Adequate Enrollment Research Articles

A systematic review of parenting interventions for child chronic health conditions.

This systematic review summarizes the parenting intervention literature for parents of children with chronic health conditions and evaluates intervention effects on parenting (parenting skills and parenting efficacy) and child (behaviour, illness severity/control and quality of life) outcomes. Systematic searches using seven electronic databases (including CINHAL, MEDLINE and PsycINFO) were used to identify relevant papers published in English between 1997 and 2017, and reference lists were searched for additional relevant articles. Ten papers reporting on eight separate studies met inclusion criteria: three studies evaluated stand-alone parenting interventions, while the remaining five studies included parenting components in broader interventions that also targeted medically oriented aspects of illness management. Results suggest that parenting interventions may lead to improved parent self-efficacy, parenting behaviour, illness severity/control, child quality of life and child behaviour; however, intervention effects were mixed and confined to parent-report outcome measures. A paucity of studies using rigorous randomized controlled trial study designs limits the conclusions that can be drawn regarding intervention efficacy. Achieving adequate enrolment and retention of families in parenting intervention trials appears to be problematic within these clinical groups. Larger samples and more diverse clinical populations will support the reliability of future evaluations of parenting interventions in this context and improve generalizability of results.

Feasibility, effectiveness, and students' attitude toward using WhatsApp in histology teaching and learning.

OBJECTIVE:The present study assessed the feasibility, effectiveness, and students’ attitude toward histology teaching using WhatsApp.MATERIALS AND METHODS:We conducted 6 months of histology teaching session on a “Histology learning WhatsApp group” consisting of 250 1st-year medical graduate students at Dr. S.N. Medical College, Jodhpur. A teacher posted a digital image of histology slides created using a mobile camera; a slide diagram sketched using hematoxylin and eosin pencil, identification points, and detail description of slide followed by discussion of queries. The feasibility was measured by adequate enrollment of students in the WhatsApp group, drop-out rate during the teaching period, acceptability of the by students based on their feedback, and perception of the teacher. To study the effectiveness, we conducted an online test pre- and posttests after every 2 months. The Student's attitude WhatsApp learning was assessed using the prevalidated feedback questionnaire.RESULTS:All the 1st-year medical graduate students admitted in the year 2016 enrolled and most of them were actively participated in the discussion conducted on WhatsApp group with zero dropout rate. Students’ feedback indicated that students enjoyed learning using WhatsApp with better participation than traditional teaching method. Students liked anytime, anywhere learning using WhatsApp and it helped them to clear doubts. The statistical difference between average pre- and posttest scores (6.54 ± 2.33 and 16.37 ± 3.32, respectively) were statistically significant.CONCLUSIONS:We conclude that histology teaching using WhatsApp learning group is feasible, effective, and student-friendly method. It should be used more frequently to complement traditional teaching.

Asian representation in clinical trials of new drugs for the treatment of cancer.

6564 Background: In the US, statistics for Asians are often aggregated with other racial groups. This poses challenges in estimating the cancer burden and in defining cancer clinical trial enrollment targets in this demographic subgroup. ‘Asian‘ refers to persons with origins in the Far East, Southeast Asia, or the Indian sub-continent. Asians comprise 6% of the US population and the largest Asian subgroups in the US are of Chinese (22%), Filipino (19%), Asian Indian (19%), Vietnamese (10%), Korean (9%), and Japanese (7%) descent. The representation of Asian patients in global clinical trials may not be reflective of the Asian subgroups in the US. FDA conducted an analysis to describe patients categorized as ‘Asian’ in clinical trials supporting the approval of new drugs. Methods: We reviewed the marketing applications of 33 new molecular entities approved for the treatment of solid tumor malignancies between 2011- 2016 to identify trials that provided the primary evidence of safety and efficacy. Results: A total of 29,941 patients were enrolled; 17 % were Asian. Most Asian patients were enrolled in Korea (20%), Taiwan (20%), mainland China (20%), Japan (16%), and US (5%). Few patients were enrolled in India (3%); the Philippines (1%); Vietnam (0). In the US, Asian patients comprised 3% of the total number of patients enrolled. Conclusions: Asian patients represented a heterogeneous mix. A large proportion was enrolled in Taiwan (20%) and Korea (20%), whereas the largest proportion of US Asians have origins in mainland China (22%), the Philippines (19%), India (19%), and Vietnam (10%). Nevertheless, although Asians share a common ancestry, it is not clear whether data from global clinical trials are generalizable to Asian patients in the US. Therefore, strategies to improve the enrollment of US Asian patients in clinical trials are needed. Among patients enrolled in the US, 3% were Asians, a proportion that is below US Asian population estimates (6%). While most site-specific cancer incidence and death rates are lower in US Asians compared to Whites, the rates of some cancers (e. g., stomach and liver) are higher in this group. Therefore, studies are needed to determine adequate enrollment targets in this demographic subgroup.

