSA) as a screening test for prostate cancer, it is needle biopsy—and the PSA test result—that actually establishes the diagnosis of prostate cancer.”

With that as background, H. Gilbert Welch and colleagues at Dartmouth and other Medical Centers studied Medicare claims to determine the proportion of men, aged 65 years and older, who have prostate cancer after a needle biopsy (removal of prostatic tissue by inserting a thin needle through the rectum and into several sections of the prostate). Their study was published in the September 19 issue of the Journal of the National Cancer Institute

The researchers found: Over 10,000 needle biopsies were performed in 1993 through 2001 in 8,273 men, age 65 and older. The overall proportion of needle biopsies found to contain cancer was 32%, and it increased with age—35% for men in their late 70s and 41% for men over age 80.

The risk of finding prostate cancer increased with repeat biopsies in those initially found to be cancer-free, with 50% of the men diagnosed with prostate cancer after two biopsies, 62% after three biopsies and 68% after four biopsies.

The odds of finding cancer go up not only with the age of the man undergoing a needle biopsy but also the number of tissue samples taken. Over the years, the needle biopsy has become more and more aggressive. Initially, needle biopsies consisted of jabs for prostate tissue in six different sites. Now many urologists advocate 12 or more and some even advocate “saturation biopsy,” which involves 32 to 38 jabs, say Welch and colleagues, “the more biopsies taken, the more cancer is found.” The incidence of biopsy-induced infection was not recorded in this study.

Maryann Napoli, Center for Medical Consumers ©
November 2007

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Anemia Drug Update

Posted by medconsumers on June 1, 2007

On May 10, 2007, the FDA held an emergency meeting of its Oncologic Drugs Advisory Committee to discuss the anemia drugs that supposedly help people cope with chemotherapy. But several recent studies were halted prematurely because these drugs—Epogen, Procrit, Aranesp—caused an increased death rate, cancer progression, deep-vein blood clots and heart damage (see last month’s newsletter). Ultimately, the FDA advisory committee asked for better studies and voted to put more stringent warnings on the labels for these drugs, known collectively as EPO. Unfortunately, few doctors ever read warning labels (one in ten, according to one survey), and the FDA has no authority over how they prescribe drugs.

As is often the case with drugs found to be risky long after they came on the market, the future of EPO comes down to money. There are huge financial incentives for oncologists to overprescribe EPO. Amgen and Johnson & Johnson, makers of EPO, sell their drugs directly to doctors and thanks to rebates (a.k.a. kickbacks) from the drug companies, many oncologists are making a fortune.

That was made clear the day before the FDA meeting in a front-page New York Times article entitled, “Doctors Reaping Millions for Use of Anemia Drugs.” A former business manager for a six-oncologist practice in the Pacific Northwest provided the Times with documentation showing that the six doctors received $2.7 million from Amgen for prescribing $9 million worth of its drugs last year. The rebates are available for cancer drugs other than those self-administered by the patient. The rebates are in addition to the reimbursements doctors get from Medicare and private insurers.

Normally, the FDA steers clear of drug costs, sticking solely to safety and efficacy issues, but the Times article loomed over the FDA meeting. When the advisory committee discussed how to inform patients of the adverse effects of EPO, one oncologist said it should be left to doctors. But another committee member Otis Brawley, MD, head of Atlanta’s Grady Hospital, objected. “The problem is at my hospital doctors get $1200 for every dose they give patients. And they don’t have to sign conflict-of-interest statements like we do,” he said, referring to the FDA requirement that each committee member reveal any financial ties to drug companies prior to participation.

Another oncologist on the committee expressed fury about the uncertainties regarding the safety of the doses currently in use. “Yes, we have a burning question: Are these drugs killing people?” asked Silvana Martino, MD. “What are the doses that are reasonable and appropriate?”
The misleading EPO advertising aimed at the public would never have come up at this meeting were it not for consumer advocates. Five advocates attacked Johnson & Johnson’s ads for Procrit, which fraudulently sold the drug as the cure for chemotherapy-induced fatigue in an ad campaign that ran from 1998 to 2005. They pushed the FDA to force Johnson & Johnson to mount a corrective ad campaign because there is no proof for its claim.

There is no proven quality-of-life benefit for EPO. The drugs were initially approved as a safer alternative to blood transfusions for a chemotherapy-induced drop in red blood cells. But transfusions are not as risky as they were 15 years ago when the first EPO was approved. One basic question lingered: What is the purpose of this drug?

