One basic assumption we must make in the new Culture of Drug Safety is that there will be continuing focus on drug risk and
hazards throughout a drug's marketing. The Culture of Safety raises many questions for pharmaceutical companies: What types
of studies and which risk-mitigation tools will be employed? What will be their direct impact on drug use and their indirect
impact on the general acceptance and use of medications? How do we provide sufficient information to regulators, prescribers,
and drug users about the benefits of our products so that a fair decision can be made on the marketing, prescribing, and usage
of our drugs? Generally, how do we steward our drugs in the dynamic but "hazard heavy" environment so that they can be used
Underlying all these questions is a sea change in how the risk/benefit ratio is perceived by key stakeholders. We've known
all along that the risk/benefit ratio is not fixed, that it can evolve through time. But now, the perception has shifted in
a very important way. Now, FDA's leadership is expressing the idea that risk/benefit is dynamic and fundamentally unknowable
premarketing. Here, for example, is how FDA's Deputy Commissioner and Chief Medical Officer Janet Woodcock expressed the idea
at a recent hearing:
"The premarket clinical trials that are done to get products onto the market can't identify all the potential risks, as we
know, or even the future changes in use patterns that are going to occur once that product gets out there," she said. "Therefore,
full knowledge of benefit/risk doesn't exist at the time of product approval, and often not at the time of treatment decision
making.... Therefore, timely and effective postmarket surveillance and risk communication—in other words, communication of
the evolving information as rapidly as possible—is critical to reduce the knowledge gap and foster better-informed treatment
decisions and actually keep people safe."
The emphasis in the new Culture of Drug Safety will be on reassessing and recalculating the risk/benefit ratio through the
life cycle of a drug. One area where we can look for innovations is in the way we generate new postmarketing safety signals.
FDA has already held hearings on creating a new "Sentinel Network"—a virtual, integrated, electronic nationwide medical-product-safety
network. It is highly likely that new systems will be developed based on computer review and data mining of very large databases—perhaps
100 million lives or more. It's also likely that new methods of collecting information from physicians will be sought, so
we aren't simply relying on the passive submission of adverse-event reporting forms.
As these systems develop, they will catch subtler safety signals and catch them much faster than today's adverse-event reporting
system. How much faster? At the FDA hearing on the Sentinel System, Richard Platt, a professor at Harvard Medical School and
principal investigator of the HMO Research Network, Centers for Education and Research on Therapeutics, said, using existing
databases, it would be possible to assemble a network of 100 million lives. With such a system, he predicted, the link between
Vioxx and heart attack would have been discovered in two or three months rather than 34.
Even if Platt is correct, is also likely that the focus on early detection will lower our threshold for signaling when an
observed increase in drug hazards is the sign of a serious adverse reaction. This can result in false positives and a loss
of credibility. "People reach different judgments on when to shout and when not to shout," said Robert Temple, medical director
at FDA. "It's the hardest single thing—the value and danger to screaming early."
The View from FDA