To do that, it is necessary to have extremely large databases of patients who have used the drug. Companies currently use databases for postmarketing cohort and case-control studies, and these will grow into even larger databases that can explore drug outcomes earlier and more efficiently. Look for FDA to work with other government entities such as the VA and Medicare to establish large databases, and expect companies to mirror such actions.

Certainly, early warning of safety signals for drugs on the market is an appropriate goal. Once we have a signal, we will need a safety study to determine whether the signal is real or an artifact. There is a clear evidence hierarchy in drug safety. If the signal is generated by spontaneous reports, a case-control study is needed. If it is generated by case-control studies, then a cohort study is needed. If it is generated by a prospective cohort study, then a randomized trial is needed. As in the case of Vioxx, if the signal is generated by an active-control trial, then a placebo-controlled trial is needed. As we have seen from Avandia, when the signal comes from a meta-analysis, it may require additional safety studies.

Risk Communications, the New Province of FDA

But with a string of new initiatives implemented over the last two years, FDA has stepped into the business of communicating safety information to the public. The agency has held hearings, issued a new draft guidance on risk communication, and created a new office of Drug Safety Policy and Communications. Look for a return of the long-defunct FDA Drug Bulletin, recast as a drug safety newsletter, and the creation of a Risk Communication Advisory Committee (RCAC), mandated by both IOM and Congress.

FDA has become more active at issuing alerts that inform physicians of new information that may change their prescribing. Over the past two years, FDA has issued these alerts on more than 140 drugs, from sleeping pills to antidepressants. Where once FDA would ask sponsors to perform a new safety study to quantify risk signals, the agency will now likely ask for the study—but simultaneously issue an alert.

FDA abides by the precautionary principle as the ethical basis for risk management, and it should. But there needs to be a method to inform the public about the uncertainty value of safety signals and how much confidence should be placed in risk-management messages. In general, more information and insight are needed to steer the healthcare industry through this new territory.

Certainly, the new Culture of Drug Safety demands that more drug information be posted on FDA's already rich—some call it dense—Web site. Already, approval packages providing FDA's risk/benefit analysis are available for some drugs. Based on stipulations proposed in both Congressional bills, these packages are likely to become more consistently available.

FDA and companies are placing an increased emphasis on a drug's label as a way to communicate with patients. In its initial proposal for the new drug-labeling format issued in December 2000, FDA suggested companies use an inverted black triangle to denote a newly approved product. (The agency later settled on listing the approval date.) The Senate bill calls for inclusion of the approval date, while the House bill requires the use of a unique symbol during the first two years of marketing. Other suggestions abound: IOM suggested the black triangle used in the United Kingdom to identify new drugs, singling them out for intense surveillance and greater reporting of observed adverse drug events.

Currently, drug companies and FDA negotiate the language of the label. But IOM and the Congressional bills would provide FDA with the authority to draft the label's language and require it to be updated, without negotiation. This is intended to give FDA more control over labeling and to avoid delays in implementing warnings. FDA, of course, already wields enormous influence over the language of the label and, as a result, the language of marketing materials. Thus the biggest change may be a matter of new expectations: The public will expect FDA to disseminate warnings rapidly. This will put pressure on companies and the agency to resolve differences as quickly as possible.