DC Medical Malpractice & Patient Safety Blog

A recent study published in Health Affairs either proves the superiority of U.S. medical care for cancer, or illustrates again how ignorance of basic statistical principles can lead to wrong conclusions.

The study found that U.S. cancer patients who were diagnosed between 1995 and 1999 lived, on average, 11.1 years after their diagnosis. Similar patients from 10 European countries lived an average 9.3 years. By 1999 (the last year the researchers analyzed), the average U.S. expenditure per cancer case was $70,000. That was nearly 50 percent higher than the cost in 1983. The cost in Europe was $44,000—16 percent higher for the same interval. Using standard figures for each extra year of life, the researchers concluded that the value of the U.S. survival gains outweighed the cost by an average $61,000 per case. They pronounced the additional spending on cancer care in the United States "worth it."

But a Reuters story analyzing the research begged to differ. "This study is pure folly," Dr. Don Berry, a biostatistician at MD Anderson Cancer Center in Houston, told Reuters. "It's completely misguided and it's dangerous. Not only are the authors' analyses flawed but their conclusions are also wrong."

Reuters also found the credentials of the study’s lead author, Tomas Philipson of the University of Chicago, wanting. He’s a health economist who served in the administration of President George W. Bush and advised the McCain presidential campaign on health-care issues. The point? The research might not be as unbiased as science demands.

Thirteen common cancers were examined in the study. Researchers analyzed survival—how long a patient lived after being diagnosed—in the period from 1983-1999. They looked at survival gains, or how long patients diagnosed in later years lived compared with those diagnosed earlier in the period. Those gains, they said, demonstrate the progress countries made in treating cancer.

Sounds reasonable. But survival data are tricky; they’re not cold, irrefutable numbers that can quantify success, thanks to something called lead-time bias.

Take two hypothetical people who both get the same kind of cancer on the same day. One of them gets an immediate diagnosis and lives another two years. The other is diagnosed eighteen months after the first, and lives only six months. Patient No. 1 had a "better" survival rate -- two years compared to the six months of Patient No. 2, but she didn't live any longer. She just knew she was sick earlier. Both patients lived two years. That's "lead-time bias" at work.

That’s why, as the Reuters analysis says, “Crediting medical care with ‘improving survival’ is therefore misleading, cancer experts have long argued. Lead-time bias makes it seem patients live longer, but the only thing that is longer is the number of years they know they have cancer…”

But Philipson’s team based its conclusions on survival data, arguing that because U.S. cancer mortality rates declined faster than those of Europe, they’re evidence of survival gains.

Berry articulated a related point with which readers of this blog will be familiar: that overdiagnosis is a problem. Cancer screening, particularly for breast and prostate cancers, is more common in the U.S. than in Europe, and the more testing, the more cancer will be found. But as Berry noted for Reuters, "These are cancers that tend to be slowly growing and many would never kill anyone."

Link here and here to read our posts about the misguided use of screenings for breast and prostate cancers, respectively.

If, in a diagnostic procedure, you find what you’re looking for, does that denote a successful test? Not if it makes a healthy person a cancer patient if the tumor otherwise is not life-threatening. Including such cases, whose numbers are higher in the U.S. than in Europe, makes survival data bogus.

The Health Affairs study showed survival gains in the U.S. versus Europe were greatest for prostate cancer; breast cancer claimed the second-best U.S. survival data--the two cancers where lead-time bias figures most prominently in overdiagnosis.

It’s interesting that Europe had the survival edge in data for melanoma and colorectal and uterine cancer survival gains.

According to Reuters, U.S. cancer mortality places the U.S. in the middle of countries reporting to the Organization for Economic Co-operation and Development.

If that’s not enough to prompt questions about the “Spend More! Live Longer!” theory of cancer survival, consider this: Even the study’s researchers concede that it’s impossible to state that improved survival is a direct result of spending money on cancer care. It might result from improved screenings that detect the “pseudo-disease,” or nonaggressive, nonthreatening tumors that artificially enhance survival data.

And Philpson said, “In the last decade, spending in the U.S. has increased more than in Europe. I would be extremely surprised if the survival gains haven't continued. But it is a much more open question whether that additional spending has been accompanied by an increase in longevity."

According to Reuters, in 2004 (the last year for which figures were available), the U.S. spent $72 billion on cancer care. It also noted that Philipson’s research was supported in part by Bristol-Myers Squibb Co. That company makes a melanoma drug, Yervoy, that costs $120,000 for a full course of treatment.

Certainly the cost of cancer drugs have increased. Dendreon Corp. makes Provenge for prostate cancer at $93,000 per treatment. Bristol and Eli Lilly and Co. make Erbitux at $100,000 per year. The researchers said their analysis "does not imply that all treatments are cost-effective."

Remember, Philipson is an economist. His scholarship concerns how much an additional year of life is worth. His researchers assumed the value to be $150,000 to $360,000.

No wonder economics is referred to as “the dismal science.”

Footnote: Here is a good explanation from "the Incidental Economist" blog of the "lead-time bias" problem in medical statistics and why the correct number to focus on is death rates, not survival rates. However, important caveat from the same blog: Survival rates are very important to any individual patient, because they can tell you how long YOU might live with a particular cancer at a particular stage. The importance of death rates is on the macro level: Does early screening bend the death curve down, or not?

A recently introduced bill in the House of Representatives seeks to update legislation for “orphan” diseases and drugs. “Orphan” status denotes disorders that are extremely rare—generally afflicting 6,000 or fewer patients.

Pharmaceutical companies have no financial incentive to develop drugs and treatments for them because there aren’t enough users to pay the costs and sustain the consumer market. In order to encourage the development of drugs and other treatments for orphan diseases, the government provides incentives it doesn’t grant to more common disorders, such as easier and faster FDA approval, and extended periods for developing companies to market the drugs exclusively.

