The Critical Path Institute's approach to precompetitive sharing and advancing regulatory science.

Many successful large industries, such as computer-chip manufacturers, the cable television industry, and high-definition television developers,(1) have established successful precompetitive collaborations focusing on standards, applied science, and technology that advance the field for all stakeholders and benefit the public.(2) The pharmaceutical industry, however, has a well-earned reputation for fierce competition and did not demonstrate willingness to share data or knowledge until the US Food and Drug Administration (FDA) launched the Critical Path Initiative in 2004 (ref. 3).

Payment to healthy volunteers in clinical research: the research subject's perspective.

Although there is much discussion regarding the ethics of making payments to healthy volunteers for participating in clinical research, little data are available from the point of view of the volunteers as to what they would consider to be fair payment. The objectives of this study were to determine healthy volunteers' estimates of appropriate payments for participation in hypothetical clinical trials in order to explore the reasoning behind these estimates and to examine the association between volunteer demographics and payment expectations. Sixty participants with previous experience as healthy volunteers in research studies were presented with four hypothetical studies and interviewed about their impressions of burden and risks involved in the studies. They were also asked to estimate an appropriate payment to the volunteers for each of the studies. For each of the studies, the payment estimates made by the participants varied over a wide range. However, each individual tended to be consistent in estimate placement within this range. No demographic factor was significantly associated with the estimated study payment. Subjects frequently mentioned risk and logistical burden as factors that should determine payment levels. Healthy volunteer subjects appear to have individualized yet consistent methods of arriving at estimates of payments for participating in clinical studies. These estimates are based on each subject's perception of study burden and associated risk.

The effect of weekend versus weekday admission on outcomes of esophageal variceal hemorrhage.

BACKGROUND: Hospital staffing is often lower on weekends than weekdays, and may contribute to higher mortality in patients admitted on weekends. Because esophageal variceal hemorrhage (EVH) requires complex management and urgent endoscopic intervention, limitations in physician expertise and the availability of endoscopy on weekends may be associated with increased EVH mortality. OBJECTIVE: To assess the differences in mortality, hospital length of stay (LOS), and costs between patients admitted on weekends versus patients who were admitted on weekdays. METHODS: The United States Nationwide Inpatient Sample database was used to identify patients hospitalized for EVH between 1998 and 2005. Differences in mortality, LOS, and costs between patients admitted on weekends and weekdays were evaluated using regression models with adjustment for patient and clinical factors, including the timing of endoscopy. RESULTS: Between 1998 and 2005, 36,734 EVH admissions to 2207 hospitals met the inclusion criteria. Compared with patients admitted on weekdays, individuals admitted on the weekend were slightly less likely to undergo endoscopy on the day of admission (45% versus 43%, respectively; P=0.01) and by the second day (81% versus 75%; P<0.0001). However, mortality (11.3% versus 10.8%; P=0.20) and the requirement for endoscopic therapy (70% versus 69%; P=0.08) or portosystemic shunt insertion (4.4% versus 4.7%; P=0.32) did not differ between weekend and weekday admissions. After adjusting for confounding factors, including the timing of endoscopy, the risk of mortality was similar between weekend and weekday admissions (OR 1.05; 95% CI 0.97 to 1.14). Although LOS was similar between groups, adjusted hospital charges were 4.0% greater (95% CI 2.3 to 5.8%) for patients hospitalized on the weekend. CONCLUSIONS: In patients with EVH, admission on the weekend is associated with a small delay in receiving endoscopic intervention, but no difference in mortality or the requirement for portosystemic shunt insertion. The weekend effect observed for some medical and surgical conditions does not apply to patients with EVH.

Balancing justice and autonomy in clinical research with healthy volunteers.

In clinical research, ethics review generally first examines whether study risks are reasonable in light of benefits provided. Through informed consent, then, prospective subjects consider whether the risk/benefit balance and procedures are reasonable for them. Unique ethics issues emerge in clinical research with healthy volunteers. Certain types of studies only recruit healthy volunteers as participants. Phase 1 studies, for example, including first time in human studies of investigational drugs and vaccines, generally are conducted in healthy volunteers. Although such research carries inherent and often unknown risks, healthy subjects provide the most efficient target population in which to conduct such research, as these volunteers generally are free of concurrent diseases or medications that could confound interpretation of toxicity. Other studies enrolling healthy volunteers often are simply looking for the most scientifically sound population for the study of normal human physiology.

Privacy rules under the Gramm-Leach-Bliley Act and HIPAA.

