October 22, 2010 — Psychiatrists dominate a list of physicians receiving the most in payments from pharmaceutical companies, according to a free, interactive database of such payments launched by investigative journalism group ProPublica, in partnership with other US media outlets
So far, the database includes payments made by 7 of the biggest pharmaceutical companies — some of which the US Department of Justice has required to disclose physician payments as part of settlement agreements over illegal drug marketing — which account for a boggling $258 million in payments to roughly 17,700 physicians. The plan is to add 70 more companies.
Any US physician is searchable by name in the database.
"Receiving payments isn't necessarily wrong," says the homepage for the Dollars for Docs, "but it does raise ethical issues."
The payments covered by the project include fees for such items as speaking, consulting, meals, and travel; the different types of payments from different companies have been compiled, streamlined, and tallied by ProPublica.
The 10 highest-paid physicians in 2009 to 2010 for each of the 7 companies are listed on the site, spanning all medical disciplines.
Endocrinologist Firhaad Ismail, MD, from Las Vegas, Nevada, ranked number one in pharmaceutical industry compensation, receiving $303,558 from GlaxoSmithKline, Eli Lilly, and Merck. Dr. Ismail did not return messages left with his office requesting an interview.
Top-Paid Psychiatrist Says Payments Do Not Cloud Clinical Judgment
ProPublica researchers also compiled a list of physicians who were paid more than $100,000 (typically from more than 1 company) during the past 18 months, turning up 384 names, including 41 who earned more than $200,000 through speaking or consulting arrangements and 2 who earned more than $300,000 from 1 or more of the 7 companies.
More psychiatrists are listed in the database than any other kind of specialist. Of the 384 physicians in the $100,000 group, 116 are psychiatrists. Leading all psychiatrists was Roueen Rafeyan, MD, in Chicago, Illinois, who received $203,936 from Eli Lilly, AstraZeneca, Johnson & Johnson, and Pfizer, mostly for professional education programs.
In an interview with Medscape Medical News, Dr. Rafeyan said that compensation from pharmaceutical companies does not cloud his clinical judgment at the expense of patients.
The day I'm influenced by that is the day I'm not fit to practice medicine.
"The day I'm influenced by that is the day I'm not fit to practice medicine," Dr. Rafeyan said.
He noted that the majority of the drugs he prescribed were generics. "If someone looked at my prescribing patterns, it would be the opposite of the [pharmaceutical] money I receive," said Dr. Rafeyan, an assistant clinical professor at Rush University Medical Center in Chicago.
Dr. Rafeyan said that although the extra income is always welcome, patient well-being was his prime motivation to talk to other physicians about brand-name psychiatric drugs. "When you educate other physicians, hopefully 1 patient will benefit from it."
When asked how he found the time to earn more than $200,000 as a pharmaceutical company educator over 18 months, Dr. Rafeyan said, "I work very hard, like many other physicians. None of us have 40-hour work weeks."
Dollar Value of Psychiatric Drugs Is Enormous
The preponderance of psychiatrists on the ProPublica list may reflect the proportion of prescription activity involving psychiatric drugs. In 2009, the dollar value of antipsychotic drugs came to $14.6 billion, topping all other therapeutic classes, according to research firm IMS Health. Antidepressants occupied the number 4 spot on the list, valued at $9.9 billion.
IMS Health put the total US prescription market in 2009 at $300.3 billion.
Carol Bernstein, MD, president of the American Psychiatric Association, told Medscape Medical News that the thorny issue of pharmaceutical industry compensation went beyond her specialty.
People with high-profile, high-visibility [positions] sometimes get carried away.
"Academic medicine needs a different relationship with the pharmaceutical industry," she said. Physicians must find new ways to facilitate the development of new drugs that do not compromise their ethics or patient care.
"People with high-profile, high-visibility [positions] sometimes get carried away," she said.
Research has shown, Dr. Bernstein added, that heavy pharmaceutical marketing indeed influences physician prescribing.
The Rest of the Compensation Leader Board
After psychiatry, the next largest specialty in the $100,000 group is internal medicine. However, this is an amorphous category, because many of the 114 physicians shown as board certified in internal medicine also are certified in fields such as endocrinology, neurology, cardiovascular disease, and medical oncology.
Table. 11 Most Compensated Specialties After Psychiatry and Internal Medicine
Specialty Number of Physicians*
Endocrinology 37
Pulmonology 23
Family Medicine 23
Cardiovascular Medicine 19
Urology 19
Obstetrics/Gynecology 16
Allergy and Immunology 15
Neurology 13
Oncology 13
Pain Medicine 10
Pediatrics 10
*Some physicians are listed with more than 1 board certification.
