Role of the centers for education and research on therapeutics (CERTs) in pharmacovigilance and proper use of therapeutics.

According to the Institute of Medicine (IOM) Committee on the Assessment of the U.S. Drug Safety System, "The recent highly publicized controversies surrounding the safety of some drugs have contributed to a public perception that the drug safety system is in crisis. It seems fair to say that this perception has created an opportunity for a thorough evaluation of the U.S. drug safety system." The evaluation was focused on the U.S. Food and Drug Administration (FDA). To improve the FDA and its function in the public health system to improve therapeutics, it is critical to understand the contributions of other components.

Public health physicians: an endangered species.

BACKGROUND: Questions have arisen regarding the competency levels of the various professions within the public health sector, including those of physicians. Protection of the nation's health requires that physicians on the public health team be competent practitioners of both medicine and public health. Physicians practicing in this arena are required to possess a vast array of knowledge, skills, and attitudes to be effective contributors in the field. METHODS: Using focus groups of key informants in public health, the context of practice, inventory of required competencies, current competencies, and identified gaps in these competencies, measures to address the situation were identified and discussed. RESULTS: Recommendations from the focus groups include: use of distance-based learning, development of educational materials and programs, use of the American College of Preventive Medicine as a facilitator, improved remuneration, changes to the certification process, utilization of mentoring programs, introduction of new marketing strategies, use of professional publications, and increased governmental/agency support. Contributors to this endeavor are identified. CONCLUSIONS: While we strive to improve the physician workforce entering the field, creative strategies for continued lifelong learning are urgently needed to facilitate ongoing development of physicians in the current public health workforce. This situation presents a major research agenda for public health practice. Identification of the essential knowledge, skills, and attitudes for public health physicians is the first step toward narrowing gaps in required competencies.

Proactive safety surveillance.

Growth in health information systems presents opportunities to enhance postmarketing safety surveillance of medical products. Spontaneous suspected side effect reports provide the foundation, but we need to 'proactively' improve their quality and our strategies to seek signals. In our more familiar 'reactive' mode, we examine hypotheses from inquiries or publicity. Such responsive evaluations remain essential but may miss latent information on unsuspected risks. Efficient techniques to disclose hidden clusters and associations may emerge through adaptation of approaches from industrial quality control and other disciplines. Data-driven techniques like exploratory analysis, control charts, and time series modeling may help in sifting through accumulated data and in screening consecutive submissions to discern hints of new product hazards or of more specific understanding about previously identified potential side effects. We also need to cultivate non-spontaneous data for hypothesis generation as well as testing, the systematic epidemiologic evaluation of questions and concerns. This hypothesis testing function will assume greater importance if proactive safety surveillance methods yield larger numbers of putatively positive findings. Whether from spontaneous reports or other sources, signals that could have arisen by chance alone usually represent only clues to potential hazards until or unless they can be verified through independent studies.

Economic impact of treatment of HIV-positive pregnant women and their newborns with zidovudine. Implications for HIV screening.

OBJECTIVES: To estimate the economic impact of (1) treating pregnant women who are human immunodeficiency virus (HIV)-positive with zidovudine and (2) voluntary screening programs for pregnant women for HIV infection and offering treatment with zidovudine to those found to be HIV-positive. MAIN OUTCOME MEASURES: Number of cases of pediatric HIV infection and costs of screening, zidovudine treatment, and pediatric HIV infection treatment. DESIGN: Health care costs associated with treatment of HIV-positive pregnant women and their newborns are estimated as the costs of zidovudine and its administration and the reduction in costs of treating pediatric HIV infection. The lifetime costs of pediatric HIV infection are derived from the published literature. Estimates of the reduction in maternal-to-fetal transmission rates are taken from the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group (ACTG) Protocol 076. Costs of a voluntary screening program include costs of screening tests and counseling. Sensitivity and threshold analyses are performed to determine the impact of changes in input parameter values including zidovudine treatment costs, efficacy of treatment, costs of pediatric HIV infection, prevalence of HIV infection in pregnant women, screening test sensitivity and specificity, and pregnancy termination rates on the results. RESULTS: Assuming transmission rates are reduced from 25.5% to 8.3% as found in the ACTG 076 trial, treatment costs of $104,502 for 100 HIV-positive pregnant women and their newborns are offset by the reduction of $1,701,333 associated with fewer cases of pediatric HIV infection for a net savings of $1,596,831. The sensitivity and threshold analyses show that overall cost savings from treatment of HIV-positive pregnant women and their newborns are achieved for a wide range of possible maternal treatment costs, efficacy rates, and lifetime pediatric HIV treatment costs. In the base-case analysis for the voluntary screening program, overall cost savings are seen when HIV prevalence rate among pregnant women is greater than 4.6 per 1000. However, this threshold prevalence rate is sensitive to changes In parameter value-especially pediatric HIV treatment costs, counselling costs, efficacy of treatment, and years of additional HIV treatment for the pregnant women. CONCLUSIONS: Offering zidovudine treatment to pregnant women known to be HIV-positive will decrease the number of cases of pediatric HIV infection and reduce health care costs. Voluntary screening programs for pregnant women will further decrease the number of cases of pediatric HIV infection. The effect of a screening program on health care costs varies according to HIV prevalence and the costs associated with the screening program.

