External control arms in oncology: current use and future directions.

Although randomized control trials allow for a comparison of treatment arms with minimal concern for confounding by known and unknown factors, a randomized study is not feasible in certain disease settings. When a randomized design is not possible, incorporating external control data into the study design can be an effective way to expand the interpretability of the results of an experimental arm by introducing the ability to carry out a formal or an informal comparative analysis. This paper provides an introduction to the concepts of external controls in oncology trials, followed by a review of relevant and current research on this topic. The paper also focuses on general considerations for designing a trial that may incorporate external control data, followed by case studies of the marketing applications submitted to the Food and Drug Administration that included external control data.

Renal artery revascularization in patients with atherosclerotic renal artery stenosis and impaired renal function: conservative management versus renal artery stenting.

BACKGROUND: The impact of percutaneous renal artery angioplasty and stenting (PTRAS) for treatment of atherosclerotic renal artery stenosis (ARAS) is not fully understood, especially in patients with chronic kidney disease (CKD). The goal of this study was to compare renal outcomes in patients treated with PTRAS with those managed conservatively. METHODS: Retrospective cohort study of 118 prevalent patients with significant ARAS and moderate-to-severe CKD who were treated medically (n = 71) or with PTRAS (n = 47). The primary endpoint was change in renal function over the first year after diagnosis/treatment. RESULTS: Average age was 73 +/- 8 years, baseline glomerular filtration rate was 37 +/- 15 ml/min/1.73 m2, and average follow-up was 34 months. Baseline characteristics were similar between the two groups, with the exception of higher diastolic blood pressure in the PTRAS group (75 versus 70 mmHg, p = 0.028). There were no significant differences between the two groups during follow-up. The decline in glomerular filtration rate was similar in both groups (-1.6 ml/min/1.73 m2 in the medical group versus -1.4 ml/min/1.73 m2 in the PTRAS group, p = 0.938). Multivariate models did not indicate an association between treatment modality and changes in renal function or rates of ESRD or death. CONCLUSION: In patients with advanced kidney disease, medical therapy and renal artery stenting appear comparable in stabilizing renal function for ARAS.

Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review.

The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, but such measurements are a poor marker of acute deterioration in kidney function. We performed a systematic review of publications that evaluated the accuracy and reliability of serum and urinary biomarkers in human subjects when used for the diagnosis of established AKI or early AKI, or to risk stratify patients with AKI. Two reviewers independently searched the MEDLINE and EMBASE databases (January 2000-March 2007) for studies pertaining to biomarkers for AKI. Studies were assessed for methodologic quality. In total, 31 studies evaluated 21 unique serum and urine biomarkers. Twenty-five of the 31 studies were scored as having 'good' quality. The results of the studies indicated that serum cystatin C, urine interleukin-18 (IL-18), and urine kidney injury molecule-1 (KIM-1) performed best for the differential diagnosis of established AKI. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin, IL-18, glutathione-S-transferase-pi, and gamma-glutathione-S-transferase performed best for early diagnosis of AKI. Urine N-acetyl-beta-D-glucosaminidase, KIM-1, and IL-18 performed the best for mortality risk prediction after AKI. In conclusion, published data from studies of serum and urinary biomarkers suggest that biomarkers may have great potential to advance the fields of nephrology and critical care. These biomarkers need validation in larger studies, and the generalizability of biomarkers to different types of AKI as well as the incremental prognostic value over traditional clinical variables needs to be determined.

Predicting which patients can resume oral nutrition after percutaneous endoscopic gastrostomy tube placement.

BACKGROUND: Percutaneous endoscopic gastrostomy tubes are placed with high frequency and relative safety for a variety of indications. One of these indications is temporary nutritional support for patients expected to resume oral nutrition. AIMS: To determine if baseline clinical characteristics can predict which patients attain the clinical goal of resuming oral nutrition with consequent tube removal. METHODS: We conducted a single site observational cohort study from December 1999 to April 2001, enrolling all patients scheduled for percutaneous endoscopic gastrostomy placement. Standard descriptive and bivariate analyses were performed. Cox proportional hazard models were constructed to identify patient characteristics prior to percutaneous endoscopic gastrostomy placement that might predict resumption of oral nutrition with tube removal. RESULTS: Bivariate analyses revealed four potential clinical predictors: age < 65 years, localized head and neck cancer, serum albumin > or = 3.75 g/dL, and serum creatinine < or = 1.1 mg/dL. In multivariable analysis, age < 65 years (HR = 3.7, 95% CI: 1.0-14.3) and a diagnosis of localized head and neck cancer (HR = 4.6, 95% CI: 1.4-15.0) predicted resumption of oral nutrition with percutaneous endoscopic gastrostomy removal. CONCLUSIONS: When discussing percutaneous endoscopic gastrostomy placement, doctors should consider the likelihood of achieving clinically important outcomes such as the resumption of oral nutrition with tube removal. This clinical goal is unlikely for older patients with diagnoses other than localized head and neck cancer.

