Gerald A. Faich

The future of automated record linkage for postmarketing surveillance: A response to shapiro

Clinical Pharmacology and Therapeutics (1989) 46, 387–389; doi:10.1038/clpt.1989.155

Record linkage for postmarketing surveillance

Clinical Pharmacology and Therapeutics (1989) 46, 479–480; doi:10.1038/clpt.1989.169

A method of pharmacoepidemiologic analysis that uses computerized Medicaid

A method of pharmacoepidemiologic data analysis that utilizes computerized Medicaid data is presented. A cohort design in which Medicaid enrollees receiving drugs that are normally used to treat similar underlying conditions is described. A period of time in which Medicaid service transactions are evident is required before an individual is eligible for selection into a cohort. Selection of study subjects and descriptions of cohorts are based on Medicaid service histories occurring during the preliminary, prerequisite period. Time at risk is considered to begin after a prescription for a study drug is dispensed and continues until either a refill is dispensed, a prescription for an alternative drug within the same therapeutic class is dispensed, or a predetermined number of days has passed. Subjects are followed forward in time and relevant health care transactions that are suggestive of suspected adverse drug reactions are noted. Incidence densities associated with sequentially ranked prescriptions within sequential courses of therapy are compared. Methods to increase the accuracy of case ascertainment are briefly discussed. Separate validation studies may be used to evaluate the validity of computerized case ascertainment methods and to compensate for misclassification of outcome. The proposed method is intended to provide timely estimates of risk for selected outcomes. For outcomes that cannot be accurately ascertained from computerized data, this method may be useful in determining the feasibility of more customized studies.

Adverse Reaction Signaling and Disproportionality Analysis: An Update

There is an increased focus on signal detection, signal management, and the use of use of large collections of adverse event databases to meet the evolving regulatory mandates. The basic elements of signaling require an understanding of the different signaling methods, data mining approaches, and the strengths and limitations of disproportionality analysis. The application of signaling thresholds and the resulting statistical interpretation require an understanding of the methods themselves, as well as the strengths, limitations, and biases inherent in the adverse event data sources. This paper will highlight recent developments in these areas as well as provide cautions related to biases that affect reporting and analyses of adverse event databases.

International Drug Surveillance

Preapproval studies cannot tell us all that must be known about the safety of a drug. For this reason, post-marketing surveillance (PMS) is a crucial activity. Monitoring of adverse drug reaction reports for developing signals and conducting epidemiologic studies to test such signals are the two main activities encompassed by PMS. The FDA is giving high priority to both of these activities and is seeking to strengthen international communications in this area.

Phase IIIB and Treatment IND Safety Reporting

There are important and unique aspects of safety surveillance and reporting for Phase IIIB and treatment investigational new drug (IND) studies. These studies typically involve large numbers of heterogenous patients and thus are likely to result in new safety information. For Phase IIIB studies in the United States, three-day, 10-day, annual, and safety update reporting are required. Treatment INDs may be done with modified safety reporting requirements if the Food and Drug Administration (FDA) grants appropriate waivers. For both types of studies, a real-time, structured process must be maintained to rapidly collect and analyze serious adverse events. Demand for safety updates can arise precipitously and require extraordinary efforts to survey study sites and complete data collection. Studies of rifabutin and nabumetone described in this article exemplify these needs.

Postmarketing Surveillance: Lessons Learned

From 1983 to 1990 a number of lessons about postmarketing surveillance (PMS) were learned at FDA. Adverse drug reaction (ADR) reporting, regulations, processing and outputs changed during this period. While improved, reporting needs to be further stimulated and processing of reports must keep abreast of the inflow. Investigation of ADR signals requires a careful methodical approach. Pharmacoepidemiology must be seen, in addition to ADR monitoring, as the second critical element of PMS. Epidemiologically-based periapproval studies, use of linked databases and the conduct of cohort studies will become more prominent if regulatory and industry resource commitments are made.

Review of Drug Safety Data: How to Analyze, Summarize, and Interpret to Determine Risk

Correspondence Address Gerald Faich. UBC, 920 Hawest. Blue Bell. PA 19422. DRUG SAFE7Y DATA: HOW TO ANALYZE, SUMMARIZE, AND INTERPRET TO DETERMZNE RISK by Michael Klepper and Barton Cobert. Sudbury, MA: Jones & Bartlett Learning; 2010. The collection, processing, analysis, and submission of adverse drug events is a complex process that is crucial to pharmaceutical approval and use. Since most drugs are taken as treatments for illnesses that manifest adverse events as part of their natural history (cough followed by pneumonia; viral infections and rash), sorting out whether an observed event is due to the treatment or the illness is challenging. Equally important is the context of observation and reporting, for example. a trial setting or clinical practice. In trials events are typically collected in a relatively complete manner regardless of attribution, while in clinical practice after marketing, events are underreported and attribution is assumed. Consequently, defining the incidence of events can also be difficult. The era of modern comparative clinical trials for efficacy began in the United States with amendments to the FDC Act in 1962. Requirements for dealing with adverse events and clinical safety information came later; beginning in the late 1970s. regulatory authorities began to codify and structure adverse drug event surveillance. Prior to this the process was haphazard, inefficient, and tardy-witness the thalidomide disaster. In the mid-l980s, the format and content for safety reporting events was clarified with the rewriting of New Drug Application and Investigational New Drug Application regulations and guidelines to define seriousness, reporting submission dates (eg, 15 days), and unexpectedness. Subsequently, much work was done on coding of event terms to allow for grouping reports and dealing with verbatim language. Throughout this period and continuing in the present, the management and analysis of safety information for regulatory purposes, including preparation of package inserts, has evolved. Additionally, there has been heightened interest in risk management and pharmacovigilance since the Vioxx brouhaha of 2004. International harmonization, requirements for periodic reporting, and intensified postmarketing surveillance have increased regulatory complexity and make processes for dealing with clinical safety information in the aggregate an imperative. Unfortunately, large volumes of adverse event reports and the difficulty of meeting complex regulatory requirements have, at times, obscured the very purpose of collection and analysis of safety information. Thus, the availability of Klepper and Coberts practical, pragmatic, and thorough book, Drug Safety Data, is most welcome. It provides a comprehensive, succinct, and clear presentation of crucial safety topics. Further, it serves as a workbook and training manual for applied pharmacovigilance and regulatory issues related to