FDA piloting safety studies of NMEs, revamping AERS, based on IOM recommendations.

At a March 12 meeting of the Institute of Medicine--designed to follow up on FDA's implementation of the September 2006 landmark report, "The Future of Drug Safety: Promoting and Protecting the Health of the Public"--Center for Drugs officials said the agency is embarking on a pilot study of safety profiles of new molecular entities and is trying to revamp its Adverse Event Reporting System (AERS II).

One step the IOM recommended in the report was for FDA to bring in post-marketing safety experts during the approval process for new drugs--specifically to "assign joint authority to the Office of New Drugs and Office of Surveillance and Epidemiology for post-approval regulatory actions related to safety."

Ellis Unger, M.D., Acting Deputy Director for Science in the Office of Surveillance and Epidemiology, told the meeting at IOM headquarters in Washington that CDER is "evaluating the feasibility of involving OSE staff earlier in reviews." Such staff members are already included in trade name reviews and risk minimization plans, he noted. "CDER is evaluating models for more significant involvement of OSE in post-marketing decision making."

However, he noted problems with IOM's recommendation that CDER review teams should not only "regularly and systematically" analyze post-market study results but also "make public their assessment of the significance of the results with regard to the integration of risk and benefit information." Much of that information, Unger said, is "predecisional" and its release "could have adverse public health impacts." Decisions about disclosure of postmarketing safety assessments "have to be made on a case-by-case basis."

CDER Director Steven Galson, M.D., told the meeting that the Center has initiated a pilot program to assess safety profiles of newly approved products. The program involves review of adverse events, data mining analyses, epidemiological data, postmarketing clinical trial data and periodic safety update reports to identify safety concerns for selected new molecular entities 18 months after approval. The purpose of the pilot is to "evaluate whether such a look back can identify potential safety concerns early in the product lifecycle," he explained.

The need to better understand the factors that put some patients at higher risk of adverse events than others was emphasized by both Galson and FDA Deputy Commissioner Janet Woodcock. In discussing urgent research needs to help improve drug safety, Woodcock stated that many adverse events "result from individual sensitivity based on drug target status," and also noted "slow metabolizers are at risk for serious AEs." She noted that genetic tests becoming available to help identify patients at greater risk for adverse events, but that FDA needs outcome studies in populations and is exploring the creation of consortia to study drug metabolizing enzymes.

Galson reported that FDA is now collaborating on development of "a pharmacogenetic algorithm to help personalize dosing of warfarin," and also working on a project to determine "how such factors as age, gender and weight might influence patient response to warfarin."

But the need for new research goes beyond efforts to individualize therapy, Woodcock said. Other critical research areas include toxicological studies in such areas as nano-scale products and drugs used in pregnancy; predictive safety biomarkers and additional research on common drug toxicities such as hepatotoxicity; the abuse potential of drugs; and the root causes of medication error, from drug names that look and sound alike to confusion about various drug strengths.

Among IOM's key recommendations was that CDER conduct a systematic, scientific review of the existing AERS system to "improve the generation of new safety signals and hypotheses," noted Gerald Dal Pan, M.D., Director of CDER's Office of Surveillance and Epidemiology.

To that end, FDA is working to update AERS II to improve and expand its functionalities and allow more efficient use of the database. FDA recently sponsored a two-day workshop on the creation of a Sentinel Network, at which ideas for integrating public and private sector post-market safety monitoring systems were discussed. Also in response to IOM recommendations, CDER is working to expand its intramural and extramural programs by accessing additional databases, such as that of the Center for Medicare and Medicaid Services; hire additional epidemiologists and increase partnerships with other federal agencies.

The acquisition of more and better data from public and private sources is critical to the development of a 21st-century system for post-marketing drug safety, said Mark McClellan of the Brookings-AEI Joint Center for Regulatory Studies at Stanford University and former FDA Commissioner.

McClellan noted the present AERS system "is improving, but most adverse events are missed or not captured in a timely, consistent manner." To create a more effective safety system, he said, FDA needs "a better mechanism for pooling relevant data from private and public electronic databases on prescription use and outcome," such as those that exist in private health plans, Medicare and the Veteran's Administration health system. Public-private collaboration in analyzing data would further strengthen the system, he said, adding that "methods and results should be made available for public comment."

Galson agreed that "transparency in decision-making is critical" for the future of a credible postmarket safety monitoring system. He noted that FDA is "improving our use of advisory committees" and issuing new guidance documents to "improve Advisory Committee operations by making them more consistent, transparent and predictable."

In addition, risk communication was a key issue in the IOM report and at the conference. Galson reported that FDA is establishing "a new advisory committee on communication to obtain input to improve the agency's communication policies and practices." That committee will include "patients and consumers as well as experts in risk and crisis communication." Further, FDA this year will begin to regularly publish a web-based newsletter containing summaries of the results of FDA post-marketing reviews, information on emergency safety issues and on recently approved products "to inform providers and encourage reporting of adverse events to FDA."

Woodcock noted that research is also needed in the area of risk communication, including "effective ways to convey risks in drug ads and prescriber communications." It is critical, she said, to learn "how to communicate effectively to change prescriber behaviors."

In any efforts to improve post-market drug monitoring and drug safety, an overriding issue is "resources, resources, resources," McClellan said. "More resources and greater technical capabilities at FDA are essential to carry out IOM recommendations successfully," he said. "Additional regulatory authorities, organizational change and better information are not sufficient, and in fact, require more resources." FDA must provide more clarity about its resource needs, he added, noting that FDA "is spending a lot now on safety in the health care system--and will be spending more."

By Rebecca Mashaw

Managing Editor