More to Come
By 2013, 70 additional companies will be required to disclose payments under federal healthcare reform legislation, a notion originally brought forward as the Physician Payments Sunshine Act.
ProPublica says it has launched a "rolling series" of stories generated by their research. The first addresses the high number of physicians paid to speak for drug companies who also have limited credentials or have faced disciplinary actions, criminal convictions, malpractice lawsuits, hospital sanctions, or US Food and Drug Administration warning letters.
Two of ProPublica's partners, the Chicago Tribune and the Boston Globe, have also used the database to research their own stories. The Globe's article focuses on payments to physicians at Harvard University and other Boston-area institutions, noting that "numerous doctors at Beth Israel Deaconess Medical Center and Boston Medical Center" also received payments, "despite hospital policies saying physicians cannot be paid speakers unless they control the content of the talks." The Tribune article zeroes in on payments being made to 4 Chicago-area practices: the psychiatry department at Rush University Medical Center, a headache clinic, a suburban urology practice, and a psychiatric hospital.
An editor's note on the ProPublica Web site urges interactivity and collaboration, inviting patients to search for their physicians and email the Web site with comments or stories. It also notes that stories of the kind being generated from this list would, in the past, have been "scoops" for single news organizations.
"We think we can achieve our primary mission at ProPublica — journalism that spurs change — by working in concert with other talented journalists and with the tens of thousands of people who will view, hear, and read stories by this partnership."
Medscape Medical News © 2010 WebMD, LLC
Send press releases and comments to news@medscape.net.
Sunday, October 24, 2010
Wednesday, September 29, 2010
Vitalux for prevention of age related macular degeneration
An earlier, Cochrane Database Review of publications to 2007 found that the use of vitamin and mineral supplements, alone or in combination, by the general population had no effect on age-related macular degeneration,[34] a finding echoed by another review.[35] A 2006 Cochrane Review of the effects of vitamins and minerals on the slowing of ARMD found that positive results mainly came from a single large trial in the United States (the Age-Related Eye Disease Study, with funding from the eye care product company Bausch & Lomb who also manufactured the supplements used in the study[36]), and questioned the generalization of the data to any other populations with different nutritional status. The review also questioned the possible harm of such supplements, given the increased risk of lung cancer in smokers with high intakes of beta-Carotene, and the increased risk of heart failure in at-risk populations who consume high levels of vitamin E supplements.[37]
Tuesday, September 14, 2010
National drug plan could save billions: study
A universal prescription drug plan could chop more than $10 billion off Canada's annual health-care bill, according to a new policy study that its authors say "explodes the fallacy" that such a plan is unaffordable.
A new study on Canada's pharmaceutical policies concludes that a universal drug plan could save up to $10.7 billion a year in total drug expenditures. (Nati Harnik/Associated Press)
The report, released on Monday by the Canadian Centre for Policy Alternatives, concludes the existing patchwork of private and public plans in Canada is inequitable, inefficient and costly.
"Canada’s pharmaceutical policies are a total failure," the study's author, Marc-André Gagnon, told reporters on Monday in Ottawa.
The report also finds that Canada is either the third or fourth most expensive country for brand-name drugs every year — after the United States, Switzerland and Germany — because it deliberately inflates drug prices in order to attract pharmaceutical investment.
P.O.V.:
Would you support a universal pharmacare plan? Take our poll.
Meanwhile, Canada has one of the highest annual growth of drug costs among industrialized countries — much higher than countries that have universal pharmacare programs, such as France, Australia and Sweden, said Gagnon, a professor of public policy at Carleton University.
"The cost of such policies far exceed the benefits to Canadians from having a domestic pharmaceutical industry," he said.
The current system is also unfair, Gagnon said, because Canadians receive different coverage depending on what plan they're in and where they live.
Lower administrative costs
Universal pharmacare would lead to savings of nearly $3 billion a year if Canada keeps its current policy, Gagnon said.
But the savings could increase to $10.7 billion, or 43 per cent of annual drug costs, if Canada cut all privileges to the pharmaceutical industry for drug costs, according to the report.
Much of what Canadians spend on prescription drugs is eaten up by administration costs from hundreds of different private, public and company plans, according to the report.
