Conflicts-of-Interest

Discussion in 'Men's Health Forum' started by Michael Scally MD, Jul 2, 2010.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    While this is a process moving towards full disclosure, you can bet that this will never be a fully open process. PhRMA with their billions of dollars on the line will always game the system. In my opinion, the best and only sure fire way to recognize bias, etc, is to read the study and understand it within those previously published and the science. The biggest mistake is believing the hype, anecdotes, and word of mouth reports.


    Conflicts-of-Interest Form Modified
    Medical News: Conflicts-of-Interest Form Modified - in Public Health & Policy, Health Policy from MedPage Today

    The International Committee of Medical Journal Editors (ICMJE) has tweaked its uniform financial disclosure form.

    The major change was removal of questions about potential conflicts of interest of authors' spouses and minor children and about nonfinancial conflicts, Jeffrey Drazen, MD, editor-in-chief of the New England Journal of Medicine, and colleagues wrote in an editorial.

    Those sections of the uniform disclosure form received largely negative feedback when the form was introduced last year, according to the authors.

    However, because of the possibility that indirect or nonfinancial factors could influence -- or appear to influence -- researchers, those questions were replaced by an open-ended question asking, "Are there any other relationships or activities that readers could perceive to influence, or that give the appearance of potentially influencing, what you wrote in the submitted work?"

    The new question "has the advantage of being less intrusive than the previous queries, while providing a locus where authors can report nonfinancial relationships that may be perceived as potential conflicts of interest," Drazen and his colleagues wrote.

    The uniform disclosure form was adopted by all ICMJE member journals in October. Major journals that signed on included NEJM, Annals of Internal Medicine, The Lancet, CMAJ, BMJ, and the Journal of the American Medical Association.

    However, after asking for -- and receiving -- feedback on the disclosure form, ICMJE decided to modify it.

    Minor changes were also made to improve clarity.

    In addition, for the benefit of non-native English speakers, the committee members created a glossary of terms used in the form and will be posting guidelines for translating the form into other languages.

    "The complexity, subjectivity, and emotionality of conflict disclosure ensure that some will consider this vehicle for reporting to be excessively burdensome, while others will think it falls short in one area or another," the authors wrote. "We cannot, however, let the perfect be the enemy of the good."

    "We hope that the revised ICMJE form will be another step toward simplifying and standardizing reporting of conflicts of interest," they concluded.


    Drazen JM, de Leeuw PW, Laine C, et al. Toward More Uniform Conflict Disclosures -- The Updated ICMJE Conflict of Interest Reporting Form. N Engl J Med:NEJMe1006030.

    The great variability in the processes that different journals use to ask about and report authors' potential conflicts of interest creates confusion for authors, readers, and the public. To help lessen this confusion, the International Committee of Medical Journal Editors (ICMJE) developed an electronic uniform disclosure form and placed it in the public domain in October 2009. The ICMJE member journals piloted the form, encouraged other journals to use it, and invited feedback. We recognized that the reporting of competing interests is complex and nuancedand sometimes contentious and thus anticipated modifying the form on the basis of feedback received. We are grateful to the many authors, editors, and other interested parties who took the time to comment on the form and its implementation. The issues raised ranged from technical problems about the correct deployment of the form (to function, it requires the user todownload the free Adobe Reader, version 8.0 or higher [Adobe Systems]) to concerns about the ethics of inquiring about nonfinancial associations. The Committee considered these valuable comments and revised the form at our most recent meeting.

    We made several modifications. The major change in the reporting instrument is the removal of the queries about potential competing interests of authors' spouses and minor children and about nonfinancial competing interests. We made this change on the basis of the largely negative feedback that we received about these sections. People who commented about this issue made it clear that there is immense difficulty in defining competing interests beyond those that involve the direct exchange of money from an interested party to an individual author or the author's institution. Because the Committee continues to believe that there are situations in which indirect or nonfinancial factors could influence (or appear to influence) the conduct or interpretation of work, we replaced the specific questions with a single open-ended query (new Section 4) that asks, "Are there any other relationships or activities that readers could perceive to influence, or that give the appearance of potentially influencing, what you wrote in the submitted work?" This change places the onus on the person completing the form to identify and report appropriate nonfinancial competing interests. It has the advantage of being less intrusive than the previous queries, while providing a locus where authors can report nonfinancial relationships that may be perceived as potential conflicts of interest.

    In response to comments about the clarity of the form, each field in the form now has a numeric designation. We have modified the language in the instructions and in the individual queries. To make the form more useful to nonnative English speakers, we are creating a glossary of terms used in the form and will be posting guidelines for translation of the form's instructions into multiple languages. The translation of this form is particularly challenging because translations must capture the essence of the queries rather than their literal meaning. The glossary and instructions will be available at ICMJE: Uniform Requirements for Manuscripts Submitted to Biomedical Journals in the next few months; translations will be posted on the ICMJE Web site as they become available.

    The new form, in English, is currently available on the ICMJE Web site and the Web sites of our member journals. Authors who have completed the older version of the form in conjunction with a journal submission need not complete the new form, but the new form will be the standard for new submissions. We welcome continued input from the user community. Comments can be sent via the "contact us" link at ICMJE: Uniform Requirements for Manuscripts Submitted to Biomedical Journals. The Committee will consider comments received before May 1, 2011, when we prepare the next iteration of the uniform conflict of interest disclosure form.

    The complexity, subjectivity, and emotionality of conflict disclosure ensure that some will consider this vehicle for reporting to be excessively burdensome, while others will think it falls short in one area or another. We cannot, however, let the perfect be the enemy of the good. We hope that the revised ICMJE form will be another step toward simplifying and standardizing reporting of conflicts of interest. A more uniform reporting process will alleviate the confusion that prevails when multiple journals use different reporting formats and will ease the reporting burden on the members of the biomedical research community so they can pursue the research that will improve the care that we can deliver to our patients. With these thoughts in mind, we encourage all journals to adopt the new version of the uniform disclosure form.

    Jeffrey M. Drazen, M.D.
    Editor-in-Chief, New England Journal of Medicine

    Peter W. de Leeuw, M.D., Ph.D.
    Editor-in-Chief, Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine)

    Christine Laine, M.D., M.P.H.
    Editor, Annals of Internal Medicine

    Cynthia Mulrow, M.D., M.Sc.
    Secretary, ICMJE
    Senior Deputy Editor, Annals of Internal Medicine

    Catherine D. DeAngelis, M.D., M.P.H.
    Editor-in-Chief, JAMA

    Frank A. Frizelle, M.B., Ch.B.
    Editor-in-Chief, The New Zealand Medical Journal

    Fiona Godlee, M.B., B.Chir., B.Sc.
    Editor-in-Chief, BMJ

    Charlotte Haug, M.D., Ph.D., M.Sc.
    Editor-in-Chief, Tidsskrift for Den norske legeforening (Journal of the Norwegian Medical Association)

    Paul C. Hébert, M.D., M.H.Sc.
    Editor-in-Chief, Canadian Medical Association Journal

    Astrid James, M.B., B.S., B.Sc.
    Deputy Editor, The Lancet

    Sheldon Kotzin, M.L.S.
    Associate Director for Library Operations, National Library of Medicine

    Ana Marusic, M.D., Ph.D.
    Editor-in-Chief, Croatian Medical Journal

    Humberto Reyes, M.D.
    Editor, Revista Médica de Chile

    Jacob Rosenberg, M.D., D.Sc.
    Editor, Journal of the Danish Medical Association

    Peush Sahni, M.S., Ph.D.
    Representative and Past President, World Association of Medical Editors

    Martin B. Van Der Weyden, M.D.
    Editor, The Medical Journal of Australia

    Getu Zhaori, M.D.
    Editor-in-Chief, Chinese Medical Journal

    This article (10.1056/NEJMe1006030) was published on July 1, 2010, at NEJM.org.

    Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

    Editor's note: This editorial is being published simultaneously in all ICMJE member journals.

    Disclaimer: Dr. Sahni's affiliation as representative and past president of the World Association of Medical Editors (WAME) does not imply endorsement by WAME member journals that are not part of the ICMJE.
     
    Last edited: Nov 30, 2010
  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: Conflicts-of-Interest Form Modified

    Funding May Affect Reporting of Trial Results
    Medical News: Funding May Affect Reporting of Trial Results - in Public Health & Policy, Clinical Trials from MedPage Today

    Among drug trials registered in ClinicalTrials.gov, those primarily funded by industry were more likely to report positive outcomes than those funded through other sources, researchers found.

    The vast majority of published industry-funded trials (85.4%) had positive findings, compared with 50% of those funded by government and 71.9% of those funded by nonprofit or nonfederal organizations (P<0.001), according to Florence Bourgeois, MD, MPH, Children's Hospital Boston, and colleagues.

    Industry-funded trials were also less likely to be published within two years of completion (P=0.005), the researchers reported in the Aug. 3 issue of theAnnals of Internal Medicine.

    "For trial registries to maximize transparency around clinical trials and ensure the validity and quality of the resulting scientific evidence, timely, accurate, and expanded information entry and results disclosure are required," they wrote.

    Bourgeois and her colleagues searched ClinicalTrials.gov for safety and efficacy trials for five classes of medications -- anticholesteremics, antidepressants, antipsychotics, proton pump inhibitors, and vasodilators -- conducted between 2000 and 2006.

    Of the 546 trials identified, 63% were primarily industry-funded, 14% were government-funded, and 23% were funded by nonprofit or nonfederal organizations; 4% of the government-funded and 48% of the nonprofit and nonfederal organization-funded trials also received contributions from industry.

    Trials funded by industry were more likely to be phase III or IV trials, to use an active comparator in controlled trials, to be multicenter, and to enroll more participants than the other trials (P?0.01 for all).

    Overall, about two-thirds (66.3%) of the trials had published results, the authors reported.

    And, among those published results, trials funded by industry were more likely to report positive outcomes.

    Also, of the trials primarily funded by nonprofit or nonfederal sources, those that had received additional contributions from industry were more likely to report positive findings than those without such additional funding (85% versus 61.2%, P=0.013).

    The researchers conducted a post-hoc, multivariate analysis to determine whether the increased likelihood of positive findings in industry-funded trials was influenced by trial characteristics.

    However, after controlling for drug class, approval status of indication, study phase, multicenter status, anticipated sample size, mean age of the patients, comparator type, and study length, the primary funding source remained a significant predictor of favorable published outcomes.

    Rates of trial publications within two years of study completion ranged from 32.4% for industry-funded trials, 39% for trials primarily funded by nonprofit and nonfederal organizations with additional industry funding, 53.7% for government-funded trials, and 56.2% for trials primarily funded by nonprofit and nonfederal organizations without additional industry funding (P=0.005 across groups).

    The researchers noted some limitations of their analysis, including the inability to confirm the publication status of every drug trial, and the fact that many data fields in the registry had missing values.

    Additional information on study protocols and comprehensive trial results were also not available, precluding further evaluation of factors that might have explained the association between funding source and outcome reporting.

    "This limitation may be addressed in the future by proposed changes to ClinicalTrials.gov, such as incorporating study protocols and amendments into trial registrations and making FDA drug reviews public, including their statistical analyses and comprehensive summaries of trial results by independent experts," the researchers wrote.


    Bourgeois FT, Murthy S, Mandl KD. Outcome Reporting Among Drug Trials Registered in ClinicalTrials.gov. Annals of Internal Medicine;153(3):158-66.

    Background: Clinical trial registries are in widespread use to promote transparency around trials and their results.

    Objective: To describe characteristics of drug trials listed in ClinicalTrials.gov and examine whether the funding source of these trials is associated with favorable published outcomes.

    Design: An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006.Setting: ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999.Measurements: Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations.

    Results: Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; PÂ < 0.001 across groups), to use an active comparator in controlled trials (36.8%; PÂ = 0.010 across groups), to be multicenter (89.0%; PÂ < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; PÂ < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization funded trials (PÂ < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; PÂ = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization funded trials without industry contributions (PÂ = 0.005 across groups).Limitations: The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting.

    Conclusion: In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources.

    Primary Funding Source: National Library of Medicine and National Institute of Child Health and Human Development, National Institutes of Health.
     
  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Dollars for Doctors

    Dollars for Doctors - Is your doctor taking payments from drug companies for speaking and consulting? ProPublica compiled thousands of records to track the financial ties between doctors and drug companies. http://www.propublica.org/topic/dollars-for-doctors

    Docs on Pharma Payroll Have Blemished Records, Limited Credentials
    http://www.propublica.org/article/dollars-to-doctors-physician-disciplinary-records

    by Charles Ornstein , Tracy Weber and Dan Nguyen
    Oct. 18, 2010

    The Ohio medical board concluded that pain physician William D. Leak had performed “unnecessary” nerve tests on 20 patients and subjected some to “an excessive number of invasive procedures,” including injections of agents that destroy nerve tissue.

    Yet the finding, posted on the board’s public website, didn’t prevent Eli Lilly and Co. from using him as a promotional speaker and adviser. The company has paid him $85,450 since 2009.

    In 2001, the U.S. Food and Drug Administration ordered Pennsylvania doctor James I. McMillen to stop “false or misleading” promotions of the painkiller Celebrex, saying he minimized risks and touted it for unapproved uses.

    Still, three other leading drug makers paid the rheumatologist $224,163 over 18 months to deliver talks to other physicians about their drugs.

    And in Georgia, a state appeals court in 2004 upheld a hospital’s decision to kick Dr. Donald Ray Taylor off its staff. The anesthesiologist had admitted giving young female patients rectal and vaginal exams without documenting why. He’d also been accused of exposing women’s breasts during medical procedures. When confronted by a hospital official, Taylor said, “Maybe I am a pervert, I honestly don’t know,” according to the appellate court ruling.

    Last year, Taylor was Cephalon's third-highest-paid speaker out of more than 900. He received $142,050 in 2009 and another $52,400 through June.

    Leak, McMillen and Taylor are part of the pharmaceutical industry’s white-coat sales force, doctors paid to promote brand-name drugs to their peers — and if they’re convincing enough, get more physicians to prescribe them.

    Drug companies say they hire the most-respected doctors in their fields for the critical task of teaching about the benefits and risks of their drugs.

    But an investigation by ProPublica uncovered hundreds of doctors on company payrolls who had been accused of professional misconduct, were disciplined by state boards or lacked credentials as researchers or specialists.

    This story is the first of several planned by ProPublica examining the high-stakes pursuit of the nation’s physicians and their prescription pads. The implications are great for patients, who in the past have been exposed to such heavily marketed drugs as the painkiller Bextra and the diabetes drug Avandia — billion-dollar blockbusters until dangerous side effects emerged.

    "Without question the public should care," said Dr. Joseph Ross, an assistant professor of medicine at Yale School of Medicine who has written about the industry’s influence on physicians. "You would never want your kid learning from a bad teacher. Why would you want your doctor learning from a bad doctor, someone who hasn’t displayed good judgment in the past?"

    To vet the industry’s handpicked speakers, ProPublica created a comprehensive database that represents the most accessible accounting yet of payments to doctors. Compiled from disclosures by seven companies, the database covers $257.8 million in payouts since 2009 for speaking, consulting and other duties. In addition to Lilly and Cephalon, the companies include AstraZeneca, GlaxoSmithKline, Johnson & Johnson, Merck & Co. and Pfizer.

    Although these companies have posted payments on their websites — some as a result of legal settlements — they make it difficult to spot trends or even learn who has earned the most. ProPublica combined the data and identified the highest-paid doctors, then checked their credentials and disciplinary records.

    That is something not all companies do.

    A review of physician licensing records in the 15 most-populous states and three others found sanctions against more than 250 speakers, including some of the highest paid. Their misconduct included inappropriately prescribing drugs, providing poor care or having sex with patients. Some of the doctors had even lost their licenses.

