Tackling standardization in clinical research workforce hiring using competency-based job classifications.

In 2016, Duke reconfigured its clinical research job descriptions and workforce to be competency-based, modeled around the Joint Taskforce for Clinical Trial Competency framework. To ensure consistency in job classification amongst new hires in the clinical research workforce, Duke subsequently implemented a Title Picker tool. The tool compares the research unit's description of job responsibility needs against those standardized job descriptions used to map incumbents in 2016. Duke worked with human resources and evaluated the impact on their process as well as on the broader community of staff who hire clinical research professionals. Implementation of the tool has enabled Duke to create consistent job classifications for its workforce and better understand who composes the clinical research professional workforce. This tool has provided valuable workforce metrics, such as attrition, hiring, etc., and strengthened our collaboration with Human Resources.

Now is the time to fix the clinical research workforce crisis.

The clinical and translational research enterprise is recognized by many as the "evidence generation system." While there have been several calls to revolutionize this enterprise to more effectively deliver the fruits of biomedical science to patients and society, significant issues across the clinical research workforce are pervasive. Perhaps the most visible sign is the widening gap between supply and demand for competent staff. Underpinning this, is a perfect storm of complex issues. Now reaching crisis point, this problem is far bigger than a staffing issue and ultimately jeopardizes the "engine" of drug and device development. With the current perilous state of the workforce, proposed enterprise fixes are likely to languish far out of reach, given that even "business as usual" is under threat. In fact, a glaring disconnect is evident between the visionary discourse on how to revolutionize the clinical research enterprise and the sober recognition that operationalization of any such vision rests on the shoulders of a workforce that's in dire straits. In this article, we provide a brief forensic analysis of the workforce problem and an initial indication of where solutions may lie.

Leveraging retooled clinical research infrastructure for Clinical Research Management System implementation at a large Academic Medical Center.

Quality clinical research is essential for health care progress and is the mission of academic health centers. Yet ensuring quality depends on an institution's ability to measure, control, and respond to metrics of trial performance. Uninformed clinical research provides little benefit to health care, drains institutional resources, and may waste participants' time and commitment. Opportunities for ensuring high-quality research are multifactorial, including training, evaluation, and retention of research workforces; operational efficiencies; and standardizing policies and procedures. Duke University School of Medicine has committed to improving the quality and informativeness of our clinical research enterprise through investments in infrastructure with significant focus on optimizing research management system integration as a foundational element for quality management. To address prior technology limitations, Duke has optimized Advarra's OnCore for this purpose by seamlessly integrating with the IRB system, electronic health record, and general ledger. Our goal was to create a standardized clinical research experience to manage research from inception to closeout. Key drivers of implementation include transparency of research process data and generating metrics aligned with institutional goals. Since implementation, Duke has leveraged OnCore data to measure, track, and report metrics resulting in improvements in clinical research conduct and quality.

Development and implementation of an on-demand competency-based onboarding program for clinical research professionals in academic medicine.

Over the past 7 years, Duke has implemented competency-based job classifications for clinical research professionals (CRPs) with a defined pathway for career advancement. The workforce is defined specifically as the collection of staff employed across the clinical research enterprise to operationalize clinical research and human participatory protocols through the hands-on conduct of protocol activities including participant enrollment, regulatory coordination, study documentation, data collection and management, and sponsor engagement. The competency framework for this critical workforce laid the foundation for a centrally developed on-demand onboarding program at Duke. The self-paced program is designed to engage learners through competency-based learning modules, guided mentor/manager discussions, and applied learning activities. Consisting of an initial E-Learning orientation to clinical research at Duke, called Express Start, followed by a 90-day role-based Onboarding Learning Plan, our onboarding program includes training in foundational pre-defined core competency areas and customizable learning paths. Associated Engagement Activity Packets for many clinical research competencies encourage mentor and/or manager involvement and hands-on learning for the employee through suggested enrichment activities. The program has been widely adopted for CRPs within the Duke University Schools of Medicine and Nursing, and newly hired CRPs and their managers have expressed satisfaction with these centrally offered tools. In this paper, we describe the methods used to develop and implement our competency-based onboarding program. We will share an evaluation of the program and planned next steps for expanding the suite of onboarding resources.

Development and evaluation of a novel training program to build study staff skills in equitable and inclusive engagement, recruitment, and retention of clinical research participants.