Another advantage lawmakers hope to grant to orphan drug development is the routine use of a “surrogate endpoint.” Before drugs are given FDA approval, generally they must pass rigorous clinical muster; they must be tested in studies that identify the risks and side effects as well as the benefits of the treatment using meaningful numbers of real subjects. A surrogate endpoint substitutes for a real, observable, provable clinical result—the surrogate endpoint doesn’t necessarily have a guaranteed relationship with a clinical result like actual cure or extension of life, but it has a “biomarker,” according to the National Institutes of Health, that researchers can accept as indicative of clinical benefit, harm or the lack thereof.

Surrogate markers are used if the number of subjects that might be suitable for a clinical trial is so small that it wouldn’t result in a statistically significant result. It would be impractical to conduct a clinical trial in such circumstances, but the people who suffer—the people stricken with an orphan disease—still need treatment, so the surrogate endpoint, the more relaxed standard, is critical to their well-being.

The proposed law is called the Unlocking Lifesaving Treatments for Rare-Diseases Act, or ULTRA. Specifically, according to the FDA Law Blog, it would permit the FDA to approve an application for a drug designated both as an orphan drug and as a fast-track product by allowing the surrogate endpoint standard.

Currently, the FDA is able to “fast track” approval for a product that addresses a serious or life-threatening illness, and when it provides a meaningful therapeutic benefit to patients beyond the existing treatments.

If a product meets the criteria, the FDA may grant marketing approval based on a demonstrated effect on a surrogate endpoint reasonably likely to predict clinical benefit. Also, the manufacturer must commit to completing studies after marketing approval that confirm its benefits.

In the latest edition of “will they ever learn,” tobacco industry studies conclude that additives such as menthol do not make cigarettes more toxic.

Except, of course, they do.

As reported on MedPage Today, more objective researchers—who had to sue for access to the industry studies in question—concluded that the smoke of cigarettes with flavor and other additives was significantly more toxic and higher in total particulate matter than cigarettes made of plain tobacco.

Industry players reported their study results as neutral, thanks to changes they made to adjust away significance, the researchers wrote in the December issue of PLoS Medicine. But from a solid-science perspective, the industry’s protocols were wanting, and their results reporting was … selective.

"These findings show that the tobacco industry scientific research on the use of cigarette additives cannot be taken at face value," the PLoS editors concluded.

Such is the long history of big tobacco. Remember how it manipulated the scientific results on secondhand smoke?

Manufacturers tinker with tobacco, adding ingredients to make smoke less irritating to the respiratory system or to make it taste better. Additives can affect bioavailability—the amount of drug that is absorbed from a given dose—and entice people to start smoking. And they can make it more difficult to stop.

In 2009, the FDA prohibited flavor additives except for menthol, despite concluding that “it is ‘biologically plausible’ that adding menthol to cigarettes makes them more addictive and harder to quit and that companies that sell menthol cigarettes target minorities and kids with their advertising.”

Long before 2009, Philip Morris anticipated regulation of tobacco by the FDA, and embarked on research to influence any proposed regulation. The result was four "Project MIX" papers published in 2002. Big surprise: They concluded that there was no evidence of substantial toxicity from different combinations of 333 additives found in commercially available cigarettes.

The PloS researchers took issue not with how the data were collected, but how they were analyzed and interpreted.

The 51 constituents of smoke from the test and control cigarettes were subjectively chosen; missing from the analysis was certain carcinogenic compounds. And although levels of ammonia were assessed, those data weren’t published either.

Originally, the studies were supposed to analyze the additives on a per-cigarette basis. But the published paper fudged the biological importance of this result by “normalizing” the toxin results by total particulate matter (TPM).

Such an adjustment showed that only 5 of 31 toxins increased with the additives; 15 showed decreases. But people smoke whole cigarettes. For a whole cigarette, 31 of 51 chemicals increased with at least one of the additive groups.

Other problems with the industry-manipulated report include the use of only nine rats per group, a short exposure period and equally insufficient follow-up period. That means researchers would be unlikely to observe side effects that take longer to present. And screening tests were used exclusively instead of more sensitive dose-response measures. That means you can’t determine changes in potential harm with additives.

Without the ability to see tobacco industry study protocols and the raw data, as well as what it chooses to publish, the FDA is ill-equipped to make decisions about the complete danger of its products.

Sadly, consumers and patient advocates long ago learned that you can’t underestimate the venality of the tobacco industry.

We’ve come to expect inflated or simplistic “news” offered by careless, undertrained and/or headline-hungry media covering medical and health topics. Now, even the people in charge of publicizing a recent scientific study published in BMJ (formerly called the British Medical Journal) are guilty of pandering at best and dumbing down at worst.

“It’s official – chocolate linked to heart health” read the headline on the journal’s news release announcing publication of the study. As noted by Kevin Lomangino, editor of Clinical Nutrition Insight and a reviewer for HealthNewsReview.org , “Intrigued by the headline …, I searched the release for an indication that some prestigious independent body -- the Institute of Medicine? a World Health Organization expert committee? -- had come together to evaluate the evidence on chocolate's cardiovascular effects. As unlikely as I found that prospect, I recognized that it could justify an ‘official’ declaration of an association between chocolate and heart disease outcomes.

“But no: the ‘official’ designation was apparently bestowed by a headline writer in the BMJ press office.”

It was just another attempt to suck you into a sexy story, not unlike the exuberant teaser by NBC news anchor Brian Williams: “The science that just might justify an American addiction.”

But the network reporting wasn’t done by a science or medicine reporter, and it made the same mistake so many such stories do: It claimed things not proved by the study, whose results invited further research, not categorical conclusions.

Although the BMJ news release did include the caveats to the study, much, if not most, of the popular reporting found them uninteresting. Irrelevant.

Yes, the study did find a correlation between high levels of chocolate intake and lower risk of cardiovascular disease and stroke. But if you value useful information over partial information, you need to know, as the researchers noted:

• the study had many important limitations;


• the available literature on this topic is “limited and novel";


• more studies are required "to confirm or refute the results";


• the results might be explained "by some other unmeasured (confounding) factor" besides chocolate.

