The future of population-based postmarket drug risk assessment: a regulator's perspective.

The US Food and Drug Administration emphasizes the role of regulatory science in the fulfillment of its mission to promote and protect public health and foster innovation. With respect to the evaluation of drug effects in the real world, regulatory science plays an important role in drug risk assessment and management. This article discusses opportunities and challenges with population-based drug risk assessment as well as related regulatory science knowledge gaps in the following areas: (i) population-based data sources and methods to evaluate drug safety issues; (ii) evidence-based thresholds to account for uncertainty in postmarket data; (iii) approaches to optimize the integration and interpretation of evidence from different sources; and (iv) approaches to evaluate the real-world impact of regulatory decisions. Regulators should continue the ongoing dialogue with multiple stakeholders to strengthen regulatory safety science and address these and other critical knowledge gaps.

Safety monitoring of drugs granted exclusivity under the Best Pharmaceuticals for Children Act: what the FDA has learned.

The Best Pharmaceuticals for Children Act (BPCA) was signed into law on 4 January 2002, shortly after the pediatric exclusivity provision of the Food and Drug Administration (FDA) Modernization Act expired on 1 January 2002. This Act provides six months of marketing exclusivity for a drug when a pharmaceutical company studies that drug for use in the pediatric population as requested by the FDA. Section 17 of the BPCA specifically requires that the FDA review all adverse events reported for drugs that receive pediatric exclusivity. In most of the cases, no unexpected adverse events were reported in the pediatric population; however, in some cases, this focused safety review provided information important to the safety of medication use in children.

The Aberdeen Indian Health Service infant mortality study: design, methodology, and implementation.

Of all Indian Health Service areas, the Aberdeen Area has consistently had the highest infant mortality rate. Among some tribes in this area the rate has exceeded 30/ 1000 live birth and half the infant deaths have been attributed to Sudden Infant Death Syndrome,a rate four to five times higher than the national average. The Indian Health Service, Centers for Disease Control and Prevention, National Institute of Child Health and Human Development, and the Aberdeen Area Tribal Chairmen's Health Board collaborated to investigate these high rates with the goals of refining the ascertainment of the causes of death, improving cause-specific infant mortality rates and identifying factors contributing to the high rates. Ten of the 19 tribes or tribal communities, representing 66%of the area population, participated in a 4-year prospective case-control study of infants who died after discharge from the hospital. Infant care practices and socio-demographic, economic, medical, health care, and environmental factors were examined. The study included parental interviews, death scene investigations, autopsies, neuropathology studies, medical chart abstractions, blood cotinine assays, and a surveillance system for infant deaths. Controls were the previous and subsequent infants born on the case mother's reservation. From December 1,1992 until November 30,1996,72 infant deaths were investigated. This report describes the study methods and the model employed for involving the community and multiple agencies to study the problem of infant mortality among Northern Plains Indians. Data gathered during the investigations are being analyzed and will be published at a later date.

Are interpregnancy intervals between consecutive live births among black women associated with infant birth weight?

OBJECTIVES: The purpose of this study was to determine whether the length of interpregnancy intervals between consecutive live births among Black women had any significant effect on mean birth weight as had previously been reported in another study. DESIGN: We examined a sample (1,048 women, 66% of study participants) from a study of non-Hispanic Black women whose infants were born at a large, inner-city, public hospital in Georgia from October 1988 through August 1990. Data were evaluated for the 494 women whose current and immediately previous pregnancies ended in the birth of a live infant weighing 500 grams or more. METHODS: Linear regression and analysis of covariance models were developed. RESULTS: The median interpregnancy interval was 15 months (range 1 to 207 months), with 19 (4%) of the women having intervals of less than 3 months. After adjustment for parity, gestational age (in weeks), and smoking status, the mean birth weight associated with an interpregnancy interval of three or more months was 3,106 grams, 215 grams greater than that for an interval of less than three months (P = .06). CONCLUSIONS: Although longer birth spacing has been associated with certain positive social and health effects, the population attributable effect on infant birth weight may not be very significant.

Changes in the epidemiologic profile of sudden infant death syndrome as rates decline among California infants: 1990-1995.

