"No Comment" On Annotated 483s Deemed Ambiguous By Firms At PDA

"No comment" responses on annotated FDA-483 forms are ambiguous and leave companies with questions as to how the term is interpreted, industry representatives said Dec. 1 at the PDA annual meeting in Washington, D.C.

The term can have a wide range of meaning, one meeting participant noted. She said "no comment" could be interpreted as disagreement with an inspector's observation or the need for more time to formulate a response.

Another representative observed that, despite the ambiguity of the term, the opportunity still exists to respond in writing.

Bristol-Myers Squibb GCP/GMP Technical Evaluations Director Robert Dana cautioned that "the idea of [annotated] 483s is not to see how fast we as an industry can fix problems that investigators find."

Annotated 483s are part of a pilot program using pre-announcement of FDA inspections as a streamlining effort. The annotations correspond with a company's corrective action plan. The PDA session served as a sounding board for industry feedback.

FDA Baltimore District Office Supervisory Investigator David Gallant acknowledged that the no comment response "doesn't look good on a 483, and I can understand why you as an industry are concerned with that, but we are restricted by the policy that is in the Federal Register."

Inspectors can use four types of annotation: corrected but not verified; corrected and verified; correction promised by a certain date; or "no comment."

"There is no wiggle room for us" in the type of annotation, Gallant said. He suggested one way for companies to avoid repeatedly receiving "no comment" was to "give a date a little further out in the horizon that provides a safety net for a reasonable time for correction."

Gallant stressed that "the default mode is to annotate"; that unless a company requests a traditional FDA-483, the pilot program will be in effect.

The annotation of 483s is one of three components of the expansion of initiatives first used for the medical device industry. Gallant indicated that ineligibility to participate in the pre-announced inspection portion of the program does not preclude participation in the annotated 483s and post-inspection notification.

The one-year pilot program concludes Dec. 31. One industry representative speculated that the agency may be backing away from the program. FDA says it is discussing mechanisms to evaluate industry feedback as the current pilot program did not have an accompanying survey.

The agency expects pre-announcement of inspections to continue after the end of the year if a decision has not been made to adopt them permanently.

The Center for Devices & Radiological Health adopted the program after a survey from the pilot program found 91% of responding companies were satisfied with the pre-announcement program and the resulting efficiency. Eighty-four percent of FDA inspectors also assessed the program favorably. Gallant said inspectors are spending a day or two less at facilities because of pre-inspection phone calls.

Meeting participants were somewhat concerned about the growing possibility of off-site inspections becoming electronic. One participant reported that an inspector reviewed reports online. He questioned whether anyone other than employees should tap into databases and suggested including a technical person as part of the team escorting the FDA inspectors.

One benefit of relying on electronic reports is a shortened visit to the facility, the participant noted. The inspector requested to see all data available concerning manufacturing of a product. However, since the company's databases are all inclusive, the participant was reluctant to open the databases, fearing the unsegmented data could produce skewed trends if improperly analysed. Dana indicated "constructing the database going in is going to be an important thought process."

Dana also noted the lack of progress in FDA's proposed first party audit program. He said, "There is basically not much in it for the industry....There has to be something for us or we are not going to play." PDA and other groups have expressed willingness to help with suggestions for modifying the original proposal, which was set to begin in January 1999.