    More than 40 have received FDA warnings for research misconduct, lost hospital privileges or been convicted of crimes. And at least 20 more have had two or more malpractice judgments or settlements. This accounting is by no means complete; many state regulators don’t post these actions on their web sites.

    In interviews and written statements, five of the seven companies acknowledged that they don’t routinely check state board websites for discipline against doctors. Instead, they rely on self-reporting and checks of federal databases. Only Johnson & Johnson and Cephalon said they review the state sites.

    ProPublica found 88 Lilly speakers who have been sanctioned and four more who had received FDA warnings. Reporters asked Lilly about several of those, including Leak and McMillen. A spokesman said the company was unaware of the cases and is now investigating them.

    “They are representatives of the company,” said Dr. Jack Harris, vice president of Lilly’s U.S. medical division. “It would be very concerning that one of our speakers was someone who had these other things going on.”

    Leak, the pain doctor, and his attorney did not respond to multiple messages. The Ohio medical board voted to revoke Leak’s license in 2008. It remains active as he appeals in court, arguing that the evidence against him was old, the witnesses unreliable and the sentence too harsh.

    In an interview, McMillen denied nearly all of the allegations in the FDA letter and blamed his troubles on a rival firm whose drug he had criticized in his presentations.

    “I’m more cautious now than I ever was,” said McMillen, who said he also does research. “That’s why I think a lot of the companies use me. I’m not taking any risks.”

    Taylor said that the allegations against him were “old news” from the 1990s and that regulators had not sanctioned him. “It had nothing to do with my skills as a physician,” said Taylor, noting that he speaks every other week around the country and sometimes abroad. “Even my biggest detractors in that situation lauded my skills as a physician. That’s what’s most important.”

    Disclosures are just the start

    Payments to doctors for promotional work are not illegal and can be beneficial. Strong relationships between pharmaceutical companies and physicians are critical to developing new and better treatments.

    There is much debate, however, about whether paying doctors to market drugs can inappropriately influence what they prescribe. Studies have shown that even small gifts and payments affect physician attitudes. Such issues have become flashpoints in recent years both in courtrooms and in Congress.

    All told, 384 of the approximately 17,700 individuals in ProPublica’s database earned more than $100,000 for their promotional and consulting work on behalf of one or more of the seven companies in 2009 and 2010. Nearly all were physicians, but a handful of pharmacists, nurse practitioners and dietitians also made the list. Forty-three physicians made more than $200,000 — including two who topped $300,000.

    Physicians also received money from some of the 70-plus drug companies that have not disclosed their payments. Some of those interviewed could not recall all the companies that paid them, and certainly not how much they made. By 2013, the health care reform law requires all drug companies to report this information to the federal government, which will post it on the Web.

    The busiest — and best compensated — doctors gave dozens of speeches a year, according to the data and interviews. The work can mean a significant salary boost — enough for the kids’ college tuition, a nicer home, a better vacation.

    Among the top-paid speakers, some had impressive resumes, clearly demonstrating their expertise as researchers or specialists. But others did not –contrary to the standards the companies say they follow.

    Forty five who earned in excess of $100,000 did not have board certification in any specialty, suggesting they had not completed advanced training and passed a comprehensive exam. Some of those doctors and others also lacked published research, academic appointments or leadership roles in professional societies.

    Experts say the fact that some companies are disclosing their payments is merely a start. The disclosures do not fully explain what the doctors do for the money — and what the companies get in return.

    In a raft of federal whistleblower lawsuits, former employees and the government contend that the firms have used fees as rewards for high-prescribing physicians. The companies have each paid hundreds of millions or more to settle the suits.

    The disclosures also leave unanswered what impact these payments have on patients or the health care system as a whole. Are dinner talks prompting doctors to prescribe risky drugs when there are safer alternatives? Or are effective generics overlooked in favor of pricey brand-name drugs?

    "The pressure is enormous. The investment in these drugs is massive,” said Dr. David A. Kessler, who formerly served as both FDA commissioner and dean of the University of California, San Francisco School of Medicine. “Are any of us surprised they’re trying to maximize their markets in almost any way they can?”

    From drug reps to doc reps

    For years, drug companies bombarded doctors with pens, rulers, sticky notes, even stuffed animals emblazoned with the names of the latest remedies for acid reflux, hypertension or erectile dysfunction. They wooed physicians with fancy dinners, resort vacations and personalized stethoscopes.

    Concerns that this pharma-funded bounty amounted to bribery led the industry to ban most gifts voluntarily. Some hospitals and physicians also banned the gift-givers: the legions of drug sales reps who once freely roamed their halls.

    So the industry has relied more heavily on the people trusted most by doctors — their peers. Today, tens of thousands of U.S. physicians are paid to spread the word about pharma’s favored pills and to advise the companies about research and marketing.

    Recruited and trained by the drug companies, the physicians — accompanied by drug reps — give talks to doctors over small dinners, lecture during hospital teaching sessions and chat over the Internet. They typically must adhere to company slides and talking points.

    These presentations fill an educational gap, especially for geographically isolated primary care doctors charged with treating everything from lung conditions to migraines. For these doctors, poring over a stack of journal articles on the latest treatments may be unrealistic. A pharma-sponsored dinner may be their only exposure to new drugs that are safer and more effective.

    Oklahoma pulmonologist James Seebass, for example, earned $218,800 from Glaxo in 2009 and 2010 for lecturing about respiratory diseases “in the boonies,” he said. On a recent trip, he said, he drove to “a little bar 40 miles from Odessa,” Texas, where physicians and nurse practitioners had come 50 to 60 miles to hear him.

    Seebass, the former chair of internal medicine at Oklahoma State University College of Osteopathic Medicine, said such talks are “a calling,” and he is booking them for 2011.

    The fees paid to speakers are fair compensation for their time away from their practices, and for travel and preparation as well as lecturing, the companies say.

    Dr. Samuel Dagogo-Jack has a resume that would burnish any company’s sales force: He is chief of the division of endocrinology, diabetes and metabolism at the University of Tennessee Health Science Center. Dagogo-Jack conducts research funded by the National Institutes of Health, has edited medical journals and continues to see patients.

    While most people are going home to dinner with their families, he said, he is leaving to hop on a plane to bring news of fresh diabetes treatments to non-specialist physicians “in the trenches” who see the vast majority of cases.

    Since 2009, Dagogo-Jack has been paid at least $257,000 by Glaxo, Lilly and Merck.

    “If you actually prorate that by the hours put in, it is barely more than minimum wage,” he said. (A person earning the federal minimum wage of $7.25 would have to work 24 hours a day, seven days a week for more than four years to earn Dagogo-Jack’s fees.)

    For the pharmaceutical companies, one effective speaker may not only teach dozens of physicians how to better recognize a condition, but sell them on a drug to treat it. The success of one drug can mean hundreds of millions in profits, or more. Last year, prescription drugs sales in the United States topped $300 billion, according to IMS Health, a healthcare information and consulting company.

    Glaxo’s drug to treat enlarged prostates, avodart — locked in a battle with a more popular competitor — is the topic of more lectures than any of the firm’s other drugs, a company spokeswoman said. Glaxo’s promotional push has helped quadruple Avodart’s revenue to $559 million in five years and double its market share, according to IMS.

    Favored speakers like St. Louis pain doctor Anthony Guarino earn $1,500 to $2,000 for a local dinner talk to a group of physicians.

    Guarino, who made $243,457 from Cephalon, Lilly and Johnson & Johnson since 2009, considers himself a valued communicator. A big part of his job, he said, is educating the generalists, family practitioners and internists about diseases like fibromyalgia, which causes chronic, widespread pain — and to let them know that Lilly has a drug to treat it.

    “Somebody like myself may be able to give a better understanding of how to recognize it,” Guarino said. Then, he offers them a solution: “And by the way, there is a product that has an on-label indication for treating it.’’

    Guarino said he is worth the fees pharma pays him on top of his salary as director of a pain clinic affiliated with Washington University. Guarino likened his standing in the pharma industry to that of St. Louis Cardinals first baseman Albert Pujols, named baseball player of the decade last year by Sports Illustrated. Both earn what the market will bear, he said: “I know I get paid really well.”

    Is anyone checking out there?

    Simple searches of government websites turned up disciplinary actions against many pharma speakers in ProPublica’s database.

    The Medical Board of California filed a public accusation against psychiatrist Karin Hastik in 2008 and placed her on five years’ probation in May for gross negligence in her care of a patient. A monitor must observe her practice.

    Kentucky’s medical board placed Dr. Van Breeding on probation from 2005 to 2008. In a stipulation filed with the board, Breeding admits unethical and unprofessional conduct. Reviewing 23 patient records, a consultant found Breeding often that gave addictive pain killers without clear justification. He also voluntarily relinquished his Florida license.

    New York’s medical board put Dr. Tulio Ortega on two years’ probation in 2008 after he pleaded no contest to falsifying records to show he had treated four patients when he had not. Louisiana’s medical board, acting on the New York discipline, also put him on probation this year.

    Yet during 2009 and 2010, Hastik made $168,658 from Lilly, Glaxo and AstraZeneca. Ortega was paid $110,928 from Lilly and AstraZeneca. Breeding took in $37,497 from four of the firms. Hastik declined to comment, and Breeding and Ortega did not respond to messages.

    Their disciplinary records raise questions about the companies’ vigilance.

    “Did they not do background checks on these people? Why did they pick them?” said Lisa Bero, a pharmacy professor at University of California, San Francisco who has extensively studied conflicts of interest in medicine and research.

    Disciplinary actions, Bero said, reflect on a physician’s credibility and willingness to cross ethical boundaries.

    "If they did things in their background that are questionable, what about the information they’re giving me now?” she said.

    ProPublica found sanctions ranging from relatively minor misdeeds such as failing to complete medical education courses to the negligent treatment of multiple patients. Some happened long ago; some are ongoing. The sanctioned doctors were paid anywhere from $100 to more than $140,000.

    Several doctors were disciplined for misconduct involving drugs made by the companies that paid them to speak. In 2009, Michigan regulators accused one rheumatologist of forging a colleague’s name to get prescriptions for viagra and cialis. Last year, the doctor was paid $17,721 as a speaker for Pfizer, Viagra’s maker.

    A California doctor who was paid $950 this year to speak for AstraZeneca was placed on five years’ probation by regulators in 2009 after having a breakdown, threatening suicide and spending time in a psychiatric hospital after police used a Taser on him. He said he’d been self-treating with samples of AstraZeneca’s anti-psychotic drug Seroquel, medical board records show.

    Other paid speakers had been disciplined by their employers or warned by the federal government. At least 15 doctors lost staff privileges at various hospitals, including one New Jersey doctor who had been suspended twice for patient care lapses and inappropriate behavior. Other doctors received FDA warning letters for research misconduct such as failing to get informed consent from patients.

    Pharma companies say they rely primarily on a federal database listing those whose behavior in some way disqualifies them from participating in Medicare. This database, however, is notoriously incomplete.

    The industry’s primary trade group says its voluntary code of conduct is silent about what, if any, behavior should disqualify physician speakers.

    “We look at it from the affirmative — things that would qualify physicians,” said Diane Bieri, general counsel and executive vice president of the Pharmaceutical Research and Manufacturers of America.

    Some physicians with disciplinary records say their past misdeeds do not reflect on their ability to educate their peers.

    Family medicine physician Jeffrey Unger was put on probation by California’s medical board in 1999 after he misdiagnosed a woman’s breast cancer for 2½ years. She received treatment too late to save her life. In 2000, the Nevada medical board revoked Unger’s license for not disclosing California’s action.

    As a result, Unger said, he decided to slow down and start listening to his patients. Since then, he said, he has written more than 130 peer-reviewed articles and book chapters on diabetes, mental illness and pain management.

    “I think I’ve more than accomplished what I’ve needed to make this all right,” he said. During 2009 and the first quarter of 2010, Lilly paid Unger $87,830. He said he also is a paid speaker for Novo Nordisk and Roche, two companies that have not disclosed payments.

    The drug firms, Unger said, “apparently looked beyond the record.”

    Companies make their own experts

    Last summer, as drug giant Glaxo battled efforts to yank its blockbuster diabetes drug Avandia from the market, Nashville cardiologist Hal Roseman worked the front lines.

    At an FDA hearing, he borrowed David Letterman’s shtick to deliver a “Top Five” list of reasons to keep the drug on the market despite evidence it caused heart problems. He faced off against a renowned Yale cardiologist and Avandia critic on the PBS NewsHour, arguing that the drug’s risks had been overblown.

    “I still feel very convinced in the drug,” Roseman said with relaxed confidence. The FDA severely restricted access to the drug last month citing its risks.

    Roseman is not a researcher with published peer-reviewed studies to his name. Nor is he on the staff of a top academic medical center or in a leadership role among his colleagues.

    Roseman’s public profile comes from his work as one of Glaxo’s highest-paid speakers. In 2009 and 2010, he earned $223,250 from the firm — in addition to payouts from other companies.

    Pharma companies often say their physician salesmen are chosen for their expertise. Glaxo, for example, said it selects “highly qualified experts in their field, well-respected by their peers and, in the case of speakers, good presenters.”

    ProPublica found that some top speakers are experts mainly because the companies have deemed them such. Several acknowledge that they are regularly called upon because they are willing to speak when, where and how the companies need them to.

    “It’s sort of like American Idol,” said sociologist Susan Chimonas, who studies doctor-pharma relationships at the Institute on Medicine as a Profession in New York City.

    “Nobody will have necessarily heard of you before — but after you’ve been around the country speaking 100 times a year, people will begin to know your name and think, ‘This guy is important.’ It creates an opinion leader who wasn’t necessarily an expert before.”

    To check the qualifications of top-paid doctors, reporters searched for medical research, academic appointments and professional society involvement. They also interviewed national leaders in the physicians’ specialties.

    In numerous cases, little information turned up.

    Las Vegas endocrinologist Firhaad Ismail, for example, is the top earner in the database, making $303,558, yet only his schooling and mostly 20-year-old research articles could be found. An online brochure for a presentation he gave earlier this month listed him as chief of endocrinology at a local hospital, but an official there said he hasn’t held that title since 2008.

    And several leading pain experts said they’d never heard of Santa Monica pain doctor Gerald Sacks, who was paid $249,822 since 2009.

    Neither physician returned multiple calls and letters.

    A recently unsealed whistleblower lawsuit against Novartis, the nation’s sixth-largest drug maker by sales, alleges that many speakers were chosen “on their prescription potential rather than their true credentials.”

    Speakers were used and paid as long as they kept their prescription levels up, even though “several speakers had difficulty with English,” according to the amended complaint filed this year in federal court in Philadelphia.

    Some physicians were paid for speaking to one another, the lawsuit alleged. Several family practice doctors in Peoria, Ill., “had two programs every week at the same restaurant with the same group of physicians as the audience attendees.”

    In September, Novartis agreed to pay the government $422.5 million to resolve civil and criminal allegations in this case and others. The company has said it fixed its practices and now complies with government rules.

    Roseman, who has been a pharma speaker for about a decade, acknowledged that his expertise comes by way of the training provided by the companies that pay him. But he says that makes him the best prepared to speak about their products, which he prescribes for his own patients. Asked about Roseman’s credentials, a Glaxo spokeswoman said he is an “appropriate” speaker.

    Getting paid to speak “doesn’t mean that your views have necessarily been tainted,” he said.

    Plus pharma needs talent, Roseman said. Top-tier universities such as Harvard have begun banning their staffs from accepting pharma money for speaking, he said. “It irritates me that the debate over bias comes down to a litmus test of money,” Roseman said. “The amount of knowledge that I have is in some regards to be valued.”
     