A national drug plan would allow governments to buy drugs in bulk and be the sole administrator, which would mean billions of dollars in savings, agreed Dr. Michael Rachlis, a health policy analyst who teaches medicine at the University of Toronto.
"We reduce the administrative costs because private insurance is much more expensive to administer than public insurance, which is one of the reasons why U.S. health care costs are so much higher than ours," Rachlis said.
The report comes as provincial and territorial health ministers meet in St. John's, where rising health-care and drug costs are high on the agenda.
"Rising costs in health care are affecting every province, and any time that we can look at a program that will help contain those costs it's certainly worth looking at," Saskatchewan's Health Minister, Don McMorris, said in an interview from St. John's on Monday.
Timing right?
At the close of Monday's session in St. John's, Ontario Health Minister Deb Matthews said her province spends about $4 billion a year on drugs, and provinces collectively spend about $10 billion. The ministers think they can get better prices by working together, Matthews told reporters.
A national pharmacare program would require agreement from all provinces and territories.
The timing could be right for such a program, said Steve Morgan, a health economist with Centre for Health Service and Policy Research at the University of British Columbia.
For the first time in decades, drug prices are starting to fall as patents for "blockbuster" drugs like those used to control high blood pressure and cholesterol start to expire, Morgan said. The U.S. is already seeing a slight slowdown in spending, he said.
Meanwhile, the federal and provincial governments are looking for a new plan to replace the Canada Health Accord, which expires in 2014.
Morgan said universal pharmacare could signal a renewal that would benefit all Canadians. So far, the federal government has shown little interest.
The health ministers' meeting wraps up on Tuesday.
A new study on Canada's pharmaceutical policies concludes that a universal drug plan could save up to $10.7 billion a year in total drug expenditures. (Nati Harnik/Associated Press)
The report, released on Monday by the Canadian Centre for Policy Alternatives, concludes the existing patchwork of private and public plans in Canada is inequitable, inefficient and costly.
"Canada’s pharmaceutical policies are a total failure," the study's author, Marc-André Gagnon, told reporters on Monday in Ottawa.
The report also finds that Canada is either the third or fourth most expensive country for brand-name drugs every year — after the United States, Switzerland and Germany — because it deliberately inflates drug prices in order to attract pharmaceutical investment.
P.O.V.:
Would you support a universal pharmacare plan? Take our poll.
Meanwhile, Canada has one of the highest annual growth of drug costs among industrialized countries — much higher than countries that have universal pharmacare programs, such as France, Australia and Sweden, said Gagnon, a professor of public policy at Carleton University.
"The cost of such policies far exceed the benefits to Canadians from having a domestic pharmaceutical industry," he said.
The current system is also unfair, Gagnon said, because Canadians receive different coverage depending on what plan they're in and where they live.
Lower administrative costs
Universal pharmacare would lead to savings of nearly $3 billion a year if Canada keeps its current policy, Gagnon said.
But the savings could increase to $10.7 billion, or 43 per cent of annual drug costs, if Canada cut all privileges to the pharmaceutical industry for drug costs, according to the report.
Much of what Canadians spend on prescription drugs is eaten up by administration costs from hundreds of different private, public and company plans, according to the report.
A national drug plan would allow governments to buy drugs in bulk and be the sole administrator, which would mean billions of dollars in savings, agreed Dr. Michael Rachlis, a health policy analyst who teaches medicine at the University of Toronto.
"We reduce the administrative costs because private insurance is much more expensive to administer than public insurance, which is one of the reasons why U.S. health care costs are so much higher than ours," Rachlis said.
The report comes as provincial and territorial health ministers meet in St. John's, where rising health-care and drug costs are high on the agenda.
"Rising costs in health care are affecting every province, and any time that we can look at a program that will help contain those costs it's certainly worth looking at," Saskatchewan's Health Minister, Don McMorris, said in an interview from St. John's on Monday.
Timing right?
At the close of Monday's session in St. John's, Ontario Health Minister Deb Matthews said her province spends about $4 billion a year on drugs, and provinces collectively spend about $10 billion. The ministers think they can get better prices by working together, Matthews told reporters.
A national pharmacare program would require agreement from all provinces and territories.
The timing could be right for such a program, said Steve Morgan, a health economist with Centre for Health Service and Policy Research at the University of British Columbia.
For the first time in decades, drug prices are starting to fall as patents for "blockbuster" drugs like those used to control high blood pressure and cholesterol start to expire, Morgan said. The U.S. is already seeing a slight slowdown in spending, he said.
Meanwhile, the federal and provincial governments are looking for a new plan to replace the Canada Health Accord, which expires in 2014.
