Witness Testimony

Good morning Mr. Chairman and members of the Subcommittee on Oversight and Investigations.

My name is Dr. Ron Marcus, and I am an executive director of neuroscience global clinical development at the Bristol-Myers Squibb Company's Pharmaceutical Research Institute. I am also a board certified clinical psychiatrist. Today, I am here representing my company to briefly describe our efforts to responsibly report the results of pediatric clinical trials involving our anti-depressant nefazodone, which is also known by its branded commercial name - Serzone.

Serzone was approved almost ten years ago by the FDA. Upon approval, FDA requested that Bristol-Myers Squibb conduct studies to evaluate the use of nefazodone in children and adolescents with depression. In response to this request Bristol-Myers Squibb, initiated two pediatric clinical studies involving Serzone. One was a pharmacokinetic and safety study in children and adolescents, and the other was an efficacy and safety study in adolescents. Additionally, in 1999 FDA issued a Written Request for pediatric studies with Serzone. In response to this request, Bristol-Myers Squibb initiated a third post-approval study - one that examined Serzone's efficacy and safety in pediatric patients.

Bristol-Myers Squibb fulfilled its commitment to the FDA and completed all three pediatric studies of Serzone. Each of these studies was carefully designed and their protocols were reviewed by the FDA.

The results of the three studies were disclosed in a manner that would appropriately inform the psychiatric community of the studies' results. Specifically, the results of the pharmacokinetic study in children and adolescents were published in the well-respected Journal of the American Academy of Child Adolescent Psychiatry. The results of our efficacy and safety study in adolescents were presented in scientific posters at the Annual Meeting of the American Psychiatric Association - the premier psychiatric conference in this country, as well as at the New Clinical Drug Evaluation Unit conference. Finally, the results of our third study that looked at Serzone's efficacy and safety in pediatric patients were included in the posters detailing the adolescent study presented at the APA meeting.

Bristol-Myers Squibb also submitted the clinical trial results to the FDA. After reviewing the clinical trial data, the FDA advised the company that the safety and efficacy of Serzone in individuals below 18 years of age had not been established through the clinical trials. The Serzone product label expressly states that the "safety and effectiveness in individuals below 18 years of age have not been established."

Bristol-Myers Squibb Company is committed to the principle that clinical trial results that could have a bearing on patient care and treatment should be made available to physicians making medical decisions regarding the use of our medicines. Our commitment to this principle was most recently highlighted by our response to the results of the TIMI-22, or "PROVE-IT," trial. The trial demonstrated that patients with a recent acute coronary syndrome benefited significantly when treated with an intensive statin regimen using high doses of a competitor's drug when compared to a regimen using standard doses of Bristol-Myers Squibb's statin drug. Clearly, the results could be interpreted as favoring the competitor's product. But because the study data could have an immediate impact on patient care, we worked closely with the investigators to ensure that presentation and publication of the data were achieved in the shortest possible time.

Consistent with our company's commitment to the principle of disclosure described above, we support the PhRMA Principles on the Conduct of Clinical Trials and Disclosure of Results. Further, we are in the process of developing a mechanism for making these clinical results publicly available. Bristol-Myers Squibb also registers clinical trials on www.clinicaltrials.gov for life-threatening or serious diseases.

Regarding Serzone, clearly our company disclosed the results of pediatric trials in an appropriate manner, and Serzone's label continues to provide a warning to physicians regarding Serzone's use with pediatric patients.

Beyond Serzone, Bristol-Myers Squibb's is absolutely committed to open and timely reporting of clinical trial results of our medicines when the welfare of patients could be affected. As demonstrated by the company's approach to the TIMI-22 trial on statin drugs, Bristol-Myers Squibb will openly disclose important data, regardless of result, that could have a real impact on patient care.¹

ADDITIONAL BACKGROUND

1 OVERVIEW OF THE NEFAZODONE PEDIATRIC STUDIES

On December 22, 1994, FDA approved Serzone® (nefazodone hydrochloride) with a post-approval commitment to conduct studies to evaluate the use of nefazodone in children and adolescents with depression. In response to this commitment and a written Request for pediatric studies with Serzone issued by FDA in 1999, BMS has conducted three nefazodone pediatric studies: CN104-136, CN104-141 and CN104-187.

Study CN104-136: "An Open Label Pharmacokinetic Trial of Nefazodone in Depressed Children and Adolescents"

CN104-136 was a trial designed primarily for the evaluation of pharmacokinetics and the assessment of safety and tolerability in children and adolescents; it is uninformative on the evaluation of efficacy because it is an open-label, uncontrolled trial (i.e., no placebo or comparator arms). BMS submitted the Final Study Report for the Acute Phase to FDA on August 21, 1997; the results were presented at the Annual Meeting of the American Academy of Child and Adolescent Psychiatry in October, 1997. The Final Study Report for the Extension Phase was submitted to FDA on January 20, 1999; these results were published in August, 2000. Findling R.L., Preskorn S.H., Marcus R.N., et al., Nefazodone pharmacokinetics in depressed children and adolescents, J. American Academy Child Adolescent Psychiatry 2000; 39;1008-16.

