Preoperative vaginal estrogen and midurethral sling exposure: a retrospective cohort study.

INTRODUCTION AND HYPOTHESIS: We evaluated whether the use of estrogen vaginally prior to synthetic midurethral sling insertion mediates the risk of mesh exposure. A secondary aim was to evaluate other factors that may be associated with mesh exposure. METHODS: We performed a retrospective cohort study of patients undergoing midurethral sling insertion from January to December 2010 within the Southern California Permanente Medical Group. Women who used estrogen vaginally prior to surgery were classified as those who filled a prescription between 1 and 45 days before surgery or whose medical records indicated its use at the time of preoperative evaluation. Logistic regression analysis was used to calculate odds ratios (OR) and 95 % confidence intervals (CI) for factors associated with mesh exposure while controlling for confounding variables. RESULTS: A total of 1544 patients met inclusion criteria, of whom 248 (16.1 %) used estrogen vaginally prior to surgery. Mean age was 53.7 years (range 27-89). Thirty-seven (2.4 %) women were diagnosed with mesh exposure, of whom 19 underwent surgical reoperation. In multivariate logistic regression analysis, preoperative use of estrogen vaginally was not associated with the risk of mesh exposure (OR 0.79, CI 0.26-2.38, p = 0.67). Age, body mass index, menopausal status, use of hormone replacement therapy, smoking status, and diabetes were not associated with risk of mesh exposure. CONCLUSIONS: Preoperative use of estrogen vaginally did not appear to mediate the risk of mesh exposure following midurethral sling placement in this cohort.

No association between TNF inhibitor and methotrexate therapy versus methotrexate in changes in hemoglobin A1C and fasting glucose among psoriasis, psoriatic arthritis, and rheumatoid arthritis patients.

BACKGROUND: The use of tumor necrosis factor inhibitors (TNFi) has been associated with a reduced incidence of type 2 diabetes mellitus. OBJECTIVE: To compare changes in hemoglobin A1C and fasting glucose for patients exposed to TNFi. METHODS: In this retrospective cohort study, patients with at least 3 recorded diagnosis codes for psoriasis, psoriatic arthritis, or rheumatoid arthritis between January 1, 2004 and July 31, 2011. Patients were Kaiser Permanente Southern California members for at least 1 year prior to the index date. RESULTS: For hemoglobin A1C, there were 344 patients in the MTX cohort, and 118 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, the TNFi+MTX cohort had a lower mean change in hemoglobin A1C of -0.18 mg/dL (95% CI: -0.35, -0.01) compared to the MTX cohort, although the difference is small and this model was not complete as there were significant interactions. For fasting glucose, there were 524 patients in the MTX cohort, and 121 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, change in fasting glucose was not significantly different between groups: -0.58 mg/dL (95% CI: -5.05, 3.88) for the TNFi+MTX cohort compared to the MTX cohort, although this model was not complete as there was a significant interaction. CONCLUSIONS: The use of TNF inhibitors with MTX was not associated with a significant difference in the change of hemoglobin A1C or fasting glucose compared to MTX alone.

Risk of myocardial infarction in psoriasis patients: a retrospective cohort study.

BACKGROUND: Psoriasis may or may not be associated with a higher risk for myocardial infarction (MI). We sought to assess differences in MI incidence between control, mild psoriasis and severe psoriasis patients. METHODS: We performed a retrospective cohort study of Kaiser Permanente Southern California members with psoriasis between 1 January 2004 and 30 June 2012, assessing the risk and incidence rates of MI. RESULTS: There were 50,865 control patients matched to 10,173 patients with mild psoriasis and 19,205 control patients matched to 3841 patients with severe psoriasis. The MI incidence per 1000 person-years for mild psoriasis controls, mild psoriasis, severe psoriasis controls and severe psoriasis were 4.9, 6.7, 3.7 and 5.1, respectively. Upon multivariable analysis, mild psoriasis patients had a significantly higher risk of MI compared to matched control patients {hazard ratio (HR) = 1.31 [95% confidence interval (CI): 1.14, 1.51]} and severe psoriasis patients had a significantly higher risk of MI compared to matched control patients [HR = 1.28 (95% CI: 1.02, 1.60)]. CONCLUSION: Patients with psoriasis are at higher risk for MI compared to control patients.

Osteochondritis dissecans of the ankle in children and adolescents: demographics and epidemiology.

