Evaluating protocol lifecycle time intervals in HIV/AIDS clinical trials.

BACKGROUND: Identifying efficacious interventions for the prevention and treatment of human diseases depends on the efficient development and implementation of controlled clinical trials. Essential to reducing the time and burden of completing the clinical trial lifecycle is determining which aspects take the longest, delay other stages, and may lead to better resource utilization without diminishing scientific quality, safety, or the protection of human subjects. PURPOSE: In this study, we modeled time-to-event data to explore relationships between clinical trial protocol development and implementation times, as well as to identify potential correlates of prolonged development and implementation. METHODS: We obtained time interval and participant accrual data from 111 interventional clinical trials initiated between 2006 and 2011 by National Institutes of Health's HIV/AIDS Clinical Trials Networks. We determined the time (in days) required to complete defined phases of clinical trial protocol development and implementation. Kaplan-Meier estimates were used to assess the rates at which protocols reached specified terminal events, stratified by study purpose (therapeutic, prevention) and phase group (pilot/phase I, phase II, and phase III/IV). We also examined several potential correlates to prolonged development and implementation intervals. RESULTS: Even though phase grouping did not determine development or implementation times of either therapeutic or prevention studies, overall we observed wide variation in protocol development times. Moreover, we detected a trend toward phase III/IV therapeutic protocols exhibiting longer developmental (median 2½ years) and implementation times (>3 years). We also found that protocols exceeding the median number of days for completing the development interval had significantly longer implementation. LIMITATIONS: The use of a relatively small set of protocols may have limited our ability to detect differences across phase groupings. Some timing effects present for a specific study phase may have been masked by combining protocols into phase groupings. Presence of informative censoring, such as withdrawal of some protocols from development if they began showing signs of lost interest among investigators, complicates interpretation of Kaplan-Meier estimates. Because this study constitutes a retrospective examination over an extended period of time, it does not allow for the precise identification of relative factors impacting timing. CONCLUSION: Delays not only increase the time and cost to complete clinical trials but they also diminish their usefulness by failing to answer research questions in time. We believe that research analyzing the time spent traversing defined intervals across the clinical trial protocol development and implementation continuum can stimulate business process analyses and re-engineering efforts that could lead to reductions in the time from clinical trial concept to results, thereby accelerating progress in clinical research.

Flexible modeling of multiple nonlinear longitudinal trajectories with censored and non-ignorable missing outcomes.

Multivariate nonlinear mixed-effects models (MNLMMs) have become a promising tool for analyzing multi-outcome longitudinal data following nonlinear trajectory patterns. However, such a classical analysis can be challenging due to censorship induced by detection limits of the quantification assay or non-response occurring when participants missed scheduled visits intermittently or discontinued participation. This article proposes an extension of the MNLMM approach, called the MNLMM-CM, by taking the censored and non-ignorable missing responses into account simultaneously. The non-ignorable missingness is described by the selection-modeling factorization to tackle the missing not at random mechanism. A Monte Carlo expectation conditional maximization algorithm coupled with the first-order Taylor approximation is developed for parameter estimation. The techniques for the calculation of standard errors of fixed effects, estimation of unobservable random effects, imputation of censored and missing responses and prediction of future values are also provided. The proposed methodology is motivated and illustrated by the analysis of a clinical HIV/AIDS dataset with censored RNA viral loads and the presence of missing CD4 and CD8 cell counts. The superiority of our method on the provision of more adequate estimation is validated by a simulation study.

Qualitative systematic review of homeopathic outcome studies in patients with HIV/AIDS

Background and aims: Systematic reviews of high-quality randomized controlled trials (RCTs) are crucial in evidence-based medicine (EBM). The aim of the present review was to investigate whether there is enough evidence on the efficacy of homeopathy in individuals with HIV/AIDS based on clinical trials. Methods: The present is a criteria-based systematic review of cumulative research, and assessment of the methodological quality of published studies. The quality of the trials was evaluated using a list of validated and predefined criteria, and their outcomes were interpreted based on their quality. The main outcome measure was the methodological quality of the studies in terms of the threats to external, internal, construct, and statistical conclusion validity. Results: Among the 6 clinical outcome studies located, 3 were open-label, non-randomized, non-controlled trials, 2 were RCTs, and one was a single-set replication study. The trials were too few in number, and did not exhibit very high quality. The results showed a positive trend regardless of the quality of the trials, or the variety of homeopathic treatment used. The results of the present review may be complicated by publication bias. Conclusion: The currently available evidences do not suffice to infer definitive conclusions. Therefore, further evaluation of homeopathic treatment by means of appropriate RCTs with high methodological quality is required.

As revisões sistemáticas de estudos randomizados controlados (RCTs) são essenciais na medicina baseada em evidências (MBE). O objetivo deste estudo foi estabelecer se há evidência suficiente a favor da eficácia da homeopatia em pacientes com HIV/AIDS a partir de ensaios clínicos. Trata-se de uma revisão sistemática da pesquisa acumulada baseada em critérios, com avaliação daqualidade metodológica dos estudos publicados. A qualidade dos estudos foi avaliada medianteuma lista de critérios validados e predefinidos e os resultados foram interpretados a partir de suaqualidade. O desfecho principal analisado foi a qualidade metodológica dos estudos nos termos das ameaças a sua validade externa, interna, de construto e conclusão estatística.Dos 6 estudos clínicos informando resultados que foram localizados, 3 eram ensaios abertos, não randomizados e não controlados, 2 eram RCTs e um era um estudo de replicação com um único grupo. O número de ensaios clínicos localizados foi muito pequeno e de qualidade não muito alta. Os resultadosapontaram uma tendência positiva independentemente da qualidade dos ensaios e do tipo de tratamento homeopático utilizado. Os resultados desta revisão podem sofrer de viés depublicação. As evidências disponíveis atualmente são insuficientes para conclusões definitivas.Portanto, o tratamento homeopático ainda precisa de maior avaliação, através de RCTs adequados e de alta qualidade metodológica.

Las revisiones sistemáticas de estudios controlados aleatorizados(ECC) son esenciales en la medicina basada en evidencia (MBE). El objetivo de este estudio fue evaluar si hay evidenciasuficiente a favor de la eficacia de la homeopatía en pacientes con VIH/SIDA a partir de ensayosclínicos. Se trata de una revisión sistemática basada en criterios de la investigación acumulada,con evaluación de la calidad metodológica de los estudios publicados. La calidad de los estudiosfue evaluada mediante una lista de criterios validados y predefinidos ylos resultados fueron interpretados a partir de su calidad .El principal resultado medido fue la calidad metodológica de los estudios expresa como amenazas a su validez externa, interna, de constructo y conclusiónestadística. De los 6 estudios clínicos de resultados localizados, 3 eran ensayos abiertos, no aleatorizados y no controlados, 2 eran ECC y uno un estudio de replicación con un único grupo. El número de estudios clínicos localizados fue muy bajo y su calidad no muy alta. Los resultados indican una tendencia positiva independiente de la calidad de los estudios y el tipo de tratamiento homeopático efectuado. Los resultados de esta revisión pueden adolecer de sesgo de publicación. La evidencia actualmente disponible no permite inferir conclusiones definitivas. El tratamiento homeopático necesita mayor evaluación mediante ECC adecuados y de alta calidad metodológica.