Collaborative study for the establishment of the WHO 3(rd) International Standard for Endotoxin, the Ph. Eur. endotoxin biological reference preparation batch 5 and the USP Reference Standard for Endotoxin Lot H0K354.

An international collaborative study was organised jointly by the World Health Organization (WHO)/National Institute for Biological Standards and Control (NIBSC), the United States Pharmacopeia (USP) and the European Directorate for the Quality of Medicines & HealthCare (EDQM/Council of Europe) for the establishment of harmonised replacement endotoxin standards for these 3 organisations. Thirty-five laboratories worldwide, including Official Medicines Control Laboratories (OMCLs) and manufacturers enrolled in the study. Three candidate preparations (10/178, 10/190 and 10/196) were produced with the same material and same formulation as the current reference standards with the objective of generating a new (3(rd)) International Standard (IS) with the same potency (10 000 IU/vial) as the current (2(nd)) IS, as well as new European Pharmacopoeia (Ph. Eur.). and USP standards. The suitability of the candidate preparations to act as the reference standard in assays for endotoxin performed according to compendial methods was evaluated. Their potency was calibrated against the WHO 2(nd) IS for Endotoxin (94/580). Gelation and photometric methods produced similar results for each of the candidate preparations. The overall potency estimates for the 3 batches were comparable. Given the intrinsic assay precision, the observed differences between the batches may be considered unimportant for the intended use of these materials. Overall, these results were in line with those generated for the establishment of the current preparations of reference standards. Accelerated degradation testing of vials stored at elevated temperatures supported the long-term stability of the 3 candidate preparations. It was agreed between the 3 organisations that batch 10/178 be shared between WHO and EDQM and that batches 10/190 and 10/196 be allocated to USP, with a common assigned value of 10 000 IU/vial. This value maintains the continuity of the global harmonisation of reference materials and unitage for the testing of endotoxins in parenteral pharmaceutical products. Based on the results of the collaborative study, batch 10/178 was established by the European Pharmacopoeia Commission as the Ph. Eur. Endotoxin Biological Reference Preparation (BRP) batch 5. The same batch was also established by the Expert Committee on Biological Standardisation (ECBS) of WHO as the WHO 3(rd) IS for Endotoxin. Batch 10/190 was adopted as the USP Endotoxin Reference Standard, lot H0K354 and vials from this same batch (10/190) will serve as the United States Food and Drug Administration (USFDA) Endotoxin Standard, EC-7.

Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization.

To better characterize infants presenting with diminished immunoglobulin levels and intact antibody formation, we present 49 such infants, correlating presenting characteristics with history and time to immunoglobulin normalization. Term infants with the following characteristics were included: 1) one or more immunoglobulin classes > 2SD below mean, 2) protective antibody titer to tetanus and diphtheria, 3) intact cellular immunity, 4) no features of other syndromes. The children were 69.4% male and had recurrent otitis media (77.6%), wheezing (61.2%), and atopy (26.5%). Diminished IgA (95.9%) was most common, but 65.3% had multiple isotypes diminished. During follow-up, 25/49 (51%) normalized immunoglobulins, of whom 80% were male; only 48% normalized in infancy. Female immunoglobulin normalization was significantly delayed (p < .001). No deaths or serious infections occurred. This phenotype is predominantly seen in male infants with otitis media and wheezing. Female infants have significantly delayed immunoglobulin normalization. Transient hypogammaglobulinemia of infancy can be diagnosed only retrospectively.

Evaluating home environments of persons with dementia: interrater reliability and validity of the Home Environmental Assessment Protocol (HEAP).

PURPOSE: This article reports on an interrater reliability and preliminary validity study of an investigator-developed tool, the Home Environmental Assessment Protocol (HEAP) for use in homes of persons with dementia. METHOD: The HEAP consists of 192 items that are summed into separate indices representing the number of hazards, adaptations, and level of clutter and comfort in eight areas of the home. Interrater reliability was examined among four raters, two environmental experts and two non-experts, who observed 22 dementia households. RESULTS: The Kappa statistic was used to evaluate agreement level for each measured item and found that agreement ranged from slight to almost perfect. Intraclass correlations (ICCs), were used to evaluate agreement level for indices. The hazard index in each room ranged from fair (0.36) to moderate (0.66) for all raters. For the adaptation, clutter and comfort indices in each room, ICCs ranged from 0.51 to 0.90 for all raters. Agreement level between expert and non-expert raters differed minimally for all indices. Adaptations to dining rooms (r= -0.080, p = 0.001), kitchens (r = -0.52, p = 0.02) and bedrooms (r = -0.76, p = 0.001) were associated with patient deficits such that more adaptations were made in homes of dependent persons. Low Mini-Mental Status Examination scores were associated with fewer hazards, more adaptations, and less clutter. CONCLUSION: Findings show that both experts and non-expert raters use the HEAP consistently. Also, measured attributes are related to cognitive and functional status in the expected direction.

