Institutional Review Board Requirements Research Articles

HIDDEN BARRIERS TO ENGAGING HOME- AND COMMUNITY-BASED SERVICES IN DEMENTIA CARE RESEARCH

Abstract The high prevalence of dementia in the United States has resulted in a reliance on home-and community-based services (HCBS) to assist in the provision of care for community-dwelling persons living with dementia. Partnering with HCBS organizations, like Adult Day Services (ADS), is beneficial to disseminating evidence-based dementia care interventions as it is an existing service that can be leveraged to foster relationships between research staff and clients. While benefits exist, challenges in identifying community-partner organization, ethical approval, and community-partner staffing can be unintended barriers. Using the ADS Plus Program as a case-study, this presentation will detail hidden barriers in engaging HCBS partnerships into dementia care research. Specifically, we will discuss barriers to 1) developing relationships to implement a multi-site national-trial, 2) high touch points necessary to engage sites from underrepresented populations, 3) institutional review board requirements (e.g. CiTi training, Federal Wide Assurance Forms), and 4) staff readiness to participate in research. We also offer recommendations based on lessons learned from the ADS Plus Program to enhance the pipeline from engagement with HCBS to participate in research to implementing an evidence-based interventions. Lessons learned from the ADS Plus Program demonstrates that changes are needed to improve the efficiency of the pipeline from community-based participation into dementia care research and implementation of evidence-based interventions.

Access to the Kidney Transplant Waitlist for People With HIV.

The Advisory Committee on Blood and Tissue Safety and Availability recently voted to remove the statutory National Institutes of Health research criteria and institutional review board requirements for performing kidney transplantation using kidneys from donors with HIV. This policy change may subsequently increase utilization of such organs.1 Despite excellent kidney transplant outcomes, single-center studies have demonstrated significantly lower kidney transplant waitlist addition rates for people with HIV (PWH) in the United States as compared with those without HIV, a requisite step for deceased donor kidney transplantation.2-4 Should adoption of transplantation using kidneys from donors with HIV increase following the implementation of this policy, understanding waitlist addition nationally is imperative. Acknowledging the lack of granularity in HIV-specific data, we used the United States Renal Data System and accompanying Medicare claims data to identify a cohort of PWH (January 1, 2007–December 31, 2016) with end-stage kidney disease (ESKD) and compared waitlist addition rates among PWH with ESKD patients without HIV. This study was approved by the Institutional Review Board at the University of Alabama at Birmingham. Among 602 006 incident patients whose primary payer was Medicare,5 HIV status was defined using the Chronic Conditions Data Warehouse algorithm (sensitivity: 93.2%; specificity: 99.4%). PWH with claims for an opportunistic infection within 90 d of dialysis initiation were excluded. Cox proportional hazards and Fine and Gray competing risks regressions were used to examine the likelihood of waitlist addition. The 6250 PWH were younger, more commonly African American, and more commonly reported alcohol dependence, drug dependence, and tobacco use. Cumulative incidence of waitlist addition within 5 y of dialysis initiation was 11.1% among PWH and 15.3% among ESKD patients without HIV. Following adjustment for demographics, comorbid conditions, and geography, HIV was associated with 52% lower likelihood of waitlist addition (adjusted hazard ratio: 0.48; 95% confidence interval, 0.43-0.52; P < 0.001; Table 1). After accounting for competing risks of death and living donor kidney transplantation before waitlist addition, a similar inequity was observed (adjusted subdistribution hazard ratio: 0.45; 95% confidence interval, 0.42-0.49; P < 0.001). TABLE 1. - Unadjusted and adjusted likelihood of waitlist addition among ESKD patients within 5 y and within all observed time following dialysis initiation 5 y, HR (95% CI) a Full follow-up, HR (95% CI) a Unadjusted PWH (ref: HIV–) 0.90 (0.83-0.98) 0.64 (0.54-0.75) PWH (ref: HIV–) b 0.93 (0.86-0.99) 0.62 (0.58-0.68) aHR (95% CI) b aHR (95% CI) b Adjusted PWH (ref: HIV–) 0.48 (0.43-0.52) 0.27 (0.21-0.35) PWH (ref: HIV–) b 0.45 (0.42-0.49) 0.25 (0.20-0.32) Bold values indicate significance at P < 0.05.aAdjusted for age, race, ethnicity, sex, WHO obesity class, alcohol abuse, drug abuse, diabetes, hypertension, cancer, peripheral vascular disease, nonambulatory status, assistance needed for daily activities, atherosclerotic heart disease, cerebrovascular disease, amputation, coronary obstructive pulmonary disease, institutionalized (yes/no), functional status, tobacco use, rurality, ESKD network, and year of dialysis initiation.bCompeting risk model.aHR, adjusted HR; CI, confidence interval; ESKD, end-stage kidney disease; HIV–, HIV negative; HR, hazard ratio; PWH, people with HIV; WHO, World Health Organization. This disparity in waitlist addition experienced by PWH has been described in single-center data,2-4 and commonly attributed to clinical factors, specifically severity of HIV infection as defined by CD4 counts, HIV viral loads, presence of opportunistic infections, substance use, and failure to complete transplant evaluation. Reported substance use was included in our analysis, but, despite attempts to account for HIV-specific characteristics through the exclusion of PWH with opportunistic infections, we were unable to completely account for such, nor could we assess where this disparity manifests, including referral rates or evaluation completions. Reliance upon Medicare claims data also resulted in an older cohort, potentially resulting in lower waitlist addition rates. Thus, the magnitude of the disparity between PWH and ESKD patients with HIV may have been overestimated or developed earlier at referral or evaluation. Despite these limitations, this observed inequity is confirmed by studies that collected HIV-specific characteristics, referral, and evaluation data. Given advances in transplantation for PWH, national data collection should be revised to capture early steps in transplantation and HIV-specific characteristics to ensure equitable access to and outcomes of transplantation.2-4

