Twas the night of Halloween

It’s that time of the year again, when scary stories of spooky dangers hiding behind every door go into high gear. It’s not ghosts and goblins some parents fear, but candy and sweets, razor blades in apples, and Halloween madmen.

Trick-or-treating has long been a night of fun, when kids get to dress up, eat gobs of candy and bring their fantasies to life, but for some parents it’s a witching night that threatens to permanently tempt children to the dark side of unhealthy eating.

Some candyphobics even believe it’s a sugar-holiday invented by evil candy companies, writes Rebecca Rich in the University of Ottowa’s Fulcrum. She counters such beliefs with a fun review of the history of Halloween, trick-or-treating, and Jack-o-lanterns. The origins of Halloween actually can be traced back to Celtic civilizations in the fifth century, she said. Interviewing Shelley Rabinovitch, a professor at the university’s Department of Classics and Religious Studies, best know for teaching witchcraft and magic, she learned that trick-or-treating isn’t new, either:

Rabinovitch explained that it was once believed that spirits could roam freely among the living and, because of this, certain superstitions developed. People began to travel from house to house, dressed in costume in order to distract or frighten the impish spirits away. As this service was considered a tremendous help to the homeowner, residents would often give small gifts to the group. This ‘treat’ often consisted of food and has developed more recently—to many parents’ chagrin—into candy.
Over the years, in many rural areas, if the homeowner did not provide a treat of some sort to the group, people would often respond by tipping the home’s outhouse, thus inserting the “trick” into the tradition of trick-or-treating.

According to the History Channel film The Real Story of Halloween, outside of Celtic custom, trick-or-treating was also related to the English tradition of giving soul cakes on All Souls’ Day in return for a promise to pray for a dead family member. Soul cakes were round cakes left at tombstones for the dead with the belief it would free a soul from purgatory. This practice was altered by the Catholic church as children were encouraged to “go a-souling”, or travel from house to house gathering food, alcohol, or money for their families instead of leaving the gathered goods for the dead.

Halloween and trick-or-treating first appeared in North America in the early 19th century, when Scottish, Irish and English were immigrating in high numbers, according to Nicholas Rogers, a York University history professor and author of Halloween: From Pagan Ritual to Party Night. “Immigrants brought along their culture and traditions but as religion played less and less of a role in their lives, so too did the religious aspects of Halloween. Trick-or-treating became exclusively a children’s event in the early 1900s and has been ever-present to this day.”

Trick-or-treating, however, is a night of horror for candyphobics. It turns parents into sugar witches, writes a mother in West Hartford, Connecticut, in an opinion piece for the Hartford Courant:

Why Be Sugar Witch? A Better Trick To Treats

It's that time again — time for pumpkins to appear on doorsteps, children to dream up the perfect costume, and parents to scheme about how to take their kids' candy away within hours of the jack-o'-lanterns' going dark tomorrow. Easter and Valentine's Day, alongside Halloween, are holidays that provoke candy anxiety among parents worried about obesity and tooth decay. Parents scheme to replace the edible loot with some other kind of loot. I once read about two families that have rituals involving the Great Pumpkin and the Sugar Witch, who appear after Halloween to relieve the kids of their candy. In return, they leave a small toy.

Extreme candyphobia goes beyond holidays. Some schools have a zero-tolerance policy on candy. A friend's daughter came home from kindergarten in tears after being chastised because her mom included a Hershey's Kiss in her lunch. This demonization of candy does nothing to make kids healthier or teach them about reasonable indulgence.

There is something just plain stingy, even a little mean, about taking candy from children. Does no one remember the thrill of having a pile of Halloween candy, knowing that it was all yours to sort and savor as you wished?... This Halloween night, I'll watch my kids dump their candy on the floor, sort it by type and then carefully choose which kind to eat first. Instead of fussing about how soon I can get that candy out of their hands, I'll forage through our trick-or-treat leftovers, trying to figure out whether I like Reese's peanut butter cups or Kit Kats better, and realize I need to try just one more of each before making my final decision.

Amidst today’s absorption with healthy eating, few parents can admit they let their children eat candy without, in the next breath, describing the healthy food they feed her children. Fears that today’s children eat vast amounts of sweets and won’t really be able to titrate their hauls and savor them at their own pace are even hard for well-intentioned parents to totally overcome. “Our rules for holiday candy are simple,” she writes. “On the holiday, the children can eat as much as they want”… then it’s confiscated. Countless dieters will recognize the similarity to the pig-out the night before beginning the next diet.

Connecticut parents aren’t the only ones with children worried about sweets being packed in their school lunches for fear of being singled out. In Newburyport, Massachusetts, public schools have made candy illegal (whole milk, too), telling parents what is allowed in their child’s lunch boxes from home. “The ban is part of the school district's newly adopted wellness policy, which [Superintendent Kevin] Lyons said, was developed over the past year in an attempt to address the rising tide of childhood obesity and skyrocketing number of cases of childhood onset diabetes,” according to the Newburyport News.

Another Halloween legend

Halloween brings out another trick-or-treat fear among parents: of a madman handing out razor blades in apples and poisoned candy.

Did you know that, just like evil sugar stories, the Halloween sadist is an urban legend, too?

Professor Joel Best with one of his undergraduate students, Gerald T. Horiuchi, at California State University in Fresno, investigated 25 years of news stories about Halloween sadists giving children dangerous treats on Halloween. They found that the Halloween sadist is a myth, an urban legend that originated during the 1970s. These stories are spread primarily by word of mouth, not as much by news media, they said. All of the Halloween sadism stories were debunked in some way and nearly all of the stories of sharp objects in apples or other treats turned out to be pranks.

Their findings were published in a fascinating paper in the sociology journal, Social Problems. [The full text is available here.] Essentially, they found that like all urban legends, this one gave expression to growing fears about the safety of children, the dangers of crime and other social stresses. During the 1960s and 1970s, even doctors and social workers were promoting child abuse as a major social problem and the popular press responded with dozens of dramatic stories of cruelly treated innocent children. The Halloween sadist urban legend emerged as an expression of fears that children were threatened by modern society and no longer safe in the United States, fears of crime, and society’s growing distrust of others. The sadist is an anonymous, invisible, unprovoked assailant who preys on society’s most vulnerable members. This legend has persisted, as most do, because our culture feeds off fear, and anxieties about the future flourish. It’s natural to translate those anxieties into overestimations of the dangers faced by our children.

But no child has died or been seriously injured by a Halloween sadist even nowadays. “The same appears to be true in the UK,” the Times UK reported. “The Metropolitan Police Force, for example, says that there are no records of any major incident involving a child at Halloween.”

