W. NICHOLSON PRICE II
TRADITIONALLY, THE FDA process of regulating drugs—like that of other agencies around the world—has focused on evaluating the drug before permitting the drug to be marketed. This section reflects the growing recognition that the realities of modern drug development mean that a heavy focus on premarket approval is no longer sufficient. Premarket clinical trials are slow by the standards of bringing new drugs to market but relatively small and short term by the standards of fully evaluating long-term effects in large populations. Thus, they fail in opposite ways: the requirement of clinical trials creates delays and keeps patients from accessing the new drugs they see coming down the pipeline, but they also fail to prevent completely the occurrence of significant adverse effects that are either too rare or too slow to be observed in small and relatively short trials.
This section includes three chapters addressing the context, contours, and challenges of appropriately timing and managing the entry of drugs into the market. A central theme across all chapters is recognition that the current system is insufficient to address the problems mentioned above. If adverse events and effectiveness in diverse populations cannot be determined in premarket clinical trials, postmarket surveillance must supply this information. But current postmarket surveillance mechanisms, comprised of an alphabet soup of FDA programs, are inadequate: those applying to all drugs are weak, those applying to new drugs are only marginally less so, and all are poorly enforced. More and better postmarket surveillance is needed, especially in a lifestyle regime under which more drugs come to market faster.
Within this general theme of increased surveillance, one key distinction is how postmarket surveillance should impact the balance of regulation across a drug’s lifespan. Gibson and Lemmens express concerns that postmarket surveillance not result in a loosening of the standards for premarket approval. Charo, on the other hand, notes that this may be an inevitable trade-off, given pressure for faster drug development and the limitations of the current clinical-trial regime.
Differences also exist regarding implementation, particularly whether FDA already has the necessary tools to bring about a more effective postmarket surveillance regime. Parasidis provocatively suggests that the existence of off-label use could be enough to give FDA a statutory hook to mandate active surveillance. Charo, Gibson, and Lemmens suggest that more-direct legislative action may be required, especially to implement the possibility of phased or conditional approval.
This section grapples further with the incentive questions raised by postmarket surveillance. Mechanisms like phased or conditional approval challenge the current financial landscape for drugs, where the majority of profits are earned in the earlier part of a drug’s lifespan. Similarly, the entrenchment of a profitable status quo makes regulatory action threatening that status quo harder; withdrawing drugs once they have entered the market is much more difficult than preventing the same drug from entering the market in the first place.
Though it may not seem an obvious connection, all three chapters in this section note a connection between postmarket surveillance/regulation and the expanding limits placed on FDA’s regulatory authority by First Amendment free-speech jurisprudence. As discussed elsewhere in this volume, the Second Circuit held in United States v. Caronia that the FDA’s prosecution of a drug-company representative for promoting off-label uses of an approved drug violated the First Amendment. Such off-label prescription is itself legal, but FDA regulation of marketing regarding such off-label uses has been an important tool in limiting the impact of unapproved uses. This ruling—and reasoning like it—may make it difficult for FDA to integrate marketing restrictions into a program of postmarket surveillance.
Ironically, in a realm of greater postmarket surveillance, Caronia and its ilk may prove a mixed blessing for the drug industry. If FDA cannot impose marketing restrictions on the basis of a postsurveillance finding of ineffectiveness of adverse effects in a particular subpopulation or for a particular indication, it might need to resort to more drastic measures, such as withdrawing the drug from the market or requiring the institution of severe Risk Evaluation and Mitigation Strategies (REMS) to prevent certain uses entirely.
Several questions remain open about timing and postmarket surveillance, particularly regarding implementation. An advantage to the current systemic dichotomy between pre- and postmarket phases is its clarity; a drug is approved or not, and it has a specific set of label indications. The regulatory submission to seek drug approval is presented as a unified body of data to answer specific questions: safety and efficacy for specific populations and specific indications. FDA can then evaluate whether those questions have been adequately answered. As a larger volume of more equivocal and more granular information arises from postmarket surveillance, how should FDA address it? Should FDA generally seek to translate such information into direct action—label changes, new REMS, or drug withdrawals—or should it instead simply be passed on to consumers and doctors through new information portals?
If an information-sharing approach is preferred, how should that occur? Should raw reports from surveillance be made available, despite likely problems with data quality and the possibility of competitor gamesmanship? If the information is instead to be curated and collected before distribution, should FDA fill that role or should the drug sponsor? The sponsor has responsibility for the drug’s safety and the greatest expertise—but that is true under the current regime, which has clearly inadequate postmarket surveillance. As Parasidis notes, limitations on state tort suits may limit the already-insufficient incentives for collecting and responding to postmarket surveillance information. Are there regulatory or tort incentives available to encourage more active management by sponsors, or will any such incentive invariably pale beyond the financial gains of keeping drugs broadly available on the market?
Translating postmarket surveillance information into regulatory action requires answering similar issues. Must sponsors suggest regulatory actions and changes, or should FDA be charged with initiating such actions? And should third parties have the right—or the responsibility—to intervene (perhaps through the mechanism of Citizen Petitions), which would depend on access to detailed surveillance information?
All of these questions, of course, are complicated by the presence of generic drugs. When issues of quality control may differ among manufacturers, how should surveillance information be segregated? Should generic companies have the same surveillance obligations as brand-name drug sponsors, or should their responsibilities be tempered by the different treatment of generic firms under federal preemption doctrine?
Even given broad acceptance that much greater postmarket surveillance is needed, these questions require answers. At the extremes, the proper response may be relatively clear: the Vioxx scandal clearly called for regulatory action, and individual reports of minor side effects would almost as clearly not require action. But there is a vast area in between, and how FDA reacts to those in-between cases will powerfully impact the landscape of drug regulation going forward.
Overall, postmarket surveillance promises to fill some of the problematic information gaps that result from the current evolving system of drug approval. But as the shortcomings of the optimistically implemented current surveillance mechanisms demonstrate, implementation of surveillance is difficult. Even assuming that information is accurately collected and analyzed, knowing what to do with that information presents its own set of significant challenges.