Answers will take years, but Wall Street reacted immediately. Within days of the FDA meeting, Amgen shares dropped more than 15%.

Maryann Napoli, Center for Medical Consumers© June 2007

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Anemia Drugs for People on Chemotherapy

Posted by medconsumers on May 10, 2007

Testimony Submitted to the FDA Oncologic Drugs Advisory Committee Meeting , May 10, 2007
Maryann Napoli, Associate Director,
The Risks of Erythropoiesis-stimulating Agents For Use In The Treatment Of Anemia Due To Cancer Chemotherapy

I’m Maryann Napoli, associate director of the Center for Medical Consumers in New York City. We have never taken pharmaceutical industry funding. (No drug company has ever wanted to give us any.) I write often about cancer and drugs because our mission, as an organization, is encouraging people to look for and to understand the evidence that supports their treatment decisions.

The story of these anemia drugs and how they were oversold to the public and how financial incentives encouraged oncologists to overprescribe them is truly outrageous. Like me, many Americans probably first became aware of them while watching the evening news. Those ubiquitous Procrit TV ads all had the same scenario – the cancer patient undergoing chemotherapy cannot continue the work he or she loves because of disabling fatigue. Procrit quickly turns things around, and the cancer patient is back on track enjoying work again.

Who among us on chemotherapy would not ask their doctors for this drug? And even if you didn’t have cancer at the time of this ad campaign—very likely the message would stay with you. There is a drug that quickly cures chemotherapy-caused fatigue.

Imagine my surprise when I read two months ago of a FDA press briefing about the new warnings to be added to the labels of all anemia drugs. Dr. Richard Pazdur announced that there has never been any evidence to support the claims that anemia drugs can increase energy or ease fatigue in patients undergoing cancer chemotherapy.

Why, then, did the FDA allow Johnson & Johnson to run those Procrit ads?

I’m glad that the FDA sent warning letters to members of professional organizations, but what about the cancer patients? There are numerous cancer patient groups across the country. Surely, they should have been notified, too.

I’m glad the FDA held that press briefing. But what about the TV-watching public? That is the majority, after all. As a result of the press briefing, some articles appeared in the print media. But the newly identified risks of anemia drugs and the circumstances in which they are likely to occur are simply too complicated for TV medical reporters. They would have to explain off-label use; and how the greatest harm appears to be associated with off-label use; that raising hemoglobin isn’t equivalent to reducing fatigue; how anemia can be caused by chemotherapy or the cancer itself; that deep-vein blood clots and heart damage occur when anemia drugs are given in excessively high doses.

Weigh these complicated concerns against that simple TV message about Procrit. No Procrit ad that I ever saw had a cancer patient saying, “This drug helped me avoid a blood transfusion.”

Johnson & Johnson was allowed to train current and future cancer patients to demand these expensive drugs for what we now know is an evidence-free indication. Given what we now know about the increase in deaths, deep-vein blood clots, and heart damage associated with anemia drugs, the FDA should require J & J to run a corrective ad campaign. These ads should be run on prime time TV—shows with the same demographics as the evening TV news and at the same frequency.

The huge expense and the range of pricing of these anemia drugs are troubling, especially since the FDA views the three as equivalent. From what we have known for years about financial incentives—that is, the deep discounts offered by the drug companies for the most expensive drugs to oncologists in outpatient practices —it is likely that these discounts have fueled the inappropriate use of anemia drugs, which are among the 20 highest-expenditure drugs covered by Medicare

And we know from a 2006 study in Health Affairs that these deep discounts achieved what the drug companies had in mind. They increased the use of the most expensive drugs. This is due to the fact that the most costly drugs came with the largest discounts, and therefore the most generous profit margins for oncologists in outpatient practice.

Federal laws may prohibit drug companies from paying doctors to prescribe drugs given in pill form that are purchased by patients at the pharmacy. But companies are allowed to rebate part of the price of the drugs given by injection or intravenously in doctors’ offices. Doctors receive the rebates after they buy the drugs from the companies. In other words, they receive reimbursement from Medicare or private insurers for the drugs, often at a large markup over the doctors’ purchase price. And on top of that, the oncologists get rebates (i.e., kickback) based on the amount of drugs they have purchased.

Oncologists are, in effect, running their own pharmacies. Consumers would naturally be suspicious of the herbalist recommending and selling his own herbal medicine or the vitamin doctor selling vitamins to her patients. It’s time for the public to understand that things are far worse at the oncologist’s office.

Fifteen years after these anemia drugs went on the market, we learn that they can hasten death and cause severe injuries. Why did it take so long to know this?

