AHRP Letter to Harvard Re: Dr. Biederman’s Research

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ALLIANCE FOR HUMAN RESEARCH PROTECTION
A catalyst for public debate
142 West End Avenue Suite 28P
New York, NY  10023

 

Updated  

 

RESPONSE LETTERS (please click below)

Harvard University Response.pdf

Massachusetts General Hospital Response.pdf

 

 

April 13, 2009

 

Dr. Drew Gilpin Faust                                      Dr. Peter L. Slavin          
President                                                         President                              

Dr. Steven Hyman                                           Massachusetts General Hospital

Provost                                                            (Partners Healthcare)

Harvard University                                          55 Fruit Street

Massachusetts Hall                                         Boston, MA 02114                 

Cambridge, MA 02113    

       

Dr. Jeffrey Flier
Dean
Harvard Medical School
25 Shattuck Street
Boston, MA 02115

RE: Integrity of Dr. Joseph Biederman’s research

Dear Drs. Faust, Slavin, Flier, and Hyman:

Internal drug industry documents uncovered during federal litigation confirm that partnerships and financial ties between drug manufacturers and academia undermine the integrity of medical research and, by extension, the practice of medicine. 

In particular, given the absence of a validated scientific base, [1] commercialization in psychiatry has resulted in the adoption of clinical guidelines formulated by psychiatric leaders with significant financial and other ties to psychotropic drug manufacturers.  http://www.ahrp.org/cms/content/view/565/61/  Psychiatry’s diagnostic and treatment guidelines rely in large measure upon industry-sponsored research studies intended solely to market pharmaceutical products. [2]

Harvard University is under a cloud of suspicion that it turned a blind eye to possible ethical and scientific misconduct by certain faculty members in the Department of Psychiatry. At least four of the most prominent faculty members who conduct research on children at the Harvard-affiliated Massachusetts General Hospital (MGH) are presently under federal investigations.

In particular, the scope of the allegations described in the attached Appendix raises serious doubts about the validity and reliability of Dr. Joseph Biederman’s research, his ethics, professional integrity, and the viability of safeguards for children enrolled in clinical trials at MGH. Dr. Biederman is a Full Professor at Harvard University and Chief of the Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD at MGH.

The only way to remove the cloud of suspicion currently hovering over MGH and Harvard University with respect to its pediatric psychiatry faculty, and for these institutions to regain the public trust, is to undertake a fresh and unbiased review of Dr. Biederman’s entire production of published (and unpublished) research conducted at MGH. 

The essence of empirical science is its verifiability. The Alliance for Human Research Protection (AHRP) proposes that a multi-disciplinary team of independent scientists with expertise in medical and drug research, biostatistics, epidemiology and medical ethics, be convened to review ALL of Dr. Biederman’s publications and supporting documents, including: research protocols, consent forms, and the original (of course, anonymized) data sets with associated code books for all pediatric studies.  The reviewers should be provided with adequate competent support staff to facilitate an expeditious review. AHRP recommends the following accomplished and well respected, independent researchers as potential reviewers:

David DeMets PhD, Professor and Chair, Department of Biostatistics & Medical Informatics. University of Wisconsin;
Lawrence
Friedman MD, Former Director, Div. of Epidemiology and Clinical Applications,  National Heart Lung Blood Institute (NHLB);
Curt D Furberg MD,
Director, Academic Program Development, Wake Forest University;
Stephen Hulley MD, Professor, Clinical Epidemiology, University of California, San Francisco;
Richard Kronmal PhD, Professor Biostatistics, University of Washington, Seattle;
Harlan Krumholz MD,
Professor, Medicine /Epidemiology / Public Health, Yale University;
Steven Nissen MD, Chairman, Cardiovascular Medicine, Cleveland Clinic
Bruce Psaty MD,  PhD, Professor, Medicine/ Epidemiology/ Health Services University of Washington, Seattle

As documented in the attached Appendix, sufficient grounds exist for undertaking an expeditious independent review. If only because of their sheer number, Dr. Biederman’s publications have exerted inordinate influence on: clinicians’ pharmacological treatment of children’s behavioral problems in the United States. His influence extends to FDA-approved drug labels; current official pediatric practice guidelines in psychiatry; and public and private insurance reimbursement policies favoring the off-label use of powerful psychotropic drugs in children.  Indeed, Medicaid’s unrestricted reimbursement policy (in most states) for off-label use of psychotropic drugs for children is testament to his influence.