    Last edited: Oct 19, 2010
  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: Conflicts-of-Interest Form Modified

    'Positive Outcome' Bias Found in Peer Review
    Medical News: &apos;Positive Outcome&apos; Bias Found in Peer Review - in Public Health & Policy, Ethics from MedPage Today

    By John Gever, Senior Editor, MedPage Today
    Published: November 23, 2010

    One reason that so-called negative studies often fail to be published may be "positive-outcome bias" in peer review, said researchers who conducted a randomized trial.

    Presented with a fictitious study showing that one treatment was superior to another, peer reviewers at two orthopedics journals were significantly more likely to recommend publication than when given an otherwise identical manuscript that indicated no difference between treatments, according to Seth Leopold, MD, and colleagues at the University of Washington in Seattle.

    Moreover, they reported in the Nov. 22 issue of Archives of Internal Medicine, it appeared that reviewers gave "heightened scrutiny" to the no-difference study. Methods in the two versions of the manuscript were identical, but reviewers gave lower grades to the methodological quality in the one indicating no difference between treatments.

    Leopold and colleagues concluded that their findings constitute "evidence of positive-outcome bias" in manuscript review and therefore in publication.

    "To the extent that positive-outcome bias exists, it would be expected to compromise the integrity of the literature in many important ways, including, but not limited to, inflation of apparent treatment effect sizes when the published literature is subjected to meta-analysis," they wrote.

    In the study, the researchers randomly sent one of the two nearly identical manuscripts to 102 reviewers for the American edition of the Journal of Bone and Joint Surgery (JBJS) and 108 reviewers for Clinical Orthopaedics and Related Research (CORR). The editors of these journals when the study was conducted were investigators in the study.

    Reviewers for these journals were informed beforehand that, as part of a study of peer review, they might receive a manuscript for review and they could opt out if they wished. Those not opting out were not told which manuscript was part of the study nor were they informed about the study's aims.

    The manuscripts themselves reported a randomized trial of surgical antibiotic prophylaxis in which all details were identical except for the primary outcome result and the corresponding conclusions. One version indicated that an particular antibiotic regimen was significantly superior to another, whereas the other reported no difference.

    Also, five errors were intentionally included in the manuscripts, including two mathematical mistakes, two erroneous reference citations, and switching of results in a data table.

    Leopold and colleagues wrote that the manuscripts "represent[ed] an extremely well-designed, multicenter, surgical, randomized controlled trial." They also noted that the experiment took place before public trial registration became mandatory at these journals, so the fabricated study's absence from Clinicaltrials.gov would not have raised suspicions.

    The positive version of the manuscript drew recommendations to publish from 97.3% of the reviewers at both journals, with little difference between them.

    Only 80.0% of reviewers recommended publishing the no-difference version (P<0.001). The disparity was most pronounced at the JBJS, where 71.2% of reviewers favored publication (versus 98.0% for the positive manuscript, P=0.001).

    At CORR, 89.6% of reviewers indicated the no-difference manuscript should be accepted (versus 96.7% favorable toward the positive version, P=0.28).

    At both journals, reviewers were significantly more likely to detect the deliberately placed errors in the no-difference version of the manuscript. The average was 0.85 overall in the no-difference version versus 0.41 for the one with positive outcome (P<0.001). CORR reviewers were slightly more adept at picking up errors in both versions relative to their JBJS counterparts, but the gap in detection rates for the two versions was the same at both journals.

    The review process at both journals also involved scoring the quality of methods.JBJS reviewers downgraded the methods in the no-difference manuscript significantly (mean 7.66 versus 8.68, P=0.005).

    At CORR, there was a nonsignificant trend toward lower methods scores for the no-difference version (mean 7.38 versus 7.87, P=0.22).

    But the overall mean scores at both journals combined remained significantly higher for the manuscript with the positive outcome.

    Leopold and colleagues noted that other forces besides reviewers' bias may favor publication of positive-outcome studies, including an increased likelihood that such studies will be submitted in the first place.

    "If so, then that, along with the evidence identified in this experimental study, highlights the importance of sensitivity to this issue during peer review," they argued.

    They suggested that journals should do more to foster publication of high-quality studies with negative results -- encouraging authors to submit them and giving them higher priority for publication, perhaps in nontraditional forms such as online appendices.

    Limitations to the study included differences in the review processes at the two journals and the possibility that some reviewers detected the fabrication.


    Emerson GB, Warme WJ, Wolf FM, Heckman JD, Brand RA, Leopold SS. Testing for the Presence of Positive-Outcome Bias in Peer Review: A Randomized Controlled Trial. Arch Intern Med 2010;170(21):1934-9.

    Background - If positive-outcome bias exists, it threatens the integrity of evidence-based medicine.

    Methods - We sought to determine whether positive-outcome bias is present during peer review by testing whether peer reviewers would (1) recommend publication of a "positive" version of a fabricated manuscript over an otherwise identical "no-difference" version, (2) identify more purposefully placed errors in the no-difference version, and (3) rate the "Methods" section in the positive version more highly than the identical "Methods" section in the no-difference version. Two versions of a well-designed randomized controlled trial that differed only in the direction of the finding of the principal study end point were submitted for peer review to 2 journals in 2008-2009. Of 238 reviewers for The Journal of Bone and Joint Surgery and Clinical Orthopaedics and Related Research randomly allocated to review either a positive or a no-difference version of the manuscript, 210 returned reviews.

    Results - Reviewers were more likely to recommend the positive version of the test manuscript for publication than the no-difference version (97.3% vs 80.0%, P < .001). Reviewers detected more errors in the no-difference version than in the positive version (0.85 vs 0.41, P < .001). Reviewers awarded higher methods scores to the positive manuscript than to the no-difference manuscript (8.24 vs 7.53, P = .005), although the "Methods" sections in the 2 versions were identical.

    Conclusions - Positive-outcome bias was present during peer review. A fabricated manuscript with a positive outcome was more likely to be recommended for publication than was an otherwise identical no-difference manuscript.
     

    Attached Files:

  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Drug Maker Wrote Book Under 2 Doctors’ Names, Documents Say
    http://www.nytimes.com/2010/11/30/business/30drug.html

    By DUFF WILSON
    Published: November 29, 2010

    Two prominent authors of a 1999 book teaching family doctors how to treat psychiatric disorders provided acknowledgment in the preface for an “unrestricted educational grant” from a major pharmaceutical company.

    But the drug maker, then known as SmithKline Beecham, actually had much more involvement than the book described, newly disclosed documents show. The grant paid for a writing company to develop the outline and text for the two named authors, the documents show, and then the writing company said it planned to show three drafts directly to the pharmaceutical company for comments and “sign-off” and page proofs for “final approval.”

    “That doesn’t sound unrestricted to me,” Dr. Bernard Lo, a medical ethicist and chairman of an Institute of Medicinegroup that wrote a 2009 report on conflicts of interest, said after reviewing the documents. “That sounds like they have ultimate control.”

    The 269-page book, “Recognition and Treatment of Psychiatric Disorders: A Psychopharmacology Handbook for Primary Care,” is so far the first book among publications, namely medical journal articles, that have been criticized in recent years for hidden drug industry influence, colloquially known as ghostwriting.

    “To ghostwrite an entire textbook is a new level of chutzpah,” said Dr. David A. Kessler, former commissioner of the Food and Drug Administration, after reviewing the documents. “I’ve never heard of that before. It takes your breath away.”

    The book has never been in wide circulation and has not been sold for a few years. Guidelines restricting the use of industry money to support medical journal articles or doctors’ research have come into wide acceptance within the last several years, to try to minimize the influence of companies’ marketing on medical practices.

    The book’s listed co-authors were Dr. Charles B. Nemeroff, chairman of psychiatry at theUniversity of Miami medical school since 2009 and Emory University before that, and Dr. Alan F. Schatzberg, who was chairman of psychiatry at the Stanford University School of Medicine from 1991 until last year.

    The letter documenting the relationship between Dr. Nemeroff, a writing company and SmithKline was dated Feb. 4, 1997. It and a “preliminary draft” of the book, dated Feb. 21, 1997, and adding Dr. Schatzberg’s name were released Monday by the Project on Government Oversight, a Washington advocacy group. They were attached to a letter of complaint to Dr. Francis S. Collins, director of the National Institutes of Health. In the letter, Danielle Brian, executive director of the project, and Paul Thacker, an investigator, formerly with the staff of Senator Charles Grassley of Iowa, also cited other examples of what they termed ghostwriting and asked the N.I.H. for better policing of such practices.

    The documents were separately obtained by The New York Times from the Los Angeles law firm of Baum Hedlund, which received them as part of discovery in lawsuits against the drug company, now known as GlaxoSmithKline, involving Paxil. Leemon B. McHenry, a bioethicist with California State University, Northridge, who consults for the law firm, said many similar documents remain sealed. “This is only the tip of the iceberg,” he said.

    Responding to questions by e-mail last week, Dr. Nemeroff and Dr. Schatzberg emphasized the “unrestricted” nature of the grant from the drug maker to develop the book and said they did most of the work. SmithKline “had no involvement in content,” Dr. Schatzberg said, adding, “An unrestricted grant does not give the company any right of sign-off on content and in fact they had no sign-off in content.”

    Dr. Nemeroff said he and Dr. Schatzberg “conceptualized this book, wrote the original outline and worked on all of the content.”

    But the writing company, Scientific Therapeutics Information of Springfield, N.J., had developed “a complete content outline” for Dr. Nemeroff’s comment, according to the 1997 letter from one of the company’s officials. The company also said it had “begun development of the text.” The writing company did not respond to requests for comment.

    Kevin G. Colgan, a spokesman for GlaxoSmithKline, said the company’s role in the book was described in its preface. In recent years, he added, the company has tightened its internal guidelines for medical writers.

    Ron McMillen, chief executive of American Psychiatric Publishing, which published the book, said he reviewed files on it Monday and found no evidence of influence by the writing company or GlaxoSmithKline. But Mr. McMillen also said he had been unaware of the plan outlined in the two-page letter to Dr. Nemeroff.

    “This would show more involvement than we would accept,” he said after reviewing it.

    The book sold about 26,000 copies, including 10,000 bought by SmithKline Beecham for American family doctors and 10,000 purchased by the Dutch pharmaceutical company Organon, Mr. McMillen said. The authors together received a 15 percent royalty of the $120,000 sales, or about $18,000, he said.

    Since there are about 100,000 family physicians in the United States, the book reached only a small percentage of them and has probably declined in usage since 1999. Dr. Howard A. Brody, an author, blogger and professor of family medicine at the University of Texas Medical Branch at Galveston, speculated that family doctors may have had some resistance to a book from a psychiatric press.

    Mr. McMillen said the book was co-published with the American Medical Association. He said it was distributed until a few years ago.

    Dr. Nemeroff said the book was written to fill an unmet need in educating family doctors and primary care physicians on how to provide adequate treatment for people with mental illness. “Remarkably, the book remains quite accurate and relevant to clinical practice today,” he said.

    Dr. Nemeroff said he and Dr. Schatzberg “scrutinized every page and rewrote and edited as we deemed necessary,” keeping control of the final draft.

    Dr. Schatzberg said he had not seen the 1997 letter to Dr. Nemeroff. He termed it “a theoretical proposal that bears little, if any relationship to what actually happened.”

    Dr. Lo, who is a professor of medicine and director of the medical ethics program at theUniversity of California, San Francisco, said that medical textbooks and handbooks should make it clear — as peer-reviewed journals now do — whose idea it was, who wrote the first draft, and who edited. Dr. Lo and other experts said ghostwriting has receded in recent years with tougher journal standards.

    Dr. Nemeroff and Dr. Schatzberg have been listed on other titles, including co-editors of the Textbook of Psychopharmacology, a book for psychiatrists and medical students, whose third edition appeared in 2003. In 2008, Emory University imposed a two-year ban on Dr. Nemeroff receiving N.I.H. grants after a Senate inquiry found that he had failed to disclose at least $1.2 million in industry financing over seven years from pharmaceutical companies, including GlaxoSmithKline.


    COMMENTARY: Alliance for Human Research Protection - Psychiatry Texbook Penned by Two Academic Leaders --GSK Ghosted
     
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    6,485 Overseas Clinical Trials and Counting
    6,485 Overseas Clinical Trials and Counting - NYTimes.com

    December 2, 2010, 1:49 PM
    By DUFF WILSON

    The venerable investigative reporters Donald L. Barlett and James B. Steele turn their focus to overseas clinical trials in an article in this month’s Vanity Fair.

    With their trademark exhaustive research – did you know there were 6,485 clinical trials overseas in 2008 on drugs intended for American use, 23 times more than the 271 in 1990? – the reporters note, several times, a gap in the system.

    Nobody keeps track of all those trials.

    “Data is made available to the public on a purely voluntary basis,” they wrote. “Its accuracy is unknown. The oversight that does exist often is shot through with the kinds of ethical conflicts that Wall Street would admire.”

    Barlett and Steele found the F.D.A. does occasional inspections, visiting 0.7 percent of trial sites outside the country in 2008, compared with 1.9 percent inside the United States.

    But they seem to distrust some of the research done by overseas contractors in places with much less regulation and more willing, low-income subjects, and cite case after case. The article is titled “Deadly Medicine,” so you get the point.

    Barlett and Steele wrote:

    The reporting partners, who live in Philadelphia, are contributing editors to Vanity Fair magazine. They are known for thorough research leading to sweeping conclusions about important subjects, and this article fits that billing. The pair have won two Pulitzer Prizes, two National Magazine Awards, and written seven books including the 1992 best-seller “America: What Went Wrong?”


    Deadly Medicine
    Deadly Medicine | Politics | Vanity Fair

    Prescription drugs kill some 200,000 Americans every year. Will that number go up, now that most clinical trials are conducted overseas—on sick Russians, homeless Poles, and slum-dwelling Chinese—in places where regulation is virtually nonexistent, the F.D.A. doesn’t reach, and “mistakes” can end up in pauper’s graves? The authors investigate the globalization of the pharmaceutical industry, and the U.S. Government’s failure to rein in a lethal profit machine.

    BY DONALD L. BARLETT AND JAMES B. STEELE•
    JANUARY 2011

    You wouldn’t think the cities had much in common. Ia?i, with a population of 320,000, lies in the Moldavian region of Romania. Mégrine is a town of 24,000 in northern Tunisia, on the Mediterranean Sea. Tartu, Estonia, with a population of 100,000, is the oldest city in the Baltic States; it is sometimes called “the Athens on the Emajõgi.” Shenyang, in northeastern China, is a major industrial center and transportation hub with a population of 7.2 million.

    These places are not on anyone’s Top 10 list of travel destinations. But the advance scouts of the pharmaceutical industry have visited all of them, and scores of similar cities and towns, large and small, in far-flung corners of the planet. They have gone there to find people willing to undergo clinical trials for new drugs, and thereby help persuade the U.S. Food and Drug Administration to declare the drugs safe and effective for Americans. It’s the next big step in globalization, and there’s good reason to wish that it weren’t.

    Once upon a time, the drugs Americans took to treat chronic diseases, clear up infections, improve their state of mind, and enhance their sexual vitality were tested primarily either in the United States (the vast majority of cases) or in Europe. No longer. As recently as 1990, according to the inspector general of the Department of Health and Human Services, a mere 271 trials were being conducted in foreign countries of drugs intended for American use. By 2008, the number had risen to 6,485—an increase of more than 2,000 percent. A database being compiled by the National Institutes of Health has identified 58,788 such trials in 173 countries outside the United States since 2000. In 2008 alone, according to the inspector general’s report, 80 percent of the applications submitted to the F.D.A. for new drugs contained data from foreign clinical trials. Increasingly, companies are doing 100 percent of their testing offshore. The inspector general found that the 20 largest U.S.-based pharmaceutical companies now conducted “one-third of their clinical trials exclusively at foreign sites.” All of this is taking place when more drugs than ever—some 2,900 different drugs for some 4,600 different conditions—are undergoing clinical testing and vying to come to market.

