Sen. Grassley Letter to Harvard: Biederman Research Protocol Breaches

A letter to Judge Happas from the lawfirm Hogan and Hartson representing Dr. Joseph Biederman, requests the court to "protect" Dr. Biederman from The New York Times.

Essentially, the request asks the Court to protect Dr. Biederman from his own testimony under oath which suggests that he engaged in research methods that raise ethical and scientific concerns. That is, he promised to deliver commercially useful, positive results to his corporate sponsors– even before commencing with the research.

However, Dr. Biederman and his lawyers have far greater issues to be concerned about than the Times report.
Below is a copy of the text of a letter sent by Sen. Charles Grassely (March 20) to the presidents of Harvard and Mass. General Hospital in which he asks probing questions about numerous ethical-legal concerns involving Dr. Biederman’s research activities.

The most shocking disclosure is that Dr. Biederman’s study testing powerful antipsychotics in PRESCHOOL CHILDREN "was beset by breaches of research protocol," according to a letter from Mass General Hospital’s Institutional Review Board (IRB) monitoring the experiment.

The WSJ health blog reports that there were AT LEAST SIX breaches of the preschool protocol.  In one instance, which the research committee deemed “a serious breach of the protocol procedures and provisions,” a child in the 2005 study was given a 12.5 milligram dose of Zyprexa (olanzapine), although the maximum dose allowed in the study was 7.5 milligrams.  

Prescribing–indeed forcing–high doses of neuroleptic drugs is an example of medical abuse, if not, torture.  This abusive use of neuroleptic / antipsychotic drugs harks back to Soviet psychiatrists who used such drugs on political dissidents.

The age of the child in Dr. Biederman’s study wasn’t specified in the letter, but the children in the study ranged 4 to 6 years old.

Sen. Grassley notes: "Based upon the materials in my possession [Attachment I], when this issue was brought to Dr. Biederman’s attention in 2004, the human research committee at MGH reported that this was the sixth protocol violation for the study. "

What does this say about the safety of children in drug experiment conducted by Harvard child psychiatrists?
What does this say about the integrity of the science in drug trial conducted by Dr. Biederman?

Sen. Grassley states: "If a study is supported with federal funds, then such violations should have been reported to the Office for Human Research Protection (OHRP) at the Department of Health and Human Services."

"Additionally, when the study was apparently published in 2005, the article listed support from the Stanley Medical Research Institute and the National Institute of Mental Health.[4] However, OHRP informed me that it was never notified of any protocol violations for this study."

The study was published in journal Biological Psychiatry. Dr. Biederman reported that treating preschoolers with Eli Lilly’s Zyprexa or Johson & Johnson / Janssen’s Risperdal  “may result in a rapid reduction of symptoms of mania in preschool children with” bipolar disorder. [1]

Among numerous examples of other concerns raised by Dr. Biederman’s own slides, Sen. Grassley cites the following:

I. Attachment A: Slides in Attachment A, highlight several “Key Projects for 2005,” and state:

  • Concerta for the treatment of ADHD NOS in adolescents
  •  Extend to adolescents positive findings with Concerta in ADHD NOS in adults
  •  Randomized Clinical Trial of Risperidone vs. Placebo in children younger than 10 years of age with bipolar disorder
  •  Will complement registration efforts of studies with older youth
  •  Will provide Janssen with critical competitive data on safety and efficacy of risperidone in children (80% of referrals)

If the research sought to answer a bone fide scientific question, the results could go either way. That means that at the start of the research there would be no way of knowing whether the result would be positive or negative–that is what scientists call equipoise.

Sen. Grassley asks the Presidents of Harvard and Mass General to explain:
Why do these slides suggest an expectation of positive outcomes for the drugs prior to the commencement of the clinical trials?

He notes that the slides in Attachment D suggest that" a study, which had not yet commenced “will support the safety and effectiveness of….” any particular drug and “complement” other efforts.

Is it possible , he asks, "that the study proposed in Attachment D would not support the safety and effectiveness of risperidone in pre-schoolers and if this is the case, why ould the slide not so state?"

