FDA Updates Oversight, Encourages Innovation

Regulating and monitoring clinical trials has become an increasingly complex and challenging business for the Food and Drug Administration and other government agencies that fund and oversee biomedical research. There are more clinical studies in the United States and abroad, many involving multiple sites, complex study designs, and more research participants. Many studies deal with complex biotech therapies, medical devices, and combination products and call for greater participation of vulnerable subjects, including children.

Jill Wechsler

Efforts to better manage the flood of data from these research programs is generating a number of electronic record keeping and processing methods and systems that, in turn, require new rules. These developments impose new challenges for IRBs and research institutions, which continue to evolve to meet new requirements.

Regulatory overhaul

To cope with these developments, FDA has launched an initiative to update its Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) program to reflect this larger, more decentralized global research enterprise. Announced by Deputy Commissioner for Operations Janet Woodcock in June [View from Washington, August 2006], the project aims to safeguard study participants and ensure that trials produce high-quality data, while also bolstering public confidence in clinical research activities and in FDA's oversight.

Who Will Lead SACHRP?

An HSP/BIMO steering committee headed by Woodcock has established working groups to tackle key issues, which include:

• Updating inspection and compliance policies to establish a more risk-based approach to selecting research sites for inspection and better defining what constitutes quality clinical data.

• Revising investigator disqualification procedures to facilitate the removal of unethical researchers more quickly while ensuring due process.

• Clarifying adverse event reporting policies to help IRBs deal with the overwhelming volume of adverse event reports they now receive and advising investigators more clearly on what information has to be filed.

• Revising FDA's internal governance of BIMO programs across centers to establish a more unified system.

• Finalizing a proposed rule for ensuring that sponsors maintain ethical standards in foreign clinical studies not conducted under IND rules.

Changing roles

Linda Tollefson, FDA assistant commissioner for science and deputy director of the Office of Science and Health Coordination, who reports to FDA Associate Commissioner for Science Norris Alderson, now is more involved in the BIMO initiative as the acting director of FDA's Good Clinical Practice Program. Tollefson also directs FDA's Offices of Women's Health and Orphan Product Development and chairs the agency's internal IRB, which oversees human subject research conducted by FDA scientists.

David Lepay, who has headed the Good Clinical Practice Program (GCPP) for the past decade, remains a special assistant to Alderson, but now is working out of FDA's San Diego office and focusing more attention on international clinical research policy and programs. A main project for Lepay has been to develop a final rule on FDA acceptance of data from foreign clinical trials, which is moving through the review process. Lepay is also involved with efforts to extend harmonized standards on good clinical practices (GCPs) beyond the United States, Europe, and Japan as a way to achieve common oversight approaches in the developing world. To this end, Lepay is working with the World Health Organization and conducting educational programs in Asia and South America on research ethics policies and practices.

Lepay also seeks to finish a number of FDA guidances and policies under development at FDA. In recent months, the agency has issued guidance documents on IRB registration, use of data monitoring committees, and dealing with falsification of information and exceptions from informed consent for emergency research. In addition to a final rule on foreign clinical data, Lepay is involved with updating policies to assure the integrity of clinical information in computerized data systems and on reporting adverse events to IRBs.

Meanwhile, Tollefson seeks to strengthen the GCCP operation. In addition to Lepay moving to the West Coast, his long-time deputy Stan Woollen retired from the agency. A new addition to the program is biophysicist Jean Toth-Allen, who comes from the Center for Devices and Radiological Health (CDRH) where she was involved with its BIMO program for devices. Patricia Block, Bonnie Lee, and Carolyn Hommel complete the GCPP staff.

GCCP's small size requires it to collaborate with other FDA science and policy offices. Lepay's work on international research issues involves him more directly with the Office of International Activities and Strategic Initiatives headed by FDA Deputy Commissioner Murray (Mac) Lumpkin. One growing component of Lumpkin's office is the Office of Pediatric Therapeutics, which recently added ethicist Robert (Skip) Nelson to its staff. Nelson is responsible for providing guidance and advice related to pediatric clinical trial conduct and design, as required by Congress; he replaces Sara Goldkind, who has become more involved in the Critical Path and BIMO initiatives.

Encouraging innovation

FDA's efforts to update clinical trial oversight and policies fit with its broader campaign to spur the development of more innovative treatments under its Critical Path Initiative. To this end, the Center for Drug Evaluation and Research (CDER) established a new Office of Translational Sciences (OTS) last May (2006) to coordinate CPI activities and other cross-cutting science initiatives. This new "super office" headed by Shirley Murphy provides a new home for important drug review activities: the Office of Clinical Pharmacology headed by Larry Lesko and the Office of Biostatistics under Robert O'Neill. These offices review data on applications while also playing a central role in encouraging the development of new biomarkers for clinical research and adaptive trial designs.

OTS provides a focal point for launching and tracking what FDA officials hope will be a growing number of Critical Path collaborative efforts. Agency leaders set the stage for moving forward in this area by unveiling the Critical Path Opportunities List last March, which outlines 76 projects that could speed the pace of turning biomedical discoveries into new therapies. Since then, FDA has announced several new consortia for developing predictive biomarkers plus efforts to develop new statistical approaches and designs for trials.

Focus on safety

The formation of OTS was part of a larger CDER reorganization to also address concerns about drug safety. CDER Director Steven Galson established the Office of Surveillance and Epidemiology (OSE) headed by Gerald Dal Pan, former director of CDER's Office of Drug Safety. OSE has three divisions for drug risk evaluation; surveillance, research, and communications support; and medication errors and technical support.

At the same time, Paul Seligman, who formerly directed this operation, moved up to head a new Safety Policy and Communication Staff directly under Galson. Seligman's office oversees FDA's Drug Safety Oversight Board and MedWatch program for reporting adverse events to the agency.

A related change was to shift the Division of Scientific Investigations (DSI) out of Bob Temple's Office of Medical Policy and back into its former slot in the Office of Compliance, now headed by Deborah Autor. Joseph Salewski has been acting director of DSI since the departure of Joanne Rhoades several months ago.

Push for disclosure

CDER efforts to address public concerns about drug safety reflect continued pressure on clinical research sponsors for more data transparency. Researchers, patient advocates, and policy makers are demanding broader disclosure of trial results, including failed studies. Patient and disease organizations also seek more timely and accurate trial listings, putting pressure on pharma companies to post more study information on clinicaltrials.gov.

A related campaign is to require pharma companies to complete promised postapproval studies. Industry's poor record in this area has generated considerable criticism, and new mandates for listing trials and disclosing results are being discussed as part of drug safety legislation slated for public consideration next year.

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