    Some medical researchers question whether the results of clinical trials conducted in certain other countries are relevant to Americans in the first place. They point out that people in impoverished parts of the world, for a variety of reasons, may metabolize drugs differently from the way Americans do. They note that the prevailing diseases in other countries, such as malaria and tuberculosis, can skew the outcome of clinical trials. But from the point of view of the drug companies, it’s easy to see why moving clinical trials overseas is so appealing. For one thing, it’s cheaper to run trials in places where the local population survives on only a few dollars a day. It’s also easier to recruit patients, who often believe they are being treated for a disease rather than, as may be the case, just getting a placebo as part of an experiment. And it’s easier to find what the industry calls “drug-naïve” patients: people who are not being treated for any disease and are not currently taking any drugs, and indeed may never have taken any—the sort of people who will almost certainly yield better test results. (For some subjects overseas, participation in a clinical trial may be their first significant exposure to a doctor.) Regulations in many foreign countries are also less stringent, if there are any regulations at all. The risk of litigation is negligible, in some places nonexistent. Ethical concerns are a figure of speech. Finally—a significant plus for the drug companies—the F.D.A. does so little monitoring that the companies can pretty much do and say what they want.

    Consent by Thumbprint

    Many of today’s trials still take place in developed countries, such as Britain, Italy, and Japan. But thousands are taking place in countries with large concentrations of poor, often illiterate people, who in some cases sign consent forms with a thumbprint, or scratch an “X.” Bangladesh has been home to 76 clinical trials. There have been clinical trials in Malawi (61), the Russian Federation (1,513), Romania (876), Thailand (786), Ukraine (589), Kazakhstan (15), Peru (494), Iran (292), Turkey (716), and Uganda (132). Throw a dart at a world map and you are unlikely to hit a spot that has escaped the attention of those who scout out locations for the pharmaceutical industry.

    The two destinations that one day will eclipse all the others, including Europe and the United States, are China (with 1,861 trials) and India (with 1,457). A few years ago, India was home to more American drug trials than China was, thanks in part to its large English-speaking population. But that has changed. English is now mandatory in China’s elementary schools, and, owing to its population edge, China now has more people who speak English than India does.

    While Americans may be unfamiliar with the names of foreign cities where clinical trials have been conducted, many of the drugs being tested are staples of their medicine cabinets. One example is Celebrex, a non-steroidal anti-inflammatory drug that has been aggressively promoted in television commercials for a decade. Its manufacturer, Pfizer, the world’s largest drug company, has spent more than a billion dollars promoting its use as a pain remedy for arthritis and other conditions, including menstrual cramps. The National Institutes of Health maintains a record of most—but by no means all—drug trials inside and outside the United States. The database counts 290 studies involving Celebrex. Companies are not required to report—and do not report—all studies conducted overseas. According to the database, of the 290 trials for Celebrex, 183 took place in the United States, meaning, one would assume, that 107 took place in other countries. But an informal, country-by-country accounting by VANITY FAIR turned up no fewer than 207 Celebrex trials in at least 36 other countries. They ranged from 1 each in Estonia, Croatia, and Lithuania to 6 each in Costa Rica, Colombia, and Russia, to 8 in Mexico, 9 in China, and 10 in Brazil. But even these numbers understate the extent of the foreign trials. For example, the database lists five Celebrex trials in Ukraine, but just “one” of those trials involved studies in 11 different Ukrainian cities.

    The Celebrex story does not have a happy ending. First, it was disclosed that patients taking the drug were more likely to suffer heart attacks and strokes than those who took older and cheaper painkillers. Then it was alleged that Pfizer had suppressed a study calling attention to these very problems. (The company denied that the study was undisclosed and insisted that it “acted responsibly in sharing this information in a timely manner with the F.D.A.”) Soon afterward the Journal of the Royal Society of Medicine reported an array of additional negative findings. Meanwhile, Pfizer was promoting Celebrex for use with Alzheimer’s patients, holding out the possibility that the drug would slow the progression of dementia. It didn’t. Sales of Celebrex reached $3.3 billion in 2004, and then began to quickly drop.

    “Rescue Countries”

    One big factor in the shift of clinical trials to foreign countries is a loophole in F.D.A. regulations: if studies in the United States suggest that a drug has no benefit, trials from abroad can often be used in their stead to secure F.D.A. approval. There’s even a term for countries that have shown themselves to be especially amenable when drug companies need positive data fast: they’re called “rescue countries.” Rescue countries came to the aid of Ketek, the first of a new generation of widely heralded antibiotics to treat respiratory-tract infections. Ketek was developed in the 1990s by Aventis Pharmaceuticals, now Sanofi-Aventis. In 2004—on April Fools’ Day, as it happens—the F.D.A. certified Ketek as safe and effective. The F.D.A.’s decision was based heavily on the results of studies in Hungary, Morocco, Tunisia, and Turkey.

    The approval came less than one month after a researcher in the United States was sentenced to 57 months in prison for falsifying her own Ketek data. Dr. Anne Kirkman-Campbell, of Gadsden, Alabama, seemingly never met a person she couldn’t sign up to participate in a drug trial. She enrolled more than 400 volunteers, about 1 percent of the town’s adult population, including her entire office staff. In return, she collected $400 a head from Sanofi-Aventis. It later came to light that the data from at least 91 percent of her patients was falsified. (Kirkman-Campbell was not the only troublesome Aventis researcher. Another physician, in charge of the third-largest Ketek trial site, was addicted to cocaine. The same month his data was submitted to the F.D.A. he was arrested while holding his wife hostage at gunpoint.) Nonetheless, on the basis of overseas trials, Ketek won approval.

    As the months ticked by, and the number of people taking the drug climbed steadily, the F.D.A. began to get reports of adverse reactions, including serious liver damage that sometimes led to death. The F.D.A.’s leadership remained steadfast in its support of the drug, but criticism by the agency’s own researchers eventually leaked out (a very rare occurrence in this close-knit, buttoned-up world). The critics were especially concerned about an ongoing trial in which 4,000 infants and children, some as young as six months, were recruited in more than a dozen countries for an experiment to assess Ketek’s effectiveness in treating ear infections and tonsillitis. The trial had been sanctioned over the objections of the F.D.A.’s own reviewers. One of them argued that the trial never should have been allowed to take place—that it was “inappropriate and unethical because it exposed children to harm without evidence of benefits.” In 2006, after inquiries from Congress, the F.D.A. asked Sanofi-Aventis to halt the trial. Less than a year later, one day before the start of a congressional hearing on the F.D.A.’s approval of the drug, the agency suddenly slapped a so-called black-box warning on the label of Ketek, restricting its use. (A black-box warning is the most serious step the F.D.A. can take short of removing a drug from the market.) By then the F.D.A. had received 93 reports of severe adverse reactions to Ketek, resulting in 12 deaths.

    During the congressional hearings, lawmakers heard from former F.D.A. scientists who had criticized their agency’s oversight of the Ketek trials and the drug-approval process. One was Dr. David Ross, who had been the F.D.A.’s chief reviewer of new drugs for 10 years, and was now the national director of clinical public-health programs for the U.S. Department of Veterans Affairs. When he explained his objections, he offered a litany of reasons that could be applied to any number of other drugs: “Because F.D.A. broke its own rules and allowed Ketek on the market. Because dozens of patients have died or suffered needlessly. Because F.D.A. allowed Ketek’s maker to experiment with it on children over reviewers’ protests. Because F.D.A. ignored warnings about fraud. And because F.D.A. used data it knew were false to reassure the public about Ketek’s safety.”

    Trials and Error

    To have an effective regulatory system you need a clear chain of command—you need to know who is responsible to whom, all the way up and down the line. There is no effective chain of command in modern American drug testing. Around the time that drugmakers began shifting clinical trials abroad, in the 1990s, they also began to contract out all phases of development and testing, putting them in the hands of for-profit companies. It used to be that clinical trials were done mostly by academic researchers in universities and teaching hospitals, a system that, however imperfect, generally entailed certain minimum standards. The free market has changed all that. Today it is mainly independent contractors who recruit potential patients both in the U.S. and—increasingly—overseas. They devise the rules for the clinical trials, conduct the trials themselves, prepare reports on the results, ghostwrite technical articles for medical journals, and create promotional campaigns. The people doing the work on the front lines are not independent scientists. They are wage-earning technicians who are paid to gather a certain number of human beings; sometimes sequester and feed them; administer certain chemical inputs; and collect samples of urine and blood at regular intervals. The work looks like agribusiness, not research.

    What began as a mom-and-pop operation has grown into a vast army of formal “contract-research organizations” that generate annual revenue of $20 billion. They can be found conducting trials in every part of the world. By far the largest is Quintiles Transnational, based in Durham, North Carolina. It offers the services of 23,000 employees in 60 countries, and claims that it has “helped develop or commercialize all of the top 30 best-selling drugs.”

    Quintiles is privately owned—its investors include two of the U.S.’s top private-equity firms. Other private contractors are public companies, their stock traded on Wall Street. Pharmaceutical Product Development (P.P.D.), a full-service medical contractor based in Wilmington, North Carolina, is a public company with 10,500 employees. It, too, has conducted clinical trials all around the world. In fact, it was involved in the clinical trials for Ketek—a P.P.D. research associate, Ann Marie Cisneros, had been assigned to monitor Dr. Anne Kirkman-Campbell’s testing in Alabama. Cisneros later told the congressional investigating committee that Kirkman-Campbell had indeed engaged in fraud. “But what the court that sentenced her did not know,” Cisneros said, was that “Aventis was not a victim of this fraud.” Cisneros said she had reported her findings of fraud to her employer, P.P.D., and also to Aventis. She told the congressional committee, “What brings me here today is my disbelief at Aventis’s statements that it did not know that fraud was being committed. Mr. Chairman, I knew it, P.P.D. knew it, and Aventis knew it.” Following her testimony the company released a statement saying it regretted the violations that occurred during the study but was not aware of the fraud until after the data was submitted to the F.D.A.

    The F.D.A., the federal agency charged with oversight of the food and drugs that Americans consume, is rife with conflicts of interest. Doctors who insist the drug you take is perfectly safe may be collecting hundreds of thousands of dollars from the company selling the drug. (ProPublica, an independent, nonprofit news organization that is compiling an ongoing catalogue of pharmaceutical-company payments to physicians, has identified 17,000 doctors who have collected speaking and consulting fees, including nearly 400 who have received $100,000 or more since 2009.) Quite often, the F.D.A. never bothers to check for interlocking financial interests. In one study, the agency failed to document the financial interests of applicants in 31 percent of applications for new-drug approval. Even when the agency or the company knew of a potential conflict of interest, neither acted to guard against bias in the test results.

    Because of the deference shown to drug companies by the F.D.A.—and also by Congress, which has failed to impose any meaningful regulation—there is no mandatory public record of the results of drug trials conducted in foreign countries. Nor is there any mandatory public oversight of ongoing trials. If one company were to test an experimental drug that killed more patients than it helped, and kept the results secret, another company might unknowingly repeat the same experiment years later, with the same results. Data is made available to the public on a purely voluntary basis. Its accuracy is unknown. The oversight that does exist often is shot through with the kinds of ethical conflicts that Wall Street would admire. The economic incentives for doctors in poor countries to heed the wishes of the drug companies are immense. An executive at a contract-research organization told the anthropologist Adriana Petryna, author of the book When Experiments Travel: “In Russia, a doctor makes two hundred dollars a month, and he is going to make five thousand dollars per Alzheimer’s patient” that he signs up. Even when the most flagrant conflicts are disclosed, penalties are minimal. In truth, the same situation exists in the United States. There’s just more of a chance here, though not a very large one, that adverse outcomes and tainted data will become public. When the pharmaceutical industry insists that its drugs have been tested overseas in accordance with F.D.A. standards, this may be true—but should provide little assurance.

    The F.D.A. gets its information on foreign trials almost entirely from the companies themselves. It conducts little or no independent research. The investigators contracted by the pharmaceutical companies to manage clinical trials are left pretty much on their own. In 2008 the F.D.A. inspected just 1.9 percent of trial sites inside the United States to ensure that they were complying with basic standards. Outside the country, it inspected even fewer trial sites—seven-tenths of 1 percent. In 2008, the F.D.A. visited only 45 of the 6,485 locations where foreign drug trials were being conducted.

    The pharmaceutical industry dismisses concerns about the reliability of clinical trials conducted in developing countries, but the potential dangers were driven home to Canadian researchers in 2007. While reviewing data from a clinical trial in Iran for a new heart drug, they discovered that many of the results were fraudulent. “It was bad, so bad we thought the data was not salvageable,” Dr. Gordon Guyatt, part of the research group at McMaster University in Hamilton, told Canada’s National Post.

    In addition to monitoring trials abroad, which it does not really do, the F.D.A. is responsible for inspecting drug-manufacturing plants in other countries, which it also does not really do. In 2007 and 2008, hundreds of patients taking the blood thinner heparin, which among other purposes is used to prevent blood clots during surgery and dialysis, developed serious allergic reactions as a result of a contaminant introduced at a Chinese manufacturing facility. It took months for the F.D.A., its Chinese counterpart, and Baxter International, the pharmaceutical company that distributed the drug, to track the source of contamination to Changzhou, a city of 3.5 million on the Yangtze River.

    The delay was perhaps understandable, given the manufacturing process. The raw material for Baxter’s heparin comes from China’s many small pig farms. To be precise, it’s derived from the mucous membranes of the intestines of slaughtered pigs; the membranes are mixed together and cooked, often in unregulated family workplaces. By the time the source of the contaminant was pinpointed, many more patients in the United States had experienced severe reactions, and as many as 200 had died. It later turned out that the F.D.A. had indeed inspected a Chinese plant—but it was the wrong one. The federal regulators had confused the names.

    The good news was that, in this instance, the F.D.A. at least knew which country the heparin had come from. The bad news is that it does not always know where clinical trials are being conducted, or even the names or types of drugs being tested, or the purpose for which they will be prescribed once approved. Companies may withhold the foreign test data until they actually submit the application to the F.D.A. for approval. By then the agency has lost the ability to see whether the trials were managed according to acceptable standards, and whether the data collected was manipulated or fabricated.

    $350 per Child

    If the globalization of clinical trials for adult medications has drawn little attention, foreign trials for children’s drugs have attracted even less. The Argentinean province of Santiago del Estero, with a population of nearly a million, is one of the country’s poorest. In 2008 seven babies participating in drug testing in the province suffered what the U.S. clinical-trials community refers to as “an adverse event”: they died. The deaths occurred as the children took part in a medical trial to test the safety of a new vaccine, Synflorix, to prevent pneumonia, ear infections, and other pneumococcal diseases. Developed by GlaxoSmithKline, the world’s fourth-largest pharmaceutical company in terms of global prescription-drug sales, the new vaccine was intended to compete against an existing vaccine. In all, at least 14 infants enrolled in clinical trials for the drug died during the testing. Their parents, some illiterate, had their children signed up without understanding that they were taking part in an experiment. Local doctors who persuaded parents to enroll their babies in the trial reportedly received $350 per child. The two lead investigators contracted by Glaxo were fined by the Argentinean government. So was Glaxo, though the company maintained that the mortality rate of the children “did not exceed the rate in the regions and countries participating in the study.” No independent group conducted an investigation or performed autopsies. As it happens, the brother of the lead investigator in Santiago del Estero was the Argentinean provincial health minister.