 Sen. Grassley repeatedly notes his difficulty in understanding how Dr. Biederman could promise a positive conclusion to research before he even began the trial. So, he reached out to a to a physician researcher "for an independent review of the slides attached to this letter. In response to my inquiry, the physician researcher said that it appeared that the slides discussed in this letter were nothing more than marketing tools, as opposed to discussions of independent scientific research."

Sen Grassley also puts the National Institute of Mental Health on notice:

IV. The Janssen Study
    "We also learned that these slides did result in funds being paid to Dr. Biederman and that he eventually published a Janssen supported study that found a 30% reduction in ADHD symptoms in 29% of study subjects when taking risperidone. This study was published in 2008 and its finding seem to correlate with the slides that were apparently produced years earlier and attached to this letter.[3] More specifically, Dr. Biederman’s study concluded, “treatment with risperidone is associated with tangible but generally modest improvement of symptoms of ADHD in children with bipolar disorder.”

    "Even more troubling, the published study lists support from Janssen, the Stanley Medical Research Institute, and the NIH. In fact, the NIH funding for this study raises still more concerns in that federal dollars may have been used to support research when the results may have been “predicted” before the study began."

It is clear that medical research institutions–much as the financial banking institutions–have run amock and betrayed the public trust. In the abscence of independent checks and balances–including independent inspections and auditing– violations are rampant. Perhaps more so, at prestigious academic institutions where  powerful senior physician researchers have free rein.  They must be brought under stringent regulatory compliance to restore the moral imperative of medicine, and the integrity of science .

Sen. Grassley’s letter and all attachments (63 pages) is posted at: http://s.wsj.net/public/resources/documents/WSJ-Major_Protocol_Violation_Letters032009.pdf

Reference:
1. Joseph Biedermana, Eric Mickab, Paul Hammernessab, Theresa Harpoldab, Megan Aleardia, Meghan Doughertya, Janet Wozniak.Open-Label, 8-Week Trial of Olanzapine and Risperidone for the Treatment of Bipolar Disorder in Preschool-Age Children Biological Psychiatry, Volume 58: 589-594 2005.
    