The situation points to the necessity of major changes. The FDA should be given the power to require better safety studies in the pre-approval process, and the agency must have the power to exact a large penalty on any drug company that does not follow through on FDA recommendations, such as those made at the Oncologic Drug Advisory Committee’s 2004 meeting.

Thank you for giving me this opportunity to speak.

1. GAO Report-01-1118 Medicare payments for drugs exceeds providers’ cost. September 2001.
2. Jacobson, Mireille. Does reimbursement influence chemotherapy treatment for cancer patients? Health Affairs, Mar/Apr 2006
3. Berenson A, Pollack A. Doctors reaping millions for use of anemia drugs. New York Times, May 9, 2007.

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Anemia Drugs Increase Risk of Death, Blood Clots and Heart Damage

Posted by medconsumers on May 9, 2007

Serious doubts surround the expensive anemia drugs widely prescribed for the fatigue associated with cancer chemotherapy and kidney dialysis. They were initially approved to decrease the need for blood transfusions. But the latest studies show that these injectable drugs, sold under the brand names of Aranesp, Procrit and Epogen (Eprex in Canada), increase the risk of death, deep vein blood clots and heart damage. Several recent trials had to be stopped prematurely because the drugs either caused the cancer to progress more rapidly or the cancer patients to die sooner. In some trials, the harms are caused by excessively high doses.

The FDA has taken the unusual step of calling a special meeting of its Oncologic Drugs Advisory Committee to review the new data on these drugs. Aranesp, Procrit and Epogen are all versions of erythropoietin, or EPO, which is a synthetic form of a protein produced by the kidneys that stimulates production of red blood cells. EPO drugs were approved by the FDA for the treatment of anemia in patients with kidney failure and in cancer patients undergoing chemotherapy. Anemia, a deficiency of red blood cells, is a common side effect of chemotherapy, which suppresses red blood cell production. EPO drugs are good at elevating and maintaining red blood cell levels, but now their effectiveness in treating fatigue has been called into question.

Yet fatigue in cancer patients undergoing chemotherapy was the heavily advertised reason for the TV ad campaign for Procrit. If you’re over the age of 55, these ads will be quite familiar because they appeared regularly during the Network evening news and other venues likely to have an older audience. In the standard scenario for a Procrit ad, the cancer patient cannot continue the work he or she loves because chemotherapy has produced disabling fatigue. Procrit quickly turns things around, and the cancer patient is back on track enjoying life.

At a March press briefing about the new warnings to be added to the labels of all EPO drugs, the FDA’s Richard Pazdur, MD, announced that there has never been any evidence to support the claims that EPO can increase energy or ease fatigue in patients undergoing cancer chemotherapy.

EPO drugs are heavily marketed worldwide, accounting for more than $11 billion in combined sales last year. Amgen, the world’s largest biotechnology company, makes both Aranesp (the most expensive of the three EPO drugs at $1,300 to $2,000, a shot) and Epogen. Clinical trial results announced just in the last eight months alone generated enough alarm and FDA warning letters (to health professionals) to warrant the aforementioned FDA meeting this month.

Off-Label Uses Prove Deadly

These recent trials were intended to expand the market for EPO drugs for uses beyond those initially proven according to FDA pre-approval requirements. Off-label use, as it is known in FDAspeak, refers to the prescribing of a drug for an unproven indication—a common, though questionable, practice. EPO drugs, for example, are already prescribed off-label to treat anemia unrelated to chemotherapy. (Anemia can be caused by chemotherapy or the cancer itself.) It is in a drug company’s interest (sometimes) to prove an off-label use in a clinical trial because that would allow it to openly and aggressively promote the use to doctors and the public; expand the market; and make more money.

Unfortunately, the newer trials testing off-label uses have produced disastrous results. In January, Amgen reported preliminary results from a large randomized trial that found Aranesp hastened death by 23%. The 851 participants were anemic cancer patients not currently under treatment with either chemotherapy or radiation. There were 250 deaths in the Aranesp group and 215 in the placebo group.

Another trial, conducted last year in Denmark, showed that cancer progressed sooner in the Aranesp-treated study participants undergoing radiation therapy for advanced head and neck cancers. Amgen failed to publicly disclose that this long-awaited Danish trial was stopped prematurely last fall. In February, the Journal of Clinical Oncology published an online paper about a Canadian trial in which 70 lung cancer patients on Eprex (Epogen in the U.S.) were dying sooner. Most of the participants were not receiving chemotherapy.

