CDER to eye field offices, trend warning letters; devices lead CBER letters.

Dear Reader,

The Center for Drugs plans to do trend analyses of warning letters to gauge the consistency of citations issued by field districts.

Addressing the PDA-FDA Joint Conference in Bethesda, MD, Sept. 29, Joseph Famulare, director of the Center's Division of Manufacturing and Product Quality, Office of Compliance, said: "We are looking at direct reference authority and try to track and trend what the problems are and what we can do better to manage those problems."

"Direct reference authority" is FDA's way of giving field offices leeway to issue warning letters

without headquarters' clearance. When former Commissioner Dr. David Kessler, M.D., created warning letters in 1991 previously called "regulatory letters" he gave the field authority to issue most of them without headquarters' clearance. Before that time, most regulatory letters required approval by agency higher-ups.

In recent years, however, the Office of Regulatory Affairs (ORA), which supervises field operations, has been steadily reclaiming such authority, notably in infractions involving medical device design controls and "Team Biologics" inspections. In addition, virtually all bioresearch monitoring warning letters are issued by FDA headquarters in Rockville, MD, as are letters involving foreign inspections.

Part of the reason FDA has been curtailing direct reference authority is due to the backlash against the districts' alleged heavy-handed attitude under Kessler.

Famulare did not indicate whether ORA will revoke direct reference authority, nor did he reveal in which areas such authority might be eliminated. However, most of his talk concerned proposed reforms to the Center's pre-approval inspection compliance program, largely the criteria that trips such an audit.

Since 1994, FDA has audited all priority drugs, narrow therapeutic index drugs, the first three generics approved and the top 200 selling drugs in the U.S.

He said CDER is reconsidering this criteria and giving the field more leeway to choose when to inspect a firm prior to approving its drug.

"We want to set up in this compliance program having CDER's Office of Compliance examine direct reference for trending," Famulare explained. "We want to study warning letters more carefully to look at consistency from district to district and from region to region, to see how the field is using direct reference authority."

The review also could be viewed as the precursor for CDER to embrace the medical device warning letter pilot, which began in April, sources speculated. Continued next page...

Under that pilot, device firms can avoid a warning letter if they adequately respond to the 483 (See June 14 issue, page 1). CDER and the Center for Biologics in November launched a test of the medical device inspection reforms, such as pre-announced inspections and annotated 483s. Officials of both centers said that once the device warning letter pilot concludes, a similar test could be conducted with drugs and biologics.

CBER Office of Compliance and Biologics Quality Director Steven Masiello told PDA that devices appear to be the Center's latest compliance problem.

He said warning letters for CBER-regulated devices outpaced all other categories of products in fiscal 1999, which ended Sept. 30.

According to his slides -- which did not present actual numbers, but bar charts -- about 13 letters were slapped on makers of in vitro diagnostics and blood banking equipment, versus 12 in fiscal 1998. Con-sidering that plasma derivatives, therapeutics, vaccines and allergenics combined for a total of less than ten, Masiello said the device totals "really jump out. It's fairly high from the last few years, meaning there are issues that need to be addressed there." Plasma derivative makers got four warning letters in fiscal 1999, out of 19 inspections, he said.

Sincerely,

The Editors

Famulare's slides, which detail inspection trends and ideas for revising pre-approval audits, is $17 plus retrieval, Doc. 108731M. Masiello's outline, which includes data on recalls and error and accident reports, is $5, Doc. 110019R. Retrieval fees added per order, not per document.

A more complete discussion of proposed reforms of pre-approval inspections of pharmaceutical firms appears in the October issue of "Inspection Monitor." Call for a copy: [phone], or

E-mail: [e-mail].