The following letter to the president of Brown University requests that she writes to the editor of the Journal of the American Academy of Child & Adolescent Psychiatry supporting our request for retraction of a journal article that misrepresented the efficacy and safety of paroxetine for depressed adolescents. The letter was written by Healthy Skepticism members Jon Jureidini and Leemon McHenry and signed by additional Healthy Skepticism members and others. Jon and Leemon's campaign for retraction of the misleading article has been endorsed as a Healthy Skepticism campaign by the Healthy Skepticism international management group.
4 October 2011
President Ruth J. Simmons
Office of the President
Brown University
1 Prospect Street
Campus Box 1860
Providence, Rhode Island 02912Dear President Simmons,
Study 329: A multi-center, double blind, placebo controlled study of paroxetine and imipramine in adolescents with unipolar major depression
We write to you about our ongoing concerns regarding a journal article that originated at the Department of Psychiatry and Human Behavior, under the leadership of Dr. Martin Keller.
Between 1993 and 1998, SmithKline Beecham (subsequently GlaxoSmithKline) provided $800,000 to Brown University for its participation in the above study.[1] The results were published in 2001 by Keller et al. in a journal article, 'Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial',[2] in the Journal of the American Academy of Child & Adolescent Psychiatry.
The article was ghostwritten by agents of the manufacturer, and seriously misrepresented both the effectiveness and the safety of paroxetine in treating adolescent depression.
While problems with study 329 and the Keller et al paper have been thoroughly exposed in legal actions,[3] the bioethical and medical literature,[4] a book,[5] and a BBC Panorama documentary[6], the paper continues to be cited uncritically in the medical literature as evidence of the efficacy of paroxetine for treatment of adolescent depression.[7],[8] Our main concern is that adolescents are being harmed because well-intentioned physicians have been misled.
Moreover, the misrepresentation has been compounded by the following:
1) The Journal was asked by two of the undersigned, Drs. Jureidini and McHenry, to retract the article, but has refused to do so.
2) In a letter of May 13, 2008, from Pamela D. Ring to Dr. David Egilman, Brown University refused to release information about its internal investigation into Dr. Keller's conflicts of interest and scientific misconduct.Study 329 reveals the pervasive influence of GlaxoSmithKline's marketing objectives on the preparation and publication of a 'scientific' manuscript and peer-reviewed journal article. GlaxoSmithKline's own internal documents disclosed in litigation show that company staff were aware that the study 329 did not support a claim of efficacy but decided that it would be "unacceptable commercially" to reveal that.[9]
The data were therefore selectively reported in Keller et al.'s article, in order to "effectively manage the dissemination of these data in order to minimise any potential negative commercial impact".9 As it turns out, the Keller et al. article was used by GlaxoSmithKline's to ward off potential damage to the profile of paroxetine and it was used to promote off-label prescriptions of Paxil® and Seroxat® to children and adolescents, some of whom became suicidal and self-harmed as a result.[10]
The unretracted article is a stain on Brown University's reputation for academic excellence. The University cannot claim to be a leader in scientific research and moral integrity while failing to act to redress this article that negligently misrepresents scientific findings.
In its accreditation document for the New England Association of Schools and Colleges (NEASC), Brown University claims in relation to 'Standard Eleven: Integrity' that 'The institution manages its academic, research and service programs, administrative operations, responsibilities for students and interactions with prospective students with honesty and integrity', that it 'expects that members of its community, including the board, administration, faculty, staff, and students, will act responsibly and with integrity', and that 'Truthfulness, clarity, and fairness characterize the institution's relations with all internal and external constituencies'.[11] The University's inaction in relation to study 329 casts doubt on the validity of these claims.
We ask that you write to the editor, Dr. Andres Martin, Journal of the American Academy of Child & Adolescent Psychiatry supporting our request for retraction of the journal article.
We are making this letter available to interested parties and it will be posted on the Healthy Skepticism website (www.healthyskepticism.org).
