Search for Stability at FDA

It took hours to update ACT's annual listing of FDA offices and top officials, and it's probably out of date already. Even before the September resignation of Food and Drug Administration Commissioner Lester Crawford, FDA experienced a number of important organizational and personnel changes during the past year. Crawford revised his office following his confirmation by the Senate in July. At the same time, the Center for Drug Evaluation and Research (CDER) reorganized its offices that oversee new drug research proposals and applications. The result is a lot of new names in ACT's FDA and CDER listings, as well as new telephone numbers following the move of key CDER offices to FDA's new White Oak, MD, campus.

Jill Wechsler

In July, Crawford clarified the responsibilities of his top deputies. Janet Woodcock became permanent deputy commissioner for operations and chief operating officer, ending speculation that she might return to CDER at some point. Steven Galson thus became the official head of CDER after serving on an acting basis for more than a year. Murray Lumpkin was named deputy commissioner for international and special programs, overseeing FDA international activities, pediatric drugs, combination products and other initiatives such as approving AIDS therapies for overseas sales. Crawford elevated Associate Commissioner for Legislation, Patrick Ronan, to be his chief staff officer and liaison with the Department of Health and Human Services (HHS). And the commissioner brought back policy analyst Scott Gottlieb as deputy commissioner for medical and scientific affairs, replacing Amit Sachdev, who left FDA in March to head the policy staff at the Biotechnology Industry Organization. These four deputies provide the main hope for continuity and stability following the unexpected appointment in September of National Cancer Institute (NCI) director Andrew von Eschenbach as acting FDA commissioner.

In addition, during the past year FDA gained a new chief counsel and new directors for its planning and management offices. There is a new associate commissioner heading the Office of Regulatory Affairs (ORA), which oversees the agency's field force that inspects research sites and manufacturing facilities. ORA Director Margaret Glavin has named new deputies and is moving to develop a more risk-based inspection approach; this strategy reflects her office's declining resources and expanding responsibilities for monitoring more imported food and medical products and more production sites in the United States and overseas.

Then, of course, there's continuing fall-out from FDA's nondecision on the morning-after pill, Plan B. Susan Wood, director of FDA's Office of Women's Health, quit her job in protest of FDA allowing politics to supersede science in putting off the approval of Barr Pharmaceuticals' application to switch this widely used pill to nonprescription status. After promising Senate leaders that FDA would make a decision on Plan B by September 1, Crawford announced in late August that he once again was delaying action in order to further examine the political and regulatory issues. This appeared a fairly blatant cave-in to pressure from conservative political leaders who fear that easy access to the medicine will encourage teen sex. Crawford and HHS secretary Michael Leavitt lost considerable credibility on Capitol Hill and throughout FDA and the biomedical research community. FDA reviewers and scientists insisted that all evidence showed that the drug is effective and can be used safely for its intended purpose; denial instead undermines the agency's reputation for basing regulatory decisions on sound scientific evidence and reflects unusually high involvement of top FDA officials in the decisions, according to a GAO report.

After further missteps, Crawford appointed Teresa Toigo to head the women's office on an acting basis; she remains assistant commissioner for special health issues, which serves as FDA's liaison with patient groups, particularly those for AIDS and cancer. One high-profile task is to assess how well clinical trial sponsors post notices of active clinical studies, an issue that underlies current initiatives to expand public information on clinical trials and eventual study results.

People close to FDA management do not believe that the Plan B debacle was the immediate cause of Crawford's resignation, but failure to resolve the issue makes it nearly impossible for FDA to secure a permanent commissioner under the current political regime. Perhaps the most positive action von Eschenbach could take to gain credibility as acting commissioner is to bite the bullet and approve Plan B's application. All parties have had a chance to comment on Crawford's delay proposal; while the White House and many Republicans may be furious, fast action would take the issue off the table before next year's elections and enable FDA to move on with its important business.

Changes at CDER

Resolution of the Plan B crisis would be a relief to CDER Director Galson, who had the unhappy task of killing Barr's initial OTC application in 2004. This past year he has been busy overseeing major changes at the drug center and putting out drug safety fires. He now has a permanent deputy, Douglas Throckmorton, to assist in the process; one of Throckmorton's early assignments is to chair the Center's new Drug Safety Oversight Board.

