Clinical Research Faces Scrutiny in Year Ahead

Democrats are back on top in Congress and are mapping out a broad agenda that puts drug pricing and access high on the priority list. The biomedical research community is optimistic that the new leadership will boost support for embryonic stem cell research and other scientific undertakings. At the same time, pharmaceutical R&D could be stymied by demands for more intense oversight of clinical research, broader disclosure of research programs, and challenges to new research approaches.

Jill Wechsler

The bottom line for sponsors and researchers will be more and larger clinical trials. Regulators want more data to document drug efficacy and safety; payers seek more comparative analysis to support premium prices for new products; and all parties demand more postapproval studies to address safety issues in real-world patients. Clinical trial registration and results disclosure will be championed as ways to protect trial participants and patients, but may make research programs more cumbersome and costly.

Scrutinizing clinical studies

Legislators and regulators are examining a host of research activities and issues under the umbrella of assuring patient safety, while a number of government watchdog agencies are pursuing a range of investigations. Some of the hot topics include:

"Shortcut" study designs. Members of Congress have attacked the Food and Drug Administration's approval of sanofi-aventis' antibiotic Ketek (telithromycin) based on data from non-inferiority trials. This has led to a broader scrutiny of whether innovative study designs may harm trial participants as well as subsequent patients. Sen. Charles Grassley (R-Iowa), who has been highly critical of many FDA activities as chairman of the Senate Finance Committee, blocked confirmation of Acting Commissioner Andrew von Eschenbach for several months to pressure FDA to respond to questions related to his probe of Ketek. The new Finance panel leader, Max Baucus (D-Mont), has supported Grassley's concerns, and the Government Accountability Office (GAO) is investigating these issues.

Emergency research. FDA is reassessing its 10-year-old policy that permits research on patients without informed consent under certain pre-specified emergency situations. FDA held a meeting in October to discuss possible revisions in a new draft guidance to assist investigators, sponsors, and institutional review boards (IRBs) in developing and conducting such research protocols.

Clinical trial inspections. The HHS Office of the Inspector General (OIG) is examining FDA's clinical trial inspection process as part of ongoing scrutiny of IRBs, study recruitment practices, and the integrity of research data. Similarly, FDA's Office for Good Clinical Practice is revising guidance on inspection of clinical investigators.

Investigator practices. A rising number of investigator disqualifications is prompting FDA to develop guidance on its enforcement procedures. Separately, the OIG is assessing whether sponsors and the FDA adequately monitor financial interest disclosures of investigators.

Clinical trial listings. Industry's poor record for posting information on new trials on the clinicaltrials.gov Web site has prompted legislative proposals to mandate such listings. Along these lines, the OIG is investigating how well sponsors submit trial protocol information to the Web site, the completeness of registration information, barriers that might prevent full listings, and government monitoring capability.

IRB operations. FDA is working with other government agencies and professional organizations to encourage wider use of central IRBs and more streamlined review of adverse events. These efforts are addressing IRB concerns over liability and resources to build support for innovative approaches to research oversight.

Postmarketing study completion. A prime target for Congress and federal investigators is industry's low rate for fulfilling postapproval study commitments. The OIG issued a report last July calling for FDA to develop better systems for tracking the status of postmarketing study commitments and for assessing adequacy of resulting reports. Several bills before Congress would authorize FDA to levy fines on firms that fail to meet report deadlines.

Disclosure of research results. It's no longer a question of whether to disclose research results, but the scope and timing of such data disclosure. Key issues are whether disclosure applies to all early trials vs. Phase III and IV; covers proprietary information such as trial enrollment and endpoints; and how long sponsors can delay disclosure in order to publish results first in peer-review journals.

Push for PDUFA

While it will be a challenge to respond to Congressional probes and to oppose damaging legislative proposals, the larger task for the pharmaceutical industry is to gain Congressional reauthorization of the Prescription Drug User Fee Act (PDUFA) before the program expires Sept. 30, 2007 [see sidebar: New Faces in Charge]. A PDUFA bill also would renew user fees for medical devices and continue the pediatric drug exclusivity program, which has greatly expanded the volume and scope of clinical trials involving children.

New Faces in Charge on Capitol Hill

With Democrats and Republicans unlikely to agree much on health care legislation, both sides will eye any PDUFA bill as a ready vehicle for enacting broader measures on drug safety, generic drug access, and drug importing. There may even be a move to give FDA the authority to regulate tobacco.

Members of Congress have proposed drug safety legislation that changes FDA pre- and postapproval assessment of safety issues. These measures levy penalties on firms that fail to register clinical trials to disclose results appropriately and to adequately report adverse events. One proposal would expand the scope of risk management plans for new drugs with potential safety concerns, while others want to establish new FDA offices to monitor drug safety.

Another goal of many Congressional leaders is to speed more new generic drugs to market. The current debate centers on whether to give FDA specific authority to approve generic versions of biotech therapies, an admittedly more complex task that could require more clinical testing of candidate products.

"All these issues will be in play," acknowledges Jim Greenwood, president of the Biotechnology Industry Organization (BIO) and formerly a leading Republican on the House Energy & Commerce Committee. Industry's task is to identify a working majority in the House and Senate that can "deal with these issues responsibly," he says; with PDUFA, "we can't play veto games."

FDA and industry leaders have been discussing user fee issues and options for several months. As with the last three re-authorizations, the agency aims to present an agreed-on user fee plan to Congress early this year. This will include proposed fees, timelines for application processing, and the range of FDA activities that fees will support.

The new five-year agreement is expected to boost user fees by one-third to reach about $400 million, bringing the cost of filing a new drug application well over the $1 million mark. Added fees will support more timely review of pharma company advertising and marketing materials and also significantly expand FDA drug safety oversight activities.

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