Joel Best, now a professor of sociology and criminal justice at the University of Delaware, published an update of his earlier investigation of the evidence behind Halloween sadism. It remains an urban legend. [Text available here.] He was quoted in the Gainesville Times yesterday as saying that hospitals offering to X-ray candy for worried parents and reputable organizations issuing advisories telling parents to inspect their children’s treats, only fuel the urban legend. “Hospitals shouldn’t be doing this because it just buys into this sort of general anxiety that there are maniacs out there trying to kill children,” he said. In fact, his research has been unable to find a connection between sex offenders and Halloween, either. “But it’s part of this panic we have that sex offenders are out to get children at every opportunity.”

Of course, there are reasonable and prudent safety precautions parents take any time, but the greatest safety concern for children associated with Halloween isn’t from candy or maniacs, but being hurt by their costumes or hit by cars. It’s a night when millions of kids are out in the dark. According to a Safe Kids Coalition spokesperson, children are more than twice as likely to be hit and killed by a car on Halloween than any other night of the year. “Be safe and be seen.” Halloween safety tips are just a click away at Keep Kids Healthy.

Happy Halloween!

Be afraid, very afraid. This is Halloween — all for fun, of course.

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Banana bread diet

Remember Google Health? Sure you do. We were invited to type in personal information about ourselves — diet and lifestyle habits, smoking and alcohol intake, medical history, family history, screening and lab tests, prescription medications, weight, age, ethnicity, etc. — at Google Weaver online. In return, Google would offer custom “health guides” that would provide health information targeted for us by Google’s trusted advisors to help us make the right healthcare decisions. While there’s no legal protection for how that personal information about us can be used or who it can be shared with or sold to, we were told to trust Google to keep it private.

At Harvard Medical School in Boston on Tuesday, Google co-founder, Adam Bosworth (no longer at Google), revealed more insights into his newest healthcare marketing enterprise, called Keas, Inc.. He said this new online technology will offer a highly personalized web-based program “to enable people to change their lifestyles — to make them part of the solution.”

“The solution to what?”

Obesity.

According to Healthcare IT News, “Bosworth called obesity a ‘human disaster.’” HIT editor, Bernie Monegain, said “if he’s successful, it could mean fat Americans would become fit and healthy.”

As HIT reported, Bosworth told the audience that he had recently lost 60 pounds and plans to apply it to what he knows best: building mass market technology:

Banana bread story offers glimpse into Google co-founder's healthcare venture

… Bosworth called obesity "a human disaster," It's responsible for numerous illnesses, pain and suffering and, by Bosworth's calculations, a $500 billion chunk of the nation's $2.3 trillion annual healthcare costs. In his view, it's $500 billion in avoidable costs. "Bad lifestyles have consequences," Bosworth said. "A lot more people are getting sick a lot more expensively." The people who are costing us the money are the people with two or three risk factors, like high blood pressure or diabetes, he said…

Bosworth also called for rewarding both the patient and the healthcare provider who helps keep the patient healthy. Today's healthcare system pays physicians only when they treat people who are sick. Healthcare could take a cue from the car insurance business, which rewards good drivers with lower premiums….

One reason people have not been successful at staying healthy, Bosworth said, could be illustrated by his own experience with banana bread. He was in the habit of walking to and from work everyday and picking up a piece of banana bread at the coffee shop along the way. The banana bread, it turned out, erased most of the walk's benefits by adding 500 calories…

There’s not much information at the website for Keas, yet. But Mr. Bosworth talked about the vision for his new company, created with partner George Kassabgi, on his blog last December, writing:

If you are one of the many at risk of losing your health, Keas will help you keep healthy. If you’re recovering from an illness Keas will help you to recover and stay well. If you suffer from a chronic disease Keas will help you be as well as you can be. Today no one helps you. You can’t assemble your health data to get the best care possible. Even if you can, your doctors rarely help because the system doesn’t pay them to keep you healthy. You don’t have tools that work online to help in these situations, partly because insurance doesn’t pay for them. Because of these problems people suffer both personal hardship and fear and economic deprivation, sometimes irreversibly. What is more we all pay enormous medical costs for this, and there are costs to society and to the competitiveness of our companies in lost productivity. It is our mission at Keas to fix this for you…

How many false working assumptions did you count?

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Update from UK: fat children taken by the state

As a particularly vocal anti-obesity group in the UK continues to call for fat children to be taken away from their parents and put into state care until they lose weight, earlier this month the Association of Directors of Children’s Services had denied that it was happening. A spokesperson had told The Independent that fat children had not been removed from their parents by child protective authorities. But reporters kept digging. Finally, Councils just released the information following a request filed under the Freedom of Information Act.

As is being reported in newspapers across England this morning, at least seven children have been taken by state social services officials over concerns they were too fat — the youngest was a boy in Derby just six years old and another girl from Cumbria was just eight. [Her story was covered here.]

Earlier this month, Tam Fry, a board member of the National Obesity Forum, had said child obesity should be treated like child abuse and that state child protective services must remove these children from their parents and force them to lose weight, while their parents are rehabilitated by social services. In today’s Mirror, the National Obesity Forum appears to be setting its sights on babies, as Dr. Colin Waine, also with group, called for closer monitoring of infants. JFS readers will remember when earlier this year, Mr. Fry was talking of an alarming crisis of fat babies, which proved to be false.

Will the medical evidence and actual government statistics which negate the need or efficacy of these draconian actions reach public officials? We can only hope reason prevails for the welfare of children and their families.

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No statistically significant risks seen for prostate cancer or diabetes ...

Thousands of men and their loved ones may have been frightened this week by news that the National Cancer Institute had announced it was halting a major multi-center prostate cancer study due to safety concerns. It was a randomized clinical trial of vitamin E and selenium and its suspension brought others to fear their vitamins could be putting them at risk for prostate cancer or diabetes. While the precise findings which led to the decision to prematurely end this trial have not been made public, a better understanding of the science and what is known may help lessen fears and put things into perspective.

Background

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a major, phase III, randomized, placebo-controlled, double-blind clinical trial of selenium and vitamin E (individually or together). Its goals are to see if the vitamins have an effect on preventing prostate cancer, as well as lung cancer, colon cancer, Alzheimer’s disease, age-related macular degeneration and cataracts, and to determine if the supplements have any affect on lung function and chronic obstructive lung disease, serious cardiovascular events and overall survival. SELECT is registered at ClinicalTrials.gov (NCT00006392) and began in July 2001.

This study is the largest prostate cancer prevention trial ever conducted. It was designed to enroll a total of 32,400 men, 55 years of age and over (50 years and over for African American men) who were free of prostate cancer or elevated PSA levels. The study randomized the men into four arms to receive selenium (200 micrograms/day of L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) or a placebo. The men’s medical conditions were to be closely followed for a minimum of 7 years and up to 12 years.

This study has been conducted at more than 400 medical centers in the United States, Puerto Rico and Canada. It is coordinated by the Southwest Oncology Group (SWOG), one of the largest cancer clinical trials cooperative groups in the United States. Funding for this study included about $114 million from the NCI and $4.5 million from the National Center for Complementary and Alternative Medicine (NCCAM). The ancillary studies have each received additional funding. For example, the National Institute on Aging granted $7 million to evaluate Alzheimer’s and cognitive affects; the National Eye Institute provided $2 million to evaluate age-related macular degeneration and cataracts; and the National Heart, Lung and Blood Institute (NHLBI) gave more than $3 million for the lung function evaluations. The point being, a lot is riding on this study and it is inconceivable it would be discontinued lightly.