The intense scrutiny given to the privacy implications of the Gramm-Leach-Bliley Act and the Health Insurance Portability and Accountability Act has led to much confusion regarding which applies to specific entities. The authors attempt to clarify when these Acts would define how confidential medical data are used.

Safety assessment of encapsulated morphine delivered epidurally in a sustained-release multivesicular liposome preparation in dogs.

We have shown that the epidural (EPI) delivery of morphine encapsulated in multivesicular liposomes (DepoFoam drug delivery system) produces a sustained clearance of morphine and a prolonged analgesia. We have sought to subsequently determine the likelihood of deleterious effects on local tissue of repetitive epidural injections of this encapsulated morphine preparation (C0401). Beagle dogs were prepared according to protocol approved by the Institutional Animal Care and Use Committee under volatile general anesthesia with chronic lumbar EPI catheters and subcutaneous injection ports. Male and female dogs (three groups) received a total of 4 EPI injections at 8-day intervals of 3 mL of C0401 (10 mg/mL morphine) (N = 6), DepoFoam vehicle (N = 6), or 0.9% sodium chloride (N = 6). Following EPI-C0401, but not saline or DepoFoam vehicle, there were transient (< 72 hr) decreases in food consumption, arousal, hindlimb muscle tone, and body temperature. Heart rate was unaltered, but there were modest decreases in blood pressure and respiratory rate, which persisted for 24-72 hr after C0401. No persistent changes in sensory/motor function, body weight, or stool/urine production were observed. Cerebrospinal fluid, blood chemistry, and urinalysis performed at surgery and on the day of sacrifice (24 hr after the last dose) were within normal ranges. Gross pathology at necropsy was unremarkable. Spinal histopathology findings were judged to be minimal (e.g., modest pericatheter inflammation and fibrosis) and present in all dogs. However, a statistical trend in the rank order of pathology scores was noted (Saline < DepoFoam vehicle < C0401). Repeated EPI injection of C0401 at the maximum dose that could be administered (30 mg) resulted in moderate, transient behavioral and physiological effects after each injection, consistent with morphine administration, and a modest effect on cord histopathology. This level of pathology is reflected in the lack of change observed in cerebrospinal fluid and lack of neurological findings. These results suggest that C0401 is without significant pathological effects at this dose after repeated epidural delivery in dogs.

The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C.

Infection with hepatitis A virus (HAV) occasionally leads to acute liver failure and has a higher fatality rate in patients with chronic hepatitis C virus (HCV). Vaccination of patients with HCV against HAV is effective and well tolerated. This study examines the cost-effectiveness of HAV vaccination in North American patients with chronic HCV. A decision analysis model was constructed to compare 3 HAV vaccination strategies in adult patients with chronic HCV over a period of 5 years: (1) vaccinate no patients (treat none); (2) vaccinate only susceptible (anti-HAV negative) patients (selective); or (3) vaccinate all patients without prior testing of immune status (universal). Probabilities and direct costs were estimated from hospital data and the literature. The cost per patient for the 3 vaccination strategies were: treat none, $2.00; selective, $56.00; and universal, $82.00. For every 1,000,000 patients with HCV vaccinated over a 5-year period, the selective strategy prevented 128 symptomatic cases of HAV, 3 liver transplantations, and 3 deaths owing directly to HAV compared with the treat none strategy. In addition, the selective strategy costs an additional $427,000 per patient with HAV prevented, and $23 million per HAV-related death averted, compared with the treat none strategy. The results were most sensitive to the incidence of HAV infection; vaccination increased costs if the annual rate of infection was less than 0.56% (baseline, 0.01%). Vaccination of North American patients with chronic HCV against HAV infection is not a cost-effective therapy.

No evidence of linkage between the very-low-density lipoprotein receptor gene and fasting serum insulin or homeostasis model assessment insulin resistance index: the National Heart, Lung, and Blood Institute Family Heart Study.

