Role of postmarketing surveillance in contemporary medicine.

Contemporary medicine is a large and complex system involving many participants, all of whom play a critical role in managing the risks intrinsic to medical product use. Despite the robust premarket review and approval process of the U.S. Food and Drug Administration (FDA), new information will inevitably be learned in the postmarketing period about the safety of medicines and how they are and should be used. For much of this information, FDA relies on public reports about possible adverse events. In turn, the public depends on FDA to communicate the most up-to-date safety information on medical products to better inform treatment decisions. Expanding the scope and strengthening the capabilities of the drug safety surveillance system are among key FDA projects designed to reduce avoidable injury and death from medication use. Although improving drug safety is our goal and obligation to the public, FDA cannot protect the public adequately without the active involvement of all participants in healthcare.

Challenges, successes and hopes in the development of novel TB therapeutics.

Despite efficacious drugs for treatment, TB continues to affect enormous numbers of patients throughout the world. Failure to control TB may be related to the biological characteristics of Mycobacterium tuberculosis, the nature of susceptible hosts often impoverished and poorly supported by healthcare infrastructure and the complex treatment regimens that must be used. Challenges to anti-TB drug development include the organism's slow replication, the ability of M. tuberculosis to survive in a dormant state and to persist despite therapy, its impregnable cell wall and its capacity to develop resistance to drugs. The need for extended therapy using combinations of drugs remains a practical obstacle to effective control in poor, malnourished and diseased communities most susceptible to TB. High-throughput screening of candidate agents and investigation of drugs already in use for other infections are yielding promising new candidates for TB treatment. New families of drugs entering clinical trials include 5-nitroimidazoles, diarylquinolines and ethylene diamines. Increasing funding initiatives, advances in the biology of TB and strategies for drug discovery have rejuvenated the pipeline of new drugs for TB, promising an expanding armamentarium of effective drugs with improved tolerability and potential to treat drug-resistant cases.

Developing new drugs for the treatment of drug-resistant tuberculosis: a regulatory perspective.

Simplifying and shortening treatment for drug-sensitive tuberculosis and providing new treatment options for drug-resistant tuberculosis constitute two principal goals in the development of novel drugs for tuberculosis. Demonstration of clinical efficacy in drug-sensitive tuberculosis is challenging, given high success rates for existing regimens, concerns about substituting an investigational agent for the most effective agents in a regimen and difficulties in determining the effect size of the components of a combination regimen. Large and prolonged studies would be needed either to show superiority over existing regimens or statistically defensible non-inferiority compared to existing regimens. In contrast, exploring efficacy of novel treatments in the setting of drug-resistant disease may present certain opportunities. In drug-resistant disease, the efficacy of existing regimens is comparatively poor, and companion drugs used to treat drug-resistant disease are weak or ineffective, enabling demonstration of the effect of the new drug. Other advantages of this approach, which has been used successfully in the development of antiretroviral agents, include the possibility of demonstrating drug efficacy using smaller studies, the possibility of accelerated approval based on a surrogate endpoint and the opportunity to address an urgent public health need. Experience with the activity and the safety of new agents in drug-resistant disease may provide a platform from which their indication can be broadened to include drug-sensitive disease.