Generalizability Of Clinical Trials Research Articles

Is nonoperative management of appendicitis safe and effective in multi-morbid patients?

BackgroundThe purpose of this study was to (1) compare post-treatment outcomes of operative and nonoperative management of acute appendicitis in multi-morbid patients and (2) evaluate the generalizability of prior clinical trials by determining whether outcomes differ in multi-morbid patients compared to the young and healthy patients who resemble prior clinical trial participants. MethodsWe conducted a retrospective cohort study using the National Inpatient Sample from 2004 to 2017. We included 368,537 patients with acute, uncomplicated appendicitis who were classified as having 0 or 2+ comorbidities. We compared inpatient morbidity, mortality, length of stay, and costs using propensity scores. Unmeasured confounding was addressed with probabilistic sensitivity analysis. ResultsOverall, 5% of patients without comorbidities were treated nonoperatively versus 20% of multi-morbid patients. Compared to surgery, nonoperative management was associated with a 3.5% decrease in complications (95% confidence interval 3%–4%) for multi-morbid patients, but there was no significant difference for patients without comorbidity. However, nonoperative management was associated with a 1.5% increase in mortality for multimorbid patients (95% confidence interval 1.3%–1.7%). Costs and length of stay were lower for all patients treated with surgery. Probabilistic sensitivity analysis showed that results were robust to the effects of unmeasured confounding. ConclusionOur results raise concerns about the generalizability of clinical trials that compared nonoperative and operative management of appendicitis because (1) those trials enrolled mostly young and healthy patients, and (2) results in multi-morbid patients differ from outcomes in younger and healthier patients.

Beyond patient-level barriers: Evaluation of rural residency and area-level deprivation and clinical trial (CT) participation.

e19068 Background: Residents of rural and socioeconomically deprived areas have worse cancer outcomes and are less likely to participate in CTs. It is unknown whether these area-level attributes predict CT participation after accounting for individual sociodemographic variables. Methods: We combined data from two SWOG national survey studies. S0316, a multi-center prospective survey, was combined with data from a large web-based survey. Both studies examined CT treatment decision making from diagnosis in patients with common cancers. Zip codes of residences were classified as rural or urban using Rural-Urban Continuum Codes (urban, 1-3, vs. rural, 4-9) and a 3-level ordinal variable (urban, 1-3, vs. rural, 4-7, vs. very rural, 8-9). We identified socioeconomically deprived areas (SDAs) as those with an Area Deprivation Index (ADI) in the upper quartile. We also examined areas by ADI quartile. Multivariable logistic regression was used to evaluate the association of rural residency and area-level socioeconomic deprivation with CT participation after adjusting for important individual-level factors (age, sex, race/ethnicity, income, and education), stratified by study and cancer type. Results: Among 7080 patients, 1299 (18.5%) were from rural areas, 653 (9.4%) were from SDAs; and 715 (10.1%) participated in a CT. Patients had breast (56.1%), prostate (21.8%), lung (13.6%), and colorectal (8.4%) cancer. In univariate analysis, rural patients were 23% less likely to participate in a CT (OR=0.77, 95% CI: 0.62-0.95, p=.016); in multivariate analysis, results were similar (OR=0.80, 95% CI: 0.64-0.99, p=.037). Very rural residents were 34% less likely to participate than urban patients (OR=0.66, 95% CI, 0.55-0.80, ordinal p=.031). There was no statistically significant association between residence in SDAs and CT participation (p>.30). Rural patients were more likely to have >1 comorbid conditions (45.4% vs. 39.5%, p=.001), to be concerned about how to pay for their care (40.6% vs. 32.4%, p<.0001), and to travel farther for care (median 50.0 vs. 12.0 miles, p<.0001). Conclusions: Our findings are the first to show that rural residents are less likely to participate in CTs even after accounting for confounding individual factors. These results agree with prior observations that rural patients must travel longer distances for care, including for CT care. Reducing the travel burden for rural cancer patients could improve their CT participation and the generalizability of CT results to all patients.