Assessment of linkages from HIV testing to enrolment and retention in HIV care in Central Mozambique.

IntroductionEffectiveness of the rapid expansion of antiretroviral therapy (ART) throughout sub-Saharan Africa is highly dependent on adequate enrolment and retention in HIV care. However, the measurement of both has been challenging in these settings. This study aimed to assess enrolment and retention in HIV care (pre-ART and ART) among HIV-positive adults in Central Mozambique, including identification of barriers and facilitators.MethodsWe assessed linkages to and retention in HIV care using a mixed quantitative and qualitative approach in six districts of Manica and Sofala provinces. We analyzed routine district and health facility monthly reports and HIV care registries from April 2012 to March 2013 and used single imputation and trimmed means to adjust for missing values. In eight health facilities in the same districts and period, we assessed retention in HIV care among 795 randomly selected adult patient charts (15 years and older). We also conducted 25 focus group discussions and 53 in-depth interviews with HIV-positive adults, healthcare providers and community members to identify facilitators and barriers to enrolment and retention in HIV care.ResultsOverall, 46% of the monthly HIV testing reports expected at the district level were missing, compared to 6.4% of the pre-ART registry reports. After adjustment for missing values, we estimated that the aggregate numbers of adults registered in pre-ART was 75% of the number of persons tested HIV-positive in the six districts. In the eight health facilities, 40% of the patient charts for adults enrolled in pre-ART and 44% in ART were missing. Of those on ART for whom charts were found, retention in treatment within 90 and 60 days prior to the study team visit was 34 and 25%, respectively. Combining these multiple data sources, the overall estimated retention was 18% in our sample. Individual-level factors were perceived to be key influences to enrolment in HIV care, while health facility and structural-level factors were perceived to be key influences of retention.ConclusionsEfforts to increase linkages to and retention in HIV care should address individual, health facility, and structural-level factors in Central Mozambique. However, their outcomes cannot be reliably assessed without improving the quality of routine health information systems.

Network meta-analyses on in-stent restenosis treatment: dealing with complexity to clarify efficacy and safety.

Major advances have occurred during the last decade in the prevention of in-stent restenosis (ISR). Notably, drug-eluting stents (DES) drastically reduced the incidence of ISR as compared with that seen with bare-metal stents (BMS) (1). However, DES-ISR still occur especially when these devices are used in adverse clinical and anatomic scenarios (1). In addition, BMS are frequently used in selected patient subsets, including those unable to maintain a prolonged dual antiplatelet regimen and those at high bleeding risk (1). Therefore, nowadays treatment of ISR still represents a real challenge in every day clinical practice (2-4). Although the acute results obtained by repeated interventions are largely favorable the long-term outcome of these patients is frequently shadowed by clinical recurrences (2-4). Of concern, the underlying anatomic substrate of DES-ISR appears to be particularly complex and prone to recurrent ISR (2). Furthermore, recent evidence suggest that ISR presentation, formerly considered a benign phenomenon, is frequently associated with unstable symptoms, including a significant number of patients fulfilling current criteria for myocardial infarction (2). Many randomized clinical trials have compared different therapeutic strategies in patients with ISR (2-4). These include plain balloon angioplasty (BA), cutting balloon angioplasty, BMS, ablative devices, brachytherapy, DES and drug-coated balloons (DCB). Recent clinical practice guidelines suggest that both DES and DCB are effective (recommendation/evidence IA) for patients suffering from ISR (5). Nevertheless, the therapy of choice for these patients currently remains unsettled. Indeed, most randomized trials used surrogate late angiographic parameters (including percent diameter stenosis, binary restenosis, minimal lumen diameter and late lumen loss) as a measure of efficacy (2-4). This was a reasonable strategy to ensure an adequate enrollment of the required number of patients presenting with this relatively rare condition within a short time frame. Indeed, these trials provided major evidence on relative efficacy of these interventions. However, most randomized studies eventually enrolled a limited number of patients and, therefore, additional evidence is still warranted in order to establish the relative clinical efficacy and safety of these competing interventions.