As Lomangino reminds us, most of the chocolate we love has a lower concentration of cocoa flavonoids -- the plant molecules responsible for the salutary effects researchers confirmed -- and lots of sugar, fat and calories. The more you eat of the latter, the higher your risk of developing a cardiovascular problem. So we need to study the particular constituents of chocolate that confer health benefits, and how to consume more of them and fewer of their unhealthful partners.

That’s not a wild claim, that’s science.

Common sense says that putting stents into blocked arteries in the brain should help prevent strokes, just like propping open heart arteries cuts heart attacks.

But Medicare asked for a scientific study before it started paying for widespread use of the brain stents. So doctors tested stents versus medical therapy in high-risk patients. After one month, a dramatic answer: in one group, 6 in 100 patients got a stroke, but in the other group, 15 in 100 had strokes.

Problem is that the stent group was the one that had more than double the strokes of the medical treatment group.

The result was so big that doctors pulled the plug on the study, as they could no longer ethically put patients into the stent group.

This is yet another example of how therapies that seem like they should work, based on our knowledge of the body and medicine, turn out not to work. We have a lot left to learn.

In the case of brain arteries, bypass surgery to put in a new artery to go around blockages, also similar to what's done in the heart, also has failed to prove out in scientific studies.

You can read the new stent study in the New England Journal of Medicine.

You have lupus, the chronic inflammatory disease in which the body's immune system attacks its tissues and organs. Sometimes the symptoms resemble the joint stiffness and swelling of arthritis; sometimes they present as skin rashes; sometimes your kidneys malfunction. There are four different kinds of lupus whose treatment might involve a variety of behavioral interventions and so many drug options you need a scorecard to keep track.

Even medical professionals specializing in auto-immune disorders can’t keep up with the research and vast body of knowledge required to be expert in such a complicated disease, not to mention scores of other disorders whose treatment is situational and varied.

In these days of government that can seem to do no right, one federal program is planning to improve access to the body of medical research knowledge. Established by Congress via the 2010 Patient Protection and Affordable Care Act, the Patient-Centered Outcomes Research Institute (PCORI) is tasked with identifying the best available information to help patients and their health-care providers make informed decisions about their care.

PCORI, an independent, nonprofit entity, is all about the science.

As noted by Kaiser Health News in collaboration with Philly.com, "'comparative effectiveness research'" is a relatively new concept in the United States. In fact, the U.S. health system, which largely follows a model that pays doctors and hospitals for any service provided, generally has not embraced comparative effective research.”

If PCORI brings a much-needed objective, science-based standard to the health-care landscape, that doesn’t mean there aren’t challenges to its success. After all, it was created by the political process, and when does that ever yield a purely feel-good result?

KHN/Philly.com enumerates several obstacles for the new agency:

• identifying research priorities for patients based on the study of hundreds of medical conditions and the questions they pose;


• avoiding political criticism from opponents who argue that PCORI will ration care, some even calling it a "death panel";


• maintaining support from medical device makers and drug companies concerned that the institute will be simply a cost-control mechanism; and


• devising strategies for conducting studies to provide meaningful results.

PCORI is reviewing past comparative effectiveness research in the hope of making several grants by the end of this year to identify what it needs to find out from patients. For example, should it use social media to ask people what kind of information they want to have before making decisions?

It also wants to warm up the cold, bureaucratic face public programs often present. “[I]in addition to enhancing the quality of the research,” said KHN/Philly.com, “reaching out to patients can help the institute shed concerns about rationing that were raised by opponents in the health care debate.”

To protect its objectivity, PCORI is forbidden to consider the cost of different treatments as part of setting its research agenda or drawing conclusions. That makes medical device manufacturers and drug companies, who always are concerned about discussions of cost, more comfortable.

PCORI leaders are highly and widely respected, which also helps solidify its neutrality and depth. The nonpartisan Government Accountability Office selected most of its board members; directors of the National Institutes of Health and the Agency for Healthcare Research and Quality chose the others. The board chairman is vice chancellor health sciences at UCLA and dean of its medical school.

“The basic mission is to insure that patients are well-informed and can have informed conversations with doctors,” Dr. Harold C. Sox, former editor of the Annals of Internal Medicine told KNH/Philly.com . “Shared decision-making is not a blue-red issue.”

PCORI wants and needs consumer input throughout its mission. This month, it’s soliciting input from the public about initial topics for pilot projects. To learn more, link here. To stay informed about what PCORI wants to know from consumers, and to contribute to the conversation, link here.

The road from conception to useful application for a new drug therapy, when properly navigated, is fully mapped, carefully followed, scientfically rigorous and honestly appraised. Not so with a big study of the lucrative drug Neurontin, according to Yale researchers.

In the case of Neurontin, a drug to treat epilepsy, critical parts of that journey took a few unauthorized detours, according to a report in the Archives of Internal Medicine.

Researchers at the Yale School of Medicine reviewed documents relating to the epilepsy drug gabapentin, a drug patented as Neurontin by Pfizer in 1994, that they concluded were misrepresented by the pharmaceutical company as a clinical trial.

Instead, they said, it was a “seeding trial,” which they described as “An important and expensive form of marketing, … a study of an approved drug or device in which the primary objective may not be to answer an important scientific question but rather to introduce a new product and induce clinicians to use it.”

In other words, seeding trials juice the market by enticing practitioners to sample and prescribe a drug that’s already FDA-approved.

Joseph Ross, M.D., said that Study of Neurotonin: Tritrate to Effect, Profile of Safety (STEPS) “was a seeding trial posing as a legitimate scientific study. The trial itself, not trial results, was part of a marketing strategy used to promote gabapentin and increase prescribing among investigators without informing trial patients or investigators."

As noted in the Los Angeles Times, the STEPS study also was intended to fend off efforts by a competitor to introduce a rival drug.

The breach wasn’t against the law, but it wasn’t ethical because the purpose was primarily to promote, not to discover, and because trial participants and physicians might be unaware of the studies’ true purpose.