These recent trials are not the first to show deadly EPO-induced harms for off-label uses. The first hint that EPO causes cancer to progress faster showed up in a 2003 German trial testing whether the drug enhances the effects of radiation therapy. The next year, a trial of women with metastasized breast cancer was stopped after four months when a higher rate of death and fatal “thrombotic events” was shown in those on Epogen and chemotherapy compared to those on chemotherapy alone. This trial was testing two off-label uses: 1) higher than normal doses of EPO; 2) in patients who weren’t anemic.

Bottom Line

All EPO trials will be reviewed this month by the FDA, which will likely generate new prescribing guidelines. The newly revised warning labels now tell doctors to use the lowest doses needed to avoid blood transfusions. Potentially fatal deep-vein blood clots and heart problems appear to be related to the administration of EPO in excessively high doses. These drugs were originally introduced to reduce blood transfusions, a procedure that was riskier in the early years of EPO use (early 1990s) than it is today.

To access the newly revised warning labels for EPO drugs on the Internet, type the words label Aranesp or label Procrit into the search box. These 22- to 42-page documents start with the new warnings to doctors. The Aranesp label describes some of the trials that had to be stopped prematurely.

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Those Ubiquitous Gardasil Ads

Posted by medconsumers on March 1, 2007

The first thing you notice about the Gardasil TV ads, featuring teen-age girls engaged in various athletic activities, is that there is no mention of the fact that the Gardasil vaccine is for the prevention of a sexually transmitted disease.

The voiceover says, “Every year thousands of women die of cervical cancer. I want to be one less woman who will battle cancer.” The first sentence is entirely true (3,700 in the U.S.); the second is merely a wish.

One version of these ads, which features mothers and daughters, was found to be cleverly manipulative by a New York Times reporter, Claire Dederer. The ad shows cool, self-reliant girls involved in cool, self-reliant physical activities with the repeat message: I want to be one less woman who will battle cancer.

“The mothers appear about halfway through [the ad] and they’ve got the bad news,” writes Dederer. “In loving tones they break it to their daughters: ‘Gardasil may not fully protect everyone,’ they say. Tenderly they list the side effects.This is an ingenious ploy: the cool girls want to be ‘one less’; the moms are the ones putting on the brakes. Having mothers voice the downside of Gardasil reinforces the message that if you get this vaccination, you’re the rebellious, independent thinker: ‘forget the side effects. Forget Mom. I’m getting vaccinated.’”

Maryann Napoli, Center for Medical Consumers© March 2007

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A Critical Evaluation of the Pap Test and Its Role in Reducing Cervical Cancer Deaths

Posted by medconsumers on March 1, 2007

Widespread use of the Pap test has successfully reduced cervical cancer incidence and mortality. This bit of medical wisdom has largely gone unchallenged with one noteworthy exception in 1978, when Anne-Marie Foltz and Jennifer L. Kelsey co-authored “The Annual Pap Test: A Dubious Policy Success” in the Milbank Memorial Fund Quarterly. This critique is worth recalling today, now that the Pap test is an integral part of the discussion surrounding the merits of the new HPV vaccine. Many consumer advocates who are against mass HPV vaccinations see Pap testing as the safer alternative.

Would that things could be that simple.

The Pap test’s role in the much-heralded “dramatic” decline in the cervical cancer death rate is overstated, according to Foltz and Kelsey, because the rate began to drop well before the Pap test became widely used. Moreover, they report that estimates of the effect of hysterectomy on this decline vary from 10% to 25%. (Hysterectomy involves the removal of the cervix which is the neck of the uterus.)Foltz and Kelsey estimated that one in five American women are without a uterus. After their paper was published, the U.S. hysterectomy rate eventually rose to one in three women. At very least, this would explain why the incidence of cervical cancer has declined in the last 50 years.

Whatever the reasons, the decline in cervical cancer deaths can hardly be described as dramatic. In 1968, there were 7,108 cervical cancer deaths in the U.S. (by 1973, nearly 50% of women reported having had one Pap test during the previous year). In 1976, there were 5,525 deaths. [In 2006, it was 3,700 deaths. For the role of the Pap test in half these deaths in 2006, see below.]

Cervical cancer is not a major cause of death in the U.S. or other Western countries, wrote Foltz and Kelsey, who pointed out that screening people for a disease of low prevalence flies in the face of the medical research standards set by leading thinkers of the time. “The lower the prevalence, the less likely it is that a positive test will correctly identify a woman who really has cancer. This means that many women with positive test results but without disease will be referred unnecessarily for further diagnostic tests and treatment, with concomitant costs and worry,” explained Foltz and Kelsey, respectively, of the Graduate School of Public Administration, New York University; and the Department of Epidemiology and Public Health, Yale School of Medicine.

