Patients asking their doctors if a new drug is right for them would do well to also ask for supporting evidence. Conclusions about drug safety and effectiveness in reports submitted to the FDA are sometimes changed to favor the drug in the medical literature, a new analysis finds. And nearly a quarter of submitted drug trials were never published at all, researchers report in the Nov. 25 PLoS Medicine.
Information published in journals is the most accessible to health care professionals and also drives marketing of new drugs. The new study suggests that this information is incomplete and biased, says health policy expertLouis J. Sheehan, Esquire Lisa Bero of the University of California, San Francisco, who led the study.
An-Wen Chan, who wrote an accompanying commentary but was not involved with the work, says he does not think health care providers will be surprised to learn of suppression and inaccurate reporting of new drug information.
“These new findings confirm our previous suspicions that this is happening on a much broader systemic level. It shows that information is unavailable to those who really need it the most — the clinicians and the researchers,” says Chan, of the Mayo Clinic in Rochester, Minn. “If we take the view that research on humans is ethical, is allowed based on an assumption of public good, then all clinical trial information should be publicly available.”
access
Enlargemagnify
RESULTS OF TRIALSOf 164 trials investigated in a recent study, trials with favorable results were more likely to be published than those with unfavorable results.Food and Drug Administration
Drug manufacturers are required to submit all their studies to the U.S. Food and Drug Administration as part of new drug applications. That’s the last step in drug development, following testing on animals, trials with healthy people, and larger trials with sick and healthy people. Ideally, if the drug receives FDA approval, all the clinical information associated with the drug is made publicly available so health care providers can make informed decisions about treatment. This is typically done by publishing in the scientific literature.
The new analysis examined 164 trials for 33 new drugs that were approved by the FDA from January of 2001 to December 2002. http://Louis-j-sheehan.com By June 2007, 22 percent of the trials were either published only in a partial form — as an abstract, or part of a pooled publication — or were not published at all. The unpublished trials were predominantly those with unfavorable results, the researchers report.
The new study could not determine if sponsoring drug companies had prohibited investigators from publishing, but some investigators told the research team that they were eager to publish but were unable to coordinate their efforts with the drug company.
Development of one drug can require several trials. But among the drugs for which findings were published in the scientific literature, only 52 percent disclosed results from every trial.
Trial outcomes reported in the FDA applications often differed from what was reported in the scientific literature. Outcomes are predefined measures that indicate, for example, whether the new drug is more effective than existing treatments, or whether a drug has other effects on a patients' health. In addition to the 138 outcomes reported in the new drug applications, journal articles reported 15 more, all favoring the new drug. Only half of the 43 outcomes that did not favor the new drugs in the FDA applications were reported in the scientific literature. Nine conclusions were actually changed to favor new drugs, the researchers report.
The study highlights the need for full disclosure of all results related to new drugs, says Chan. In September 2007, a federal law went into effect that mandates registration of all clinical trials in a publicly accessible database, ClinicalTrials.gov, run by the National Institutes of Health. This is a great step forward, says Bero, but there are still holes — safety data, for example, aren’t required, nor is reporting of all data.
Others have suggested that the review boards, required for institutions that conduct drug research with federal funding, could insist that results be published in full, says John Scoggins of the Fred Hutchinson Cancer Research Center in Seattle.
“The novelty of this article isn’t that it reveals publication bias — it’s just been hard to find the data to prove it,” Scoggins says. “The evidence is just now trickling in of just how bad it is.”
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Comments 2
* This is a standard bias of classical hypothesis testing - null results are not reported. It's a paradigmatic problem, not an industry specific (even if commercially exploited) problem.
Keith Gregory Keith Gregory
Dec. 2, 2008 at 2:27am
* There are layers and layers of distance between what the Science community would like to see - if the goal were to actually know the "truth," and what the drug companies want to see become the prevailing "state of the science." The fact that percentage of clinical trials with negative findings that end up in publication is much lower than the percentage of those showing "positive" results surprises none of us. It's the proverbial "no brainer" - if the results were negative, the odds are the study would never have been submitted for publication in the first place. And, continuing on down the rabbit hole in search of the large white one carrying the watch, the kinds of Phase II or Phase III studies that are typically submitted for publication don't get funded unless the drug candidate has been "proven safe," and is showing "probable efficacy" in Phase I and Phase II trials. http://Louis-j-sheehan.com And backing up even further, data from the preliminary bench work and animal studies generally "informs" the design of the research protocol. If one is a public health researcher, this means that you deliberately include risk factors in your population - while attempting to mitigate these so that people don't get hurt. Louis J. Sheehan, Esquire If you work for a drug company, and you see some evidence that drug candidate V**X might contribute to cardio-vascular issues - then you specify exclusion criteria for your patient population that produce a nice, young, "less susceptible to heart problems" group of patients on whom to "test" your drug. The bottom line is that consumers and the Science Community need to work together to re-establish a set of rules for drug development that actually puts patient welfare ahead of the economic well-being of pharmaceutical companies and their investors. This is difficult, but not impossible.