Feasibility of Two Educational Methods for Teaching New Mothers: A Pilot Study.

BackgroundPrinted health educational materials are commonly issued to prepare patients for hospital discharge. Teaching methods that engage multiple senses have been shown to positively affect learning outcomes, suggesting that paper materials may not be the most effective approach when educating new mothers. In addition, many written patient educational materials do not meet national health literacy guidelines. Videos that stimulate visual and auditory senses provide an alternative, potentially more effective, strategy for delivering health information. The acceptability of these methods, as perceived by nurses executing patient education initiatives, is important for determining the most appropriate strategy.ObjectiveThe purpose of this study was to determine the feasibility of 2 educational methods for teaching new mothers how to care for themselves and their infants after hospital discharge. Feasibility was measured by adequate enrollment, acceptability of the intervention to patients and nurses, and initial efficacy.MethodsNew mothers (n=98) on a Mother-Baby Unit received health information focused on self-care and infant care delivered as either simple printed materials or YouTube videos on an iPad. Mothers completed a pretest, post-test, and an acceptability survey. Following completion of the initiative, nurses who participated in delivering the health education using one of these 2 methods were asked to complete a survey to determine their satisfaction with and confidence in using the materials.ResultsMothers, on average, were 26 years old; 72% had a high school education; and 41% were African American. The improvement in knowledge scores was significantly higher for the iPad group (8.6% vs 4.4%, P=.02) compared to the pamphlet group. Group (B=4.81, P=.36) and time (B=6.12, P<.001) significantly affected scores, while no significant interaction effect was observed (B=5.69, P=.09). There were no significant differences in responses between the groups (all P values >.05). The nurses had a mean age of 44.3 years (SD 13.9) and had, on average, 16.6 years of experience (SD 13.8). The nurses felt confident and satisfied administering both educational modalities.ConclusionsThe pamphlet and iPad were identified as feasible and acceptable modalities for educating new mothers about self-care and infant care, though the iPad was more effective in improving knowledge. Understanding the acceptability of different teaching methods to patient educators is important for successful delivery of informational materials at discharge.

Feasibility of a Randomized Clinical Trial for Treatment of Femoroacetabular Impingement of the Hip.

Background:Symptomatic femoroacetabular impingement (FAI) is currently corrected by surgery. However, it is possible that nonsurgical treatment could resolve symptomatic FAI in some patients; thus, uncertainty about the necessity of surgical treatment exists. The current equipoise concerning FAI treatment presents an opportunity to conduct a randomized controlled trial (RCT) of surgical and nonsurgical treatment options. Given the unique challenge of adequate patient enrollment in RCTs, it is important that a preliminary study is done to appraise the feasibility of conducting an RCT.Purpose:To estimate enrollment rates of a planned future RCT to compare surgical and nonsurgical treatments for symptomatic FAI and to identify factors associated with patients’ willingness to participate in the randomized trial.Study Design:Cross-sectional study; Level of evidence, 4.Methods:Patients diagnosed with FAI at 2 orthopaedic centers were presented with a hypothetical randomized trial comparing 2 treatment options for FAI. All patients completed forms providing information regarding their willingness to participate and treatment preferences.Results:A total of 75 patients participated in the study: 53 and 22 from 2 centers, respectively. Twenty-eight percent indicated absolute willingness to participate in the trial, 40% were probably willing or unsure, and 32% were definitely not willing; 18.7% had a strong preference for surgery while 2.7% strongly preferred nonsurgical treatment. The majority (78.6%) had no strong preference for either treatment arm. There were correlations between treatment preferences and willingness to participate. Patients with a strong treatment preference and/or a preference for surgery were less likely to be willing to participate.Conclusion:The study findings suggest that sufficient patient accrual for a randomized trial of FAI treatment is currently feasible while equipoise still exists among patients and surgeons.

