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The pharmaceutical industry has an obligation to identify adverse reactions to drug products during all phases of drug development, including the post-marketing period. Estimates of population exposure to pharmaceutical products are important to the post-marketing surveillance of drugs, and provide a context for assessing the various risks and benefits, including drug safety, associated with drug treatment. This paper describes a systematic approach to estimating post-marketing drug exposure using ex-factory shipment data to estimate the quantity of medication available, and dosage information (stratified by indication or other factors as appropriate) to convert the quantity of medication to person time of exposure. Unlike the non-standardized methods often used to estimate exposure, this approach provides estimates whose calculations are explicit, documented, and consistent across products and over time. The methods can readily be carried out by an individual or small group specializing in this function, and lend themselves to automation. The present estimation approach is practical and relatively uncomplicated to implement. We believe it is a useful innovation.

Recent regulatory initiatives and consensus documents have altered the conventional approach to evaluating and communicating pharmacovigilance information. While these trends may initially seem to provide opportunities to combine certain aspects of the premarketing and postmarketing safety evaluation functions, they also have the potential to obscure the substantial differences between comprehensive risk assessment in investigational and postmarketing settings. Personnel involved in evaluation of safety data from clinical trials (including studies for new indications for currently marketed products) must give special consideration to those regulatory, legal, scientific, and ethical issues that are unique to the premarketing environment. In this paper, we approach this complex topic by contrasting the risk assessment of investigational products, as summarized in the investigator's brochure, with similar, well-described risk evaluation processes that are carried out for marketed products.

AE signal detection and its techniques are part of the continuum of public health surveillance, borrowing from both its theory and application (171). Like public health surveillance networks, whose major goals are to identify early signs of new outbreaks, pinpoint new organisms, and monitor designated illnesses, AE signaling and surveillance systems attempt to provide early warnings of previously unsuspected product-AE pairs, hypothesize potential drug-event relations, identify populations "at risk," and facilitate case ascertainment and definition. In both examples, definitive research is often subsequently undertaken to quantify the strength of relations that may be proposed. As with any public health surveillance effort, AE surveillance provides an infrastructure for the ongoing collection of health data and its direct integration into the health regulatory policy (172), including its keystone role in risk assessment and management. However, unlike many surveillance systems, postmarketing AE systems collect case information that is often relatively incomplete and imperfect, estimate exposure based on surrogate values (e.g., sales data), and are used by both governmental and the private sector for preventive planning. These factors make AE signaling and surveillance more ambiguous, regulatory oriented, and complex than its disease counterparts (173). Despite such issues, AE signaling methods continue to evolve in extent, complexity, and acceptance (4, 131, 174). Undoubtedly, this is largely due to the widespread practical experience that has been gained with spontaneous reporting systems over the past 4 decades and the cumulative usefulness that has been demonstrated.

Using Maxwell-Boltzmann and Bose-Einstein models, we derive formulae for the exact probability that an adverse event (AE) report series will present with additional (ie, second, third, etc.) reports from a single geographical reporting region, under the assumption that each region has an equal probability of report generation. These formulae are used to calculate critical values for the number of regions beyond which the probability of additional same-region reporting falls below a predefined level. The results using either model suggest that for widely distributed drugs, the presence of even a single additional same-region AE report is extremely unlikely and provides reasonable evidence for differential reporting rates between regions with multiple versus single reports. Multiple same-region reports, therefore, provide evidence against the validity of report-based tests for a generalized increase in frequency, and evidence for the presence of a localized increase in frequency. These calculations imply th...

The recent implementation of the International Conference on Harmonization’s E2C Guidelines was an important step toward globalizing the activities of drug safety departments. While many details have not yet been addressed, the primary objective of this initiative is clear: the preparation and worldwide submission of standardized periodic reviews of a marketed product’s safety record. This article presents a strategy for integrating sureillance activities and epidemiological principles into periodic safety update reporting (PSUR), while at the same time meeting the regulatory requirements set forth in the ICH E2C Guidelines. A stepwise approach to PSUR compilation, interpretations of critical subsections of the ICH E2C Guidelines, and issues unique to the United States reporting environment are discussed.