Wrong Women are Getting Pap Test
Making a point that is relevant today in the promotion of Gardasil, a 1976 editorial in The New England Journal of Medicine raised the issue of whether the wrong women were being screened, “since it was the middle-class low-risk women who were coming in for Pap tests, while the low-income high-risk women were not being seen in clinics.”

If low-risk women are the major customers for the Pap test, their odds of false alarm test results will be unacceptably high, but that was never a major concern to the promoters of cervical cancer screening, chief among them, the American Cancer Society. “The accuracy and reliability of the Pap test have not been established despite its use for over 30 years,” wrote Foltz and Kelsey in 1978.

In other words, no clinical trial has ever been conducted to determine the value of the Pap test because its promotion predated the introduction of the “gold standard” of medical research. Had a large trial randomly assigned women to a Pap test or no Pap test, its efficacy and harms would have been established. And the harms are many, especially in the early days of the Pap screening, according to Foltz and Kelsey. The primary purpose of the Pap test was to detect cancer or tiny lesions that may be pre-cancerous. But by 1978, it was known that these so-called “early,” pre-cancers, carcinoma in situ detected so frequently on a Pap test do not always progress to become deadly, if left untreated.

According to Foltz and Kelsey, this was acknowledged by pathologists, but it took time for the word to get out to the surgeons (i.e., gynecologists). The unnecessary hysterectomies, oophorectomies (surgical removal of the ovaries), and biopsies for “cancers” that would have spontaneously regressed went uncounted. The focus was entirely on the decline in cervical cancer deaths.

Today, a hysterectomy following a Pap test-discovered pre-cancerous lesion or a carcinoma in situ (Latin for cancer in place) is no longer as common. But then again, who’s counting? What were cancers or precancers in another era have long since been renamed as LSIL (see the quote below) or ASCUS, which stands for atypical squamous cells of uncertain significance. The latter nicely describes the unknowns that continue to surround most of what is currently detected on a Pap test.

Today, other harms are acknowledged to result from mass Pap screening. The following quote is from the National Cancer Institute’s Web site www.cancer.gov. “Based on solid evidence, regular screening with the Pap test leads to additional diagnostic procedures (e.g., colposcopy) and treatment for low-grade squamous intraepithelial lesions (LSIL), with uncertain long-term consequences on fertility and pregnancy. These harms are greatest for younger women, who have a higher prevalence of LSIL, lesions that often regress without treatment.”

Maryann Napoli, Center for Medical Consumers© March 2007

Half of the 9,710 U.S. women who develop cervical cancer have not had a Pap test. The other half of all cervical cancers occur in women who have had one. Imperfect testing is estimated to be responsible for 30% of all cervical cancers in women who have had Pap test and improper follow-up of abnormal test results for another 10%. Even under the best screening circumstances, an incidence rate of two to three per 100,000 women can be expected. Some risk factors for not having a Pap test are lack of insurance, poverty, geographic isolation, and lack of provider.

From the American Cancer Society Guidelines for Human Papilloma Virus (HPV) Use to Prevent Cervical Cancer and Its Precursors reported in CA: A Journal for Clinicians, January 23, 2007.

CDC: HPV Prevalent, But Not Cancer-Causing Types

Could it be a coincidence? Just as the media was losing interest in Gardasil, the Centers for Disease Control and Prevention (federal promoters of all vaccines) published a study in the Journal of the American Medical Association entitled, “Prevalence of HPV Infection Among Females in the U.S.” (Why no study of prevalence in males?)

The short of it is this: HPV is much more common than previously thought. In fact the prevalence is highest among those aged 20 to 24 years. The overall prevalence is 26.8%, but the overall prevalence of the high-risk HPV types was only 2.6%. Though this study also noted previous research showing that “approximately 90% of infections clear within two years,” the new findings have already begun to play out in the media as: HPV is prevalent, get your Gardasil shots.