Study CN104-141: "A Multicenter, Double-Blind, Placebo-Controlled Trial of Nefazodone in Depressed Adolescents"

CN104-141 was a double-blind, placebo-controlled trial involving only adolescents designed primarily for the evaluation of efficacy and safety in pediatric patients. The Final Study Report of the Acute Phase and the Ongoing Study Report of the Extension Phase were submitted to FDA on April 16, 2002. The study results were presented in a poster at the Annual Meeting of the American Psychiatric Association, the premier psychiatric conference, on May 20, 2002. M.A. Rynn, R.L. Findling, G.J. Emslie, R.N. Marcus, L.A. Fernandes, M.F. D'Amico, S.A. Hardy, Efficacy and Safety of Nefazodone in Adolescents with MDD. The study results were also presented in a poster at the New Clinical Drug Evaluation Unit conference on June 12, 2002. G.J. Emslie, R.L. Findling, M.A. Rynn, R.N. Marcus, L.A. Fernandes, M.F. D'Amico, S.A. Hardy, Efficacy and Safety of Nefazodone in the Treatment of Adolescents with Major Depressive Disorder.

Study CN104-187: "A Multicenter, Double-Blind, Placebo-Controlled Trial of Two Dose Ranges of Nefazodone in the Treatment of Children with a Major Depressive Episode"

CN104-187 was a double-blind, placebo-controlled trial involving children and adolescents designed primarily for the evaluation of efficacy and safety in pediatric patients. BMS submitted to FDA the Final Study Report of the Acute Phase and the Ongoing Study Report of the Extension Phase on April 16, 2002. While the results of the study were not formally presented nor published, the two posters for CN104-141 stated: "In a second depression trial in pediatric patients (aged 7-17), nefazodone did not differentiate from placebo." BMS submitted to FDA the Final Study Report of the Extension Phase on September 3, 2004.

2 ADVERSE EVENTS IN THE PEDIATRIC STUDIES

Adverse Events Concerning Worsening Depression, Suicidal Ideation, and Rate of Self-Injury

The risk of worsening depression, suicidal ideation, and rate of self-injury can only, truly, be assessed in the double-blind, placebo-controlled efficacy studies, such as CN104-141 and CN104-187. BMS assessed these risks through the tabulation of adverse events and an analysis of a CDRS-R item related to suicidal ideation.

A review of patient-reported adverse events in the short-term and long-term phases of CN104-141 and CN104-187 was done to evaluate the incidence of worsening depression. Altogether there were two reports of worsening depression in the nefazodone group and no reports in the placebo group, on therapy, in the short-term phase of the efficacy studies; this finding was not statistically significant and therefore did not provide evidence that there is an increased risk of depression with short-term use of nefazodone. In the long-term phase of CN104-141, there was one patient with worsening depression in the placebo group and no patients in the nefazodone group.

The risk of worsening suicidal ideation was assessed by evaluating the incidence of patients with a baseline score of 1 or 2 on item 13 of the CDRS-R (Suicidal Ideation) that increased to a score of 3 or higher. The results of this analysis show no statistical difference in the incidence of worsening suicidal ideation between nefazodone-treated patients and placebo-treated patients in the short-term phases of CN104-141 and CN104-187. In the long-term phase of CN104-141, no patients on either nefazodone or placebo had worsening suicidal ideation as assessed on item 13 of the CDRS-R.

BMS received a number of requests from FDA beginning on July 2, 2003 for data and information on nefazodone and suicidality in pediatric patients. In response to those requests, BMS has made four submissions to FDA. The review revealed that no suicides occurred in either study. Two nefazodone patients and no placebo patients had on-therapy suicide-related or self-injury events during the short-term phase of the study. One nefazodone patient had self-injurious behavior (minor self-mutilation), during the screening phase, prior to dosing. There were no statistically significant differences between nefazodone and placebo on the incidence of suicidal-related adverse events.

3 COMMUNICATIONS WITH FDA

As discussed above, BMS conducted nefazodone pediatric studies in response to a request from FDA. BMS submitted to FDA the Final Study Reports for CN104-136 on August 21, 1997, and January 20, 1999. BMS submitted to FDA the Final Study Reports for the Acute Phases and the Ongoing Study Reports of the Extension Phases for CN104-141 and CN104-187 on April 16, 2002. Based upon the results of these studies, FDA told BMS that nefazodone is not indicated for use in pediatric patients and the product label specifically notes that the safety and efficacy in individuals below 18 years of age has not been established.

Thank you for the opportunity to testify on this important issue this morning.