The Yale team said STEPS’ stated purpose was to examine doses of gabapentin within a patient population of 2,759. Two articles about its results were published in scientific journals, but, the team noted, outside sources had questioned the study’s design as uncontrolled (that is, it didn’t include a separate, or "control," group of participants who didn’t receive the drug). In addition, it was not a blind study. Scientific rigor demands that study participants remain unaware—blind—about whether they are receiving a drug or a placebo (fake drug).

There's more. The Yale team said, "Data quality during the study was often compromised," and some documents appeared to suggest that marketing personnel helped to collect data and witnessed the trial, not just the results.

Article first published as Neurontin Research Was So Flawed It Deserved to Be Called Marketing, Not Science on Technorati.

Only someone who suffers from asthma can understand the panic that comes with a sudden attack that feels as though you’re suffocating. Many such victims reach for an inhaler to dispense the drug albuterol, which provides lung relief.

Now, a new study published in the New England Journal of Medicine confirms not only the drug’s benefit, but a whole lot more -- about how caring can enhance treatment.

It found that asthma patients given a placebo (inert drug, aka fake treatment) or no treatment felt better despite measurable differences in lung function improvement as compared with those receiving drug treatment.

One of the study’s authors, Ted J. Kaptchuk, associate professor of medicine at Harvard Medical School, described for WebMD the elegance of the research: "Disease is what doctors search for--the underlying physical thing they can detect with labs and imaging and can express in hard numbers," he said. "Illness is what a patient experiences. ...There is a difference between what doctors find and what patients experience."

What the asthma study demonstrates is that making patients better requires treating illness as well as treating disease. Thirty-nine asthma patients stopped taking the drugs prescribed for their condition. Then they randomly underwent four different regimens during which lung function was tested regularly. They were:

• treatment with an albuterol inhaler;


• treatment with an inhaler with no active drug (a placebo);


• treatment with bogus acupuncture (the device appeared to puncture the skin like acupuncture needles, but didn’t); and


• no treatment.

As expected, the albuterol treatment registered improved lung function by 20%. And not unexpected was that the placebo treatments improved lung function somewhat--7%. It was interesting that patients who got no treatment also improved by 7%.

But truly surprising was how patients reported their condition. Asked how much better they felt, they said 50% better with the albuterol; 46% better after fake acupuncture and 45% better after using the inert inhaler. The latter two positive reports could be attributed to the “placebo effect,” which is often seen among study subjects who don’t know that they’re not receiving the real McCoy. But even after knowingly receiving no treatment, they said they felt 21% better.

As lead study author Michael E. Wechsler, M.D. told WebMD, "with this study we saw that part of taking care of the discomfort … is being there. …There is definitely some mind-body interaction in asthma that relates to the shortness of breath that patients feel."

People who study the placebo effect draw a distinction between objective medical outcomes (in this study, lung function) and the subjective medical outcomes of patient-based feelings (in this study, less shortness of breath).

They hope to raise consciousness that, sometimes, medical research dismisses subjective results to overwhelmingly favor objective results. But the artful practice of medicine addresses the reason for the suffering as well as the suffering itself.

That said, it would be foolish to ignore the whole picture painted by the asthma study. Treatment with a proven drug clearly resulted in superior lung function. And without the availability of that treatment, people will experience preventable asthma attacks. The goal is for patients to receive medical treatment and medical care.

Generally, a gut-check is an informal, instinctive assessment. But researchers at the University of San Diego Health System took matters literally in studying the impact of gender in major gastrointestinal surgery. They found that women are more likely than men to survive the procedure.

Published in the Journal of Surgical Research, “The Battle of the Sexes: Women Win Out in Gastrointestinal Surgery” examines the major differences that affect treatment success, and aims to create new therapies that improve survivability of surgical patients.

“[M]edical outcomes could be optimized by tailoring therapies based upon each individual’s unique genetic make-up as well as other characteristics. Gender is among the most important traits,” said Carrie Y. Peterson, M.D., lead author of the study. Among the procedures that fell under her scientific knife: stomach, intestinal, liver and pancreatic surgeries.

“The results suggest that female hormones might enhance the immune system -- a process previously shown in animal models and also observed in trauma patients,” said Peterson. “Thus, there is a hope that negating the effects of testosterone or giving estrogen to male patients could be considered part of a treatment plan.”

Other factors that might contribute to higher survivability rates:

• females have more elective operations;


• females have surgery more often in teaching hospitals; and


• when symptoms occur, females seek medical attention sooner than men.

A drug prescribed for smoking cessation is linked to an increased risk of heart problems, according to a study published July 4 in CMAJ (Canadian Medical Association Journal). Varenicline, known by the brand name Chantix, was associated with a 72% increased risk of a serious cardiovascular "event."

That sounds huge, but the scientific number-crunching shakes out a bit differently. Although attention must be paid, many critical minds are not ready to dump the drug. Fifty-two (1.06%) of the participants who took Chantix had serious cardiovascular events compared with 27 (0.82%) of those who took a placebo.

One bottom line for smokers who may want to rationalize continuing to puff: It's always better to stop smoking. No excuses.

When varenicline was launched in 2006, the FDA noted that it could raise the risk of cardiac problems, and the federal agency recently updated the label for Chantix to reflect that risk among smokers with heart disease. And we wrote about the drug a couple of years ago. But the new study's authors said, "These increased risks ... are seen in smokers with or without heart disease."

The irony, of course, is that one major risk of smoking is heart disease.

The Chantix-using subjects of this trial were able to abstain from smoking at a significantly higher rate, an achievement that should potentially confer a cardiovascular benefit. Many members of the medical community believe the drug should remained a valuable treatment option, given the devastating effects of smoking. Apart from heart issues, nicotine and the other ingredients of cigarette smoke, of course, compromise lung function and can lead to lung cancer, and also increase the risk of stroke and diabetes.

The results were based on a review of 14 studies of approximately 8,200 smokers or users of smokeless tobacco. Most had no history of heart disease. They were followed for as long as a year, a comparatively short term that gives many researchers pause. It's possible, for example, that the risk diminishes over time.