Safety of acyclovir: a summary of the first 10 years experience.

The era of pharmacoepidemiology has introduced profound changes in the ability of the sector to monitor the post-marketing safety of new products. We report on the population-based assessment by Wellcome of the safety of Zovirax reflected in a program of unprecedented scope, diversity, and, most important, utility. The program couples epidemiologic intelligence--analysis of adverse experience reports arising spontaneously from practice and reported directly to the manufacturer, regulators, or in the published literature--with more structured formal epidemiologic research approaches. Taken together, the absence of major medical problems emerging from the monitoring system for spontaneous reports from the medical practice experience among over 20 million persons treated worldwide over the past decade, complemented by the similar absence of "signals" from structured epidemiologic studies closely monitoring the experience of over 50,000 patients, constitutes a persuasive body of information concerning the general safety of this important therapeutic intervention.

Postmarketing surveillance study of permethrin creme rinse.

BACKGROUND: An observational, epidemiological study was undertaken to evaluate the safety of permethrin 1% creme rinse (Nix) for treatment of head lice infestations. METHODS: Thirty-seven local public health departments enrolled a total of 38,160 patients for 47,578 treatments with permethrin or other pediculicides from September 1, 1986, through January 31, 1988. Follow-up safety information was collected between 7 and 14 days following treatment via return visit or telephone contact. RESULTS: One hundred three adverse events were reported among 41,955 evaluable treatments. The rates of reported adverse events were 2.2 per 1000 treatments among permethrin treatments, 3.4 per 1000 treatments among lindane treatments, and 1.5 per 1000 treatments among other over-the-counter treatments. No serious, unexpected adverse events were detected in the 18,950 patients treated with permethrin. CONCLUSIONS: This study confirmed the safety profile of permethrin in conditions of general use, as seen in clinical trials. Postmarketing safety monitoring in public health departments of drugs used to treat public health conditions was shown to be feasible.

Occurrence of neoplasia in patients with rheumatoid arthritis enrolled in a DMARD Registry. Rheumatoid Arthritis Azathioprine Registry Steering Committee.

The Rheumatoid Arthritis Azathioprine Registry (RAAR) was established in 1982 to examine the safety of azathioprine (AZA) and other disease modifying agents (DMARD) in the treatment of RA. In yearly followup over the past 7 years, 20 malignant conditions have been reported in 530 DMARD treated adult patients with RA. Incidence density ratios (IDR) and standardized morbidity ratios (SMR) were calculated to assess cancer risk. For all cancers the SMR was 1.52 (95% CI 0.90-2.60). For men the SMR was 1.71 (95% CI 0.84-3.52); for women the SMR was 1.52 (95% CI 0.89-2.60). Adjusted for age, the IDR was highest in the 70-79-year-old study population (3.41). The age and sex adjusted SMR for lymphoproliferative disorders and myeloma was 8.05 (95% CI 3.30-20.81). The SMR for lung cancer (n = 6) was also increased (3.37; 95% CI 1.58-7.34). Compared with the general population, patients with RA requiring DMARD therapy may be at increased risk of malignancy, particularly lymphoproliferative disorders. The RAAR is an important prospective technique which will ultimately permit assessment of neoplasia risk by type and duration of DMARD therapy.

A population-based study of Stevens-Johnson syndrome. Incidence and antecedent drug exposures.

To determine the incidence of Stevens-Johnson syndrome, a descriptive epidemiology study was performed using computerized Medicaid billing data from 1980 to 1984 from the states of Michigan, Minnesota, and Florida. The ratio of persons hospitalized with a discharge diagnosis of erythema multiforme (ICD-9-CM code 695.1) to persons with any claim for medical service was first used as an estimate of the incidence rate of the disease. Then, since the ICD-9-CM code for erythema multiforme includes other illnesses in addition to Stevens-Johnson syndrome and because these illnesses are frequently misdiagnosed, the information provided by a review of medical records for a subset of cases of erythema multiforme was used to determine the proportion of patients with true Stevens-Johnson syndrome. The incidence rates of Stevens-Johnson syndrome were 7.1 (6.1 to 8.2), 2.6 (1.6 to 4.0), and 6.8 (4.3 to 10.3) per million per year in each state, respectively. Penicillins, especially aminopenicillins, were frequently used in the 19 patients judged to be true cases of Stevens-Johnson syndrome. In conclusion, Stevens-Johnson syndrome is a uncommon condition. The excess risk of Stevens-Johnson syndrome due to any drug must, therefore, be very low.

Using a claims database to investigate drug-induced Stevens-Johnson syndrome.