Posted by  Vera Hassner Sharav

~~~~~~~~~

Sen. Charles Grassley

Senate Finance Committee
March 20, 2009
Via Electronic Transmission

Dr. Drew Gilpin Faust            Dr. Peter L. Slavin
President                               President
Harvard University                Massachusetts General Hospital (Partners Healthcare)
Massachusetts Hall                  55 Fruit Street
Cambridge, MA 0213                Boston, MA 02114

Dear Drs. Faust and Slavin:

The United States Senate Committee on Finance (Committee) has jurisdiction
over the Medicare and Medicaid programs and, accordingly, a responsibility to the more
than 80 million Americans who receive health care coverage under these programs. As
Ranking Member of the Committee, I have a duty to protect the health of Medicare and
Medicaid beneficiaries and safeguard taxpayer dollars appropriated for these programs.
The actions taken by thought leaders, like those at Harvard Medical School, often have a
profound impact upon taxpayer funded programs like Medicare and Medicaid and the
way that patients are treated and funds expended.

I have also taken an interest in the almost $24 billion annually appropriated to the
National Institutes of Health (NIH) to fund grants at various institutions such as yours.
As you know, institutions are required to manage a grantee’s conflicts of interest.[1] But I
continue to learn that this task is sometimes made difficult because physicians do not
consistently report all the payments received from drug companies. To encourage
transparency, Senator Kohl and I introduced the Physician Payments Sunshine Act (Act).
This Act will require drug companies to report publicly any payments that they make to
doctors, within certain parameters.

Recently, I was provided a number of documents, including slides, that became
available during ongoing litigation.[2] A number of the documents reviewed by my staff
relate to, among other matters: Dr. Joseph Biederman of Harvard University (Harvard)
and Massachusetts General Hospital (MGH/Partners), (collectively, the Institutions); and
to the Johnson & Johnson Center for Pediatric Psychopathology Research (Center). As
part of the litigation, Dr. Biederman produced several slide sets, and my staff have pulled
several slides from these various presentations. I am not certain if these slides sets were
created by Dr. Biederman, and I am not certain if he has ever presented these slides
publicly. However I do know that they were produced by Dr. Biederman.

The slides raise potential concerns about, among other matters, Dr. Biederman
and the Center. My main concern is whether or not the attached slides suggest a
predisposition to specific findings and conclusions prior to the studies being commenced.
My other concern is whether or not NIH was aware that Dr. Biederman was performing
research sponsored by J&J on psychiatric disorders when it awarded him a grant to
collaborate with other doctors to study those same psychiatric disorders. I am also
wondering if the physicians Dr. Biederman was collaborating with under the NIH grant
were notified of Dr. Biederman’s corporate sponsored research.

Accordingly, this letter seeks, among other things, your guidance as to whether or
not the materials discussed in this letter are in compliance with all applicable rules
followed by the Institutions. In addition, I would like to better understand the role played
by the Institutions when proposals are drafted by professors, and whether those policies
and procedures were followed with regard to the materials attached to this letter.

I. Attachment A
Slides in Attachment A, highlight several “Key Projects for 2005,” and state:

  • Concerta for the treatment of ADHD NOS in adolescents
  •  Extend to adolescents positive findings with Concerta in ADHD NOS in adults
  •  Randomized Clinical Trial of Risperidone vs. Placebo in children younger than 10 years of age with bipolar disorder
  •  Will complement registration efforts of studies with older youth
  •  Will provide Janssen with critical competitive data on safety and efficacy of risperidone in children (80% of referrals)

Please explain:
1) Why do these slides suggest an expectation of positive outcomes for the drugs prior to the commencement of the clinical trials?

II. Attachments B and C
Slides set forth in Attachment B seem to explain what MGH would provide Johnson & Johnson in return for the funding. As part of the “deliverables,” the slide reads:

  •  Research posters at major national and international meetings
  • Research publications in peer reviewed journals
  • Programs and symposia at major national and international meetings
  • Help J&J develop state of the art, data based CME [continuing medical [education] programs and educational materials

Several of the deliverables set forth in this slide are typical deliverables when performing
scientific research, with the exception of the statement that the Center will in some way
be helping J&J to create “state of the art, data based” CME programs. Accordingly
please explain the following:

1) According to protocols and policies of Harvard/MGH, is it appropriate that a
portion of the deliverables include the development of “state of the art data
based CME programs and educational materials” for a particular
pharmaceutical sponsor, in this case J&J? Please explain.

The slides in Attachment C describe, among other things the “Benefits” of the
J&J Center. One slide reads:

  •  Supports research on the disorders that J&J products treats:
  •  Concerta
  • Risperdal
  • Reminyl
  • Topamax

Another slide in Attachment C says the following:

  • Provides rationale to treat chronically and aggressively highly morbid child psychiatric disorders

And yet another slide reads:

  • Provides ongoing consultation for protocol development of new J&J products or new uses for existing compounds
  • Concerta for adult ADHD NOS
  • Reminyl for ADHD

1) Please explain why the slides set forth above suggest that the study being proposed could find new uses for J&J products?

III. Attachments D and E
The slides in Attachment D highlight several additional issues. The first is entitled “Key Projects for 2004” and says:

  • Comparative effectiveness and tolerability of Risperidone vs. competitors in the management of pediatric bipolar disorder: acutely and chronically
  • Will clarify the competitive advantages of risperidone vs. other atypical neuroleptics

Another slide in Attachment D reads, in pertinent part:

  • Effectiveness and safety of Risperdone in pre-schoolers
  • Will support the safety and effectiveness of risperidone in this age group

The slides in Attachment E titled “Planned Investigator Initiated Studies” seem to complement those in Attachment D and say:

  • Randomized Clinical Trial of Risperidone vs. Placebo in children younger than 10 years of age with bipolar disorder
  • Will complement registration efforts of studies with older youth
  • Will provide Janssen with critical competitive data on safety and efficacy of risperidone in children (80% of referrals)

Accordingly, please respond to the questions below regarding Attachments D and E.

1) Please explain how these slides could suggest that a study, which had not yet commenced “will support the safety and effectiveness of….” any particular drug and “complement” other efforts?
2) Is it possible that the study proposed in Attachment D would not support the safety and effectiveness of risperidone in pre-schoolers and if this is the case, why would the slide not so state?