    In New Delhi, 49 babies died at the All India Institute of Medical Sciences while taking part in clinical trials over a 30-month period. They were given a variety of new drugs to treat everything from high blood pressure to chronic focal encephalitis, a brain inflammation that causes epileptic seizures and other neurological problems. The blood-pressure drugs had never before been given to anyone under 18. The editor of an Indian medical journal said it was obvious that the trials were intended to extend patent life in Western countries “with no consequence or benefit for India, using Indian children as guinea pigs.” In all, 4,142 children were enrolled in the studies, two-thirds of them less than one year old. But the head of the pediatrics department at the All India Institute maintained that “none of the deaths was due to the medication or interventions used in clinical trials.”

    For years, American physicians gave anti-psychotic medicines to children “off label,” meaning that they wrote prescriptions based on testing for adults, sometimes even for different conditions. That didn’t work out so well for the children, who, when it comes to medicine, really are not just little adults. To provide the pharmaceutical industry with an incentive to conduct clinical trials on children’s versions of adult drugs, Congress in 1997 enacted legislation, known as the Pediatric Exclusivity Provision, extending the patent life of certain drugs by six months. It worked so well that the industry has, in the ensuing years, been able to put younger and younger children on more and more drugs, pocketing an extra $14 billion. Between 1999 and 2007, for instance, the use of anti-psychotic medications on children between the ages of two and five more than doubled.

    A study of 174 trials under the Pediatric Exclusivity Provision found that 9 percent of them did not report the location or number of sites of the clinical trials. Of those that did, two-thirds had been conducted in at least one country outside the United States, and 11 percent were conducted entirely outside the United States. Of the 79 trials with more than 100 subjects participating, 87 percent enrolled patients outside the United States. As is the case with adult studies, many children’s trials conducted abroad are neither reported nor catalogued on any publicly accessible government database. There is no public record of their existence or their results.

    In the mid-90s, Glaxo conducted clinical trials on the antidepressant Paxil in the United States, Europe, and South America. Paxil is a member of a class of drugs called selective serotonin re-uptake inhibitors. The class includes Zoloft, Prozac, and Lexapro. In the United Kingdom, Paxil is sold as Seroxat. The clinical trials showed that the drug had no beneficial effect on adolescents; some of the trials indicated that the placebo was more effective than the drug itself. But Glaxo neglected to share this information with consumers; annual sales of the drug had reached $5 billion in 2003. In an internal document obtained by the Canadian Medical Association Journal, the company emphasized how important it was to “effectively manage the dissemination of these data in order to minimize any potential negative commercial impact.” The memo went on to warn that “it would be commercially unacceptable to include a statement that efficacy had not been demonstrated.” After the document was released a Glaxo spokesperson said that the “memo draws an inappropriate conclusion and is not consistent with the facts.”

    “Smoke and Mirrors”

    It may be just a coincidence, but as controversy swirls around new drugs, and as the F.D.A. continues to slap medicines with new warning labels—especially the black-box warnings that indicate the most serious potential reactions—most of the problematic drugs have all undergone testing outside the United States. Clinical-trial representatives working for GlaxoSmithKline went to Ia?i, Romania, to test Avandia, a diabetes drug, on the local population. Glaxo representatives also showed up in other cities in Romania—Bucure?ti, Cluj-Napoca, Craiova, and Timi?oara—as well as multiple cities in Latvia, Ukraine, Slovakia, the Russian Federation, Poland, Hungary, Lithuania, Estonia, the Czech Republic, Bulgaria, Croatia, Greece, Belgium, the Netherlands, Germany, France, and the United Kingdom. That was for the largest of the Avandia clinical trials. But there have been scores of others, all seeking to prove that the drug is safe and effective. Some took place before the drug was approved by the F.D.A. Others were “post-marketing” studies, done after the fact, as the company cast about for ways to come up with more positive results so it could expand Avandia’s use for other treatments. Based on the initial evaluations, Avandia was expected to—and did—become another Glaxo multi-billion-dollar best-seller.

    While sales soared, so, too, did reports of adverse reactions—everything from macular edema to liver injury, from bone fractures to congestive heart failure. In 2009 the Institute for Safe Medication Practices, a Pennsylvania-based nonprofit group that monitors the prescription-drug field, linked the deaths of 1,354 people to Avandia, based on reports filed with the F.D.A. Studies also concluded that people taking the drug had an increased risk of developing heart disease, one of the very conditions that doctors treating diabetics hope to forestall. The risk was so high that worried doctors inside and outside the F.D.A. sought to have the drug removed from the market, an incredibly difficult task no matter how problematic the medicine. As always, the F.D.A. was late to the party. In 2008 the American Diabetes Association and the European Association for the Study of Diabetes had warned against using Avandia. The Saudi Arabian drug-regulatory agency yanked it from the market, and the Indian government asked Glaxo to halt 19 of its Avandia trials in that country. In September 2010 the European Medicines Agency pulled Avandia from the shelves all across Europe. The F.D.A. still could not bring itself to take decisive action. This even though the F.D.A. knew that Glaxo had withheld critical safety information concerning the increased risk of heart attacks, and the F.D.A. itself had estimated that the drug had caused more than 83,000 heart attacks between 1999 and 2007. The agency settled for imposing new restrictions on the availability of the drug in the United States. Glaxo released a statement saying that it “continues to believe that Avandia is an important treatment for patients with type 2 diabetes,” but that it would “voluntarily cease promotion of Avandia in all the countries in which it operates.”

    The Avandia case and others like it have prompted the U.S. Justice Department to mount an investigation under the Foreign Corrupt Practices Act. While it is legal for doctors in this country to accept money from drug companies for acting as consultants, this is not the case abroad, where doctors often are government employees, and such payments can be considered bribes. There are other legal issues. So far, Glaxo has paid out more than $1 billion to settle lawsuits arising from claims against Avandia and other drugs. The Senate Finance Committee calculates that, since May 2004, seven drug companies have paid out more than $7 billion in fines and penalties stemming from unlawful drug dealings. Pfizer paid the largest such fine in history—$2.3 billion for promoting off-label uses of the arthritis drug Bextra.

    In theory, pharmaceutical companies are barred from selling a drug for any purpose other than the one that the F.D.A. has approved on the basis of clinical testing. But the reality is different. The minute a drug receives the green light from the F.D.A. for a specific treatment, the sponsoring company and its allies begin campaigns to make it available for other purposes or for other types of patients. The antidepressant Paxil was tested on adults but sold off-label to treat children. Seroquel, an anti-psychotic, was marketed as a treatment for depression. Physicians, often on retainer from pharmaceutical companies, are free to prescribe a drug for any reason if they entertain a belief that it will work. This practice turns the population at large into unwitting guinea pigs whose adverse reactions may go unreported or even unrecognized.

    To secure the F.D.A.’s approval for Seroquel, which ultimately would go to treat schizophrenia, bipolar disorders, and manic episodes associated with bipolar disorder, AstraZeneca, the fifth-largest pharmaceutical company, conducted clinical trials across Asia, Europe, and the United States. Among the sites: Shenyang and more than a dozen other cities in China, and multiple cities in Bulgaria, Estonia, Hungary, Latvia, Lithuania, Croatia, Indonesia, Malaysia, Poland, the Russian Federation, Serbia, Ukraine, and Taiwan. The F.D.A. initially approved the drug for the treatment of schizophrenia. But while schizophrenia may have opened the door, off-label sales opened the cash register. Money poured in by the billions as AstraZeneca promoted the drug for the treatment of any number of other conditions. It was prescribed for children with autism-spectrum disorders and retardation as well as for elderly Alzheimer’s patients in nursing homes. The company touted the drug for treatment of aggression, anxiety, anger-management issues, attention-deficit hyperactivity disorder, dementia, and sleeplessness. Up to 70 percent of the prescriptions for Seroquel were written for a purpose other than the one for which it had been approved, and sales rose to more than $4 billion a year.

    It turned out, however, that AstraZeneca had been less than candid about the drug’s side effects. One of the most troubling: patients often gained weight and developed diabetes. This meant a new round of drugs to treat conditions caused by Seroquel. In an internal e-mail from 1997 discussing a study comparing Seroquel with an older anti-psychotic drug, Haldol, a company executive praised the work of the project physician, saying she had done a great “smoke-and-mirrors job,” which “should minimize (and dare I venture to suggest) could put a positive spin (in terms of safety) on this cursed study.” After the e-mail was disclosed, in February 2009, the company said that the document cannot “obscure the fact that AstraZeneca acted responsibly and appropriately as it developed and marketed” the drug. In April, AstraZeneca reached a half-billion-dollar settlement with the federal government over its marketing of Seroquel. The U.S. attorney in Philadelphia, where the settlement was filed, declared that the company had “turned patients into guinea pigs in an unsupervised drug test.” Meanwhile, the company was facing more than 25,000 product-liability lawsuits filed by people who contended the drug had caused their diabetes.

    Death Toll

    The only people who seem to care about the surge of clinical trials in foreign countries are the medical ethicists—not historically a powerhouse when it comes to battling the drug companies. A team of physician-researchers from Duke University, writing last year in the New England Journal of Medicine, observed that “this phenomenon raises important questions about the economics and ethics of clinical research and the translation of trial results to clinical practice: Who benefits from the globalization of clinical trials? What is the potential for exploitation of research subjects? Are trial results accurate and valid, and can they be extrapolated to other settings?” The Duke team noted that, in some places, “financial compensation for research participation may exceed participants’ annual wages, and participation in a clinical trial may provide the only access to care” for those taking part in the trial. In 2007, residents of a homeless shelter in Grudziadz, Poland, received as little as $2 to take part in a flu-vaccine experiment. The subjects thought they were getting a regular flu shot. They were not. At least 20 of them died. The same distorting economic pressures exist for local hospitals or doctors, who may collect hundreds of dollars for every patient they enroll. In theory, a federal institutional review board is supposed to assess every clinical trial, with special concern for the welfare of the human subjects, but this work, too, has now been outsourced to private companies and is often useless. In 2009 the Government Accountability Office conducted a sting operation, winning approval for a clinical trial involving human subjects; the institutional review board failed to discover (if it even tried) that it was dealing with “a bogus company with falsified credentials” and a fake medical device. This was in Los Angeles. If that is oversight in the U.S., imagine what it’s like in Kazakhstan or Uganda. Susan Reverby, the Wellesley historian who uncovered the U.S. government’s syphilis experiments in Guatemala during the 1940s, was asked in a recent interview to cite any ongoing experimental practices that gave her pause. “Frankly,” she said, “I am mostly worried about the drug trials that get done elsewhere now, which we have little control over.”

    The pharmaceutical industry, needless to say, has a different view. It argues that people participating in a clinical trial may be getting the highest quality of medical care they have ever received. That may be true in the short term. But, unfortunately, the care lasts only until the trial is completed. Many U.S. medical investigators who manage drug trials abroad say they prefer to work overseas, where regulations are lax and “conflict of interest” is a synonym for “business as usual.” Inside the United States, doctors who oversee trials are required to fill out forms showing any income they have received from drug companies so as to guard against financial biases in trials. This explains in part why the number of clinical-trial investigators registered with the F.D.A. fell 5.2 percent in the U.S. between 2004 and 2007 while increasing 16 percent in Eastern Europe, 12 percent in Asia, and 10 percent in Latin America. In a recent survey, 70 percent of the eligible U.S. and Western European clinical investigators interviewed said they were discouraged by the current regulatory environment, partly because they are compelled to disclose financial ties to the pharmaceutical industry. In trials conducted outside the United States, few people care.

    In 2009, according to the Institute for Safe Medication Practices, 19,551 people died in the United States as a direct result of the prescription drugs they took. That’s just the reported number. It’s decidedly low, because it is estimated that only about 10 percent of such deaths are reported. Conservatively, then, the annual American death toll from prescription drugs considered “safe” can be put at around 200,000. That is three times the number of people who die every year from diabetes, four times the number who die from kidney disease. Overall, deaths from F.D.A.-approved prescription drugs dwarf the number of people who die from street drugs such as cocaine and heroin. They dwarf the number who die every year in automobile accidents. So far, these deaths have triggered no medical crusades, no tough new regulations. After a dozen or so deaths linked to runaway Toyotas, Japanese executives were summoned to appear before lawmakers in Washington and were subjected to an onslaught of humiliating publicity. When the pharmaceutical industry meets with lawmakers, it is mainly to provide campaign contributions.

    And with more and more of its activities moving overseas, the industry’s behavior will become more impenetrable, and more dangerous, than ever.
     
    Last edited: Dec 2, 2010
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Doctor Faces Suits Over Cardiac Stents
    http://www.nytimes.com/2010/12/06/health/06stent.html

    December 5, 2010
    By GARDINER HARRIS

    Word quickly reached top executives at Abbott Laboratories that a Baltimore cardiologist, Dr. Mark Midei, had inserted 30 of the company’s cardiac stents in a single day in August 2008, “which is the biggest day I remember hearing about,” an executive wrote in a celebratory e-mail.

    Two days later, an Abbott sales representative spent $2,159 to buy a whole, slow-smoked pig, peach cobbler and other fixings for a barbecue dinner at Dr. Midei’s home, according to a report being released Monday by the Senate. The dinner was just a small part of the millions in salary and perks showered on Dr. Midei for putting more stents in more patients than almost any other cardiologist in Baltimore.

    The Senate Finance Committee, which oversees Medicare, started investigating Dr. Midei in February after a series of articles in The Baltimore Sun said that Dr. Midei at St. Joseph Medical Center, in Towson, Md., had inserted stents in patients who did not need them, reaping high reimbursements from Medicare and private insurance.

    The senators solicited 10,000 documents from Abbott and St. Joseph. Their report, provided in advance to The New York Times, concludes that Dr. Midei “may have implanted 585 stents which were medically unnecessary” from 2007 to 2009. Medicare paid $3.8 million of the $6.6 million charged for those procedures.

    The report also describes the close relationship between Dr. Midei and Abbott Labs, which paid consulting fees to the cardiologist after he left the hospital. “The serious allegations lodged against Dr. Midei regarding the medically unnecessary implantation of cardiac stents did not appear to deter Abbott’s interest in assisting him,” the report states.

    The case has turned into a legal quagmire for Dr. Midei and St. Joseph, which have been sued by hundreds of patients who claim they received unnecessary implants. Some doctors say the case has revealed a level of inappropriate care that is more common than most patients know.

    “What was going on in Baltimore is going on right now in every city in America,” said Dr. Steven Nissen, chief of cardiovascular medicine at the Cleveland Clinic, who said he routinely treats patients who have been given multiple unneeded stents. “We’re spending a fortune as a country on procedures that people don’t need.”

    Dr. Midei’s lawyer, Stephen L. Snyder, said that his client’s treatment of his patients was entirely appropriate and that Dr. Midei, who has recently practiced medicine at the Prince Salman Heart Center in Saudi Arabia, would be exonerated.

    “This is all trumped up to hide the hospital’s criminal conduct,” said Mr. Snyder, who filed a $60 million lawsuit against St. Joseph on Dr. Midei’s behalf accusing the hospital of damaging Dr. Midei’s reputation by making false claims about his care. (The hospital responded that the assessments of Dr. Midei’s care were done by independent experts.)

    Last month, St. Joseph agreed to pay a $22 million fine to settle charges that it paid illegal kickbacks to Dr. Midei’s medical practice, MidAtlantic Cardiovascular Associates, in exchange for patient referrals; the hospital did not admit wrongdoing. St. Joseph said in a statement Friday that it now conducts monthly random reviews of stent cases “to assure such a situation cannot occur again.”

    As for Abbott Labs, a spokesman wrote in an e-mail that its affiliation with Dr. Midei ended early this year. “Dr. Midei has been a highly regarded physician in his field, with whom Abbott had consulted in the past,” said the spokesman, Jonathan Hamilton. “We have no further comment at this time.”

    The case has had wide repercussions. Over the past year, St. Joseph has told hundreds of Dr. Midei’s patients that they did not need the expensive and potentially dangerous stents that the doctor inserted because their arteries were not as obstructed as he had claimed. Now, state health officials are investigating other local cardiologists who inserted a suspiciously high number of stents, which are tiny wire mesh devices inserted to prop open clogged arteries in the heart.