Available information on the study’s suspension

According to SWOG, the Data and Safety Monitoring Committee for the SELECT trial met last month to review the blinded data since the trial commenced, along with the study investigators and the National Cancer Institute. Together, it was decided to stop the trial due to concerns that the vitamins could slightly raise the men’s’ chances of getting diabetes and prostate cancer. The NCI provided more details on the SELECT page, saying that independent reviews of the study were done in September and October and reported:

[S]elenium and vitamin in E supplements, taken either alone or together for an average of five years, did not prevent prostate cancer. The data also showed two concerning trends: a small increase in the number of prostate cancer cases in men taking only vitamin E and a small increase in the number of cases of diabetes in men taking only selenium. Neither of these findings proves an increased risk from the supplements and may be due to chance. Additional analyses of the data are under way and the investigators will produce a peer-reviewed publication of these initial results soon.

While no specifics have yet been published on precisely what the safety data showed, the key points highlighted on the NCI’s SELECT Q&A page is where we learn the risks would appear to be minimal, and may not even be real at all. There, they state that the trends were not even statistically significant.

The SELECT data showed two concerning, but not statistically significant, trends: there were slightly more cases of prostate cancer in men taking only vitamin E and slightly more cases of diabetes in men taking only selenium. Neither of these findings proves an increased risk from the supplements and may be due to chance.

With no demonstrated benefit of the antioxidants in reducing prostate cancer (the study’s primary endpoint), they said that as a precaution they told all of the men to stop taking their study supplements yesterday. The men will continue to have their health monitored by the researchers for about three years. The NCI says that the study will continue to be blinded during these follow-up years to attempt to preserve reliable evaluations of the study objectives, but men will be told what supplements or placebo they were receiving if they request.

Balancing unknowns with what we know

With unknowns, it’s natural to feel worried or to let suspicions get the better of us, even when we’ve been told the risks aren’t beyond what might have surfaced by random chance. But examining the body of evidence to date will hopefully provide some additional reassurance and help to put things into perspective.

The NCI’s SELECT Q&A page provides little information on the entire body of evidence, noting only the inconclusiveness in studies of selenium or vitamin E published since SELECT began. That’s probably left many feeling even more unsettled about the unknowns and their possible risks.

The NCI notes that each of the observational (epidemiological) papers examining the correlations between selenium supplementation and blood sugars had reached different conclusions (increased risk, no association and lower risk for diabetes).

It notes only one published paper of a clinical trial of selenium supplementation, but it was a secondary analysis of a randomized, double-blind, placebo-controlled trial of selenium supplements taken by 1,202 people being seen at a dermatology clinic and reported only self-reported cases of type 2 diabetes. The authors published their findings last year in Annals of Internal Medicine and said that after an average of 7.7 years of follow-up, type 2 diabetes was seen in 1.26% people/year of those with the highest selenium blood levels compared to 0.84% among those with the lowest selenium levels. Because the study wasn’t designed to evaluate diabetes or determine the presence of diabetes at the beginning of the trial period, the authors urged caution in generalizing the findings but said a clinical trial to examine the potential risk for diabetes was warranted. The NCI said that the SELECT study will examine its data to evaluate this potential risk.

Finally, the NCI cites only one randomized, double-blind, placebo-controlled trial of vitamin E. This was a report of the international HOPE trials, which had enrolled 9,541 older adults with heart disease or diabetes, following them for 4.5 years, with HOPE-TOO following 7,030 of the participants for an additional 2.5 years. These trials saw no affect with natural vitamin E supplementation on the incidences of cancer or cancer deaths, on major cardiovascular events or death from any cardiovascular cause, or in deaths from any cause. It did report slightly higher rates of heart failure (14.6% in vitamin group versus 12.6% in placebo). The NCI said that the SELECT study will also examine its data for this potential risk.

Not included on the NCI Q&A webpage was mention of the largest review of every available randomized, placebo-controlled, double-blind clinical trial of antioxidant vitamins conducted since 1945. This meticulous undertaking was recently published by Cochrane Database of Systematic Reviews, the world’s most respected source of systematic reviews of the evidence. Evaluating each trial for the quality of its methodology and to ensure it was unbiased, the experts found that no clinical trial done in over 60 years has found a credible benefit for taking antioxidant supplements. Similarly, there was no significant difference in mortality among those taking the antioxidant supplements compared to a placebo — regardless of the doses, antioxidants taken individually or in combination, in any population studied or after14 years of follow-up. As reviewed here, every relative risk hugged either side of null (1:1 = same risk of death in those taking supplements and in those not), all within the range of random chance and margin of error.

In other words, men, the best clinical trial evidence to date suggests that the overall risks of taking vitamin supplements at the dosages in this study are not significant. Going to the Cochrane report itself where the clinical trials of vitamin E and selenium, used singly or with other antioxidants, were specifically examined, the findings are similarly reassuring. The reviewers found no significant effect of vitamin E on mortality when including all 54 trials and after excluding high-bias trials. Some of these trials had used doses of 1,000IU and higher, many times higher than those used in the SELECT study. Selenium also had no significant effect on mortality in all of the low-bias risk trials.

Nor is there any evidence that any vitamins or antioxidant supplements offer any health benefits when a specific deficiency doesn’t exist, as reviewed last year. Yet, beliefs continue that antioxidants, as in lots of fruits and vegetables or super foods, can prevent cancers and chronic diseases of aging. The scientific expert review of anti-aging medicine done for the National Institutes of Aging emphatically concluded “there are no lifestyle changes, surgical procedures, vitamins, antioxidants, hormones or techniques of genetic engineering available today that have been demonstrated to influence the processes of human aging.”

Antioxidant and free radical myths

Both the reasons for the continued failure of antioxidant vitamins to demonstrate health benefits for degenerative diseases of aging in clinical trials, and for some studies to even suggest possible risks at doses above normal dietary levels, has to do with popularized misconceptions of the benefits of antioxidants and dangers of free radicals. Things aren’t as black and white as that. Free radicals actually play a role in normal, healthy physiological processes like our immune system and promote beneficial oxidation; while in excess they can produce harmful oxidation that causes cell damage. Similarly, many vitamins and supplements classified as antioxidants are actually redox agents, meaning they act as antioxidants in some instances and pro-oxidants in others and can produce harmful levels of free radicals.

An editorial in the Journal of the American Medical Association accompanying the HOPE trials, written by researchers at the University of Washington School of Medicine in Seattle, said that the HOPE trials add to a growing list of null clinical trials of vitamin E and effectively closes the door on the prospect of a major protective effect of this supplement for heart disease or cancer. More importantly, the carefully done HOPE trial “reemphasizes the importance of controlled clinical trials for testing important hypotheses deriving from basic biological findings or from epidemiological observations. The latter can mislead; well designed clinical trials rarely do.”