The validity of Dr. Biederman’s controversial pediatric diagnoses and aggressive pharmacological treatment recommendations are being questioned the world over. [3] His studies, testing aggressive pharmacological treatments in children, were highly lucrative: he received millions of dollars from drug manufacturers as well as financing from the National Institute of Mental Health to test the same drugs. [4] His studies have supported industry’s marketing goals, but evidence suggests the drugs are harmful for children.

In 1981 Harvard Medical School was confronted with a case of fraud involving John Darsee, M.D, a brilliant cardiologist. Harvard drew harsh criticism for delaying a review of  Darsee’s work for three years, during which time he continued publishing. Eventually,  three separate investigations were conducted, by Harvard, Emory University, and the National Institutes of Health.  And outsider academics including the dean of Johns Hopkins Medical School and professors from Arts and Sciences and Law were brought in to investigate.  Dr. Darsee’s publications, which ensnared 47 coauthors (including his supervisor, Eugene Braunwald, M.D.) had to be retracted. [5]   http://www.nytimes.com/1983/06/14/science/notorious-darsee-case-shakes-assumptions-about-science.html

We cannot prejudge what will be learned from an independent review of Dr. Biederman’s pediatric research, but it is time for Harvard University to act by convening such an independent review panel whose members have been vetted to ensure against conflicts of interest, and by making its findings known promptly to the relevant communities of scientists, clinicians, and policymakers.

The AHRP is concerned about protecting the interests of children whose prescribing physicians, parents-not to mention insurance carriers and taxpayers paying the bills-have relied on Dr. Biederman’s seemingly authoritative recommendations. His influence continues to be spread through his copious "high impact" publications made possible by extremely generous industry [6] (and government) support, and through industry funded, MGH-CME courses which continue to promote Dr. Biederman’s radical treatment protocol: even children as young as two are prescribed major (atypical) tranquillizers. Within the last six months alone, Dr. Biederman has published 20 papers as first or co-author. 

The agreement between Mass General Hospital and Dr. Biederman, temporarily suspending his participation in company-sponsored trials and presentations on behalf of drug companies, while continuing to conduct research testing the same drugs in government-funded trials raises yet further concerns about the integrity of research funded by taxpayers.  http://tmap.wordpress.com/2008/12/30/psychiatrist-to-curtail-industry-funded-activities/

Should the administrators of Harvard University fail to undertake a timely independent review as outlined above, Senator Grassley may be inclined to do so. 

Thank you for your timely positive consideration of our request in the interests of legitimate science, physicians seeking valid and reliable guidelines for treating misbehavior in children and, of course, ensuring that children’s best interests are served.

Sincerely,

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Vera Hassner Sharav, President
Alliance for Human Research Protection

Cc:
Harvard Corporation
Harvard Board of Overseers
Harvard Alumni Association
Harvard Medical School Board of Trustees
Harvard Medical School Scientific Advisory Board
Massachusetts General Hospital Board of Trustees

Thomas Insel MD, Director, National Institute for Mental Health
Office of Research Integrity
Senator Charles Grassley, Ranking Member, Senate Finance Committee
US Attorney in Massachusetts, Michael J. Sullivan
Health and Human Services Inspector General, Daniel R. Levinson
Massachusetts Attorney General
International Committee of Medical Journal Editors
Council of Science Editors
American Psychiatric Association
American Medical Association

American Academy of Child and Adolescent Psychiatry

 

Appendix

Documented Allegations Concerning Pediatric Psychiatric Research Conducted by Dr. Joseph Biederman, Harvard University and Massachusetts General Hospital

At issue are cash payments from pharmaceutical companies, some disguised as "educational grants," and the psychiatrists’ role in the illegal marketing of psychotropic drugs for off-label use in children. 

The New York Times reported that a subpoena for all documents produced in litigation relating to Joseph Biederman, MD, Thomas J. Spencer, MD, and Timothy E. Wilens, MD was issued by the Federal District Court for the Massachusetts District on behalf of the United States attorney in Massachusetts, and the Department of Health and Human Services inspector general. http://www.nytimes.com/2009/03/28/health/policy/28subpoena.html

A fourth Harvard University faculty member, Jeffrey Bostic, MD, Director of school psychiatry, MGH, was charged by Federal prosecutors with having been paid by Forest Laboratories to promote their antidepressants Celexa and Lexapro. http://www.boston.com/news/education/higher/articles/2009/03/06/us_cites_boston_psychiatrist_in_case_vs_drug_firm/

The most prominent among the four Harvard University professors is Dr. Biederman, a tenured Full Professor and Chief of the Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD at MGH, and founder and Chief of the Johnson & Johnson Center for Pediatric Psychopathology Research at MGH from 2002 to 2005.