Yours sincerely
Jon Jureidini
Child Psychiatrist
Clinical Professor, University of AdelaideLeemon McHenry
Department of Philosophy, California State University, NorthridgeJerome Biollaz
Professor Emeritus of Medicine, Centre Hospitalier Universitaire Vaudois, LausanneAlain Braillon
Stephen Bezruchka
Senior Lecturer, School of Public Health, University of WashingtonRuud Coolen van Brakel, director
Sandra van Nuland, consultant
Martine van Eijk, MD PhD
Instituut voor Verantwoord Medicijngebruik (Dutch Institute for Rational Use of Medicine)Marc-Andre Gagnon,
Research Fellow, Edmond J. Safra Center for Ethics, Harvard UniversityKen Harvey
Adjunct Senior Lecturer, School of Public Health, La Trobe University, MelbourneDavid Healy
Professor in Psychological Medicine, Cardiff University School of MedicineAndrew Herxheimer,
Emeritus Fellow, UK Cochrane Centre, OxfordJerome Hoffman
Professor of Emergency Medicine, University of Southern CaliforniaJoel Lexchin
Professor, School of Health Policy and Management, York University, Toronto, Canada
Melissa Raven
Adjunct Lecturer, Discipline of Public Health, Flinders University, Australia
Dee Mangin
Associate Professor, Director Primary Care Research Unit, Christchurch School of Medicine
Peter Mansfield
Director, Healthy SkepticismDan Mayer
Professor of Emergency Medicine, Albany Medical College, New YorkDavid Menkes
Associate Professor of Psychiatry, University of AucklandRobert Purssey
Senior Lecturer, University of QueenslandNicholas Rosenlicht
Clinical Professor of Health Sciences, University of California, San FranciscoJorg Schaaber
President, International Society of Drug Bulletins (ISDB)Arthur Schafer
Director, Centre for Professional and Applied Ethics, University of ManitobaMichael Wilkes
Professor of Medicine, University of California, DavisJim Wright
Co-Managing Director, Therapeutics InitiativeLiliya E. Ziganshina
Head, Professor, Department of Basic and Clinical Pharmacology, Kazan Federal University, Russian Federation
[1] Keller M. (2011). Martin B. Keller, MD. Providence, RI: Brown University; 2011. http://research.brown.edu/pdf/1100924449.pdf
[2] Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, McCafferty JP. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2001 Jul;40(7):762-72.
[3] The People of the State of New York vs. SmithKline Beecham Corp. (Case No. 04-CV-5304 MGC), Beverly Smith vs. SmithKline Beecham Corp. (Case No. 04 CC 00590), Engh vs. SmithKline Beecham Corp. (Case No. PI 04-012879), Teri Hoormann vs. SmithKline Beecham Corp. (Case No. 04-L-715) and Julie Goldenberg and Universal Care vs. SmithKline Beecham Corp. (Case No. 04 CC 00653)
[4] Jureidini JN, McHenry LB, Mansfield PR. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk Saf Med 2008;20:73-81. http://www.pharmalot.com/wp-content/uploads/2008/04/329-study-paxil.pdf
[5] Bass A. Side effects: A prosecutor, a whistleblower, and a bestselling antidepressant on trial. Chapel Hill, NC: Algonquin Books; 2008.
[6] BBC. Seroxat – Secrets of the Drugs Trials. Panorama. BBC one; 2007 Jan 29. http://news.bbc.co.uk/2/hi/programmes/panorama/6291773.stm
[8] Jureidini J, McHenry L. Conflicted medical journals and the failure of trust. Accountability in Research 18:45-54.