OBJECTIVES: To evaluate changes in the rates and epidemiologic patterns of sudden infant death syndrome (SIDS) after implementation of public health campaigns to promote back sleeping and reduce exposure to cigarette smoke and environmental risk factors for SIDS. METHODS: California vital statistics data were used to evaluate changes in SIDS rates (deaths/1000 live births) and in the proportions of SIDS deaths by age and season of occurrence for California infants of black or other races from 1990 through 1995. RESULTS: From 1990 through 1995, 3508 SIDS deaths occurred. SIDS rates declined from 2.69 to 2.15 for black infants and from 1.04 to 0.61 for others between 1990 and 1995. Most SIDS deaths occurred during the 2nd to 4th months of life; the proportion of SIDS deaths during this period was unchanged for blacks but decreased for others from 70% to 65%. Of all SIDS deaths, 62% occurred during the colder season (October through March); the proportion of deaths in each season did not change for either race. CONCLUSION: California SIDS rates declined 20% for blacks and 41% for others between 1990 and 1995. Declines coincided with campaigns to reduce environmental risk factors for SIDS. Blacks continue to be at increased risk for SIDS compared with others, and the SIDS rate for blacks relative to others has increased. Reductions in SIDS mortality coinciding with interventions were smaller for blacks than for others. New strategies are needed to reduce further SIDS rates and narrow the gap between blacks and others.

Changes in the black-white infant mortality gap from 1983 to 1991 in the United States.

BACKGROUND: The long-standing difference in infant mortality in the United States between black and white infants has increased in recent years. To help identify the cause, we evaluated changes in birthweight distributions (BDs) and birthweight-specific mortality rates (BSMRs) among black and white infants born in the United States between 1983 and 1991. METHODS: Using national linked birth and death certificate data, we limited analyses to singleton births that occurred in the United States to resident, non-Hispanic black and white women. Birthweight data were analyzed in 500 g increments. The black-white gap was partitioned into deaths due to differences in BDs and BSMRs. RESULTS: The black-white infant mortality rate ratio increased from 2.1 in 1983 to 2.4 in 1991. Decreases in BSMRs among infants weighing from 500 to 2499 g occurred in both groups but were smaller among black than white infants; consequently, the percentage of excess deaths to black infants due to differences in BSMRs almost doubled during the study period, from 6.5% to 11.9%. Rates of very low birthweight (VLBW, < 1,500 g) increased for black infants, but the BD for white infants changed little. Although about 90% of the excess deaths to black infants resulted from differences in BDs, the changes in BDs had a minimal effect on the widening infant mortality gap. CONCLUSIONS: A significant reduction in the black-white infant mortality gap will require a reduction in VLBW and low birthweight (LBW, < 2,500 g). To keep the gap from growing, we must also investigate why decreases in BSMRs were smaller among black than white infants between 1983 and 1991.

Trends and predictors of infant sleep positions in Georgia, 1990 to 1995.

BACKGROUND: In recent years, the prone sleeping position has emerged as the strongest modifiable risk factor for sudden infant death syndrome, the leading cause of infant mortality between 1 month and 1 year of age in the United States. Since April 1992, sudden infant death syndrome risk-reduction strategies have included the promotion of the back or side sleeping position (nonprone) for healthy infants younger than 1 year of age. Most recently, the back position has been advocated as the best sleeping position and the side position as an alternative. METHODS: To evaluate trends in prevalence of the prone position from 1990 to 1995, we used data available from the Georgia Women's Health Survey, a random digit-dialed telephone survey of 3130 women 15 to 44 years of age. We examined the position in which women put their infant to sleep in the first 2 months of life for their most recent live birth (N = 868) and determined independent predictors of prone sleep position among women who consistently used the prone or the back/side position (n = 636) using multiple logistic regression. RESULTS: The prevalence of mothers who put their infant to sleep in the prone position significantly decreased, from 49% in 1990 to 15% in 1995. This decrease is primarily attributable to a major shift to the side position rather than to the back. Using multiple logistic regression, we found the prone sleeping position to be significantly higher among women who entered prenatal care after the first trimester (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.4-9.2), were black (OR, 2.1; 95% CI, 1.4-3.1), had less than a high school education (OR, 2.2; 95% CI, 1.4-3.4), and were living in rural Georgia (OR, 1.9; 95% CI, 1.3-2.7). For the period after April 1992, women who had previous children were 2.6 (OR, 95% CI, 1.7-4.1) times more likely to use the prone sleep position than were first-time mothers. CONCLUSIONS: The prevalence of the use of the prone sleep position for infants decreased significantly over the study period. This decrease coincided with national efforts to promote the back or side sleeping position. Increased efforts should target groups who are more likely to use the prone position to attain the national goal of

Postneonatal mortality surveillance--United States, 1980-1994.