Patient preferences for treatment of rheumatoid arthritis.

OBJECTIVE: To elicit treatment preferences of patients with rheumatoid arthritis (RA) for disease modifying antirheumatic drugs (DMARDs) with varying risk profiles. METHODS: Patient values for 16 DMARD characteristics were ascertained using published data about side effects, effectiveness, and cost. Patient preferences were determined by Adaptive Conjoint Analysis, an interactive computer program that predicts preferences by asking patients to make trade-offs between specific treatment characteristics. Simulations were run to derive preferences for four drugs: methotrexate, gold, leflunomide, and etanercept, under different risk-benefit scenarios. Infliximab was not included because it is given with methotrexate, and we did not include preferences for combination therapy. Based on each patient's expressed preferences, and the characteristics of the treatments available at the time of the study, the option that best fitted each patient's perspective was identified. RESULTS: 120 patients (mean age 70 years) were interviewed. For the base case scenario (which assumed the maximum benefits reported in the literature, a low probability of adverse effects, and low equal monthly "co-pays" (out of pocket costs)), 95% of the respondents preferred etanercept over the other treatment options. When all four options were described as being equally effective, 88% continued to prefer etanercept owing to its safer short term adverse effect profile. Increasing etanercept's co-pay to $30.00 decreased the percentage of patients preferring this option to 80%. CONCLUSIONS: In this study, older patients with RA, when asked to consider trade-offs between specific risk and benefits, preferred etanercept over other treatment options. Preference for etanercept is explained by older patients' risk aversion for drug toxicity.

Hyperglycaemia in patients with acute ischaemic stroke: how often do we screen for undiagnosed diabetes?

BACKGROUND: Hyperglycaemia is common among patients with acute ischaemic stroke, and may be due to the physiological stress of the acute stroke event or reflect underlying diabetes mellitus. The under-diagnosis of diabetes in the general population, combined with the association of diabetes and stroke, suggests a rationale for screening for diabetes among hyperglycaemic stroke patients. AIM: To determine how often clinicians screen for diabetes among hyperglycaemic stroke patients without a prior diagnosis of diabetes. DESIGN: Retrospective medical record review. METHODS: We reviewed the records of acute ischaemic stroke patients admitted at any of ten Connecticut hospitals from May 1996 through December 1998. RESULTS: We identified 90 acute stroke patients with no prior history of diabetes. The prevalence of hyperglycaemia varied from 31% down to 6%, depending on the maximum glucose cut-off used to define hyperglycaemia: from > or = 140 mg/dl (7.8 mmol/l) to > or = 200 mg/dl (11.1 mmol/l). Only one of the hyperglycaemic patients (1/90, 1%) had any evidence that a clinician screened or planned to screen for undiagnosed diabetes: one patient had a haemoglobin A1c measured during the hospitalization, none received oral glucose tolerance testing while hospitalized, and no discharge summary included a plan to screen for diabetes as an out-patient. DISCUSSION: Hyperglycaemic stroke patients without a previous diagnosis of diabetes are not routinely screened for diabetes. This situation represents an opportunity, currently unused, to identify an important and modifiable condition.

Unwillingness of rheumatoid arthritis patients to risk adverse effects.

