Abbott ADR Reporting Cited In FDA Warning Letter On Meridia, Norvir, Biaxin 

Abbott expects that continued improvements to its Adverse Event Global Information System (AEGIS) will address ADR reporting problems cited in an ¹ FDA warning letter.

The letter, issued by FDA's Chicago district office, lists several instances of late, inaccurate or undocumented adverse event reports for Abbott's Meridia (sibutramine), Norvir (ritonavir), Biaxin (clarithromycin) and ProSom (estazolam).

FDA noted that the failure of Abbott's foreign affiliate in Japan "to relay 15-day follow-up information to Abbott International in a timely manner appears to have been the cause of [its] late submission of expedited reports" on serious and unexpected adverse drug experiences.

Abbott has been using the AEGIS system since March 2001 to integrate its ADR data into one central database with that of Knoll, which Abbott acquired during the first quarter of 2001. Abbott completed the data integration Feb. 4.

FDA's warning letter notes that some of the reporting problems were inherited by Abbott in the acquisition. "We note that several of the identified deficiencies arise from the product safety operations of Knoll Pharmaceuticals before Abbott" acquired the company.

However, Knoll "is now a subsidiary of your firm, and you have completed integration of the Knoll product safety operations into Abbott's operations," FDA said. "As such, your firm has assumed responsibility for reporting adverse drug experiences for that subsidiary."

The letter is based on two FDA inspections (in January and March-April) that resulted in two 483s (filed on Jan. 28 and April 3).

FDA's Chicago district office expects to meet with Abbott soon after the company files its response to the warning letter. Abbott's response is due Aug. 15.

Sanofi received an FDA warning letter in October 2001 on similar reporting problems for overseas ADRs. Other recent FDA warning letters for delayed or incorrectly categorized postmarketing ADR reports have been issued to Bristol-Myers Squibb (1999), Berlex (1999), Roche (1998), Novartis (1998) and Pfizer (1996).

Of the drugs mentioned in the Abbott warning letter, only the obesity drug Meridia came from the Knoll acquisition. The problems cited by FDA include a lack of documentation on seven deaths associated with Meridia.

Abbott "did not always maintain records of raw data and correspondence related to adverse drug experiences. Raw data pertaining to follow-up investigations for seven deaths associated with Meridia...were not maintained and available for review," FDA said. Abbott is providing FDA with that information.

The letter also notes one Meridia death that was unreported by Abbott and objects to Abbott's explanation for the omission.

"Your explanation - that the caller mentioned this serious and unexpected adverse drug event was a 'rumor' - does not affect the requirement to report this event," the letter says. "Since the necessary data elements were available [in source documents], your firm was required to promptly report the serious, unexpected adverse event to FDA."

Abbott has now confirmed the report and plans to report the death in its response to the warning letter.

Three additional adverse drug experience reports for deaths associated with Meridia are cited in the letter for inaccurate or incomplete information.

"You submitted adverse drug experience information in reports to FDA which was inaccurate in some cases, or did not completely reflect information available in the source documents, such as in three reports of death associated with the use of Meridia."

The warning letter also cites late and inaccurate adverse event reports and follow-up reports for the AIDS drug Norvir, the antibiotic Biaxin and the insomnia treatment ProSom.

In 18 cases between Jan. 1, 2000 and Oct. 31, 2001, reports required within 15 days were instead received 63 to 377 days after the event occurred, FDA says. Other reports included inaccurate dates.

The letter notes that some of the reporting delays were due to "serious and unexpected adverse events reports" (which require reporting within 15 days) being incorrectly categorized as "periodic adverse drug experience reports," which are required at quarterly intervals.

FDA noted that although Abbott has taken corrective actions since the agency's inspections, "you have not addressed many of our concerns....Of the deficiencies you address in your letter of April 18, 2002, we find many of your responses inadequate."

The warning letter asks Abbott to provide the agency with information on how it has modified its reporting procedures. FDA also asked Abbott how it will ensure its standard operating procedures are fully implemented for adverse event reporting.

Abbott is identifying improvements that need to be made to its AEGIS system and is continuing to improve training.

FDA is reviewing petitions from Public Citizen's Health Research Group on Meridia safety and adverse event reporting, and is expected to issue a response this fall.

HRG petitioned FDA in March to withdraw Meridia due to safety concerns with the drug (² (Also see "Meridia Fatality Rate “Substantially Lower” Than Obese Population – Abbott" - Pink Sheet, 25 Mar, 2002.), p. 21). The group reported that since Meridia's launch in 1998 through Sept. 30, 2001, the drug had been associated with 29 deaths, including 19 from cardiovascular adverse events.

HRG now says that the number of deaths has increased to 32, with the three additional adverse events all attributable to a cardiovascular event.

FDA said that as of March 12, it has received reports of 24 deaths associated with Meridia.

In May, HRG wrote to FDA calling for a criminal investigation of Abbott based on assertions that Meridia adverse event information was improperly reported (³ (Also see "Meridia Growth Forecast Is 50% In 2002, Despite Italian Withdrawal – Abbott" - Pink Sheet, 17 Jun, 2002.), p. 16).

As part of its review of the petitions, FDA is believed to be comparing Meridia postmarketing adverse events with that of Roche's obesity drug Xenical (orlistat), and conducting interviews with a former Knoll employee on reporting procedures at the firm.

Abbott plans to generate more Meridia safety data through a 25,000-patient, seven-year cardiovascular/ diabetes outcome study, expected to begin by the end of the year.