FDA proposes changes to ensure drug safety

The Institute of Medicine (IOM) issued a report in September 2006 urging FDA to make major changes to better balance the agency's assessment of the risks and benefits of new drugs. FDA commissioner Andrew von Eschenbach, MD, has responded with a report that details the agency's plans to improve procedures for detecting and assessing drug safety problems. "The Future of Drug Safety" describes proposals for developing safety "report cards" on new drugs to better inform prescribers and patients about new safety concerns and to more quickly detect drug safety signals.

The report focuses on changes that FDA could implement on its own and does not address IOM proposals that would require congressional action, such as allowing public access to the results of clinical trials or granting FDA the authority to levy fines on pharmaceutical marketers that fail to complete promised postapproval studies; nor does it address the IOM's recommendations for special warning symbols on high-risk products or limits on direct-to-consumer advertising of newly approved drugs.

In the meantime, legislators have continued to propose FDA organizational and policy changes to improve drug safety. Sen Charles Grassley (R–Iowa) and Sen Christopher Dodd (D–Conn) support a bill that would establish a separate FDA drug safety office. Sen Michael Enzi (R– Wyo) and Sen Edward Kennedy (D–Mass) have introduced a bill that would require risk-mitigation strategies for all new drugs and that would mandate clinical trial registration.

MORE DISCLOSURE

The FDA plan includes improvements to its methods of assessing and communicating risk information, including the development of an online newsletter for patients and prescribers. The newsletter would include information from postapproval studies and adverse event reports, including postmarketing drug reviews, new safety data, and information on newly approved products. A related initiative would assess the effectiveness of Risk Management Plans (RiskMAPs); FDA would review 1 or 2 RiskMAPs per year to evaluate whether the programs improve public awareness of serious safety issues.

FDA has launched a pilot program to test the merit of re-evaluating newly approved drugs after they have been on the market for 1 year. The agency will review adverse event reports and additional information for 2 or 3 new molecular entities (NMEs); the first assessments will be completed in approximately 18 months and will be made public. The pilot program could be extended to all new drugs if it succeeds in providing a more complete picture of safety issues throughout the product life cycle.

REDUCING CONFLICTS

The role of advisory committees in assessing drug safety information was questioned after rofecoxib was recalled, as consumer advocates criticized panel members for their close ties to pharmaceutical companies. In response, FDA plans to develop a protocol to handle advisors' conflicts of interest, to present postmarketing safety issues to advisory committees, and to include additional pharmacoepidemiology experts in advisory committee meetings that address safety issues. FDA also plans to create a new advisory committee on communication to gain more outside expertise on conveying risk and crisis information. Although these actions may not satisfy those who would like to rid the committees of all experts with industry ties, FDA officials say they hope these more clear-cut procedures will address most of the concerns.

A central issue raised by the IOM is the need for adequate evaluation of the risks and benefits of new drugs by the Center for Drug Evaluation and Research (CDER). CDER director Steven Galson, MD, MPH, has planned organizational changes that would give CDER's Office of Surveillance and Epidemiology (OSE) staff a clear role in the approval of NDAs and in requesting postmarket studies and future label changes. Each new drug review office would have a high-level safety manager and a new electronic tracking system to integrate multiple agency databases.

FDA also seeks to tap electronic health information systems for more information on drug utilization and health outcomes. The agency is collaborating with the Veterans Administration, Medicare, and other government agencies to access data on medical product use in federal healthcare systems. A proposed FDA Sentinel Network would link private and public databases to establish a national medical product safety network.

STRESS ON SCIENCE

An underlying theme of FDA's drug safety program is that new developments in biomedical science can help researchers detect risk issues earlier in drug development. FDA deputy commissioner and chief medical officer Janet Woodcock, MD, heads up a number of programs to accelerate risk assessment by sponsors and FDA, many of which are part of the Critical Path Initiative, an effort by FDA to modernize the development process of drugs, biological products, and medical devices.

FDA's Critical Path Opportunities List was issued in March 2006 and updated in a January 2007 report on collaborations and research activities initiated in 2006.

The aim of this program is to "build safety into products" by better understanding the genetic basis of adverse events, Dr Woodcock said.

FDA is collaborating with the pharmaceutical industry and academia to develop new tests for organ toxicity and to identify cardiovascular risks associated with drugs. The Predictive Safety Consortium, composed of 5 major pharmaceutical companies and the Critical Path Institute and overseen by FDA, is sharing data to cross-validate preclinical safety biomarkers. Another consortium of manufacturers, FDA, and the NIH plans to assess biomarkers that can spark development of new treatments, beginning with therapies for lung cancer and lymphoma.

Dr Woodcock said these approaches can screen out toxic compounds early in the process and can identify patients most likely to experience adverse events or to respond well to an investigational medication. FDA, she said, wants to "make products safer from the get-go."

FEES FOR SAFETY

All of these initiatives would gain needed support from the PDUFA IV proposal unveiled by FDA in January, and 8 are dependent on its passage. Pharmaceutical and biotechnology companies and the Academy of Managed Care Pharmacy (AMCP) support PDUFA IV, which, through the collection of annual fees, would generate nearly $400 million to fund FDA review and oversight of new drugs.

The PDUFA proposal would allocate approximately $30 million to drug safety oversight and assessment throughout a product's life cycle, instead of only during the first 2 to 3 years a drug is on the market. The increased payments would help expand FDA's safety review staff and capabilities for adverse event analysis.

The PDUFA plan would also provide an additional $4 million per year to establish a completely automated application submission and review system for NDAs, with 2-way communication capability and improved tracking systems. Another $4 million would support Critical Path efforts, including FDA participation in research collaborations.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.