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.

Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis.

BACKGROUND: In an adaptive clinical trial (ACT), key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts' views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. METHODS: We used a convergent, mixed-methods design employing a 22-item ACTs beliefs survey with visual analog scales and open-ended questions and mini-focus groups. We developed a coding scheme to conduct thematic searches of textual data, depicted responses to visual analog scales on box-plot diagrams, and integrated findings thematically. Fifty-three clinical trial experts from four constituent groups participated: academic biostatisticians (n = 5); consultant biostatisticians (n = 6); academic clinicians (n = 22); and other stakeholders including patient advocacy, National Institutes of Health, and U.S. Food and Drug Administration representatives (n = 20). RESULTS: The respondents recognized potential ethical benefits of ACTs, including a higher probability of receiving an effective intervention for participants, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges voiced include developing procedures so trial participants can make informed decisions about taking part in ACTs and plausible, though unlikely risks of research personnel altering enrollment patterns. CONCLUSIONS: Clinical trial experts recognize ethical advantages but also pose potential ethical challenges of ACTs. The four constituencies differ in their weighing of ACT ethical considerations based on their professional vantage points. These data suggest further discussion about the ethics of ACTs is needed to facilitate ACT planning, design and conduct, and ultimately better allow planners to weigh ethical implications of competing trial designs.

Interpretation of the Sexual Functioning Questionnaire in the presence of vulvar pain.

OBJECTIVE: This study aimed to assess whether the domains identified by items on the Sexual Functioning Questionnaire (SFQ) apply to women with vulvodynia. MATERIALS AND METHODS: Forty-one women with vulvodynia and 43 asymptomatic controls, between the ages 18 and 70 years, were assessed with a physician evaluation and a written survey that included the SFQ. RESULTS: Women with vulvodynia had a higher likelihood of female sexual dysfunction than did controls as indicated by 5 of the seven individual SFQ domains (desire, arousal-lubrication, pain, enjoyment, and partner domains, p < .05). Scored on individual items relating to pain or penetrative sex differed more by vulvodynia presence than did items related to arousal and emotions. Compared with published SFQ psychometrics, factor analysis among women with vulvodynia demonstrated similar factor loadings in 6 of the 7 domains of the SFQ (desire, arousal-sensation, arousal-lubrication, orgasm, partner, and pain), but the enjoyment domain intermingled substantially with these other domains. CONCLUSIONS: The SFQ factor structure is generally valid among women with vulvodynia. However, vulvodynia may impact responses to individual items on questions about pain and/or penetration, which may potentially result in erroneous interpretations.

Impact of a single-session psychosocial counseling intervention for women with vulvodynia.

OBJECTIVE: To evaluate the impact of a single session of psychosocial counseling on patients with vulvodynia. METHODS: Patients diagnosed with vulvodynia at a vulvovaginal specialty clinic were randomly assigned to receive either a one-on-one 30- to 45-min psychosocial counseling session with a psychosexual counselor plus written educational materials (intervention group) or written materials alone (control group). They completed a survey before and 6 weeks after randomization that included demographic information and validated measures of sexual function and illness perception. RESULTS: Thirty-one of 38 (81.6%) women approached chose to participate; 26 of the 31 (83.9%) completed the 6-week follow-up survey. Only the intervention group showed improvement in knowledge about vulvovaginal and sexual health, as well as in most measures of improvement in illness perception, as measured by the Brief Illness Perception Questionnaire (P < 0.05). When compared directly with those in the control group, patients in the intervention group reported increased understanding of their vulvar symptoms (P < 0.005) and lessened emotional impact of these symptoms (P = 0.035). CONCLUSION: Patients receiving one session of the one-on-one psychosocial counseling intervention reported improved understanding and lessened emotional impact of their vulvar symptoms, compared with the control group. This study suggests that improvement may occur following minimal intervention and supports the need for further study.

Prevalence and demographic characteristics of vulvodynia in a population-based sample.