Complete diagnostic evaluation in colorectal cancer screening: research design and baseline findings.

BACKGROUND: While indicated by guidelines, complete diagnostic evaluation, or CDE (i.e., colonoscopy or combined flexible sigmoidoscopy plus barium enema X ray), is often not recommended and performed for persons with an abnormal screening fecal occult blood test (FOBT) result. We initiated a randomized trial to assess the impact of a physician-oriented intervention on CDE rates in primary care practices. METHODS: In 1998, we identified 1,184 primary care physicians (PCPs) in 584 practices whose patients received FOBTs that are mailed annually by a managed care organization screening program. A total of 470 PCPs in 318 practices completed a baseline survey. Practices were randomly assigned either to a Control Group (N = 198) or to an Intervention Group (N = 120). Control Group practices received the screening program. Intervention Group practices received the screening program and the intervention (i.e., CDE reminder-feedback plus educational outreach). Practice CDE recommendation and performance rates are the primary outcomes to be measured in the study. RESULTS: Baseline CDE recommendation and performance rates were low and were comparable in Control and Intervention Group practices (54 to 57% and 39 to 40%, respectively). PCPs in the practices tended to view FOBT screening and CDE favorably, but had concerns about screening efficacy, time involved in CDE, and patient discomfort and adherence. Control Group physicians were more likely than Intervention Group physicians to believe that a mail-out FOBT screening program helps in the practice of medicine. CONCLUSIONS: We were able to enroll a high proportion of targeted primary care practices, measure practice characteristics and CDE rates at baseline, and develop and implement the intervention. Study outcome analyses will take into account baseline differences in practice characteristics.

Limits of 80%-125% for AUC and 70%-143% for Cmax. What is the impact on bioequivalence studies?

OBJECTIVE: The US Food and Drug Administration (FDA) currently uses bioequivalence (BE) limits for fasting BE studies that are based on the 90% confidence interval for the ratio of difference of the test and reference products Cmax and AUC falling within 80% to 125%. The FDA has also proposed that BE limits be used similarly for AUC and Cmax measurements from fed BE studies. In some cases, regulatory agencies have considered a wider BE limit for Cmax, because of the typically higher variability of Cmax compared to AUC. We investigated the consequences of changing from an 80%/ 125% limit for both pharmacokinetic measures to one that uses a limit of 80%/125% for AUC and 70%/143% for Cmax. METHODS: We computed the sample sizes required for BE studies using 80%/125% for AUC and 70%/143% for Cmax as BE limits. We also determined the range of the ratios of Cmax and AUC values in a study that could meet the 70%/143% and 80%/125% BE limits. RESULTS: The sample size for the study, in order to have adequate power with 80%/125% for AUC and 70%/143% for Cmax, will be determined primarily by the intrasubject variability of AUC, though with a substantial proportion of studies (about one third) still determined by the variability of Cmax. The ratio of mean Cmax values that can pass a wider 70%/143% BE limit could easily be as high as 128%. CONCLUSION: Without further scientific or clinical rationale, we find it difficult to justify widening the bioequivalence limit for Cmax to 70%/143% for either fasting or fed BE studies.

Assessment of lung cancer response after nonoperative therapy: tumor diameter, bidimensional product, and volume. A serial CT scan-based study.

