BIOLOGICS FACILITY ROUTINE INSPECTIONS WILL SCRUTINIZE RECALL SYSTEMS, FDA SAYS; BLOOD PRODUCTS GROUP TO PRESENT RECALL PROPOSAL AT MARCH ADVISORY PANEL

Routine FDA inspections of biological products manufacturing facilities will include increased evaluation of recall systems to determine appropriateness and efficacy.

"We will be focusing...more closely on firms' recall procedures to be sure, (1) that they have them in place, and (2) how those procedures are laid out and whether they seem to be adequate for the products that firm makes," Center for Biologics Evaluation & Research Office of Compliance Deputy Director Michael Dubinsky said at the agency's informational meeting on notification of plasma product withdrawals and recalls, held Nov. 19 at the National Institutes of Health in Bethesda, Md.

Recall systems will be "part of our control and inspection protocol," Dubinsky said. "We recognize the need, for biologics in particular, to look closely at [recall systems] because the plasma derivatives experiences have raised it to a high level in our program area." Moreover, the "experiences that have prompted meetings like this are not limited in terms of their standing at FDA to just the Center for Biologics," Dubinsky said. "At the Offices of Compliance throughout the centers, we have shared these experiences and concerns" about "the need to be more sensitive to recall situations overall."

Manufacturers should be responsible for disseminating information about recalls to end users of the product, FDA officials and patient groups emphasized.

"The information must flow in both directions," CBER Director Kathryn Zoon, PhD. said at an international conference on viral safety of plasma derivatives Nov. 20 at NIH. "When circumstances and evidence suggest risk to patients, swift and appropriate action must be taken, but the affected patient population must also be notified. Knowledge in this context is fundamental to the ability to self-protect."

"Only with [recall] information can the patient and the physician working together properly weigh the risks and benefits of" remaining on treatment, National Hemophilia Foundation medical advisory panel member Bruce Ewenstein, MD, stated at the recalls meeting. "We recommend that notification of patients be based on medical and scientific judgment, coupled with algorithms and decision trees to assist FDA in objectively determining when patient notification should be" performed, Ewenstein said.

NHF recommends that a "primary notification system" should "track product from manufacture through the entire path" of distribution to ensure information reaches the end users of products.

The plasma derivative products manufacturers are developing a plan for active product recall notification. The plan is scheduled to be presented at a March meeting of the FDA Blood Products Advisory Committee.

American Blood Resources Association President James Reilly emphasized the importance of maintaining the involvement of learned intermediaries in the process of informing consumers about investigations and recalls. Reilly noted concerns that frequent notification of unconfirmed risks associated with plasma products could lead to "consumer desensitization" to recalls.

Representatives from NHF strongly disagreed, stating that the relatively well-informed plasma product user population would prefer to receive as much information as possible so as to be able to make an informed choice.

One obstacle to reaching end users of plasma products is that the tracking of lot numbers frequently breaks down at the distributor or consignee level, Reilly noted.

Caremark's Mike Dwyer told the meeting that Caremark tracks lot numbers to individual patients and providers through the use of a centralized database. Caremark runs an automated notification center, where pharmacists typically call physicians to notify them of a recall situation and decide in consultation with the provider who should contact the consumer.

FDA is establishing a new, monthly category of adverse event reports for infectious disease transmissions associated with biological products that would not be classified as serious and unexpected and thus would not fall under the 15-day "urgent" alerts already required.

"The timing of this monthly reporting requirement was selected, among other reasons, to permit the acquisition of patient information, including clinical evaluation, sufficient to help in the timely assessment of a causal connection between the biological product and possible or documented infectious disease transmission," CBER's Zoon wrote in an Oct. 7 letter to manufacturers and to the American Blood Products Association.

"This monthly reporting requirement applies only to infectious disease transmission," Zoon noted. "Periodic reports should continue to be submitted on the quarterly or annual basis that is appropriate to each licensed biological product for all other adverse experiences not reportable under" priority notification regulations.

The letter also includes general warning statements for plasma derivative product labeling. Packaging must state: "Discuss the risks and benefits of this product with your physician."

The new boxed warning states: "Products made from human plasma may contain infections agents, such as viruses, that can cause disease." The statement summarizes viral reduction measures and notes: "Despite these measures, such products can potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. All infections should be reported directly to your physician and" the manufacturer.

The initiatives in the Oct. 7 letter are "a major improvement in making sure that consumers are able to identify the risks as well as benefits of taking plasma products, and to make sure that, if there is transmission of an agent, that transmission is detected in the most rapid possible time," National Hemophilia Foundation Blood Safety Working Group Chairman Glenn Pierce, MD/PhD commented at the recalls meeting.

A Nov. 5 memo from Zoon to biologics companies warns firms not to use recalled lots of Centeon albumin in manufacturing.

CBER "is aware that albumin is used as an in-process additive, component or excipient in the manufacture of other biological products," Zoon said. The agency wants "to ensure that all biological product manufacturers who use albumin in the manufacture of approved or investigational products are aware of the Centeon recall."

"Manufacturers should determine whether or not the production of their products included the use of recalled albumin," the memo states. "If so, the matter must be thoroughly investigated to determine whether there is any potential impact on the final product." Centeon recalled all lots of Albuminar and Plasma Plex Oct. 9 as a precaution following reports of suspected bacterial contamination in one lot ("The Pink Sheet" Oct. 14, T&G-7).

FDA is opening two new communications channels for plasma and blood recall information, the agency announced Nov. 15. A toll-free 24-hour telephone line, 888-CBER-BPI, and an electronic mailing list will supplement CBER's home page, consumer information line and fax system. The mailing list can be joined by sending the message "subscribe bprecall" and an e-mail address to FDALISTSwww.fda.gov.

The recalls meeting will not result in a formal document or action plan, but it is a "foregone conclusion" that FDA will continue to work with industry on the refinement of recall procedures, Office of Biologics Research & Review Director Jay Epstein, MD concluded.