A major gene effect on the fasting insulin level and insulin resistance has been suggested in previous studies. Several candidate genes for insulin resistance in rare syndromes have been proposed. However, there has been limited success in finding genes for common forms of insulin resistance. There is accumulating evidence of a relationship between insulin resistance and a disturbance of free fatty acid (FFA) metabolism. The very-low-density lipoprotein (VLDL) receptor, which is associated with FFA metabolism, could serve as a possible candidate gene for insulin resistance. We performed linkage analyses between the VLDL receptor gene and fasting insulin and the homeostasis model assessment (HOMA) insulin resistance index (fasting insulin x fasting glucose/22.5) in 1,050 sibpairs participating in the phase II physical examination of the National Heart, Lung, and Blood Institute Family Heart Study (FHS). Data analyses were completed using the SIBPAL component of the SAGE software package (SAGE, Statistical Analysis for Genetic Epidemiology, Version 3.1; Computer program package available from the Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, 1997). We did not find evidence for linkage of the fasting insulin or the HOMA insulin resistance index with a polymorphic marker at the VLDL locus (P = .316 and .402, respectively). Adjustment of fasting insulin and the HOMA insulin resistance index for the body mass index (BMI) did not change the results (P = .319 and .472, respectively). In conclusion, no evidence was found for a linkage between a locus controlling the fasting insulin level or HOMA insulin resistance index and a VLDL polymorphism in the present study. Additional adjustment of fasting insulin or the HOMA insulin resistance index for the BMI did not change the linkage results significantly.

Whole-body PET imaging with [18F]fluorodeoxyglucose in management of recurrent colorectal cancer.

HYPOTHESIS: Metabolic imaging by positron emission tomography (PET) using [18F]fluorodeoxyglucose will be more accurate than anatomic imaging by computed tomography (CT) for detection of recurrent colorectal cancer. More accurate staging of recurrent tumor by PET will lead to more appropriate management decisions. DESIGN: Prospective blinded study comparing PET with CT, using histologic diagnosis, serial CT imaging, and clinical follow-up as criterion standards, with a fully blinded, retrospective reinterpretation of PET studies. Changes in diagnosis resulting from PET findings were correlated with subsequent treatment and surgical findings. Potential cost savings resulting from use of PET for preoperative staging were calculated. SETTING: Private practice in an outpatient tertiary referral center. PATIENTS: A group of 155 consecutive patients with imaging for diagnosis or staging of recurrent colorectal cancer. Twenty-one patient (14%) were excluded due to lack of a criterion standard. Computed tomographic scans were available for comparison for 115 patients. RESULTS: Positron emission tomographic scan sensitivity and specificity were 93% and 98%, respectively, compared with 69% and 96% for CT. Ninety-five percent confidence intervals for the differences between the modalities were 16% to 32% for sensitivity and 1% to 5% for specificity. The sensitivity of both modalities varied with anatomic site of recurrence. Positron emission tomographic scans were true positive in 12 (67%) of 18 patients with elevated serum carcinoembryonic antigen levels and negative CT findings. In 23 (29%) of 78 preoperative studies in which CT showed a single site of recurrence, PET showed tumor at additional sites. At surgery, nonresectable, PET-negative tumor was found in 7 (17%) of 42 patients who had PET evidence of localized recurrence only. Potential savings resulting from demonstration of nonresectable tumor by PET were calculated at $3003 per preoperative study. CONCLUSIONS: Positron emission tomography was more sensitive and specific than CT for detection of recurrent colorectal cancer. Preoperative detection of nonresectable tumor by PET may avoid unnecessary surgery, and thereby reduce the cost of patient treatment.

Assessment of spatial normalization of PET ligand images using ligand-specific templates.

Recent advances allow robust computation of parametric maps of ligand-receptor binding from PET data sets. Parametric maps may be statistically analyzed at the voxel level, given suitable techniques for both the spatial normalization of image data into a standard space and the application of appropriate statistical tests. The purpose of this study was to spatially normalize parametric maps of [carbonyl-11C]WAY-100635 and [11C]raclopride binding using SPM 96 and ligand-specific templates. Ligand-specific templates were created from integral images taken from healthy subjects. For this, a MRI-based spatial normalization was used: T1-weighted MRI scans were coregistered to the PET integral images, and the spatial normalization of the MRI to the SPM 96 T1 MRI template was applied to the integral images. These integral images were meaned and smoothed to form [carbonyl-11C]WAY-100635 and [11C]raclopride templates. Reliability of spatial normalization using the ligand template method and the previous MRI-based spatial normalization was investigated by using a second set of integral images taken from a different cohort: Landmark coordinates were defined on all spatially normalized integral images. Mean coordinates were found in order to produce an overall (average) landmark for each location. For each image, at each location, the distance from the landmark coordinates to the overall landmark were found. A multivariate analysis of variance was used to examine the effects of observer variance, landmark location, and the method used. Visually acceptable templates were created. While observer variance was not significant, the landmark x method interaction was significant. The ligand template method had significantly smaller distances: Among the landmark locations with this method, the mean distances between individual image landmarks and overall image landmarks ranged from 1. 1 to 4.9 mm. The ligand template method provides a reliable approach for spatial normalization of PET ligand images.

