PRESS RELEASE: FDA Sends Sanofi Warning Letter for Ketek Study

FDA Sends Sanofi Warning Letter for Ketek Study

ROCKVILLE, Md., Oct. 24, 2007--The FDA posted on its web site a letter to Sanofi-aventis regarding a study with the antibiotic Ketek.

Food and Drug Administration
Rockville MD 20857


Gregory Irace
Chief Executive Officer
Sanofi-Aventis U.S. LLC.
55 Corporate Drive
Bridgewater, NJ 08807
Ref: 07-HFD-45-1002

Dear Mr. Irace:

This Warning Letter is to inform you of objectionable conditions found during the U.S. Food and Drug Administration's (FDA) investigation into Aventis Pharmaceuticals' (hereafter referred to as Aventis) role as sponsor of study HMR3647Al3014 (study 3014) entitled "Randomized, Open-Label, Multicenter Trial of the Safety and Effectiveness of Oral Telithromycin [Ketem] and Amoxicillin-Clavulanic Acid [Augmentin] in Outpatients with Respiratory Tract Infections in Usual Care Settings" of the investigational drug, Ketek (telithromycin). We note that the issues addressed in this letter pertain to the time period prior to the merger of Sanofi-Synthelabo and Aventis Pharmaceuticals in August 2004. FDA notes that the legal name of the current firm is Sanofi-Aventis and that Sanofi-Aventis is the current sponsor of the Ketek New Drug Application (NDA).

This investigation is a part of FDA's Bioresearch Monitoring Program which is designed to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects of those studies have been protected. Another objective of the program is to ensure that data submitted in support of New Drug Applications are scientifically valid and accurate.

In July 2002, Aventis submitted to FDA the clinical study results obtained from study 30 14 in support of NDA 21,144. Subsequent FDA data validation inspections of several clinical investigators participating in study 3014 revealed multiple and significant violations of FDA regulations codified at 21 CFR 3 12 that affected the integrity of data submitted to NDA 21,144. As a result of these findngs, FDA requested in its January 24, 2003 Approvable Letter that Aventis provide information on its sponsor monitoring and auditing of clinical investigator sites for study 3014. Aventis submitted this information to the FDA in July 2003 (preliminary response) and October 2003 (final response). FDA obtained additional information related to Aventis's oversight of study 3014 in a subsequent investigation.

From our review of these records, we conclude that Aventis did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations. We wish to emphasize the following:

1. Failure to secure investigator compliance with the investigational plan and applicable FDA regulations [21 CFR 312.56(b)].

Under FDA regulations, a sponsor who discovers that an investigator is not complying with the signed investigator agreement [Form FDA 15721, the general investigational plan, or the requirements of applicable FDA regulations shall promptly either secure compliance or discontinue shipment of the drug to the investigator, terminate the investigator's participation, and notify FDA. Our investigation found that despite several clinical monitoring visits from Aventis's designated monitors, PPD Development (hereafter referred to as PPD), and Aventis's own audits documenting serious protocol violations and regulatory noncompliance by multiple clinical investigators, these violations persisted. We were unable to find evidence that Aventis promptly secured compliance or terminated participation of these clinical investigators and notified FDA. For example: a. Review of PPD monitoring records, Aventis Quality Assurance (QA) audit records, and email communications between PPD and Aventis disclosed that Aventis knew of pervasive problems at the clinical investigator site of Dr. Maria Anne Campbell aka Anne Kirkman Campbell (hereafter referred to as Dr. Kirkman Campbell), a solo practitioner in rural Alabama who had never previously conducted an FDA-regulated study, but randomized 407 subjects into Study 3014 over a 3 month time period (i.e., November 2001-January 2002.)

FDA's October 2002 routine data validation inspection of this investigator raised numerous concerns with her conduct of study 3014, including potential fabrication of study subjects, fabrication of study data, and enrollment of ineligible subjects. FDA investigated Dr. Kirkman Campbell and found that she falsified Case Report Forms (CRFs) that were submitted to the sponsor and falsified documentation to support the existence of a fictitious subject. Dr. Kirkman Campbell subsequently pled guilty to one count of mail fraud in connection with this fictitious subject and was sentenced to 57 months in federal prison.

While study 3014 was ongoing, PPD conducted monitoring visits of Dr. Kirkman Campbell on November 29,2001, after 65 subjects were enrolled; on February 18-21,2002, after all 407 subjects were enrolled; on April 1-5,2002, after all the subjects completed the study, and on October 8-10,2002, to prepare the site for the upcoming FDA inspection. In addition, Aventis conducted a quaIity assurance (QA) audit at this site on January 17-18,2002.

Our review found that PPD identified significant problems at Dr. Kirkman Campbell's site and subsequently informed Aventis of its findings and concerns. We note that Aventis failed to promptly secure compliance from Dr. Kirkman.