Generalizability of pharmacologic and psychotherapy trial results for late-life unipolar depression

Objectives Despite evidence of low representativeness of clinical trial results for depression in adults, the generalizability of clinical trial results for late-life depression is unknown. This study sought to quantify the representativeness of pharmacologic and psychotherapy clinical trial results for late-life unipolar depression. Method Data were derived from the 2004–2005 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of 34,653 adults from the United States population. To assess the generalizability of clinical trial results for late-life depression, we applied a standard set of eligibility criteria representative of pharmacologic and psychotherapy clinical trials to all individuals aged 65 years and older in NESARC with a DSM-IV diagnosis of MDE and no lifetime history of mania/hypomania (n = 273) and in a subsample of individuals seeking help for depression (n = 78). Results More than four of ten respondents and about two of ten respondents would have been excluded by at least one exclusion criterion in a typical pharmacologic and psychotherapy efficacy trial, respectively. Similar results (i.e.41.1% and 25.9%, respectively) were found in the subsample of individuals seeking help for depression. Excess percentage of exclusion in typical pharmacologic studies was accounted for by the criterion “significant medical condition”. We also found that populations typically included in pharmacologic and psychotherapy clinical trials for late-life unipolar depression may substantially differ. Conclusion Psychotherapy trial results may be representative of most patients with late-life unipolar depression in routine clinical practice. By contrast, pharmacologic clinical trials may not be readily generalizable to community samples.

Short Diagnosis-to-Treatment Interval Is Associated with Higher Levels of Circulating Tumor DNA in Aggressive B-Cell Non-Hodgkin Lymphoma

BACKGROUND Selection biases can impair the generalizability of clinical trials. Studies investigating aggressive diseases such as Diffuse Large B-cell Lymphoma (DLBCL) can be particularly affected by such biases since clinical urgency and need for therapy may not allow the requisite extensive screening and consent processes for trials. Diagnosis-to-Treatment Interval (DTI) has recently been proposed as a novel metric to capture this phenomenon (Maurer et al, JCO, 2018), and short DTI is associated with both adverse clinical factors and adverse clinical outcomes. Intriguingly, DTI was independent of clinical risk factors like the International Prognostic Index (IPI) suggesting that widely applied prognostic scores do not adequately reflect risk factors considered for clinical decision making. In this study, we aim to assess whether pretreatment levels of circulating tumor DNA (ctDNA) are associated with shorter DTI and may constitute an objective measure of clinical urgency. METHODS We quantified pretreatment ctDNA levels in plasma samples from 178 patients treated in 5 US and European centers for large cell lymphoma (DLBCL, Follicular lymphoma grade 3b, or High-grade-B-cell-lymphoma) using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) as previously described (Kurtz, JCO 2018; Scherer, STM 2016). Pretreatment ctDNA levels were correlated with DTI, clinical factors and treatment outcome. RESULTS Pretreatment ctDNA was detectable in 175/178 cases. Median number of single nucleotide variants (SNV) detected per patient was 129 (range 0-628). Pretreatment ctDNA levels ranged from 0 - 1.4 x105 haploid genome equivalents per milliliter of plasma (hGE/ml, median 239). Median DTI was 19 days (range 0-141, Figure 1A) and was similar in distribution to 2 previously described cohorts from the US and Europe (Maurer et al, JCO 2018). Shorter DTI was associated with higher ctDNA levels (RS=-0.39, P= 1.4 x10-7, Figure 1B). Patients with longer DTI had improved Event-Free Survival (EFS, Hazard Ratio (HR) for DTI: 0.9/week, P= 0.03). However, this association was lost when adjusting for pretreatment ctDNA levels (HR for DTI: 0.95/week, P= 0.39; HR for log10(ctDNA): 1.7, P= 5.8 x10-5). In a multivariate analysis including DTI, ctDNA and IPI, only ctDNA levels were significantly associated with EFS (HR for log10(ctDNA): 1.6, P= 0.002, n=178, Figure 1C). Pretreatment ctDNA levels remained the only prognostic factor for EFS in a second multivariate analysis also considering pretreatment metabolic tumor volume (MTV, HR for log10(ctDNA): 1.8, P= 0.01, n=93, Figure 1D). DISCUSSION Shorter DTI is associated with higher pretreatment ctDNA levels in patients with aggressive B-cell lymphomas. When comparing to established factors (DTI, IPI, MTV), pretreatment ctDNA levels appear to best predict clinical outcomes. This suggests that quantification of ctDNA better reflects disease burden and treatment urgency than existing clinical biomarkers. Pretreatment ctDNA level may therefore be a valuable metric for disease aggressiveness of patients included in clinical trials, and may help identify studies suffering from selection bias. This may be particularly useful for noncontrolled Phase I/II single arm trials, but also for stratification in randomized trials. Disclosures Kurtz: Roche: Consultancy. Dührsen:Alexion: Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria; Takeda: Consultancy, Honoraria; Celgene: Research Funding; CPT: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Teva: Honoraria; Roche: Honoraria, Research Funding. Hüttmann:Takeda: Honoraria; Gilead: Honoraria; University Hospital Essen: Employment. Westin:Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria. Rossi:Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Diehn:Novartis: Consultancy; BioNTech: Consultancy; AstraZeneca: Consultancy; Quanticell: Consultancy; Roche: Consultancy. Alizadeh:Pfizer: Research Funding; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Roche: Consultancy.