In order to explore a priori hypotheses about drug-induced Stevens-Johnson Syndrome (SJS), a case-control study was initiated using data from COMPASS, a computerized data base consisting of Medicaid claims data. The records of 3.8 million patients in five U.S. states were searched to identify patients with an inpatient diagnosis of ICD-9-CM code 695.1 (erythema multiforme-EM). Out of the total of 367 cases that were identified, primary medical records for 249 were sought and 128 (51.4 per cent) of these were obtained. The remainder could not be obtained because: in 36 (29.8 per cent) the hospital refused to provide medical records; in 33 (27.3 per cent) there were transcription errors; in 20 (16.5 per cent) the state could not translate the identification number, primarily because the patients lost Medicaid eligibility too long before our request; in 27 (22.3 per cent) the hospital could not locate the patient's record; and in 5 (4.1 per cent) there were other reasons. Of those with a medical record, 121 (94.5 per cent) had a skin diagnosis and 109 (85.2 per cent) had a diagnosis compatible with ICD-9-CM code 695.1 specified on their discharge summary. However, in 35 (27.3 per cent) an expert reviewer felt that the discharge diagnosis was incorrect. In 50 (39 per cent) the computer diagnosis was incorrect. Only 19 (14.8 per cent) were judged by the expert reviewer to truly have Stevens-Johnson Syndrome, and an additional 37 (28.9 per cent) were judged to have erythema multiforme minor. Thus, the computerized diagnosis agreed very well with the diagnoses specified on the discharge summary. However, EM is frequently misdiagnosed, ICD-9-CM code 695.1 contains multiple other diagnoses which are not EM, and much of hospitalized EM is EM minor. Thus, studies of SJS cannot be performed except in patients whose medical records are available.

Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.

An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.

Major advances in international pharmacoepidemiology.

Pharmacoepidemiology applies the principles of epidemiology to the problems of pharmacotherapy--particularly addressing society's need to know more about drug safety issues than the highly structured pre-approval clinical trials programs can provide. Thus, the concerns are truly international, and the approaches must also be international, tempered by the ability to generalize from one nation's experience, and by the availability of specialized research resources. Studying the impact of medical and medicinal interventions, the field is especially well-served by the major advances in computer system's support of medical settings and the multipurpose linked automated data base, linking automated pharmacy-dispensing data with same-population automated hospital discharge and other medical and demographic data. The development of such resources, the direction of their fruits to complement the hard work of hands-on traditional epidemiologic approaches in this field, the recruitment and support of trained researchers in the field, and the international coordination of policy and practice realistic to the capacity while responsive to the demand are all among the exciting challenges ahead.

Acyclovir use and its surveillance in a general population.

This study examined the extent and patterns of use of acyclovir in a health maintenance organization (HMO) population. The development and implementation of a system to survey acyclovir users for possible acute adverse effects is also described. Acyclovir users were members of Kaiser Permanente (KP), Northwest Region, who received one or more prescriptions for acyclovir from an automated outpatient prescription system over a two-year period (1986 and 1987). KP members with genital herpes were identified from the automated Outpatient Utilization System, which abstracts medical record data from a random sample of about two percent of KP members. Acyclovir users with hospital admissions were identified from the automated KP hospital discharge abstract system. During the two years, there were 2940 users who received a total of 6182 prescriptions for acyclovir; 47 percent used oral acyclovir and 56 percent of prescriptions were for the oral dosage form. Females received two-thirds of the prescriptions, and people 15 through 45 years of age received 80 percent of the prescriptions. The estimated incidence density of oral acyclovir usage was 2.3/1000 KP members. Most oral acyclovir prescriptions were for the treatment of genital herpes. More than 60 percent of the prescriptions appeared to be for first treatment, more than 30 percent for repeat treatment, and about 6 percent for continuing treatment. Hospitalizations of oral acyclovir users appeared to be unrelated to the use of the drug.

Medication monitoring in the workplace: toward improving our system of epidemiologic intelligence.

There is a great deal we do not know about the safety of pharmaceutical agents, especially regarding their safe use in the workplace. Economic and scientific imperatives can lead to a new drug's approval and marketing even though testing is limited; therefore, much of the knowledge about drug toxicities must be developed in the postapproval period, through pharmacoepidemiologic methods. The system of epidemiologic intelligence depends on spontaneous, voluntary reports of adverse drug reactions and, as applied to the work force, it is fraught with problems of ascertainment, accountability, and application. Structured epidemiologic studies of these issues have been difficult to perform because of high costs, long time frames, and methodologic problems and biases. Nevertheless, large automated data bases, with the right input, hold great promise for making it easier to accumulate and analyze the data necessary for monitoring drug safety in the workplace.

Inventory of knowledge and skills relating to disease prevention and health promotion.

An inventory of the knowledge and skills appropriate for the instruction of medical students in the disciplines of disease prevention and health promotion was developed by a steering committee of medical practitioners and teachers, with the input of over 70 colleagues. The inventory, which is intended as a guide for curriculum planners, defines the fundamentals of subject areas appropriate for the general education of all physicians, including the skills and knowledge related to delivery of personal disease prevention/health promotion services, quantitative methods, health services organization and delivery, and community dimensions of medical practice, as well as attitudes and philosophy.