PURPOSE: Tumor response after nonoperative lung cancer therapy is traditionally evaluated by bidimensional measurement of maximum tumor diameters. The purpose of this analysis is to investigate whether tumor largest dimension (based on RECIST [Response Evaluation Criteria In Solid Tumors]), bidimensional tumor product, and volume correlate with each other in evaluating tumors of patients with locally advanced non-small-cell lung cancer (NSCLC). In addition, the pace of locally advanced NSCLC volumetric response over time, as well as the prognostic value of tumor size, was assessed in this report with software-assisted evaluation of sequential tumor measurement. METHODS AND MATERIALS: Patients with locally advanced NSCLC treated with thoracic radiotherapy (RT) with or without chemotherapy were included, if the following were available: a pretreatment computed tomography (CT) simulation and at least two follow-up diagnostic thoracic CT scans taken at our institution after 1996 that were available in Dicom format for electronic transfer of images from diagnostic radiology to a computer terminal with commercial statistics software (AcQsim/CMS Focus). Primary lung tumor and grossly involved lymph nodes were contoured manually on pre-RT axial images and on all follow-up CT scans. Tumor/lymph node largest dimensions, bidimensional products (BP), and volumes were measured using the same software. Data were presented as percent change in volume or unidimensional and bidimensional measurements, with the CT simulation measurements serving as baseline. RESULTS: A total of 22 patients were evaluated. The median thoracic RT dose was 62.4 Gy (range: 50.0-69.6), and all patients had a Karnofsky performance status > or =80. Chemotherapy (mostly carboplatin/paclitaxel) was given to 17 patients. Nineteen patients had Stage III NSCLC; 1 patient was in Stage I, 1 was in Stage IV, and 1 was recurrent. A total of 107 thoracic CT scans (22 pretreatment and 85 follow-up), averaging 4.9 scans per patient, were analyzed. Tumors reached the smallest volume at a median of 11.0 months from RT completion in all patients, 8.5 months in patients who subsequently failed locally (n = 8), and 11.9 months in those who did not fail locally. Failure rates were as follows: in-field, 36% (8/22); intrathoracic (lung nodules, effusion, pleura), 55% (12/22); and distant, 50% (11/22). Eleven patients are still alive, 4 free of disease. Overall median survival time (MST) is 27.3 months. The median initial tumor volume was 88.0 cc (range: 3.8-218) for all patients; median BP was 33.0 cm(2) (range: 3.1-112.1), and median tumor largest dimension was 7.6 cm (range: 2.2-13.5). The MST of patients with initial tumor volume < or =63.0 cc (n = 9) was >53.0 months and of those with tumor volume > 63.0 cc was 17.3 months. The MST of patients (n = 6) with initial bidimensional tumor product < or =16 cm(2) was >53.0 months and of those with tumor product >16 cm(2) was 17.3 months. The MST of patients with largest initial dimension < or =4 cm was >53.1 months and of those with largest dimension > 4 cm was 25.0 months. At 24 months, 79% of patients with a tumor volume < or =124.0 cc (n = 18) had locally controlled tumors, vs. 0% of patients with tumor volumes >124.0 cc. At the same time point, 93% of patients with BP < or =40 cm(2) were locally controlled, vs. 0% of those with BP > 40 cm(2); 100% of patients with tumor dimensions < or =7.5 cm were locally controlled, vs. 40% of those with dimensions >7.5 cm. The partial responses in our series (assessed as the best response obtained during observation period) were as follows: 4 patients assessed based on either dimension only, product only, or volume only; 15 partial responses based on dimension or product; 16 partial responses based on volume alone; 3 cases of no tumor response, based on dimension or product; and 2 cases based on tumor volume alone. That represents good to excellent agreement among all three methods of measurement. CONCLUSIONS: (1) The response of locally advanced NSCLC to nonoperative therapy is a slow process, with tumor volumes reaching their nadir several months after treatment. (2) Smaller initial tumor size, as measured by largest tumor dimension, bidimensional product, or tumor volume, is associated with better local control and survival than larger initial measurements. (3) Any of the three tumor measurements (largest dimension, bidimensional product, or volume) can be used as a reliable tool in assessing lung cancer response to nonoperative therapy. This confirms further the validity of RECIST and does not suggest that tumor volume is significantly superior for response evaluation.

Supercritical fluid simulated moving bed chromatography II. Langmuir isotherm.

The simulated moving bed (SMB) technology offers the possibility of scaling up single column, batch chromatographic separations to continuous operation. This has proved particularly effective for the separation of enantiomers, and has been applied in the liquid and gas phase, as well as using a supercritical fluid as eluent (SF-SMB). In the last case, the main performance improvements are due to the possibility of tuning the elution strength of the mobile phase, by changing the pressure in the four sections of the SMB unit. Thus a SF-SMB can be operated in two modes, i.e. the isocratic and the pressure gradient mode. In this research, design criteria for these two operating modes have been developed, which can be applied to systems described by linear as well as nonlinear Langmuir adsorption isotherms. The role and effect of an appropriate modifier in increasing solubility and reducing retention times have been investigated. The results reported allow to identify the operating conditions, including the pressure levels and the modifier concentration, which lead to optimal separation performance in terms of productivity and desorbent requirement.

