David L. Cohn

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

Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: a randomized, double-blind, placebo-controlled trial.

The efficacy and safety of clarithromycin and rifabutin alone and in combination for prevention of Mycobacterium avium complex (MAC) disease were compared in 1178 patients with AIDS who had < or =100 CD4 T cells/microL in a randomized, double-blind, placebo-controlled trial. MAC disease occurred in 9%, 15%, and 7% of those randomized to clarithromycin or rifabutin alone or in combination, respectively; time-adjusted event rates per 100 patient-years (95% confidence interval [CI]) were 6.3 (4.2-8.3), 10.5 (7.8-13.2), and 4. 7 (2.9-6.5). Risk of MAC disease was reduced by 44% with clarithromycin (risk ratio [RR], 0.56; 95% CI, 0.37-0.84; P=.005) and by 57% with combination therapy (RR, 0.43; 95% CI, 0.27-0.69; P=. 0003), versus rifabutin. Combination therapy was not more effective than clarithromycin (RR, 0.79; 95% CI, 0.48-1.31; P=.36). Of those in whom clarithromycin or combination therapy failed, 29% and 27% of MAC isolates, respectively, were resistant to clarithromycin. There were no survival differences. Clarithromycin and combination therapy were more effective than rifabutin for prevention of MAC disease, but combination therapy was associated with more adverse effects (31%; P<.001).

Use of the bacille Calmette-Guérin vaccination for the prevention of tuberculosis : Renewed interest in an old vaccine

The reemergence of tuberculosis, including the impact of HIV infection and multidrug-resistant tuberculosis, have renewed interest in the bacille Calmette-Guérin (BCG) vaccine. During the past 7 decades, numerous studies have shown variable efficacy of BCG vaccination, ranging from 0% to 80%. The BCG vaccine is more likely to prevent disseminated forms of tuberculosis in children than pulmonary tuberculosis in adolescents or adults. Bacille Calmette-Guérin vaccination is recommended in asymptomatic children with or at risk for HIV infection, but it rarely may cause disseminated BCG infection and should not be used in persons with symptomatic HIV infection or AIDS. In healthcare workers with exposure to Mycobacterium tuberculosis, including multidrug-resistant tuberculosis, BCG vaccination generally is not recommended. Revaccination with BCG does not confer more benefit than initial vaccination, and repeat vaccinations should be discontinued. With recent advances in technology and a better understanding of the immunopathogenesis of tuberculosis, efforts to develop a more potent and specific vaccine need to be pursued. If a more effective vaccine against tuberculosis is developed, vaccination can be expected to have an additional impact on global tuberculosis control in conjunction with current strategies of case detection, treatment of disease, and preventive therapy.

Treatment of Latent Tuberculosis Infection: Renewed Opportunity for Tuberculosis Control

New recommendations for targeted tuberculin testing and treatment of latent tuberculosis (TB) infection have recently been published. Changes in nomenclature from screening to targeted tuberculin testing and from preventive therapy to treatment of latent TB infection (LTBI) are intended to promote more widespread implementation by programs and health care providers. Targeted tuberculin testing is designed to identify persons at high risk for TB and is discouraged for persons at low risk. New recommendations for treatment of LTBI in both human immunodeficiency virus (HIV)-infected and HIV-uninfected patients include isoniazid for 9 months as the preferred regimen: isoniazid for 6 months based on local program conditions, rifampin and pyrazinamide for 2 months, and rifampin for 4 months. Treatment monitoring now places greater emphasis on clinical, rather than routine, laboratory monitoring. More widespread implementation of targeted tuberculin testing and treatment of LTBI is an important control strategy that will enhance efforts to eliminate TB in the United States.