OBJECTIVE: To evaluate patient willingness to accept the risk of adverse effects (AEs) commonly associated with arthritis medications. METHODS: Rheumatoid arthritis patients were asked to rate their willingness to take a medication associated with 17 specific AEs using a visual analogue scale. RESULTS: We interviewed 100 patients. Eighty-one were currently using one or more disease-modifying anti-rheumatic drugs (DMARDs) and 29 had previously experienced AEs related to DMARDs. Seventy-five stated that they were doing very well or well with respect to their arthritis compared with other people their age. Thirty-five per cent of those interviewed were unwilling to accept the risk of cosmetic changes, 38% were unwilling to accept the risk of temporary discomfort and 45% were unwilling to accept the risk of major toxicity. Patients who had previously experienced AEs were more willing to accept the risk of cosmetic changes (83 vs. 58%, P=0.02), temporary discomfort (79 vs. 55%, P=0.02) and major toxicity (83 vs. 44%, P=0.001) compared with those who had not previously experienced AEs. CONCLUSIONS: Many rheumatoid arthritis patients are very concerned about potential drug toxicity. However, risk adversity appeared to be attenuated by past experience with AEs. Our results suggest that certain patients, especially those with milder disease activity, might be reluctant to accept commonly used arthritis medications if they are fully informed of their potential toxicity.

Risk adjustment for older hospitalized persons: a comparison of two methods of data collection for the Charlson index.

To compare Charlson indices based on chart data and ICD-9 data for agreement overall and on rating specific comorbid conditions, and to compare mortality risks associated with these indices. Prospective cohort study. Six general medicine wards at Yale-New Haven Hospital. 524 consecutive patients who had no clinical evidence of delirium at enrollment, admitted between November 6, 1989 and July 31, 1991, aged 70 years or older. Death within 1 year of the index hospital admission date. Scores using the chart-based data were significantly higher than those using ICD-9 data. About half of the individual conditions showed fair-to-good agreement between the two scores, whereas the other half showed poor agreement. A comparison of mortality prediction indicated that the weightings assigned to individual comorbidities differed substantially from those used in Charlson's original index. While mortality prediction of each individual index was comparable, the ICD-9 and chart indices contributed independently to mortality prediction in the presence of the other. Low agreement between Charlson scores based on the two methods of data collection and their cumulative contribution to mortality prediction suggest that these indices may include different information. Our results suggest that the original Charlson index may not provide optimal risk adjustment for elderly general medicine samples. We suggest development of an empirically-derived index of comorbid conditions and weights may be warranted for older general medical patients.

Injury related infant death: the impact of race and birth weight.

OBJECTIVE: To examine the effect of race and birth weight independent of other sociodemographic factors on injury related infant death using national data. SETTING: Infants born in the United States to mothers who were white (non-Hispanic), African American, Mexican American, and Native American. METHODS: Linked infant birth and death data from the National Center for Health Statistics for 1989-91 were analyzed to calculate unadjusted and adjusted odds ratios for death due to homicide or unintentional injury within the first year of life. In addition to maternal race and birth weight, the risk of death was adjusted for maternal age, prenatal care, maternal education, paternal education, marital status, birth order, interval since last pregnancy, smoking during pregnancy, and alcohol intake during pregnancy. RESULTS: Among 10.7 million births during 1989-91, 821 homicides and 2397 unintentional deaths were reported in infants. Relative to whites, African Americans were at highest risk for homicides (unadjusted and adjusted odds ratios = 3.6 (95% confidence interval = 3.1 to 4.2) and 1.6 (1.3 to 1.9), respectively) and Native Americans at highest risk for unintentional injuries (unadjusted and adjusted odds ratios = 3.8 (3.0 to 4.8) and 2.1 (1.7 to 2.6), respectively). After accounting for other sociodemographic factors, Mexican American infants appeared protected from injury (adjusted odds ratio = 0.7 (0.6 to 1.0) for homicides and 0.7 (0.6 to 0.8) for unintentional injuries). An inverse effect of birth weight was seen-as birth weight decreased, risk of homicides and unintentional injuries increased. After adjustment for the sociodemographic factors, very low birthweight babies were still at substantially increased risk of homicides with an odds ratio of 2.1 (1.4 to 3.1) and unintentional injuries with an odds ratio of 2.9 (2.4 to 3.7). CONCLUSIONS: Using a large national data-set, the effect of race as a risk factor for fatal infant injuries was mostly explained by birth weight and other sociodemographic factors. Preventable risk factors need to be identified for African Americans and Native Americans, in particular. Birth weight is an important independent risk factor; very low birthweight babies should be monitored for both homicide and unintentional injury.

A nested case-control study of the effectiveness of screening for prostate cancer: research design.