Association of provider and patient characteristics with HIV-infected women's antiretroviral therapy regimen.

OBJECTIVE: We explored the effect of patient and provider factors on the type of antiretroviral regimen among women receiving therapy. PATIENTS: Five hundred ninety-five New York State nonpregnant HIV+ women with full Medicaid eligibility and at least 1 month of a prescribed antiretroviral regimen in federal fiscal years (FFY) 1997-1998 and intervals in FFY 1997-1998, who had delivered a liveborn baby within 5 years. MEASUREMENTS: From pharmacy claims in 4 6-month intervals in FFY 1997-1998, data were extracted on (1) an acceptable > or = 2 antiretroviral combination regimen per expert guidelines; and (2) a highly active regimen, including a protease inhibitor or nonnucleoside analog (highly active antiretroviral therapy [HAART]). RESULTS: Of 1514 woman-6-month intervals with filled antiretroviral prescriptions, 82% had an acceptable regimen, and of 1246 woman-6-month intervals on acceptable antiretroviral therapy, half demonstrated the use of HAART. Adjusted odds ratios (AORs) of acceptable antiretroviral therapy were higher (p < .05) for HIV specialty care (AOR = 1.71 for one or two visits; AOR = 2.10 for 3+ visits) or HIV clinical trials site care (AOR = 1.43; 95% confidence interval [CI]: 1.01, 2.04). Among women on acceptable antiretroviral regimens, those aged older than 25 years (AOR = 1.69; CI: 1.13, 2.53) or who were high school graduates (AOR = 1.50; CI: 1.09, 2.06) had higher odds of HAART. Methadone-treated women had twofold and nearly threefold higher AORs of acceptable antiretroviral regimens and HAART, respectively, than current drug users. CONCLUSION: Provider HIV expertise is associated with receipt of an acceptable antiretroviral regimen in women, although receipt of HAART is affected more by age, education, and current drug abuse. Methadone treatment seems to improve access to acceptable antiretroviral regimens as well as to HAART.

Regular outpatient medical and drug abuse care and subsequent hospitalization of persons who use illicit drugs.

CONTEXT: Patients and the public could benefit from identification of factors that prevent drug users' heavy reliance on inpatient care; however, optimal health care delivery models for illicit drug users remain ill-defined. OBJECTIVE: To evaluate associations of outpatient medical and drug abuse care with drug users' subsequent hospitalization rates. DESIGN AND SETTING: Retrospective cohort study of data from longitudinally linked claims for all ambulatory physician/clinic services and drug abuse services covered by the New York State Medicaid program. SUBJECTS: A total of 11 556 human immunodeficiency virus (HIV)-positive and 46 687 HIV-negative drug users. MAIN OUTCOME MEASURES: Hospitalization in federal fiscal year (FFY) 1997 compared by 4 patterns of care in FFY 1996: regular drug abuse care (>/=6 months in 1 program), regular medical care (>35% of care from 1 clinic, group practice, or individual physician), both, or neither. RESULTS: Hospitalization occurred in 55.6% of HIV-positive and 37.5% of HIV-negative drug users, with a mean of 27.5 and 24.5 inpatient days, respectively. In HIV-positive drug users, the adjusted odds ratio (AOR) for hospitalization was lowest among those with both regular medical and drug abuse care (AOR, 0.76; 95% confidence interval [CI], 0.67-0.85) followed by those with regular medical care alone (AOR, 0.82; 95% CI, 0.74-0.91) and regular drug abuse care alone (AOR, 0.85; 95% CI, 0.76-0.96) vs those with neither. In HIV-negative drug users, the AOR of hospitalization was lower for those with regular medical and drug abuse care (AOR, 0.73; 95% CI, 0.68-0.79), regular drug abuse care alone (AOR, 0.71; 95% CI, 0.66-0.76), and regular medical care (AOR, 0.91; 95% CI, 0.86-0.95) vs those with neither. Both types of care showed favorable effects for all but drug abuse-related hospitalizations. CONCLUSION: Our data indicate that regular drug abuse care with regular medical care for drug users is associated with less subsequent hospitalization.

Measuring complete diagnostic evaluation in colorectal cancer screening.

