Randall Reves

Breaking the Camel's Back: Multicenter Clinical Trials and Local Institutional Review Boards

In September 1999, all human studies were suspended at our medical center, the University of Colorado Health Sciences Center. This action was taken by the U.S. Food and Drug Administration (FDA) and the Office for Protection from Research Risks (OPRR) because issues raised in a previous audit of the local institutional review board (IRB) had not been adequately addressed. As clinical investigators, we were shocked to find our institution in this situation. Clinical trials evaluating innovative treatments were interrupted for 4 months, and even now, the effects of the suspension linger. Our purpose is not to contest the specifics of the suspension at our institution. Although we disagree with some aspects of the present IRB system, our institution had a responsibility to follow that system and failed to do so. The IRBs of other medical centers have also had similar suspensions or warnings in the past few years. Our purpose is to examine the problems underlying recent federal regulatory actions against IRBs. Federal Oversight of Local IRBs All federally sponsored human studies, except those meeting specific criteria for exemption, and human studies of drugs or devices regulated by the FDA must be reviewed by an IRB. The IRB system was developed in the 1970s in response to studies with reprehensible disregard for the safety and autonomy of patients (1, 2). Most IRBs in the United States exist locally, at the 3000 to 5000 academic medical centers, hospitals, and clinics carrying out clinical research (3). Because there is no central registry, details on the number and types of IRBs in the United States are not available (4). Federal regulations, which are administered by FDA and OPRR (recently reorganized as the Office for Human Research Protections), specify the composition and function of IRBs (5-7). The required components of IRB activity include review of fundable federal grant proposals (8), review of research protocols involving humans, approval of consent forms, and monitoring of ongoing studies (continuing review) at least annually (7). Multicenter Clinical Trials and Local IRBs Clinical research has undergone remarkable expansion in the past 25 years. According to one estimate, the number of protocols submitted to local IRBs increased 42% in just 5 years (3). Most of the expansion in clinical research has been in the form of multicenter trials (3), which present major problems for a local IRB. In addition to the sheer volume of protocols to consider, multicenter trials generate thousands of safety reports (on death and hospitalization, for example) because of the treatment, the severity of the disease, or the large numbers of participants. These protocols and safety reports are reviewed by an organization analogous to a jury. Local IRBs must include members from outside the institution, science, and medicine; in fact, no action of a local IRB is valid unless at least one designated nonscientific member is present (7). Although the IRB staff may devote their full attention to oversight of research, the members themselves, by design, do not. Given this constraint, simple mathematics illustrates the pressure cooker atmosphere (9) faced by local IRBs. Assume that an academic center has 500 new and 1000 ongoing studies per year (3, 9). All of these studies are to be reviewed by two IRBs, each of which meets 22 times per year for 3 hours per meeting. Assuming that new protocols require twice as much time to review as continuing studies, the IRB has 8 minutes per new study (11.4 per meeting) and 4 minutes per continuing review (22.7 per meeting). This simple analysis does not allow for time spent on any activity other than consideration of protocols requiring full committee review and probably overestimates the time available for protocol review. Indeed, a recent federal review found that the average local IRB meeting lasted 2.5 hours and included 18 initial reviews, 9 expedited reviews, 43 amendments, and 21 safety reports (3). Federal Regulatory Actions against Local IRBs Although it was not announced publicly, federal oversight of local IRBs recently underwent a major change (4). The number of regulatory actions by FDA and OPRR tripled from 1997 to 1999, and regulatory actions against academic medical centers increased even more sharply (1 in 1997 compared with 14 in 1999). Given the problems of local IRBs, some might suggest that the increase in regulatory actions is fully justified, even overdue. We counter that they represent the cracks in a system overloaded by outmoded regulations. The key findings in the warning letters sent to local IRBs by the FDA (available at www.fda.gov/foi/warning.htm[accessed 12 November 2000]) and the OPRR (which can obtained through a Freedom of Information Act request) in 1999 are summarized in the Table. Prominent among them are lack of substantive continuing review and inadequate review of safety reports. These actions