They added that this is a teaching opportunity:

HOPE-TOO allows physicians to educate their patients as with the following response to inquiries about vitamin E, “In nearly 68,000 patients studied to date, there is no compelling evidence that higher doses of vitamin E reduce cardiovascular risk or cancer; there are even some hints that vitamin E, in excess of normal daily intake, may slightly increase the risk of ischemic events or of heart failure. You may hear that vitamin E is a ‘natural,’ yet effective, way to prevent heart disease or cancer, but this has proven to be a false hope.

The continued resistance to accepting the null findings of many of these clinical trials on vitamin and antioxidant supplements originates in another misconception of vitamins and supplements: that only natural sources of vitamins work and that they’re different from synthetic versions. As explained in more depth here, this is a marketing concept, but has no scientific basis or biological plausibility. The molecular structure of a synthetic vitamin molecule is identical to one from natural sources and indistinguishable in all respects to our body.

Names can lead us to wrongly believe that one type of vitamin is less bioactive than another, such as vitamin E. The d-form (most often termed ‘d-alpha tocopherol’) comes form vegetable oils and other ‘natural’ sources. It’s different from the dl-form (dl-tocopherol) commonly called the ‘synthetic’ type of vitamin E. But biologically, one isn’t better than the other. That’s because, to put it simply, the dl-form is a combination of d-form and l-form, but the body only uses the d-form. The l-form is just excreted by the body. So the dosages will be different on the labels of dl-form and d-forms (half) — but the bioeffective vitamin dose is the same.

‘Natural’ vitamins are said to have hundreds of other, unknown substances found in whole foods that aren’t found in synthetic vitamins, but there are no credible clinical studies supporting such claims that these ingredients potentiate or improve the action or absorption of the vitamins or offer any special benefits. Vitamin pills extracted from foods undergo a process that changes their place in that food and it’s implausible that the miniscule amount of some unknown factor that might survive that process in a tiny pill has any special vital essences or health promoting properties.

For men and their loved ones who may have had their lives shaken up this week by news of the SELECT study being halted because of safety concerns, hopefully, realizing that the risks weren’t even statistically significant and seeing the bigger picture and the scientific evidence to date has helped.

© 2008 Sandy Szwarc

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Perhaps, even free isn’t worth the price

Tuesday’s free Medscape CME course for doctors and nurses reviewed the latest INTERHEART data dredge. As covered here, it was a null study, finding no tenable link between diet and first heart attacks. Healthcare professionals, however, were given a different interpretation of the study:

“Western Diet Increases MI Risk Worldwide.”

The Medscape CME course* for healthcare professionals was a reprint of an article published at Heartwire, a WebMD news publication for cardiology professionals. The article was written by Lisa Nainggolan. For the free 0.25 continuing education credit, doctors and nurses then answered two multiple-choice questions.

According to the text of the course, the study found “that those who consumed the prudent diet had a 30% lower risk of heart attack compared with people who ate little or no fruits and vegetables, those who ate a ‘Western’ diet had a 35% greater risk of MI [myocardial infarction]…”

Rather than an objective, informed, and critical examination of the science — describing the study’s methodological weaknesses and the significance of this correlation — the bulk of the article was devoted to giving untenable odds ratios causal roles and then as turning them into preventive health interventions and forming the basis for recommending public policy changes.

INTERHEART co-author Dr. Sonia Anand, M.D., who teaches clinical epidemiology courses in methodology and cardiovascular disease at McMaster University in Canada, told Heartwire:

“We hope [the results of our study] will allow policy makers to try to think of creative ways of making the good foods more easily accessible and affordable and the bad foods less accessible and maybe not as affordable… Because the greatest gains in changing what people eat — by country, by region, and by community — will come from those policy-level changes. It's pretty easy: the more bad things you eat and the less of the good things, the higher your risk of MI. From a public-health perspective, having a simple message is very important.”

Medscape told medical professionals: “Simply put, an unhealthy diet, as assessed by a straightforward dietary risk score, increases the risk of AMI [acute myocardial infarction (heart attack)] significantly, whereas consumption of a prudent diet is associated with lower risk… and the population-attributable risk for AMI worldwide associated with poor dietary intake is substantial.” Dr. Anand concluded by saying:

When I think of my own training — which was fairly recent — there was very little information on nutrition or dietary advice. So you come out as a specialist who can treat a patient with a heart attack, but when it comes to prevention, there is not much training. I believe physicians will welcome this advice. If the family doctor and other specialists embrace a holistic but simple approach, this could lead to a reduction in heart attacks and is very consistent with cancer-prevention guidelines. And I think the results are broadly applicable to the population at large.

It’s difficult to know if cardiology specialists really are welcoming such vapid continuing medical education that’s indistinguishable from a press release read by any local television reporter. Their heart attack patients laying in cardiac intensive care units probably hope they aren’t, and that their doctors are, instead, staying abreast of the latest science.

* The disclosure statements of the INTERHEART study were not shared with Medscape readers, the CME author was listed as reporting no conflicts of interest.

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Fears over ownership of healthcare

A calm, thoughtful article appeared this morning in the Minneapolis Post examining fears of change in who owns our healthcare coverage. For another side of this issue on everyone’s mind, attorney Peter Nelson examines some of the concerns of losing employer-provided health insurance.

Why employers won't cut and run when individuals own health insurance

Americans agree: Our health-care system needs a serious overhaul… Most of us rely on an employer for health coverage. Unless you're retired, your employer in all likelihood picks, pays and actually owns your health coverage. If the status-quo system relies on employers, and if the system needs fundamental change, then it stands to reason that we should take a hard look at revamping the employer's role. Serious health-care reforms do just that. The Mayo Clinic Health Policy Center's current reform principles focus on moving from employer ownership to individual ownership of health coverage…

Most reforms that promote individual ownership would eliminate the current tax preference for employer-paid coverage and, instead, level the field so that all Americans get the same health-care tax advantages… Individually owned coverage would fix big, systemic flaws. When individuals own their coverage, it's portable from job to job. Portability makes health coverage more secure at a time when jobs are less stable. Moreover, according to the Mayo Clinic, individual ownership "gives patients more control and choice," and because insurers would now compete for the individual, the insurer would offer more competitive rates and improved service ..

Nonetheless, many people find it tough to believe that they would be better off taking ownership over their health coverage. The trouble is that too many people mistakenly believe they will be left entirely on their own to wander the wilderness of coverage choices where the cost of whatever they choose comes entirely out of their own pocket…

Rest of article here explains why it’s not an either-or scenario and owning our health coverage does not mean being abandoned or losing employer health insurance benefits.