Morgan said universal pharmacare could signal a renewal that would benefit all Canadians. So far, the federal government has shown little interest.
The health ministers' meeting wraps up on Tuesday.
Sibutramine Increases Risk for MI and Stroke Among Patients with Heart Disease
The weight-loss drug sibutramine (Meridia) — up for review by FDA advisers on Sept. 15 — poses increased risk for cardiovascular events among adults with cardiovascular disease (CVD), according to a New England Journal of Medicine study.
Industry-supported researchers randomized nearly 10,000 overweight or obese adults with cardiovascular disease and/or diabetes to receive sibutramine or placebo. During 3.4 years' treatment, sibutramine recipients were at greater risk for nonfatal MI (4.1% vs. 3.2%) and stroke (2.6% vs. 1.9%), although not cardiovascular mortality. In subgroup analyses, the increased risks were seen among subjects with CVD and CVD plus diabetes, but not among those with diabetes alone.
The authors conclude that sibutramine "should continue to be excluded from use in patients with preexisting cardiovascular disease." Editorialists, however, take a stronger stance: "Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, [and] a worrisome cardiovascular risk profile, ... it is difficult to discern a credible rationale for keeping this medication on the market."
Industry-supported researchers randomized nearly 10,000 overweight or obese adults with cardiovascular disease and/or diabetes to receive sibutramine or placebo. During 3.4 years' treatment, sibutramine recipients were at greater risk for nonfatal MI (4.1% vs. 3.2%) and stroke (2.6% vs. 1.9%), although not cardiovascular mortality. In subgroup analyses, the increased risks were seen among subjects with CVD and CVD plus diabetes, but not among those with diabetes alone.
The authors conclude that sibutramine "should continue to be excluded from use in patients with preexisting cardiovascular disease." Editorialists, however, take a stronger stance: "Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, [and] a worrisome cardiovascular risk profile, ... it is difficult to discern a credible rationale for keeping this medication on the market."
Saturday, August 28, 2010
Dutasteride Gives Mixed Results in Preventing Prostate Cancer
Dutasteride lowers the incidence of prostate cancer, but not high-grade tumors, according to a New England Journal of Medicine study.
In a double-blind study designed by dutasteride's manufacturer, some 6700 high-risk men underwent randomization to either daily dutasteride or placebo. At entry, subjects were 50 to 75 years old, had PSA levels between 2.5 and 10 ng/mL, and had had a negative biopsy.
During 4 years' follow-up, the incidence of biopsy-detected cancer was lower in the treatment group than in controls (20% vs. 25%). The number of high-grade tumors, however, was significantly higher in the treatment group during the last 2 years of follow-up.
An editorialist concludes that the 5-alpha-reductase inhibitors like dutasteride "do not prevent ... but merely temporarily shrink tumors that have a low potential for being lethal." He adds that, because the drugs suppress PSA levels, "men may have a false sense of security," thus delaying diagnosis.
In a double-blind study designed by dutasteride's manufacturer, some 6700 high-risk men underwent randomization to either daily dutasteride or placebo. At entry, subjects were 50 to 75 years old, had PSA levels between 2.5 and 10 ng/mL, and had had a negative biopsy.
During 4 years' follow-up, the incidence of biopsy-detected cancer was lower in the treatment group than in controls (20% vs. 25%). The number of high-grade tumors, however, was significantly higher in the treatment group during the last 2 years of follow-up.
An editorialist concludes that the 5-alpha-reductase inhibitors like dutasteride "do not prevent ... but merely temporarily shrink tumors that have a low potential for being lethal." He adds that, because the drugs suppress PSA levels, "men may have a false sense of security," thus delaying diagnosis.
Tuesday, August 24, 2010
Broad Review of FDA Trials Suggests Antidepressants Only Marginally Better than Placebo
August 24, 2010 — A new review of 4 meta-analyses of efficacy trials submitted to the US Food and Drug Administration (FDA) suggests that antidepressants are only "marginally efficacious" compared with placebo and "document profound publication bias that inflates their apparent efficacy."
In addition, when the researchers also analyzed the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, "the largest antidepressant effectiveness trial ever conducted," they found that "the effectiveness of antidepressant therapies was probably even lower than the modest one reported...with an apparent progressively increasing dropout rate across each study phase.