    After reports about the Midei case and the wider state investigation, the number of stent procedures performed at St. Joseph and other area hospitals plunged, raising doubts about the appropriateness of much of the region’s cardiac care.

    A landmark 2007 study published in The New England Journal of Medicine showed that many patients given stents would fare just as well without them. Dr. Christopher J. White, president-elect of the Society for Cardiovascular Angiography and Interventions, said that inappropriate stenting was a problem, but a rare one. The federal Medicare program spent $3.5 billion last year on stent procedures.

    Prosecutors, malpractice lawyers and state medical boards are only now waking up to the issue. The Texas Medical Board last month accused a widely known cardiologist in Austin of inserting unnecessary stents. In September, federal prosecutors accused a cardiologist in Salisbury, Md., of performing unnecessary stent surgeries, and last year a Louisiana doctor was sentenced to 10 years in prison for inserting unneeded stents.

    J. Stephen Simms, a Baltimore lawyer who successfully pursued a federal whistle-blower lawsuit involving kickbacks for coronary procedures, said such cases were “the flavor of the month right now” with federal prosecutors.

    Jay Miller, another Baltimore lawyer, said he was devoting his entire practice to unnecessary stent cases. “And I don’t think this is limited to just a few Maryland hospitals,” Mr. Miller said.

    But far from questioning cardiologists who perform an unusually high number of stent procedures, many hospital executives celebrate these doctors because of the revenue they bring, which can be more than $10,000 per procedure.

    “Hospital patients expect their care to be based on medical need, not profits,” said Senator Max Baucus, Democrat of Montana and chairman of the Finance Committee. “Even more disconcerting is that this could be a sign of a larger national trend of wasteful medical device use.”

    Dr. Midei’s fall was as rapid as it was dramatic. In a June deposition for a lawsuit against him, he said: “I didn’t know what hit me. I was bewildered by what had happened.”

    He had been one of the most sought-after clinicians in his region. Trained at Johns Hopkins University, he was a co-founder of MidAtlantic, a practice with dozens of cardiologists that controlled much of the cardiac business in Baltimore’s private hospitals. Dr. Midei was one of the practice’s stars. When MidAtlantic negotiated a $25 million merger with Union Hospital in 2007, the deal was contingent on his continued employment.

    St. Joseph was so concerned about losing Dr. Midei’s business that the hospital offered a $1.2 million salary if he would leave MidAtlantic and join the hospital’s staff. When Dr. Midei agreed, the merger with Union collapsed, MidAtlantic sued, and the practice’s former chief executive vowed in a deposition to “spend the rest of my life trying to destroy him personally and professionally.”

    In the June deposition, Dr. Midei estimated that in 2005 — before research revealed that many stents were unnecessary — he performed about 800 stent procedures. Instead of dropping in subsequent years, however, the number of stents Dr. Midei inserted rose to as many as 1,200 annually, he estimated. In a 2007 internal document, Abbott Laboratories ranked Dr. Midei’s use of stents behind only five other cardiologists in the Northeast, including those at hospitals four and five times St. Joseph’s size.

    That sort of increase in volume was an obvious red flag, said Dr. William E. Boden, clinical chief of the division of cardiovascular medicine at the University of Buffalo and an author of the 2007 stent study. “For him to have this brisk increase over those years is really unusual,” Dr. Boden said.

    In stable patients, stents should be used only if X-rays show that most of the artery is blocked, and the patient has symptoms like frequent chest pain. Stent procedures can, in rare cases, cause bleeding, stroke or a heart attack. Once a stent is placed, it can result in a life-threatening clot that emerges weeks to months later. Stent patients must spend a year or more taking blood-thinning medications, which have their own risks.

    In April 2009, a patient of Dr. Midei’s who was also a St. Joseph employee complained that he had received an unneeded stent and that many other patients had as well. The hospital engaged a panel of experts who reviewed 1,878 cases from January 2007 to May 2009 and found that 585 patients might have received unnecessary stents.

    When asked to review the cases himself, Dr. Midei found far less blockage than he had initially, according to the Maryland Board of Physicians. The hospital suspended his privileges and eventually sent letters to all 585 patients. Hundreds of lawsuits against Dr. Midei and St. Joseph followed, including from patients treated well before January 2007.

    Abbott responded to the controversy by hiring Dr. Midei as a consultant. “It’s the right thing to do because he helped us so many times over the years,” an Abbott executive wrote in a January e-mail cited in the Senate report.

    The company sent Dr. Midei to Japan, but news of the controversy made his duties impossible, and he flew home. After one particularly critical story in The Baltimore Sun, David C. Pacitti, an Abbott executive, wrote in an e-mail, “Someone needs to take this writer out and kick his ass!”

    Edward Chaid, 68, a semiretired general contractor from Timonium, Md., is among those who have sued. Five years ago, Mr. Chaid decided to get his first physical examination in decades. Just to be safe, his doctor sent him for a cardiac stress test at MidAtlantic, which revealed a small “squiggle” of concern, Mr. Chaid said. He was sent to Dr. Midei to get his arteries X-rayed, and he emerged from the procedure with two stents.

    “Dr. Midei said: ‘You sure are lucky. You had 90 percent blockage.’ And the nurse said, ‘Oh yeah, you were blocked in your widow-maker.’ And I said: ‘Thank God. I guess I’m really lucky you got it when you did,’ ” Mr. Chaid said in an interview.

    Five years later, another doctor concluded that Mr. Chaid’s blockage had been minimal. “I was really shocked,” Mr. Chaid said. “I’m from a generation where doctors are thought very highly of.”

    But Mr. Snyder, Dr. Midei’s lawyer, said that his client’s care had been entirely appropriate, that doctors often interpret X-rays differently and that St. Joseph was using him as a scapegoat. A Web site created by friends of Dr. Midei lists dozens of testimonials like this one: “Plain and simple, Dr. Midei saved my life.”
     
  8. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Report Details Drug Company’s Close Ties With Disgraced Doctor
    Report Details Drug Company’s Close Ties With Disgraced Doctor - ProPublica

    by Marian Wang
    ProPublica, Dec. 6, 2010

    After a Baltimore hospital barred a cardiologist for allegedly performing unnecessary implants of heart stents, the company that manufactures the stents hired him to consult and market the devices, according to internal e-mails and memos released today in a Senate Finance Committee report.

    Abbott Laboratories manufactured the stents that Dr. Mark Midei used frequently before St. Joseph Medical Center revoked his hospital privileges in May 2009. The hospital decided to bar the head of its cardiology department after an expert panel reviewed patient records and concluded that 585 of his patients may have undergone unnecessary heart procedures to implant the stents, which are used to open blocked arteries in the heart. (Midei disputes this, and has sued the hospital for causing irreparable damage to his career.)

    From the Senate report, which you can read in our document viewer - Senate Finance Committee Report on Cardiac Stent Usage at St. Joseph Medical Center - ProPublica

    Abbott and its sales representatives had a close relationship with Midei, the documents show. In 2008, the company “paid at least $1,925 for social events at Dr. Midei’s home, including crab and barbecue dinners.”

    In August 2008, Abbott paid for the catering of a barbecue dinner the same week that the company’s executive vice president of medical devices sent Midei an e-mail congratulating him on performing 30 stent implants in a single day. The exec called it “a truly outstanding day” and thanked Midei for supporting Abbott’s product.

    “In my 15 years of being in this business, I have never seen personal relationships as strong as the ones you have developed with Dr.’s Mark Midei, [name redacted], and [name redacted],” an Abbott sales manager wrote, congratulating a sales representative who had worked closely with Midei.

    Later, when Midei’s practices came into question, Abbott sent him to consult overseas because in the United States, “the press is just too hot.” An email from February this year shows an Abbott executive recommending that the company “continue to work with him, behind the scenes, at this point. We’ve just decided not to have him doing any public type work in the U.S. right now.”

    Abbott told the Wall Street Journal that Dr. Midei "has been a highly regarded physician in his field” and said it ended its affiliation with him early this year.

    Midei's attorney, Stephen L. Snyder, asked about the Senate report, told the Baltimore Sun: "Big deal." He told the Journal that his client got “nothing extraordinary” from Abbott. Maryland’s licensing board has charged his client with violations of state law that could ultimately strip him of his medical license, the Sun reported.

    We’ve reported that hundreds of doctors who have been accused of misconduct or lacked credentials have been hired by drug companies as speakers and consultants.

    The misconduct in the cases we identified was often different from the example highlighted in today’s report, since it was often not directly related to the doctors’ practice of medicine or prescriptions. In response to our reporting, several of the nation’s pharmaceutical companies said they plan to tighten how they screen the doctors they hire.

    In a piece published today, California Watch separately reported that three San Diego doctors who accepted $20,000 or more in payments from drug companies are on a list of the state’s top prescribers of antipsychotic drugs to the poor and disabled. While this isn’t a problem if the treatments are needed, the degree to which drug company payments to physicians influences their prescriptions or causes over-prescription is a topic of continuing debate.
     
  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Dollars for Docs Payments Approach $300 Million

    by Charles Ornstein , Tracy Weber and Dan Nguyen
    ProPublica, Dec. 22, 2010, 1:36 p.m.

    Today we’ve added another $13 million in payments to our Dollars for Docs database of drug-company spending on doctors and other health professionals. That brings the total to nearly $295 million.

    Continue . . . Dollars for Docs Payments Approach $300 Million - ProPublica
     
  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    There is a very simple reason for this to occur - $$$$$$$. I wish I could say otherwise, but many unneeded and harmful procedures are done for the $$$ alone. And this does not include the use of prescriptions without any indication. More than one out of every five heart defibrillators implanted in the United States may be unnecessary, or were implanted without their doctor following the appropriate guidelines for when the devices should or should not be used, according to new research.

    The study, published this week in the Journal of the American Medical Association (JAMA), suggests that as many as 22,000 patients each year could undergo $35,000 worth of heart surgery that they do not need, which may expose them to a risk of unnecessary harm.

    Researchers looked at data on 111,707 cases from a national registry over nearly four years, and found that about 22.5% of patients who received ICDs did not meet the criteria for receiving them. They also found that those patients faced a higher risk of death or complications.

    According to the researchers, many doctors do not make evidence-based decisions on giving patients the implants according to accepted implantable cardioverter defibrillator (ICD) guidelines.

    Current medical standards for implanting the devices recommend that they not be given to patients who have recently had a heart attack or bypass surgery. They also recommend that doctors do not give them to people who have recently been diagnosed with heart failure or who have a terminal illness. Despite the recommendations for restraint, about 100,000 patients each year receive the implants.

    In addition to the health risks that may be involved with a perfectly operable implanted heart defibrillator, patients also face a potential risk of defective ICDs, which could lead to serious injury or death.



    Al-Khatib SM, Hellkamp A, Curtis J, et al. Non-Evidence-Based ICD Implantations in the United States. JAMA: The Journal of the American Medical Association 2011;305(1):43-9. Non–Evidence-Based ICD Implantations in the United States, January 5, 2011, Al-Khatib et al. 305 (1): 43 — JAMA

    Context: Practice guidelines do not recommend use of an implantable cardioverter-defibrillator (ICD) for primary prevention in patients recovering from a myocardial infarction or coronary artery bypass graft surgery and those with severe heart failure symptoms or a recent diagnosis of heart failure.

    Objective: To determine the number, characteristics, and in-hospital outcomes of patients who receive a non–evidence-based ICD and examine the distribution of these implants by site, physician specialty, and year of procedure.

    Design, Setting, and Patients: Retrospective cohort study of cases submitted to the National Cardiovascular Data Registry-ICD Registry between January 1, 2006, and June 30, 2009.

    Main Outcome Measure: In-hospital outcomes.

    Results: Of 111 707 patients, 25 145 received non–evidence-based ICD implants (22.5%). Patients who received a non–evidence-based ICD compared with those who received an evidence-based ICD had a significantly higher risk of in-hospital death (0.57% [95% confidence interval {CI}, 0.48%-0.66%] vs 0.18% [95% CI, 0.15%-0.20%]; P <.001) and any postprocedure complication (3.23% [95% CI, 3.01%-3.45%] vs 2.41% [95% CI, 2.31%-2.51%]; P <.001). There was substantial variation in non–evidence-based ICDs by site. The rate of non–evidence-based ICD implants was significantly lower for electrophysiologists (20.8%; 95% CI, 20.5%-21.1%) than nonelectrophysiologists (24.8% [95% CI, 24.2%-25.3%] for nonelectrophysiologist cardiologists; 36.1% [95% CI, 34.3%-38.0%] for thoracic surgeons; and 24.9% [95% CI, 23.8%-25.9%] for other specialties) (P<.001 for all comparisons). There was no clear decrease in the rate of non–evidence-based ICDs over time (24.5% [6908/28 233] in 2006, 21.8% [7395/33 965] in 2007, 22.0% [7245/32 960] in 2008, and 21.7% [3597/16 549] in 2009; P <.001 for trend from 2006-2009 and P = .94 for trend from 2007-2009).

    Conclusion: Among patients with ICD implants in this registry, 22.5% did not meet evidence-based criteria for implantation.
     

    Attached Files:

  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Trial in a Vacuum: Study of Studies Shows Few Citations
    http://www.nytimes.com/2011/01/18/health/research/18cite.html

    By GINA KOLATA
    Published: January 17, 2011

    Science, so the story goes, is a meticulously built edifice. Discoveries balance on ones that preceded them. Research is stimulated by studies that went on before.

    But what, then, can explain the findings by two investigators at Johns Hopkins University School of Medicine? The researchers, Karen A. Robinson and Dr. Steven N. Goodman, looked at how often published papers on clinical trials in medicine cite previous clinical trials addressing the same question.

    They report in the Jan. 4 issue of Annals of Internal Medicine what Dr. Goodman describes as “a rather shocking result.” He summarizes: “No matter how many randomized clinical trials have been done on a particular topic, about half the clinical trials cite none or only one of them.”

    “As cynical as I am about such things, I didn’t realize the situation was this bad,” Dr. Goodman said.

    It seems, Dr. Goodman said in an e-mail, that “either everyone thinks their study is really unique (when others thought it wasn’t), or they want to unjustifiably claim originality, or they just don’t know how or want to look.”

    The situation can have serious consequences for patients, said Sir Iain Chalmers, editor of the James Lind Library, which is a source of information on appropriate tests of medical treatments. He said some patients have suffered severe side effects and even died in studies because researchers were not aware of previous studies documenting a treatment’s dangers.

    “That’s the tragedy,” he said. “Not only is it unscientific, it is unethical.”

    Dr. Goodman said their results might help explain a troubling phenomenon in medicine: All too often, despite a multitude of clinical trials on a particular subject, the data do not supply the answers doctors need to treat patients.

    “This shows part of what’s behind it,” Dr. Goodman said. Failure to cite can affect hypotheses and conclusions.

    “If you are not citing the most similar studies, it is really hard to imagine that the evidence they provided played a role in the formulation of your hypothesis,” Dr. Goodman said. And, he added, if researchers do not cite other studies, they cannot play a role in formulating conclusions. “If the eighth study is positive, and the preceding seven were cold negative, is it proper to report that a treatment works?” he said. “This may not be the fire, but it’s a heck of a lot of smoke.”

    Dr. Robinson, an assistant professor in the divisions of internal medicine and health sciences informatics, and Dr. Goodman, a professor of epidemiology and biostatistics and editor of the journal Clinical Trials, began their study by identifying 227 meta-analyses, which are studies that combine relevant previous studies to glean data from pooled evidence. For example, a meta-analysis might collect all studies about a drug whose effectiveness in individual studies was sometimes equivocal. The analysis would ask whether, with all results combined, the drug may seem to work.