GENERALIZABILITY OF CLINICAL TRIALS OF DELIRIUM INTERVENTIONS

Delirium, or acute confusional state, affects up to 7 million hospitalized older adults annually, and is associated with increased risk of mortality, institutionalization, and cognitive and functional impairment. There has been a proliferation of both pharmacological and nonpharmacological clinical trials to reduce the incidence and sequelae of delirium. In other neuropsychiatric disorders, exclusion criteria prevent up to 75% of individuals with the condition under study from participating. It is unclear how well these trial samples represent the population of older adults with delirium. We selected all intervention trials registered at ClinicalTrials.gov containing the keyword “delirium” (N=131), regardless of type of intervention. We manually examined study descriptions to restrict analysis to studies with delirium as a primary or secondary outcome (N=92). Of these 92 studies, 76% enrolled only adults, with 45% enrolling only older adults. 38% of studies were restricted to surgical units, 27% to intensive care units, and 7.6% to medical units. Only 1 study examined nursing homes and 4 studies examined palliative care. 50% of studies excluded individuals with pre-existing dementia, 28% excluded individuals with psychiatric disorders, and 30% excluded individuals with neurological disorders. 34% of studies excluded individuals with alcohol or drug abuse. Overall, many intervention studies for delirium are limited to the surgical and ICU populations, and they exclude individuals with common comorbidities associated with an increased risk of delirium. Similar to other neuropsychiatric disorders, these findings raise significant concerns about the generalizability of clinical trials in delirium to the hospitalized older adult population.

High risk patients with diffuse large B cell lymphoma are not enrolled on clinical trials.

e19058 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. In this study, we explore reasons for non-enrollment in clinical trials for DLBCL and implications on trial design and interpretation. Methods: This is a retrospective analysis of patients (pts) with a pathological diagnosis of DLBCL or high grade B-cell lymphoma (HGBL) at University of Rochester (4/14-6/16) and New York-Presbyterian Hospital/Weill Cornell Medicine (NYP/WCM) (4/14-4/17).Ten clinical trials were opened during this time. Participants were divided into 3 groups: those treated in trial, those not enrolled in trial because of need for urgent treatment, and those not enrolled in trial for any other reason. We used a center-stratified Cox proportional hazards model to estimate association of trial enrollment with progression-free survival (PFS; time from start of treatment until progression/death or the last date the pt was known to be progression free) and overall survival (OS). Results: We identified 263 pts; 17% (n = 45) enrolled in a trial. Reasons for non-enrollment included not meeting eligibility criteria (n = 98), physician choice (n = 50), and pt choice (n = 38). For 32 pts, reasons were unclear. Of the 50 pts who were not enrolled because of physician choice, the primary reason for non-enrollment was the need for urgent treatment (n = 46). Pts who needed urgent treatment had higher risk clinical features compared with pts in trial (Table). Compared with those treated in trial and those not enrolled in trial for any other reason, those not enrolled in trial due to need for urgent treatment had an inferior PFS (HR 2.61, 95% CI 1.23–5.16) and OS (HR 2.27, 95% CI 1.21–4.06). Conclusions: At 2 academic institutions, 52% of patients with DLBCL or HGBL required urgent chemotherapy and failed to enroll on trials. Exclusion of such patients limits the applicability and generalizability of clinical trials in DLBCL. This barrier must be overcome so clinical trials may better reflect true DLBCL demographics. [Table: see text]

FDA analysis: Demographic trends in bladder and renal cancer trials.