are mandated in federal regulations and would seem to be critical to protecting patients in clinical trials. However, recent reviews by the Office of the Inspector General of the Department of Health and Human Services and a panel of the National Institutes of Health (NIH) concluded that the continuing review process should be completely reevaluated and that local IRBs should not be required to review off-site safety reports (3, 10). Table. Reasons for Regulatory Actions by the U.S. FDA or the Office for Protection from Research Risks against Local IRBs during 1999 Local Review of Safety Reports from Multicenter Clinical Trials The following example illustrates the problems of local IRB review of safety reports from multicenter trials. Adefovir, a drug with promising in vitro activity against HIV, hepatitis B, and several herpesviruses (11), was well tolerated in early clinical studies. However, when adefovir was given for more than 6 months, 17% to 35% of patients developed renal toxicity (12, 13). As a result, an FDA advisory panel recommended against approval, and the manufacturer stopped development of adefovir for HIV treatment. (Much lower doses are being evaluated for treatment of chronic hepatitis B.) The system worked: A promising agent was evaluated in a controlled fashion, and an unexpected toxicity was identified and appropriately managed. However, local IRB review played no role in this sequence of events. The renal toxicity was identified at the data centers of the randomized trials, and warning letters were promptly sent to investigators. Although some might take this example as further evidence of the need for local IRBs to perform substantive review of safety reports, the failure of local IRBs to detect renal toxicity of adefovir is inherent in the system. Even if given unlimited time and resources, local IRBs could not critically evaluate safety reports from multicenter trials because they lack the data elements needed for meaningful analysis: the denominators and study assignment. Without these key pieces of information, off-site safety reports become a flood of anecdotes with little meaning. For example, as clinical investigators, we reviewed and filed with the local IRB a stack of adefovir safety reports 10 inches thick; however, the aggregate was less informative than the two-page warning letter from the data centers. As summarized in the NIH review, receipt of data that are neither aggregated nor interpreted does not provide useful information to the IRB to allow it to make an informed judgement on the appropriate action to be taken, if any (10). Patient safety in multicenter trials is monitored appropriately by central data management organizations and Data and Safety Monitoring Boards, which are composed of experts in the disease being studied and the conduct of clinical trials (14-16). All NIH-sponsored phase III trials are reviewed periodically by Data and Safety Monitoring Boards (10); this requirement could be extended to industry-sponsored studies. The analysis of safety reports from multicenter trials illustrates an important theme of our concerns about research oversight: This function is critical, but it should not be a responsibility of the local IRB. The report of the Office of the Inspector General recognized this key point and recommended that federal agencies change the regulations governing local IRBs: The NIH/OPRR and FDA should work with IRBs and others in identifying the specific Federal requirements to be eliminated or modified (3). Local IRB Review of Multicenter Clinical Trials Local IRB review of off-site safety reports from multicenter trials is an example of an unnecessary redundancy that ties up the current system. Are there other such redundancies? It is reasonable to ask whether local IRBs play any meaningful role in multicenter trials. The content of federally sponsored multicenter protocols is extensively reviewed before development of a final version for study sites. As a result, it is unlikely that a local IRB will have substantive objections to the scientific content of such studies. We are uncertain whether the same considerations apply to industry-sponsored trials. There is certainly a need for IRB review of multicenter trials, but it is not clear that patient safety is enhanced by duplicating this process at the IRB of every study site. Even the much-touted role of local IRBs in assuring that consent forms be appropriate for the local population is questionable. Studies in the past 20 years demonstrate that most consent forms are written at an inappropriate reading level for most patients (17-19) and are not improved by local IRB review (20). A well-formulated central IRB with expertise in the communication of complex material may assure more appropriate consent forms than overburdened local IRBs can. For example, the National Cancer Institute used a multidisciplinary team to develop a template that markedly simplifies the language of consent forms (21). Moreover, OPRR guidelines appropriately point o