    The 227 meta-analyses cited a total of 1,523 clinical trials. For each clinical trial, the investigators asked how many of the other trials, published before it on the same topic and included with it in the meta-analysis, were cited.

    They never expected so few.

    “It is a pretty bad situation,” Dr. Goodman said. “There were rumblings of this before, but they did not show the phenomenon like this does.”

    He adds that he and Dr. Robinson did not ask whether investigators cited prior studies in their grant applications, nor do they know for sure why so little previous research is cited.

    One reason might be that investigators do not think many of the results from previous studies apply to theirs.

    That is why, in a recent paper in Hepatology, Dr. Stephen Harrison of Brooke Army Medical Center in San Antonio and his colleagues did not cite any of 10 clinical trials used in a meta-analysis that followed his paper. He was studying the effects of a weight loss drug, orlistat, on liver function in overweight patients with fatty liver disease.

    Explaining why he failed to cite the other studies, he said, “I limited my discussion mainly to therapies that had been studied in fatty liver disease, not just obesity or diabetes.”

    Dr. Beverly B. Green of Group Health in Seattle did not cite any of 21 prior trials in a meta-analysis on self monitoring of blood pressure in her study of home blood pressure monitoring.

    She explained that she had done a literature search for her grant application but that for her paper, published in The Journal of the American Medical Association, she narrowed her criteria. In choosing articles to cite, she selected only the best of the previous papers and the ones most relevant to the questions she was asking and the subjects she studied. If she had cited everything that preceded her study, she said, she easily could have had 200 to 300 references.

    There are several steps along the way to a published paper where researchers might be asked about already published papers on the same topic. Those who finance the research, the ethics committees that review some studies and the journals that publish the studies all could ask the investigators how they assured themselves they had found prior relevant results.

    But, Dr. Goodman said, none of those groups feel any official responsibility.

    “It’s sort of a blind spot,” he said. “People sort of assume researchers know the literature, know their own field, know the studies.”
     
  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Few principles are more fundamental to the scientific and ethical validity of clinical research than that studies should address questions needing to be answered, and that they are designed in a way that will produce a meaningful answer. A prerequisite for either of those goals is that relevant prior research be properly identified.


    Robinson KA, Goodman SN. A Systematic Examination of the Citation of Prior Research in Reports of Randomized, Controlled Trials. Annals of Internal Medicine 2011;154(1):50-5. A systematic examination of the citation of prior ... [Ann Intern Med. 2011] - PubMed result

    Background: A randomized, controlled trial (RCT) should not be started or interpreted without accounting for evidence from preceding RCTs addressing the same question. Research has suggested that evidence from prior trials is often not accounted for in reports of subsequent RCTs.

    Objective: To assess the extent to which reports of RCTs cite prior trials studying the same interventions.

    Design: Meta-analyses published in 2004 that combined 4 or more trials were identified; within each meta-analysis, the extent to which each trial report cited the trials that preceded it by more than 1 year was assessed.

    Measurements: The proportion of prior trials that were cited (prior research citation index), the proportion of the total participants from prior trials that were in the cited trials (sample size citation index), and the absolute number of trials cited were calculated.

    Results: 227 meta-analyses were identified, comprising 1523 trials published from 1963 to 2004. The median prior research citation index was 0.21 (95% CI, 0.18 to 0.24), meaning that less than one quarter of relevant reports were cited. The median sample size citation index (0.24 [CI, 0.21 to 0.27]) was similar, suggesting that larger trials were not selectively cited. Of the 1101 RCTs that had 5 or more prior trials to cite, 254 (23%) cited no prior RCTs and 257 (23%) cited only 1. The median number of prior cited trials was 2, which did not change as the number of citable trials increased. The mean number of preceding trials cited by trials published after 2000 was 2.4, compared with 1.5 for those published before 2000 (PÂ < 0.001).Limitation: The investigators could not ascertain why prior trials were not cited, and noncited trials may have been taken into account in the trial design and proposal stages.

    Conclusion: In reports of RCTs published over 4 decades, fewer than 25% of preceding trials were cited, comprising fewer than 25% of the participants enrolled in all relevant prior trials. A median of 2 trials was cited, regardless of the number of prior trials that had been conducted. Research is needed to explore the explanations for and consequences of this phenomenon. Potential implications include ethically unjustifiable trials, wasted resources, incorrect conclusions, and unnecessary risks for trial participants.

    Primary Funding Source: None.
     
    Last edited: Jan 18, 2011
  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    The objective of this study was to investigate the extent to which pharmaceutical industry funding and author-industry financial ties or author employment disclosed in published reports of randomized controlled trials (RCTs) of pharmacological interventions are transparently reported in meta-analyses published in high-impact general and specialty medicine journals and the Cochrane Database of Systematic Reviews. We hypothesized that few meta-analyses would report COIs disclosed in original reports of included RCTs.

    SURPRISE: "About 62 percent of the 509 trials had their funding sources listed when they were published in the key medical journals. And more than two-thirds of those had been supported at least partly by the pharmaceutical industry." However, the investigators found that "none of the meta-analyses disclosed the original authors' ties to pharmaceutical companies and only two reported the original funding sources."


    Roseman M, Milette K, Bero LA, et al. Reporting of Conflicts of Interest in Meta-analyses of Trials of Pharmacological Treatments. JAMA: The Journal of the American Medical Association 2011;305(10):1008-17. Reporting of Conflicts of Interest in Meta-analyses of Trials of Pharmacological Treatments, March 9, 2011, Roseman et al. 305 (10): 1008 — JAMA

    Context Disclosure of conflicts of interest (COIs) from pharmaceutical industry study funding and author-industry financial relationships is sometimes recommended for randomized controlled trials (RCTs) published in biomedical journals. Authors of meta-analyses, however, are not required to report COIs disclosed in original reports of included RCTs.

    Objective To investigate whether meta-analyses of pharmacological treatments published in high-impact biomedical journals report COIs disclosed in included RCTs.

    Data Sources and Study Selection We selected the 3 most recent meta-analyses of patented pharmacological treatments published January 2009 through October 2009 in each general medicine journal with an impact factor of at least 10; in high-impact journals in each of the 5 specialty medicine areas with the greatest 2008 global therapeutic sales (oncology, cardiology, respiratory medicine, endocrinology, and gastroenterology); and in the Cochrane Database of Systematic Reviews.

    Data Extraction Two investigators independently extracted data on disclosed study funding, author-industry financial ties, and author employment from each meta-analysis, from RCTs included in each meta-analysis, and on whether meta-analyses reported disclosed COIs of included RCTs.

    Results Of 29 meta-analyses reviewed, which included 509 RCTs, only 2 meta-analyses (7%) reported RCT funding sources; and 0 reported RCT author-industry ties or employment by the pharmaceutical industry. Of 318 meta-analyzed RCTs that reported funding sources, 219 (69%) were industry funded; and 91 of 132 (69%) that reported author financial disclosures had 1 or more authors with pharmaceutical industry financial ties. In 7 of the 29 meta-analyses reviewed, 100% of included RCTs had at least 1 form of disclosed COI (pharmaceutical industry funding, author-industry financial ties, or employment), yet only 1 of these 7 meta-analyses reported RCT funding sources, and 0 reported RCT author-industry ties or employment.

    Conclusion Among a group of meta-analyses of pharmacological treatments published in high-impact biomedical journals, information concerning primary study funding and author COIs for the included RCTs were only rarely reported.
     
  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Bristol-Myers Bribed Doctors in Drug Scheme, California Commissioner Says
    Bristol-Myers Bribed Doctors in Drug Scheme, California Commissioner Says - Bloomberg

    By Steven Church and Edvard Pettersson
    Mar 18, 2011

    Bristol-Myers Squibb Co. (BMY) bribed doctors to prescribe the pharmaceutical company’s drugs, according to a whistle-blower lawsuit being pursued by the California insurance commissioner.

    Commissioner Dave Jones said at a press conference today in Los Angeles that the drugmaker’s sales people in California provided physicians with trips to basketball camps and other kickbacks to boost prescriptions of its drugs, including Plavix and Pravachol. The lawsuit is the largest health-insurance fraud case pursued by a California agency, Jones said.

    California insurance companies spent $3.5 billion to cover the costs of the drugs involved in the lawsuit, according to the commissioner. The lawsuit seeks $10,000 for each fraudulent insurance claim caused by the alleged kickbacks, disgorgement of illegal profits, and triple the amount of damages.

    “This sort of fraud has long plagued our health-insurance system, leading to billions of dollars annually in added health- care costs nationally,” Jones said today in a statement.

    Three former employees of New York-based Bristol-Myers filed the whistle-blower action under seal in 2007 in Superior Court in Los Angeles. The suit was unsealed last week. The so- called qui tam lawsuit was taken over by the commissioner, who will share any recoveries with the employees.

    Kickbacks Alleged

    The lawsuit claims that the company provided illegal kickbacks to doctors in order to increase pharmaceutical sales in California. Bristol-Myers in 2007 agreed to pay $515 million to settle U.S. allegations it overcharged the government for drugs and promoted medicines for unapproved uses.

    “Bristol-Myers Squibb believes this lawsuit has no merit and the company will defend itself vigorously,” company spokeswoman Laura Hortas said today in an interview.

    The complaint alleges that Bristol-Myers sales representatives, with permission from management, held happy hours with members of the Los Angeles Lakers and that “high prescribing” physicians were routinely invited to watch Lakers home games at a luxury suit.

    The drugmaker also paid for golf outings, samba dance events for Hispanic doctors, tickets to the Los Angeles Philharmonic, and bought liquor for physicians to induce them to increase their prescriptions and to reward them for doing so, according to the complaint.

    If a physician didn’t increase his prescriptions of the company’s drugs, Bristol-Myers used a tactic called “shaking the doctors down,” whereby sales representatives would warn the physicians he wouldn’t be getting free samples or invited to dinner events and resort events, according to the complaint.

    Jones said at today’s news conference that California prosecutors had opted not to intervene in the case.

    The case is California and Michael Wilson v. Bristol Myers Squibb Inc., BC 367873, California Superior Court (Los Angeles County).
     
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Is anyone really surprised about these COI?

    Conflicts of Interest in Cardiovascular Clinical Practice Guidelines

    Clinical practice guidelines (CPGs) have become a fixture in clinical medicine. Though individual clinical trials have meaningful impacts on patient care, CPGs are often adopted as the standard of care and taught as such in training programs at all levels. CPGs also play a prominent role in quality improvement initiatives. In addition, CPGs have an emerging role in national policy to guide reimbursement and serve as the standard of care in medical malpractice cases.

    Although conflicts of interest (COIs) are found in all spheres of medicine their role in the formation of CPGs may be especially significant. Improper bias in the CPG production process can have a potentially more widespread adverse effect on patient care than individual practitioners' COIs. Charges of undue industry influence surround official recommendations in recent guidelines. A review of authors' industry links and published opinions also highlights this issue. Such situations can lead to an erosion of trust in guidelines. A recent Institute of Medicine report on COIs in medical research, education, and practice highlights the fact that the scope of COIs in CPGs has not been well studied. Nonetheless, the American College of Cardiology (ACC) and the American Heart Association (AHA) have recently placed restrictions on official participation in educational events and guidelines production in line with the Council of Medical Specialty Societies (CMSS) code for interactions with companies.


    Mendelson TB, Meltzer M, Campbell EG, Caplan AL, Kirkpatrick JN. Conflicts of Interest in Cardiovascular Clinical Practice Guidelines. Arch Intern Med 2011;171(6):577-84. Arch Intern Med -- Abstract: Conflicts of Interest in Cardiovascular Clinical Practice Guidelines, March 28, 2011, Mendelson et al. 171 (6): 577

    Background Clinical practice guidelines (CPGs) serve as standards of care in practice, quality improvement, and reimbursement. The extent of conflicts of interest (COIs) in cardiology guideline production has not been well studied. Herein, we describe the scope of COIs in CPGs.

    Methods We examined the 17 most recent American College of Cardiology/American Heart Association guidelines through 2008. Using disclosure lists, we cataloged COIs for each participant as receiving a research grant, being on a speaker's bureau and/or receiving honoraria, owning stock, or being a consultant or member of an advisory board. We also cataloged the companies and institutions reported in each disclosure. "Episode" describes 1 instance of participation in 1 guideline by 1 person. "Individual" describes 1 person who may be involved in multiple episodes. "Company" describes a commercial or industry affiliation reported by an individual in a single episode. Analysis involved descriptive statistics and correlation analyses (Pearson correlation coefficient, {chi}2 and R2).

    Results Fifty-six percent of the 498 individuals reported a COI, corresponding to 56% of the 651 episodes. Being a consultant or member of an advisory board was the most common type. The percentage of episodes involving a COI varied between guidelines (range, 13%-87%). The number of episodes per individual was associated with both presence and number of disclosures (P < .001 for both comparisons). Of 478 companies, the number per guideline ranged from 2 to 242 companies (mean, 38 companies). One company was the most frequently reported company in 7 of 17 guidelines.

    Conclusion Conflicts of interest are prevalent in cardiology guidelines, but there seems to be a significant number of experienced experts without COIs.
     
  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    2nd UPDATE: SEC: J&J Pays $70M To Settle SEC, Criminal Charges
    2nd UPDATE: SEC: J&J Pays $70M To Settle SEC, Criminal Charges - WSJ.com

     
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Global Health Philanthropy and Institutional Relationships: How Should Conflicts of Interest Be Addressed? by David Stuckler, Sanjay Basu, and Martin McKee, is a groundbreaking article in PLoS Medicine, illuminating the shadows that blur major conflicts of interest in the public health arena.

    The article lifts the veil that hides an intricate web of direct and, more importantly, the indirect interconnected financial ties between private, tax-exempt foundations that are major funders of global health, and commercial corporations. Such relationships cannot but influence a foundation's agenda and funding decisions.

    By "following the money," the authors found that "despite the existence of policies explicitly designed to mitigate potential conflicts of interest, the boundaries between foundations, their investments, and their parent corporations or private funders can become blurred. Often, directors of the boards of foundations also sit on the board of private corporations, adopting multiple roles."

    The authors conducted a case study using data about the networks, activities, and funding patterns of the Bill & Melinda Gates Foundation, Ford Foundation, W. K. Kellogg Foundation, Robert Wood Johnson Foundation, and Rockefeller Foundation.

    These are the largest private global health foundations exerting inordinate influence on public health policy--those policies favor Big Pharma and their own corporate interests and endowment portfolios.


    Stuckler D, Basu S, McKee M. Global Health Philanthropy and Institutional Relationships: How Should Conflicts of Interest Be Addressed? PLoS Med 2011;8(4):e1001020. PLoS Medicine: Global Health Philanthropy and Institutional Relationships: How Should Conflicts of Interest Be Addressed?

    David Stuckler and colleagues examine five large private global health foundations and report on the scope of relationships between these tax-exempt foundations and for-profit corporations including major food and pharmaceutical companies.


    Summary Points

    • Institutional relationships in global health are a growing area of study, but few if any previous analyses have examined private foundations.

    • Tax-exempt private foundations and for-profit corporations have increasingly engaged in relationships that can influence global health.

    • Using a case study of five of the largest private global health foundations, we identify the scope of relationships between tax-exempt foundations and for-profit corporations.

    • Many public health foundations have associations with private food and pharmaceutical corporations. In some instances, these corporations directly benefit from foundation grants, and foundations in turn are invested in the corporations to which they award these grants.

    • Personnel move between food and drug industries and public health foundations. Foundation board members and decision-makers also sit on the boards of some for-profit corporations benefitting from their grants.