Stroke assessment: morphometric infarct size versus neurologic deficit.

We presently examine the relation between histologic infarct size and neurologic deficit as endpoints and seek to clarify their sensitivity in defining stroke outcome. Neurologic deficits of 76 cats subjected to middle cerebral artery occlusion were assessed daily and correlated with the corresponding infarct sizes determined morphometrically after 2 weeks' survival. A five-item neurologic deficit score included the time elapsed until hemiparesis, and forced circling resolved (if ever), presence of impaired placing reactions and time elapsed until able to stand and being alert. We then evaluated the two endpoints' statistical powers to detect group differences using two sets of comparison groups. The neurologic deficit score correlated well with infarct size (r = 0.76, p < 0.001) and each of the individual deficit score components named above, in turn, correlated with decreasing power with infarct size. Even so, the number of study subjects required to achieve the same level of statistical significance in assessing group differences was two-fold greater when using the neurologic deficit than the infarct size data: Group sizes of eight and five animals were sufficient for significant infarct size differences while the groups needed be expanded to 15 and 10 animals to similarly achieve significant neurologic score differences. Thus, infarct size emerges as a more sensitive measure of stroke outcome than does the assessment of neurologic deficits.

Developing an AHC-MCO alliance for research and care.

Academic health centers (AHCs) and managed care organizations (MCOs) appear to be on a collision course. Is it possible to develop a partnership to enable both parties to achieve their respective goals and objectives? The Kimmel Cancer Center of Thomas Jefferson University and AEtna US Healthcare, one of the nation's largest MCOs, have developed an alliance designed to generate cancer prevention and control research. This arrangement engages the participants in a collaborative effort that is aimed at creating new knowledge that can be used to enhance the provision of health care to a defined population.

Analysis of colorectal cancer stage among HMO members targeted for screening.

BACKGROUND: This study is a retrospective analysis of data collected from patient medical records, a fecal occult blood test (FOBT) screening program, and computerized health maintenance organization (HMO) claims and encounters records. OBJECTIVE: To identify factors associated with a diagnosis of early (Dukes A and B) colorectal cancer among older adults targeted for annual FOBT screening. METHODS: Study subjects were insured by the former US Healthcare Inc (Blue Bell, Pa), an independent practice association-type HMO. The HMO was recently integrated into Aetna-US Healthcare. Before diagnosis, subjects were eligible for free annual FOBT screening through the HMO's colorectal cancer screening program. The study subjects included men and women (N = 222) who were aged 50 years or older and had a diagnosis of colorectal cancer between 1987 and 1990. Variables considered were patient age, gender, socioeconomic status, medical history, screening history, length of enrollment in the HMO, and stage of disease at diagnosis. RESULTS: Univariate analyses indicate that colorectal cancer diagnosis due to FOBT screening (P = .03), frequency of FOBT screening (P = .09), and length of HMO membership (P = .10) were positively related to being diagnosed as having early stage colorectal cancer. Multivariable analysis shows that having a screen-detected colorectal cancer was significantly and positively related (P = .03) to being diagnosed as having early stage disease. CONCLUSIONS: Findings support annual FOBT screening among older adults. Results illustrate the value of applying standard methods to the collection and analysis of patient data in a managed care context. The study also highlights a need for research on patient adherence to screening and physician follow-up of abnormal screening test results.

Assessment of striatal graft viability in the rat in vivo using a small diameter PET scanner.

A small diameter positron emission tomography (PET) scanner has been used to monitor [11C]raclopride (D2 receptor) binding in vivo in either intact striatum, denervated striatum following an excitotoxic lesion with ibotenic acid, or lesioned and grafted striatum following implantation of cortical or striatal tissue grafts in rats. Binding of [11C]raclopride was localized in the intact striatum within 20 min of injection of the radioligand, and was much reduced within the lesioned striatum. Cortical grafts exhibited a similar low level of binding to the lesioned striatum, whereas striatal grafts showed specific binding at an intermediate level. The [11C]raclopride binding signal in vivo correlated well with the extent of surviving or grafted striatal tissue observed post morten by Nissl staining and acetylcholinesterase histochemistry. Thus, the distribution of dopamine receptors as seen in the PET scanner are consistent with post mortem anatomical observations of striatal, lesion and graft sizes, and suggest that PET can provide a useful tool for monitoring the viability of implanted striatal graft tissues in vivo.