Complete diagnostic evaluation, or CDE (i.e., a colonoscopy or combined barium enema X-ray and flexible sigmoidoscopy) is recommended for individuals who have an abnormal screening fecal occult blood test result. Accurate measures of CDE use are needed in colorectal cancer (CRC) screening programs. This study compares the sensitivity and specificity of different methods for measuring CDE recommendation and performance. We identified 17 primary-care practices with 120 patients who had a positive fecal occult blood test result in a CRC screening program operated by a managed-care organization. Approaches used to measure CDE recommendation and performance included external chart audit (ECA) only; internal chart audit (ICA) only; administrative data review (ADR) of electronic claims data; ICA plus ADR; and ECA plus ADR (the "gold standard"). Sensitivity and specificity of each method were assessed relative to CDE recommendation and performance as measured by ECA plus ADR. For CDE recommendation, sensitivity measures were ECA only, 0.926; ICA only, 0.790; ADR only, 0.617; and ICA plus ADR, 0.901. The specificity of each method for CDE recommendation was no less than 0.95. In terms of CDE performance, sensitivity measures were ECA only, 0.877; ICA only, 0.790; ADR only, 0.877; and ICA plus ADR, 0.965. The specificity of each method for CDE performance was 1.0. The ICA-plus-ADR method was a highly sensitive and specific measure of CDE use. This method should be considered in situations that involve primary-care physician follow-up of patients with abnormal CRC screening test results.

A randomized, controlled trial of a home environmental intervention: effect on efficacy and upset in caregivers and on daily function of persons with dementia.

PURPOSE OF STUDY: The authors determined short-term effects of a home environmental intervention on self-efficacy and upset in caregivers and daily function of dementia patients. They also determined if treatment effect varied by caregiver gender, race, and relationship to patient. DESIGN AND METHODS: Families (N = 171) of dementia patients were randomized to intervention or usual care control group. The intervention involved 5 90-min home visits by occupational therapists who provided education and physical and social environmental modifications. RESULTS: Compared with controls, intervention caregivers reported fewer declines in patients' instrumental activities of daily living (p = .030) and less decline in self-care and fewer behavior problems in patients at 3 months post-test. Also, intervention spouses reported reduced upset (p = .049), women reported enhanced self-efficacy in managing behaviors (p = .038), and women (p = .049) and minorities (p = .037) reported enhanced self-efficacy in managing functional dependency. IMPLICATIONS: The environmental program appears to have a modest effect on dementia patients' IADL dependence. Also, among certain subgroups of caregivers the program improves self-efficacy and reduces upset in specific areas of caregiving.

Preliminary report on reduction of esophagitis by amifostine in patients with non-small-cell lung cancer treated with chemoradiotherapy.

Esophagitis is a major toxicity of chemoradiotherapy for lung cancer. Twenty-four patients with non-small-cell lung cancer received induction chemotherapy (paclitaxel/carboplatin) followed by concurrent thoracic irradiation (RT) and weekly paclitaxel. Acute esophagitis was scored weekly. Since a high rate of grade 3 esophagitis was noted in the initial group of 12 patients, amifostine (AMI) 500 mg intravenously twice weekly was added to the regimen in the subsequent 12 patients. Esophagitis Index (EI) was calculated as an area under the curve reflecting esophagitis grade over time. Median number of AMI doses was 12 per patient. AMI was well tolerated. Two patients were not evaluable for esophagitis. The incidence of grade 3 esophagitis was 18% in the initial 11 patients versus 9% in the AMI-treated patients (P = not significant). Mean EI was numerically lower in the AMI-treated patients than in the initial group (5.1 vs. 11.6, P = 0.14). The product of RT dose and length of esophagus in the RT field was larger in the AMI group (934 vs. 761, P = 0.035). Median survival time for all patients was 12.4 months. Esophagitis Index, a novel measure of the severity and duration of acute esophagitis, may be reduced in lung cancer patients receiving twice-weekly AMI with thoracic RT and paclitaxel. Twice weekly AMI did not eliminate grade 3 esophagitis; therefore, dose escalation of AMI is planned. The effect of AMI was not due to the shorter irradiated esophageal length. A phase III randomized trial is now open to assess AMI's effect on esophagitis.

Sample sizes for batch acceptance from single- and multistage designs using two-sided normal tolerance intervals with specified content.