[9] SmithKline Beecham, Seroxat/Paxil adolescent depression position piece on the Phase III clinical studies, October 1998, PAR003019178; http://www.healthyskepticism.org/documents/documents/19981014PositionPiece.pdf
[10] Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006 Mar;63(3):332-9
[11] Brown University. Standard Eleven: Integrity. NEASC Accreditation; 2008. http://www.brown.edu/Project/NEASC/Standards/integrity_11.php
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At least two promising vaccines for E. coli O157:H7 are awaiting licensing approval from the Center for Veterinary Biologics (CVB) at APHIS. CVB has a long history with animal vaccines, but has primarily focused on those that improve animal health -- not human health. The E. coli vaccines under consideration are not designed to prevent illness in the animal, but could significantly decrease the amount of the pathogen present in the pre-harvest environment, and presumably in the meat that winds up on consumers' plates. Vaccines focusing on public, rather than animal, health represent fairly new ground for the agency. Given the delays in their approval, CVB may be having trouble adjusting its vision. In a series of conversations with many of the players involved -- representatives from CVB and the pharmaceutical companies awaiting licensure -- CVB's approach has been striking. Far from being enthusiastic about the public health possibilities of pre-harvest vaccines for E. coli, the agency instead seems beleaguered and adrift on the issue, even admitting in one conversation that although there's no scientific downside to the vaccines, there are some economic and practical issues to consider. Perhaps there are economic and practical issues to consider -- but that's not CVB's mission. The fiscal implications and logistical applications to these vaccines are issues for the free market to deal with, and not reasons to delay licensing of promising new technologies that could make a significant public health impact. The key issue for CVB -- indeed, the only issue the agency has authority to consider -- is whether the vaccines are pure, safe, potent, and effective. In meetings with CVB officials, the agency acknowledges that the vaccines under consideration have cleared the first three hurdles. It's the efficacy that appears to be tripping them up. CVB says that the industry wants an expectation of efficacy that would decrease summer E. coli shedding rates in cattle to approximate winter shedding rates, an efficacy of between 55 and 65 percent. This is a laudable goal, and it's useful to know what the industry would like to see from a new pre-harvest tool to combat contamination. But surely the Food Safety and Inspection Service (FSIS), the agency whose mission is to ensure the safety of meat for consumers, has an opinion on whether that expectation of efficacy is too high, too low, or just right? Unfortunately, CVB doesn't know it. From what we can tell, CVB has a bold new responsibility to consider vaccines with a possibly significant public health impact, but they haven't taken steps toward a meaningful collaboration with the relevant public health agency that sits in the same building to decide how best to exercise that power. How CVB came into its responsibility for vaccines that have a public health focus (rather than the traditional animal health focus) is somewhat mysterious. Perhaps it was simply that the agency was left without a chair when, in the early 2000s, the music stopped on a debate about where to house these types of animal vaccine approvals. True or not, the agency has entered a new era -- one where their focus on animal health must share the spotlight with a commensurate consideration for public health. It's time for CVB to embrace that new responsibility, first by re-focusing on its actual statutory mission and away from tangential issues of practicality and economy. Second, the agency must consult with FSIS and gather the relevant stakeholders to discuss how vaccines can make a contribution to public health. Third, CVB should streamline and make more transparent the entire process of vaccine approval, so that interested parties can follow the progress -- or lack thereof -- of promising technologies under consideration.
There's no guarantee about these vaccines, but even without a silver bullet, it is possible much progress can still be made. CVB has the authority and the responsibility to put yet another tool in the box to fight the scourge of E. coli. Now the agency must rise to meet its new public health role, by streamlining, prioritizing, and publicizing the vaccine approval process for those technologies that could have a significant impact on public health.
Here's a letter written by the Center for Science in the Public Interest to USDA Secretary Tom Vilsack about the delay in vaccine approvals.
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Sarah A. Klein, J.D., M.A. is Staff Attorney, Food Safety Program, at theCenter for Science in the Public Interest
Iowa State University is an Affirmative Action employer.
About SRI: SRI International, founded as Stanford Research Institute in 1946, is a leading independent research institute. SRI conducts sponsored R&D for its government, business, and foundation clients in information and engineering technologies, pharmaceuticals and biotechnology, chemistry and materials, education, health sciences, and economics.
SRI's Policy Division (www.sri.com/policy) helps government agencies, nonprofit organizations, and commercial clients solve problems and capitalize on opportunities posed by complex issues in education, training, health, economic development, and human services. Our policy experts develop research-based solutions to problems posed by rapid social, technological, and economic changes in society. The products of our research are used to shape innovations to improve productivity and the quality of life at home, at school, and in the workplace. How to apply: Apply via our web page www.sri.com/jobs to job ID number 101377. SRI is an equal opportunity employer. www.sri.com
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Ph.D. in education, early childhood education, child development, developmental psychology or related field.