OBJECTIVE: The objective of the study was to determine the prevalence and characteristics of vulvodynia among women in southeast Michigan. STUDY DESIGN: A population-based study of adult women was conducted, using telephone recruitment and completion of a self-administered survey. Weighted estimates of vulvodynia prevalence and characteristics were determined. RESULTS: Over a year, 2542 women were recruited and 2269 (89.3%) completed the self-administered survey. The weighted prevalence of vulvodynia was 8.3% (95% confidence interval, 7.0-9.8) or approximately 101,000 women in the targeted population. Prevalence remained stable through age 70 years and declined thereafter. Among sexually active women, the prevalence was similar at all ages. Of 208 women meeting vulvodynia criteria, 101 (48.6%) had sought treatment, and only 3 (1.4%) had been diagnosed with vulvodynia (unweighted values). Previous vulvodynia symptoms had resolved in 384 women (16.9%) after a mean duration of 12.5 years. CONCLUSION: Vulvodynia is common, although rarely diagnosed. Prevalence remains high among sexually active women of any age.

An overview of the adaptive designs accelerating promising trials into treatments (ADAPT-IT) project.

Randomized clinical trials, which aim to determine the efficacy and safety of drugs and medical devices, are a complex enterprise with myriad challenges, stakeholders, and traditions. Although the primary goal is scientific discovery, clinical trials must also fulfill regulatory, clinical, and ethical requirements. Innovations in clinical trials methodology have the potential to improve the quality of knowledge gained from trials, the protection of human subjects, and the efficiency of clinical research. Adaptive clinical trial methods represent a broad category of innovations intended to address a variety of long-standing challenges faced by investigators, such as sensitivity to previous assumptions and delayed identification of ineffective treatments. The implementation of adaptive clinical trial methods, however, requires greater planning and simulation compared with a more traditional design, along with more advanced administrative infrastructure for trial execution. The value of adaptive clinical trial methods in exploratory phase (phase 2) clinical research is generally well accepted, but the potential value and challenges of applying adaptive clinical trial methods in large confirmatory phase clinical trials are relatively unexplored, particularly in the academic setting. In the Adaptive Designs Accelerating Promising Trials Into Treatments (ADAPT-IT) project, a multidisciplinary team is studying how adaptive clinical trial methods could be implemented in planning actual confirmatory phase trials in an established, National Institutes of Health-funded clinical trials network. The overarching objectives of ADAPT-IT are to identify and quantitatively characterize the adaptive clinical trial methods of greatest potential value in confirmatory phase clinical trials and to elicit and understand the enthusiasms and concerns of key stakeholders that influence their willingness to try these innovative strategies.

Experience of symptoms, sexual function, and attitudes toward counseling of women newly diagnosed with vulvodynia.

OBJECTIVE: This study aimed to assess health beliefs and behaviors, experience of pain, coping mechanisms, sexual function, and attitudes toward counseling of patients newly diagnosed with vulvodynia. MATERIALS AND METHODS: Participants were enrolled from all newly diagnosed vulvodynia patients seen at the University of Michigan Vulvar Disease Clinic at Chelsea. Participants completed a questionnaire assessing perceptions and beliefs about their vulvodynia, coping ability, sexual function, and interest in counseling. RESULTS: Thirty-one women were enrolled, ranging in age from 21 to 81 years; 68% had current partners. On a scale of 1 to 10 (low to high), participants rated their symptoms as severe-(mean [SD] = 7.42 [1.50]), perceived little control over symptoms (2.61 [2.64]); were very concerned about symptoms (8.77 [1.73]); and were very emotionally affected by their disorder (7.00 [2.82]). During the previous 4 weeks, 52% reported low to no sexual desire; 71% reported being dissatisfied with their overall sex life; 26% were not comfortable saying no to partner sex; 23% to 36% did not attempt penetration; and for 36%, their pain was rated as high or very high. Sixty-one percent of women indicated that they would consider counseling for coping with vulvar pain. In addition, 29% (9/31) said they "would" and 48% (15/31) said they "maybe would" consider seeing a sex therapist for their vulvar pain. CONCLUSIONS: Women with newly diagnosed vulvodynia report substantial impact of vulvar pain but feel little control over symptoms. Sexual desire and sexual satisfaction are low. Most of the respondents would consider counseling to help address these issues.

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.

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.

Factors associated with vulvodynia incidence.