Until recently, Dr. Biederman had the reputation of being the most influential and powerful child psychiatrist in America. His influence was assured by his status at Harvard University and MGH and by the enormous volume of "high impact" publications:

"As of March 2007, Dr. Biederman has been ranked as the second highest producer of high-impact papers in psychiatry overall throughout the world with 235 papers cited a total of 7048 times over the past 10 years as determined by the Institute for Scientific Information (ISI). The same organization ranked Dr. Biederman at #1 in terms of total citations to his papers published on ADD/ADHD in the past decade." http://www.mghcme.org/organization/faculty

"High impact" is a marketing concept. Dr. Biederman’s long list of "peer reviewed" publications [7] does not guarantee their authenticity and reliability. The failure of medical journals to ferret out commercially-biased reports by authors with financial ties to drug manufacturers is the subject of hot debate. The latest example reveals that the vetting process at the Journal of the American Medical Association leaves much to be desired.  http://blogs.wsj.com/health/2009/03/13/jamaeditor-calls-critic-a-nobody-and-a-nothing/  In psychiatry the problem is magnified. [8]

Following the revelations uncovered by Senator Charles Grassley, Ranking Member of the Senate Finance Committee, documenting undisclosed financial conflicts of interest for Drs. Biederman, Spencer, and Wilens, internal Johnson & Johnson documents revealed that Dr. Biederman solicited J & J to establish the pediatric research center at MHG.  The stated "rationale" for the center was "to generate and disseminate data supporting use" of antipsychotic drugs in children; its stated goal was to "move forward the commercial goals of J & J." http://www.nytimes.com/2008/11/25/health/25psych.html
http://online.wsj.com/article/SB122755237429253763.html

The New York Times further reported that "the documents also show that J & J prepared a draft summary of a study that Dr. Biederman was said to have written" which misrepresented the study findings by claiming children’s behavior improved with Risperdal but not with placebo.
http://www.nytimes.com/2008/11/25/health/25psych.html

Dr. Biederman has emerged as the key witness in a lawsuit against Johnson & Johnson, brought on behalf of more than 2,000 patients, including children, who contend that they have been injured by psychiatric drugs known as atypical or second-generation antipsychotics.  Documents and slides submitted to the court-some submitted to Dr. Faust and Dr Salvin by Sen. Grassley [9]  illustrate that Dr. Biederman’s research was designed to support J & J’s commercial interests, including helping J & J develop new uses for its drugs-"to complement registration efforts."

The Boston Globe reported that one set of Dr. Biederman’s slides-"Key Projects for 2004"-states that the MGH center "will help clarify the competitive advantages of risperidone vs. other atypical neuroleptics" and "will support the effectiveness and safety of risperidone" in preschoolers.

Another set of slides-"Key Projects for 2005"-promises to provide Janssen (a J & J subsidiary) "with critical competitive data on safety and efficacy of the antipsychotic risperidone (Risperdal) in children" under age 10, while another talks about expanding the use of the drug Concerta for teenagers with attention-deficit hyperactivity disorder. http://www.boston.com/news/local/massachusetts/articles/2009/03/21/senator_broadens_inquiry_into_psychiatrist/

Sen. Grassley noted that some of the projects at the J & J children’s center at MGH turned into published papers. An example is one Janssen-funded study last year in which Biederman reported that he found a 30% reduction in ADHD symptoms in about one-third of children with bipolar disorder who took Risperdal. [10]

Dr. Biederman’s sworn testimony revealed, inter alia, that in one controversial pediatric drug experiment sponsored by and conducted on preschool children at MGH, [11] there were six serious research protocol violations.

According to the MGH Institutional Review Board (IRB), one child had to ingest 12.5 milligrams of Eli Lilly’s controversial antipsychotic drug, olanzapine (Zyprexa), although the study protocol called for a maximum of 7.5 milligrams. The MGH IRB described the incident as "a serious breach of the protocol procedures and provisions" but failed to report the violations to the federal Office of Human Research Protections. See http://s.wsj.net/public/resources/documents/WSJ-Major_Protocol_Violation_Letters032009.pdf.