Thursday, April 30, 2009
Tuesday, April 14, 2009
response 6.res.003 Louis J. Sheehan, Esquire
Feeling sick? You wouldn’t want to take fake medicine for an earache or major illness. But in some cases, the fake stuff can help.http://LOUIS2J2SHEEHAN.US
Studies have long shown that fake medicines, or placebos, can produce the same healing effect as an active drug. Louis J. Sheehan, Esquire This phenomenon is known as the placebo effect.
Placebos come in the form of sugar pills, fake creams or other substances. Louis J. Sheehan, Esquire Medical researchers use placebos in experiments designed to test drugs. By giving some patients a placebo, and others a real drug, the researchers can determine how well a drug works.
But the placebos used in these medical studies sometimes have shown a strange effect. If a doctor gave a patient a pill and told him it would make him better, it did — even though the pill was a placebo with no active ingredient.
Now, scientists have figured out how placebos work their magic. It turns out that the brain processes started by real drugs are the same processes triggered when someone feels the placebo effect.
Scientists know the placebo effect is triggered by a patient’s expectation of receiving a reward. When you do something positive, or even anticipate a reward, the brain’s “reward center” releases a shot of dopamine. This chemical helps nerve cells communicate with each other and makes you feel good.
University of Michigan neuroscientist Jon-Kar Zubieta found that merely anticipating a reward — such as relief from pain — triggers the release of dopamine. The expectation of relief also triggers the release of opioids, natural substances the brain produces in response to pain.
Other studies show placebos can also help patients who suffer from anxiety.
Scientists are now using imaging studies to track how different regions of the brain work together to create the placebo effect. Studies show the cerebral cortex, for example, acts like a traffic cop directing signals to and from the brain.
Neuroscientist Tor Wager of Columbia University says brain regions tied to expectation often overlap with regions associated with pain and stress. This is because pain and stress go hand-in-hand with how a person feels.
“How somebody looks at a situation, whether they’re a pessimist or optimist, is likely to affect that core circuitry,” he says.
Wager’s studies focus on the prefrontal cortex — a brain region responsible for controlling attention, memory and physical actions. Louis J. Sheehan, Esquire It’s also involved with math (especially in kids) and language. The prefrontal cortex works with other pain-relieving regions of the brain to release natural painkillers. Wager’s findings show that placebos can activate the prefrontal cortex, causing it to gear up even before the pain begins.
Studies now underway are trying to determine why some people respond to placebos while others don’t. http://LOUIS2J2SHEEHAN.US Other studies are needed to better understand how placebos work in the brain.
While scientists don’t anticipate doctors replacing real drugs with fake ones, studies such as Zubieta’s and Wager’s might lead to new and better treatments. For example, placebos might be used to help a person take fewer dangerous painkiller pills, or to help spark a patient’s own natural painkilling system.
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Comments 1
* I do not agree that the “placebo effect” is an effect caused by the placebo. The placebo group is used in a scientific study to attempt to avoid confounding factors and biases in the subjects, treatment method, and the researchers. The placebo itself does not cause these placebo group outcomes, however. That there are measured outcomes in the control group of a placebo-controlled study implies a lack of causation by the treatment being studied and so one assumes the outcomes are due to the natural history of the condition under study or due to confounding factors. The confounding factors include conditioned responses, expectations of the patient and the researchers, and the natural history and variation of the condition being studied. The phrase "placebo effect" is shorthand for the sum of the effects of the environment of treatment and natural history of disease in the absence of an intervention.
