Diversity in Medical Device Clinical Trials: Do We Know What Works for Which Patients?

Policy Points: A 1993 law required the National Institutes of Health to include women and racial and ethnic minorities in relevant research studies. Most federal health agencies adopted the same policy, but the US Food and Drug Administration (FDA) did not. A 2012 law encouraged the FDA to ensure that new medical products be analyzed for safety and effectiveness for key demographic patient groups. Our study of high-risk medical devices reviewed by the FDA in 2014-2017 found that due to lack of patient diversity and publicly available data, clinicians and patients often cannot determine which devices are safe and effective for specific demographic groups. CONTEXT: Demographic differences can influence the safety and effectiveness of medical devices; however, clinical trials of devices for adults have historically underrepresented women, people of color, and patients over age 65. The US Food and Drug Administration (FDA) Safety and Innovation Act became law in 2012, encouraging greater diversity and subgroup analyses. In 2013, the FDA reported that there was diversity in clinical trials considered "pivotal" for approval decisions and that subgroup analyses were conducted for most applications for the highest-risk medical devices. However, the FDA's report did not specify whether analyses included sufficient numbers to be meaningful, whether analyses were conducted for most major subgroups, or whether analyses included safety, effectiveness, or accuracy. METHODS: We examined publicly available documents for all 22 medical devices that the FDA designated "highest risk" or "novel," were reviewed through the premarket approval pathway, and were scrutinized at FDA public meetings from 2014 to 2017. We evaluated patient demographics and subgroup analyses for all pivotal trials. FINDINGS: Only 3 (14%) of the devices provided subgroup analyses for both effectiveness and safety or both sensitivity and selectivity for gender, race, and age. However, 55% of the devices reported both of those subgroup analyses for at least 1 of the 3 subgroups. Whether analyses were reported or not, the number of patients in most subgroups was too small to draw meaningful conclusions. Subgroup analyses were more likely to be reported to the FDA's Advisory Committees than in the FDA's public reviews or labeling. CONCLUSIONS: Despite a law encouraging more diversity and subgroup analyses in pivotal trials used as the basis for FDA approval, the results of our study indicate relatively few subgroup analyses are publicly available for the highest-risk and novel medical devices. The lack of subgroup analyses makes it impossible to inform patients or physicians as to whether many newly approved medical devices are safe and effective for specific demographic subgroups defined by gender, race, and age.

A simian hemorrhagic fever virus isolate from persistently infected baboons efficiently induces hemorrhagic fever disease in Japanese macaques.

Simian hemorrhagic fever virus is an arterivirus that naturally infects species of African nonhuman primates causing acute or persistent asymptomatic infections. Although it was previously estimated that 1% of baboons are SHFV-positive, more than 10% of wild-caught and captive-bred baboons tested were SHFV positive and the infections persisted for more than 10 years with detectable virus in the blood (100-1000 genomes/ml). The sequences of two baboon SHFV isolates that were amplified by a single passage in primary macaque macrophages had a high degree of identity to each other as well as to the genome of SHFV-LVR, a laboratory strain isolated in the 1960s. Infection of Japanese macaques with 100PFU of a baboon isolate consistently produced high level viremia, pro-inflammatory cytokines, elevated tissue factor levels and clinical signs indicating coagulation defects. The baboon virus isolate provides a reliable BSL2 model of viral hemorrhagic fever disease in macaques.

The rhesus rhadinovirus CD200 homologue affects immune responses and viral loads during in vivo infection.

UNLABELLED: Rhesus macaque rhadinovirus (RRV) is a gammaherpesvirus of rhesus macaque (RM) monkeys that is closely related to human herpesvirus 8 (HHV-8)/Kaposi's Sarcoma-associated herpesvirus (KSHV), and it is capable of inducing diseases in simian immunodeficiency virus (SIV)-infected RM that are similar to those seen in humans coinfected with HIV and HHV-8. Both HHV-8 and RRV encode viral CD200 (vCD200) molecules that are homologues of cellular CD200, a membrane glycoprotein that regulates immune responses and helps maintain immune homeostasis via interactions with the CD200 receptor (CD200R). Though the functions of RRV and HHV-8 vCD200 molecules have been examined in vitro, the precise roles that these viral proteins play during in vivo infection remain unknown. Thus, to address the contributions of RRV vCD200 to immune regulation and disease in vivo, we generated a form of RRV that lacked expression of vCD200 for use in infection studies in RM. Our data indicated that RRV vCD200 expression limits immune responses against RRV at early times postinfection and also impacts viral loads, but it does not appear to have significant effects on disease development. Further, examination of the distribution pattern of CD200R in RM indicated that this receptor is expressed on a majority of cells in peripheral blood mononuclear cells, including B and T cells, suggesting potentially wider regulatory capabilities for both vCD200 and CD200 that are not strictly limited to myeloid lineage cells. In addition, we also demonstrate that RRV infection affects CD200R expression levels in vivo, although vCD200 expression does not play a role in this phenomenon. IMPORTANCE: Cellular CD200 and its receptor, CD200R, compose a pathway that is important in regulating immune responses and is known to play a role in a variety of human diseases. A number of pathogens have been found to modulate the CD200-CD200R pathway during infection, including human herpesvirus 8 (HHV-8), the causative agent of Kaposi's sarcoma and B cell neoplasms in AIDS patients, and a closely related primate virus, rhesus macaque rhadinovirus (RRV), which infects and induces disease in rhesus macaque monkeys. HHV-8 and RRV encode homologues of CD200, termed vCD200, which are thought to play a role in preventing immune responses against these viruses. However, neither molecule has been studied in an in vivo model of infection to address their actual contributions to immunoregulation and disease. Here we report findings from our studies in which we analyzed the properties of a mutant form of RRV that lacks vCD200 expression in infected rhesus macaques.

T cell inactivation by poxviral B22 family proteins increases viral virulence.

Infections with monkeypox, cowpox and weaponized variola virus remain a threat to the increasingly unvaccinated human population, but little is known about their mechanisms of virulence and immune evasion. We now demonstrate that B22 proteins, encoded by the largest genes of these viruses, render human T cells unresponsive to stimulation of the T cell receptor by MHC-dependent antigen presentation or by MHC-independent stimulation. In contrast, stimuli that bypass TCR-signaling are not inhibited. In a non-human primate model of monkeypox, virus lacking the B22R homologue (MPXVΔ197) caused only mild disease with lower viremia and cutaneous pox lesions compared to wild type MPXV which caused high viremia, morbidity and mortality. Since MPXVΔ197-infected animals displayed accelerated T cell responses and less T cell dysregulation than MPXV US2003, we conclude that B22 family proteins cause viral virulence by suppressing T cell control of viral dissemination.