One quality control test in the pharmaceutical industry is a test for uniformity of content of a batch prior to release of the batch to market. For batch acceptance by this or other quantitative tests of batch quality, one approach uses two-sided tolerance intervals of specified content. If the tolerance interval falls entirely within an acceptance interval, the batch is accepted. This has the form of a statistical hypothesis test. Once we recognize this approach as a statistical test, we can ask what sample size is required to be able to accept the batch with a desired power. The power for a single-stage design is a bivariate noncentral t probability and can be determined using previously published algorithms. Using standard methods for interim analyses, the approach is extended to multistage designs. Power and sample size for multistage designs are validated with simulations. We demonstrate it is possible to design one- and two-stage designs for batch acceptance with desired power and specified type I level.

Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: a multivariate analysis of patients with lung cancer treated with nonoperative therapy.

PURPOSE: To identify in a multivariate analysis treatment-related factors predisposing patients (pts) with lung cancer to acute esophagitis, expressed as a severity grade or Esophagitis Index (EI). METHODS AND MATERIALS: Acute esophagitis is prospectively scored as an RTOG Grade in our institution during and after thoracic radiotherapy. Charts, toxicity forms and digitally reconstructed radiographs (DRRs) of all pts with lung cancer who received thoracic radiotherapy (RT) between 11/95 and 1/99 were reviewed. Esophagitis grades for each time point were verified by review of weekly physician and nursing treatment notes, hospital discharge summaries and referring physician notes and then plotted on graph against time. The area under the curve was calculated for each patient's graph and was defined as an Esophagitis Index. The length of esophagus was measured on each anterior DRR while assuming that esophagus overlies the vertebral bodies on the anterior films and projects over the edge of the vertebral body on the oblique DRRs. This assumption was confirmed in 10 pts by digitizing esophagus on CT simulator-derived slices and visualizing its position on DRRs. To compare RT doses delivered with different fractionation schemes to standard fractionated doses, the equivalent RT doses were calculated using the linear-quadratic formula and alpha/beta ratio of 10. Univariate and multivariate analyses of several factors potentially influencing the maximum esophagitis grade, as well as EI, were performed. RESULTS: A total of 277 pts were identified. Pts were included in the analysis (n = 105) if they fulfilled the following criteria: chart, toxicity form and DRRs were all available; parallel opposed fields (no multiple fields) were used for both the initial and off cord/cone down fields; and an equivalent dose of 45.0 Gy or more was delivered. Seventy-eight pts had Stage III; 32, Stage IV, and the remainder, Stages I, II, or recurrent lung cancer (85 non-small cell and 18, small cell). Seventy-four pts were treated with definitive intent. Chemotherapy was given concurrently with RT in 58 pts (in 7 pts, with twice daily, or b.i.d., RT) and as induction treatment, in 11. Only 2 pts required a treatment break of more than 1 week. Median total and equivalent RT doses, fraction size, and anterior esophageal length were as follows: 59.9 Gy, 59.9 Gy, 2.0 Gy, and 14 cm (range, 4.2-21). The following maximum grades of esophagitis were recorded: 1, in 54 pts; 2, in 17 pts; 3, in 13 pts, and 4, in 1 pt. The mean EI for all pts; pts treated with standard RT alone; induction chemotherapy and standard RT; concurrent chemotherapy and standard (QD) RT; and b.i.d. RT with concurrent chemotherapy, was 41. 5 (range, 0-317); 13.6; 24.5; 52.4; and 132.1, respectively (p < 0. 001). Three pts developed an esophageal stricture within 3 months beginning RT. In multivariate analysis, the following factors were significantly associated with increasing EI: concurrent chemotherapy with QD RT and concurrent chemotherapy with b.i.d. RT (p < 0.001, considered jointly). Both factors were also associated with increasing maximum esophagitis grade (p = 0.011). Esophageal length was not associated with increasing EI or esophagitis grade in either univariate or multivariate analyses. CONCLUSION: Concurrent chemotherapy and twice daily radiotherapy, especially if combined together, were associated with the highest acute maximum esophagitis grade and esophagitis index in pts with lung cancer. The duration of acute esophagitis was also longest in the concurrent chemotherapy/twice daily radiotherapy group. Esophagitis Index appeared to be a more sensitive measure of acute esophagitis than the maximum esophagitis grade. The increasing length of esophagus in the radiation field did not predict for the severity of acute esophagitis.

An individual bioequivalence criterion: regulatory considerations.