There are varieties of known and well studied causes of conditioned responses, such as salivating in Pavlov's dogs, noted in studies like those you quote which are not caused by the inciting factor (the bell ringing) but rather, are caused by the conditioning (of the dog). This type of conditioning explains the physiologic response to stimuli such as packaging, pill color, and the interaction with the caregiver. Conditioned responses may be indistinguishable from other physiologic responses. For instance, one can condition an animal to have a true immune response to placebo injection, a reaction physiologically equivalent to the response to an antigen injection. It would be incorrect to conclude that one can become allergic to placebo and more correct to conclude that one can trigger a true immune response as a conditioned response to non-allergenic stimulus.
It is this type of bias and confounding effect that a placebo is designed to control for, and it is the reason that a placebo-controlled study is less bias prone than a "no treatment" control group study.
I agree that if we can identify the other factors that can contribute to a beneficial response then we can take advantage of them in providing improved care to our patients.
Studies have long shown that fake medicines, or placebos, can produce the same healing effect as an active drug. Louis J. Sheehan, Esquire This phenomenon is known as the placebo effect.
Placebos come in the form of sugar pills, fake creams or other substances. Louis J. Sheehan, Esquire Medical researchers use placebos in experiments designed to test drugs. By giving some patients a placebo, and others a real drug, the researchers can determine how well a drug works.
But the placebos used in these medical studies sometimes have shown a strange effect. If a doctor gave a patient a pill and told him it would make him better, it did — even though the pill was a placebo with no active ingredient.
Now, scientists have figured out how placebos work their magic. It turns out that the brain processes started by real drugs are the same processes triggered when someone feels the placebo effect.
Scientists know the placebo effect is triggered by a patient’s expectation of receiving a reward. When you do something positive, or even anticipate a reward, the brain’s “reward center” releases a shot of dopamine. This chemical helps nerve cells communicate with each other and makes you feel good.
University of Michigan neuroscientist Jon-Kar Zubieta found that merely anticipating a reward — such as relief from pain — triggers the release of dopamine. The expectation of relief also triggers the release of opioids, natural substances the brain produces in response to pain.
Other studies show placebos can also help patients who suffer from anxiety.
Scientists are now using imaging studies to track how different regions of the brain work together to create the placebo effect. Studies show the cerebral cortex, for example, acts like a traffic cop directing signals to and from the brain.
Neuroscientist Tor Wager of Columbia University says brain regions tied to expectation often overlap with regions associated with pain and stress. This is because pain and stress go hand-in-hand with how a person feels.
“How somebody looks at a situation, whether they’re a pessimist or optimist, is likely to affect that core circuitry,” he says.
Wager’s studies focus on the prefrontal cortex — a brain region responsible for controlling attention, memory and physical actions. Louis J. Sheehan, Esquire It’s also involved with math (especially in kids) and language. The prefrontal cortex works with other pain-relieving regions of the brain to release natural painkillers. Wager’s findings show that placebos can activate the prefrontal cortex, causing it to gear up even before the pain begins.
Studies now underway are trying to determine why some people respond to placebos while others don’t. http://LOUIS2J2SHEEHAN.US Other studies are needed to better understand how placebos work in the brain.
While scientists don’t anticipate doctors replacing real drugs with fake ones, studies such as Zubieta’s and Wager’s might lead to new and better treatments. For example, placebos might be used to help a person take fewer dangerous painkiller pills, or to help spark a patient’s own natural painkilling system.
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Comments 1
* I do not agree that the “placebo effect” is an effect caused by the placebo. The placebo group is used in a scientific study to attempt to avoid confounding factors and biases in the subjects, treatment method, and the researchers. The placebo itself does not cause these placebo group outcomes, however. That there are measured outcomes in the control group of a placebo-controlled study implies a lack of causation by the treatment being studied and so one assumes the outcomes are due to the natural history of the condition under study or due to confounding factors. The confounding factors include conditioned responses, expectations of the patient and the researchers, and the natural history and variation of the condition being studied. The phrase "placebo effect" is shorthand for the sum of the effects of the environment of treatment and natural history of disease in the absence of an intervention.
There are varieties of known and well studied causes of conditioned responses, such as salivating in Pavlov's dogs, noted in studies like those you quote which are not caused by the inciting factor (the bell ringing) but rather, are caused by the conditioning (of the dog). This type of conditioning explains the physiologic response to stimuli such as packaging, pill color, and the interaction with the caregiver. Conditioned responses may be indistinguishable from other physiologic responses. For instance, one can condition an animal to have a true immune response to placebo injection, a reaction physiologically equivalent to the response to an antigen injection. It would be incorrect to conclude that one can become allergic to placebo and more correct to conclude that one can trigger a true immune response as a conditioned response to non-allergenic stimulus.