Promoting Reproducibility and Integrity in Observational Research: One Approach of an Epidemiology Research Community.

To increase research reproducibility, sharing of study data, analysis code, and use of standardized reporting are increasingly advocated. However, beyond reproducibility, few initiatives have addressed the integrity of how research is conducted before manuscripts are submitted. We describe a decades-long experience with a comprehensive approach based in an academic research community around prospective cohort studies that is aimed at promoting a culture of integrity in observational research. The approach includes prespecifying hypotheses and analysis plans, which are discussed in the research community and posted; presentation and discussion of analysis results; mandatory analysis code review by a programmer; review of concordance between analysis output and manuscripts by a technical reviewer; and checks of adherence to the process, including compliance with institutional review board requirements and reporting stipulations by the National Institutes of Health. The technical core is based in shared computing and analytic environments with long-term archiving. More than simply a list of rules, our approach promotes research integrity through integrated educational elements, making it part of the "hidden curriculum," by fostering a sense of belonging, and by providing efficiency gains to the research community. Unlike reproducibility checklists, such long-term investments into research integrity require substantial and sustained funding for research personnel and computing infrastructure. Our experiences suggest avenues for how institutions, research communities, and funders involved in observational research can strengthen integrity within the research process.

Do I Need Institutional Review Board Approval? Applying the 2018 Institutional Review Board Revised Common Rule to Athletic Training Educational Research

Do I Need Institutional Review Board Approval? Applying the 2018 Institutional Review Board Revised Common Rule to Athletic Training Educational Research

Determinants and barriers to junior faculty well-being at a large quaternary academic medical center: A qualitative survey

BackgroundIncreasing levels of burnout among trainees and faculty members at all levels is a major problem in academic medicine. Junior faculty members may be at unique risk for burnout and have unique needs and barriers that contribute to attrition, job satisfaction, and overall workplace well-being. MethodsTwenty-seven faculty members at the assistant professor level at a large, quaternary referral academic medical institution were interviewed. A qualitative analyst with no reporting relationship to faculty was used as the proctor. Seven scripted questions targeting faculty well-being and institutional barriers to well-being were administered, and the responses were coded for common themes between respondents. ResultsRespondents most commonly identified clinical work (26%), research (19%), and teaching (19%) as the best aspects of their job. Among respondents, 3% stated they were not able to devote as much time as they would like to work they enjoyed and found most meaningful. Of these respondents, 44% cited “insufficient help” as the root cause. Also, 33% stated time spent writing and managing institutional review board requirements was a major contributor, and 22% cited both clinical volume/performance benchmarks and administrative responsibilities as significant barriers. The most common responses to departmental factors that can be improved included moving meetings to during the workday versus after hours, establishing a similar value system/metric for all faculty, and providing more opportunities to interact with faculty across divisions. The most common barriers to change identified were difficulty hiring research support, patient volume and clinical demands, and a pervasive culture of continuing to work after the workday has ended. At an institutional level, provision of childcare and promotion of basic science research were identified as areas for improvement. More actionable items were identified at the departmental rather than institutional level (53 vs 34). ConclusionsJunior faculty well-being is most affected at the department level. Qualitative data collection from junior faculty regarding barriers to well-being and academic/clinical productivity can be invaluable for departments and institutions seeking to make cultural or systemic improvements.