Although prostate-specific antigen (PSA) and digital rectal examination (DRE) are commonly used to screen for prostate cancer, available data do not confirm that either test improves survival. This report describes the methodological aspects of a nested case-control study addressing the question of whether PSA screening, with or without DRE, is effective in increasing survival. Potential sources of bias are discussed, as well as corresponding strategies used to avoid them. Results are expected in the year 2002.

Effect of non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease.

BACKGROUND: Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit poor clinical outcomes from myocardial ischemia. This may reflect an impairment in their cardiac insulin-response system. METHODS AND RESULTS: We used AV balance and intracoronary infusion techniques to compare the intrinsic cardiac responsiveness to insulin in 26 coronary disease patients with (n=13) and without (n=13) NIDDM. During fasting, NIDDM hearts demonstrated lower fractional extraction of glucose from arterial plasma than controls (1.0+/-0.5% versus 2.1+/-0.5%, P<0.05) despite higher circulating insulin levels (26+/-5 versus 13+/-4 microU. mL, P<0.05). This was compensated for by higher circulating glucose levels, so that net cardiac glucose uptake in the 2 groups was equivalent (5.2+/-1.1 versus 5.3+/-1.1 micromol. min). Intracoronary insulin infusion produced an approximately 3-fold increase in fractional extraction and net uptake of glucose across the heart in both groups (to 3.7+/-0.4% and 18.3+/-3.5 micromol. min in NIDDM and to 5.4+/-0.7% and 17.7+/-4.3 micromol. min in controls) accompanied by an approximately 30% increase in net lactate uptake, suggesting preserved insulin action on both glucose uptake and glucose oxidation in the NIDDM heart. In nondiabetics, insulin consistently increased coronary blood flow, but this effect was absent in NIDDM. CONCLUSIONS: In contrast to their peripheral tissues and coronary vasculature, the myocardium of patients with NIDDM expresses a competent insulin-response system with respect to glucose metabolism. This suggests that insulin resistance is mediated at the level of individual organs and that different mechanisms are involved in muscle and vascular tissue.

Preference for disclosure of information among patients with rheumatoid arthritis.

OBJECTIVE: To quantify preference for disclosure of information among patients with rheumatoid arthritis (RA) and to examine sex-specific correlates of information preference. METHODS: We interviewed patients with RA and assessed preference for disclosure of information using 4 questions from the previously validated "Information Preference Seeking Scale." Three questions addressed preference for disclosure of side effects and 1 question addressed preference for disclosure of therapeutic options. Associations between preference for information and patient characteristics were examined using stepwise multiple linear regression. RESULTS: One hundred RA patients (mean age 68+/-12 years; 73% female) were interviewed; 89 respondents agreed or strongly agreed with all 4 statements reflecting a preference for full disclosure, and an additional 8 respondents agreed or strongly agreed with 3 of the 4 statements. The mean score (+/- SD) for information preference was 86+/-13, on a scale from 0 to 100 where 100 reflected a strong preference for full disclosure. In bivariate analyses, female sex and current employment were associated with stronger preferences for being informed (mean score for women 88+/-11, for men 80+/-15 [P = 0.02]; for employed 92+/-11, for unemployed 84+/-13 [P = 0.04]). Multivariate sex-specific analyses demonstrated that current employment and higher education level were positively associated with preference for disclosure among women and men, respectively. CONCLUSION: The results of our survey suggest that RA patients want to be fully informed about the risks associated with medications and about alternative options. The challenge remaining for rheumatologists is how to effectively communicate the risks and benefits related to the many options that are currently available for RA patients.

Treatment decisions for localized prostate cancer: asking men what's important.

OBJECTIVE: To identify what factors men consider important when choosing treatment for prostate cancer, and to assess why men reject watchful waiting as a treatment option. PARTICIPANTS: One hundred two consecutive men with newly diagnosed localized prostate cancer identified from hospital and community-based urology practice groups. MEASUREMENTS: Patients were asked open-ended questions about likes and dislikes of all treatments considered, how they chose their treatment, and reasons for rejecting watchful waiting. The interviews were conducted in person, after the men had made a treatment decision but before they received the treatment. MAIN RESULTS: The most common reasons for liking a treatment were removal of tumor for radical prostatectomy (RP) (n = 15), evidence for external beam radiation (EBRT) (n = 6), and short duration of therapy for brachytherapy (seeds) (n = 25). The most frequently cited dislikes were high risk of incontinence for RP (n = 46), long duration of therapy for EBRT (n = 29), and lack of evidence for seeds (n = 16). Only 12 men chose watchful waiting. Fear of future consequences, cited by 64% (n = 90) of men, was the most common reason to reject watchful waiting. CONCLUSION: In discussing treatment options for localized prostate cancer, clinicians, including primary care providers, should recognize that patients' decisions are often based on specific beliefs regarding each therapy's intrinsic characteristics, supporting evidence, or pattern of complications. Even if patients do not recall a physician recommendation against watchful waiting, this option may not be chosen because of fear of future consequences.