e18144 Background: Many publications report under representation of minorities in certain subgroups, which may limit the generalizability of clinical trial (CT) results. This analysis, investigates and reports enrollment trends in CTs submitted between 2006-2017 in support of marketing applications for drugs indicated for the treatment of urothelial (UC) and renal cancer carcinoma (RCC), and compares them to incidence rates of these diseases by Surveillance, Epidemiology, and End Results (SEER) registry and the US census bureau. Methods: We identified all marketing applications for the treatment of UC and RCC that provided the primary evidence of safety and efficacy and aggregated the demographic data across trials and disease. Using these two pooled datasets, we compared the patient proportions enrolled in each of the race, sex and age categories to the corresponding rates in US cancer population estimated based on the corresponding incidence rates reported by SEER and the US census bureau using a Chi-squared test. Results: The pooled seven UC and 14 RCC CTs provided 2035 and 6757 patients respectively. The results are summarized below for the 939 (46%) UC and 1489 (22%) RCC patients enrolled in the US. Conclusions: Our findings indicate that majority of the patients were enrolled outside of the US. There were lower proportion of Black patients (4% vs 8%), older patients, age ≥ 75 years (30% vs 48%) and males (74% vs 80%) enrolled in UC population in the US. Higher proportions were observed in both White (89% vs 85%) and Asian (4% vs 2%) patients in UC and in White (90% vs 79%) patients in RCC.[Table: see text]

External Generalizability of Clinical Trials to Developing Countries

External Generalizability of Clinical Trials to Developing Countries

Geographic Trends in Clinical Trials in Lymphoma, 1997-2017

BackgroundIn order to fulfil their medical and academic mission, clinical trials have to be available to the very populations they are intended to serve. A broad and homogenous geographic distribution is thus paramount to ensure patient fairness as well as to allow optimal generalizability of trial results to real-world populations. We aimed to investigate trends in the geographic distribution of clinical trials in lymphoma performed over the past 2 decades.MethodsWe systematically searched the Clinicaltrials.gov registry for phase 3 and 4 clinical trials in lymphoma conducted between 01/01/1997 and 12/31/2017. We divided the time period into two intervals and analysed the geographic distribution of trials during these time periods. The Gini coefficient, a statistical measure of inequality ranging from 0 (equal distribution) to 1 (most unequal distribution), was calculated for each period.ResultsWe found 633 clinical trials in lymphoma conducted between 1997 and 2017 globally. 284 and 349 trials were performed in the 1997-2007 and 2008-2017 time periods, respectively. 127 (50%) and 138 (39.5%) of the trials were done in the US. Hodgkin Lymphoma accounted for 55 (19.3%) and 42 (12.0%) studies in the two time periods. CA, TX, IL and NY were consistently in the upper one-fifth of trial-abundant states (each accounting for 3.5-4.5% of all trials). AK, WY, MT and RI were consistently in the lower one-fifth of trial-abundant states (each accounting for 0.13-0.84% of trials). The trial participation of NY and AK mildly increased during the time period while that of TX and RI decreased. In each of the time periods, the 12 most trial-intense states accounted for 41.5% of all investigations. The 12 least trial-intense states were responsible for 8.8% of all the trials. The extent of geographic inequality increased over the years with the Gini coefficient rising from 0.246 to 0.3 between the first and second study period. The geographical pattern of state-specific trial intensity was strongly mitigated after adjusting for each state's population size.ConclusionsThe geographic distribution of clinical trials in lymphoma in the U.S is not uniform. Our data suggests that the trend of geographic mal-distribution is worsening, a phenomenon that may lead to deleterious public health outcomes. As patients' enrolment continues to be linked to geographic factors, patients' ability to enter clinical trials may be limited and the representation of real-world participants may be skewed (towards particular zip codes, socio-economical status and education levels, etc), consequently affecting the yield and generalizability of clinical trials. Innovative solutions must be devised to minimise any barriers to trial participation for suitable patients. DisclosuresNo relevant conflicts of interest to declare.