PROBLEM/CONDITION: This report contains public health surveillance data that describe trends in postneonatal mortality (PNM) and that update information published in 1991. REPORTING PERIOD COVERED: 1980-1994. DESCRIPTION OF SYSTEM: National death certificate data characterizing PNM were reported by hospital physicians, coroners, and medical examiners. Data for 1980-1994 were compiled by the National Center for Health Statistics (NCHS) and obtained from NCHS public-use mortality tapes. RESULTS: The PNM rate per 1,000 live births declined 29.8% from 4.1 in 1980 to 2.9 in 1994 (31.7% decline among white infants and 25.8% among black). Most of the decline resulted from reduced mortality from infections and sudden infant death syndrome (SIDS). The PNM ratio between blacks and whites remained steady at approximately 2.1 during 1982-1988 and gradually increased to 2.4 by 1994 [corrected]. Autopsy rates for cases of SIDS increased from 82% to approximately 95% and did not differ among black infants and white infants. The decline of PNM rates for birth defects was greater for white infants than for black infants. The racial gap in PNM rates widened regionally during the study period, except in the South and the Northeast where ratios remained stable. In 1994, the largest gap persisted in the north-central region followed by the West and Northeast. INTERPRETATION: In 1994 as in 1980, PNM remained an important contributor to infant mortality, but nearly half of these deaths are caused by potentially preventable causes such as SIDS, infections, and injuries. The use of interventions for SIDS, birth defects, infections, and injuries can help reduce PNM and narrow the associated racial gap. ACTIONS TAKEN: This surveillance information, which will be distributed to administrators of state maternal and child health programs and to community-based organizations nationwide, will be useful in planning infant mortality reduction programs and to target PNM prevention efforts.

Cause-specific trends in neonatal mortality among black and white infants, United States, 1980-1995.

OBJECTIVE: Although neonatal mortality has been declining more rapidly than postneonatal mortality in recent decades, neonatal mortality continues to account for close to two-thirds of all infant deaths. This report uses U.S. vital statistics data to describe national trends in the major causes of neonatal mortality among black and white infants from 1980 to 1995. METHODS: Mortality rates were estimated as the number of deaths due to each cause (based on International Classification of Diseases, 9th Revision, codes) divided by the number of live births during the same time period. Linear regression models and smoothed rates were used to describe trends. RESULTS: During the study period, neonatal mortality declined 4.0% per year for white infants and 2.2% per year for black infants, and the black-white gap increased from 2.0 to 2.4. By 1995, disorders relating to short gestation and low birth weight were the number one cause of neonatal death for black infants and the number two cause for white infants, had the highest black-white disparity (4.6, up from 3.3 in 1980), and accounted for almost 40% of excess deaths to black infants (up from 24% in 1980). Congenital anomalies were the number two cause of neonatal death for black infants and the highest ranked cause for white infants in 1995, and it is the only cause for which there was not a substantial excess risk to black infants. CONCLUSIONS: Large declines in neonatal mortality have been achieved in recent years, but not in the black-white gap, which has increased. Declines were slower for black than white infants overall and for almost all causes. Prevention of preterm delivery and low birth weight continue to be a priority for reducing neonatal mortality, particularly among black infants. Although congenital anomalies do not contribute substantially to the black-white gap, their diagnosis, treatment, and prevention is critical to reducing overall neonatal mortality.

Proceedings of "Workshop on Guidelines for Scene Investigation of Sudden Unexplained Infant Deaths"--July 12-13, 1993.