"We found that out of the 4041 patients initially started on the SSRI [selective serotonin reuptake inhibitor] citalopram in the STAR*D study, and after 4 trials, only 108 patients had a remission and did not either have a relapse and/or dropped out by the end of 12 months of continuing care," lead study author Ed Pigott, PhD, a psychologist with NeuroAdvantage LLC in Clarksville, Maryland, told Medscape Medical News.
Sustained Benefit "Jaw Dropping"
"In other words, if you're trying to look at sustained benefit, you're only looking at 2.7%, which is a pretty jaw-dropping number," added Dr. Pigott.
Overall, "the reviewed findings argue for a reappraisal of the current recommended standard of care of depression," write the study authors.
"I believe there are likely some people where [antidepressants] are truly beneficial beyond placebo. The problem right now is that we simply have no way of knowing who those people are," noted Dr. Pigott. "My hope is that this kind of analysis creates 'more oxygen' for looking at other kinds of approaches to treatment."
The study was published in the August issue of Psychotherapy and Psychosomatics.
When registering new drug application trials with the FDA, drug companies must prespecify the primary and secondary outcome measures, the investigators report. "Prespecification is essential to ensure the integrity of a trial and enables the discovery of when investigators selectively publish the measures that show the outcome the sponsors prefer following data collection and analysis, a form of researcher bias known as HARKing or 'hypothesizing after the results are known'," they write.
For this article, Dr. Pigott and his team reviewed the following meta-analyses:
•1. Rising and colleagues (reviewed all efficacy trials for new drugs between 2001 and 2002)
•2. Turner and colleagues (reviewed 74 past trials of 12 antidepressants)
•3. Kirsch and colleagues, 2002 (reviewed 47 trials of 6 FDA-approved antidepressants)
•4. Kirsch and colleagues, 2008 (reviewed depression severity and efficacy in 35 trials)
The researchers also sought to reevaluate the methods and findings of STAR*D, a randomized, controlled trial of patients with depression. Its prespecified primary outcome measure was the Hamilton Rating Scale for Depression (HRSD), whereas the Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C30) was secondary for identifying remitted and responder patients.
"STAR*D was designed to identify the best next-step treatment for the many patients who fail to get adequate relief from their initial SSRI trial," the study authors write.
"When I first read about STAR*D's step 1 phase, it just seemed biased to me," explained Dr. Pigott. "I thought of it as the 'tag, you're healed' research design. Patients who were scored as having a remission during the first 4 to 6 weeks of up to 14 weeks of acute care treatment were counted as remitted, taken out of the subject pool, and put into the follow-up care phase. In other words, they didn't have the ability to have a relapse. But as most people know, depression ebbs and flows.
"So what made me want to continue to follow this study was that it became clear that the only way that people were really going to be able to evaluate the antidepressants' effectiveness was to wait for the publication of the follow-up findings," he added. "After their major final summary study was published, I felt as though the results weren't really being portrayed in a manner that was consistent with the study's prespecified criteria."
High Dropout, Low Remission Rates
In addition to reporting on low efficacy of antidepressants compared with placebo, the 4 meta-analyses "also document a second form of bias in which researchers fail to report the negative results for the prespecified primary outcome measure submitted to the FDA, while highlighting in published studies positive results from a secondary or even a new measure, as though it was their primary measure of interest," the investigators write.
For example, they note, the meta-analysis from Rising and colleagues found that studies with favorable outcomes were almost 5 times more likely to be published and that over 26% of primary outcome measures were left out of journal articles. Turner and colleagues found that antidepressant studies were 16 times more likely to be published if favorable compared with those with unfavorable outcomes.
In reanalyzing the STAR*D methods, the researchers found that the high dropout rate resulted in frequently missed exit HRSD and IDS-C30 interviews. So the revised statistical analytical plan dropped the IDS-30 for the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), which was given at each visit.
"Even with the extraordinary care of STAR*D, only about one fourth of patients achieved remission in step 1 [and] the dropout rate was slightly larger than the success rate," the study authors write. Steps 2 through 4 also each showed increasingly fewer success rates and larger dropout rates.
Of the 4041 patients at the study's initiation, 370 (9.2%) dropped out within 2 weeks, and only 1854 patients (45.9%) obtained remission "using the lenient QIDS-SR criteria." Of these, 670 dropped out within a month of their remission, and only 108 "survived continuing care" and underwent the final assessment.
Dr. Pigott described reanalyzing STAR*D as being "a bit like an onion. Each time we thought we understood the results, we found another layer. It wasn't until about a year and a half ago that we discovered that the secondary outcome measure, the QIDS-SR, was not originally supposed to be used as a research measure. What was particularly disconcerting to me was that in their summary article, they basically used the QIDS-SR to report all of the results, which clearly had an inflationary effect on the outcome."