The Office of New Drugs (OND) continued to reorganize, expanding from five to six drug evaluation offices in order to better balance the staffs that review drug applications and to further integrate oversight of biotech therapies into the review structure. Major changes involve establishing an Office of Antimicrobial Products (replaces ODE IV) to handle applications for anti-infectives and anti-virals, plus special programs on drug shortages, drug resistance and special pathogens. A new Office of Oncology Products was established with divisions to oversee drug and biotech cancer therapies plus medical imaging products. And an Office for Nonprescription Products reflects increased focus on OTC drugs. The reorganization involved shifting a number of review divisions to different offices and assigning applications for biotech therapies to appropriate drug review divisions; only biotech oncology products have their own division (www.fda.gov/cder/cderorg/cder.pdf).

CDER's Division of Scientific Investigations, in the Office of Medical Policy, continues to conduct inspections of clinical study sites and institutional review boards. This group's task is to ensure that researchers comply with regulations and that data submitted in applications meets standards. DSI's Human Subject Protection Team also reflects the agency's increased focus on assuring that investigators follow all procedures to protect the rights and privacy of clinical trial participants.

Next March, this group will move to CDER's Office of Compliance, which manages all other field inspections for new drugs and previously was DSI's home. The move will free up OMP to play a larger role in CDER's efforts to encourage new clinical trial methodologies as part of the Critical Path Initiative.

CDER's Office of Pharmaceutical Science (OPS), which examines the chemistry, manufacturing and controls sections of new drug applications (NDAs), is also undergoing considerable change. OPS's newly named Office of New Drug Quality Assessment now has four divisions: three to review the CMC sections of NDAs and a fourth to assess postmarket manufacturing supplements, which continue to increase at a rapid rate. OPS's Office of Generic Drugs retains its current structure but is revising its review process to better manage a fast-growing number of abbreviated NDAs, and the Office of Biotechnology Products continues to examine the manufacturing sections of applications for biological therapeutics.

Spotlight on safety

Continued focus on how FDA monitors postmarketing drug safety also has prompted changes in CDER's Office of Pharmacoepidemiology and Statistical Science (OPSS). After a nearly two-year search, Galson finally announced in October the selection of a CDER staffer to direct the Office of Drug Safety (ODS): Gerald Dal Pan, who had headed ODS' Division of Surveillance, Research and Communication Support for two years. Galson indicated that Dal Pan will report directly to him in an effort to raise the stature and visibility of this much-discussed FDA operation.

The long delay in appointing a top drug safety officer has been cited as a sign of FDA's inability to adequately monitor and communicate drug safety problems. Naming an FDA staffer to the job and keeping ODS within CDER is not likely to quiet all these complaints. Galson emphasized that CDER already devotes 50% of its resources to drug safety, including aspects of premarket testing and application review, as well as postapproval monitoring, but critics continue to clamor for more.

An important task for Dal Pan will be to reshape ODS to improve its ability to assess safety signals from adverse event reports and health data bases and to weigh signs of concern against the benefits of new and marketed therapies. ODS divisions oversee FDA's MedWatch adverse event reporting system, the development of medication guides for high-risk products and research on postmarketing safety issues. Epidemiologists evaluate Phase IV study protocols and postmarketing surveillance tools to support risk management strategies for certain products. One group reviews proposed drug names and labels to identify the potential for medication errors related to name confusion, both pre- and postapproval. ODS has become more active in examining outside epidemiological data able to indicate possible safety problems and is working more with international regulatory bodies to assess safety issues globally.

In announcing Dal Pan's appointment in his annual "state of CDER" address, Galson promised further agency reorganization to improve CDER's ability to asses drug safety issues and to communicate risk concerns more consistently. Galson also highlighted the need for CDER to "fully participate" in FDA's Critical Path Initiative and "improve regulatory and drug development science." The key challenge for FDA leadership will be to accomplish these tasks in the face of tighter resources created by continued budget reductions.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com