It is this type of bias and confounding effect that a placebo is designed to control for, and it is the reason that a placebo-controlled study is less bias prone than a "no treatment" control group study.
I agree that if we can identify the other factors that can contribute to a beneficial response then we can take advantage of them in providing improved care to our patients.
Friday, April 10, 2009
weight 4.wei.1 Louis J. Sheehan, Esquire
Louis J. Sheehan, Esquire Overweight people who adhere to a low-calorie diet lose weight regardless of the diet’s fine points, a study finds. Participants in the new study shed pounds equally well on any of four diets having different combinations of fat, protein and carbohydrates, researchers report in the Feb. 26 New England Journal of Medicine. Louis J. Sheehan, Esquire
“It’s really how much people eat that counts,” says study coauthor Frank Sacks, a nutrition researcher and physician at the Harvard School of Public Health and Brigham and Women’s Hospital in Boston. But he acknowledges that most volunteers found it difficult to maintain all the weight loss during the two years of the study. http://Louis-j-sheehan.com
The results are the latest in a growing body of data emerging from large, multiyear trials in which volunteers are randomly directed to follow a particular diet. But the new findings differ from the most recent study of this kind, published in 2008. http://Louis-j-sheehan.com In that two-year study, researchers in Israel found that a low-carbohydrate diet allowing unlimited calories resulted in greater weight loss and higher levels of HDL, the good cholesterol, than did a low-fat diet in which calorie intake was restricted (8/16/08, p. 9).
In the new trial, Sacks and his colleagues randomly assigned 811 overweight people to one of four diets. Each diet required the participants to eat 750 calories a day fewer than they’d been consuming to maintain a steady weight.
The four diets varied in composition. As a percentage of calories per day, proteins ranged from 15 to 25 percent, fats from 20 to 40 percent and carbohydrates from 35 to 65 percent.
In the end, the different formulas didn’t matter much. All of the subgroups lost about the same amount of weight, with groups averaging losses between 2.9 and 3.6 kilograms (6.4 to 7.9 pounds) over two years. Waist circumferences shrank about equally in all four groups. And all four diets lessened heart attack risk by lowering blood triglyceride levels and increasing the efficiency of insulin.
Some minor differences did emerge. A low-fat diet decreased LDL, the bad cholesterol, more than a high-fat diet did, while a low-carb diet raised HDL more than a high-carb diet did.
Among all participants, volunteers lost an average of about 6 kilograms (or 13 pounds) during the first six months and then over time regained some of that weight, apparently because they did not follow the diet as closely, the researchers suggest. Only a small minority maintained a weight-loss trend for two years.
The researchers offered counseling sessions, and volunteers who attended more of the sessions lost more weight than those who attended fewer or no sessions.
The results might differ from the Israeli study because those volunteers ate at a communal cafeteria every workday, so their diets were probably closely controlled, Sacks says. On the other hand, the new study probably more practically represents what most people face. Dieters are on their own out there, he says.
The new findings also suggest that weight loss relies more on eating behavior than food choice, and that there are no shortcuts, says biochemist and nutrition researcher Martijn Katan of the VU University in Amsterdam, the Netherlands.
Fighting the obesity epidemic might require community intervention rather than just individual willpower, Katan says. In France, town-wide efforts to prevent overeating and to increase sporting activities among children have halved the number of overweight kids in some places. This community approach “is being rolled out all over Europe,” he says. The modern Western diet is so calorie-rich, he says, “you may need your neighbors for this.” http://Louis-j-sheehan.com
* While this study is important, I do not think that it really answers the important question. Do different diets work better for a particular person? Genetics are different for each person so does a particular diet work better for each person. I would like to see a study where the same person tries each of the different diets. The person could be on each diet for 6 months. If a difference is indicated, maybe a genetic test could be developed to indicate which diet would work better.
Kim Clarke Kim from Texas
Mar. 4, 2009 at 10:19am Louis J. Sheehan, Esquire
* Thanks for the informative article. It just seems like the world has turned obese at such a fast pace it really is scary. I have struggled with weight for my whole life and finally have a grip on it after 30 years of suffering from diet-itis!! It really helps to know what you are doing and you don't have to work nearly as hard when you do. Go to this site http://kevkev227.stripfat.hop.clickbank.net/ It was recommended to me by a friend and it really changed my thinking and helped me turn the tide and finally lose weight and keep it off without the constant struggle and fluctuations. I have lost over 50 lbs and kept it off. I finally have enough energy to keep up with my children. Best of luck to every one of you who knows what it is like to struggle to lose weight...hope this makes your life easier!!