BACKGROUND: Osteochondritis dissecans (OCD) of the ankle is a disorder of the talar or distal tibial subchondral bone and articular cartilage whose incidence in children is not clearly known. PURPOSE: To assess the demographics and epidemiology of OCD of the ankle in children. STUDY DESIGN: Descriptive epidemiologic study. METHODS: A retrospective chart review of an integrated health system was conducted on patients with ankle OCD aged 2 to 19 years from 2007 to 2011, with >1 million patients in this cohort. Lesion location, laterality, and all patient demographics were recorded. Ankle OCD incidence was determined for the group as a whole and by both sex and age group (divided into age groups of 2-5, 6-11, and 12-19 years). The risk for ankle OCD for age group, sex, and ethnicity was assessed using multivariate logistic regression models. RESULTS: A total of 85 patients fit the inclusion criteria, and 71.8% of lesions found were in the medial talus, 56.5% of lesions were right sided, and none were bilateral. No ankle OCD lesions were found in 2- to 5-year-olds. The incidence of ankle OCD in patients aged 6 to 19 years was 4.6 per 100,000 overall and 3.2 and 6.0 per 100,000 for male and female patients, respectively. Patients aged 12 to 19 years represented the vast majority of those with OCD, with an incidence of 6.8 per 100,000 compared with 1.1 per 100,000 in those 6 to 11 years of age. In those aged 6 to 11 and 12 to 19 years, female patients had a respective incidence of 1.5 and 8.9 per 100,000, whereas male patients had a respective incidence of 0.7 and 4.8 per 100,000. The overall female/male ratio of ankle OCD was 1.6:1. Multivariate logistic regression analysis revealed a 6.9 times increased risk for ankle OCD in patients aged 12 to 19 years compared with those aged 6 to 11 years (95% CI, 3.8-12.5; P < .0001), and female patients had a 1.5 times greater risk for ankle OCD than male patients (95% CI, 1.0-2.3; P = .06). On the basis of race and ethnicity, non-Hispanic whites had the highest relative risk for disease and African Americans the lowest risk. CONCLUSION: In this population-based cohort study of pediatric ankle OCD, female patients had a greater incidence of OCD and a 1.5 times greater risk for ankle OCD compared with male patients. Teenagers had nearly 7 times the risk for ankle OCD compared with children 6 to 11 years of age.

The demographics and epidemiology of osteochondritis dissecans of the knee in children and adolescents.

BACKGROUND: Osteochondritis dissecans (OCD) is a disorder of subchondral bone and articular cartilage whose incidence in children is not clearly known. PURPOSE: The purpose of this study was to assess the demographics and epidemiology of OCD of the knee in children. STUDY DESIGN: Descriptive epidemiology study. METHODS: A retrospective chart review of an integrated health system was performed on patients with OCD of the knee aged 2 to 19 years from 2007 to 2011, with over 1 million patients in this cohort. Lesion location, laterality, and all patient demographics were recorded. The incidence of OCD was determined for the group as a whole and by sex and age group (2-5 years, 6-11 years, and 12-19 years). Patient differences based on age, sex, and ethnicity were analyzed, and using multivariable logistic regression models, associations between age, sex, ethnicity, and diagnosis of OCD of the knee were evaluated. RESULTS: One hundred ninety-two patients with 206 OCD lesions of the knee fit the inclusion criteria. No OCD lesion of the knee was found in 2- to 5-year-old children. One hundred thirty-one (63.6%) lesions were in the medial femoral condyle, 67 (32.5%) were in the lateral femoral condyle, 96 (50.0%) lesions were right sided, 82 (42.7%) were left sided, and 14 (7.3%) were bilateral. The incidence of patients with OCD of the knee aged 6 to 19 years was 9.5 per 100,000 overall and 15.4 and 3.3 per 100,000 for male and female patients, respectively. Those aged 12 to 19 years represented the vast majority of OCD, with an incidence of 11.2 per 100,000 versus 6.8 per 100,000 for those aged 6 to 11 years. For those aged 6 to 11 and 12 to 19 years, female patients had an incidence of 2.3 and 3.9 per 100,000, respectively, while male patients had an incidence of 11.1 and 18.1 per 100,000, respectively. Multivariable logistic regression analysis revealed a 3.3-fold increased risk of OCD of the knee in patients aged 12 to 19 years compared with those aged 6 to 11 years (P < .001; 95% confidence interval [CI], 2.37-4.48), and male patients had 3.8 times a greater risk of OCD of the knee than female patients (P < .001; 95% CI, 2.71-5.41). Based on race and ethnicity, blacks had the highest odds ratio of OCD of the knee compared with all other ethnic groups. CONCLUSION: In this population-based cohort study of pediatric OCD of the knee, male patients had a much greater incidence of OCD and almost 4 times the risk of OCD compared with female patients. Also, patients aged 12 to 19 years had 3 times the risk of OCD of the knee as compared with 6- to 11-year-old children.

Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.

OBJECTIVE: We sought to assess whether the type of TNF inhibitor therapy (soluble receptor versus monoclonal antibody) has an effect on MI risk; and determine whether length of TNF inhibitor therapy has an effect on MI risk. DESIGN: Retrospective cohort study. SETTING: Between January 1, 2004 and November 30, 2010. PARTICIPANTS: At least 3 ICD9 codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI). INTERVENTION: None. MAIN OUTCOME MEASURE: Incident MI. RESULTS: In the 3 subgroups of TNF inhibitors, 976 received etanercept; 217 received monoclonal antibody; and 480 received etanercept or monoclonal antibody, in addition, 5075 received topical therapy and 2097 received oral therapy. In the Cox proportional hazards analysis, etanercept (HR, 0.53; 95% CI, 0.31-0.92) was associated with a significant reduction of MI risk, compared to topical agents and, monoclonal antibody only (HR, 0.25; 95% CI, 0.06-1.03), and etanercept or monoclonal antibody (HR, 0.53; 95% CI, 0.27-1.06) were associated with a non-significant reduction of MI risk compared to topical agents. Using year 1 as reference, those who received TNF inhibitor therapy at year 2 (HR, 1.15; 95% CI, 0.30-4.44), at year 3 (HR, 1.89; 95% CI, 0.64-5.58), and at year 4 and above (HR, 1.16; 95% CI, 0.46-2.94) had a non-significant increase of MI risk. CONCLUSIONS: Treatment with etanercept, compared to treatment with topical agents, was associated with a significant decreased risk of MI in psoriasis patients. Treatment with monoclonal antibody and etanercept or monoclonal antibody, compared to treatment with topical agents, was associated with a non-significant decreased risk of MI risk in psoriasis patients. There were no statistically significant changes in risk of MI associated with length of TNF inhibitor treatment.

Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography.

PURPOSE: To report the fluorescein angiography (FA) and optical coherence tomography (OCT) results of a clinical trial of epimacular brachytherapy (EMBT) used for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Pivotal multicenter, active-controlled, randomized clinical trial. PARTICIPANTS: A total of 494 participants with treatment-naïve, neovascular AMD. METHODS: Participants with classic, minimally classic, and occult lesions were randomized to receive (a) EMBT and 2 mandated monthly ranibizumab injections followed by pro re nata (PRN) ranibizumab or (b) 3 mandated monthly ranibizumab injections followed by mandated quarterly plus PRN ranibizumab. Participants underwent FA at screening and at months 1, 6, 12, 18, and 24. Optical coherence tomography scans were undertaken monthly for 24 months. The FA and OCT images were analyzed at respective independent reading centers. MAIN OUTCOME MEASURES: Change at 24 months in mean FA total lesion size and choroidal neovascularization (CNV) size and change in mean OCT centerpoint thickness. RESULTS: The mean (standard deviation) changes in FA total lesion size in the EMBT and control arms were +1.9 (8.7) and -3.0 (7.2) mm(2), respectively, with a mean change in total CNV size of +0.4 (8.4) and -4.7 (6.5) mm(2), respectively. Mean (standard deviation) changes in OCT centerpoint thickness were -144 (246) and -221 (185) µm, respectively. Retrospective subgroup analyses showed no significant difference between treatment arms in mean centerpoint thickness in some subgroups, including eyes with classic lesions. The control arm showed a significantly larger reduction in mean total lesion size and mean CNV size than the EMBT arm in all subgroups analyzed. Nine eyes in the EMBT arm showed features consistent with mild, nonproliferative radiation retinopathy, but with a mean gain of 5.0 Early Treatment Diabetic Retinopathy Study letters. CONCLUSIONS: Both FA and OCT suggest that EMBT with PRN ranibizumab results in an inferior structural outcome than quarterly plus PRN ranibizumab. Some subgroup analyses suggest that classic lesions may be more responsive than occult lesions, although generally both subgroups are inferior to ranibizumab. A non-vision-threatening radiation retinopathy occurs in 2.9% of eyes over 24 months, but longer follow-up is needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET).

