FDA Shakes Things Up

DA's September announcement that it plans to transfer some therapeutic biologic review functions from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER) caught most agency officials and Washington observers by surprise. The plan is for CBER to retain authority over vaccines, blood, and blood products, and a previously announced new office that will oversee gene therapies, somatic cell products, tissues, and other "cutting edge" technologies. But review of monoclonal antibodies and proteins will move to CDER. In his memo to staff, deputy commissioner Lester Crawford said that for most of the past year he examined many options for improving the review processes of drugs and biologics and that shifting therapeutics to CDER made more sense than completely combining the two centers.

Though unexpected, consolidation is not a radical idea. FDA has combined and separated oversight for drugs and biologics frequently in the past, establishing the current CBER–CDER structure in 1987. Since then, the agency has launched numerous initiatives to harmonize data requirements and filing procedures. Several streamlining initiatives were codified in the FDA Modernization Act of 1997 (FDAMA), and the Prescription Drug User Fee Act (PDUFA) established common standards and time frames for reviewing market applications for drugs and biologics. Industry succeeded in adding provisions to the PDUFA 3 agreement reached earlier this year (May 2002) to further streamline development and review of new therapies.

This latest plan attests to the continued maturation of biotech manufacturing and quality control processes. Manufacturers and regulators recognize that adherence to good manufacturing practices (GMPs) and validation methods can ensure reliable production of therapies that meet standards for potency, purity, and quality.

The move also reflects continued industry dissatisfaction with CBER review procedures. Manufacturers point out that the biologics center takes much longer than the drug center to approve license applications for standard new therapies. A main complaint is that CBER too often fails to approve applications in the first review cycle, indicating problems in negotiating product development plans with sponsors. The issue came under the spotlight during the Congressional investigation into ImClone's development of the colorectal cancer therapy Erbitux (cetuximab). At a hearing before the House Energy & Commerce Committee in June, members of Congress criticized CBER officials for permitting the company to file a license application on what appeared to be an inadequate development program. The investigation by the House panel into the resulting insider trading scandal prompted further Congressional inquiries into significant differences between CBER and CDER regulatory practices.

Generic Concerns

Some biotech industry executives say privately that they wanted only to improve CBER's management and systems and never pressed for a transfer of biologics oversight to CDER. Manufacturers are worried that they may have to meet different standards and follow new procedures at CDER, where reviewers won't have full understanding of biotechnology science. Probably biotech companies' biggest fear is that the shift to CDER will open the door to generic biologics.

Companies welcomed assurances from Crawford that there would be no change in statutes governing biologics, which currently set a high barrier to generic versions. But those products will now be regulated by CDER officials who are very familiar with generic drug policies and have indicated more interest in exploring options for the development of "therapeutically equivalent" biotech therapies.

FDA is expected to implement its new regulatory structure during the next year. The switch will be orchestrated by a high-level working group headed by FDA senior associate commissioner Murray Lumpkin, who previously directed CDER's new drug application review and approval process.

CDER director Janet Woodcock and CBER director Kathryn Zoon will participate, along with a cadre of their top aides and representatives of FDA administrative offices.

Deciding the details of which programs and personnel will move will not be easy. CBER funding will be a critical topic because that center stands to lose about three-quarters of its user-fee revenues. Crawford noted that there will be no staff reductions, but there is considerable uncertainty about how the change will affect CBER's "research review" model. In addition to moving reviewers, some CBER compliance and advisory functions also may shift, possibly including staff responsible for examining marketing and advertising materials.

Biotech companies planning to file new license applications in the next few months fear a slowdown in the approval process. The long-term expectation is that a more streamlined regulatory and review process will spur biotech research and development of new therapies, but change is always disruptive and will present short-term challenges to regulators and to industry.

Changes in the Field

Another important FDA change involves the leadership of the agency's field force and enforcement staff. Last month, Crawford named John Taylor as senior associate commissioner for regulatory affairs, a title that elevates the position and reflects a move to exert tighter headquarters control on FDA field offices. Taylor replaces Dennis Baker, who has headed the Office of Regulatory Affairs (ORA) since 1999. After a transition period, Baker will return to Texas to be in charge of FDA's regional office in Dallas.

Taylor is the first lawyer to head ORA. He previously worked at FDA's Office of the Chief Counsel (OCC) and in the commissioner's office and has headed ORA's Office of Enforcement for the past two years. In that recent position, he was involved in implementing FDA's new policy requiring OCC review of all warning letters before sending them out to manufacturers.

Changes at DDMAC

Those key organizational and management changes at FDA indicate that Crawford has had a fairly free rein by the Bush administration to function as FDA commissioner pending nomination of an official agency leader. Yet, the White House has sent out signals in recent months that it plans to name health policy advisor Mark McClellan to the job. McClellan was too involved in negotiations over Medicare policy and prescription drug coverage to change hats earlier this year. He is a physician and an economist and is considered "confirmable" even by a Democratic-controlled Senate. At press time, the McClellan nomination appeared imminent, with hopes for Senate confirmation this year.