Challenges of conducting clinical trials in Asia

<p class="abstract">Unlike North America and European Union (EU), Asian continent appears to be an ideal destination for conducting cost-effective clinical trials utilizing the pool of treatment naïve subjects. With a population approaching 4.5 billion, recruitment of subjects can be done without a fear of limited patient pool across Asia. The burden of infectious and chronic diseases is also higher in Asian countries. The emerging clinical trial markets particularly China, South Korea, and Taiwan offers genetic diversity in population group, thus promoting the quality and generalizability of clinical trial’s data. Nonetheless, several challenges also exist for the Western sponsors in majority of the Asian countries; regulatory, operational and infrastructural challenges are at the forefront. Challenges under the heads regulatory, operational, infrastructural, language and cultural, ethics, and future challenges have been discussed. SWOT analysis of Asian clinical trial’s market exhibits enormous opportunities for study sponsors with manageable threats.</p>

An evaluation of race, ethnicity, age, and sex-based representation in phase I to II renal cell carcinoma clinical trials in the United States

IntroductionEnrollment of a representative study population permits generalizable and reliable results for clinical trials. We sought to evaluate whether patients enrolled in trials for advanced renal cell carcinoma (RCC) are representative of the overall population of advanced RCC patients in the United States. Materials and methodsThe clinicaltrials.gov results database was queried for interventional clinical trials directed at clinically advanced (stage III/IV) RCC that enrolled patients from the US only. We identified 375 patients from 18 phase I to II trials that met eligibility criteria. The American College of Surgeons′ National Cancer Database (NCDB) which includes data on approximately 70% of all US cancer diagnoses was queried and we identified 75,308 patients with advanced (stage III/IV) RCC. Demographic characteristics were summarized and compared between the 2 populations. ResultsCompared to the US population of advanced RCC (NCDB), significant under-representation in clinical trials was observed for patients aged 65+ (26.3% vs. 50.4%; P<0.001) and among those with Hispanic ethnicity (2.7% vs. 7.2%; P = 0.005). A trend toward under-representation was observed for black patients (7.0% vs. 9.8%, P = 0.076) but not for white patients (89.9% vs. 87.0%, P = 0.107) or other racial groups (P>0.05 for all). Female patients made up 30.3% of trial enrollees and 33.3% of the US advanced RCC population (P = 0.221). ConclusionSignificant under-representation was observed for elderly and Hispanic patients with a trend toward under-representation for black and female patients in phase I to II RCC clinical trials. Greater efforts to include underrepresented populations are necessary to improve the effectiveness and generalizability of clinical trials in kidney cancer.

Generalizability of clinical trials in metastatic melanoma.

e21004 Background: Results from clinical trials are not always generalizable to real world patients (pts). Clinicians may not adhere to the studies’ original inclusion/exclusion criteria because of differences in clinical circumstances or institutional variations in treatment policies. Our aims were to determine the pattern in which melanoma trial findings are applied in a population-based setting and to describe the treatment outcomes of these pts. Methods: We focused on melanoma as several novel therapies have been recently introduced. Pts with unresectable disease from 2013 to 2014 and referred to any 1 of 6 cancer centers in British Columbia were reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified pts into trial eligible (TE) and ineligible (TI) and those treated and untreated with these agents. During the study period, Vem was approved for 1st line use in BRAF mutant pts and Ipi was funded for 2nd line use. Results: We identified 185 pts with known BRAF status for the Vem analysis and 114 pts for the Ipi analysis: median ages 64 and 59 years, 57% and 61% men, and 89% and 88% ECOG 0-1, respectively. For Vem, BRAF wild type was the most common reason for being TI. Of the remaining 86 BRAF mutant pts, 59 (69%) were considered TE of whom 51 (86%) received treatment. For Ipi, poor ECOG including rapidly progressive disease was a prevalent cause of being TI. In the Ipi cohort, 96 (84%) cases were deemed TE of whom 63 (66%) received therapy. Factors most frequently associated with non-treatment in both Vem and Ipi TE pts included comorbidities (41%), pt refusal (23%), and toxicities from prior treatments (14%). Compared to TI pts as well as those considered TE but did not receive treatment, pts deemed TE and received treatment achieved the best survival (adjusted HR 0.53, 95% CI 0.28-1.00 for Vem and adjusted HR 0.33, 95% CI 0.13-0.83 for Ipi). Conclusions: There was favorable uptake of new melanoma treatments, but a fair number of pts were considered TI, suggesting the need for trials with better external validity. Non-use of novel agents in TE pts was due to physician factors, pt preferences, and concerns about toxicities, highlighting areas that limit real world effectiveness of new melanoma drugs.