About SRI: SRI International, founded as Stanford Research Institute in 1946, is a leading independent research institute. SRI conducts sponsored R&D for its government, business, and foundation clients in information and engineering technologies, pharmaceuticals and biotechnology, chemistry and materials, education, health sciences, and economics.
SRI's Policy Division (www.sri.com/policy) helps government agencies, nonprofit organizations, and commercial clients solve problems and capitalize on opportunities posed by complex issues in education, training, health, economic development, and human services. Our policy experts develop research-based solutions to problems posed by rapid social, technological, and economic changes in society. The products of our research are used to shape innovations to improve productivity and the quality of life at home, at school, and in the workplace. How to apply: Apply via our web page www.sri.com/jobs to job ID number 101376. SRI is an equal opportunity employer. www.sri.com
Ph.D. in education, special education, clinical child psychology, school psychology, child development, developmental psychology, or related field.
Men are far more likely to have the sexually transmitted human papillomavirus (HPV) in their mouths than women, the Daily Mail has reported. The Mail has outlined research into the prevalence of HPV, which is a risk factor mouth cancer and other cancers. Researchers found that HPV was more commonly found in people who engaged in all kinds of sexual activity – including vaginal, anal and oral. The Mail reports that the researchers suggest that HPV vaccination for men needs investigating to see whether it could help stop oral HPV and, potentially, oral cancer.
Mouth cancer has risen more than 20% in the past 30 years. Tobacco use and prolonged, heavy alcohol drinking are the biggest risk factors, but the presence of oral HPV is also a clear risk factor for the disease.
The latest research set out to estimate the proportion of people infected with oral HPV in the United States, and any factors associated with infection. It found that approximately 7% of the US population aged 14 to 69 years were infected with this virus, and that men were more likely to be infected than women.
This study shows a marked difference in oral HPV infection between men and women in the US, but does not necessarily reflect how many people in the UK are infected. There are many different types of HPV, and not everyone who is infected will go on to develop cancer.
HPV is known to cause cervical cancer, and a vaccine campaign for girls aims to reduce its prevalence among women, and so reduce the number of cervical cancers. It remains unclear whether vaccinating men would have an effect on the presence of oral HPV or reduce the number of cancers.
Where did the story come from?
The study was carried out by researchers from Ohio State University, the US National Cancer Institute and a US company called Information Management Services. The research was funded by Ohio State University, the US National Cancer Institute, John and Nina Cassils and the pharmaceutical company Merck. Merck is the manufacturer of Gardasil, the cervical cancer jab that targets several strains of HPV, including type 16, which is most commonly associated with oral cancer.
The study was published in the peer-reviewed Journal of the American Medical Association.
This research was covered appropriately in the media, with the Daily Mail emphasising that the prevalence estimate was drawn from a US population, and pointing out that not all individuals infected with oral HPV will go on to develop oral cancer. The BBC was careful to point out that it is not known if the existing vaccines against HPV used for preventing cervical cancer are effective against oral HPV infection and that vaccination cannot be recommended for the primary prevention of oropharyngeal cancer.
What kind of research was this?
This was a cross-sectional study that examined the number of people aged 14 to 69 infected with oral HPV in the United States.
Cross-sectional studies are a useful way to generate estimates of the number of cases in a population. However, they only collect information at one point in time, and cannot tell us why things are related, or how things change over time. This study provides a snapshot of the number of infections in one time period (between 2009 and 2010), but it does not attempt to link these numbers to the risk of developing oral cancer.
Background information supplied by the researchers suggests that the number of cases of oral cancer has increased over the past 30 years in several countries, and HPV has been directly implicated as the underlying cause.
What did the research involve?