Ethical and methodological challenges slowing progress in primary care-based suicide prevention: Illustrations from a randomized controlled trial and guidance for future research

IntroductionDespite the pressing need for primary care-based suicide prevention initiatives and growing acknowledgement of recruitment difficulties and Institutional Review Board (IRB) challenges in suicide research, we are aware of no illustrative examples describing how IRB decisions in the design of a primary care trial can compound recruitment challenges. MethodsThe CDC-funded trial (NCT02986113) of Men and Providers Preventing Suicide aimed to examine the effects of a tailored computer program encourage men with suicidal thoughts (n = 304, ages 35–64) to discuss suicide with a primary care clinician and accept treatment. Before a visit, participants viewed MAPS or a non-tailored control video. Post-visit, both arms were offered telephone collaborative care, as mandated by the institutional review board (IRB). We previously showed that exposure to MAPs led to improvements in communication about suicide in a primary care visit. In this paper, we report data on the study's primary outcome, suicide preparatory behaviors. ResultsAfter screening nearly 4100 men, 48 enrolled. Recruitment challenges, which were exacerabted by an IRB mandate narrowing post-intervention patient management differences between trial arms, limited detection of the effects of MAPS on suicide preparatory behaviors. ConclusionsWhile primary care settings are key sites for suicide prevention trials, issues such as recruitment difficulties and overly restrictive IRB requirements may limit their utility. Methodological innovation to improve recruitment and ethical guidance to inform IRB decision-making are needed.

Multi-Sector Collaboration for Improving Home-Based Nutrition Supports: Process Findings from a Clinical Trial

In-home supports and proper nutrition are critical to post-acute recovery and long-term health management for adults 60 and older. At the same time, such supports are often difficult to deploy in rural settings. To address these challenges, a unique multi-sector consortia was formed between a local Area Agency on Aging, a healthcare system, a health technology company, and a university to conduct a clinical trial of a novel in-home health technology program coupled with customized chronic care nutrition support. Early stage clinical trial development required coordination across health and community-based organizations to develop a pathway for older adults to access the in-home project supports. At the conclusion of the year one, six project partners were interviewed using a semi-structured interview protocol examining the strengths of early project design and challenges inherent in the early phases of a community-based clinical trial. Thematic analysis uncovered six themes instructive in formulating efficacious clinical trial methodologies: 1) Logistical challenges related to the pandemic, including reduced patient numbers and the curtailing of in-hospital recruitment; 2) Partner collaboration as essential to designing preferred project modifications; 3) The challenge of converting project referrals into project enrollees; 4) A new appreciation among community partners regarding institutional review board requirements; 5) Recommendations for addressing emerging staffing challenges; and 6) The overriding importance of engaging older adults in their own care and health promotion post-discharge. Results will inform construction of a replicable model for establishing novel research partnerships that span healthcare, social services, the business sector, and higher education.

Navigating Ethical Issues in Photovoice: Balancing the Principles of Community-Based Participatory Research Ethics with Institutional Review Board Requirements.

This article reflects on ethical issues that arose during the course of two different evaluation projects that used photovoice method to engage with marginalized populations. The evaluations serve as case studies for a critical discussion about potential barriers that researchers may face when employing photovoice method while trying to balance the principles of community-based participatory research with the requirements of Institutional Review Boards. We reflect on ethical dilemmas related to the meaning of photography within the cultural context of participants' lives, the compensation of participants as collaborators, and the representation and dissemination of participant photos. We conclude by examining how researchers may approach ethical requirements without compromising the important collaborative relationships central to photovoice method. We additionally call on researchers to engage with ethics review committees to create a new "participant-researcher" category with its own set of protocols that recognizes the nuanced role members of disenfranchised communities play in the research process.