Enrollment of high-risk patients with diffuse large B-cell lymphoma in clinical trials.

6536 Background: Contemporary precision medicine trials in DLBCL often require real-time central pathology review for enrollment. Central review may lead to treatment delays and prevent high risk patients (pts) with aggressive presentations from enrolling onto clinical trials. We explored reasons pts with DLBCL were not enrolled on trials and the implication of non-enrollment on trial design and interpretation. Methods: We retrospectively analyzed all pts with histologic diagnosis of DLBCL or HGBL from 4/14 to 6/16 at the University of Rochester. Therapeutic trials open during this time included 3 sponsored and 2 NCTN studies. The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS; time from start of treatment until progression/death or until the last date the patient was known to be progression free) and overall survival (OS). Results: 140 pts were identified; 22% enrolled on a trial. Reasons for non-enrollment included: 1) Protocol ineligibility (n=58); (2) Physician choice (n=24) and; 3) Patient choice (n=20). Reasons were unclear in 8 pts. Of the 24 pts who were not enrolled due to physician choice, 21 required urgent treatment secondary to symptoms or rapid progression. Compared to pts treated on trial, pts with rapid progression had higher risk clinical features (table). There was a trend towards a lower 1-year PFS rate in pts who required urgent treatment compared to those on trial (72.1% vs. 56.1%; p=0.08). There was no statistical difference in OS. Conclusions: At our institution, for patients with DLBCL meeting trial eligibility criteria, 42% required urgent chemotherapy and failed to enroll. Exclusion of these high risk patients in precision medicine trials has important implications in the interpretation and generalizability of clinical trials in DLBCL. In this curable malignancy, excluding high risk patients from trials limits the event rate, and associated power to demonstrate impact of novel therapies. [Table: see text]

Evaluating the generalizability of clinical trials of direct-acting antivirals for HIV-hepatitis C virus coinfection.

Evaluating the generalizability of clinical trials of direct-acting antivirals for HIV-hepatitis C virus coinfection.

A Mycobacterial Perspective on Tuberculosis in West Africa: Significant Geographical Variation of M. africanum and Other M. tuberculosis Complex Lineages.

BackgroundPhylogenetically distinct Mycobacterium tuberculosis lineages differ in their phenotypes and pathogenicity. Consequently, understanding mycobacterial population structures phylogeographically is essential for design, interpretation and generalizability of clinical trials. Comprehensive efforts are lacking to date to establish the West African mycobacterial population structure on a sub-continental scale, which has diagnostic implications and can inform the design of clinical TB trials.Methodology/Principal FindingsWe collated novel and published genotyping (spoligotyping) data and classified spoligotypes into mycobacterial lineages/families using TBLineage and Spotclust, followed by phylogeographic analyses using statistics (logistic regression) and lineage axis plot analysis in GenGIS, in which a phylogenetic tree constructed in MIRU-VNTRplus was analysed. Combining spoligotyping data from 16 previously published studies with novel data from The Gambia, we obtained a total of 3580 isolates from 12 countries and identified 6 lineages comprising 32 families. By using stringent analytical tools we demonstrate for the first time a significant phylogeographic separation between western and eastern West Africa not only of the two M. africanum (West Africa 1 and 2) but also of several major M. tuberculosis sensu stricto families, such as LAM10 and Haarlem 3. Moreover, in a longitudinal logistic regression analysis for grouped data we showed that M. africanum West Africa 2 remains a persistent health concern.Conclusions/SignificanceBecause of the geographical divide of the mycobacterial populations in West Africa, individual research findings from one country cannot be generalized across the whole region. The unequal geographical family distribution should be considered in placement and design of future clinical trials in West Africa.

Survival among metastatic colorectal patients in clinical trials compared to the real world.

