CBER's Quarterly Safety Review Procedures Less Centralized Than CDER's

Under FDAAA, both centers are required to publish evaluations of AERS data. CBER’s review effort is more specialized, while CDER’s procedures are more centralized.

When a potentially serious safety signal associated with a drug or biologic crops up and FDA publishes it in the quarterly list of adverse events, sponsors may find a more centralized review of the signal if the product is regulated by the Center for Drug Evaluation and Research, but a more specialized review if the product is regulated by the Center for Biologics Evaluation and Research.

CBER has just published its Standard Operating Procedures and Policies for posting the online quarterly lists of potential signals of serious risk in the products it regulates, a requirement under Section 921 of the Food and Drug Amendments Act of 2007 (Also see "FDA List Of Potential Safety Signals Has 3 Pfizer Drugs, Echoes Drug Watch Site" - Pink Sheet, 8 Sep, 2008.).

CDER Manual of Policies and Procedures from March 29 similarly outlines how the quarterly safety signal summaries under its aegis are to be prepared. For both CDER and CBER, only signals identified through AERS, or where AERS "heavily contribute[d]," are to be included in these lists.

That leaves a wide range of signals that are not to be included, such as signals reported by the sponsor to trigger a labeling change, those reported by foreign or international regulatory bodies, and those gleaned from other sources such as clinical trials, epidemiologic studies, registries or the medical literature.

According to CBER SOPP 8420, which took effect Nov. 1, medical officers in CBER's Division of Epidemiology, a part of the Office of Biostatistics and Epidemiology, conduct routine safety monitoring through the agency's Adverse Events Reporting System database.

It is each medical officer's responsibility to "review each serious and direct AERS report for his/her assigned products within one business day of receipt at OBE to identify new safety information that may represent a possible safety issue associated with use of a product."

OBE, DE and the relevant Product Office discuss such possible signals at a "DE Safety Assessment Meeting," and if the DE division director decides it is warranted, the signal is included in the quarterly list to be posted on the Internet.

Similar End, Different Procedures

By contrast, in CDER there is a "921 Team" (named after the FDAAA section) that is "responsible for identifying the potential signals if serious risks and safety issues in the previous quarter and prepar[ing] the potential signals list for posting on the AERS website."

The 921 Team members review the "tracked safety issues" from AERS that have been entered into CDER's "Document Archiving, Reporting and Regulatory Tracking System," a system that has no parallel at CBER.

“Because of the smaller volume of CBER regulated products falling under Section 921, we do not require a system such as DARRTS for this purpose,” CBER said.

However, the center added that it "does maintain an inventory of safety issues once they are identified in AERS, and they are maintained and tracked in this inventory as they are routed through appropriate clearance and approval for posting, as described in the SOPP."

At CDER, the 921 Team members are directed to "review the list of TSIs from the source data, share the list with relevant staff from their respective organizations and compile information to help determine inclusion or exclusion of issues relevant to their divisions or offices."

The 921 Team project manager collates the information, which must cleared by CDER's Office of Surveillance and Epidemiology, Office of New Drugs and Office of Generic Drugs, as well as CBER staff, if relevant.

"CDER uses the safety issues listed in the DARRTS TSI as its data source when developing the public posting," the center explained. "Each quarter, CDER generates a list of safety issues from the DARRTS TSI (which contains safety issues identified from many sources, including, but not limited to, AERS, studies, literature and industry submissions). The list is reviewed by the 921 Team to determine which of the safety issues (product-event pairs) were related to AERS data; these are the safety issues that will be posted."

This process might seem to leave less scope for individual expertise than at CBER, but CDER said that in determining whether or not a safety issue is entered into the DARRTS TSI, it may use "the expertise of medical officers, safety evaluators, epidemiologists and/or other CDER staff."

CBER's "FDAAA Safety Working Group" appears to have a more passive role than CDER's "921 Team." The former merely reviews the draft quarterly Internet report for compliance with FDAAA and decides whether draft postings warrant review by the CBER director. However, the two bodies coordinate with each other, with the CBER SWG submitting information to the CDER 921 Team for postings related to CBER-regulated products.

But the clearance process is not necessarily less cumbersome at CBER than at CDER. For example, CBER's Office of Communication, Outreach, and Development/Electronic Disclosure Team is responsible for "provid[ing] web/disclosure clearance of draft potential signals."

Vaccine safety signals go through a separate process, with the relevant reports being submitted to the Vaccine Adverse Event Reporting System, which is jointly managed and reviewed for safety signals by CBER and the Centers for Disease Control and Prevention.

Example Cases Provide Clarity

Both CDER’s SOPP and CDER MaPP (the centers even have different terms for their internal guidance documents) devote space to sample cases where the decision about whether to include a potential safety signal in the quarterly report may not be immediately obvious.

For instance, in the CBER SOPP, a case where "a Medical Officer has been monitoring case reports of seizures with product X and notifies the Branch Chief of a safety issue" is given as an example of what to include in the quarterly summary because "the safety issue was clearly identified as a potential signal due to one or more reports in AERS." The CDER MaPP gives a similar example, except that "a safety evaluator" is the monitor, and he/she initiates it as an OSE-identified issue.

A case where the World Health Organization's "WHO Signal publication is released which addresses the new issue of statin products and suicide" is to be excluded, the CBER SOPP says, even though "this signal had not previously been identified by FDA as a potential signal," because it originated from a foreign regulatory agency. The CDER MaPP has an almost identical exclusionary example.