Application of the BRAT framework to case studies: observations and insights.

The BRAT Framework is a set of flexible processes and tools that provides a structured approach to pharmaceutical benefit-risk decision making in drug development and post approval settings. A work in progress, it consists of six steps that produce representations of key tradeoffs, with appropriate documentation of the rationale for decisions and the assumptions made in their development. This article describes insights, gained from case studies, into the Framework's performance in a variety of constructed benefit-risk scenarios, focusing on a hypothetical example of a triptan for migraine. The scenarios described illustrate the challenges inherent in arriving at many of the regulatory decisions, including obtaining data for matching populations for all outcomes, finding data of consistent quality, addressing correlated outcomes (e.g., elevated liver function tests and hepatitis rates), dealing with rare but serious adverse events (AEs), and understanding and making decisions based on information for many outcomes simultaneously. The Framework provides a structure for organizing, interpreting, and communicating relevant information, including heterogeneity in results and the quality and level of uncertainty of data, in order to facilitate benefit-risk decisions.

Determinants of healthcare-seeking behaviour among subjects with irritable bowel syndrome.

BACKGROUND: Doctor visits for irritable bowel syndrome are associated with high medical costs. Predictors of medical consultation for irritable bowel syndrome remain poorly understood. AIM: To determine factors associated with healthcare seeking for irritable bowel syndrome. METHODS: Subjects from previous US population-based survey were contacted 2 years later. Those who continued to have irritable bowel syndrome were included. RESULTS: 49% of subjects sought medical care for abdominal symptoms in the past year. Healthcare seeking did not differ significantly between males and females, but more females received an irritable bowel syndrome diagnosis. Predictors of irritable bowel syndrome healthcare seeking differed by gender. In multivariate analysis, age > or = 55 years (OR = 2.8, 95% CI: 1.5-5.4), fear abdominal symptoms relates to serious illness (OR = 1.7, 95% CI: 0.95-3.1), decreased bowel movements (OR = 1.8, 95% CI: 0.98-3.2), dyspepsia (OR = 1.7, 95% CI: 0.94-3.2) and pelvic pain (OR = 2.3, 95% CI: 1.2-4.4) were associated with seeking care in females. Among males, being disabled (OR = 11.6, 95% CI: 2.4-56.1) and abdominal cramping (OR =4.3, 95% CI: 1.2-15.4) were associated with seeking care. Healthcare seekers had lower irritable bowel syndrome-related quality of life. Neither pain severity nor mental health status was associated with seeking care. CONCLUSION: Healthcare-seeking behaviour among irritable bowel syndrome patients was determined by presence of comorbidities and extent that irritable bowel syndrome affected quality of life, not physical symptoms or mental health status.

Stability of irritable bowel syndrome using a Rome II-based classification.

BACKGROUND: As there is no biological marker for irritable bowel syndrome, a diagnosis is made using symptom-based criteria. AIM: To evaluate the stability of self-reported symptoms consistent with Rome II-based irritable bowel syndrome classification. METHODS: Irritable bowel syndrome subjects identified in a 2001 population-based study by modified Rome II criteria were re-contacted 2 years later. Data were collected via a web-based questionnaire. RESULTS: Of the 697 subjects, 30% remained in the same irritable bowel syndrome subtype in both surveys, 18.4% changed irritable bowel syndrome subtype and 52% no longer met the irritable bowel syndrome criteria at follow-up. Subjects continuing to meet the irritable bowel syndrome criteria were more likely to have been initially classified in the alternating irritable bowel syndrome subtype and had more psychological impairment and lower irritable bowel syndrome-related quality of life than subjects not fulfilling the irritable bowel syndrome criteria at follow-up. Lack of pain caused more subjects to fall out of the irritable bowel syndrome criteria than the absence of non-painful bowel symptoms. However, the majority of subjects that did not fulfill the pain component of the irritable bowel syndrome criteria continued to report abdominal pain of at least moderate severity. CONCLUSION: In a US population-based follow-up study using modified Rome II criteria, we found irritable bowel syndrome is episodic in nature and current classification is limited in capturing fluctuation of disease over time.