He also noted that STAR*D did not have a placebo design. "Because the patients knew they were receiving the active medication, I would have expected a higher remission rate than what you'd find normally in a placebo-controlled study.
"The inescapable conclusion from the STAR*D results is that we need to explore more seriously other forms of treatment (and combination thereof) that may be more effective. This effort will require developing new service delivery models to ensure that as treatments are identified, they are widely implemented," the investigators conclude.
Need for Biomarkers
"For STAR*D, we wanted to do a study that other people could then reanalyze and look at. So I'm very glad that these authors reexamined it and saw it slightly differently, which came mainly from ways of analyzing data," Maurizio Fava, MD, STAR*D trial investigator and executive vice chair of the Department of Psychiatry at Massachusetts General Hospital in Boston, told Medscape Medical News.
"I think their analysis is reasonable and not incompatible with what we had reported," added Dr. Fava, who was not involved with this review.
He noted that the review's message for clinicians is that "there's been a failure of the field to demonstrate robust advantages of antidepressants over placebo. It's doesn't mean that clinicians shouldn't use antidepressants, but they should recognize that there's a limitation. On the other hand, we have very plausible, reasonable explanations for such failure, including the fact that patients who don't actually have the disease have often been enrolled in the studies. Therefore, this failure may have to do with imperfect clinical trial design and conduct."
In addition, Dr. Fava said that the review points to a lack of long-term efficacy for antidepressants, although "this may be due to things such as inadequate management of patients without dose adjustments and other things that can increase the likelihood of remaining well.
"Regardless of how you look at it, this study suggests the importance of developing biomarkers to identify patients who really need these antidepressants both in the short and the long term," concluded Dr. Fava. "I'd say there's a real opportunity here for that."
Dr. Pigott reports consulting in the past 3 years for CNS Response, Midwest Center for Stress and Anxiety, and SmartBrain Technologies. Dr. Fava reports several disclosures, which are listed in the original STAR*D papers
In addition, when the researchers also analyzed the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, "the largest antidepressant effectiveness trial ever conducted," they found that "the effectiveness of antidepressant therapies was probably even lower than the modest one reported...with an apparent progressively increasing dropout rate across each study phase.
"We found that out of the 4041 patients initially started on the SSRI [selective serotonin reuptake inhibitor] citalopram in the STAR*D study, and after 4 trials, only 108 patients had a remission and did not either have a relapse and/or dropped out by the end of 12 months of continuing care," lead study author Ed Pigott, PhD, a psychologist with NeuroAdvantage LLC in Clarksville, Maryland, told Medscape Medical News.
Sustained Benefit "Jaw Dropping"
"In other words, if you're trying to look at sustained benefit, you're only looking at 2.7%, which is a pretty jaw-dropping number," added Dr. Pigott.
Overall, "the reviewed findings argue for a reappraisal of the current recommended standard of care of depression," write the study authors.
"I believe there are likely some people where [antidepressants] are truly beneficial beyond placebo. The problem right now is that we simply have no way of knowing who those people are," noted Dr. Pigott. "My hope is that this kind of analysis creates 'more oxygen' for looking at other kinds of approaches to treatment."
The study was published in the August issue of Psychotherapy and Psychosomatics.
When registering new drug application trials with the FDA, drug companies must prespecify the primary and secondary outcome measures, the investigators report. "Prespecification is essential to ensure the integrity of a trial and enables the discovery of when investigators selectively publish the measures that show the outcome the sponsors prefer following data collection and analysis, a form of researcher bias known as HARKing or 'hypothesizing after the results are known'," they write.
For this article, Dr. Pigott and his team reviewed the following meta-analyses:
•1. Rising and colleagues (reviewed all efficacy trials for new drugs between 2001 and 2002)
•2. Turner and colleagues (reviewed 74 past trials of 12 antidepressants)
•3. Kirsch and colleagues, 2002 (reviewed 47 trials of 6 FDA-approved antidepressants)
•4. Kirsch and colleagues, 2008 (reviewed depression severity and efficacy in 35 trials)
The researchers also sought to reevaluate the methods and findings of STAR*D, a randomized, controlled trial of patients with depression. Its prespecified primary outcome measure was the Hamilton Rating Scale for Depression (HRSD), whereas the Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C30) was secondary for identifying remitted and responder patients.