Posted in Cancer, Screening, vaccines, Women's Health | Tagged: , , , , | Comments Off

Support for FDA Regulation of “Home Brew” Diagnostic Tests

Posted by medconsumers on February 8, 2007

Support for FDA Regulation of “Home Brew” Diagnostic Tests

On February 8, 2007, the FDA held a meeting to discuss the agency’s plan to regulate certain diagnostic laboratory tests for cancer and many other diseases. The central question of the day was:  Should the FDA have regulatory power over “home brew” tests, which are multi-gene profiles? These tests will be used to diagnose cancer, determine the most effective treatment, as well as seeing who is at high risk of getting the disease. Traditionally, the FDA has not regulated tests, such as these, that are not done in one central lab. However, the agency has recently designated these tests, called in vitro diagnostic multivariate index assays, as devices. This opens the door to regulation.

At the public comment portion of the meeting breast cancer advocate, Helen Schiff, presented her position on behalf of the Center for Medical Consumers. Her testimony follows:

My name is Helen Schiff. I am a breast cancer survivor and a member of SHARE a breast and ovarian cancer organization in New York City. I am also a patient consultant for the FDA.

The potential for complex biomarkers known as IVDMIAs (In vitro diagnostic multivariate index assays) to change the face of breast cancer treatment is tremendous. For too long we have been plagued with a one size fits all approach to treatment. Even though many women are cured with surgery they have to suffer through radiation, chemotherapy, and 5 years of hormonal treatment because there is no way to know with certainty what treatment a woman really needs, IF ANY. While this treatment strategy has had a small impact onbreast cancer mortality, it has meant that many women have been exposed needlessly to the lethal and life altering effects of all these modalities. Just to name some of the worst ones: leukemia, cardiomyopathy, endometrial cancer, stroke, pulmonary embolism, infertility, lymphedema, “chemobrain,” and loss of libido.

So we welcome a new technology that has the potential to customize our treatments. To give us only what we need. To even tell us which chemotherapy, hormonal treatment, monoclonal antibodies, or small molecule will be optimal for our specific tumors. And we know that in the future IVDMIAs will also have the potential to find breast cancer earlier than is now possible and to do a better job than the Gail model at determining who is really at high risk for getting breast cancer.

Nevertheless, it is very important to be aware of the pitfalls that have plagued biomarker research over the years. In almost half a century of breast cancer biomarker research only TWO biomarkers have proved to be of clinical value: ER and Her2. The significance of what PR means is still disputed. We know for a fact that problems with assays have led to erroneous assessments, less than optimal treatment, and most importantly, premature loss of many lives. Unfortunately, recent studies indicate that there are still problems, for example, with accurate ER and Her2 assays. For example the cut point for ER positivity varies from 1 to 25% of cells with estrogen receptors. A recent study showed that 20% of Her2 tests were not accurate. As many have said, a treatment is only as good as its biomarker, and hence they too need to be rigorously regulated.

One of the most important recommendations of the National Breast Cancer Coalition’s Strategic Consensus Report on Breast Cancer Biomarkers is “to incorporate the best components of drug development to guide the development and validation of biomarker assays.” This new FDA Guidance for IVDMIAs is an important first step in that direction. It will assure that IVDMIAs are: 1) examined before they are marketed; 2) that their results are reproducible by an independent body; 3) that they are tested for accuracy; and 4) that they have clinical relevance. The writing of the IVDMIA label, as with new drugs, must be over seen by the FDA to ensure that there are no false claims and that the results of an INDMIA assays are understandable to both doctors and patients. It is clear to me that neither CLIA, the Federal Trade Commission, nor any other agency in HHS has the depth of the experience, the capabilities, or the resources to undertake such a job, nor do they have the regulatory power.

One need only look to the Ova Check experience to see why this kind of regulatory power is so important. Ova Check was developed as a blood test for the early detection of ovarian cancer in high risk women by Correlogic, a private company, in partnership with scientists from the FDA and the NCI. However, the FDA said that it would not allow Ova Check to be marketed until it published clinical evidence that it WORKED in patients. Keith Baggerly, a bioinformatics specialistat MD Anderson, when trying to replicate the study, found, among other problems, that test results were influenced by the order in which the assay was run. According to an article by David Ransohof in the Journal of the National Cancer Institute Ova Check had not been properly validated its finding in an independent data set and there was a possible problem with over-fitting and bias. Three years later, it has still not been approved to be marketed, confirming its problems were serious. If it were up to CLIA or the Federal Trade Commission, Ova Check would have been marketed-because they do not have the power to stop it. And we all know how hard it is to get something off the market once it is on. Not to mention the irreparable damage it would have done to women.