Dr. Taylor Hays from the Mayo Clinic opined, "Although these results suggest a measure of caution should be taken in prescribing varenicline for tobacco dependence treatment ... [T]he risk for cardiovascular events is low and is far outweighed by the benefits of diminishing the truly 'heartbreaking' effects of cigarette smoking."

If you're taking Chantix, don't stop without consulting your doctor. If you're unable to stop smoking via other methods, discuss the cost-benefit question of treatment with Chantix.

Nobody wants to get lung cancer. Nobody who has it looks forward to the radical treatment such a diagnosis usually demands. But a recent research study lifted a bit of the dark cloud hovering over these patients. It found a significant decrease--20%--in deaths among lung cancer patients screened annually for three years with a certain type of CT scan compared with conventional chest X-rays.

This being lung cancer, and this being an evolving technology, caveats are in order: More than 90% of positive screening tests using both techniques were false positives, and the study did not assess the costs of false positive tests.

The high rate of false-positive results carries the potential for overdiagnosis and overtreatment. "Before public policy recommendations are crafted, the cost-effectiveness of low-dose CT screening must be rigorously analyzed," Christine Berg, M.D., of the National Cancer Institute, and co-authors wrote in their discussion of the results in the New England Journal of Medicine. "The reduction in lung-cancer mortality must be weighed against the harms from positive screening results and overdiagnosis, as well as the costs."

Approximately 157,000 Americans die from lung cancer every year; the study suggests that as many as 27,000 of them might be saved by CT screening. And although the key finding was that the technology resulted in fewer deaths, the study is notable as well for demonstrating no significantly harmful side effects. The landmark nature of the science was described by some authorities, including Dr. Otis Brawley, chief medical officer of the American Cancer society, as second in significance only to the surgeon general's 1964 report linking smoking to lung cancer.

Critical scrutiny now shifts from "does it help?" to "who does it help and how much does it cost?" Medicare pays about $300 for a CT scan, but positive results in lung cancer patients prompt additional testing, and where that ends is anybody's guess.

One observer casting a wary eye over not over the science but how it is represented to laypeople is Gary Schwitzer, blogging at MedPage Today. His beef isn't solely with the unknown costs of the increased use of CT scans, but in how the media chooses to present the findings with, in his estimation, little regard for the full story. Exemplary of such shoddy coverage, he says, is a national TV broadcast network for failing to offer any discussion of false positives and cost but sparing nothing in the hyperbole department. The network, he said, called CT scans "simple," a term with which he takes issue. Also, he said, "it cited a cost of a 'mere $99'--not to be matched in many locations across the U.S. and failing to take into account the follow-up costs of the considerable number of false positives."

Schwitzer claimed that the network "promoted screening advice that simply hasn't been established and didn't cite the source of that advice." He said it "offered to help viewers find hospitals who could scan them--journalism or advertising?"

Raising the flag of skepticism higher in hopes that the technology's end user--you, the patient--salutes, Schwitzer quotes Harry Demonaco, director of the Innovation Support Center at the Massachusetts General Hospital. The study, Demonaco says,"is really a tour de force that was masterfully crafted and operationalized. The authors presented the results in a well-balanced fashion. Unfortunately, the [broadcast news] report did not.

"There are 94 million smokers at risk for lung cancer in the United States today. According to the [study's] authors, only about 7 million of them would meet the eligibility criteria to have been included in the study. This is important because the results may not be generalizable to the remaining 87 million smokers."

Schwitzer concludes, "We know that journalists struggle with screening stories. A simple reminder may help them do a better job: All screening tests do harm; some may also do good. If you don't reflect that in your story, you're probably doing harm as well."

And might we just add: Harm comes in many forms--physical, financial and emotional. As a medical consumer, we hope you try to stay abreast of developments in medicine and technology that affect you and the ones you love. Remember, like everything else, if you read or hear news about something that seems to good to be true, you might not have the full story.

A couple of months ago we gave a shout-out to a physician who had written a commentary about Genentech's efforts to have the FDA bless the use of its drug Avastin for treatment of certain breast cancers. He had objected to the use of patient testimonials as compelling evidence to support such appeals because they're not science, they're marketing.

In what the company and its supporters probably consider honorable tenacity but thinking minds ascribe to naked greed and abuse of taxpayer resources, the FDA again this week is hearing the case for approving Avastin as a conditional treatment for certain breast cancers, never mind that studies have shown it to be neither life-prolonging nor markedly life-enhancing. In the face of life-threatening side effects, Genentech still champions the drug because it has helped some patients. Yes, Virginia, and some people make a living swallowing swords and eating fire, but such activity isn't, as they say in FDA-land, "generally recognized as safe."

Two editorials appearing this week in the New England Journal of Medicine speak in favor of science and respect for human life.

Genentech presented four arguments against the FDA’s proposed withdrawal of Avastin for breast cancer: one, the move has no precedent; two, the possibility of some patients benefiting justifies continued approval; three, individual patient choice should prevail; and four, ruling against Avastin will make future drug development confusing and discourage innovation. And, like the kid who throws the ball over the fence because he doesn't like the ump's call, Genentech also took a shot at the FDA committee considering the matter, calling it biased and requesting different judges.

We won’t dignify Genentech’s hissy fit, but, in order, here's why Genentech's appeal is folly.

One: Precedent for removing a drug’s indication for a specific disease is part and parcel of U.S. drug regulatory process.

Two: Just because some patients might benefit doesn’t mean there is enough benefit to outweigh the harm to many other patients taking this highly toxic drug. Such lazy extrapolation ignores the absence of Avastin data identifying the patient characteristics that are associated with the benefit. That's incomplete science, and it’s dangerous.

Three: Genentech’s position that “conflicting interpretations of data should be resolved in favor of retaining access and choice” is a direct contradiction of the FDA's mandate. As the NEJM commentary stated, "In a democratic republic, access and choice represent two among many values. The FDA must also protect scientific rigor, the integrity and legitimacy of federal regulations and guidance, and the public’s health. The agency’s reputation for using science to guide regulatory decisions in the public interest is its most critical institutional asset."