Prevention strategies for Mycobacterium avium-intracellulare complex (MAC) infection : A review of recent studies in patients with AIDS

SummaryIn patients with AIDS, disseminated Mycobacterium avium-intracellulare complex (MAC) infection is a common bacterial infection and is associated with considerable morbidity and mortality.In placebo-controlled studies, rifabutin, clarithromycin and azithromycin (administered as single agents) have been shown to prevent the development of MAC bacteraemia in patients with advanced HIV disease. Clarithromycin also conferred a survival benefit over placebo, but this was not initially observed with either rifabutin or azithromycin.Subsequently, the efficacy of single agent therapy was compared with that of combination treatment as prophylaxis against the development of disseminated MAC. In the AIDS Clinical Trials Group (ACTG) 196/Community Programs for Clinical Research on AIDS (CPCRA) 009 study, clarithromycin monotherapy and clarithromycin and rifabutin combination therapy regimens were both more effective than rifabutin monotherapy in reducing the incidence of MAC bacteraemia. However, the combination regimen was generally not well tolerated. In the California Consortium Treatment Group (CCTG)/Multiple Opportunistic Prevention Prophylactic Strategy (MOPPS) study, azithromycin plus rifabutin was significantly more effective than either agent administered alone, and azithromycin was more effective than rifabutin. However, azithromycin (alone or in combination with rifabutin) caused frequent gastrointestinal adverse events. Emergence of resistance in those failing prophylaxis appeared to be higher with clarithromycin than with azithromycin or rifabutin. The use of the combination regimen of clarithromycin plus rifabutin did not reduce the selection of clarithromycin-resistant isolates.Several issues need to be considered in the choice of MAC prophylaxis for the individual patient. On the basis of efficacy and potential drug interactions with protease inhibitors, clarithromycin or azithromycin is preferred to rifabutin. However, rifabutin is less likely to result in the emergence of resistance than the macrolides, and is likely to prevent tuberculosis, whereas azithromycin and clarithromycin will prevent some bacterial infections. Combination therapy for prophylaxis is not indicated in most situations.

Subclinical Tuberculosis in HIV-Infected Patients: Another Challenge for the Diagnosis of Tuberculosis in High-Burden Countries?

For the more than 2 decades that tuberculosis has been recognized as a major op-portunistic infection in patients with HIV infection/AIDS, the extraordinary spectrum of clinical presentations has made the diagnosis of tuberculosis very challenging. This spectrum includes both pulmonary and extrapulmonary disease, which often has atypical clinical and ra-diographic manifestations in HIV-infected patients, compared with those in HIV-negative patients [1]. The problem is compounded even more in developing countries where rates of Mycobacterium tuberculosis and HIV coinfection are high [2] and the resources and facilities for both radiographic and microbiologic diagnoses are often limited or nonexistent. For example , in many parts of the world, sputum smears for detection of acid-fast bacilli (AFB)—but not cultures—are used for the diagnosis of pulmonary tuberculosis. In resource-poor settings, diagnosis and treatment of active tuberculosis are the most important—and, sometimes, the only—components of tuberculosis-control programs (i.e., parts of the DOTS strategy). However, given the high incidence of tuberculosis among HIV-infected patients, where resources permit, the World Health Organization (WHO) has recommended the use of preventive therapy for HIV-infected persons who are tu-berculin positive with latent tuberculosis infection (LTBI) or are at high risk for LTBI (e.g., household contacts of patients with tuberculosis) [3]. This control strategy necessitates a distinction between the diagnosis of active tuberculosis, for which patients require multidrug therapy, and the diagnosis of LTBI, for which isoniazid alone is effective. As the use of antiret-roviral therapy increases in developing countries, and because opportunistic infection prophylaxis (including treatment of LTBI) will be offered as part of a package of care, the need for this distinction is becoming even more important [4]. The study by Mtei et al. [5] in this issue of Clinical Infectious Diseases presents a potential new challenge for the diagnosis of subtle tuberculosis in asymptomatic patients, and it may have implications with regard to treatment decisions (i.e., therapy for active disease vs. therapy for LTBI). As part of a study of an investi-gational mycobacterial vaccine for HIV-infected patients with CD4 cell counts of 1200 cells/mm 3 and no evidence of active tuberculosis, subjects in Tanzania underwent screening for tuberculosis, with an assessment for symptoms (weight loss and cough or fever), performance of tuber-culin skin tests (TSTs), chest radiography, obtainment of sputum and blood specimens for cultures for AFB, and in vitro immunologic studies. Patients with active tuberculosis were referred elsewhere for treatment with a multidrug regimen, and …