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Election day: Freedom of health care choice

In one week, Arizona voters may make the most important vote in the country. George Will explained why on Sunday:

On Election Day, Arizonans can give the nation the gift of a good example. They can enact a measure that could shape the health care debate that will arrest or accelerate the nation's slide into statism. Proposition 101, "The Freedom of Choice in Health Care Act," would put the following language into Arizona's Constitution:

"Because all people should have the right to make decisions about their health care, no law shall be passed that restricts a person's freedom of choice of private health care systems or private plans of any type. No law shall interfere with a person's or entity's right to pay directly for lawful medical services, nor shall any law impose a penalty or fine, of any type, for choosing to obtain or decline health care coverage or for participation in any particular health care system or plan."

What do those people favor who oppose Proposition 101? Some support ... a severe single-payer system, proscribing private health insurance in the state and requiring almost everyone not on Medicare to enroll in a state health care program. Under that program, a state commission would stipulate the menu of services and medications, and could even decide which hospitals could add which technologies… Opponents of Proposition 101 are against what it would guarantee, including the right of individuals to pay directly for medical services without needing the permission of a third party. Proposition 101 would emancipate service providers from requirements that they either charge fees set by the state, or charge nothing.

Proposition 101 would prevent employer or individual mandates of the sort imposed in Massachusetts. That is, it would prevent "pay or play" systems, under which employers must either pay for employees' health insurance or pay into a state pool that finances insurance for them….

“Proposition 101 would protect Arizonans not only against abridgements of their liberties by their state government,” wrote Mr. Will, “but also perhaps against comparable actions by the federal government.”

The Constitution preserves a fundamental checks and balances over federal government tyranny over United States citizens. Some Americans continue to believe that the U.S. Constitution does not represent the fundamental flaw of this country. Clint Bolick, director of the Goldwater Institute's Center for Constitutional Litigation said: “It is a bedrock principle of constitutional law that the federal Constitution established the floor for the protection of individual liberties…If Arizonans pass Proposition 101, residents of other states will have a template for resistance to contemporary liberalism's next lunge toward its unvarying goal — enlargement of government supervision of our lives.”…

Full column also here.

Hat tip to Dr. Wes.

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Are P4P measures discriminatory?

Government-funded healthcare through the Centers for Medicare and Medicaid Services has a pay-for-performance system that links reimbursements to hospitals according to their adherence to certain process performance measures. Hospitals are also graded based on these P4P measures and the CMS makes their grades public record, to increase the incentives of hospitals to abide by them. A new study evaluating a P4P program for the management of heart attack patients has been reported in this week’s news as finding that hospitals caring for vulnerable populations — the elderly, women, the poor, uninsured and minorities — are most penalized by Medicare P4P measures and receive less funding than those caring for young, wealthier, insured and white Americans.

That’s not quite what the study found. The story is more complex than that and doesn't just affect hospitals, but each of us.

Pay-for-Performance measures have been covered here in depth. They are basically procedure metrics — prescriptions written, preventive screening tests ordered, labwork monitored, and procedures done on all patients according to their diagnoses or characteristics — issued by third-party payers (insurers and CMS) that are used to grade, and financially reward and penalize healthcare providers and hospitals based on their adherence. Third-party payers call them measures of “quality” of care, leading most people to mistakenly believe that these measures have been shown to improve patient outcomes, reduce mortality, or to be cost effective. P4P are controversial, with a variety of concerns raised about them by medical professionals, including the fact they are not always supported by the best clinical evidence, are influenced by troubling conflicts of interest, may not reflect the preferences of patients or be medically best for all patients and allow doctors to apply their clinical judgement, raise prescription and healthcare costs, expose some patients to unnecessary risks, and could have unintended consequences of disincentivizing the care of the sickest and most difficult to treat patients. The CMS, alone, currently has 134 performance measures for doctors’ practices, as Dr. Wes last counted a week ago.

This new report** was published in the current issue of the Journal of the American Medical Association and was conducted by researchers with the American Heart Association’s Get With the Guidelines program, funded in part by Merck-Schering Plough pharmaceuticals. This program uses a Web-based patient management tool to collect clinical data, guide providers’ decisions (like the “ding dings” Dr. Wes described), and provide real-time electronic medical record reporting. The authors analyzed data from 574 hospitals that participated in the AHA’s Get With the Guidelines program from January 2, 2000 to March 28, 2008.

They compared the hospitals’ performance on eight P4P measures included in the CMS score for 148,472 patients with confirmed diagnoses of an acute heart attack. The P4P measures included were all interventions administered in the hospital after an acute heart attack and included: aspirin at admission and on discharge, beta-blockers at admission and on discharge, angiotensinconverting enzyme inhibitors for left ventricular systolic dysfunction, smoking cessation counseling, thrombolytics within 30 minutes of arrival, and primary percutaneous coronary interventions (commonly known as angioplasty) within 90 minutes of arrival.

As the authors explained: “CMS rewards hospitals performing in the top 20% in the pay-for-performance program based on their composite adherence score, such that the top 10% are eligible to receive a 2% bonus payment from CMS and the next 10% are eligible to receive a 1% bonus payment. In contrast, hospitals performing in the bottom 20% are likely to receive reductions in their payments in the future.”

These authors used the same methods as those used by the CMS, for public reporting and for P4P reimbursements, to calculate each hospital’s composite adherence score. They found that compliance with the P4P process measures varied considerably, from 96% for giving aspirin at discharge to 40.4% for giving fibrinolytic therapy within 30 minutes of admission. They ranked hospitals according to their performance on each of these eight hospital P4P measures in the AHA program.

As quoted in news reports, Dr. Eric Peterson, M.D., M.P.H., of Duke Clinical Research Institute in Durham, NC, and coauthors concluded that “hospitals serving large groups of the elderly, women, poor, uninsured, or African-American patients might have problems competing with institutions whose patients are younger, wealthy, insured, and white.” According to the news and the AHA press release, hospitals’ ability to qualify for financial incentives is affected by the patients’ age, race/ethnicity, income, insurance status and gender. “Under the current model, hospitals may be doing everything right and still be penalized,” the lead author stated.

But, these are hospital-based P4P measures, meaning every patient with the same diagnosis is supposed to get the same ‘evidence-based’ care. The patients’ income, ethnicity, insurance status, etc. should have nothing to do with whether the hospitals comply with the P4P measures. Dr. Peterson is quoted in the press release as saying that their study revealed the need to level the playing field so that hospitals serving more minority, elderly, sick or uninsured can compete fairly with others. While no one would argue that providers who care for sicker, minority patients should not be penalized, is that what’s really going on? Or is the failure of smaller hospitals with fewer resources to comply with P4P measures more about a problem with the P4P programs and these hospitals seeing less justification for the expense and regulatory paperwork and little difference in patient outcomes? Did this study really support pointing the blame on patients?