Interferon-γ Release Assays and Tuberculin Skin Testing for Diagnosis of Latent Tuberculosis Infection in Healthcare Workers in the United States

RATIONALE IFN-γ release assays (IGRAs) are alternatives to tuberculin skin testing (TST) for diagnosis of latent tuberculosis infection. Limited data suggest IGRAs may not perform well for serial testing of healthcare workers (HCWs). OBJECTIVES Determine the performance characteristics of IGRAs versus TST for serial testing of HCWs. METHODS A longitudinal study involving 2,563 HCWs undergoing occupational tuberculosis screening at four healthcare institutions in the United States, where the average tuberculosis case rate ranged from 4 to 9 per 100,000 persons. QuantiFERON-TB Gold In-Tube (QFT-GIT), T-SPOT.TB (T-SPOT), and TST were performed at baseline and every 6 months for 18 months between February 2008 and March 2011. MEASUREMENTS AND MAIN RESULTS A total of 2,418 HCWs completed baseline testing, which was positive for 125 (5.2%) by TST, 118 (4.9%) by QFT-GIT, and 144 (6.0%) by T-SPOT. A baseline positive TST with negative IGRAs was associated with bacillus Calmette-Guérin (BCG) vaccination (odds ratio: 25.1 [95% confidence interval: 15.5, 40.5] vs. no BCG). Proportions of participants with test conversion during the study period were 138 of 2,263 (6.1%) for QFT-GIT, 177 of 2,137 (8.3%) for T-SPOT, and 21 of 2,293 (0.9%) for TST (P < 0.001 for QFT-GIT vs. TST and for T-SPOT vs. TST; P = 0.005 for QFT-GIT vs. T-SPOT). Of the QFT-GIT and T-SPOT converters, 81 of 106 (76.4%) and 91 of 118 (77.1%), respectively, were negative when retested 6 months later. There was negative/positive discordance for 15 of 170 (8.8%) participants by QFT-GIT and for 19 of 151 (12.6%) by T-SPOT when blood was drawn 2 weeks later. CONCLUSIONS Most conversions among HCWs in low TB incidence settings appear to be false positives, and these occurred six to nine times more frequently with IGRAs than TST; repeat testing of apparent converters is warranted.

Spread of strain W, a highly drug-resistant strain of Mycobacterium tuberculosis, across the United States.

Strain W, a highly drug-resistant strain of Mycobacterium tuberculosis, was responsible for large nosocomial outbreaks in New York in the early 1990s. To describe the spread of strain W outside New York, we reviewed data from epidemiologic investigations, national tuberculosis surveillance, regional DNA fingerprint laboratories, and the Centers for Disease Control and Prevention Mycobacteriology Laboratory to identify potential cases of tuberculosis due to strain W. From January 1992 through February 1997, 23 cases were diagnosed in nine states and Puerto Rico; 8 were exposed to strain W in New York before their diagnosis; 4 of the 23 transmitted disease to 10 others. Eighty-six contacts of the 23 cases are presumed to be infected with strain W; 11 completed alternative preventive therapy. Strain W tuberculosis cases will occur throughout the United States as persons infected in New York move elsewhere. To help track and contain this strain, health departments should notify the Centers for Disease Control and Prevention of cases of tuberculosis resistant to isoniazid, rifampin, streptomycin, and kanamycin.

