Eric M. Meslin

A Lifecycle Approach to the Evaluation of FDA Approval Methods and Regulatory Actions: Opportunities Provided by a New IOM Report

IN THE POSTMARKET SETTING,THE REGULATION OF MEDICINES requires an assessment of the balance between their benefits and risks and, as new information becomes available, may require regulatory actions that range from changes in the product label to withdrawal of a drug from the market. A series of unforeseen consequences of drug administration to vulnerablepatientshas shaped themodernhistoryof the regulation of medications. In the 1960s, for instance, thalidomide given to pregnant women resulted in birth defects or death in several thousand of their offspring. The framework for modern drug regulation largely emerged from the development of various measures to prevent similar drug-safety disasters. A series of highly publicized drug withdrawals, including rofecoxib (Vioxx) in 2004, prompted recent action. In 2005, the European Commission required companies to submit plans about how they would assess and manage the risks of new drugs submitted for licensing. Other countries including Canada and Australia also took similar actions. In 2006 the US Food and Drug Administration (FDA) invited the Institute of Medicine (IOM) to review the system of drug-safety assessment in the United States. The centerpiece of the 2007 IOM report was the recommendation that the FDA should monitor and evaluate the benefits and risks of drug therapies not only prior to their approval but throughout their entire market life. This so-called lifecycle approach involves the pursuit and active management of emerging knowledge about the benefit-risk balance as drugs become more widely used by larger numbers of increasingly diverse patients. The FDA Amendments Act (Pub L No. 110-85) of 2007 provided the agency with new resources to evaluate drug-safety issues and with new authorities to require studies in the postmarket setting. Between 2007 and 2010, the FDA used its new authorities to mandate 290 studies of drug safety, about a third of which were randomized trials. The FDA Amendments Act also called for the introduction of a new active surveillance system, the Sentinel Initiative, which, when implemented, will provide timely information about drug safety. The FDA now assembles and releases quarterly summaries of potential signals of serious safety risks identified by spontaneous reports. In the United States, improvements in the Adverse Event Reporting System (AERS), a passive surveillance system that uses spontaneous reports of drug safety, produced 153 early but uncertain warnings in the FDA summary reports between 2008 and 2010; 74 of the 153 early warnings (48%) led to changes to product labels, most commonly to sections on warnings and precautions. For example, the warnings section for adalimumab was updated to include optic neuritis in December 2011. In some instances, postmarket safety issues may not become apparent until several years after approval. In 1999, for instance, marketing authorization was granted both in the United States and Europe for rosiglitazone (Avandia) and pioglitazone (Actos) for the treatment of type 2 diabetes, a condition that substantially increases the risk of cardiovascular disease. The basis of regulatory approval for both these drugs was the beneficial effects seen on blood glucose levels and glycated hemoglobin levels, which, as surrogate markers, were assumed to predict clinical and cardiovascular benefit. In 2004, a World Health Organization report raised questions about an association of these agents with cardiac disease, and in 2007, new evidence of an increase in cardiovascular events associated with rosiglitazone became apparent. This experience stimulated new requirements for sponsors of drugs used to treat type 2 diabetes. The revised FDA guidance requiresmanufacturers toassess cardiovascular events in all phase 2 and phase 3 clinical trials and to submit these to meta-analysis. The upper 95% confidence level of the association with cardiovascular disease risk is considered in the regulatory decisions about drug approval and postmarketing requirements for additional trials. Although the current acceptable upper 95% confidence level for cardiovascular risk may require future revisions, the new guidance advanced approval methods; and the requirement for a preplanned metaanalysis of data from preapproval trials may spread to other drug classes such as antiobesity agents. Concerns about the cardiovascular risks of rosiglitazone served in part as the impetus for a new IOM report on the ethi-

The Moral Costs of the Ontario Physicians' Strike

In a strike to permit extra billing, physicians in Ontario, Canada, sought to balance their concerns for professional autonomy with their primary call to beneficence. But the right to reasonable compensation within a nationalized health care system is not on the same moral plane as the publics right to health care. Having failed to convince either the provincial government or the public of the soundness of their position, Ontarios doctors must now repair the damage done to the relationship with their patients.

REVIEWS: Adding to the Canon The Final Report

Book reviewed in this article: Final Report: White House Advisory Committee on Human Radiation Experiments, (061-000-00-848-9).

When Policy Analysis Is Carried Out in Public

Policy discussions involving bioethical topics most often cap ture the attention of the public, health professionals, and elected officials when the topics are controversial and do not readily give rise to clear-cut solutions. Much has been written about the role of ethics, ethical principles, and ethical theory in the formation of public policy, and especially policy involving bioethical subjects such as end-of-life care, allocation of high technology resources in hospitals, reproductive decision making, cloning, and stem cell research. Those familiar with the bioethics literature will recognize two broad types of discussions. The first are discussions that tend to illuminate and resolve particular conceptual problems, such as the appropriate definition of terms: moral rights, capacity to consent, or just allocation of resources. The second type of discussion focuses on specific prescriptive tasks: regulations or guidelines for the protection of human subjects in federallz sponsored research; legislation to enhance access to health care; or plans to allocate organs for transplantation.

Protection for human subjects in medical research.

Menstrual difficulties post TBI may be a sign of neuroendocrine irregularities which may affect other health issues such as cognition and mood. However, these relationships need to be studied further. In the study we conducted, we did not collect information, for example, on hormonal changes or on stress. We are only speculating at this point. We know that TBI is one of the etiologies for hypopituitarism found in up to 59% of patients several months, and even years, post TBI. We also know that low levels of sex hormones associated with hypopituitarism can cause amenorrhea and other menstrual disorders. Unfortunately though, screening for this after TBI is not typically done so this area is relatively under-diagnosed. We are leading an international taskforce on girls and women with TBI to study this area further. Please view our study for more information: Colantonio, et al. (2010). Women’s health outcomes after traumatic brain injury. Journal of Women’s Health, 19(6), 1109-1116.