PURPOSE: To evaluate the safety and efficacy of epimacular brachytherapy (EMBT) for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, randomized, active-controlled, phase III clinical trial. PARTICIPANTS: Four hundred ninety-four participants with treatment-naïve neovascular AMD. METHODS: Participants with classic, minimally classic, and occult lesions were randomized in a 2:1 ratio to EMBT or a ranibizumab monotherapy control arm. The EMBT arm received 2 mandated, monthly loading injections of 0.5 mg ranibizumab. The control arm received 3 mandated, monthly loading injections of ranibizumab then quarterly injections. Both arms also received monthly as needed (pro re nata) retreatment. MAIN OUTCOME MEASURES: The proportion of participants losing fewer than 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline visual acuity (VA) and the proportion gaining more than 15 ETDRS letters from baseline VA. RESULTS: At 24 months, 77% of the EMBT group and 90% of the control group lost fewer than 15 letters. This difference did not meet the prespecified 10% noninferiority margin. This end point was noninferior using a 20% margin and a 95% confidence interval for the group as a whole and for classic and minimally classic lesions, but not for occult lesions. The EMBT did not meet the superiority end point for the proportion of participants gaining more than 15 letters (16% for the EMBT group vs. 26% for the control group): this difference was statistically significant (favoring controls) for occult lesions, but not for predominantly classic and minimally classic lesions. Mean VA change was -2.5 letters in the EMBT arm and +4.4 letters in the control arm. Participants in the EMBT arm received a mean of 6.2 ranibizumab injections versus 10.4 in the control arm. At least 1 serious adverse event occurred in 54% of the EMBT arm, most commonly postvitrectomy cataract, versus 18% in the control arm. Mild, nonproliferative radiation retinopathy occurred in 3% of the EMBT participants, but no case was vision threatening. CONCLUSIONS: The 2-year efficacy data do not support the routine use of EMBT for treatment-naïve wet AMD, despite an acceptable safety profile. Further safety review is required.

Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study.

BACKGROUND: Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. METHODS: We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT00104247. FINDINGS: 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9.7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) micromol/L in patients assigned to receive sapropterin, and 888 (323) micromol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) micromol/L, compared with a 3 (240) micromol/L increase in the placebo group (p<0.0001). After 6 weeks, 18/41 (44%) patients (95% CI 28-60) in the sapropterin group and 4/47 (9%) controls (95% CI 2-20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 micromol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0.0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0.80). Upper respiratory tract infections were the most common disorder. INTERPRETATION: In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.

Post-trial access to tested interventions: the views of IRB/REC chair, investigators, and research participants in a multinational HIV/AIDS study.

Controversy exists regarding an ethical requirement to make products proven effective in research available after the trial. Little is known about the views of several stakeholders. Phone or self-administered questionnaires were completed by 65 IRB/REC chairs, 117 investigators, and 500 research participants in a multinational HIV trial to assess their views about posttrial access to interventions proven effective in the study. A total of 83% of research participants, 29% of IRB/REC chairs, and 42% of researchers (p = 0.046) thought IL-2 should be guaranteed for every HIV-infected person in the world if proven effective. Most European and Latin American research participants thought IL-2 should be provided free, while North American, Australian, and Thai participants commonly said at a price the average person could afford (p < 0.001). Most IRB/REC chairs and researchers thought the CIOMS "reasonable availability" requirement applied to people in the country where the study was conducted and meant a drug should be available at a price the average person could afford and that host country governments had primary responsibility for making it available. Most research participants believe an HIV drug proven effective in research should be made available to everyone in the world who needs it. IRB/REC chairs and researchers were less expansive both in who and how they thought a drug should be guaranteed.

Tests for treatment group differences in the hazards for survival, before and after the occurrence of an intermediate event.

In many settings, one would expect that the hazard for a terminal event would change with the occurrence of an intermediate event. For example, in an AIDS clinical trial, it is of interest to assess whether there is a difference between treatments in the hazards for death prior to drop in Karnofsky performance score and in the hazards subsequent to the drop in Karnofsky score. Tests for the effect of treatment on these hazard functions, separately or jointly, are useful in conjunction with tests of overall survival. We consider four Cox regression models for the hazard function, constructed by allowing for various combinations of time-dependent stratification and time-dependent covariates, both of which are based on the occurrence of the intermediate event. Assuming a Markov transition model from the intermediate to the terminal event, partial likelihoods can be used for inference, enabling the use of standard statistical software for computation. We develop analytic approximations for the power of the derived score tests for treatment differences in the hazard functions and evaluate them through simulations. We apply our results to AIDS Clinical Trials Group (ACTG) protocol 021.

Nadir CD4+ T cell count predicts response to subcutaneous recombinant interleukin-2.