Barriers to Clozapine Use for Competency Restoration and the Value of Further Study.

Hospital-based restoration of adjudicative competence can be challenging, especially for patients who have treatment-resistant psychosis. Clozapine, which has helped many such individuals in the community, has not been well-studied in individuals who are incapable of proceeding with trial. In their small study, Ghossoub and colleagues have brought attention to the potential for this protocol and advocate for further study. This commentary examines potential barriers to conducting larger studies, including Institutional Review Board requirements for research with individuals who are under court supervision. Also, factors that can result in patients relapsing and being readmitted to the hospital for competency restoration due to poor treatment adherence are described. This adverse outcome burdens the judicial and health care systems and prolongs the time between the patient's arrest and trial. Clozapine may be a promising treatment for competency restoration as long as we are cognizant of barriers to further study and treatment adherence.

Landscape of circulating tumor DNA profiling of advanced pancreatic cancer (PDAC).

289 Background: PDAC has limited treatment options. Genomic analyses have led to development of targeted therapies now in several clinical trials, and may enable the discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Data regarding circulating tumor DNA (ctDNA) profiling in PDAC during real time clinical practice is limited. Methods: We performed ctDNA NGS analysis in pts with advanced PDAC (December 2014–August 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA), which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance (TR) was defined as possible treatments within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic Institutional Review Board requirements. Results: Among 171 pts and 206 total samples, ctDNA NGS revealed at least one genomic alteration in 150 pts (88%). Median number of alterations per patient was 3 [range, 1-15]. The total number of unique alterations was 450 with the most commonly altered genes being: TP53 (181 alterations, 40%), followed by KRAS (118 alterations, 26%), CDKN2A (23 alterations, 5%), SMAD4 (15 alterations, 3%), EGFR (11 alterations, 2.4%), PIK3CA (9 alterations, 2%), GNAS (8 alterations, 1.5%). Amplifications were noted in 16 genes, including BRAF, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, KIT, KRAS, MET, MYC, PDGFRA, PIK3CA and RAF1. Therapeutically relevant alterations were seen in 95 pts of the 150 pts (63%). Tissue based profiling (Results to be shown) was done in 56 (33%) pts of total 171 pts with a median of 130 days between ctDNA and tissue biopsy. KRAS and TP53 were the most common gene mutations found in patients with both liquid and tissue biopsy results. Conclusions: ctDNA plasma profiling of pts with advanced PDAC is a feasible alternative method to gather comprehensive genomic data.