While the news leads most readers to attribute the greatest differences in adherence of these P4P programs to the patients, caution is warranted in interpreting those correlations. In the JAMA report itself, the authors said that smaller, nonacademic hospitals — more often inner city hospitals in the Northeast and the South serving more minority populations — are generally under-resourced (including staffing shortages, lack electronic medical records/IT support, are shorter on capital and operate on smaller budgets. These hospitals, they reported, are less likely to comply with the CMS and Get With the Guideline program measures. These are the hospitals that also depend more on Medicare’s payments and other government subsidies to enable them to devote more resources to performance (i.e. P4P) improvements, noted the authors.

The most significant differences between the highest and lowest complying hospitals were characteristics seen in the hospitals: size (407 versus 161 beds), being a teaching hospital (42.6% versus 37.3%), and geographic location (32.8% versus 11.4% in the Midwest, for example, and 22.9% versus 35.9% in the South). Whites were 17% more prevalent among the higher ranking hospitals compared with the lowest (81.7% versus 64.4%, respectively), a correlation most explained by the hospitals’ locations.

The hospitals also differed in the services and procedures provided. Most notably, fewer of the smaller, nonacademic hospitals offered angioplasty, which means they automatically missed credit for that P4P measure.

In contrast with news stories, the study’s data reported no statistical differences in the ages or BMIs of the patient populations in the highest and lowest ranking hospitals, and only a 1.3% difference in gender. Uninsured patients were more prevalent among the larger top-ranking hospitals, compared with the smaller hospitals (7.8% versus 5.3%). And no patient household income, education or poverty data was even reported.

While the authors reported that hospitals with poor adherence to P4P measures were more likely to have patients with a history of comorbidities such as diabetes, heart failure, chronic atrial fibrillation, renal insufficiency, and lower left ventricular ejection fraction; the patients were less likely to have a history of chronic obstructive pulmonary disease, hypertension, previous heart attack, renal dialysis or strokes. The comorbidities were different, but not greater in number among the high and low ranking hospitals. Only 6 of the 14 comorbidities and health risk factors in patient’s medical histories were higher among the lowest complying hospitals.

According to the JAMA article, the authors then adjusted the P4P reimbursement calculations “for patient case mix and treatment opportunity.” That means they recalculated reimbursements primarily according to the patient’s comorbid conditions that might have medically influenced the appropriateness of adhering to their P4P guidelines, and according to the angioplasties, which influenced the ability of a hospital to adhere to their guidelines. This is about the efficacy of the P4P reimbursements.

It had much less to do with adjusting for discriminatory patient characteristics such as income, insurance, gender, and BMI, which were not reported as being significantly associated with poor hospital adherence. And there is no medical basis for P4P compliance to vary based on a patient’s skin color.

The authors reported that changing the P4P adherence calculations used for determining reimbursements changed the rank of 16.5% of the hospitals — half moving up and half moving down. No detailed information was provided on the hospital characteristics with these new calculations and how this might have leveled the playing field, but their Table 3 suggests that the hospitals were slightly less segregated by size, which would bolster the financial incentives for smaller hospitals to adopt the P4P measures. “Thus, our data suggest that the current method of ranking hospitals based on an unadjusted performance measures composite score, as done for the pay-for performance system, may be less than optimal,” they concluded.

The press release and news stories had other information that likely confused readers:

Study authors noted the need for all hospitals to show quality performance among high risk patient groups. They also suggest the need for hospitals to collect and report comprehensive clinical data that will allow them to identify and close treatment gaps that arise based on their patient mix. "This study further illustrates the important role that the American Heart Association's Get With The Guidelines program is playing in advancing the science of measuring and improving the quality of cardiovascular care" said Gregg C. Fonarow, M.D., FACC, FAHA, chairman of the American Heart Association's Get With the Guidelines Steering Committee.

While P4P programs are perfecting the electronic gathering and surveillance of data on patients and provider practices, and the management of healthcare processes, few medical professionals or consumers would equate those with quality of care. What matters to people isn’t how many “ding dings” are checked off a list, how many prescriptions are written, and how many procedures are done according to a third-party guideline, but if the care doctors provide patients actually improves clinical outcomes, reduces suffering and disease, and saves lives.

Get With the Guidelines has not published a single study demonstrating that compliance with the program reduces mortality or improves clinical outcomes for cardiac patients. Going back years, every study cited on the website examines process metrics and adherence to the guidelines. The latest study described in an AHA press release in support of the program, for instance, was published last month in Archives of Internal Medicine. It examined adherence to performance measures among the 223 hospitals participating in the AHA program compared to other hospitals in the Hospital Compare database. No paper has been posted, however, to reveal how much ROMI revenue these P4P programs bring to pharmaceutical companies or the health IT industry.

In this new JAMA paper, the authors also cautioned that a limitation of their analysis was that while the AHA electronic medical management program “contained editing capabilities to ensure data entered were consistent with plausible ranges, Get With the Guidelines has not, to date, performed a national audit of its database” to verify the accuracy or reliability of the data.

Quality of care measures are not the same as measures that improve clinical outcomes. As recently examined here in detail, the two recent large studies of P4P measures for heart patients found these expensive programs have not been shown to reduce mortality or improve outcomes for the patients.

In the first, researchers performed a 3-year analysis of the CMS Hospital Quality Incentive Demonstration project — billed as the largest federally-sponsored P4P program to date in the United States, costing $17.5 million tax dollars for the first two years. They found no improvement in health outcomes or mortality rates among the heart attack patients. The second study examined the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) project, the largest national hospital-based P4P program for patients hospitalized with heart failure in the United States. There was no statistical significant change in post-discharge mortality, rehospitalizations or in-hospital mortality.

As the chairman of cardiovascular medicine at the Cleveland Clinic, Dr. Steven E. Nissen, told the Wall Street Journal, on June 6th, these results “suggest we ought to slow down a minute before going into pay-for-performance.” Throwing more money at them or redistributing the reimbursements won’t change the fundamental issues.

© 2008 Sandy Szwarc

** Financial Disclosures:

Dr Hernandez reports receiving research support from GlaxoSmithKline, Johnson & Johnson (Scios Inc), Medtronic, Novartis, and Roche Diagnostics; and honoraria from Astra-Zeneca, Novartis, Sanofi-Aventis, and Thoratec Corporation.

Dr Peterson reports receiving research support from Schering Plough, BMS/Sanofi; and serving as the principal investigator for the American Heart Association’s (AHA’s) Get With the Guidelines Analytical Center.

Drs Hernandez and Peterson report detailed listings of financial disclosures at http://www.dcri.duke.edu/research/coi.jsp.

Dr Rumsfeld reports receiving an honorariun for participating on the scientific research advisory board of United Healthcare.

Dr Fonarow reports receiving research grants from GlaxoSmithKline, Medtronic, Merck, Pfizer, and the National Institutes of Health; consulting for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Sanofi-Aventis, and Schering Plough; receiving honoraria from AstraZeneca, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Sanofi-Aventis, and Schering Plough; and serving as chair of the AHA’s Get With the Guidelines Steering Committee.