Community Program for Clinical Research on AIDS 059 was a multicenter study conducted among human immunodeficiency virus (HIV)-infected individuals with CD4+ cell counts > or =300 cells/mm3 who were randomly assigned to receive antiretroviral therapy with or without intermittent subcutaneously administered recombinant interleukin-2 (rIL-2). To identify factors associated with a response to IL-2, a secondary analysis was performed that included the subset of rIL-2 recipients who were able to complete all 3 initial treatment cycles. Predictors of a change in CD4+ cell count between baseline and 1 month after the start of treatment cycle 3 were examined in a multivariate model that included sex, race, body surface area, rIL-2 dose, HIV load, and both baseline and nadir CD4+ cell count. The combination of race and sex (P=.027) and the nadir CD4+ cell count (P=.005) were significant predictors of mean CD4+ cell count response. Baseline CD4+ cell count had no significant effect. The strong association between nadir CD4+ cell count and CD4+ cell count response suggests that immunologic losses resulting from HIV-mediated CD4+ cell depletion may be irreversible.

Local likelihood analysis of the latency distribution with interval censored intermediate events.

The distribution of time between an intermediate event and a terminal event is frequently of interest both in studying the behaviour of populations and in predicting outcomes for individuals. Current methods for estimating this latency distribution have either imposed assumptions on the hazard for the terminal event following the occurrence of the intermediate event or on the parametric form of the hazards. Here, local likelihood estimation is applied to the underlying hazard functions of a three-state process in which the time of the intermediate event may be interval censored and the time of the terminal event is either observed or right censored. Smooth non-parametric estimates of the latency distribution, along with bootstrap confidence intervals, are calculated, and tests for the comparison of two latency distributions are presented. The method is applied to two studies: a cohort of haemophiliacs who were infected with HIV by contaminated blood factor and followed for AIDS onset, and an AIDS clinical trial in which the intermediate event is the time to 50 per cent drop in CD4 count and the terminal event is AIDS or death. Simulations are presented to assess the performance of the estimation procedure.

Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm3: CPCRA 059.

The effect of intermittent courses of recombinant interleukin-2 (rIL-2) on HIV-1 load in patients receiving combination antiretroviral therapy remains uncertain. CPCRA 059 was an open-label, randomized, multicenter trial in which 511 patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm3 who were receiving antiretroviral therapy were assigned to receive no rIL-2 (255 patients [controls]) or subcutaneous rIL-2 in dosages of 4.5 MIU (130) or 7.5 MIU (126) twice daily for 5-day courses every 8 weeks to maintain CD4+ cell counts that were twice the baseline value or > or = 1,000/mm3. The primary objective of this study was to compare the effects of the two doses of rIL-2 and no rIL-2 on viral load and CD4+ cell counts over 12 months. There was no difference in the following viral load measurements between the rIL-2 treatment groups and the control treatment group: percentage of patients with viral loads of <50 copies/mL at 12 months (p =.55), time to viral load of > or = 50 copies/mL for patients who had baseline viral loads of <50 copies/mL (p =.35), and change in viral load from baseline for patients who had viral loads of > or = 50 copies/mL at baseline (p =.63). At each follow-up visit, the change in CD4+ cell count from baseline was significantly greater in the rIL-2 treatment groups than in the control treatment group, with a mean difference of 251/mm3 at month 12 (95% confidence interval, 207-295; p <.0001). No unanticipated adverse experiences were seen in this trial, to our knowledge the largest randomized evaluation of rIL-2 treatment conducted to date.

Regulatory approvals in a large multinational clinical trial: the ESPRIT experience.

While accepted as serving an important function to safeguard human subjects, the process of obtaining regulatory approvals to conduct clinical trials is generally regarded as cumbersome and time-consuming. For large multinational trials, U.S. federally sponsored human subject research abroad involves specific U.S. regulatory requirements, in addition to those of the host country, that act as further hurdles. These requirements may include obtaining an Assurance of Protection for Human Subjects from the Office of Human Research Protection of the U.S. Department of Health and Human Services, maintaining specific Ethics Committee/Institutional Review Board (EC/IRB) composition, and incorporating mandated elements in informed consents, all of which may differ from local policies and guidelines. Specific examples of issues that led to delays in regulatory approvals for sites participating in the multinational clinical trial entitled Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) are presented here. While the goal of these requirements is to protect the rights and welfare of human subjects, they may create substantial delays and engender resentment over the notion of lack of respect for individual country sovereignty. Substudies within ESPRIT have been undertaken to obtain feedback from EC/IRB chairpersons, site personnel responsible for processing the required assurances, ESPRIT investigators, and study participants regarding aspects of current U.S. regulatory requirements related to human subject protection and ethical issues in multinational research. The purpose of these substudies is to compare the attitudes and experiences across countries regarding important ethical issues associated with conducting ESPRIT. One objective of the substudies is to gather additional insight to the impact of U.S. regulatory processes. Another is to help to inform the debate about how to best maximize the rights and welfare of clinical trial participants without delaying the initiation of research, while respecting the importance of national sensitivities.