Prospective Comparison of the Tuberculin Skin Test and 2 Whole-Blood Interferon-γ Release Assays in Persons with Suspected Tuberculosis

BACKGROUND Interferon-gamma release assays (IGRAs) are attractive alternatives to the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection. However, the inability to definitively confirm the presence of most M. tuberculosis infections hampers assessment of IGRA accuracy. Although IGRAs are primarily indicated for the detection of latent tuberculosis infection, we sought to determine the sensitivity of the TST and 2 whole-blood IGRAs (QuantiFERON-TB assay [QFT] and QuantiFERON-TB Gold assay [QFT-G]) in situations in which infection is confirmed by recovery of M. tuberculosis by culture. METHODS We conducted a prospective, multicenter, cross-sectional comparison study in which 148 persons suspected to have tuberculosis were tested simultaneously with the TST, QFT, and QFT-G. RESULTS M. tuberculosis was cultured from samples from 69 (47%) of 148 persons suspected to have tuberculosis; the TST induration was > or = 5 mm for 51 (73.9%) of the 69 subjects (95% confidence interval [CI], 62.5%-82.8%). The QFT indicated tuberculosis infection for 48 (69.6%) of the 69 subjects (95% CI, 57.9%-79.2%) and was indeterminate for 7 (10.1%). The QFT-G yielded positive results for 46 (66.7%) of the 69 subjects (95% CI, 54.9%-76.7%) and indeterminate results for 9 subjects (13.0%). If subjects with indeterminate QFT-G results were excluded, 46 (76.7%) of 60 subjects (95% CI, 64.6%-85.6%) had positive TST results, and the same number of subjects had positive QFT-G results. HIV infection was associated with false-negative TST results but not with false-negative QFT-G results. CONCLUSIONS The TST, QFT, and QFT-G have similar sensitivity in persons with culture-confirmed infection. As with the TST, negative QFT and QFT-G results should not be used to exclude the diagnosis of tuberculosis in persons with suggestive signs or symptoms.

Riboflavin to treat nucleoside analogue-induced lactic acidosis

Fetal blood was obtained by transabdominal cardiac puncture. In each case, a detailed transvaginal ultrasound was done to confirm gestational age and to assess spontaneous and reflex fetal movements. Written consent was obtained from each woman after receiving complete information on the procedure. This study was approved by the University College London Hospitals Committee on the Ethics of Human Research. The fetal samples were collected between 5 and 20 min following intravenous (IV) administration of a bolus of 3 mg/kg of propofol (Diprivan 1%, Zeneca, Macclesfield, UK) to the mother. Peripheral maternal venous blood was collected simultaneously. Anaesthesia was maintained by spontaneous breathing of 70% nitrous oxide with 0·5–1% isoflurane in oxygen via a laryngeal mask. The propofol concentration was determined by high-performance liquid chromatography with fluorescence. The method has a lower limit of sensitivity of 0·1 g/mL and the intra-assay and interassay coefficients of variation were both 5%. No spontaneous fetal movements or reflux responses were observed in any case during the time interval between induction of anaesthesia and the surgical procedure or during the sampling procedure. Propofol was detected in all maternal and fetal serum samples. No propofol was found in coelomic or amniotic fluid samples at any stage of gestation. Propofol concentration decreased exponentially with time in both maternal (r=0·73, p<0·0001) and fetal (r=0·58, p<0·0001) serum. Maternal serum concentration of propofol was always higher than fetal serum concentration. In 14 matched samples, the mean propofol concentration was 1·96 g/mL (95% CI 1·49–2·42) in maternal serum and 0·90 g/mL (95% CI 0·68–1·11) in fetal serum. Over the 20 min interval between injection and sampling, little change was observed in the fetal/maternal propofol concentration ratio. This finding can be explained by the fact that propofol binds 97–98% to albumin, which is in much lower concentration in fetal serum during the first half of pregnancy. Overall, the pharmacodynamics of propofol found in pregnant women at 12–18 weeks of gestation are similar to those described at term 1–3 indicating that our data can be extrapolated to the period of gestation between 24 and 37 weeks and that our model can be used to study the placental transfer of other analgesic drugs in early pregnancy. Propofol has no known teratogenic effect in humans and our results also indicate that, during short maternal general

Review of False-Positive Cultures for Mycobacterium tuberculosis and Recommendations for Avoiding Unnecessary Treatment

