System reset in 2008
Years of negative publicity over adverse effects of drugs and unrelenting political pressure to minimize risks have reshaped the American regulatory environment, effectively creating new requirements for approval that sponsors and investors ignore at their peril.
Legal criteria for approvals haven't changed, but the FDA Amendments Act of 2007 (FDAAA) and energetic congressional oversight over the last four years have reset the regulatory mechanism.
FDA and its overseers in Congress are adopting new benchmarks and priorities. The agency is imposing stricter standards for demonstrating safety and efficacy - in some cases raising the bar after companies have invested in development programs predicated on less stringent requirements.
Lawmakers have made it clear they expect FDA to apply laws and regulations in ways that minimize the incidence of negative surprises. Regulatory risk-aversion is making certain kinds of drug development more risky, creating expectations for different kinds of data, and rendering all efforts to bring new therapies to patients more expensive.
Going forward, drug developers will have to demonstrate safety in the context of a much lower threshold for risk, in an era of increased transparency, and in an environment where the absence of robust evidence of safety is treated as evidence of hazard.
More than ever, regulators are asking not whether a drug is better than placebo, but if it provides a large enough benefit over existing therapies to justify known or hypothetical risks.
The law requires FDA to approve drugs that are safe and effective, and Congress has specifically ruled out comparative efficacy requirements. But the agency is nonetheless imposing superiority requirements to meet benefit-risk requirements. It is becoming increasingly reluctant to approve drugs that may pose safety risks - a characteristic of virtually all drugs - unless they address an unmet medical need.
The questions are going beyond specific drugs to implicit challenges to merits of developing any drugs for certain conditions such as self-limiting infections, acute atrial fibrillation, or insomnia.
While some former regulators argue the new paradigm ultimately will reward true innovation, for the foreseeable future drug developers will be living in an unpredictable landscape that prior FDA reform efforts had aimed to eradicate.
The contours of the new regulatory environment are still being shaped and will become clearer as FDA makes landmark approval decisions in 2008 and begins to implement FDAAA's mandates for new pre- and post-market authorities.
Swing of the pendulum
FDAAA is Congress' third attempt to reset the regulatory system in the era of modern drug development. As with previous reform efforts, it followed a period of intense congressional oversight and media attention that set some changes in motion before legislation was enacted.
Frustration with the U.S. system for reviewing drugs reached the boiling point in the early 1990s as AIDS activists reinvented the formerly genteel art of advocating changes in the methods and pace of evaluating new medical products, transforming the process into a form of guerrilla theater. As advocates for other