Background: Adequate equitable recruitment of underrepresented groups in clinical research and trials is a national problem and remains a daunting challenge to translating research discoveries into effective healthcare practices. Engagement, recruitment, and retention (ER&R) training programs for Clinical Research Professionals (CRPs) often focus on policies and regulations. Although some training on the importance of diversity and inclusion in clinical research participation has recently been developed, there remains a need for training that couples critical equity, diversity, and inclusion (EDI) concepts with skill development in effective recruitment and retention strategies, regulations, and best practices. Approach and methods: We developed the ER&R Certificate program as a holistic approach to provide Duke University CRPs the opportunity to build competency in gap areas and to increase comfort in championing equitable partnerships with clinical research participants. The thirteen core and elective courses include blended learning elements, such as e-learning and wiki journaling prompts, to facilitate meaningful discussions. Pre- and post-assessments administered to CRP program participants and their managers assessed program impact on CRP skills in ER&R tasks and comfort in equitable, diverse, and inclusive engagement of clinical research participants. Results and discussion: Results from the first two cohorts indicate that CRPs perceived growth in their own comfort with program learning objectives, especially those centered on participant partnership and EDI principles, and most managers witnessed growth in competence and responsibility for ER&R-related tasks. Results suggest value in offering CRPs robust training programs that integrate EDI and ER&R training.

Impact of implementing a competency-based job framework for clinical research professionals on employee turnover.

INTRODUCTION: A new competency-based job framework was implemented for clinical research professionals at a large, clinical research-intensive academic medical center. This study evaluates the rates of turnover before and after implementation of the new framework. Turnover in this workforce (as with most) is costly; it contributes to wasted dollars and lost productivity since these are highly specialized positions requiring extensive training, regardless of experience in the field. METHODS: Trends in employee turnover for 3 years prior to and after the implementation of competency-based job framework for clinical research positions were studied using human resources data. Employee demographics, turnover rates, and comparisons to national statistics are summarized. RESULTS: Employee turnover within the clinical research professional jobs has decreased from 23% to 16%, a 45% reduction, since the implementation of competency-based job framework. CONCLUSION: The new jobs and career ladders, both of which are centered on a competency-based framework, have decreased the overall turnover rate in this employee population. Since little is known about the rates of turnover in clinical research, especially in the academic medical setting, the results of this analysis can provide important insights to other academic medical centers on both employee turnover rate in general and the potential impact of implementing large-scale competency-based job changes.

HLA class II-Restricted CD8+ T cells in HIV-1 Virus Controllers.

A paradigm shifting study demonstrated that induction of MHC class E and II-restricted CD8+ T cells was associated with the clearance of SIV infection in rhesus macaques. Another recent study highlighted the presence of HIV-1-specific class II-restricted CD8+ T cells in HIV-1 patients who naturally control infection (virus controllers; VCs). However, questions regarding class II-restricted CD8+ T cells ontogeny, distribution across different HIV-1 disease states and their role in viral control remain unclear. In this study, we investigated the distribution and anti-viral properties of HLA-DRB1*0701 and DQB1*0501 class II-restricted CD8+ T cells in different HIV-1 patient cohorts; and whether class II-restricted CD8+ T cells represent a unique T cell subset. We show that memory class II-restricted CD8+ T cell responses were more often detectable in VCs than in chronically infected patients, but not in healthy seronegative donors. We also demonstrate that VC CD8+ T cells inhibit virus replication in both a class I- and class II-dependent manner, and that in two VC patients the class II-restricted CD8+ T cells with an anti-viral gene signature expressed both CD4+ and CD8+ T cell lineage-specific genes. These data demonstrated that anti-viral memory class II-restricted CD8+ T cells with hybrid CD4+ and CD8+ features are present during natural HIV-1 infection.

Advancement of multidisciplinary education and research in translational sciences: MERITS program development at Duke University.

INTRODUCTION: The Duke Multidisciplinary Education and Research in Translational Sciences Program provides educational resources for faculty and trainees in translational research. METHODS: To aid in program development, we assessed perceptions of translational science through focus groups targeting different career stages. RESULTS: In total, 3 essential themes emerged: collaboration, movement toward application, and public health impact. Facilitators and barriers varied among groups. CONCLUSION: Training programs must provide specific strategies for collaboration and selectively accelerating discoveries to therapies.