To me the arguments that FDA regulation of IVDMIAs will hinder development and commercialization, or that this new regulation is unfair, are non red herrings. Don’t we want to find out which IVDMIAs work and which ones don’t, regardless of when they were developed or by whom? If anything will hold up development in this field it will be the premature marketing of more Ova Checks. As we see this is not just a matter ofj “colorful characters” or fly by night companies as suggested in a recent GAO report. Reputable scientists can make honest mistakes.

As an advocate I think we need to introduce rigor and oversight into the biomarker field and I think the FDA Guidance on IVDMIAs is an important step in that regard. I certainly don’t follow the logic that when IVDMIAs are homebrews they should not be regulated by the FDA. My logic leads in the other direction. All biomarkers, including home brews, when used in the CLINIC should be regulated by the FDA. Otherwise we leave the successful commercialization of IVDMIAs to companies who write the best press release, do the most advertising or try and court advocacy groups.

Posted in Advocacy, Cancer | Tagged: , , , , | Comments Off

How Vaccine Policy is Made: The Story of Merck and Gardasil

Posted by medconsumers on February 1, 2007

Much has happened since the November HealthFacts took the position that the new cervical cancer vaccine should not be mandated. By now, most of the U.S. is probably aware that donations from Merck, maker of the Gardasil vaccine, influenced Governor Rick Perry’s decision to make Texas the first state to mandate Gardasil vaccinations for all girls entering the sixth grade.

Behind the scenes, Merck was found to be bankrolling similar mandates under consideration in at least 20 other states. In doing so, the company moved from the usual pharmaceutical industry hucksterism (hype the disease, hype the new drug) to blatantly purchasing a public policy that is clearly a windfall for the one and only company that sells a cervical cancer vaccine.

The prolonged nationwide publicity given Merck’s actions frequently overlooked a key element to the question of whether mass cervical cancer vaccinations make sense whether they are mandated or voluntary. Cervical cancer is, by any measure, a rare disease in the U.S., afflicting fewer than 10,000 women and causing about 3,700 deaths each year.

And then there’s the proverbial elephant in the room that no one seems to want to address. It has been known for over three decades who is most likely to get cervical cancer. In fact, it is known by geographical region. So why not save taxpayers’ money, especially at a time when the states are running out of health dollars for children, and provide the vaccine for the girls most in need?

All medical decisions made by and for healthy people boil down to probabilities. What are the odds of dying of the disease that the vaccine protects against? (There are three cervical cancer deaths for every 100,000 women in the U.S.) How protective is the vaccine? (70%, according to Merck) What are the odds of serious harm from the vaccine itself?

The last question is not answerable because the vaccine has only been available for eight months, and several hundred thousand girls must be vaccinated and followed for many years before any rare or even uncommon serious adverse reactions can be documented. The longest follow-up is 4 ½ years, so how long the protection lasts is another unknown.

What makes this vaccine different from virtually all others currently given to babies and young children is the fact that cervical cancer is a sexually transmitted disease. (The hepatitis B vaccine given to newborns since 1991 is the other exception.) There are more than 100 different types of human papilloma virus (HPV), but only 23 are considered high risk. “Rarely can an infection with high-risk HPV develop into precancer or cancer. The majority of HPV infections go away on their own and do not cause any abnormal cell growth,” according to the National Cancer Institute’s Edward L. Trimble, MD. Gardasil protects against two of the cancer-causing strains that account for about 70% of all cases of cervical cancer
Typically, a new vaccine goes into use gradually, and a mandate comes only after several years. The haste with which Gardasil became mandatory in Texas is challenged. “This [cervical cancer] is not a public health emergency, so the government has no right tell parents or kids to have the vaccine or even to opt out,” said Michael Policar, MD, associate clinical professor of Obstetrics, Gynecology and Reproductive Science at the University of California, San Francisco. “You can’t get this disease from someone sitting next to you on a bus. If you have TB, a judge can tell you to take your drugs because you can give the disease to other people and if you don’t take the drugs, the judge can have you confined,” Dr. Policar said in a telephone interview.

Physicians and public health experts quoted in the media were unanimous in their recommendation of the vaccine, though some, like Dr. Policar, do not like the mandate. And all insist that strong evidence supports its safety and efficacy. Physicians seem untroubled by the fact that no published HPV vaccine trial had participants under the age of 15. The CDC recommends the HPV vaccine for 11- and 12-year-old girls, and the American Cancer Society sees the vaccine as appropriate for girls as young as nine years of age. The girls must receive the vaccination before they become sexually active or else it will not be effective.