Prevalence and demographics of irritable bowel syndrome: results from a large web-based survey.

BACKGROUND: Irritable bowel syndrome is a common gastrointestinal disorder, and its prevalence and demographics have been evaluated by different methodologies with varying results. AIM: To evaluate irritable bowel syndrome demographic and prevalence characteristics utilizing a web-enabled panel. METHODS: From an existing 150 000-member panel, 31 829 individuals were randomly selected and sent screening questionnaires to evaluate irritable bowel syndrome symptoms. Individuals who agreed to participate and completed the screening questionnaire received a second questionnaire related to a diagnosis of irritable bowel syndrome, a more detailed symptom description, and additional burden of illness data. RESULTS: Irritable bowel syndrome prevalence was 7%. Prevalence was higher in women vs. men, unmarried individuals vs. married individuals and unemployed individuals vs. employed individuals. Of those completing the second questionnaire, 51% had seen their physicians for irritable bowel syndrome symptoms in the past year and most had an episode within the past 3 months. During the past year, approximately half of the participants had used a prescription medication, and over 90% had used an over-the-counter medication for irritable bowel syndrome. Participants with irritable bowel syndrome demonstrated quality-of-life reductions relative to norms of the United States population. CONCLUSIONS: Web-enabled data collection represents a novel tool for rapidly surveying a large population of individuals with irritable bowel syndrome symptoms.

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment.

OBJECTIVE: Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN: The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS: The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION: None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Epidemiology in the pharmaceutical industry.

A survey assessing the practice of epidemiology in the pharmaceutical industry was sent to all member companies and research affiliates of the Pharmaceutical Research and Manufacturers of America (PhRMA) and to six non-member companies. Eighty-three companies were surveyed. Screening questions established whether or not a company employed epidemiologists, had an epidemiology department, or contracted work to epidemiologists outside the company. The survey included questions about organizational structure, functional role of epidemiologists, epidemiology department activities within the company, and collaboration with external partners. The response rate was 90.4%. Of the responding companies, 40% employed epidemiologists, 20% had epidemiology departments, and 36% utilized epidemiologists contracted outside the company. Eighty per cent of companies that employed epidemiologists also contracted epidemiology services outside of the company, while 6.7% of companies that did not employ epidemiologists utilized outside epidemiology services. Among all companies 42.7% employed or utilized epidemiologists. Differences were found in the extent to which large, medium and small pharmaceutical companies employ and utilize epidemiologists. The survey demonstrates that epidemiologists perform many roles within the pharmaceutical industry; that there are many potential opportunities for epidemiologists in this industry and that increased emphasis on safety will require more epidemiology training and recruitment efforts. Copyright (c) 2000 John Wiley & Sons, Ltd.

The Pregnancy Registry program at Glaxo Wellcome Company.

Registries can be used to provide an early warning system for potential teratogenic effects associated with the use of specific medications during pregnancy. Glaxo Wellcome has developed 5 international registries: (1) the Acyclovir Pregnancy Registry, (2) the Antiretroviral Pregnancy Registry, (3) the Lamotrigine Pregnancy Registry, (4) the Sumatriptan Pregnancy Registry, and (5) the Bupropion Pregnancy Registry. The purpose of these registries is to gain more information about the potential teratogenicity of these drugs during pregnancy. Two potential limitations of such registry data are recognized: (1) the utility of the data collected depends on the size of the sample; and (2) the registered patients may not be representative of all patients using the medication. However, these types of registry reports can be a valuable and cost-effective way to collect data regarding the use of medications during pregnancy when conventional methods (eg, cohort studies) are not appropriate or feasible.

Present of a toxin in the salivary glands of the marine snail Cymatium intermedius that targets nicotinic acetylcholine receptors.