Multidisciplinary Mentoring Programs to Enhance Junior Faculty Research Grant Success.

PROBLEM: Junior faculty face challenges in establishing independent research careers. Declining funding combined with a shift to multidisciplinary, collaborative science necessitates new mentorship models and enhanced institutional support. APPROACH: Two multidisciplinary mentorship programs to promote grant success for junior faculty were established at the Duke University School of Medicine beginning in 2011. These four-month programs-the Path to Independence Program (PtIP) for National Institutes of Health (NIH) R applicants and the K Club for NIH K applicants-use multiple senior faculty mentors and professional grant-writing staff to provide a 20-hour joint curriculum comprising a series of lectures, hands-on workshops, career development counseling, peer groups, and an internal study section. In March 2016, the authors analyzed the success rate for all NIH grants submitted by participants since program enrollment. In a 2015 postprogram survey, participants rated their feelings of support and competency across six skill factors. OUTCOMES: From October 2011 to March 2016, the programs engaged 265 senior faculty mentors, 145 PtIP participants, and 138 K Club participants. Success rates for NIH grant applications were 28% (61 awards/220 decisions) for PtIP participants-an increase over the 2010 Duke University junior faculty baseline of 11%-and 64% (38/59) for K Club participants. Respondents reported significantly increased feelings of support and self-ratings for each competency post program. NEXT STEPS: The authors plan to expand the breadth of both the mentorship pool and faculty served. Broad implementation of similar programs elsewhere could bolster success, satisfaction, and retention of junior faculty investigators.

Transcriptional and posttranscriptional regulation of cytokine gene expression in HIV-1 antigen-specific CD8+ T cells that mediate virus inhibition.

UNLABELLED: The ability of CD8+ T cells to effectively limit HIV-1 replication and block HIV-1 acquisition is determined by the capacity to rapidly respond to HIV-1 antigens. Understanding both the functional properties and regulation of an effective CD8+ response would enable better evaluation of T cell-directed vaccine strategies and may inform the design of new therapies. We assessed the antigen specificity, cytokine signature, and mechanisms that regulate antiviral gene expression in CD8+ T cells from a cohort of HIV-1-infected virus controllers (VCs) (<5,000 HIV-1 RNA copies/ml and CD4+ lymphocyte counts of >400 cells/µl) capable of soluble inhibition of HIV-1. Gag p24 and Nef CD8+ T cell-specific soluble virus inhibition was common among the VCs and correlated with substantial increases in the abundance of mRNAs encoding the antiviral cytokines macrophage inflammatory proteins MIP-1α, MIP-1αP (CCL3L1), and MIP-1ß; granulocyte-macrophage colony-stimulating factor (GM-CSF); lymphotactin (XCL1); tumor necrosis factor receptor superfamily member 9 (TNFRSF9); and gamma interferon (IFN-γ). The induction of several of these mRNAs was driven through a coordinated response of both increased transcription and stabilization of mRNA, which together accounted for the observed increase in mRNA abundance. This coordinated response allows rapid and robust induction of mRNA messages that can enhance the CD8+ T cells' ability to inhibit virus upon antigen encounter. IMPORTANCE: We show that mRNA stability, in addition to transcription, is key in regulating the direct anti-HIV-1 function of antigen-specific memory CD8+ T cells. Regulation at the level of RNA helps enable rapid recall of memory CD8+ T cell effector functions for HIV-1 inhibition. By uncovering and understanding the mechanisms employed by CD8+ T cell subsets with antigen-specific anti-HIV-1 activity, we can identify new strategies for comprehensive identification of other important antiviral genes. This will, in turn, enhance our ability to inhibit virus replication by informing both cure strategies and HIV-1 vaccine designs that aim to reduce transmission and can aid in blocking HIV-1 acquisition.

Initial HIV-1 antigen-specific CD8+ T cells in acute HIV-1 infection inhibit transmitted/founder virus replication.

CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8(+) T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8(+) responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8(+) T cells during AHI. Autologous and heterologous CD8(+) T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8(+) T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8(+) antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8(+)-mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8(+) T cell-mediated inhibition of virus replication. CD8(+) T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies.

Dynamic antibody specificities and virion concentrations in circulating immune complexes in acute to chronic HIV-1 infection.

