WASHINGTON – U.S. Rep. Joe Barton R-Texas, chairman of the House Energy and Commerce Committee, and U.S. Rep. James Greenwood R-Pa., chairman of the Oversight and Investigations Subcommittee, today released a letter sent to the Government Accountability Office Comptroller General David M. Walker, requesting information on the use of antidepressants by children and the possibility of increased suicidal behavior from that usage, as well as details on the FDA’s handling of this information.

(The following is a copy of the letter sent to the Honorable David M. Walker.)

June 10, 2004

The Honorable David M. Walker
Comptroller General
U.S. General Accounting Office
441 G Street, N.W.
Washington, D.C. 20548

Dear Comptroller General Walker:

We write to request that the General Accounting Office (GAO) examine how the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) manages internal disagreements with officials in CDER’s Office of Drug Safety (ODS) over the handling of drug safety issues.

Our request is prompted by the FDA’s handling of a safety review of data from clinical trials of antidepressants in children, a subject that is part of the Committee’s ongoing investigation into reports that antidepressants may increase the risk of suicide-related behavior in children and adolescents. In its April 14, 2004 letter to the Committee, the FDA indicated that in June 2003 a CDER manager requested that Dr. Andrew Mosholder, a scientist in the ODS, perform a consultative review of newly submitted safety data on antidepressants in children. Based on his review, the ODS scientist believed that the available data were sufficient to reach a conclusion about an association between the use of antidepressants and suicidality in children and to recommend that additional regulatory action would be appropriate without delay. The FDA stated in the April 14, 2004 letter:

“However, the other members of the review team, including his direct supervisors, did not agree with his regulatory conclusion that no further analyses were needed and continued to believe that additional analyses should be conducted before the Agency could reach a conclusion on these data. There was a discussion within the review team as to whether Dr. Mosholder’s regulatory conclusions on the data should be presented in some form at the February 2, 2004 meeting. After considering the issue carefully, CDER staff decided that the data from which Dr. Mosholder reached his conclusions would be presented to the Advisory Committee meeting and that they would acknowledge as part of their presentation to the Committee that some reviewers had reached a conclusion that the data at this time were sufficient to conclude that there was a link between antidepressant use and suicidality in children. However, given the Agency’s concerns regarding the limitations of the data and the plans to pursue case reclassification and more in-depth analyses, CDER decided that having Dr. Mosholder present his conclusion to the Advisory Committee, with the appearance that it was an Agency’s determination, would be potentially harmful to public health as it might lead patients who were actually benefiting from the use of these drugs to inappropriately discontinue therapy. CDER believed that disclosure of the available data to the Advisory Committee at the meeting along with a description of the limitations of those data in supporting a definitive conclusion, as well as a description of the Agency’s plans to further evaluate the data was the best way to serve the public health on the very complex and important issue.”

In further explaining the basis for not allowing Dr. Mosholder to present the clinical trial data or his conclusions at the Advisory Committee, the FDA stated:

“In summary, the Center’s review process involves a multidisciplinary approach to ensure that expertise from various areas of the Agency and from outside groups is brought to bear on an issue to ensure that a comprehensive and rigorous scientific analysis is completed that serves as the basis for the Agency’s conclusions and actions. The review process honors and explicitly encourages individual reviewers to share their conclusions and recommendations with the review team to help inform the Center’s decisions and actions. In some cases, the opinion of an individual reviewer may not be consistent with the Center’s position on an issue. This occurs regularly and is to be expected in a large scientific organization that values open discussion of issues. In such cases the Center has procedures in place to ensure that the reviewer’s position is documented, fully considered, and addressed by managers as part of the process.”

While continuing to determine the circumstances surrounding the FDA’s decision not to allow Dr. Mosholder to present his conclusions on the antidepressant data to the Advisory Committee, the Committee has information raising questions about the handling of other disagreements between CDER and some reviewers in ODS on safety issues related to, but not limited to, the following drugs: Accutane, Arava, Cisapride/Propulsid, and Rezulin.

Given the importance of the FDA’s drug-safety reviews and the need to gain a better understanding of how the FDA manages internal disagreements on such reviews, the Committee requests the following:

Examine past examples of disagreements between CDER management and ODS reviewers.

Determine whether the FDA’s decisions in each of these cases resulted in appropriate regulatory action, based upon the available clinical and scientific information.

Determine whether the disagreements represented regular interactions that would be expected in large scientific organizations, or represent an unusual, systemic problem at the FDA.

Determine whether FDA management of these disagreements is in compliance with its applicable rules and regulations, and are appropriate for a large, scientific organization.

Make recommendations as appropriate.

We further request that GAO staff meet with the Committee staff to discuss the details on individual case studies. If you have any questions on this matter, please contact Alan Slobodin at (202) 225-2927 or Kelli Andrews at (202) 226-2424 of the Committee Staff.

Sincerely,

_______________________________ _______________________________

Joe Barton                                                     James C. Greenwood

Chairman                                                         Chairman

                                                                      Subcommittee on Oversight

                                                                       and Investigations