Designing effective drug and device development programs for hospitalized heart failure: A proposal for pretrial registries

Recent international phase III clinical trials of novel therapies for hospitalized heart failure (HHF) have failed to improve the unacceptably high postdischarge event rate. These large studies have demonstrated notable geographic and site-specific variation in patient profiles and enrollment. Possible contributors to the lack of success in HHF outcome trials include challenges in selecting clinical sites capable of (1) providing adequate numbers of appropriately selected patients and (2) properly executing the study protocol. We propose a "pretrial registry" as a novel tool for improving the efficiency and quality of international HHF trials by focusing on the selection and cultivation of high-quality sites. A pretrial registry may help assess a site's ability to achieve adequate enrollment of the target patient population, integrate protocol requirements into clinical workflow, and accomplish appropriate follow-up. Although such a process would be associated with additional upfront resource investment, this appropriation may be modest in comparison with the downstream costs associated with maintenance of poorly performing sites, failed clinical trials, and the global health and economic burden of HHF. This review is based on discussions between scientists, clinical trialists, and regulatory representatives regarding methods for improving international HHF trials that took place at the United States Food and Drug Administration on January 12th, 2012.

Practical Aspects of Recruitment and Retention in Clinical Trials of Rare Genetic Diseases: The Phenylketonuria (PKU) Experience

Bringing treatments for rare genetic diseases to patients requires clinical research. Despite increasing activism from patient support and advocacy groups to increase access to clinical research studies, connecting rare disease patients with the clinical research opportunities that may help them has proven challenging. Chief among these challenges are the low incidence of these diseases resulting in a very small pool of known patients with a particular disease, difficulty of diagnosing rare genetic diseases, logistical issues such as long distances to the nearest treatment center, and substantial disease burden leading to loss of independence. Using clinical studies of phenylketonuria as an example, this paper discusses how, based on the authors' collective experience, partnership among clinicians, patients, study coordinators, genetic counselors, dietitians, industry, patient support groups, and families can help overcome the challenges of recruiting and retaining patients in rare disease clinical trials. We discuss specific methods of collaboration, communication, and education as part of a long-term effort to build a community committed to advancing the medical care of patients with rare genetic diseases. By talking to patients and families regularly about research initiatives and taking steps to make study participation as easy as possible, rare disease clinic staff can help ensure adequate study enrollment and successful study completion.

Motivations of patients with pulmonary arterial hypertension to participate in randomized clinical trials

There is substantial need to rigorously evaluate existing and new therapies for pulmonary arterial hypertension (PAH) and other severe and relatively rare conditions affecting younger patients. However, the ability to conduct meaningful randomized clinical trials (RCTs) in such contexts often is limited by difficulties obtaining adequate patient enrollment. To understand the motivations of patients with PAH for participating in RCTs so as to facilitate enrollment in future trials among patients with similar diseases. We conducted semistructured interviews of a diverse sample of patients with World Health Organization (WHO) Group I PAH. We purposefully recruited a diverse sample of participants until theoretical saturation was reached. We randomly assigned patients to review hypothetical RCTs that did or did not allow continuation of background PAH therapies and elicited their reasons for or against enrolling. Interviews were transcribed and analyzed using constant comparison techniques to code and sort data into discrete themes. The 26 PAH patients enrolled before theoretical saturation was reached identified 24 factors that would influence their RCT enrollment decisions. These factors grouped naturally into four themes: (1) personal medical benefits, (2) personal medical risks/harms, (3) nonmedical benefits, and (4) nonmedical burdens. Personal benefits were cited as commonly as altruistic motives. One third of the patients (9/26) suggested that they would defer enrollment decisions to their treating clinicians. Seventy-nine percent of patients (11/14) assigned to consider trials without background therapies expressed concerns about clinical deterioration (vs. 17% (2/12) among patients assigned to consider trials allowing background therapies). The sample was recruited from a single academic center. Furthermore, the use of hypothetical trials may not elicit identical decision-making processes as may be used among patients contemplating actual trial participation. For PAH patients considering RCT enrollment, the potentials for personal benefit and risk are at least as important as altruistic motives. Minimizing the time demands of participating, financial remuneration, and allowing participants to continue current therapies are factors, which might enhance enrollment to trials in similar disease areas.