Updated Rules for Human Research Become Effective in January

Back to table of contents Previous article Next article Professional NewsFull AccessUpdated Rules for Human Research Become Effective in JanuaryNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:26 Oct 2018https://doi.org/10.1176/appi.pn.2018.11a15AbstractForthcoming changes to the Federal Policy for the Protection of Human Subjects are hoped to reduce the administrative burdens facing clinical trial designers while also simplifying the consent forms given to participants.After more than six years of extensive deliberation and review, the Department of Health and Human Services (HHS) will finally implement a host of changes to the rules governing the use of human subjects in clinical research. The updated Federal Policy for the Protection of Human Subjects, popularly known as the Common Rule, will go into effect on January 21, 2019.Robert K. Chin/Alamy These are the first revisions made to the Common Rule since it was officially codified by HHS in 1991. Many of the regulations involving human research subjects, however, had been in place since the mid-1970s.“The intent of these changes is to streamline the administrative requirements involved in the oversight of clinical trials, while also providing more clarity to participants and researchers about how information and biological specimens can be used,” said Philip Wang, M.D., Ph.D., director of APA’s Division of Research.The updates were a needed response to the increase in size and complexity of clinical trials over the past three decades. Today, multisite clinical trials and the use of digital tools to create and store large amounts of data are the norm in clinical research. Many researchers believed that the Common Rule requirements have not kept up with these changes, making the administrative portion of clinical trials costly and cumbersome.The most significant change overall is that multisite clinical studies will no longer require an Institutional Review Board (IRB) at every trial site. IRBs are independent entities that oversee every clinical trial, with the power to stop a trial if deemed necessary. Researchers conducting large, multisite studies will now be able to use a single IRB, which will make coordination much easier. However, since it may take a while for some researchers to select a central IRB and determine how to coordinate information, HHS has pushed back this requirement until January 2020.For mental health researchers, perhaps the most significant change involves reducing the IRB requirements for studies with minimal risk. Currently, all clinical trials must undergo an annual review. However, starting next year, studies considered “minimal risk” will no longer have this requirement.One class of studies that falls under this low-risk category is “benign behavioral interventions,” which includes any cognitive or behavioral trial that is not overly long or potentially causing emotional distress in participants.Research studies that conduct secondary analyses of existing clinical trial data are also exempt from IRB reviews, so long as patient information remains protected.Another important change is that researchers conducting clinical trials that collect identifiable biospecimens—samples such as DNA that could be traced back to an individual—can ask participants to give “broad consent” on how the biospecimen is used. That way, future trials can use that specimen rather than having to reacquire patient consent or seek a waiver through the IRB.“This is a sensible change that will greatly benefit research,” Wang told Psychiatric News. “We don’t know what the important research questions in mental health will be five or 10 years from now. Broad consent provides the flexibility to address unexpected changes, while still ensuring that individuals who give samples are protected.”While researchers will benefit from many of these changes, so will participants. One example concerns today’s overly complex consent forms that can perplex even seasoned lawyers. The updated rule requires consent forms to contain a simple and concise explanation at the beginning of the document about the key elements of the clinical trial. These elements include the purpose of the research, its risks and benefits, and alternative treatments that might be beneficial to the prospective subject. Consent forms must also clearly state the circumstances when clinically relevant research findings (for example, a genetic analysis reveals a strong risk of some disease) will be shared with the subject. ■ More information on the Common Rule, including the new updates, can be accessed here. ISSUES NewArchived

Using Photovoice to examine adolescents' experiences receiving mental health services in the United States.

In the U.S., fewer than half of children and adolescents who report mental disorders receive care and the needs of those who receive care have yet to be explored. There is a scarcity of studies examining the needs of adolescents with mental conditions and at risk for suicide. Learning directly from the adolescents can fill in this gap by providing insight that clinicians and researchers lack about adolescents' experience. This study uses Photovoice, a Community-Based Participatory Research method that involves focus groups and the use of cameras by participants to visually capture their reality and express their ideas through photographs. By using Photovoice, this study aims to provide an opportunity for adolescents to voice their own perspectives and for researchers and clinicians to gain an understanding of adolescents' life experience away from the treatment setting, as well as their experience as consumers of mental health services. Four participants, including two 15 year olds and two 17 year olds, were recruited from a mental health clinic in New York City. Parental consent and adolescent assent were collected per Institutional Review Board requirements. Thematic analysis was used to identify and report response patterns. Four themes emerged: (i) sense of self, (ii) family, (iii) suicidal ideation and (iv) treatment. Findings suggest that Photovoice is valued by adolescents and leads to critical thinking, self-reflection, discovering strengths and social support. Adolescents reported feeling empowered, which is the ultimate goal of Photovoice. Photovoice presents a powerful opportunity to be used as therapeutic strategy with adolescents that demands further research.

Easy-to-Read Informed Consent Form for Hematopoietic Cell Transplantation Clinical Trials: Results from the Blood and Marrow Transplant Clinical Trials Network 1205 Study

Because of the complexity of hematopoietic cell transplant trial treatments, informed consent forms are often long and difficult to read. We evaluated a 2-column easy-to-read informed consent (ETRIC) form that incorporates elements of health literacy and readability in participants and centers participating in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) clinical trials. In a randomized study 198 adult patients from 25 centers potentially eligible to participate in 4 BMT CTN interventional trials were randomized to the ETRIC form or a standard consent form for that trial. Both forms were written at no more than an eighth-grade reading level. The primary endpoint was objective comprehension score on the Quality of Informed Consent, part A (QuIC-A) instrument. In a parallel evaluation study, 2 moderators conducted semistructured interviews of 49 investigators, research staff, and institutional review board (IRB) members at 9 BMT CTN trial sites. The mean QuIC-A scores were comparable in 152 patients (77%) assessable for the primary endpoint (ETRIC form, 80.5; standard form, 81.8; P = .37). In regression analysis there was no significant association between the consent type and QuIC-A score. In the evaluation study dominant themes identified on qualitative analyses included general comfort and willingness to use the ETRIC template and that its formatting and layout enhancements would offer additional value to research participants, investigators, and IRBs. IRB language preferences and requirements, length, and prior experience with alternative consent formats were perceived as barriers. Among patients considering participation in BMT CTN clinical trials, the formatting enhancements of the ETRIC form did not alter comprehension of the trial. Despite local challenges to implementation, trial sites generally viewed the ETRIC form favorably and expressed willingness to use it over standard consent form.