We reviewed reports of false-positive cultures for Mycobacterium tuberculosis and here propose guidelines for detecting and managing patients with possible false-positive cultures. Mechanisms of false-positive cultures included contamination of clinical devices, clerical errors, and laboratory cross-contamination. False-positive cultures were identified in 13 (93%) of the 14 studies that evaluated > or = 100 patients; the median false-positive rate was 3.1% (interquartile range, 2.2%-10.5%). Of the 236 patients with false-positive cultures reported in sufficient detail, 158 (67%) were treated, some of whom had toxicity from therapy, as well as unnecessary hospitalizations, tests, and contact investigations. Having a single positive culture was a sensitive but nonspecific criterion for detecting false-positive cultures. False-positive cultures for M. tuberculosis are not rare but are infrequently recognized by laboratory and clinical personnel. Laboratories and tuberculosis control programs should develop procedures to identify patients having only 1 positive culture. Such patients should be further evaluated for the possibility of a false-positive culture.

Protection against infection with Giardia lamblia by breast-feeding in a cohort of Mexican infants

To determine whether breast-feeding protects infants against symptomatic and asymptomatic infection by Giardia lamblia, we followed 197 infants in a poor area of Mexico City from birth to 18 months of age; symptoms and feeding status were recorded weekly. Stool specimens were collected every 1 to 2 weeks and tested for Giardia by enzyme-linked immunosorbent assay. A mean of 1.0 Giardia infection per child-year was detected; 94 infants had a total of 139 infections; 17% of infections were symptomatic. Ninety-one percent of infants were breast fed from birth and 38% were breast fed at 1 year of age. Lack of breast-feeding was a significant risk factor for first Giardia infection at all ages. The adjusted incidence rate ratio for first Giardia infection for none versus complete breast-feeding was 5.0 (confidence interval (CI) 1.5 to 16.9; p = 0.009), and for none versus any breast-feeding, 1.8 (CI 1.1 to 2.8; p = 0.013). Symptomatic Giardia infection was also associated with lack of breast-feeding (none vs any: incidence rate ratio = 2.5; CI 0.9 to 6.8; p = 0.077), but breast-feeding did not protect against chronic carriage of Giardia. Other significant risk factors for Giardia infection were presence of animals in the household (p = 0.005) and the use of water or nonmilk liquid for infant feedings (p = 0.035). We conclude that breast-feeding protects infants against Giardia by mechanisms that include preventing the establishment of infection.

Conventional and molecular epidemiology of trimethoprim-sulfamethoxazole resistance among urinary Escherichia coli isolates

BACKGROUND Antibiotic resistance is increasing in Escherichia coli, the most common cause of urinary tract infections, but its epidemiology has not been well described. We evaluated the epidemiology of trimethoprim-sulfamethoxazole-resistant E. coli in a large, public health care system in Denver, Colorado. METHODS Outpatients with E. coli urinary tract infections during the first 6 months of 1998 were evaluated retrospectively. A prospective study was then performed to confirm the rate of trimethoprim-sulfamethoxazole resistance. We used several strain-typing methods (pulsed-field gel electrophoresis, ribotyping, serotyping) to evaluate the molecular epidemiology of the resistance. RESULTS The rate of trimethoprim-sulfamethoxazole resistance was similar in the retrospective (24% [161/681]) and prospective (23% [30/130]) phases of the study (P = 0.89). Almost all trimethoprim-sulfamethoxazole-resistant strains (98%) were resistant to at least one other antibiotic. Risk factors for infection with a resistant strain included age < or =3 years, Hispanic ethnicity, recent travel outside the United States, and a prior urinary tract infection. However, rates of resistance were >15% among nearly all of the subgroups. Most strains had high-level resistance (>1000 microg/mL) to trimethoprim-sulfamethoxazole. Of the 23 resistant isolates evaluated, 10 (43%) belonged to the clone A group. There was no correlation between conventional epidemiologic characteristics and the molecular mechanism of resistance or strain type. CONCLUSION Resistance to trimethoprim-sulfamethoxazole among E. coli isolates among patients in a Denver public health care system is common, with high rates of resistance even among patients without risk factors.