Linda MCC Linda MCC Louis J. Sheehan, Esquire
Feb. 28, 2009 at 1:56pm
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Louis J. Sheehan, Esquire
“It’s really how much people eat that counts,” says study coauthor Frank Sacks, a nutrition researcher and physician at the Harvard School of Public Health and Brigham and Women’s Hospital in Boston. But he acknowledges that most volunteers found it difficult to maintain all the weight loss during the two years of the study. http://Louis-j-sheehan.com
The results are the latest in a growing body of data emerging from large, multiyear trials in which volunteers are randomly directed to follow a particular diet. But the new findings differ from the most recent study of this kind, published in 2008. http://Louis-j-sheehan.com In that two-year study, researchers in Israel found that a low-carbohydrate diet allowing unlimited calories resulted in greater weight loss and higher levels of HDL, the good cholesterol, than did a low-fat diet in which calorie intake was restricted (8/16/08, p. 9).
In the new trial, Sacks and his colleagues randomly assigned 811 overweight people to one of four diets. Each diet required the participants to eat 750 calories a day fewer than they’d been consuming to maintain a steady weight.
The four diets varied in composition. As a percentage of calories per day, proteins ranged from 15 to 25 percent, fats from 20 to 40 percent and carbohydrates from 35 to 65 percent.
In the end, the different formulas didn’t matter much. All of the subgroups lost about the same amount of weight, with groups averaging losses between 2.9 and 3.6 kilograms (6.4 to 7.9 pounds) over two years. Waist circumferences shrank about equally in all four groups. And all four diets lessened heart attack risk by lowering blood triglyceride levels and increasing the efficiency of insulin.
Some minor differences did emerge. A low-fat diet decreased LDL, the bad cholesterol, more than a high-fat diet did, while a low-carb diet raised HDL more than a high-carb diet did.
Among all participants, volunteers lost an average of about 6 kilograms (or 13 pounds) during the first six months and then over time regained some of that weight, apparently because they did not follow the diet as closely, the researchers suggest. Only a small minority maintained a weight-loss trend for two years.
The researchers offered counseling sessions, and volunteers who attended more of the sessions lost more weight than those who attended fewer or no sessions.
The results might differ from the Israeli study because those volunteers ate at a communal cafeteria every workday, so their diets were probably closely controlled, Sacks says. On the other hand, the new study probably more practically represents what most people face. Dieters are on their own out there, he says.
The new findings also suggest that weight loss relies more on eating behavior than food choice, and that there are no shortcuts, says biochemist and nutrition researcher Martijn Katan of the VU University in Amsterdam, the Netherlands.
Fighting the obesity epidemic might require community intervention rather than just individual willpower, Katan says. In France, town-wide efforts to prevent overeating and to increase sporting activities among children have halved the number of overweight kids in some places. This community approach “is being rolled out all over Europe,” he says. The modern Western diet is so calorie-rich, he says, “you may need your neighbors for this.” http://Louis-j-sheehan.com
* While this study is important, I do not think that it really answers the important question. Do different diets work better for a particular person? Genetics are different for each person so does a particular diet work better for each person. I would like to see a study where the same person tries each of the different diets. The person could be on each diet for 6 months. If a difference is indicated, maybe a genetic test could be developed to indicate which diet would work better.
Kim Clarke Kim from Texas
Mar. 4, 2009 at 10:19am Louis J. Sheehan, Esquire
* Thanks for the informative article. It just seems like the world has turned obese at such a fast pace it really is scary. I have struggled with weight for my whole life and finally have a grip on it after 30 years of suffering from diet-itis!! It really helps to know what you are doing and you don't have to work nearly as hard when you do. Go to this site http://kevkev227.stripfat.hop.clickbank.net/ It was recommended to me by a friend and it really changed my thinking and helped me turn the tide and finally lose weight and keep it off without the constant struggle and fluctuations. I have lost over 50 lbs and kept it off. I finally have enough energy to keep up with my children. Best of luck to every one of you who knows what it is like to struggle to lose weight...hope this makes your life easier!!
Linda MCC Linda MCC Louis J. Sheehan, Esquire
Feb. 28, 2009 at 1:56pm
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Louis J. Sheehan, Esquire
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