Drs Mehta and Liang and Ms Karve report no disclosures.

Role of the Sponsor:

Merck and Schering Plough had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The AHA provides Get With the Guidelines program management with a volunteer steering committee and AHA staff. The manuscript was submitted to the AHA for review and approval prior to submission.

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Ovarian cancer screening — a developing story that can help us, too

Today, one of the nation’s largest commercial clinical laboratories took a new ovarian cancer screening blood test off the market after the U.S. Food and Drug Administration had issued the company a warning letter on September 29^th. The company revealed its decision Friday in a filing with the Securities and Exchange Commission. Some news stories are suggesting that this has raised questions about whether the FDA should be regulating medical diagnostic tests and that it’s just an attempt to squelch innovation and universities from profiting from their research — after all, everyone knows screening tests save lives.

That’s not even close to the real story.

This is a story of the FDA actually working to safeguard the public; of the peer review process actually working swiftly; of some medical professionals commendably speaking out for sound science; and how the enormous potential commercial value in the development of the first effective screening test for ovarian cancer can blemish the integrity of science.

This entire saga has many valuable take-home lessons, so let’s poke around…

Background

With no screening test yet available that can accurately detect ovarian cancer early, the race as been on for years to develop one. Several universities have been rivals in trying to be the first to develop, patent and license an ovarian cancer screening test. Companies are standing in line wanting to negotiate deals to commercialize the tests in development, said Anna Lokshin, assistant professor of medicine and pathology and a researcher at the University of Pittsburgh Medical Center, at the 2006 annual meeting of the American Association for Cancer Research. UPMC is developing its own test, which it was reporting at this meeting had achieved a specificity of 98% and a sensitivity of 93%.

Yale University had been developing one based on four protein biomarkers, and had already exclusively licensed its ovarian cancer screening test to Laboratory Corporation of America in the United States in February of 2005. On June 12, 2006, Yale University announced it had granted an exclusive license to SurExam Life Science & Technology Company for the commercialization of its ovarian cancer screening test in China. Teva Pharmaceuticals in Israel has been granted the license for the test there.

Yale’s preliminary report on its screening assay had been published in the Proceedings of the National Academy of Sciences on May 24, 2005, which described a study on 58 cancer patients and 28 healthy controls. As the Yale researchers reported, their screening assay had only achieved 95% specificity. In that paper, they noted that not only was the specificity too poor to be adopted as a screening test, another problem was that the bio markers were not specific to ovarian cancer, but also found in other cancers such as breast and uterine, which needs to be “investigated rigorously.” It means that a positive result may call for a larger range of follow-up tests/imaging, biopsies and surgeries to confirm or rule out each potential cancer diagnosis.

These degrees of accuracy might sound impressive, but not to scientists and medical professionals. Even according to the Yale authors in their introduction, because ovarian cancer occurs at such low rates among the general population (0.04% of postmenopausal women), in order for the potential benefit of early detection in a screening test to outweigh the risks from complications of additional follow-up tests and surgeries among those with false-positive results, an ovarian screening test must achieve a minimum of 99.6% specificity. Unlike a positive mammogram which can be confirmed with a biopsy or further imaging, for instance, a positive screening test for ovarian cancer can only be confirmed with surgery. Even low levels of false positives will result in large numbers of women being incorrectly told they have ovarian cancer.

Dr. Noah Kauff, director of Ovarian Cancer Screening and Prevention at Memorial Sloan-Kettering Cancer Center, explained this in more detail several years ago to the Genome Web publication, Proteo Monitor. The incidence of ovarian cancer in post-menopausal women is only about one per 2,500 women per year. So, even if an ovarian cancer screening test had 100% sensitivity, if it had 98% specificity that would mean that if 2,500 women had the test, one woman would correctly have her ovarian cancer detected, but 49 women would have false positives and undergo unnecessary surgery, with risk of associated complications. The goal up to this point, he said, is to develop a screening test for ovarian cancer that leads to one cancer found in every ten surgeries done as the result of an abnormal screen, which would require a test to have a 99.6% specificity to achieve this.

*** Please see the sidebar:“Understanding screening tests: sensitivity versus specificity, false positives and false negatives, and probabilities of having a disease.” Then come back….

Fast forward to 2008

Most Americans probably first learned of the ovarian cancer screening test, OvaSure™, this past February when Yale University issued a press release announcing that it had developed a new blood test for early stage ovarian cancer, using six biomarkers, that was 99% accurate. At that time, the news media across North America reported the story pretty much verbatim from the press release:

“The ability to recognize almost 100 percent of new tumours will have a major impact on the high death rates of this cancer,” lead author Gil Mor, associate professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at Yale, was quoted as saying. “We hope this test will become the standard of care for women having routine examinations.”

In a Phase 2 clinical trial, researchers tested the blood serum of 350 patients without ovarian cancer and 150 ovarian cancer patients. The number of proteins in each participant's blood were counted. Once the results were tabulated, the Early Detection Research Network of the National Cancer Institute independently evaluated the findings… A Phase 3 trial is now underway, with 2,000 patients enrolled.

It appeared no medical writers had gone to the study they were reporting on or fully understood it. The news had, however, provided one clear piece of information that would have alerted informed consumers that the headlines and news stories were going beyond the science. Did you catch it?

It was a phase II trial. As reviewed here, all studies are not created equal. When new medical treatments, drugs, preventatives, diagnostics and screenings are being developed, they are clinically tested in phases, with each phase study investigating different things.

A Phase I clinical trial is the very first introduction of an investigational new drug or treatment in humans. These studies are done on a small group of people (20-80) to determine a drug’s metabolic and pharmacologic actions in people, the active dose, initial risks and side effects, and gather enough evidence to justify the design of a scientifically valid phase II trial.

A Phase II trial is the initial study to gain preliminary data on the possible effectiveness of a drug or treatment for a particular indication or to see if it acts on a specific disease or condition. It also looks for common short-term side effects to help evaluate a drug’s initial degree of safety. It is conducted on a slightly larger group of people (50-300).

A Phase III trial is done after a phase II suggests some effectiveness for a particular condition. A phase III trial is conducted on a larger group of people (1,000-3,000) more representative of end users, to evaluate if a drug is effective and works better than current standard treatment over a period of time, and also that it has an overall favorable benefit-risk ratio. These findings are submitted to the FDA to get approval for marketing and labeling requirements.

A Phase IV trial is a study occasionally done after a drug has been on the market to learn more about its longer-term risks, benefits, and optimal use.

So, when you hear glowing reports about a phase II trial, remember that it’s still years away from proving to be safe and effective for its intended application, and most importantly, to have shown that potential benefits appear to outweigh the risks for most people. [The National Institutes of Health also goes into detail about clinical trials at clinicaltrials.gov and the FDA/Center for Drug Evaluation and Research describes the drug development, review and approval processes in their CDER Handbook. Investigational/experimental interventions for life-and-death situations are a separate topic.]