Multiple Cytokines Are Released When Blood from Patients with Tuberculosis Is Stimulated with Mycobacterium tuberculosis Antigens

Background Mycobacterium tuberculosis (Mtb) infection may cause overt disease or remain latent. Interferon gamma release assays (IGRAs) detect Mtb infection, both latent infection and infection manifesting as overt disease, by measuring whole-blood interferon gamma (IFN-γ) responses to Mtb antigens such as early secreted antigenic target-6 (ESAT-6), culture filtrate protein 10 (CFP-10), and TB7.7. Due to a lack of adequate diagnostic standards for confirming latent Mtb infection, IGRA sensitivity for detecting Mtb infection has been estimated using patients with culture-confirmed tuberculosis (CCTB) for whom recovery of Mtb confirms the infection. In this study, cytokines in addition to IFN-γ were assessed for potential to provide robust measures of Mtb infection. Methods Cytokine responses to ESAT-6, CFP-10, TB7.7, or combinations of these Mtb antigens, for patients with CCTB were compared with responses for subjects at low risk for Mtb infection (controls). Three different multiplexed immunoassays were used to measure concentrations of 9 to 20 different cytokines. Responses were calculated by subtracting background cytokine concentrations from cytokine concentrations in plasma from blood stimulated with Mtb antigens. Results Two assays demonstrated that ESAT-6, CFP-10, ESAT-6+CFP-10, and ESAT-6+CFP-10+TB7.7 stimulated the release of significantly greater amounts of IFN-γ, IL-2, IL-8, MCP-1 and MIP-1β for CCTB patients than for controls. Responses to combination antigens were, or tended to be, greater than responses to individual antigens. A third assay, using whole blood stimulation with ESAT-6+CFP-10+TB7.7, revealed significantly greater IFN-γ, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1β, and TNF-α responses among patients compared with controls. One CCTB patient with a falsely negative IFN-γ response had elevated responses with other cytokines. Conclusions Multiple cytokines are released when whole blood from patients with CCTB is stimulated with Mtb antigens. Measurement of multiple cytokine responses may improve diagnostic sensitivity for Mtb infection compared with assessment of IFN-γ alone.

Disseminated Mycobacterium genavense infection : clinical and microbiological features and response to therapy

ObjectiveMycobacterium genavense is a newly described pathogen that causes disseminated infection in AIDS. It is difficult to detect and identify due to its slow growth and fastidious nature. There is little information available about therapy for this new pathogen. We describe clinical and laboratory features and response to therapy in four patients with advanced AIDS complicated by disseminated M. genavense infection from Denver, Colorado, USA. Design and methodsRetrospective analysis of four cases identified in an AIDS clinic affiliated with a municipal hospital in Denver, Colorado. Clinical samples were inoculated onto BACTEC 12B, Lowenstein-Jensen, and Middlebrook 7H11 media. ResultsThe clinical features mimicked those of disseminated M. avium complex infection, with invasion of liver, spleen and lymph nodes with acid-fast bacilli (AFB). Acid-fast smears of blood and lymph nodes were positive; there was a modest increase in the growth index in BACTEC broth and tiny colonies appeared on Middlebrook agar. Patients were treated with combinations of antimycobacterial agents. Blood smears and cultures reverted to negative in treated patients. The best clinical response was associated with clarithromycin therapy. ConclusionsDisseminated disease due to M. genavense should be suspected among patients with the clinical presentation of disseminated M. avium complex infection and low growth index on BACTEC cultures for AFB. The diagnosis of M. genavense may be facilitated by performing acid-fast stains of samples from BACTEC bottles in such individuals. Clarithromycin therapy is associated with clinical improvement and clearance of bacteremia.