Four: FDA action to restrict a drug's use from some applications is common and practically perfunctory. Instead of chilling R&D, such a situation might effect more aggressive drug development--if Avastin offers little promise for patients with metastatic breast cancer, won't pharmaceutical companies be inspired to develop a better product? After all, that’s where the money is, and we all know what motivates Big Pharma.

The push to make hospitals and doctors more accountable for health care quality means more attention must be paid to the accuracy and reliability of measures used to evaluate caregivers, according to Johns Hopkins patient safety expert Peter Pronovost.

There is little consensus as to which measures are scientifically valid and accurate assessments of quality, and this risks misinforming patients who may make decisions based on metrics that poorly reflect the state of health care, Pronovost wrote in the April issue of Health Affairs.

Pronovost supports the bipartisan effort to pay for value rather than volume with health care, but says serious work needs to be done to create a “whole library of outcome measures” such efforts require. Failure to create such measures “could ultimately lead to a failure to make improvements in hospitals where quality is judged to be better than it is,” he says.

Pronovost maintains that despite the substantial, persistent shortcomings in the quality of care that causes needless patient harm and increases health care costs, fixes can’t be put in place until rigorous scientific data show exactly where systems are broken, and until hard comparative evidence points to what types of repairs work best.

In the absence of such safety and efficacy science, he says, there will remain little consensus among hospitals and physicians about the best methods to judge quality or improvement. He points to overall hospital death rates as an example of an imperfect reflection of quality of care that in many cases is the only measure used.

Pronovost notes that physicians typically support the use of outcome measures if they are valid and reliable enough to enable conclusions to be drawn about the quality of care. Unfortunately, too often they aren’t.

For example, he says, some states penalize institutions for what they deem are preventable complications contracted by patients during their hospital stays, even though the hospitals don’t know exactly what they are being judged on because those states use a proprietary algorithm (commonly referred to as a "black box") created by a private company to determine which hospitals are “successful” and which ones should be sanctioned. Clinicians and the public end up not knowing how accurate the measures are or how they were calculated.

Source: The Johns Hopkins University Gazette

You can read the abstract of the article in Health Affairs here.

Medical mistakes account for between 18 and 45 cents of every health care dollar spent in the U.S., and a medical error or adverse effect occurs in one out of every three hospital admissions, researchers say.

According to studies published in the journal Health Affairs, the single most expensive cause of harm is infection after surgery, with more than 252,000 infections costing $3.36 billion reported in 2008, while pressure ulcers (bedsores) are the most common preventable event, with with nearly 375,000 cases in 2008 costing $3.27 billion.

Following a shocking 1999 report that showed that as many as 98,000 people die annually due to medical mistakes, hospitals have tried to reduce such adverse effects, but serious mistakes persist. In 2006, for instance, medical mistakes contributed to as many as 187,135 deaths and 6.1 million injuries that cost between $393 billion and $958 billion.

“There are some examples of excellence; we have many [intensive-care units] that have eradicated central line infections. But surrounding those examples of excellence we have serious adverse events going on,” said Dr. Mark Chassin, president of the Joint Commission, a nonprofit organization that accredits health care programs. “Every week in the United States, up to 40 patients undergo a procedure meant for somebody else or the wrong body part,” he said.

The costliest medical errors were:

1. Infections after surgery (252,695 in 2008, cost $3.36 billion)

2. Pressure ulcers - Bedsores (374,964 in 2008, cost $3.27 billion)

3. Complications from noncardiac implants and grafts (60,380, cost $1.07 billion)

4. Complications from lower back surgery (113,823, cost $1 billion)

5. Excessive bleeding complicating a procedure (78,216, cost $680 million)

You’ll find more information about the Health Affairs studies here.

Drug manufacturers claim their products are pricey because of the high cost and high risks involved in getting new drugs to market. But a recent study shows that these high cost estimates have been constructed by industry-supported economists and that R&D costs are not the barrier to drug development the drug companies maintain they are.

The study, by researchers at Stanford and the University of Medicine and Dentistry of New Jersey and published online in Biosocieties journal, also shows that current incentives reward companies for developing new medicines of little advantage that compete for market share at high prices, rather than clinically superior medicines with public funding that would reduce the price of drugs to consumers and actually lower risk to the pharmaceutical companies.

The study takes aim at drug companies’ inflated cost estimates and shows exactly where they are wrong. For example, figures typically bandied about -- $800 million or $1.3 billion to develop a new drug – do not include the 39% contribution made by taxpayers through tax write-offs for R&D. Furthermore, the study shows that the industry-based figures are based on clinical trials (and number of participants) that are much larger than actual trials reported by the FDA and the National Institutes of Health.

Even worse, as much as half of the industry estimates are not real costs, but exaggerated estimates of profits that companies might have made if they put their money in the stock market instead of developing the drug. And even if the notion that foregone profits should be included as a cost – which, according to the study authors, no other industry does – U.S. government guidelines call for using three percent, not the 11 percent used to arrive at the $800 million figure.

In essence, the study argues, pharmaceutical companies “have it both ways,” treating R&D costs as though they were long-term capital investments even though the the taxman treats them like ordinary, fully deductible business expenses.

The study concludes that the real cost per "self-originated" drug product is closer to $180-231 million, noting that “the mythic costs of R&D are but one part of a larger, dysfunctional system that gives us mostly new medicines that have few or no advantages and serious side adverse reactions that have become a leading cause of hospitalization and death.”

Source: Alison Bass blog

You can read the report here.

The vast majority of medical devices recalled by the U.S. Food and Drug Administration (FDA) were subject to a less stringent regulatory process that requires only that the device prove that it's similar to something already on the market, according to a recently published study.