Why is there so little public discussion among doctors about the wisdom of vaccinating all young girls for a rare disease? “Great question,” responded Dr. Policar. “Certain people are very tied into vaccines—pediatricians, infectious disease doctors, public health doctors—these people have never seen a vaccine they didn’t like. The pressure to vaccinate comes not only from them, but also from industry.”

The rush to make a new vaccine compulsory appears to be all about Merck making as much money as possible before Cervarix, GlaxoSmithKline’s version of the HPV vaccine, comes on the market. “Merck started three to four years ago convincing us that HPV is a dangerous infection,” said Dr. Policar, noting that the company has been overdoing it. “HPV is a marker for sexual activity. The majority of us are infected with it and that doesn’t mean we’ll all get cancer. This is another industry-created disease,” he explained, stressing that all HPV-vaccinated women should have regular Pap tests. (For a critique of the Pap test, see page 4.) Dr. Policar is favorably inclined toward the vaccine, but has reservations about the excessive cost and possible need for booster shots (“it took 30 years to learn that the pertussis vaccine needs a booster”). Dr. Policar said he has been “a paid lecturer on occasion for Merck regarding Gardasil.”

More and more parents worry about the growing number of vaccines now given to babies and young children, according to Barbara Loe Fisher of the National Vaccine Information Center, who notes that 40 vaccine doses are already mandated for babies and young children. Fisher, an advocate for vaccine safety, is concerned that doctors are not giving enough attention to possible harmful effects of Gardasil when combined with other vaccines.

She advises parents to inform themselves. But this is difficult when the trials are funded by the vaccine companies and the last place parents will get an unbiased evaluation of any vaccine are the U.S. Centers for Disease Control and Prevention (federal promoters of vaccines in general) or the American Academy of Pediatrics (represents the specialty that sees all vaccines as a medical triumph). In fact, Fisher’s Web site www.909shot.com is the only evidence-based independent Web site on this topic.

Science seemed to take a back seat in the prolonged media coverage last month. The one trial that proved “sustained efficacy up to 4.5 years” was funded by GlaxoSmithKline, and published last year in The Lancet. This is the longest follow-up. The majority of the participants were over 18. About half of these 776 study participants were randomly assigned to receive the HPV vaccine, thus the longest follow-up involves less than 400 women.

And now for the elephant in the room. Cervical cancer is largely a disease associated with extreme poverty, smoking, lack of education, and less than sanitary living conditions. According to a 2005 National Cancer Institute report, most cervical cancer deaths occur in black women in the rural South, Hispanic women living along the Texas-Mexico border, white women in Appalachia, American Indians in the Northern Plains, Vietnamese-American women and Alaskan Natives. These groups are also more likely than other U.S. women to be diagnosed with other diseases like breast cancer, colorectal cancer and heart disease.

Wouldn’t it make sense to aim the Gardasil vaccine recommendation at these women? Or better yet, given the limited federal health dollars, why not spend some money to improve their health in general? The answer, of course, is that this would not suit Merck, who appears to be setting the national agenda on cervical cancer. Nor does it suit the federal government and the special interests—so aptly represented in Congress—who want to do everything to keep companies from shunning the vaccine business as risky and unprofitable. Merck needs to make as much money as quickly as possible from Gardasil before Cervarix goes on the market. Each year in the U.S., about a million girls turn 11. Mandating a $360* series of three injections means an estimated $360 million-a-year market.

It didn’t take long for Merck to experience a well-deserved backlash. Within three weeks of Governor Perry’s announced mandate at the end of January, Merck revealed that it would stop lobbying state legislatures to mandate Gardasil. (Texas legislators are reportedly at work undoing the mandate.) But Merck is not the only company to provide “unrestricted educational grants” to Women in Government, a Washington, DC based advocacy organization of female state legislators. This group, the conduit for Merck donations, has also received funding from Glaxo, as well as Digene, a company that makes a test that detects HPV.

The funding paid off as female state legislators were highly visible in the media coverage given Gardasil last month. The legislators were presenting themselves as champions of women’s health and spreading the word about the dangers of HPV, often quoting worldwide cervical cancer statistics (500,000 deaths annually!! Second leading cause of cancer deaths!!) as if these numbers pertained to U.S. women. The Merck people probably knew that a vaccine company presenting itself as champions of women’s health wouldn’t fly with the public. Much better to send in the female legislators to shill for them.

*This is the most widely quoted price, but a random survey by the National Vaccine Information Center found the price varies considerably and can be as high as $825 plus office visit charges.

Maryann Napoli, Center for Medical Consumers© March 2007

Posted in Cancer, Children's Health | Tagged: , , | Comments Off

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