New approaches to postmarketing surveillance

As part of a large-scale ongoing project exploring new pharmacy-based methods of postmarketing surveillance, we are comparing a patient-initiated monitoring system to a staff-initiated approach. Here we report data only from staff-initiated, computer-directed telephone interviews with 231 outpatients approximately 2 weeks after they had been prescribed a target drug chosen from two markedly different pharmacological classes for which adverse drug reactions (ADRs) are well-documented. Our results indicate that spontaneous patient reports of new or unusual symptoms obtained from a standardized staff-initiated telephone interview can be quite reliable, leading to accurate detection of known tricyclic antidepressant and antibiotic ADRs.     

Assessing risk in postmarketing surveillance

We need to find some way to assess the probability of risk for individuals taking medications for a prolonged period of time either singly or, as is usually more likely, in combinations. It is not possible to perform detailed, controlled studies for all combinations of drugs, not even those most commonly administered. Therefore, we must rely primarily on data from various case studies of attending physicians. Since this data is not collected in a controlled setting, we require a statistical technique that can do the following: be modified to handle data sequentially as information continues to accumulate, bevery robust for dependent data, make minimal assumptions concerning the underlying distribution of the data, and be used for multivariate data. A statistical technique—nonparametric density estimation—is available that will satisfy all of the above requirements. We will demonstrate its use in postmarketing surveillance.     

Assessing risk in postmarketing surveillance.

We need to find some way to assess the probability of risk for individuals taking medications for a prolonged period of time either singly or, as is usually more likely, in combinations. It is not possible to perform detailed, controlled studies for all combinations of drugs, not even those most commonly administered. Therefore, we must rely primarily on data from various case studies of attending physicians. Since this data is not collected in a controlled setting, we require a statistical technique that can do the following: be modified to handle data sequentially as information continues to accumulate, be very robust for dependent data, make minimal assumptions concerning the underlying distribution of the data, and be used for multivariate data. A statistical technique--nonparametric density estimation--is available that will satisfy all of the above requirements. We will demonstrate its use in postmarketing surveillance.     

European postmarketing surveillance of ramipril in hypertension

A prospective observational cohort study of the angiotensin inhibitor, ramipril, was undertaken in four countries within the European Community-Netherlands, United Kingdom, Germany and Belgium. A total of 10,377 consecutive patients with essential hypertension were recruited to the study with the aim of follow-up for one year. Overall 37% of doctors who agreed to participate in the study actually enrolled at least one patient. One third of the doctors who enrolled patients in the study entered two thirds of patients studied. Some 15% of participating males and 27% of females were aged over 70 years.Newly diagnosed hypertensives comprised 22% of the study cohort, the proportion being highest in UK and Netherlands, whereas 53% were established hypertensives of two or more years' duration, the proportion being highest in Germany and Belgium. There were substantial differences among the participating countries in the concurrent treatment these patients were receiving for hypertension, with two or more co-therapies being most frequent in Germany and Belgium. There were also substantial differences in co-therapies for concurrent diseases among the participating countries, reflecting both standard therapeutic practices in local areas and differences in marketing of drugs in the different countries.This report describes the initial findings of this multinational study and emphasises the need to consider several major potentially confounding variables in the analysis of the outcome events both in this study and in other collaborative observational international monitoring schemes for adverse drug reactions.     

Long-term versus short-term amitriptyline side effects as measured by a postmarketing surveillance system

As part of a large-scale postmarketing surveillance study, the adverse clinical events (ACEs) reported by 85 outpatients taking amitriptyline were investigated. Two discrete groups of patients were identified based on their duration of amitriptyline treatment: 45 had started the drug within 2 weeks of their interview (mean = 10.1 days, SD = 1.6 days), while 40 were much longer term tricyclic antidepressant patients (mean = 227.2 days, SD = 135 days). Our analysis of amitriptyline side effects reported by each of these two discrete groups challenges the common clinical impression that tricyclic side effects, in general, abate with continued treatment. Shorter term patients were much better able to correctly attribute their adverse clinical events to their drug therapy. Anticholinergic side effects were reported as new symptoms by the long-term patients just as frequently with similar ratings of subjective severity. These reports of adverse drug reactions of recent onset by long-term amitriptyline users may reflect the fact that such symptoms fluctuate in their occurrence and may not be recognized as potentially drug-induced until some threshold for patient tolerance is exceeded.     

The role of databases in drug postmarketing surveillance

This paper describes the role of databases used for postmarketing surveillance of drugs at the United States Food and Drug Administration (FDA). First we describe the Adverse Event Reporting System (AERS), the largest database of adverse event reports in the world. Next, we explain the methods we have used for assembling these adverse event reports into a case series and analysing them, as well as techniques for employing drug use databases to construct reporting rates in the evaluation of drug safety issues. Finally, we discuss the FDA's use of the databases it accesses through its Cooperative Agreement Program to conduct high priority studies to support regulatory decision‐making. Published in 2001 by John Wiley & Sons, Ltd.     