Evaluating Sex Differences in Medical Device Clinical Trials

THE SAFETY AND EFFECTIVENESS OF MEDICAL TREATments can differ in men and women for many reasons related to different epidemiologic characteristics, physiology, and body size. In general, women have higher bleeding rates and procedural morbidity and mortality than men, which means that their risk/benefit ratios for many implanted medical devices can differ from men. Therefore, sex-specific safety and effectiveness data are necessary for informed patient decision making. In 2008, the US Food and Drug Administration (FDA) convened 2 workshops on this topic that included multiple stakeholders— patient groups, medical device industry representatives, academia, and government officials. In December 2011, the FDA released a draft guidance informed by these workshops, entitled “Evaluation of Sex Differences in Medical Device Clinical Studies.” This document discusses the underrepresentation of women in medical device clinical trials and provides recommendations for increasing enrollment of women and performing sex-specific analyses. A 90-day public comment period began on December 19, 2011. The FDA draft guidance document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials. For studies that have not yet been completed, the draft guidance recommends keeping enrollment open until a prespecified number of women are enrolled. Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women. The draft guidance document also recommends that outcomes data be analyzed by sex. By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. This approach is laudable; the difference between men and women in terms of effectiveness and safety of medical devices has long been understudied. The recommendations in this draft guidance may help ensure safe and effective use of medical devices in both sexes. However, the notation on this guidance stating that it “Contains Nonbinding Recommendations” raises the fundamental question of whether these important guidelines will be followed. This is not a new question. In 1994, FDA issued a “Gender Bias” directive stating that FDA Summaries of Safety and Effectiveness Data, which are released on premarket approval for all high-risk medical devices, should examine clinical trial data for differences in safety and efficacy by sex. However, an examination of compliance with this directive found that it is routinely ignored. Among 78 high-risk cardiovascular devices approved during the years 2000 through 2007, the overall patient population in these studies was 67% men with no increase in the enrollment of women over time, although women make up 46% of all patients with cardiovascular disease. The analyses by sex specified in the 1994 FDA directive occurred in only 41% of studies (51/123). When these analyses were completed, 26% (12/47) identified some difference in device safety or effectiveness by sex. In 28% of device studies (34/123), no sex distribution of the patient population was stated. As a result, clinically important sex-specific differences related to use of many medical devices are unknown. For example, the implantable cardioverter-defibrillator (ICD), a device shown to be lifesaving in selected populations, is commonly implanted in men and women. At the time of device approval, there were gaps in the data because of very low enrollment of women in the pivotal studies. In 2003 the Medicare Coverage and Advisory Committee was convened pursuant to a manufacturer’s request for expanded Medicare coverage of ICDs for primary prevention (which was granted). During the meeting, when asked why there were so few women in the pivotal Multicenter Automatic Defibrillator Implantation Trial II, the trial’s principal investigator stated, “we are contemplating a trial in the

Stepwise examination of prostate clinical trials participation to reduce accrual barriers.

157 Background: Adequate and representative enrollment in therapeutic clinical trials is important to an NCI cancer center. Clinical trial participation is a string of 6 sequential patient and physician decisions beginning with an available therapeutic trial to enrollment in the trial. Opportunities for participation may be lost at any one of these steps. The objective of this study was to calculate transitional probabilities that measure patient, especially minority patient, accrual to clinical trials at the Sidney Kimmel Comprehensive Cancer Center and to describe the barriers for those dropping out at each step. Methods: Records for “first visit” medical oncology patients seen by three SKCCC physicians from January to April 2010 were abstracted. Prostate cancer case reports from the hospital cancer registry and a medical record review provided age, race, Hispanic ethnicity, place of residence, tumor characteristics, and prior treatment history. At each transition step, we calculated the proportion of patients who remained enrollable. Results: Overall, prostate cancer clinical trial participation was 17% (16/94). Minority accrual was similar to Caucasian accrual at 19% and 17% , respectively. Retention at each step of trial participation was highest for “discussed” (98%), “enrolled” (94%), “eligibility” for available trials (79%), and “consented” (71%). Two bottlenecks were qualitatively identified: “trial availability” (65%) and “patient interest” (51%). Forty-two percent of those for whom there was no trial available were older than 70 years and 33% were patients with rising PSA after local therapy and hormone-naïve. The “patient interest” step was shaped primarily by disinterest due to distance to SKCCC (83%). Conclusions: For prostate cancer patients, recruitment to medical oncology clinical trials is robust. Minority patients however are only 17% of all patients seen and half drop out when no trial is available and half of those remaining judged distance to be a problem (hence, no interest). This study approach has clarified which factors are likely to be barriers to participation and is likely useful to making adjustments that can reduce identified barriers by adding to trial portfolio as an example.