Validation of a staging system for evaluating prognosis in prostate cancer.

BACKGROUND: The purposes of our research were to validate a previously published clinical-anatomic staging system for evaluating prognosis in prostate cancer and to explore the predictive ability of additional factors. METHODS: All patients diagnosed with prostate cancer by physicians affiliated with Yale-New Haven Hospital during 1991 were eligible for the study. Patient and tumor characteristics at baseline were extracted from medical records with up to five-year follow-up for mortality. The original system was validated using Cox proportional hazards analysis and conjunctive consolidation. Prostate specific antigen (PSA) and Gleason score were also explored as factors to be included in an updated staging system. RESULTS: Five-year survival was 76% among 121 patients included in the study. The original staging system, when applied to the current cohort, was validated: Five-year survival ranged from 100% (low-risk) to 27% (high-risk). PSA and Gleason score were associated with survival but did not change results substantially in this population. CONCLUSION: By predicting distinct mortality outcomes in men with prostate cancer, prognostic staging systems can be used to help patients and physicians make informed treatment decisions.

Cervical cancer practice patterns and appropriateness of therapy.

OBJECTIVE: This study was undertaken (1) to describe practice patterns for treatment of cervical cancer on a national scale, including patient characteristics associated with receiving appropriate versus inappropriate therapy, and (2) to determine whether mortality rate differences exist between patients who were treated appropriately and those who were treated inappropriately. STUDY DESIGN: We defined treatment appropriateness in cases of cervical cancer according to general recommendations for therapy for each International Federation of Gynecology and Obstetrics stage. In an analysis of data obtained from the Surveillance, Epidemiology, and End Results Program for 1988 through 1994 we determined the associations of patient demographic characteristics and tumor characteristics with treatment appropriateness. The association between treatment appropriateness and overall mortality for as long as 7 years of follow-up was adjusted for age; marital status; Surveillance, Epidemiology, and End Results Program location; International Federation of Gynecology and Obstetrics stage of disease; lymph node status; tumor grade; and histologic classification. RESULTS: Overall 90% of all patients were found to have received appropriate therapy. Important variables significantly associated with being treated inappropriately versus appropriately included age <40 years, positive nodal status, and International Federation of Gynecology and Obstetrics stage IB disease. Important variables significantly associated with receiving no therapy versus receiving appropriate therapy were age >/=60 years, International Federation of Gynecology and Obstetrics stage IV disease, positive nodal status, and unknown nodal status. In a comprehensive model that included demographic factors and tumor characteristics, the adjusted hazard ratio for mortality among patients who were treated inappropriately versus appropriately was 0.87 (95% confidence interval, 0.70-1.09). The adjusted hazard ratio for mortality among patients who did not receive therapy versus those who were treated appropriately was 2.92 (95% confidence interval, 2.44-3.48). CONCLUSIONS: In an analysis of data from a tumor registry, cervical cancer practice patterns were generally found to follow accepted treatment guidelines. Appropriateness of therapy did not vary widely according to demographic variables. Although patients who received no therapy had an elevated risk of death with respect to that of patients who were treated appropriately, patients who were treated inappropriately had a mortality rate similar to that among those who were treated appropriately (perhaps because of limitations in Surveillance, Epidemiology, and End Results Program data). Results of this preliminary study suggest a need for further research on effectiveness of cervical cancer therapies in the general population.

Randomized, controlled trials, observational studies, and the hierarchy of research designs.