The study* of the new ovarian screening test, published in the February 15, 2008 issue of the journal Clinical Cancer Research, had tested a larger group of biomarkers (leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125) that are associated with ovarian cancer. The authors collected the blood samples that had been drawn on 156 women newly clinically diagnosed with various stages of ovarian cancer (stage I to IV/X) at their gynecology oncology clinic between August 2002 and November 2006.

To explain it simply, they found that these six biomarkers were associated with 91.6% of the 36 cases of stage I and II cancers in their cohort, whereas 119 of the 120 stage II and IV samples had the biomarkers, a 100% level of accuracy. In other words, the test misclassified 11% of the early stage I and II samples. Of the 17 women who had come into their oncology clinic who had surgically been found to have had benign masses, their test misclassified 11% of those as having cancer and correctly identified the remaining 88% as normal.

They then compared these results among cancer patients to blood samples drawn on 118 matched healthy women who had come into their clinic for regular check-ups, and who were cancer free for 6 months after the blood samples were collected. They found the biomarker panels were significantly higher among the cancer patients compared to the healthy controls.

The authors conducted various statistical modelings using logistic regression on each of the markers singly and together, and calculated the sensitivity, specificity and total positive predictive value of their test. They concluded:

"Therefore, the statistical results for the final model are sensitivity 95.3% and specificity 99.4%. The PPV = TP/(TP+FP) for the test sample is 99.3% and the negative predictive value = TN/[FN+TN] is 99.2%. The final model provides more optimistic results compared with the test group, because it includes the training set; however, there are not major differences in terms of specificity and sensitivity for either model. Nevertheless, this final model will be validated in a multicenter validation study.

This study was clearly a Phase II trial and the screening test had not gone to Phase III trial stage yet to actually begin to be evaluated as it would be used among the public. Disconcertingly, too, neither this Phase II clinical trial or any upcoming Phase III trial has been registered at ClinicalTrials.gov.

Never the less, on June 23^rd, LabCorp had announced the availability of OvaSure on the market to screen for early state ovarian cancer in high-risk women, at $220 to $240 each. Its press release and notice to shareholders cited the February study as having shown the test able to discriminate between disease-free women and ovarian cancer patients with high specificity and sensitivity.

Did you catch some of the problems in this study design as to why it cannot credibly be used to claim to be able to screen for ovarian cancer and ready for marketing as a screening test?

A test that finds certain markers to be more associated with cancer patients (people already known to have cancer) than in another group of known healthy women, does not translate to those markers being able to accurately predict the cancer among a group of seemingly healthy women being screened. Do you see the jump in logic? The study was carried out on two different and very selective populations, and was unable to show that it could accurately identify early cancer among a screening population. Nor has it shown that the screening test actually improves outcomes. These are just some of the flaws in the misuse of a preliminary Phase II trial that caught the attention of the FDA and other medical professionals.

No one doesn’t want a sound diagnostic test that can truly help women, and everyone supports researchers rigorously going forward with research to discover one. The problem comes in when commercial interests step ahead of the science. The FDA’s actions were not over some mundane issue with regulatory paperwork and the fact that the company hadn’t gotten FDA approval before commercially marketing the lab test. As Dr. Steven I. Gutman, M.D., MBA, FDA director of the Office of In Vitro Diagnostic Device Evaluation and Safety, and the Center for Devices and Radiological Health, wrote in a letter to the president of LabCorp on August 7^th:

It appears that you are marketing the OvaSure™ Test with performance characteristics (specifically, 95.3% sensitivity and 99.4% specificity) that are identical to those reported in [the February study in Clinical Cancer Research]. We note that this research was carried out, and performance derived, on two populations that are strongly clinically biased for being healthy and normal, and for having already experienced ovarian cancer [selection bias]. Based on the available information, we do not believe the scientific community would consider the reported study sufficient to establish performance characteristics of a test in “high risk women who might have ovarian cancer”, i.e., in a clinical setting, as claimed in your intended use and promotional materials

Based on our review of your promotional materials and the research publication cited above, we believe you are offering a high risk test that has not received adequate clinical validation [completed phase III trials],and may harm the public health. We would like to discuss with you your offer of this test, and any validation strategies you have undertaken beyond those reported in the publication cited above.

We look forward to discussing this with you, and are committed to working with you as we strive to protect the public health without unnecessarily imposing regulatory burdens on the marketing of products of potential clinical importance.

During the post-publication peer review process, medical professionals described other problems with this study’s interpretations of its data, and with the premature commercial marketing of this screening test. Gynecologic oncologists with the Society of Gynecological Oncologists stated that they believed the test needed more rigorous testing. The editors of the journal actually issued a correction, which it posted with the article online, after finding the authors had not correctly calculated the study’s positive predictive value which were used to support its use for screening. It stated:

In the article on diagnostic markers for early detection of ovarian cancer in the February 15, 2008, issue of Clinical Cancer Research, the authors indicated that the novel blood test described has a PPV for the general population above the suggested 0.10 necessary to be used as a screening test. However, data were not provided to support this claim. The PPV of this test for the general population is 6.5%, or 0.065. Therefore, it was incorrect to suggest that this test may be used for screening the general population, and the authors do not support the use of this test for screening the general population.

After the FDA’s alert, the scientific community and media began coming forward with concerns. “You really need evidence that screening actually saves lives, or at least prolongs survival,” Dr. Robert Bast Jr., an ovarian biomarker expert at M.D. Anderson Cancer Center, cautioned on CNN on September 15^th. Dr. Nicole Urban with the Fred Hutchinson Cancer Center in Seattle, WA, said that we don’t know how early various biomarkers give a signal of early ovarian cancer developing. The research is just beginning. Tracking seemingly healthy women well before their cancer is diagnosed is the only way to prove a test finds cancer early, said Dr. Michael Birrer of the National Cancer Institute. Yale University has not issued a statement.

The St. Louis Beacon published a good article for the public last month, describing the concerns of medical doctors and the cautions surrounding the potential harms of unsound ovarian cancer screening. It was written by a former editor of the St. Louis Post-Dispatch who had been diagnosed with ovarian cancer two years ago.

The continued marketing of the screening test to the public and through technical bulletins to doctors finally led the FDA to issue its Warning Letter on September 29^th stating that marketing of the test is in violation of the law. According to the FDA warning, the company does not have premarket approval or an approved application for an investigational device exemption, nor did it notify the FDA of its intent to introduce the test into commercial distribution as required before marketing it. For all of the grief the FDA seems to get lately, it’s valuable to hear another side of the story once in awhile and, more importantly, to understand the scientific process in action when it works.

And hopefully, readers have garnered a few valuable take-home points for those other times when the scientific process doesn’t work so well.

© 2008 Sandy Szwarc

* Study disclosure statement:

Grant support: Nicholas Brady, EDRN/NIH, and Laboratory Corporation of America. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact.

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