OT3-01-16: A Phase 2 Study of Ridaforolimus (RIDA) and Dalotuzumab (DALO) in Estrogen Receptor Positive (ER+) Breast Cancer.

Abstract Background: Activation of the PI3K/AKT/mTOR pathway is common in breast cancer. Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase 1 study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents and with dose limiting toxicity of stomatitis, similar to RIDA as monotherapy. A preliminary signal of anti-tumor activity, including partial responses and prolonged progression free survival, was observed in ER+ breast cancer, especially in high proliferation tumors. This observation is supported by data from tumor profiling and preclinical data suggesting that ER+ high proliferation breast cancer may be responsive to the RIDA-DALO combination. Methods: This is a two-part, adaptive design study intended to first test the combination of RIDA-DALO against a standard agent, exemestane, for ER+ positive breast cancer that has progressed after aromatase inhibitors. The trial is a multi-center, international, randomized study with PFS as the primary endpoint. Patients (pts) are stratified into high and low proliferation strata based on baseline Ki67, and the low proliferation stratum is capped to ensure adequate enrollment of high proliferation pts. If Part A shows a PFS benefit for RIDA-DALO, Part B is intended to show the PFS benefit of the combination over the single agents by comparing RIDA-DALO to RIDA and DALO. Part B will be further adapted based on whether the PFS benefit in Part A is observed in all-comers or the high proliferation subset. Tumor tissue is collected for molecular profiling and analysis of intrinsic subtype, with an efficacy analysis based on classification of tumors using the genomic grade index (GGI) as an exploratory objective. This trial design is intended to establish proof of concept that RIDA-DALO can prolong PFS in ER+ breast cancer in all-comers or a high proliferation subset by Ki67, while efficiently addressing the development of two investigational agents in combination and leading to a two-arm Phase 3 design. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-16.

Strategies for Recruitment and Retention of Participants in Clinical Trials

CLINICAL TRIALS AND THE CONSEQUENT BENEFITS TO society are in jeopardy in the United States because of a decline in the ability to recruit patients in a timely manner to trials addressing key clinical issues. Current initiatives (eg, the Clinical Trials Transformation Initiative and the proposed National Center for Advancing Translational Sciences) and the recent Institute of Medicine report each recognize that successful recruitment and retention of participants in clinical trials is critical for improving the efficiency and effectiveness of phase 3 and 4 clinical trials and that action to ensure adequate enrollment is urgently needed. Too often trial enrollment fails or is significantly delayed, leading to substantial additional costs to the sponsor. Of particular concern is the failure of US trials to meet desired participant enrollment and the trend toward increasing emphasis on recruitment abroad. The National Heart, Lung, and Blood Institute (NHLBI) and cosponsors convened a workshop on December 7 and 8, 2010, in Bethesda, Maryland, to review, compile, and recommend successful recruitment and retention strategies in phase 3 and 4 clinical trials. Barriers to successful recruitment and key recommendations were discussed, including policies, guidelines, and reimbursement for studies involving human research participants and clinical trial enrollment experience and practice. Seventy-five participants included clinical researchers, private advocacy groups, federal sponsors, regulatory agencies, and industry. Several critical barriers to successful recruitment were identified. First, the importance of health care professionals as gatekeepers for clinical trial participation cannot be overstated. However, many clinicians are either not aware of active trials or do not refer their patients for participation in trials. Some have questioned the ethics of physicians involving their own patients in clinical trials, whereas others note the challenge of achieving equipoise when physicians have firm opinions about treatment choices. This is compounded by patients’ lack of knowledge about clinical trials for which they may be eligible, availability of experimental intervention in the community, and entrenched cultural and historical views and suspicions of clinical research. Second, the financial realities of funding clinical trials must be estimated accurately and met. Understated infrastructure needs or reimbursement costs associated with recruitment and retention can lead to failure. Substantial costs are necessary to enroll and retain diverse populations, and these additional costs compete for available funds in a fiscal climate in which cost containment is expected. Women and minority populations are more difficult and more costly to recruit and retain in trials because, for women, the costs of child care, transportation, and even usual health care are often out-of-pocket additional expenses for their participation. For minorities, extra time is needed to gain individual and community acceptance. Balancing the need to enroll these understudied populations and developing outreach strategies to support their participation is an ongoing challenge. Third, administrative burdens and regulatory requirements present unprecedented challenges, even for experienced trialists. Institutional policies that govern clinical investigation often create barriers for clinician investigators rather than encouraging their participation. Moreover, the entire concept of indirect costs related to clinical trials needs review, critical analysis, and optimization. Clinical trials are essential to evaluate new therapies and improve health care. Successful enrollment is pivotal for the success of every trial. The following are recommendations to help promote enrollment success.