"STAR*D was designed to identify the best next-step treatment for the many patients who fail to get adequate relief from their initial SSRI trial," the study authors write.
"When I first read about STAR*D's step 1 phase, it just seemed biased to me," explained Dr. Pigott. "I thought of it as the 'tag, you're healed' research design. Patients who were scored as having a remission during the first 4 to 6 weeks of up to 14 weeks of acute care treatment were counted as remitted, taken out of the subject pool, and put into the follow-up care phase. In other words, they didn't have the ability to have a relapse. But as most people know, depression ebbs and flows.
"So what made me want to continue to follow this study was that it became clear that the only way that people were really going to be able to evaluate the antidepressants' effectiveness was to wait for the publication of the follow-up findings," he added. "After their major final summary study was published, I felt as though the results weren't really being portrayed in a manner that was consistent with the study's prespecified criteria."
High Dropout, Low Remission Rates
In addition to reporting on low efficacy of antidepressants compared with placebo, the 4 meta-analyses "also document a second form of bias in which researchers fail to report the negative results for the prespecified primary outcome measure submitted to the FDA, while highlighting in published studies positive results from a secondary or even a new measure, as though it was their primary measure of interest," the investigators write.
For example, they note, the meta-analysis from Rising and colleagues found that studies with favorable outcomes were almost 5 times more likely to be published and that over 26% of primary outcome measures were left out of journal articles. Turner and colleagues found that antidepressant studies were 16 times more likely to be published if favorable compared with those with unfavorable outcomes.
In reanalyzing the STAR*D methods, the researchers found that the high dropout rate resulted in frequently missed exit HRSD and IDS-C30 interviews. So the revised statistical analytical plan dropped the IDS-30 for the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), which was given at each visit.
"Even with the extraordinary care of STAR*D, only about one fourth of patients achieved remission in step 1 [and] the dropout rate was slightly larger than the success rate," the study authors write. Steps 2 through 4 also each showed increasingly fewer success rates and larger dropout rates.
Of the 4041 patients at the study's initiation, 370 (9.2%) dropped out within 2 weeks, and only 1854 patients (45.9%) obtained remission "using the lenient QIDS-SR criteria." Of these, 670 dropped out within a month of their remission, and only 108 "survived continuing care" and underwent the final assessment.
Dr. Pigott described reanalyzing STAR*D as being "a bit like an onion. Each time we thought we understood the results, we found another layer. It wasn't until about a year and a half ago that we discovered that the secondary outcome measure, the QIDS-SR, was not originally supposed to be used as a research measure. What was particularly disconcerting to me was that in their summary article, they basically used the QIDS-SR to report all of the results, which clearly had an inflationary effect on the outcome."
He also noted that STAR*D did not have a placebo design. "Because the patients knew they were receiving the active medication, I would have expected a higher remission rate than what you'd find normally in a placebo-controlled study.
"The inescapable conclusion from the STAR*D results is that we need to explore more seriously other forms of treatment (and combination thereof) that may be more effective. This effort will require developing new service delivery models to ensure that as treatments are identified, they are widely implemented," the investigators conclude.
Need for Biomarkers
"For STAR*D, we wanted to do a study that other people could then reanalyze and look at. So I'm very glad that these authors reexamined it and saw it slightly differently, which came mainly from ways of analyzing data," Maurizio Fava, MD, STAR*D trial investigator and executive vice chair of the Department of Psychiatry at Massachusetts General Hospital in Boston, told Medscape Medical News.
"I think their analysis is reasonable and not incompatible with what we had reported," added Dr. Fava, who was not involved with this review.
He noted that the review's message for clinicians is that "there's been a failure of the field to demonstrate robust advantages of antidepressants over placebo. It's doesn't mean that clinicians shouldn't use antidepressants, but they should recognize that there's a limitation. On the other hand, we have very plausible, reasonable explanations for such failure, including the fact that patients who don't actually have the disease have often been enrolled in the studies. Therefore, this failure may have to do with imperfect clinical trial design and conduct."
In addition, Dr. Fava said that the review points to a lack of long-term efficacy for antidepressants, although "this may be due to things such as inadequate management of patients without dose adjustments and other things that can increase the likelihood of remaining well.
"Regardless of how you look at it, this study suggests the importance of developing biomarkers to identify patients who really need these antidepressants both in the short and the long term," concluded Dr. Fava. "I'd say there's a real opportunity here for that."