Understanding the interactions between human immunodeficiency virus type 1 (HIV-1) virions and antibodies (Ab) produced during acute HIV-1 infection (AHI) is critical for defining antibody antiviral capabilities. Antibodies that bind virions may prevent transmission by neutralization of virus or mechanically prevent HIV-1 migration through mucosal layers. In this study, we quantified circulating HIV-1 virion-immune complexes (ICs), present in approximately 90% of AHI subjects, and compared the levels and antibody specificity to those in chronic infection. Circulating HIV-1 virions coated with IgG (immune complexes) were in significantly lower levels relative to the viral load in acute infection than in chronic HIV-1 infection. The specificities of the antibodies in the immune complexes differed between acute and chronic infection (anti-gp41 Ab in acute infection and anti-gp120 in chronic infection), potentially suggesting different roles in immunopathogenesis for complexes arising at different stages of infection. We also determined the ability of circulating IgG from AHI to bind infectious versus noninfectious virions. Similar to a nonneutralizing anti-gp41 monoclonal antibody (MAb), purified plasma IgG from acute HIV-1 subjects bound both infectious and noninfectious virions. This was in contrast to the neutralizing antibody 2G12 MAb that bound predominantly infectious virions. Moreover, the initial antibody response captured acute HIV-1 virions without selection for different HIV-1 envelope sequences. In total, this study demonstrates that the composition of immune complexes are dynamic over the course of HIV-1 infection and are comprised initially of antibodies that nonselectively opsonize both infectious and noninfectious virions, likely contributing to the lack of efficacy of the antibody response during acute infection.

Secretion of MIP-1ß and MIP-1α by CD8(+) T-lymphocytes correlates with HIV-1 inhibition independent of coreceptor usage.

CD8(+) T-lymphocytes can utilize noncytolytic mechanisms to suppress HIV-1 replication through the secretion of soluble factors. The secretion of MIP-1ß, MIP-1α, IP-10, MIG, IL-1α, and interferon gamma correlated most strongly with soluble noncytolytic suppression (p<0.0001). Since the noncytolytic response is impaired by histone hyperacetylation, we examined the ability of histone hyperacetylation to alter the expression of immune-related genes. MIP-1α and IP-10 were also among the genes that were down-regulated by histone hyperacetylation. We define a multifactorial cytokine profile of CD8(+) T-lymphocytes capable of mediating noncytolytic suppression of CXCR4-tropic HIV-1 replication.

CD8(+)T-cell-mediated control of HIV-1 and SIV infection.

A detailed understanding of the cellular response to human immunodeficiency virus (HIV-1) infection is needed to inform prevention and therapeutic strategies that aim to contain the AIDS pandemic. The cellular immune response plays a critical role in reducing viral load in HIV-1 infection and in the nonhuman primate model of SIV infection. Much of this virus suppressive activity has been ascribed to CD8(+)T-cell-directed cytolysis of infected CD4(+)T cells. However, emerging evidence suggests that CD8(+)T cells can maintain a lowered viral burden through multiple mechanisms. A thorough understanding of the CD8(+)T-cell functions in HIV-1 infection that correlate with viral control, the populations responsible for these functions, and the elicitation and maintenance of these responses can provide guidance for vaccine design and potentially the development of new classes of antiretroviral therapies. In this review, we discuss the CD8(+)T-cell correlates of protection in HIV-1 and SIV infection and recent advances in this field.

Epigenetic regulation of CD8(+) T-lymphocyte mediated suppression of HIV-1 replication.

CD8(+) T-lymphocytes from HIV-1 infected individuals express unidentified factors that suppress viral replication by inhibiting HIV-1 gene expression. We examined the role of epigenetics in modulating the HIV-1 suppressive factors expressed by primary CD8(+) T cells from subjects naturally controlling virus replication. HIV-1 suppression by CD8(+) T-lymphocytes was reversed up to 40% by the addition of a histone deacetylase (HDAC) inhibitor. Noncytolytic suppression was not dependent on epigenetic changes within the target cells, as HDAC1 within the target cell was dispensable, and HIV-1 LTR histone acetylation remained unchanged in the presence of CD8(+) T-lymphocytes. Histone deacetylation within CD8(+) T-lymphocytes was necessary for potent HIV-1 suppression. Blocking HDACs impairs the ability of CD8(+) T-lymphocytes to repress HIV-1 transcription, demonstrating that expression of a portion of the suppressive factors is regulated by epigenetics. These data provide a way to focus the search for the suppressive factors and to potentially modulate their expression.