An Open-Label, Long-Term Safety and Tolerability Trial of Diclofenac Sodium 1% Gel in Patients with Knee Osteoarthritis

Objective: To evaluate the long-term safety and tolerability of topical diclofenac sodium 1% gel (DSG) in the treatment of knee osteoarthritis (OA) for up to 12 months. Methods: This was a multicenter open-label, extension of two 3-month, randomized, double-blind studies of DSG in patients with knee OA (NCT ID: NCT00171691, “Safety of Diclofenac Sodium Gel in Knee Osteoarthritis”). To ensure adequate enrollment, some DSG-naïve patients with OA who had not participated in the double-blind studies were also enrolled. Patients applied 4 g DSG to 1 or both knees 4 times daily for 9 to 12 months. Safety was evaluated through adverse event (AE) reporting, physical examination, and laboratory investigations. Patients completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and physical function scales every 3 months to assess long-term effectiveness. Results: The extension study enrolled 583 patients; 294 patients completed the study. Use of DSG was documented for 578 patients (safety population). The mean age was 62.3 years, and 63.7% of patients were women. Overall, 112 (19.4%) patients reported ≥ 1 treatment-related AE, and the only treatment-related AE occurring in ≥ 1% of patients was application-site dermatitis. Treatment-related gastrointestinal, renal-function, hepatic-function, and cardiovascular AEs were reported by 3, 1, 2, and 0 patients, respectively. There were no serious AEs or deaths. At 1 year, improvements from baseline for WOMAC pain, stiffness, and physical function scale scores were 39.8%, 33.4%, and 36.9%, respectively. Conclusion: The long-term safety profile of DSG was consistent with previous 12-week studies, and DSG remained effective for a 1-year period.

Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice

Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. We assessed the 5-year cumulative incidence, starting in 2003-05, of cervical cancer and CIN3 or worse for 331,818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. In 315,061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3.8 per 100,000 women per year, slightly higher than for the 306,969 who were both negative by HPV and Pap testing (3.2 per 100,000), and half the cancer risk of the 319,177 who were negative by Pap testing (7.5 per 100,000). 313,465 (99.5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16,757 positive by HPV testing (12.1%vs 5.9%; p<0.0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0.86%vs 0.16%; p=0.004). 12,208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, [corrected] 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.

A phase II study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor-positive (ER+) breast cancer.

TPS110 Background: Activation of the PI3K/AKT/mTOR pathway is common in breast cancer. Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase I study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents and with dose limiting toxicity of stomatitis, similar to RIDA as monotherapy. A preliminary signal of anti-tumor activity, including partial responses and prolonged progression free survival, was observed in ER+ breast cancer, especially in high proliferation tumors. This observation is supported by data from tumor profiling and pre-clinical data suggesting that ER+ high proliferation breast cancer may be responsive to the RIDA-DALO combination. Methods: This is a two-part, adaptive design study intended to first test the combination of RIDA-DALO against a standard agent, exemestane, for ER+ positive breast cancer that has progressed after aromatase inhibitors. The trial is a multi-center, international, randomized study with PFS as the primary endpoint. Patients (pts) are stratified into high and low proliferation strata based on baseline Ki67, and the low proliferation stratum is capped to ensure adequate enrollment of high proliferation pts. If Part A shows a PFS benefit for RIDA-DALO, Part B is intended to show the PFS benefit of the combination over the single agents by comparing RIDA-DALO to RIDA and DALO. Part B will be further adapted based on whether the PFS benefit in Part A is observed in all-comers or the high proliferation subset. Tumor tissue is collected for molecular profiling and analysis of intrinsic subtype, with an efficacy analysis based on classification of tumors using the genomic grade index (GGI) as an exploratory objective. This trial design is intended to establish proof of concept that RIDA-DALO can prolong PFS in ER+ breast cancer in all-comers or a high proliferation subset by Ki67, while efficiently addressing the development of two investigational agents in combination and leading to a two-arm phase III design.