Researchers recruited a sample of individuals that was intended to be representative of the US population. They conducted interviews and a physical examination. During the interview, participants provided information about:
- sociodemographic factors – such as age, sex, education, socioeconomic status, sexual orientation and marital status
- substance use – including tobacco, alcohol and marijuana
- sexual behaviour – including ever having had sex, ever having performed oral sex, age at first sex, number of sexual partners and history of sexually transmitted infection
During the physical examination samples of cells were taken from the inside of the mouth. These samples were sent to a laboratory where researchers isolated DNA from the cells to determine whether the individual was infected with oral HPV and, if so, to identify the virus type. They tested for 37 HPV types, of which 18 were ‘high-risk’ DNA types.
The researchers then analysed the data, arriving at overall estimates of the number of infections in the US population. They also conducted an analysis that accounted for sociodemographic and behavioural factors.
What were the basic results?
There were 5,579 participants in the beginning of the study. Of these 5,501 (98.6%) were included in the analysis. The researchers found that overall:
- 6.9% of participants were infected with HPV (95% confidence interval (CI) 5.7% to 8.3%)
- 3.7% of participants were infected with a type of HPV classified as having a high risk of causing cancer (95% CI 3.0% to 4.6%)
- 3.1% of participants were infected with a low-cancer-risk type of HPV (95% CI 2.5% to 3.9%)
- the most prevalent type of virus detected was HPV-16 (1.0%, 95% CI 0.7% to 1.3%)
When the researchers accounted for sociodemographic and behavioural factors in their analysis, they found that the following variables were independently associated with oral HPV infection:
- Age: infections peaked at two distinct age groups - in those aged 30 to 34, and again in those aged 60 to 64. This pattern was stronger for men than women.
- Sex: men had more than twice the number of infections as women (10.1% male versus 3.6% female; prevalence ratio (PR) 2.33, 95% CI 1.66 to 3.26). When looking at the most common HPV type (HPV-16) this increased to a nearly fivefold difference (1.6% male versus 0.3% female; PR 5.41, 95% CI 2.12 to 13.83).
- Lifetime number of sexual partners: those with two or more partners had significantly more infections than those who had no sexual partners. The prevalence of infection increased with increasing numbers of lifetime partners.
- Current smoking intensity: those who smoked 10 or more cigarettes a day had significantly more infections than those who had never smoked or who no longer smoked. This association was stronger for women than for men.
Ethnicity, marital status and alcohol and marijuana use were not independently associated with oral HPV infection.
How did the researchers interpret the results?
The researchers concluded that approximately 7% of the US population between the ages of 14 and 69 were infected with oral HPV. They say that this is significantly lower than infection with genital HPV.
Conclusion
This was a relatively large cross-sectional study that estimated the number of oral HPV infections in the US among 14 to 69 year olds. These estimates cannot be directly generalised to the UK.
The researchers say that their data provide evidence that oral HPV infection is mainly sexually transmitted. This is because infection was uncommon among participants with no previous sexual partners, but was up to eight times higher among those with previous partners, and increased significantly as the number of partners increased. The researchers do point out, however, that their study did not collect information on possible non-sexual transmission methods.
While policy decisions regarding HPV infection generally focus on genital HPV among females, this research demonstrated that, at least in the US, men are more likely to be infected with oral HPV. As high-risk types of oral HPV have been shown to cause mouth cancer, this research may open up discussions on the need to address these risks. Options for reducing the risk of infection include targeting modifiable behaviours, such as smoking and sexual behaviour. Whether current vaccines against HPV can prevent oral cancer is unknown and this research does not provide any evidence as to how effective any vaccine might be.
All in all, this was a well conducted cross-sectional study that estimated the prevalence of oral HPV infections in the United States. However, it does not provide any information on the number of participants who went on to develop oral cancer. It is important to remember that there are many different types of HPV, and not everyone who is infected will go on to develop cancer. This study cannot tell us the rates of oral HPV infection in the United Kingdom, but may provide information on risk factors for infection that apply to populations outside the US.
Links To The Headlines
More men 'have oral cancer virus'. BBC News, January 27 2012
More than 16 million Americans have oral HPV. Daily Mail, January 26 2012
Links To Science
Gillison ML, Broutian T, Pickard RKL, et al. Prevalence of oral HPV infection in the United States, 2009-2010. Journal of the American Medical Association. Published online January 26 2012
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