Phenotypic and functional profile of HIV-inhibitory CD8 T cells elicited by natural infection and heterologous prime/boost vaccination.

Control of HIV-1 replication following nonsterilizing HIV-1 vaccination could be achieved by vaccine-elicited CD8(+) T-cell-mediated antiviral activity. To date, neither the functional nor the phenotypic profiles of CD8(+) T cells capable of this activity are clearly understood; consequently, little is known regarding the ability of vaccine strategies to elicit them. We used multiparameter flow cytometry and viable cell sorts from phenotypically defined CD8(+) T-cell subsets in combination with a highly standardized virus inhibition assay to evaluate CD8(+) T-cell-mediated inhibition of viral replication. Here we show that vaccination against HIV-1 Env and Gag-Pol by DNA priming followed by recombinant adenovirus type 5 (rAd5) boosting elicited CD8(+) T-cell-mediated antiviral activity against several viruses with either lab-adapted or transmitted virus envelopes. As it did for chronically infected virus controllers, this activity correlated with HIV-1-specific CD107a or macrophage inflammatory protein 1beta (MIP-1beta) expression from HIV-1-specific T cells. Moreover, for vaccinees or virus controllers, purified memory CD8(+) T cells from a wide range of differentiation stages were capable of significantly inhibiting virus replication. Our data define attributes of an antiviral CD8(+) T-cell response that may be optimized in the search for an efficacious HIV-1 vaccine.

Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus.

Enfuvirtide (ENF), the first approved fusion inhibitor (FI) for HIV, is a 36-aa peptide that acts by binding to the heptad repeat 1 (HR1) region of gp41 and preventing the interaction of the HR1 and HR2 domains, which is required for virus-cell fusion. Treatment-acquired resistance to ENF highlights the need to create FI therapeutics with activity against ENF-resistant viruses and improved durability. Using rational design, we have made a series of oligomeric HR2 peptides with increased helical structure and with exceptionally high HR1/HR2 bundle stability. The engineered peptides are found to be as much as 3,600-fold more active than ENF against viruses that are resistant to the HR2 peptides ENF, T-1249, or T-651. Passaging experiments using one of these peptides could not generate virus with decreased sensitivity, even after >70 days in culture, suggesting superior durability as compared with ENF. In addition, the pharmacokinetic properties of the engineered peptides were improved up to 100-fold. The potent antiviral activity against resistant viruses, the difficulty in generating resistant virus, and the extended half-life in vivo make this class of fusion inhibitor peptide attractive for further development.

Envelope diversity, coreceptor usage and syncytium-inducing phenotype of HIV-1 variants in saliva and blood during primary infection.

OBJECTIVE: To determine whether oral fluids can serve as a model for studying HIV-1 shedding, we compared the genetic diversity, coreceptor use, and syncytium-inducing (SI) phenotype of viral variants in saliva and blood during primary HIV-1 infection. DESIGN: Observational cross-sectional cohort study. METHODS: Blood plasma and saliva were sampled from 17 men early in primary HIV-1 infection. Viral diversity, predicted X4/R5 genotype and SI phenotype in samples were determined by heteroduplex tracking assays (HTAs) targeting the V1/V2 and V3 gp120 regions, sequence analyses and MT-2 cell assay. RESULTS: Identical or very similar HTA banding and deduced amino acid sequence patterns in the V1/V2 and V3-encoding regions were observed between paired fluids of each subject. As assessed by V1/V2 HTA, 10 subjects had a single major viral variant and seven subjects exhibited multiple yet highly related variants. Two subjects had V1/V2 variants in blood that were identical to saliva but present in different relative abundances. A sexual transmission pair exhibited genetically dissimilar variants, suggesting transmission of a minor variant or rapid evolution during initial viremia. All subjects harbored R5 non-SI variants. CONCLUSIONS: Relatively homogenous viral populations detected in plasma and saliva prior to seroconversion suggests that HIV-1 is disseminated to oral fluids early in infection and reflects the quasispecies in blood. These findings suggest that the oral cavity may serve as an easily accessible surrogate model for studying the dynamics of HIV-1 shedding at mucosal sites.