Dr. Pigott reports consulting in the past 3 years for CNS Response, Midwest Center for Stress and Anxiety, and SmartBrain Technologies. Dr. Fava reports several disclosures, which are listed in the original STAR*D papers
Saturday, August 14, 2010
National Center for Complementary and Alternative Medicine
Criticism
Critics attest that despite the publicized intentions at its founding, NCCAM and its predecessor, the Office of Alternative Medicine, have spent more than $800 million on such research since 1991 but have neither succeeded in demonstrating the efficacy of a single alternative method nor declared any alternative medicine treatment ineffective. "The NCCAM continues to fund and promote pseudoscience. Political pressures and the Center's charter would seem to make this inevitable," said Kimball C. Atwood IV, M.D.[5]
A policy forum in Science stated,
We believe that NCCAM [National Center for Complementary and Alternative Medicine] funds proposals of dubious merit; its research agenda is shaped more by politics than by science; and it is structured by its charter in a manner that precludes an independent review of its performance...In view of the popularity of alternative therapies, it is appropriate to evaluate the efficacy and safety of selected treatments.
but research falls below the standards of other NIH institutes. NCCAM budget for 2005 was $123.1 million. The charter said that 12 of the 18 members of the NCCAM Advisory Council "shall be selected from among the leading representatives of the health and scientific disciplines...in the area of complementary and alternative medicine. Nine of the members shall be practitioners licensed in one or more of the major systems with which the Center is involved". Clinical trials of St. John's wort, echinacea, and saw palmetto have been published; none was more effective than placebo, but manufacturers said the studies were flawed, and these studies are unlikely to change practices. 70% said they would continue using a supplement that a government agency said was ineffective. NCCAM is funding a study of EDTA chelation therapy for coronary artery disease with 2,300 patients, even though smaller controlled trials have found chelation ineffective. Another negative trial won't modify the practice of individuals who choose to ignore existing negative evidence. NCCAM is also funding a trial of gemcitabine with the Gonzalez regimen for stage II to IV pancreatic cancer, in the belief that cancer is caused by a deficiency of pancreatic proteolytic enzymes that would normally eliminate toxins; severe adverse effects are associated with the Gonzalez regimen. No evidence in peer-reviewed journals supports the plausibility or efficacy of chelation therapy or the Gonzalez protocol[6] and a test of the protocol reported in 2009 found patients receiving the treatment had worse quality of life and died faster than conventionally treated counterparts.[7]
Critics attest that despite the publicized intentions at its founding, NCCAM and its predecessor, the Office of Alternative Medicine, have spent more than $800 million on such research since 1991 but have neither succeeded in demonstrating the efficacy of a single alternative method nor declared any alternative medicine treatment ineffective. "The NCCAM continues to fund and promote pseudoscience. Political pressures and the Center's charter would seem to make this inevitable," said Kimball C. Atwood IV, M.D.[5]
A policy forum in Science stated,
We believe that NCCAM [National Center for Complementary and Alternative Medicine] funds proposals of dubious merit; its research agenda is shaped more by politics than by science; and it is structured by its charter in a manner that precludes an independent review of its performance...In view of the popularity of alternative therapies, it is appropriate to evaluate the efficacy and safety of selected treatments.
but research falls below the standards of other NIH institutes. NCCAM budget for 2005 was $123.1 million. The charter said that 12 of the 18 members of the NCCAM Advisory Council "shall be selected from among the leading representatives of the health and scientific disciplines...in the area of complementary and alternative medicine. Nine of the members shall be practitioners licensed in one or more of the major systems with which the Center is involved". Clinical trials of St. John's wort, echinacea, and saw palmetto have been published; none was more effective than placebo, but manufacturers said the studies were flawed, and these studies are unlikely to change practices. 70% said they would continue using a supplement that a government agency said was ineffective. NCCAM is funding a study of EDTA chelation therapy for coronary artery disease with 2,300 patients, even though smaller controlled trials have found chelation ineffective. Another negative trial won't modify the practice of individuals who choose to ignore existing negative evidence. NCCAM is also funding a trial of gemcitabine with the Gonzalez regimen for stage II to IV pancreatic cancer, in the belief that cancer is caused by a deficiency of pancreatic proteolytic enzymes that would normally eliminate toxins; severe adverse effects are associated with the Gonzalez regimen. No evidence in peer-reviewed journals supports the plausibility or efficacy of chelation therapy or the Gonzalez protocol[6] and a test of the protocol reported in 2009 found patients receiving the treatment had worse quality of life and died faster than conventionally treated counterparts.[7]
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