A subpoena has been issued by the Federal District Court for the Massachusetts District on behalf of the United States attorney in Massachusetts, Michael J. Sullivan, and Health and Human Services inspector general, Daniel R. Levinson, for all documents produced in litigation relating to Drs. Biederman Spencer, and Wilens. http://www.nytimes.com/2009/03/28/health/policy/28subpoena.html

Given the considerable industry support Dr. Biederman has received-including research funding from 15 companies, and payment for being a speaker or adviser to seven of them [12]-the sheer volume of his publications raises questions about the extent to which he is serving as industry’s portal to flood the field with promotional studies aimed at expanding the market for powerful psychotropic drugs for unapproved, off-label uses-even for preschool children. [13]

Dr. Biederman’s influence might be measured by the fact that since he began promoting pediatric bipolar disorder and recommending the off-label use of second-generation antipsychotics for children, [14] there has been a 40-fold increase in the diagnosis of pediatric bipolar disorder in America (1994-2003), along with skyrocketing rates of off-label prescribing of these drugs for children. http://www.nytimes.com/2008/11/25/health/25psych.html  

The influence exerted by Dr. Biederman and his Harvard-MGH team is most direct within the context of the MGH Psychiatry Academy, a multi-million dollar industry-sponsored program that describes itself as "revolutionary… unbiased and clinically applicable continuing medical education…" [15] http://carlatpsychiatry.blogspot.com/2008/02/new-mgh-psychiatry-academy-take-money.html

The drugs discussed and recommended by the MGH faculty are manufactured by the sponsors of the Academy. They are the most toxic drugs prescribed for non-life-threatening conditions.  Risperdal, Zyprexa, Abilify, and Seroquel carry FDA-mandated Black Box warnings about cardiac arrest and sudden death. They have been found to increase the death rate by 60% in the geriatric population with dementia-related behavioral disorders.  These drugs’ labels also warn about the risk of metabolic disorders, hyperglycemia, diabetes mellitus, and irreversible, disfiguring, involuntary movements-tardive dyskinesia. Children are particularly vulnerable to these drugs’ adverse effects.

No other country in the world medicates children as frequently or with such potentially toxic drugs as those recommended by Dr. Biederman and his Harvard-MGH team of child psychiatrists.

Contrary to Dr. Biederman’s assurances about the safety and effectiveness of these drugs even for young children, America‘s children have suffered irreparable harm: From 1993 through the first three months of 2008, there were 1,207 serious adverse event reports for children given Risperdal, including 31 deaths. Among the deaths was a 9-year-old with attention deficit problems who suffered a fatal stroke 12 days after starting therapy with Risperdal. 

An FDA review of its Adverse Event Reporting System (AERS) database found that since its approval of Zyprexa (1996 to February 10, 2008) there were 949 Adverse Event Reports involving children. Of these, 44 died-among them, 6 were suicides, 5 from a metabolic syndrome, and 4 from cardiac arrest.

The severe risks linked to these drugs led an FDA pediatric advisory committee in November 2008 to unanimously recommend increased warnings, stating that the current warnings were insufficient. The committee’s concerns are part of a growing chorus of complaints about the increasing use of antipsychotic drugs in children and teenagers 

 

It is vitally important to establish whether the recent, massive increase in psychotropic drug prescribing for children is justified.  Has it led to demonstrable long-term benefit in the recipients, or has it produced harm?  Is it a scientific or a marketing phenomenon? 

__________________________

[1] Shuchman M and Hebert PC, Bringing a research base to psychiatry, Editorial, Canadian Medical Association Journal, May 6, 2008; 178(10): 1257-1258.

[2] Lisa Cosgrove, PhD and Harold J. Bursztajn, MD. Toward Credible Conflict of Interest Policies in Clinical Psychiatry,Psychiatric Times. Vol. 26 No. 1 January 1, 2009; Cosgrove L, Krimsky S, Vijayraghavan M, Schneider L. Financial ties between DSM-IV panel members and the pharmaceutical industry. Psychother Psychosom. 2006;75:154-160; Moynihan R. The making of a disease: female sexual dysfunction. BMJ. 2003:326:45-47.