Over the years, concerns have been raised regarding the appropriateness of using the average bioequivalence approach for evaluation of comparability between formulations. In lieu of average bioequivalence, scientists from academia, industry and regulatory agencies have spent considerable effort and time in exploring the concepts of population and individual bioequivalence, and developing the statistical methods to assess the bioavailability metrics using these approaches. Recently, the Food and Drug Administration (FDA) has published a preliminary draft guidance entitled 'In vivo bioequivalence studies based on population and individual bioequivalence approaches'. The concept of prescribability and switchability underscores the difference between the population and individual bioequivalence approaches. The most important consideration for individual bioequivalence, the focus of this paper, rests on the assurance that products deemed bioequivalent can be used interchangeably in the target population (switchability). In addition to the comparison of averages, the individual bioequivalence approach compares within-subject variabilities and assesses subject-by-formulation interaction. The proposed criterion represents substantial departure from the current practice and thus has resulted in extensive public discussion. In contrast to the current average bioequivalence procedure, the proposed individual bioequivalence approach offers flexible equivalence criteria based on the individual therapeutic window and variability of the reference drug product. The proposed criterion rewards manufacture of less variable drug products, allows scaling criteria for highly variable/narrow therapeutic range drugs, and promotes the use of subjects from the general population in bioequivalence studies. The FDA is currently considering various approaches for resolution of issues raised from the public debate on the subject-by-formulation interaction term, statistical methods and resource implications.

Antiretroviral use and pharmacy-based measurement of adherence in postpartum HIV-infected women.

BACKGROUND: Antiretroviral treatment for HIV-infected women is standard during pregnancy to prevent vertical transmission, but data on postpartum therapy for the mother are lacking. OBJECTIVE: The objective of this study was to examine the impact of provider and patient characteristics on receipt of antiretroviral therapy and pharmacy-based measurement of adherence by postpartum HIV-infected women. RESEARCH DESIGN: This was a retrospective cohort study. SUBJECTS: The study included 2,648 New York State Medicaid-enrolled HIV-infected women who delivered from January 1993 through October 1996 and were followed up through September 1997. MEASURES: From Medicaid claims in the first postpartum year, the study examined any prescribed antiretroviral therapy and, among women treated >2 months, adherence, defined as > or =80% days covered by prescribed therapy from first to last antiretroviral prescription. RESULTS: Antiretroviral therapy was prescribed for 681 (26%) study women. Of 292 women treated >2 months, 28% were adherent on the basis of the pharmacy-based measure. The proportion of treated women was highest in 1996 (40%), and adherence was best in 1995 (44%) when most women took monotherapy. The adjusted odds ratios (AORs) of treatment were 1.67 (95% CI, 1.24 to 2.25) for women receiving HIV-focused services and 2.71 (95% CI, 1.99 to 3.69) for women with a provider in an HIV-related specialty. The AORs of adherence were greater for women with HIV-focused services (2.13; 95% CI, 1.05 to 4.30) and for former illicit drug users versus nonusers (2.40; 95% CI, 1.05 to 5.50). CONCLUSIONS: This population-based pharmacy analysis reveals improving antiretroviral use but continuing poor pharmacy-based adherence by postpartum HIV-infected women. Receipt of HIV-focused services appears to be particularly beneficial in increasing the likelihood of treatment and adherence.

Prenatal zidovudine use and congenital anomalies in a medicaid population.

OBJECTIVES: To examine the association of prescribed zidovudine (ZDV) during pregnancy with congenital anomalies in a population-based cohort. METHODS: Medicaid claims were used to assess prescribed ZDV and children's major congenital anomalies in 1932 liveborn deliveries from 1993 to 1996 to HIV-infected women in the state of New York (NYS), U.S.A. Prevalence of anomalies in the cohort was compared with that of a general NYS population. Within the cohort, adjusted odds of any anomaly were compared by receipt of ZDV and by trimester of first prescription. RESULTS: The adjusted prevalence of any anomaly in the study cohort was 2.76 times greater than in the general population (95% confidence interval [CI], 2.36-3. 17). Children of study women who were prescribed ZDV had increased adjusted odds of any anomaly (adjusted odds ratio [OR], 1.55; 95% CI, 1.01-2.29). Adjusted ORs (with CIs) by trimester of first prescription were 1.20 (0.58-2.51), 1.47 (0.85-2.55), and 1.84 (1. 04-3.25) for the first, second, and third trimesters, respectively. CONCLUSION: Children of HIV-infected women in this cohort had a greater prevalence of major anomalies than did the general NYS population. An increased risk of major anomalies was not evident for first trimester exposure when the association would have been most biologically plausible.

Low serum insulin-like growth factor 1 (IGF-1): a significant association with prostate cancer.