Of the 113 devices recalled from 2005 to 2009 because the FDA determined they could cause serious health problems or death, 80 (71%) were reviewed using the “510(k) process,” which is meant to assess devices deemed to involve low or moderate risk. Only 21 devices (19%) had been approved through the more rigorous premarket approval (PMA) process, which requires clinical testing and inspections. (Eight other devices were exempt from any FDA regulation.)

Cardiovascular devices, chiefly external defibrillators, made up nearly a third of the recalled medical products from 2005 through 2009, the time covered by the review. A 2006 study linked defibrillator failure to more than 300 deaths over a 10-year period.

Originally, the 510(k) process was specifically intended for devices with less need for scientific scrutiny, such as surgical gloves and hearing aids. It did not require clinical trials or manufacturing inspections to demonstrate safety and efficacy. Instead, it only required proof that the device was substantially equivalent in materials, purpose, and mechanism of action to another device that was already on the market, with the previous device serving as the “predicate” device with which the new device would be compared.

This approach was justified as a way to give manufacturers the opportunity to make small improvements on the devices already on the market and to allow companies with new products to compete with very similar devices without using the more extensive PMA process. If the FDA determined that the product was reasonably safe and effective according to the 510(k) review, it was said to be cleared for market rather than approved.

However, in 2002, Congress passed the Medical Device User Fee and Modernization Act, which shifted the regulatory standard to "the least burdensome approach in all areas of medical device regulation." This had the practical effect of making 501(k) the dominant mechanism for new device clearance, with the FDA now reviewing only 1% of medical devices using the more rigorous PMA process.

To decrease the number of high-risk recalls, the study recommends:

1. The FDA fully implements current law that subjects "life-saving and life sustaining" (Class III) devices to the PMA process.
2. The FDA's definition of a high-risk device takes into account the potential risks if the device fails.
3. The FDA expands the use of their authority to inspect the manufacturing of 510(k) devices just as they do for devices approved through the PMA process; and
4. The FDA strengthens their authority to use special controls for 510(k) devices as they do for PMA devices, such as postmarket surveillance, performance standards, and product-specific and general guidance documents.

Source: The Los Angeles Times

You can read the complete study here.

Many women with early breast cancer do not need to have their armpit lymph nodes removed, according to a new study. Currently, this painful procedure has long been routine, as physicians believed it would prolong women’s lives by keeping the cancer from spreading or coming back. However, the study shows that removing the cancerous lymph nodes is unnecessary when women receive chemotherapy and radiation, which wipes out most of the disease in the nodes.

The study indicates that for about 20% of women (40,000 women a year in the U.S.), the removal of the cancerous lymph nodes doesn’t (a) alter the treatment plan for the patient; (b) improve survival rates; or (c) make the cancer less likely to recur. And it has a downside, since it can cause complications like infection and lymphedema, a chronic swelling in the arm.

Experts say that the new findings, combined with similar ones from earlier studies, should change medical practice for many patients. However, they warn that change may come slowly because the notion that the nodes must be removed is very deeply ingrained.

The current approach to surgical treatment of breast cancer is to cut out obvious tumors — because lumps big enough to detect may be too dense for drugs and radiation to destroy — and to use radiation and chemotherapy to wipe out microscopic disease in other places. Until now, physicians believed that even microscopic disease in the lymph nodes should be cut out to improve the odds of survival.

The new results do not apply to all patients, only to women whose disease and treatment meet the criteria in the study, which were:

Early tumors at clinical stage T1 or T2 (i.e. less than two inches across).

Biopsies of one or two armpit nodes found cancer, but the nodes were not enlarged enough to be felt during an exam, and the cancer had not spread anywhere else.

The women had lumpectomies, and most also had radiation to the entire breast, and chemotherapy or hormone-blocking drugs, or both.

The study included 891 patients with their median age in the mid-50s. After an initial "sentinel" node biopsy, the women were assigned at random to have 10 or more additional nodes removed, or to leave the nodes alone. In 27 percent of the women who had additional nodes removed, those nodes were cancerous. But over time, the two groups had no difference in survival: more than 90 percent survived at least five years. Recurrence rates in the armpit were also similar, less than 1 percent.

Dr. Grant W. Carlson, a professor of surgery at the Winship Cancer Institute at Emory University, who authored an editorial that accompanied the study, said that by routinely taking out many nodes, “I have a feeling we’ve been doing a lot of harm.”

Source: The New York Times

You can read an abstract of the study here.

The news this week from the Centers for Disease Control and Prevention that as many as 48 million U.S. adults have high levels of bad cholesterol, and aren’t doing enough to control it, left out one conspicuous controversy: Should lots more Americans be taking statin drugs, or would it be a huge waste of money?

Statins like Crestor and Lipitor lower cholesterol in the blood by decreasing cholesterol synthesis in the liver. Since plaques in coronary arteries are mostly composed of cholesterol, lowering cholesterol cuts the rate of formation of plaque, and in some cases, even shrinks it.

For people with diagnosed heart disease, statins are mainstream, non-controversial medical treatment. But for patients who just have high cholesterol, but no known heart disease yet, the drugs have modest if any benefit. And this is the group that is the main target of drug manufacturers for expanding sales of statins.

A cautionary statement about the questionable role of statin drugs in "primary prevention" of heart disease was recently released by the British-based Cochrane Collaboration, which conducts rigorous reviews of medical studies to see how the evidence measures up.

The authors of the new Cochrane review criticized much of the studies sponsored by drug manufacturers for leaving out key data. They concluded:

Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.

Doctors who are slow to turn healthy people into medical patients are careful about whom they prescribe statins for. For example, Dr. Robert Lemmon, a South Carolina family practice doctor and medical blogger, wrote an analysis of the published studies and concluded that statins were "overrated" and did not much help people who don't have heart disease. Noting that other cautious reviewers had reached the same conclusion, even though it cuts against drug manufacturer hype, he wrote: "This post is blasphemy. Fortunately I am in good company."