We recently demonstrated morphine-6-hemisuccinate-human serum albumin conjugate (M-6-HS-HSA)-specific IgG in serum from ethic narcotics-manufacturing workers. In this article, we present results of epicutaneous tests to opiate compounds and lung-function studies in these same workers. Thirty-nine workers, exposed to opiates, were evaluated for possible work-related changes in lung function and were administered a questionnaire concerning opiate exposure and health history in February 1988. In December 1988, 33 employees with occupational exposure to opiates, six other workers (New Jersey referent) employed at the same factory with minimal exposure to opiate compounds, and 17 nonexposed individuals from Cincinnati, Ohio, were subjected to epicutaneous threshold testing with a panel of six opiate compounds and nine common aeroallergens. In opiate-exposed workers, significantly lower epicutaneous threshold concentrations were detected (compared to New Jersey referent and Cincinnati control subjects) for dihydrocodeine (p less than 0.01), hydrocodone (p less than 0.05), codeine (p less than 0.01), and morphine (p less than 0.05). Significant associates existed among epicutaneous threshold concentrations between the agents tested; that is, individuals with a positive morphine skin test would generally have a positive codeine skin test, etc. Atopic status (positive cutaneous test results to two or more of nine common aeroallergens) was not significantly associated (p greater than 0.05) with positive opiate skin sensitivity. Although the mean cross-shift decrements in FEV1 for all workers were nonsignificant, five opiate-exposed individuals demonstrated cross-shift decrements in FEV1 of greater than 10%. Daily maximum-minus-minimum changes in workweek PEFR (PEFRmax-min) were significantly reduced for Monday through Thursday (p less than 0.05) compared to PEFRmax-min changes during a nonwork, nonexposure 3-day weekend. Ten exposed workers demonstrated daily PEFRmax-min changes of greater than 20%, suggesting acute airway obstruction. Increased cutaneous reactivity to opiate compounds among opiate-exposed workers may reflect development of pharmacologic hyperresponsiveness to opiate compounds.

Spontaneous reporting of suspected adverse drug reactions (ADRs) has long been a cornerstone of pharmacovigilance. With the increasingly large volume of ADRs, regulatory agencies, scientific/academic organizations and marketing authorization holders have applied statistical tools to assist in signal detection by identifying disproportionate reporting relationships in spontaneous reporting databases. These tools have generated large numbers of signals defined as drug-ADR reporting associations that meet specified statistical criteria. The challenge is to identify which signals are most likely to be medically important and therefore warrant priority for further investigation. Decisions related to signal triage are often complex and are based on a combination of clinical, epidemiological, pharmacological and regulatory criteria. There are no specific regulations, guidelines or standards that provide an objective basis for these decisions. This paper describes preliminary work to identify and quantify the specific factors that contribute to a decision to prioritize a specific drug-ADR combination for further in-depth review. We applied a tool from the discipline of decision analysis to systematically assess the important attributes of spontaneously reported ADRs. A model was created that integrates these assessments and produces rankings for the signals generated from quantitative signalling methods. Although more research is necessary to evaluate the performance of this model fully, preliminary results suggest that the use of formal decision analysis approaches to support signal triage can provide potential benefit and will help meet an important need.

We measured sensitive indicators of renal damage in three different populations occupationally exposed to cadmium, and examined the degree of variation in damage and the relative sensitivity of different types of indicators. The three studies included (1) men exposed in a cadmium recovery plant, (2) men exposed in a nickel/cadmium battery plant, and (3) women exposed in the latter plant. The indicators of renal damage were urinary proteins in three categories: (1) the high molecular weight enzymes alanine aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase (NAG), (2) the intermediate molecular weight protein albumin (ALB), and (3) the low molecular weight proteins retinol-binding protein (RBP) and beta 2-microglobulin (B2M). These tests indicate that exposed groups with higher urine cadmium levels had varying degrees of renal damage. All exposed groups showed evidence of renal damage when compared with their respective control groups. A higher percentage of elevated protein levels was noted in the exposed group of Study 1 than in the exposed groups of Studies 2 and 3. In Study 1, the means of all five protein levels and ALB, RBP, and B2M fractional clearances were significantly elevated in the group with higher urine cadmium concentrations when compared with the groups with lower urine cadmium concentrations. Highly significant dose-response relationships for all of the urinary protein tests, including fractional clearances, were found. All of the tests were more sensitive in detecting evidence of subclinical renal damage than serum creatinine, a commonly used indicator of renal function. The order of test sensitivity in men was determined by considering three factors: (1) the magnitude of the correlation coefficient between the test and the urine cadmium concentration in the study with the most advanced damage, (2) the relative cadmium level predicted by the dose-response model at which there is a 10% chance of observing an elevated test value, and (3) the ability of the tests to detect renal effects in the population with less advanced damage. The tests in order of decreasing sensitivity in men are ALB, AAP, NAG, RBP approximately B2M. The women with higher urine cadmium levels in Study 3 had a higher percentage of elevated AAP and NAG values when compared with the control group.