PURPOSE: Insulin-like growth factor 1 (IGF-1) is an important mitogenic and antiapoptotic peptide that affects the proliferation of normal and malignant cells. Contradictory reports on the association between serum IGF-1 level and prostate cancer have been highlighted in the recent literature. The purpose of this study was to investigate the relation between serum levels of IGF-1 and prostate cancer. MATERIALS AND METHODS: We analyzed a population of 57 patients who underwent radical prostatectomy (RP) for adenocarcinoma. Serum samples were collected before RP (T0), 6 months after RP (T6), and from 39 age-matched controls. IGF-1 levels were determined by the active IGF-1 Elisa kit (Diagnostic Systems Laboratories, Inc.). Parallel samples were evaluated for prostate-specific antigen (PSA) levels. Data between groups were analyzed using Welch's t-test and levels before RP and after 6 months were compared by paired t-test. RESULTS: The normal mean serum IGF-1 for case patients at T0 (124.6+/-58.2 ng/mL) was significantly lower than the control subjects (157.5+/-70.8 ng/mL; p = .0192). The normal mean serum IGF-1 for case patients at T0 (124.91+/-58.6 ng/mL) also was significantly lower when it was compared with the T6 group (148.49+/-57.2 ng/mL; p = .0056). No association was found between IGF-1 and PSA blood levels, or IGF-1 and patient weight (p = 0.2434). An inverse relation between IGF-1 levels and age in the normal controls (p = .0041) was observed. CONCLUSION: Findings of this study indicate a significant association between low serum levels of IGF-1 and prostate cancer.

Subject-by-formulation interaction in bioequivalence: conceptual and statistical issues. FDA Population/Individual Bioequivalence Working Group. Food and Drug Administration.

PURPOSE: The FDA has proposed replacing the current average bioequivalence criterion with population and individual bioequivalence criteria that consider variances in addition to the difference of averages. One of these variances in the individual bioequivalence criterion measures subject-by-formulation interaction, the extent to which the test-reference difference varies from person to person. This paper discusses conceptual and statistical issues raised in various publications and presentations with respect to the presence and estimation of such an interaction. METHODS: We focus on the importance of subject-by-formulation interaction, an understanding of what is a large interaction, and the assessment of the magnitude of this interaction in bioequivalence studies. Simulation studies, examples from the literature, and data from FDA files are used to demonstrate the magnitude of the interaction and its distribution under various conditions. RESULTS: The concept of a large interaction is tied to the concept of a large mean difference. We suggest that an interaction greater than 0.15 is a conservative criterion for a large interaction. Magnitudes of estimated interaction are affected by variability, sample size, and the selection of data sets that pass average bioequivalence. CONCLUSIONS: Examples of substantial interactions are beginning to appear. More data is needed before reaching definitive conclusions regarding the frequency and importance of observed interactions.

Recovery of upper-extremity strength in complete and incomplete tetraplegia: a multicenter study.

OBJECTIVE: To examine upper-extremity motor recovery of subjects with tetraplegia with both complete and incomplete injuries, to predict which patients and at what time they would recover a motor level. DESIGN: Prospective, multicenter clinical study of upper-extremity motor recovery in subjects with acute traumatic spinal cord injury. SETTING: Three regional spinal cord injury centers. SUBJECTS: One hundred sixty-seven individuals with acute traumatic tetraplegia (144 males [86%], and 23 females [14%]) between the ages of 15 and 75 years (mean age, 35.5 yrs). METHODS: Subjects were examined and classified using sequential manual muscle tests performed on admission, 72 hours, 1, 2, and 3 weeks, and 1, 2, 3, 6, 12, 18, and 24 months postinjury. C5 biceps, C6 extensor carpi radialis, C7 triceps, and C8 flexor digitorum profundus were evaluated using a 0-5 scale. Analyses of the right motor levels used a series of logistic regression models, and for multiple measurements on each subject, models were estimated using generalized estimating equations. RESULTS: The analysis for recovery of the biceps for the C4 group showed 70% of complete compared with 90% of incomplete injuries recovered (p < .001); of the extensor carpi radialis in the C5 group, 75% complete and 90% incomplete recovered (p < .002); and of the triceps in the C6 group, 85% of complete and 90% of incomplete injuries recovered (p < .16). CONCLUSION: Predicting future potential for upper-extremity motor recovery and for independence in self-care in groups of patients at a specific motor level is possible within the first week of injury.