Again, Dr. Faust and Dr. Slavin, I am having difficulty putting the Attachments to this letter in proper context. Indeed, I reached out to a physician researcher for an independent review of the slides attached to this letter. In response to my inquiry, the physician researcher said that it appeared that the slides discussed in this letter were nothing more than marketing tools, as opposed to discussions of independent scientific research.

IV. The Janssen Study
We also learned that these slides did result in funds being paid to Dr. Biederman and that he eventually published a Janssen supported study that found a 30% reduction in ADHD symptoms in 29% of study subjects when taking risperidone. This study was published in 2008 and its finding seem to correlate with the slides that were apparently produced years earlier and attached to this letter.[3] More specifically, Dr. Biederman’s study concluded, “treatment with risperidone is associated with tangible but generally modest improvement of symptoms of ADHD in children with bipolar disorder.” Even more troubling, the published study lists support from Janssen, the Stanley Medical Research Institute, and the NIH. In fact, the NIH funding for this study raises still more concerns in that federal dollars may have been used to support research when the results may have been “predicted” before the study began.

V. Attachment F and Possible Conflict of Interest
There is yet another aspect of documents reviewed in this matter that is concerning me. It is my understanding that Dr. Biederman was seminal in the creation of the Center and that he received almost half a million dollars [Attachment F] from the NIH to run the annual Collaborative Pediatric Bipolar Disorder Conference (2003:
$95,015, 2004: $96,631; 2005: $99,209; 2006: $101,865; 2007: $101,567). It appears that running the Center on bipolar disorder, while also running a conference for the NIH on bipolar disorder could be perceived as a conflict. Therefore, I would appreciate your views on this. I also want to advise you that the NIH told me that MGH never informed them of this possible conflict.

VI. Attachments G and H
In addition to materials regarding the Center and Dr. Biederman, I also received materials produced for ongoing litigation by J&J. It seems, based upon a review of J&J internal communications, that the collaboration between the Center and J&J was driven more by business and marketing as opposed to pure science and research. For instance, in Attachment G there are J&J slides titled “2003 Business Plan.” In one slide J&J notes that it will “leverage” the MGH Center to raise awareness of bipolar disorder in kids because “use of psychotropic medications in [children and adolescents] remains controversial.” Another slide identified as Attachment H was presented by a J&J employee and was titled “A New Initiative! J&J Pediatric Research Center at Mass General Hospital.” The relevant slide states that the initial discussions with MGH to create the Center involved participation “with marketing.” So I ask, is it typical in your experiences to include the marketing division of a sponsor company during discussions of possible collaboration with your institution?

VII. Attachment J
Another document provided to me is entitled, “PHARMA SALARY SUMMARY” is identified as Attachment J. This document appears to be a summary of payments made to Dr. Biederman over a 3 year period. Accordingly, please respond to the following questions:
1) Explain the payments made and the services provided.
2) Address whether or not these payments were reported to you by Dr. Biederman.
3) Address whether or not if these payments were reported by you to me in previous correspondence.
4) Regarding Attachment J, please explain if Dr. Biederman received compensation from these companies as detailed in the attachment. If yes, provide an annual summary from each company.

VIII. Protocol Violations
Based upon a review of still other documents produced, I see that MGH’s Institutional Review Board (IRB) found “a serious breach of the protocol and procedures nd provisions” in Dr. Biederman’s study of risperidone and olanzapine in preschool children. Based upon the materials in my possession [Attachment I], when this issue was brought to Dr. Biederman’s attention in 2004, the human research committee at MGH reported that this was the sixth protocol violation for the study. If a study is supported with federal funds, then such violations should have been reported to the Office for Human Research Protection (OHRP) at the Department of Health and Human Services.
Additionally, when the study was apparently published in 2005, the article listed support from the Stanley Medical Research Institute and the National Institute of Mental ealth.[4] However, OHRP informed me that it was never notified of any protocol violations for this study.

Accordingly, please respond to the following questions and requests for documents. For each response, first repeat the question followed by the appropriate
answer.

1) Why did Harvard/MGH not inform the NIH about Dr. Biederman’s collaboration with J&J when it applied for the NIH bipolar disorder grant?
2) Several documents that Dr. Biederman supplied to the court make note of a “JB rent fund.” What is the “JB rent fund” and to whom did the money go?
3) Why did MGH not inform OHRP about the IRB protocol violations in Dr. Biederman’s study?
4) For that particular study, please explain each IRB protocol violation and how those violations were resolved.
5) Did representatives of MGH discuss collaborating on the Center with marketing people from J&J, as Attachment H states?
6) Were the slides detailed in the attachments to this letter created by Dr. Biederman? If not, who created them?
7) Please explain if these slides were ever presented to an audience. If so, who saw these presentations?

Thank you again for your continued cooperation and assistance in this matter. As you know, in cooperating with the Committee’s review, no documents, records, data or information related to these matters shall be destroyed, modified, removed or otherwise made inaccessible to the Committee.

I look forward to hearing from you by no later than April 17, 2009. All documents responsive to this request should be sent electronically in PDF format to Brian_Downey@finance-rep.senate.gov. If you have any questions, please do not  hesitate to contact Paul Thacker at (202) 224-4515.

Sincerely,

Charles E. Grassley
Ranking Member

cc: Raynard Kington, M.D., PhD.
Acting Director
National Institutes of Health

[1] Responsibility of Applicants for Promoting Objectivity in Research for Which PHS Funding is Sought,
42 C.F.R. 50 (1995).
[2] Alma Avila, as Next Friend of Amber N. Avila, an Individual Case vs. Johnson & Johnson, et al., Docket
No.: MID- L-6661-06
(In Re Risperdal/Seroquel/Zyprexa; Superior Court of Middlesex County, New Jersey).
[3] Biederman, Joseph et al “Risperidone treatment for ADHD in children and adolescents with bipolar
disorder” Neuropsychiatr Dis Treat, Feb 2008, 4(1): pp 203-207. Published online Feb 2008.
[4] Biederman, Joseph, et al “Open-Label, 8-week Trial of Olanzapine and Risperidone for the Treatment of
Bipolar Disorder in Preschool-Age Children,” Biol Psychiatry, 2005, 58: pp 589-594.
 

See Letter and all attachments at: http://s.wsj.net/public/resources/documents/WSJ-Major_Protocol_Violation_Letters032009.pdf