Pharmacogenomic profiling in postmarketing surveillance: prospects and challenges

Adverse drug reactions (ADRs) represent a major public health and economic global problem. Growing evidence suggests that pharmacogenomics may potentially play a role in reducing drug-induced adverse events. Research efforts are increasingly directed towards this goal. However, knowledge about whether or not pharmacogenomics may be useful as a novel approach in postmarketing surveillance programs is at present rather limited. A critical analysis of some of the methodological design and ethical issues generated by the potential incorporation of pharmacogenomic profiling into pharmacosurveillance programs is presented.     

A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States

Tramadol HCl, marketed as Ultram in the USA, was introduced as a non-scheduled drug in April 1995 based on the assumption that the risk of abuse was sufficiently low to warrant a non-scheduled status. However, approval was contingent upon the development of an innovative proactive surveillance program, to be overseen by an independent steering committee, which would detect unexpectedly high levels of abuse. The postmarketing surveillance program consisted of systematic collection and scientific evaluation of reports of suspected abuse in high-risk populations surveyed through an extensive key informant network of drug abuse specialists and all spontaneous reports of abuse received through the FDA MedWatch system. Methods to estimate the number of patients prescribed tramadol were also developed. Monthly rates of abuse were calculated as an index of the risk-benefit ratio (i.e., abuse cases per 100,000 patients prescribed the drug). The data for the 3 years since the drug was introduced show that the reported rate of abuse has been low. Although a period of experimentation seemed to occur in the first 18 months after its introduction--which reached a peak rate of approximately two cases per 100,000 patients exposed--during the 2 year period prior to June 1998, the reported rate of abuse has significantly (P = 0.011) declined, reaching levels of less than one case per 100,000 patients in the last 18 months. The overwhelming majority of abuse cases (97%) have been found to occur among individuals with a history of substance abuse and the abuse has been confined to isolated pockets around the country-notably none of which have significant populations of street drug abusers. Thus, the data support the decision not to schedule tramadol and, furthermore, suggest that a proactive post-marketing surveillance program can be successfully developed to effectively monitor abuse of new medications.     

Perindopril postmarketing surveillance: a 12 month study in 47 351 hypertensive patients

Aims Both indirect-response models and effect-compartment models are used to describe the pharmacodynamics of drugs when there is a delay in the time course of the pharmacological effect in relation to the concentration of the drug. The aim of this study was to investigate whether the time of maximum response after single-dose administration at different dose levels could be used to distinguish between these models and to select the most appropriate pharmacokinetic-pharmacodynamic model for frusemide.
Methods Three doses of frusemide, 10, 25 and 40  mg were given as rapid intravenous infusions to five healthy volunteers. Urine samples were collected for 5  h after dosing. Volume and sodium losses were isovolumetrically replaced with an intravenous rehydration fluid. Diuresis and natriuresis were modelled for all three doses simultaneously, applying both an indirect-response model and an effect-compartment model with the frusemide excretion rate as the pharmacokinetic input.
Results The observed time of maximum diuretic and natriuretic response significantly increased with dose. This increase was well predicted by the indirect-response model, whereas the modelling with the effect-compartment model led to a poor prediction of the peaks. There was no difference between the observed and predicted time of maximum diuretic and natriuretic response using the indirect-response model, whereas the time of maximum response predicted by the effect-compartment model was significantly earlier than the time observed for the 25  mg ( P <0.05) and 40  mg ( P <0.05) doses.
Conclusions The time of maximum response to frusemide was better described using an indirect-response model than an effect-compartment model. Studying the time of maximum response after administration of different single doses of a drug may be used as a selective tool during pharmacokinetic-pharmacodynamic modelling.     

The role of pharmacists in the recruitment of a cohort for postmarketing surveillance

In October 1990, a recall procedure was issued regarding the drug acitretin. The recommended post-therapy contraception period after acitretin therapy was extended from 2 months to 2 years. For a postmarketing surveillance study, we recruited a cohort from the source population of women aged 15–45 years who were exposed to acitretin. Recruitment occurred through dermatologists, and pharmacists plus dispensing general practitioners. We describe the speed of and the response to the recruitment procedures, and the representativeness of the recruited cohort. We also studied whether the individuals who gave informed consent would have preferred to be recruited by either dermatologists or pharmacists, and whether the information obtained from pharmacists and dispensing general practitioners was valid. This study revealed that pharmacists and dispensing general practitioners (drug dispensers) recruited their subjects rapidly, with no or little selection; they attained a 42% response. Dermatologists recruited their subjects slowly and selectively; they attained a 24% response. The majority of women (60%) recruited by dermatologists would have given their informed consent if they would have been recruited by their pharmacists. Drug dispensers are essential contributors to the recruitment of a study population. We do advise that such recruitment for a postmarketing surveillance study occurs by means of a collaboration between pharmacists and physicians.