The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project.

OBJECTIVES: Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. METHODS: To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. RESULTS: The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. CONCLUSION: Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development.

A conceptual model for the development process of confirmatory adaptive clinical trials within an emergency research network.

BACKGROUND: Adaptive clinical trials use accumulating data from enrolled subjects to alter trial conduct in pre-specified ways based on quantitative decision rules. In this research, we sought to characterize the perspectives of key stakeholders during the development process of confirmatory-phase adaptive clinical trials within an emergency clinical trials network and to build a model to guide future development of adaptive clinical trials. METHODS: We used an ethnographic, qualitative approach to evaluate key stakeholders' views about the adaptive clinical trial development process. Stakeholders participated in a series of multidisciplinary meetings during the development of five adaptive clinical trials and completed a Strengths-Weaknesses-Opportunities-Threats questionnaire. In the analysis, we elucidated overarching themes across the stakeholders' responses to develop a conceptual model. RESULTS: Four major overarching themes emerged during the analysis of stakeholders' responses to questioning: the perceived statistical complexity of adaptive clinical trials and the roles of collaboration, communication, and time during the development process. Frequent and open communication and collaboration were viewed by stakeholders as critical during the development process, as were the careful management of time and logistical issues related to the complexity of planning adaptive clinical trials. CONCLUSION: The Adaptive Design Development Model illustrates how statistical complexity, time, communication, and collaboration are moderating factors in the adaptive design development process. The intensity and iterative nature of this process underscores the need for funding mechanisms for the development of novel trial proposals in academic settings.

Attitudes and opinions regarding confirmatory adaptive clinical trials: a mixed methods analysis from the Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT) project.

BACKGROUND: Adaptive designs have been increasingly used in the pharmaceutical and device industries, but adoption within the academic setting has been less widespread - particularly for confirmatory phase trials. We sought to understand perceptions about understanding, acceptability, and scientific validity of adaptive clinical trials (ACTs). METHODS: We used a convergent mixed methods design using survey and mini-focus group data collection procedures to elucidate attitudes and opinions among "trial community" stakeholders regarding understanding, acceptability, efficiency, scientific validity, and speed of discovery with adaptive designs. Data were collected about various aspects of ACTs using self-administered surveys (paper or Web-based) with visual analog scales (VASs) with free text responses and with mini-focus groups of key stakeholders. Participants were recruited as part of an ongoing NIH/FDA-funded research project exploring the incorporation of ACTs into an existing NIH network that focuses on confirmatory phase clinical trials in neurological emergencies. "Trial community" representatives, namely, clinical investigators, biostatisticians, NIH officials, and FDA scientists involved in the planning of four clinical trials, were eligible to participate. In addition, recent and current members of a clinical trial-oriented NIH study section were also eligible. RESULTS: A total of 76 stakeholders completed the survey (out of 91 who were offered it, response rate 84 %). While the VAS attitudinal data showed substantial variability across respondents about acceptability and understanding of ACTs by various constituencies, respondents perceived clinicians to be less likely to understand ACTs and that ACTs probably would increase the efficiency of discovery. Textual and focus group responses emerged into several themes that enhanced understanding of VAS attitudinal data including the following: acceptability of adaptive designs depends on constituency and situation; there is variable understanding of ACTs (limited among clinicians, perceived to be higher at FDA); views about the potential for efficiency depend on the situation and implementation. Participants also frequently mentioned a need for greater education within the academic community. Finally, the empiric, non-quantitative selection of treatments for phase III trials based on limited phase II trials was highlighted as an opportunity for improvement and a potential explanation for the high number of neutral confirmatory trials. CONCLUSIONS: These data show considerable variations in attitudes and beliefs about ACTs among trial community representatives. For adaptive trials to be fully considered when appropriate and for the research enterprise to realize the full potential of adaptive designs will likely require extensive experience and trust building within the trial community.

Reflections on the Adaptive Designs Accelerating Promising Trials Into Treatments (ADAPT-IT) Process-Findings from a Qualitative Study.

CONTEXT: The context for this study was the Adaptive Designs Advancing Promising Treatments Into Trials (ADAPT-IT) project, which aimed to incorporate flexible adaptive designs into pivotal clinical trials and to conduct an assessment of the trial development process. Little research provides guidance to academic institutions in planning adaptive trials. OBJECTIVES: The purpose of this qualitative study was to explore the perspectives and experiences of stakeholders as they reflected back about the interactive ADAPT-IT adaptive design development process, and to understand their perspectives regarding lessons learned about the design of the trials and trial development. MATERIALS AND METHODS: We conducted semi-structured interviews with ten key stakeholders and observations of the process. We employed qualitative thematic text data analysis to reduce the data into themes about the ADAPT-IT project and adaptive clinical trials. RESULTS: The qualitative analysis revealed four themes: education of the project participants, how the process evolved with participant feedback, procedures that could enhance the development of other trials, and education of the broader research community. DISCUSSION AND CONCLUSIONS: While participants became more likely to consider flexible adaptive designs, additional education is needed to both understand the adaptive methodology and articulate it when planning trials.

PAR1-mediated NFkappaB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism.

We have previously reported that protease-activated receptor 1 (PAR1 or thrombin receptor) is over-expressed in metastatic prostate cancer cell lines compared to prostate epithelial cells. In this study, we examined 1,074 prostate biopsies by tissue microarray analysis and demonstrated that PAR1 expression is significantly increased in prostate cancer compared to normal prostate epithelial cells and benign prostatic hyperplasia. We hypothesized that PAR1 activation contributed to prostate cancer cell progression. We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen-independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFkappaB p65 subunit. IL-6 and IL-8 levels were also elevated in conditioned media by at least two-fold within 4-6 h of PAR1 activation. This induction of cytokine production was abrogated by pretreatment of cells with the NFkappaB inhibitor caffeic acid phorbol ester. The p38 and ERK1/2 MAPK signaling cascades were also activated by PAR1 stimulation, whereas the SAPK/JNK pathway was unaffected. Inhibition of p38 and ERK1/2 by SB-203589 and PD-098059, respectively, did not abrogate NFkappaB activity, suggesting an independent induction of NFkappaB by PAR1 stimulation. Furthermore, TUNEL assay showed that activation of PAR1 attenuated docetaxel induced apoptosis through the upregulation of the Bcl-2 family protein Bcl-xL. Akt activation was not observed, suggesting that drug resistance induced by PAR1 was independent of PI3K signaling pathway. Because thrombin and PAR1 are over-expressed in prostate cancer patients, targeting the inhibition of their interaction may attenuate NFkappaB signaling transduction resulting in decreased drug resistance and subsequent survival of prostate cancer cells.