Paying Human Subjects in Research: Where are We, How Did We Get Here, and Now What?

Both international and federal regulations exist to ensure that scientists perform research on human subjects in an environment free of coercion and in which the benefits of the research are commensurate with the risks involved. Ensuring that these conditions hold is difficult, and perhaps even more so when protocols include the issue of monetary compensation of research subjects. The morality of paying human research subjects has been hotly debated for over 40 years, and the grounds for this debate have ranged from discussion of legal rights, economic rights, philosophical principles of vulnerability and altruism to bioethical concepts of consent, best-interest determination, and justice theory. However, the thought surrounding these issues has evolved over time, and the way we think about the role of the human research subject today is markedly different than the way we thought in the past. Society first thought of the research subject as an altruist, necessarily giving of his time to benefit society as a whole. As time progressed, many suggested that the subject should not need to sacrifice himself for research: if something goes wrong, someone should compensate the subject for injuries. The concept of redress evolved into a system in which subjects were offered money as an inducement to participate in research, sometimes merely to offset the monetary costs of participation, but sometimes even to mitigate the risks of the study. This article examines ethical and legal conversations regarding compensation from the 1960s through today, examining theories of the ethics of compensation both comparatively and critically. In conclusion, we put forward an ethical framework for treating paid research subjects, with an attempt to use this framework as a means of resolving some of the more difficult problems with paying human subjects in research.

Status of Women in Cardiovascular Clinical Trials

Cardiovascular disease (CVD) is the most common cause of death in American women and accounts for a full one-third of all deaths.1 Although the common perception may be that CVD affects mainly men, there is equal prevalence of this disease between the genders by the age of 40, and by the age of 60 more women than men are affected. More women than men have died from CVD causes on a yearly basis since the mid 1980s, and whereas the CVD mortality has steadily declined in men over the past 30 years, it has remained steady in women until very recently when CVD mortality was noted to decrease for both genders.2 See accompanying article on page 277 The impact of cardiovascular disease (CVD) on the health status of American women is gaining more recognition and has become the focus of public education efforts such as the “Go Red for Women” campaign sponsored by the American Heart Association and the “Red Dress” project sponsored by the Department of Health and Human Services, the National Institutes of Health (NIH), and the National Heart Lung and Blood Institute (NHLBI). These programs are, in part, a response to the increasing awareness of cardiovascular disease as a major source of morbidity and mortality in U.S. women. The importance of CVD as a major source of mortality in women was recognized early on by federally funded institutes including the Public Health Service Task Force, which brought attention to concerns about the health information available to women and the historical lack of research focus on women’s health in its 1985 Report of the Public Health Service Task Force on Women’s Health Issues .3 In response to this report, the National Institutes of Health adopted a policy for the inclusion of women in clinical research …

Number of Cervical Biopsies and Sensitivity of Colposcopy

To examine the influence that type of medical training and number of biopsies have on sensitivity of colposcopically guided biopsies. Among 408 women with an adequate enrollment colposcopy and a diagnosis of cervical intraepithelial neoplasia (CIN) 3 or cancer (CIN 3+) over 2 years in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions (ASCUS-LSIL) Triage Study, we evaluated factors influencing the sensitivity of the enrollment colposcopic procedure. We used contingency table analysis to examine confounding variables and chi(2) tests to ascertain statistical significance. Overall, 69.9% of women with a cumulative diagnosis of CIN 3+ had a "true-positive" enrollment colposcopically guided biopsy result of CIN 2 or worse (CIN 2+), the threshold that would trigger excisional therapy. The sensitivity of the procedure did not vary significantly by type of colposcopist. However, the sensitivity was significantly greater when the colposcopists took two or more biopsies instead of one (P<.01), a pattern observed across all types of colposcopists. Independent of the severity of the colposcopic impression, the frequency with which colposcopists took two or more biopsies instead of one varied (in descending order) from nurse practitioners to general gynecologists to gynecologic oncology fellows to gynecologic oncologists (P<.01). Colposcopy with guided biopsy or biopsies detects approximately two thirds of CIN 3+. Although the sensitivity of the procedure does not differ significantly by type of medical training, it is greater when two or more biopsies are taken.