673 Background: Randomized clinical trials play a central role in clinical research though only a small fraction of patients partake in clinical studies. Questions thus arise regarding the generalizability of clinical trial results to the remainder of the population. This study evaluated whether patient survival from randomized clinical trials in metastatic colorectal cancer reflects real world outcomes. Methods: A Pubmed search was used to identify randomized phase III clinical trials of first-line treatment for metastatic colorectal cancer published between 2005 and 2010. We excluded secondary or pooled analyses, second-line treatments, non-metastatic patients, non-English language, and non-randomized studies. Thirty-one clinical trials met these criteria, comprised of 79 distinct clinical trial arms. Overall survival among clinical trial patients was compared to metastatic colorectal cancer patients within the Surveillance, Epidemiology, and End Results (SEER) program. Within SEER, we restricted the analysis time-period and age of patients to match the enrollment period and age of patients within each individual clinical trial. Results: The clinical trials enrolled a total of 16,614 patients. Among all clinical trial arms the median survival ranged from 6.7-62 months, 1-year survival ranged from 30-97%, and 2-year survival ranged from 6-88%. Compared to SEER, the median survival was higher in 95% of the individual clinical trial arms by an average of 5.4 months (p&lt;0.0001). The 1-year survival was higher in 94% of the clinical trial arms by an average of 16.7% (p&lt;0.0001). The 2-year survival was higher in 71% of the clinical trial arms by an average of 7.2% (p&lt;0.0001). Conclusions: This study found substantially improved survival among clinical trial participants compared to patients in the SEER database suggesting that survival estimates from clinical trials may not generalize to the “real world.” Potential patient factors such as differences in underlying comorbidity, performance status, disease burden, as well as variation in treatment could not be addressed in this study, though these factors likely explain some of the observed survival differences.

Outcome Measures for Individuals With Stroke: Process and Recommendations From the American Physical Therapy Association Neurology Section Task Force

The use of standardized outcome measures (OMs) can support clinicians' development of appropriate care plans, guide educators in curricular decisions, and enhance the methodological quality and generalizability of clinical trials. The purposes of this case report are: (1) to describe a framework and process for assessing psychometrics and clinical utility of OMs used poststroke; (2) to describe a consensus process used to develop recommendations for stroke-related OMs in clinical practice, research, and professional (entry-level) physical therapist education; (3) to present examples demonstrating how the recommendations have been utilized to date; and (4) to make suggestions for future efforts. A task force of 7 physical therapists with diverse clinical and research expertise in stroke rehabilitation used a 3-stage, modified Delphi consensus process to develop recommendations on OM use. An evidence-based systematic review template and a 4-point rating scheme were used to make recommendations on OM use by care setting and patient acuity, for research, and for inclusion in professional education. An initial list of 77 OMs was developed based on input from numerous professional sources. Screening measures and duplicate measures were eliminated. Fifty-six OMs received full review. Measures spanned the constructs of body structure/function (21), activity (28), and participation (14). Fourteen measures received a rating of "highly recommend." Use of highly recommended OMs may provide a common set of tools enabling comparisons across patients, interventions, settings, and studies. The use of a clearly defined, comprehensive assessment template may facilitate the pooling of data on OMs and contribute to best practice guidelines. Educational recommendations may inform curricular decisions.

Are subjects in treatment trials of panic disorder representative of patients in routine clinical practice? Results from a national sample

BackgroundResearch on the generalizability of clinical trials in panic disorder is limited. The present study sought to quantify the generalizability of clinical trials' results of individuals with DSM-IV panic disorder (PD) to a large community sample. MethodsData were derived from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a large national representative sample of 43,093 adults of the United States population. We applied a standard set of eligibility criteria representative of PD clinical trials to all adults with past 12 months PD (n=907), and then to a subgroup of participants seeking treatment (n=105). Our aim was to determine the proportion of participants with PD who would have been excluded by typical eligibility criteria. ResultsWe found that more than 8 out of ten participants (80.52%; 95% CI=77.13–83.52%) with PD were excluded by at least one criterion. In the subgroup of participants who sought treatment, the exclusion rate by at least one criterion was higher (92.40%; 95% CI=84.60–96.42%). For the full sample and the treatment-seeking subsample, having currently a depression and a diagnosis of alcohol or drug abuse/dependence were the criteria excluding the highest percentage of participants. Having a lifetime history of bipolar disorder and a current significant medical condition also excluded a substantial proportion of individuals in both samples. Exclusion rates were similar when considering panic disorder with and without agoraphobia. ConclusionsClinical trials, that exclude a majority of adults with panic disorder, should carefully consider the impact of eligibility criteria on the generalizability of their results. As required by CONSORT guidelines, reporting exclusion rate estimate and reasons of eligibility should be mandatory in both clinical trials and meta-analyses.