OBJECTIVE: To assess incidence rates of and risk factors for vulvodynia. METHODS: We conducted a longitudinal population-based study of women in southeast Michigan (Woman-to-Woman Health Study) using a validated survey-based screening test for vulvodynia that was repeated at 6-month intervals over 30 months. Unadjusted incidence rates were determined using Poisson models. Demographic and symptom-related risk factors for incidence were assessed using discrete time survival analysis. RESULTS: Women who screened negative for vulvodynia at baseline and were followed through at least one additional survey (n=1,786) were assessed for onset of vulvodynia. The incidence rate was 4.2 cases per 100 person-years, and rates per 100 person-years were greater in women who were younger (7.6 cases per 100 person-years at age 20 years, compared with 3.3 cases per 100 person-years at age 60 years), Hispanic (9.5 cases per 100 person-years), married, or living as married (4.9 cases per 100 person-years); had reported symptoms of vulvar pain but did not meet vulvodynia criteria on the initial survey (11.5 cases per 100 person-years); or had reported past symptoms suggesting a history of vulvodynia (7.5 cases per 100 person-years). Increased risk of new-onset vulvodynia also included baseline sleep disturbance, chronic pain in general, specific comorbid pain disorders, and specific comorbid psychological disorders. CONCLUSIONS: The incidence rates of vulvodynia differ by age, ethnicity, and marital status. Onset is more likely among women with previous symptoms of vulvodynia or those with intermediate symptoms not meeting criteria for vulvodynia and among those with pre-existing sleep, psychological, and comorbid pain disorders. This suggests vulvodynia is an episodic condition with a potentially identifiable prodromal phase. LEVEL OF EVIDENCE: II.

Urogenital symptoms and pain history as precursors of vulvodynia: a longitudinal study.

BACKGROUND: We sought to assess vulvodynia incidence and risk factors among those with and without premorbid urogenital symptoms. METHODS: Women's Health Registry members who completed a baseline assessment in 2004 were sent a 2-year and 4-year follow-up survey containing a validated screen for vulvodynia. Subgroup analysis of vulvodynia incidence rates was performed, and risk factors associated with incidence were assessed. RESULTS: Of 1037 original enrollees, 723 (69.7%) completed consecutive surveys (initial and 2-year or initial, 2-year, and 4-year), 660 of whom did not have current or past vulvodynia at baseline. Of these 660, 71 (10.8%) first met criteria for vulvodynia within the 4-year period, for an annual incidence rate of 3.1% (95% confidence interval [CI] 2.5-4.0). Baseline strict controls were less likely to develop criteria for vulvodynia diagnosis (annual incidence rate of 1.4%) compared to those with an intermediate phenotype (presence of dyspareunia or history of short-term vulvar pain), for whom the incidence rate was 5.6% (p<0.001). Risk factors for incident vulvodynia differed between these two groups. Among the strict controls, an increased risk was noted among younger women (incidence rate ratio) [IRR] 3.6). For those with an intermediate phenotype, risk was increased among nonwhite women and those reporting pain with or after intercourse (IRR 2.2, 3.4, and 3.1, respectively). In both control groups, incident vulvodynia risk increased among those reporting urinary burning at enrollment (IRR 4.2 and 2.8 for strict and intermediate phenotype controls, respectively). CONCLUSIONS: The annual incidence of vulvodynia is substantial (3.1%) and is greater among women reporting a history of dyspareunia or vulvar pain that did not meet criteria for vulvodynia compared to those without this history, suggesting that generalized urogenital sensitivity may be a common underlying mechanism predating the clinical presentation of vulvodynia.

Correlates of putting condoms on after sex has begun and of removing them before sex ends: a study of men attending an urban public STD clinic.

This study aimed to identify possible correlates of putting condoms on after sex has begun and taking them off before sex has ended among male patients of an urban, public sexually transmitted disease clinic. Participants responded to a questionnaire and were largely African American men, 18 to 35 years old, who had used a condom during penile-vaginal intercourse at least three times in the past 3 months. In controlled analyses, men who were not highly motivated to use condoms correctly were nearly twice as likely to put a condom on after sex had begun. Men who reported erection loss during sex were about twice as likely to remove condoms before sex ended. Men reporting difficulties with the fit and feel of condoms were 2.5 times more likely to remove condoms early. Identified correlates may be amenable to clinic-based education and counseling augmented by offering a variety of condom brands and sizes to patients.