BACKGROUND: In the hierarchy of research designs, the results of randomized, controlled trials are considered to be evidence of the highest grade, whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects. We used published meta-analyses to identify randomized clinical trials and observational studies that examined the same clinical topics. We then compared the results of the original reports according to the type of research design. METHODS: A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of randomized, controlled trials and meta-analyses of either cohort or case-control studies that assessed the same intervention. For each of five topics, summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual randomized, controlled trials and the individual observational studies. RESULTS: For the five clinical topics and 99 reports evaluated, the average results of the observational studies were remarkably similar to those of the randomized, controlled trials. For example, analysis of 13 randomized, controlled trials of the effectiveness of bacille Calmette-Guérin vaccine in preventing active tuberculosis yielded a relative risk of 0.49 (95 percent confidence interval, 0.34 to 0.70) among vaccinated patients, as compared with an odds ratio of 0.50 (95 percent confidence interval, 0.39 to 0.65) from 10 case-control studies. In addition, the range of the point estimates for the effect of vaccination was wider for the randomized, controlled trials (0.20 to 1.56) than for the observational studies (0.17 to 0.84). CONCLUSIONS: The results of well-designed observational studies (with either a cohort or a case-control design) do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topic.

Prostate specific antigen: a useful screening test?

The role of prostate specific antigen (PSA) as a screening test for prostate cancer is controversial. Proponents of screening emphasize that early detection can lead to discovery of organ-confined disease and the potential for cure. Opponents point to the lack of credible evidence that screening is associated with a decrease in mortality. In addition, population-based screening (with subsequent diagnosis and treatment in many men) can be associated with considerable morbidity and mortality in the context of a disease that is often not fatal. This report examines the limitations of PSA as a screening test and supports an approach using "verbal informed consent" to identify patients who should be tested.

Claims of equivalence in medical research: are they supported by the evidence?

BACKGROUND: Most clinical studies are done to show comparative superiority, but many reports now claim equivalence between the investigated entities. These assertions may not always be supported by the methods used and the results obtained. PURPOSE: To assess the justification and support for claims of clinical or therapeutic equivalence in medical journals. DATA SOURCES: A search of MEDLINE for articles published from 1992 through 1996. STUDY SELECTION: From 1209 citations that contained the word equivalence in the title or abstract or contained the Medical Subject Heading therapeutic equivalency, we excluded 1121 studies reporting nonoriginal research, purely laboratory or other nonhuman research, and studies in which equivalence was not the main claim. The remaining 88 eligible papers were evaluated for five methodologic attributes. DATA SYNTHESIS: Only 45 (51%) of the 88 reports were specifically aimed at studying equivalence; the others either tried to show superiority or did not state a research aim. The quantitative distinctions regarded as "equivalent" ranged from 0% to 21% for direct increments and from 0% to 76% for proportionate differences. An equivalence boundary was set and confirmed with an appropriate statistical test in only 23% of reports. In 67% of reports, equivalence was declared after a failed test for comparative superiority, and in 10%, the claim of equivalence was not statistically evaluated. The sample size needed to confirm results had been calculated in advance for only 33% of reports. Sample size was 20 patients per group or fewer in 25% of reports. CONCLUSIONS: Many studies of clinical equivalence do not set boundaries for equivalence. Claims of "difference" or "similarity" are often made not by thoughtful examination of the data but by tests of statistical significance that are often misapplied or accompanied by inadequate sample sizes. These methodologic flaws can lead to false claims, inconsistencies, and harm to patients.

Beyond diagnosis: patient mix and challenges to patient care in ambulatory training sites.

BACKGROUND: Educational experiences in ambulatory medicine vary by site. PURPOSE: To evaluate variations in patient mix and challenges in patient care at 3 ambulatory training sites. METHOD: Patients (n=123) receiving care at a VA medical center (VA), an urban academic medical center's primary care center (PCC), and a community group practice (CGP) were evaluated. RESULTS: Patients at the VA (n=55), compared with those at the PCC (n=44) and the CGP (n=24), were older, more likely to be male, and white (all P<0.05). Patients at the VA and the PCC reported difficulty with functional and health status more frequently than those at the CGP (all P<0.05). Common medical diagnoses varied across sites and comorbidity scores were > or = 2 in 48% of VA subjects compared with 16% at the PCC and 29% at the CGP (P<0.05). Challenges most frequently cited were administrative issues at the VA (44%), patient-physician communication at the PCC (39%), and medical decisions at the CGP (50%) (P<0.05). CONCLUSIONS: Ambulatory training sites can differ greatly with respect to characteristics beyond diagnosis. Plans for increased and improved ambulatory training of internal medicine residents should include attention to these issues to ensure exposure to an adequate patient spectrum.