A Pathway to Improved Prospective Observational Post-Authorization Safety Studies

Abstract

Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy of drugs but not necessarily so for drug safety where inadequate power to detect either multiple or rare adverse events is a major handicap. Furthermore, the conditions under which drugs are approved for market use are often different from the settings in actual use. Indeed, with their control mechanisms, trials are by design largely inadequate for the identification of potential safety signals, especially of the rare type, hence the value of postmarketing surveillance and risk management plan-based activities. Today, clinical trials constitute only a part of the research that goes into assessing the safety of drugs. Observational studies, where the investigators merely collect data on treatments received by patients and their health status in routine clinical practice are increasing in uptake because they reflect the real-life utility of drugs, despite the absence of random treatment assignment. Although such studies generally provide less compelling evidence than RCTs, they can be far more useful to drug safety assessment activities than generally acknowledged. An increasing number of post-authorization safety studies (PASS) within the European Medicines Agency's jurisdiction are of the observational type - considered perhaps as more appropriate vehicles for exploring and documenting how products perform in the real world. A similar trend is emerging in the US following the FDA Amendments Act of 2007; since early 2010, an increasing number of post-approval commitments mandated by the FDA include observational studies. However, despite this pattern, not much is known about ongoing efforts to address many of the recognized inadequacies associated with existing methodologies and practices currently adopted in observational PASS. This current opinion presents an overview of some of the main challenges we face in prospective observational PASS, mainly from practical experience, and proposes certain steps for improvement.

Infants fed formula with added long chain polyunsaturated fatty acids have reduced incidence of respiratory illnesses and diarrhea during the first year of life

“…Thus, the pediatrician could have inadvertently introduced a recruitment bias to the current study. However, as it has been previously suggested [29], prospective, observational studies, despite inherent limitations (absence of randomization, unintentional bias, etc. ), can provide an important picture of the “real-world” utility of a study product (in this case, infant formula with added DHA/ARA).…”

Programming challenges of sampling controls to cases from the dynamic risk sets in nested case–control studies

“…[8][9][10][11] The problem of time-varying treatment arguably provides the main rationale for the popularity of the nested case-control design in safety studies and today, most published pharmacoepidemiological safety studies are based on the design despite the known problems of bias associated with the design. [11][12] To minimize the potential effects of confounding factors-the main source of bias-we match cases to controls on at least, the most important confounding covariates in preference over modeling their effects. This is a process that involves sampling of potential controls and although there are many sampling approaches, that of incidence density sampling is widely recognized as the best.…”

Exposure Misclassification in Observational Studies: We Can Do Better

“…similar error in both patients with and without the event) which can lead to bias towards the null. In other words, we may end up with exposure effect estimates suggesting little or no association when in fact an association exists [6][7][8][9][10]. the cohort and the classical nested case control designs and even more so if an appropriate group balancing instrument can also be incorporated.…”