    • While private foundations adopt standard disclosure protocols for employees to mitigate potential conflicts of interests, these do not always apply to the overall endowment investments of the foundations or to board membership appointments. The extent and range of relationships between tax-exempt foundations and for-profit corporations suggest that transparency or grant-making recusal of employees alone may not be preventing potential conflicts of interests between global health programs and their financing.
     
  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Data fraud at Emory leads to retractions of three cardiology papers
    Data fraud at Emory leads to retractions of three cardiology papers Retraction Watch

     
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Medical Complicity in Torture at Guantanamo Bay

    Background - Torture has been used throughout history for interrogation, coercion, and punishment. Ingenious methods have been devised to inflict severe physical or mental pain or suffering intentionally on an individual to obtain a confession or information, or to punish, intimidate, or coerce. Nowadays, torture is prohibited under international law and under the domestic law of most countries, and is considered to be a violation of human rights. Article 5 of the United Nations (UN) Universal Declaration of Human Rights, which was adopted in December 1948, states: “No one should be subjected to torture or to cruel, inhuman or degrading treatment or punishment.” Similarly, signatories of the Geneva Conventions, which provide protection for people who fall into enemy hands during conflicts, have agreed not to torture prisoners. Torture is also prohibited by the UN Convention against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment, which came into force in June 1987. Implementation of this Convention by participating states is monitored the UN Committee against Torture.

    Why Was This Study Done?

    After the September 11, 2001 attacks on the United States, the US government redefined acts such as waterboarding (simulated drowning), sleep deprivation, and prolonged isolation as “safe, legal, ethical, and effective” “enhanced interrogation” techniques (EITs). These EITs were previously recognized as torture by the UN Committee against Torture. US health professionals are known to have been complicit in the design and implementation of EITs. For example, the US Central Intelligence Agency (CIA) and Department of Defense (DoD) designated “non-clinical” health professionals to monitor the use of EITs at the US detainee facility at the US Navy Base at Guantánamo Bay, Cuba (GTMO), and the active role of these individuals during interrogations has been documented. Much less is known, however, about the role of health professionals assigned to the DoD to provide medical and mental health care to the GTMO detainees. Specifically, it is not known whether these health professionals accurately documented physical and psychological evidence of torture and ill treatment among the detainees. In this case series, the researchers review GTMO medical records and case files of nine detainees for evidence of documentation of ill treatment and torture by medical personnel.

    What Did the Researchers Do and Find?

    The researchers—non-governmental medical experts retained by legal representatives of GTMO detainees alleging torture and ill treatment—reviewed the medical records, client affidavits, attorney–client notes, and legal declarations of medical experts of nine GTMO detainees. In each case, the detainee alleged abusive interrogation methods consistent with torture as defined by the UN Convention against Torture. The researchers report that the medical affidavits for all the cases indicate that the allegations of torture and ill treatment were consistent with physical and psychological evidence of torture and ill treatment documented in the medical records and in evaluations by non-governmental experts. However, the medical personnel responsible for the detainees' routine medical and mental health care failed to inquire about and/or document the causes of the physical injuries and psychological symptoms that they observed. Instead, they attributed psychological symptoms to “personality disorders” and “routine stressors of confinement”. Moreover, psychotic symptoms such as hallucinations did not prompt consideration of abusive treatment. Importantly, psychological assessments conducted by non-governmental experts revealed diagnostic criteria for current major depression and/or post-traumatic stress disorder (PTSD, a common outcome of torture or ill treatment) in all the cases.

    What Do These Findings Mean?

    These findings indicate that health professionals assigned to the DoD to provide medical and mental health care to GTMO detainees neglected and/or concealed evidence of intentional harm. Because only nine cases are included in this case series, these findings may not be generalizable to other GTMO detainees. The findings are also limited by their reliance on medical records and case files that were sometimes heavily edited and on psychological assessments based on questionnaires rather than on direct examination. Nevertheless, these findings reveal new information about the potential extent of medical complicity in US torture practices, and they highlight the need for a thorough and impartial investigation of all the available information, including relevant classified information.


    The PME. Medical Complicity in Torture at Guantanamo Bay: Evidence Is the First Step Toward Justice. PLoS Med 2011;8(4):e1001028. PLoS Medicine: Medical Complicity in Torture at Guantánamo Bay: Evidence Is the First Step Toward Justice

    PLoS Medicine editors argue that the publication of new evidence of the complicity of medical personnel in torture at Guantanamo Bay (GTMO) should bolster calls for further investigation into the role of doctors at the prison.


    Iacopino V, Xenakis SN. Neglect of Medical Evidence of Torture in Guantanamo Bay: A Case Series. PLoS Med 2011;8(4):e1001027. PLoS Medicine: Neglect of Medical Evidence of Torture in Guantánamo Bay: A Case Series

    Background - In the wake of the September 11, 2001 attacks on the US, the government authorized the use of “enhanced interrogation” techniques that were previously recognized as torture. While the complicity of US health professionals in the design and implementation of US torture practices has been documented, little is known about the role of health providers, assigned to the US Department of Defense (DoD) at the US Naval Station Guantánamo Bay, Cuba (GTMO), who should have been in a position to observe and document physical and psychological evidence of torture and ill treatment.

    Methods and Findings - We reviewed GTMO medical records and relevant case files (client affidavits, attorney–client notes and summaries, and legal affidavits of medical experts) of nine individuals for evidence of torture and ill treatment and documentation by medical personnel. In each of the nine cases, GTMO detainees alleged abusive interrogation methods that are consistent with torture as defined by the UN Convention Against Torture as well as the more restrictive US definition of torture that was operational at the time. The medical affidavits in each of the nine cases indicate that the specific allegations of torture and ill treatment are highly consistent with physical and psychological evidence documented in the medical records and evaluations by non-governmental medical experts. However, the medical personnel who treated the detainees at GTMO failed to inquire and/or document causes of the physical injuries and psychological symptoms they observed. Psychological symptoms were commonly attributed to “personality disorders” and “routine stressors of confinement.” Temporary psychotic symptoms and hallucinations did not prompt consideration of abusive treatment. Psychological assessments conducted by non-governmental medical experts revealed diagnostic criteria for current major depression and/or PTSD in all nine cases.

    Conclusion - The findings in these nine cases from GTMO indicate that medical doctors and mental health personnel assigned to the DoD neglected and/or concealed medical evidence of intentional harm.


    Docs' Complicity in Gitmo Torture Alleged
    Medical News: Docs&apos; Complicity in Gitmo Torture Alleged - in Public Health & Policy, Ethics from MedPage Today

    Medical records of Guantanamo Bay detainees were consistent with their allegations of illegal torture -- but showed no indication that military physicians tried to intervene or even question the cause of the injuries, two researchers said.

    In fact, some physicians at the Guantanamo facility may have actually covered up medical evidence of torture in nine cases, charged Vincent Iacopino, MD, PhD, of the University of Minnesota, and former Brig. Gen. Stephen Xenakis, MD, a retired U.S. Army medical officer.

    Psychological symptoms detailed in the records that were consistent with torture instead were attributed to "personality disorders" and "routine stressors of confinement," Iacopino and Xenakis reported online in PLoS Medicine, after reviewing records of nine Guantanamo detainees.

    Moreover, they wrote, "temporary psychotic symptoms and hallucinations did not prompt consideration of abusive treatment."

    An accompanying commentary by PLoS Medicine's five editors said the report "adds solid, specific evidence of both human rights abuses at Guantanamo Bay and the apparent complicity of medical personnel in the abuse."

    "Crucially, although some of the physical injuries sustained by detainees that were consistent with allegations of torture were documented by medical personnel in the camp, causes of injury were not investigated by those personnel," the editors wrote.

    These failures constitute clear ethical breaches by the medical personnel at the detention center, Iacopino and Xenakis asserted.

    "The commission and/or concealment of acts of torture should never be justified by any health professionals -- clinical, nonclinical, military, or nonmilitary," the investigators wrote.

    As the Declaration of Tokyo states, 'The physician's fundamental role is to alleviate the distress of his or her fellow human beings, and no motive, whether personal, collective, or political, shall prevail against this higher purpose,'" the researchers noted.

    Iacopino and Xenakis are both associated with human rights groups and were recruited by lawyers for the nine detainees to provide independent medical review of their cases.

    The detainees have filed formal charges that they were tortured and otherwise mistreated at the Guantanamo Bay detention center, opened at the U.S. naval base there in 2002 to house and interrogate alleged terrorists captured in Afghanistan and elsewhere after the 9/11 attacks.

    The detainees alleged that they had been subjected to an average of eight different forms of "enhanced interrogation techniques" (range five to 11) including beatings, forced positions, temperature extremes, sleep deprivation, and forced nudity.

    Some of these actions were not illegal under international treaties and official policies in place at the time, but others were, according to Iacopino and Xenakis.

    Among them: beatings that resulted in broken bones or loss of consciousness, actual or threatened sexual assaults, waterboarding, and mock executions.

    Five of the detainees said they had been beaten unconscious.

    For three of the detainees, Iacopino and Xenakis wrote that "medical records documented injuries that were consistent or highly consistent with detainee allegations of abuse: contusions (2), bone fractures (3), lacerations (2), peripheral nerve damage (1), and sciatica (2). There was no mention of any cause for these injuries."

    Moreover, whereas the records indicated that none of the detainees had any personal or family history of psychological problems prior to their capture, newly emergent psychological symptoms were documented for eight of the nine prisoners.

    These included five detainees who experienced nightmares, four with suicidal ideation, three who suffered audiovisual hallucinations, and two each with recorded suicide attempts, anxiety, and dissociative states.

    "In each case, the onset of psychological symptoms was temporally related to allegations of abuse and corroborating medical information," the researchers found.

    Moreover, notes made by psychologists at Guantanamo indicated that seven detainees had symptoms consistent with post-traumatic stress disorder (PTSD).

    Yet, in no case did the records indicate that medical personnel at Guantanamo inquired about possible causes of the psychological symptoms or the PTSD.

    "Treatment for depression consisted of medications and periodic checks for suicidal/homicidal ideation," Iacopino and Xenakis wrote.

    In one case, they noted, a detainee with multiple psychological symptoms including suicidal ideation was told simply to "relax when guards are being more aggressive."

    In sum, according to the researchers, "The assessments conducted by nongovernmental medical experts [a total of five including themselves] in each of the nine cases indicate that the specific allegations of torture and ill treatment were highly consistent with and supported by physical and psychological evidence observed in all cases."

    They added, "The abuses reported in this case series could not be practiced without the interrogators and medical monitors being aware of the severe and prolonged physical and mental pain that they caused."

    In fact, several detainees indicated that access to medical care was linked to cooperation with the interrogators.

    In one case, a detainee was treated for a painful ankle injury two weeks after the alleged injury.

    In another case, medical personnel allegedly 'certified' the detainee's "fitness' to continue being interrogated after several periods of unconsciousness.

    Another detainee indicated that he observed interrogators with his medical records and that his chronic back pain was exploited by interrogators with the use of prolonged, painful stress positions.

    The study does have some limitations.

    Iacopino and Xenakis noted that the cases selected for review included only those for which they were consulted, so their findings may not be generalizable to other detainees.

    The findings were also based on medical records and case files which, in some cases, has been heavily redacted. As well, psychological evaluations in the majority of cases consisted of proxy assessments.

    The Department of Defense, which runs the Guantanamo facility, had no immediate comment on the report.

    However, a review conducted by the Navy's vice chief of operations in early 2009 found that treatment of detainees at that time conformed to rules set by the Geneva Convention on the conditions of confinement.

    Those rules ban humiliating or degrading treatment of prisoners, as well as physical abuse.
     
  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Review Casts More Doubts on a Lung Cancer Study
    Review Casts More Doubts on a Lung Cancer Study - NYTimes.com

    April 29, 2011
    By GARDINER HARRIS

    In medical experiments on human beings, every patient must sign an “informed consent” form acknowledging the risks, and researchers are required to keep track of those statements.

    But the doctors who conducted a controversial, widely publicized lung cancer study involving more than 50,000 patients at numerous hospitals were unable to locate 90 percent of the consent forms, according to a confidential review provided to The New York Times.

    The finding casts further doubt on a clinical trial that made headlines in 2006 when it concluded that fully 80 percent of lung cancer deaths could be prevented through wide use of CT scans.

    That trial, led by Dr. Claudia I. Henschke at Weill Cornell Medical College in New York City, drew sharp criticism from skeptics of cancer screening; the criticism intensified when The Times reported in March 2008 that the research was being financed in part by $3.6 million in grants from the parent company of the Liggett Group, a cigarette maker.

    The confidential report on patient consent, dated Oct. 7, 2008, recommended that the trial be stopped. But it continues to this day, although not at Weill Cornell.

    Several ethicists said the hospital was legally required to disclose the ethical problems documented by the secret review. That has not happened either.

    The confidential report was commissioned by Weill Cornell after The Times’s 2008 article and other revelations about the study in the newsletter The Cancer Letter. The hospital hired four prominent professors from other universities to undertake an independent review of Dr. Henschke’s research, known as the International Early Lung Cancer Action Program, or I-Elcap.

    In their report, the reviewers scolded Weill Cornell administrators for failing to supervise the research more closely, “especially knowing that scientific controversy has surrounded I-Elcap almost from its inception.”

    One reviewer, Dr. David P. Carbone, a professor of medicine and cancer biology at Vanderbilt, said in an interview that he and the other reviewers never found out “whether these consents were obtained and lost or whether they weren’t obtained at all.”

    He said that Dr. Henschke acted with the best of intentions, “but there’s no way for me to justify any of the problems” documented by the group’s review.

    Dr. Henschke, who has since left Weill Cornell for Mount Sinai Medical Center in New York, declined to respond to the findings of the 2008 review, saying it was confidential. But in an e-mail, she said the responsibility for keeping track of consent forms lay with all the hospitals where the experiments were done.

    “I-Elcap is a non-federally funded academic consortium of independent, autonomous sites that share certain data,” she wrote. “Accountability and responsibility for human protection lie at the local level.”

    But Dr. Henschke’s research has been supported by grants from the National Institutes of Health, and federal rules governing research conducted at multiple sites have long required that the coordinating center either collect copies of patient consent forms or ensure that they are being kept appropriately.

    “The responsible conduct of a study requires that informed consent documents be kept on file,” said Dr. P. Pearl O’Rourke, director of human research affairs at Partners HealthCare, part of Harvard University. “There should be a system so that every consent form can be found no matter if individuals were enrolled at a single site or multiple sites.”

    John D. Rodgers, a spokesman for Weill Cornell, wrote in an e-mail that the medical school followed federal research regulations “and there were no issues regarding the safety of the research subjects.”

    Dr. Bruce A. Chabner, director of clinical research at Massachusetts General Hospital Cancer Center and editor in chief of The Oncologist journal, said he would ask Weill Cornell for an explanation of the problems outlined in the 2008 scientific review, as well as a follow-up to the report. His journal has published research by Dr. Henschke, and “if we find there was no informed consent for those patients, the paper would have to retracted,” he said.

    The American Cancer Society helped finance Dr. Henschke’s research, and some of her work was published in cancer journals owned by the society. Dr. Otis W. Brawley, the society’s chief medical officer, said any study underwritten by the organization must conform to federal research rules, including those that require that problems with informed consent be reported to federal science agencies.

    He added that the society’s journals might have to correct or retract any study that proved unable to document that patients had given informed consent. “But I don’t want to prejudge the case,” Dr. Brawley said.

    In November, a huge federal study found that annual CT scans of current and former heavy smokers reduced their risk of death from lung cancer by 20 percent and, even more surprising, seemed to reduce the risks of death from other causes as well.

    Although the scale of the benefit was substantially less than Dr. Henschke claimed her research showed, the federal study was widely interpreted as confirming her longtime contention that CT screening can save lives from lung cancer, which kills more than 150,000 people each year in the United States. Most patients discover their disease too late for treatment, and 85 percent die from it.