The 1992 Senate Report #102-104 and House Report #102-121 recommended that the Interagency Panel on Sudden Infant Death Syndrome (SIDS) review and establish an updated standard death scene investigation protocol for scene investigation of unexplained infant deaths. As a result of the recommendation, the Centers for Disease Control and Prevention's (CDC) Division of Reproductive Health (DRH), and the National Institute for Child Health and Human Development (NICHD) organized a workshop entitled "Workshop on Guidelines for Scene Investigation of Sudden Unexplained Infant Deaths," which was held in Rockville, Maryland, on July 12-13, 1993. This article outlines the proceedings of the workshop. The goal of the workshop was to gather information and ideas that could be used to establish guidelines which could be useful in developing a model death scene investigation protocol. It was not a goal of this workshop to produce a specific protocol during the workshop. The workshop was successful in generating a variety of information and ideas concerning the desirable attributes of a protocol including essential items of data, identification of certain training needs, specification of procedures for data collection, reporting, and quality assurance, and proposed strategies for implementation. This information can now be considered by the HHS Interagency SIDS Panel to develop specific guidelines for developing a standard scene investigation protocol for sudden unexplained infant deaths.

The epidemiology of placenta previa in the United States, 1979 through 1987.

OBJECTIVE: Placenta previa can cause serious, occasionally fatal complications for fetuses and mothers; however, data on its national incidence and sociodemographic risk factors have not been available. STUDY DESIGN: We analyzed data from the National Hospital Discharge Survey for the years 1979 through 1987 and from the Retrospective Maternal Mortality Study (1979 through 1986). RESULTS: We found that placenta previa complicated 4.8 per 1000 deliveries annually and was fatal in 0.03% of cases. Incidence rates remained stable among white women but increased among black and other minority women (p < 0.1). In addition, the risk of placenta previa was higher for black and other minority women than for white women (rate ratio 1.3, 95% confidence interval 1.0 to 1.7), and it was higher for women > or = 35 years old than for women <20 years old (rate ratio 4.7, 95% confidence interval 3.3 to 7.0). Women with placenta previa were at an increased risk of abruptio placentae (rate ratio 13.8), cesarean delivery (rate ratio 3.9), fetal malpresentation (rate ratio 2.8), and postpartum hemorrhage (rate ratio 1.7). CONCLUSION: Our findings support the need for improved prenatal and intrapartum care to reduce the serious complications and deaths associated with placenta previa.

Impact of very low birthweight on the black-white infant mortality gap.

In recent years, the rate of decline for the black infant mortality risk (IMR) has been slower than that for whites. The resultant widening in the black-white infant mortality gap has been accompanied by an increased percentage of very low birthweight (VLBW) infants (227 g-1,499 g) among black live births. Restricting our analysis to non-Hispanic black and white single live births, we used the 1983 national linked birth-death file to assess the relative contribution of VLBW infants to the black-white gap in IMR. VLBW occurred among 2.3% of all black live births and among 0.8% of all white live births. Deaths among VLBW infants accounted for 62.5% of the black-white gap in IMR. Although VLBW newborns represent a fraction of all live births in the United States, they account for almost two-thirds of the black-white gap in IMR. Since preterm delivery is associated with most VLBW infant deaths, our findings indicate the crucial need to identify strategies that reduce preterm births, among blacks in particular, to reduce significantly the infant mortality gap in the United States.

Surveillance of postneonatal mortality, United States, 1980-1987.

In the United States, one-third of all infant deaths (deaths of infants ages 0-364 days) occurs in the postneonatal period (28-364 days). A substantial proportion of these deaths potentially could be prevented. To examine recent trends in postneonatal mortality (PNM) in the United States, the investigators analyzed birth and death certificate data for resident infants for the period from 1980 through 1987. Rates of PNM declined 11% from 3.5 to 3.1/1,000 live births among white infants and declined 16% from 7.3 to 6.1/1,000 live births among black infants. Most of the decline resulted from reduced mortality from infectious diseases and injuries. A decreased mortality attributable to sudden infant death syndrome (SIDS) among black infants additionally accounted for the decline. Autopsy rates for SIDS increased from 82% to 92% but did not differ for black infants and white infants. Birth defects-related PNM declined more among white infants than among black infants. The racial gap in PNM (rate ratio (RR) = approximately 2.0) persisted. However, the largest black/white gap occurred in the Northeast (RR = 2.5), the region with the lowest PNM. Black infants were 2.7 and 2.3 times more likely to die of infections and injuries, respectively, than were white infants. Although PNM rates declined during the 1980s, a greater rate of reduction is needed to achieve the Year 2000 objectives, especially among black infants. Such reductions are possible through improved access to comprehensive pediatric care as well as education and community-oriented prevention programs designed to reduce deaths due to infections and injuries. A better understanding of the etiology of SIDS and birth defects is critical for preventing postneonatal deaths.