Presence of a toxin in the salivary glands of the marine snail Cymatium intermedius that targets nicotinic acetylcholine receptors. Toxicon 36, 25-29, 1998.-We present evidence of a neurotoxin from the salivary glands of Cymatium intermedius that displays acetylcholine-like effects on vertebrate (mouse ileum) and invertebrate (molluscan smooth muscle; molluscan heart; leech body wall) tissues. These effects were completely blocked by (+)-tubocurarine (10-100 muM) but not by atropine (up to 200 muM) suggesting that the toxin targets nicotinic-like acetylcholine receptors. This affirms the proposal that this genus may overcome their prey with a paralytic secretion.

Isolation of serotonin from the accessory salivary glands of the marine snail Nucella lapillus.

We report here the presence of a bioactive compound in the secretion of the accessory salivary glands (ASGs) of Nucella lapillus. We have purified the compound using HPLC and identified it as serotonin by mass spectrometry, UV spectroscopy, HPLC and capillary electrophoresis. Serotonin was not found in the secretions of the acinous salivary glands or the hypobranchial gland. The amount of serotonin in the secretion of the ASGs does not show seasonal or regional variation.

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.

Acyclovir in pregnancy registry: six years' experience. The Acyclovir in Pregnancy Registry Advisory Committee.

The Acyclovir in Pregnancy Registry was established to gather data on prenatal exposure to acyclovir. Exposed pregnancies are tracked prospectively to ascertain exposure, risk factors, and pregnancy outcome. Through June 30, 1990, 312 acyclovir-exposed pregnancies had been reported and followed. Of these, 239 were exposed during the first trimester; outcomes included 24 spontaneous fetal losses, 47 induced abortions, 159 live births of infants without congenital abnormalities, and nine outcomes with congenital abnormalities. Among the 73 second- and third-trimester exposures, one infant was born with an abnormality. Exposures are also reported to the registry retrospectively, ie, after the outcome of pregnancy is known. Registry findings to date do not show an increase in the number of birth defects among the prospective reports when compared with that expected in the general population, and there is no consistent pattern of abnormalities among retrospective or prospective reports. These findings should provide some reassurance in counseling women following inadvertent prenatal exposure. The cases accumulated to date represent a sample of insufficient size for reaching reliable and definitive conclusions about the safety of acyclovir for pregnant women and their developing fetuses. Therefore, until further information is available, the Acyclovir in Pregnancy Registry Advisory Committee recommends following the 1989 Centers for Disease Control Sexually Transmitted Diseases Treatment Guidelines for the use of acyclovir in pregnancy, and encourages reporting of all prenatal exposures to the registry (1-800-722-9292, ext. 8465).

National AIDS incidence trends and the extent of zidovudine therapy in selected demographic and transmission groups.

After mid-1987 fewer than the expected number of cases of AIDS were reported in the United States in some demographic and transmission groups but not in others. Gay men (regardless of intravenous drug use), adults with hemophilia, and transfusion recipients exhibited fewer cases than expected based on previously reliable models. These favorable trends could not be explained by assuming earlier cessation of human immunodeficiency virus (HIV) infection. Favorable AIDS incidence trends were not found in heterosexual intravenous drug users or in persons infected through heterosexual contact. White gay men from New York City, Los Angeles, and San Francisco experienced markedly favorable trends, whereas little changes was observed for nonwhite gay men from nonurban areas. AIDS incidence trends were quantitatively consistent with the fraction of AIDS-free persons with severe immunodeficiency who received zidovudine in three cohorts. Gay men in San Francisco used zidovudine more frequently than did adults with hemophilia, while little was used by intravenous drug users in New York City. Data describing the initial national distribution of zidovudine (March 31-September 18, 1987) indicated relatively high use by patients with severe immunodeficiency in those groups, such as urban white gay men, that subsequently experienced fewer cases of AIDS than expected. Available data suggest that zidovudine, perhaps in combination with other therapies, has been one factor contributing to favorable AIDS incidence trends in some groups. Broader application of therapy might further retard the incidence of AIDS, especially in intravenous drug users, persons infected through heterosexual contact, minorities, women, and persons diagnosed outside major metropolitan areas.