~~~~~~~~~~~~~~~~~~~~~~ 

Wall Street Journal
Protocol Breach Reported in Biederman Study of Preschoolers
By David Armstrong
March 20, 2009

Zeprexa bottleA 2005 study from Harvard psychiatrists testing the use of powerful antipsychotics in preschoolers was beset by breaches of research protocol, according to a letter from a committee monitoring the experiment.

The study was led by Joseph Biederman, a controversial proponent of using powerful psychiatric drugs to treat children. Earlier today, we described some court papers that suggested Biederman told Johnson & Johnson, before certain trials of its drugs were started, that he expected positive results from the tests.

In the monitoring committee documents, Biederman had at least six violations of research protocol, according to an April 2004 letter from Massachusetts General Hospital’s Human Research Committee, which is responsible for monitoring patient studies at the facility. Biederman and several of his colleagues involved in the research hold dual appointments at the Boston hospital and the Harvard Medical School.

In one instance, which the research committee deemed “a serious breach of the protocol procedures and provisions,” a child in the 2005 study was given a 12.5 milligram dose of olanzapine, although the maximum dose allowed in the study was 7.5 milligrams, according to a letter from the committee to Biederman. Olanzapine, sold by Eli Lilly, is known more commonly by the brand name Zyprexa.

Biederman, in a response to the hospital committee, called the violation “serious” and wrote it “should never have occurred and is not justified.” However, he also reported that “in no way was the subject’s safety jeopardized.” He also said the higher dose was used to stabilize a “very sick child.” A lawyer for Biederman couldn’t be reached for comment today.

The age of the child wasn’t specified in the letter, but the children in the study ranged 4 to 6 years old.

The study, published in journal Biological Psychiatry in 2005, concluded that treating the preschoolers with olanzapine and risperidone, sold as Risperdal by a unit of Johnson & Johnson, “may result in a rapid reduction of symptoms of mania in preschool children with” bipolar disorder.

Take a look at this pdf, which includes a letter Sen. Chuck Grassley sent today, along with copies of some slides we referenced this morning and correspondences over the study-protocol issue.

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