Tailoring a Treatment Fidelity Framework for an Intensive Care Unit Clinical Trial

Treatment fidelity (TF) refers to methodological strategies and practices used to monitor and enhance the reliability and validity of behavioral interventions. Treatment fidelity monitoring enhances internal and external validity and is needed for study replication and generalizability. The aim of this study was to describe the implementation, monitoring, and impact of TF in an intensive-care-unit-based clinical trial testing music for anxiety self-management with mechanically ventilated patients. Development of the criteria was based on the Five-Component Treatment Fidelity Framework from the Treatment Fidelity Workgroup. Descriptive statistics were used to evaluate adherence rates to the key TF criteria and the reasons criteria were unmet. Descriptive and nonparametric statistics were used to evaluate the impact of TF on participants' use of the assigned intervention. The Treatment Fidelity Framework was adapted easily to fit the study interventions. After the initial implementation phase of monitoring, adherence to key criteria was maintained at the targeted level of 80%. The majority of barriers to adherence affected the research nurses' opportunity to interact with the participant and encourage use of the intervention. There was a trend toward increased use of equipment associated with the assigned condition after the initiation of TF; however, this difference was not statistically significant. Treatment fidelity monitoring is an iterative process that requires ongoing vigilance. Identification of barriers and the implementation of methods to enhance protocol adherence are needed to enhance the reliability, validity, and generalizability of clinical trials in the dynamic and challenging research environment of the intensive care unit.

Cardiac toxicity and adjuvant trastuzumab for breast cancer – the Cancer Centre of Southeastern Ontario experience.

Abstract Abstract #3158 Background: In May 2005 several large randomized trials reported a significant improvement in DFS following the addition of trastuzumab (T) to adjuvant chemotherapy (CT) in early stage breast cancer (BC) such that in the summer of 2005 adjuvant T became standard of care for patients (pts) whose tumors over-expressed her2. Cardiotoxicity had been reported as the main toxicity suffered by pts exposed to T. As the generalizability of clinical trial results to the 'real world' is under increasing scrutiny from the oncology community, we undertook this study to identify and follow the population of interest and to characterize cardiac toxicity related to adjuvant T as practice changed.&amp;#x2028; Methods: We conducted a retrospective review of electronic and paper records of all pts prescribed adjuvant T for early stage BC at the Cancer Centre of Southeastern Ontario from June 2005 through January 2007; collecting demographic, disease-related, and treatment-related variables, along with serial left ventricular ejection fraction (LVEF) measurements for each pt.&amp;#x2028; Results: 54 pts prescribed adjuvant T were identified in this time period, nearly half of which were still on T at the time of this analysis. Mean age was 54.4 ± 9.5 years, 38.9% had N0 disease, and 40.7% had left sided tumors, with 42.6% being ER+ and 50% being PR+. Most pts received anthracycline based CT (53.7%) and 39% received an anthracycline/taxane combination. T was concurrently with CT in 14.8% of pts, concurrently with radiotherapy in 33.3% and sequentially in the remainder. T was initiated at a mean of 91.2 days from completion of chemotherapy (range 19-365). Our local protocol mandated LVEF assessments at baseline pre CT, upon completion of CT and/or prior to initiation of T for all pts, and while on T all pts underwent LVEF assessments at 12, 24, 36, 48 and 52 weeks, and in response to any symptoms suggesting cardiac dysfunction. Mean LVEF pre CT and post CT was 64% and 62% respectively. We saw no change in LVEF post CT and pre T. We noted a significant decline in LVEF after 12 weeks on T, from 60.5 ± 6.2% to 56.5 ± 9.5% respectively (p = 0.003), with LVEF values remaining stable thereafter. However, at the time of this analysis only approximately half the pts had completed the full year of therapy. Twelve pts (22.2%) interrupted their T therapy due to a drop in LVEF of &amp;gt;10%, only one pt experienced symptomatic cardiotoxicity requiring treatment. Of these twelve, only two pts restarted T at a later date. Follow-up of those patients still on trastuzumab is ongoing.&amp;#x2028; Discussion: Adjuvant trastuzumab in general clinical practice is associated with significant decreases in LVEF that are associated with premature discontinuation of therapy. A better understanding of factors associated with LVEF decline and the trends in LVEF over time may allow for targeted interventions for pts at risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3158.