The CDC report also talks about improving diet and exercise habits as strategies to cut cholesterol. That can work in individuals very well, but as a public health strategy, education campaigns also fall short in making any notable impact. That's why public health advocates reach for systemic changes that would expose people to less temptation by strategies such as bans on use of certain bad fats in restaurants and fast food manufacturers. A provocative article on this topic was published in PLoS Medicine.

Article first published as Government Reports Millions of Americans Have Untreated High Cholesterol — But What Treatment Works? on Technorati.

Patient safety advocates and brand-name drug makers lined up against companies that make generic drugs over just how flexible the standards should be for the clinical testing of biosimilars.

These drugs, also known as biogenerics, follow-on biologics and subsequent entry biologics, are officially approved subsequent versions of biopharmaceutical products following patent and exclusivity expiration on the original product. Until now, only a handful of biosimilars have been approved in the U.S., but that is about to change.

At the hearing, patient safety advocates argued that the only way to be sure that a drug is safe is through extensive clinical trials, while generic biosimilar manufacturers and distributors maintained that dangerous and expensive clinical tests are not required because they will be based on drugs that are already proven safe.

But are they? Biosimilars exhibit high molecular complexity and may be sensitive to manufacturing process changes. In addition, the biosimilar manufacturer doesn’t have access to any of the information or substances (e.g. molecular clone or cell bank) that the originator used to create the drug. As a result, patient safety advocates worry that biosimilars might perform differently than the branded versions, and could have potentially serious health implications.

Amgen, a brand-name biopharmaceutical manufacturer, called for biosimilars to undergo rigorous testing and recommended that the FDA:

1. Use well-designed clinical trials to establish biosimilarity

2. Ensure the product manufacturer and lot number is known for all administered biologics

3. Set scientific and practical criteria for interchangeability.

Critics of a rigorous clinical testing standard say that in addition to the expense, there are ethical questions involved in repeating potentially dangerous trials in humans. To avoid repeating human trials, U.S. Senator Bernie Sanders has proposed require generics makers to pay a fee for access to clinical data used in the manufacture of the brand name biologic.

Source: Wall Street Journal blogs

You can get more information about the FDA hearing and view video of the proceedings here.

Here's a new research finding that is encouraging but discouraging at the same time for patient safety.

After 16 Michigan hospitals began to share patient safety information, surgical complication rates dropped by nearly 10 percent, according to a recent study.

That's encouraging, of course. The disquieting piece is why it would take a major research study to reach such an intuitively obvious result, and why sharing of data doesn't already happen on a wide and routine scale.

The University of Michigan study followed a program called the Michigan Surgical Quality Collaborative, which involved 300,000 patients who had general or vascular surgery between 2005 and 2007.

The greatest reductions were seen in blood infections, septic shock, prolonged ventilator use and cardiac arrest. Death rates remained the same.

According to the study’s author, Darrell A. Campbell Jr., MD, a professor of surgery and chief medical officer of the University of Michigan Health System, “the collaboration of hospitals in terms of identifying and disseminating information about best practices is actually a much more effective way of improving quality than just relying on each hospital alone to come up with what they think is a way to improve quality. In other words, sharing ideas is important and it's effective." He added that this type of program could help achieve the health care reform goals of improving quality and reducing costs.

“Surgical complications are very expensive,” Campbell says. “Once something bad happens following surgery, it takes a lot of resources for the patient to recover.”

A preventable surgical complication can add weeks to a hospital stay and thousands in added costs. Contracting pneumonia from prolonged ventilator use following a surgical procedure, for example, can add $50,000 to a hospital bill.

Given the high cost of surgical complications, authors estimate that it would take only a 1.8 percent reduction in complications a year for three years to offset the cost of supporting the pay for participation program.

“If this system was adopted nationally, not just in Michigan, I think you would find a greatly accelerated pace of surgical quality improvement,” Campbell says.

Inspired by the Michigan group, surgeons in Tennessee and upper New York have launched collaboratives. Similar ones are in the works in Pennsylvania, Virginia and Illinois.

Source: University of Michigan press release.

You can view an abstract of the study in Archives of Surgery here.

That's the provocative headline on an article by an internationally regarded skeptic of medical research. And the striking thing is that many researchers agree their field is badly flawed.

Dr. John Ioannidis bolstered his contention about the wrongness of most published research with an elaborate mathematical proof published in the on-line journal PLoS Medicine.

Anyone who follows the medical headlines even casually and has a decent memory knows that Dr. Ioannidis is right. Whether the issue is cancer screening with PSA or mammograms, or nutritional research on the value of fish oil, or a hundred other subjects, the arc of medical knowledge follows a predictable path: from excitement to widespread adoption to more careful research to disillusionment.

Here's Dr. Ioannidis's own summary of the factors that go into the wrongness of most published research, in his PLoS Medicine essay:

There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

A more accessible discussion of Dr. Ioannidis's work is published in The Atlantic this month, by David Freedman. An excerpt:

Studies have gone back and forth on the cancer-preventing powers of vitamins A, D, and E; on the heart-health benefits of eating fat and carbs; and even on the question of whether being overweight is more likely to extend or shorten your life. How should we choose among these dueling, high-profile nutritional findings? Ioannidis suggests a simple approach: ignore them all.

For starters, he explains, the odds are that in any large database of many nutritional and health factors, there will be a few apparent connections that are in fact merely flukes, not real health effects—it’s a bit like combing through long, random strings of letters and claiming there’s an important message in any words that happen to turn up. ...

Even if changing that one factor does bring on the claimed improvement, there’s still a good chance that it won’t do you much good in the long run, because these studies rarely go on long enough to track the decades-long course of disease and ultimately death. Instead, they track easily measurable health “markers” such as cholesterol levels, blood pressure, and blood-sugar levels, and meta-experts have shown that changes in these markers often don’t correlate as well with long-term health as we have been led to believe.

On the relatively rare occasions when a study does go on long enough to track mortality, the findings frequently upend those of the shorter studies.
...

And so it goes for all medical studies, he says. Indeed, nutritional studies aren’t the worst. Drug studies have the added corruptive force of financial conflict of interest.