[3] Parry P and Allison S. Pre-pubertal paediatric bipolar disorder: a controversy from America, Australasian Psychiatry, April 2008 ,Vol. 16(2): 80 – 84.

[4] Biederman J, Hammerness P, Doyle R, Joshi G, Aleardi M, Mick E. Risperidone treatment for ADHD in children and adolescents with bipolar disorder, Neuropsychiatric Disease Treatment. 2008 Feb;4(1):203-7.

[5] Broad WJ. Coping with fraud, Science 29 January 1982: Vol. 215. no. 4532, p. 479. 

[6] Disclosure on Medscape: Joseph Biederman, MD, has disclosed that he receives research support from Shire, Eli Lilly, Pfizer, McNeil, Abbott, Bristol-Myers-Squibb, New River Pharmaceuticals, Cephalon, Janssen, Neurosearch, Stanley Medical Institute, Novartis, Lilly Foundation, Prechter Foundation, NIMH, NICHD, and NIDA. He also disclosed that he is on the speaker’s bureaus of Shire, Lilly, McNeil, Cephalon, UCB Pharma, Inc., and Novartis, and is on the advisory board of Eli Lilly, Shire, McNeil, Janssen, Novartis, and Cephalon. http://www.medscape.com/viewarticle/536264 

[7] A PubMed search (March 2009) lists 347 peer reviewed articles for Dr. Biederman, while google scholar (which includes book chapters and conference presentations) lists 650. 

[8] Discredited published reports in psychiatry:

Paxil study 329: Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B et al (2001). Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 40: 762-772;

Montgomery SA, Dunner DL, Dunbar GC (1995). Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo. European Neuropsychopharmacology 5: 5-13;  

Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, Leon AC, Meltzer HY, Ryan ND, Shaffer D and Wagner KD. ACNP Task Force Report on SSRIs and Suicidal Behavior in Youth, Neuropsychopharmacology, publication 23 Nov. 2005: http://www.nature.com/npp/journal/vaop/ncurrent/full/1300958a.html;

Armstrong D. Medical Journal Editor to Quit In Wake of Disclosure Oversight, The Wall Street Journal, August 25, 2006: http://www.ahrp.org/cms/index2.php?option=com_ content&do_pdf=1&id=327

[9] See: Sen. Grassley’s letter and attachments containing 63 pages of Dr. Biederman’s documents, posted on the  The Wall Street Journal website: http://s.wsj.net/public/resources/documentsWSJ-Major_Protocol_Violation_Letters032009.pdf

[10] Joseph Biederman, Paul Hammerness, Robert Doyle, Gagan Joshi, Megan Aleardi, and Eric Mick Risperidone treatment for ADHD in children and adolescents with bipolar disorder, Neuropsychiatric Disease and Treatment, 2008 February; 4(1): 203-207.

[11] Biederman J, Mick E, Hammerness P, Harpold T, Aleardi M, Dougherty M, Wozniak J. Open-label, 8-week trial of olanzapine and risperidone for the treatment of bipolar disorder in preschool-age children, Biological Psychiatry. 2005 Oct 1;58(7):589-94.

[12] Allen S. Backlash on bipolar diagnoses in children, The Boston Globe, June 17, 2007 http://www.boston.com/yourlife/health/diseases/articles/2007/06/17/backlash_on_bipolar_diagnoses_in_children/

[13] Mick E, Biederman J, Dougherty M, Aleardi M. Comparative efficacy of atypical antipsychotics for pediatric bipolar disorder, Acta Psychiatrica Scandinavia. 2004;110, 50:29; Mick E, Biederman J, Aleardi M, Dougherty M. Open trial of atypical antipsychotics in pre-schoolers with bipolar disorder, Acta Psychiatrica Scandinavia. 2004;110,51:29

[14] Biederman J, Faraone S, Mick E, Wozniak J, Chen L, Quellette C, Marrs A, Moore P, Garcia J, Mennin D, Lelon E. Attention-deficit hyperactivity disorder and juvenile mania: An overlooked co-morbidity?  Journal of the American Academy of Child and Adolescent Psychiatry. 1996 35:997-1008.

[15]  The description appeared on the MGH-CME website as of April 3, 2009. A revised website – now lists pharmaceutical company sponsors, and descriptors such as, "revolutionary" have been replaced with language suggesting a commitment to a scientific approach to delivering CME. http://www.mghcme.org/organization/supporters