Experiences and challenges in data monitoring for clinical trials within an international tropical disease research network.

BACKGROUND: Models for the structure and procedures of data and safety monitoring boards (DSMBs) continue to evolve in response to issues of new and of old concern. Some authors have called for an open dialogue on these questions through publication of the experiences of DSMBs in addressing them. PURPOSE: The goal of this paper is to add to the current discussion about acceptable models for establishing, serving on, and reporting to monitoring committees, particularly those that oversee multiple studies in less developed countries. The paper seeks to do so by describing the establishment and subsequent operation of one such multi-trial DSMB over a five-year period. This DSMB was formed to monitor trials conducted by members of the International Centers for Tropical Disease Research (ICTDR) network of the National Institute of Allergy and Infectious Diseases (NIAID). METHODS: The operational model and experiences are summarized by the authors, who had immediate responsibilities for directing the DSMB's activities. RESULTS: The board played an active, traditional role in assuring that patient safety was maintained and that current standards for clinical research were met. In addition, both NIAID and the board members viewed education of investigators to be an important role for the board to play in this particular setting. This affected the threshold for identifying which trials would be monitored, and it impacted several procedures adopted by the board. LIMITATIONS: This report reflects the observations of those involved in managing the DSMB, including comments offered by the DSMB and by investigators, but not data gathered in a systematic way. CONCLUSIONS: The operational model described here has allowed the DSMB to fulfill its role in the oversight of the trials. We hope that the ideas we present may help others facing similar situations and may stimulate further critical thinking about DSMB structure and function.

Estimation of pertussis vaccine efficacy in the presence of covariates in three randomized trials.

We estimated efficacy of pertussis vaccines in three randomized controlled trials with adjustment for several baseline covariates: presence of one or more other children in the household, sex of the study child, and geographical area. Adjusted and unadjusted efficacy estimates differed only trivially. We also assessed the association of efficacy with time since vaccination and background pertussis incidence. The acellular vaccines, except for the two-component vaccine in the Stockholm trial, appeared to maintain their efficacy during two years of follow-up. In contrast, efficacy of a whole-cell vaccine decreased significantly in both the Stockholm and Italian trials. The relationship between efficacy and background incidence was not consistent across studies and vaccines.

Depressive symptoms as predictors of medical outcomes in HIV infection. Multicenter AIDS Cohort Study.

OBJECTIVE: To ascertain whether depressive symptoms as determined by the Center for Epidemiologic Studies-Depression scale (CES-D) predict accelerated mortality and worse medical outcomes in patients infected with human immunodeficiency virus (HIV). DESIGN: Eight-year cohort study with semiannual follow-up. SETTING: Community volunteers. PARTICIPANTS: A total of 1809 HIV-seropositive homosexual men without the acquired immunodeficiency syndrome (AIDS) who entered the Multicenter AIDS Cohort Study in 1984 or 1985. Eight-year follow-up data were available on 75% of eligible participants. OUTCOME MEASURES: Times to AIDS, death, and prophylactic treatment, and slopes describing the decline in CD4 count for each individual participant. RESULTS: Using a conventional definition of depression (CES-D > or = 16 at the first study visit), 21.3% of participants were classified as depressed. Depressed participants had lower CD4 counts and reported more AIDS-related symptoms. There were no significant differences between depressed and nondepressed participants on any of the outcome measures (P > .05 in all cases). In contrast, men reporting AIDS-related symptoms had shorter times to AIDS and to death even after adjusting for CD4 counts (P < .01). The analyses were repeated, with similar results, using different definitions of depression based on the CES-D. CONCLUSIONS: We find no evidence that depressive symptoms independently prognosticate worse outcomes in HIV infection. Because of associations of depression with symptom reports, CD4 counts, and indicators of socioeconomic status, future studies of the relationship between depression and HIV outcome should consider these variables as confounders.

Prevalence of human immunodeficiency virus type 1 p24 antigen in U.S. blood donors--an assessment of the efficacy of testing in donor screening. The HIV-Antigen Study Group.

BACKGROUND: We performed a multicenter study in 1989 to determine whether screening whole-blood donors for human immunodeficiency virus type 1 (HIV-1) p24 antigen would improve transfusion safety by identifying carriers of the virus who are seronegative for HIV-1 antibody. METHODS: More than 500,000 donations were tested at 13 U.S. blood centers with test kits from two manufacturers. Units found repeatedly reactive were retested in a central laboratory; if the results were positive, they were confirmed by a neutralization assay. A subgroup of units was also tested for HIV-1 by the polymerase chain reaction. Selected donors confirmed or not confirmed as having p24 antigen were contacted for follow-up interviews to identify risk factors and undergo retesting for HIV-1 markers. RESULTS: Positive tests for p24 antigen were confirmed by neutralization in five donors (0.001 percent of all donations tested), all of whom were also positive for HIV-1 antibody and HIV-1 by polymerase chain reaction. Three of the antigen-positive donors had other markers of infectious disease that would have resulted in the exclusion of their blood; two had risk factors for HIV-1 that should have led to self-exclusion. Of 220 blood units with repeatedly reactive p24 antigen whose presence could not be confirmed by neutralization (0.04 percent of the donations studied), none were positive for HIV-1 antibody, HIV-1 by polymerase chain reaction (120 units tested), or virus culture (76 units tested)--attesting to the specificity of confirmatory neutralization. CONCLUSIONS: The finding that no donation studied was positive for p24 antigen and negative for HIV-1 antibody suggests that screening donors for p24 antigen with tests of the current level of sensitivity would not add substantially to the safety of the U.S. blood supply.

Recreational drug use and sexual behavior change in a cohort of homosexual men. The Multicenter AIDS Cohort Study (MACS).

The relationship between use of recreational drugs and high-risk (HIV-transmitting) homosexual behavior was examined in the Multicenter AIDS Cohort Study (MACS) population. Among the 3916 men who completed both the baseline (1984) and first 6-month follow-up evaluations and were sexually active during the 6 months prior to enrollment, self-reported use of each of 10 classes of recreational drugs in conjunction with sexual activity was analyzed for both cross-sectional and prospective relationships with pattern of sexual behavior using a four-level sexual risk behavior index. At baseline, the proportion of men in the highest risk category (unprotected anal exposures with multiple partners) increased from 36 to 85% when men not using any drugs to men using three or more drugs plus volatile nitrites were examined. In multivariate logistical analyses, volatile nitrite use was significantly associated with failure to maintain or attain lower sexual risk levels after controlling for the effects of age, educational level and numbers of high-risk partners. These results suggest that volatile nitrite use may play an important role in the association between recreational drug use and high-risk sexual behavior among homosexual/bisexual men.