The Practice of Research Ethics in Lebanon and Qatar: Perspectives of Researchers on Informed Consent.

Informed consent requirements for conducting research with human participants are set by institutional review boards (IRBs) following established guidelines. Despite this, researchers continue to face challenges in seeking and obtaining informed consent. This study discusses researchers' views of such problems in Lebanon and Qatar, which vary in research regulation. We conducted in-depth interviews with 52 academic researchers from various fields of research in both countries and analyzed them using thematic analysis. Important disjunctions emerged between IRB requirements and actual practice. Variations in obtaining informed consent were affected by the research context, type of research, and the prevalent cultural norms and values. Regulatory systems and guidelines for informed consent do not necessarily ensure ethical research conduct. Implications for improvement are presented.

Revised 'Common Rule' Shapes Protections For Research Participants.

Investigators and institutions have begun to prepare for new federal protections of study participants set to take effect in 2018.

Report of the Second Asian Prostate Cancer (A-CaP) Study Meeting.

The Asian Prostate Cancer (A-CaP) Study is an Asia-wide initiative that has been developed over the course of 2 years. The study was launched in December 2015 in Tokyo, Japan, and the participating countries and regions engaged in preparations for the study during the course of 2016, including patient registration and creation of databases for the purpose of the study. The Second A-CaP Meeting was held on September 8, 2016 in Seoul, Korea, with the participation of members and collaborators from 12 countries and regions. Under the study, each participating country or region will begin registration of newly diagnosed prostate cancer patients and conduct prognostic investigations. From the data gathered, common research themes will be identified, such as comparisons among Asian countries of background factors in newly diagnosed prostate cancer patients. This is the first Asia-wide study of prostate cancer and has developed from single country research efforts in this field, including in Japan and Korea. At the Second Meeting, participating countries and regions discussed the status of preparations and discussed various issues that are being faced. These issues include technical challenges in creating databases, promoting participation in each country or region, clarifying issues relating to data input, addressing institutional issues such as institutional review board requirements, and the need for dedicated data managers. The meeting was positioned as an opportunity to share information and address outstanding issues prior to the initiation of the study. In addition to A-CaP-specific discussions, a series of special lectures was also delivered as a means of providing international perspectives on the latest developments in prostate cancer and the use of databases and registration studies around the world.

Accelerating Multisite Research in Nursing Education: Navigating Institutional Review Board Regulatory Issues.

Researchers investigating phenomena in nursing education are increasingly striving to conduct multisite studies. However, designing and managing multisite studies can be costly and time consuming. One complex and costly challenge of multisite studies can be anticipating and navigating the variations in the institutional review board requirements and expectations of different study sites. This article explores issues and regulations around protection of human subjects in multisite studies using the authors' experiences launching the 2016 National Nursing Education Research Network surveys as an exemplar. [J Nurs Educ. 2017;56(2):65-68.].

Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma.

298 Background: Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the discovery of new treatment option.However, biopsy is not routinely performed in HCC and involves risks. The utility of analyzing cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is not established. Methods: We performed 32 ctDNA NGS and 10 tissue NGS analyses in 26 patients with advanced HCC (January 2015 – October 2015). ctDNA analysis (54 to 70 genes) was performed using Guardant 360, which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations. The mutant allele fraction for detected alterations was calculated relative to wild type in ctDNA. Tissue NGS was performed using Foundation One or Molecular Health. The study ws conducted in accordance with UCSD Moores Cancer Center Institutional Review Board requirements. Results: Among 32 ctDNA NGS, at least one genomic alteration (excluding variants of uncertain significance (VUS)) was discerned in 27 samples (84.3%) (average = 2.1 alterations per patient [range, 0-5]) with a median mutant allele fraction of 0.92% (range, 0.06% - 40.57%). Ten patients had both ctDNA NGS and tissue NGS. The median time difference between the date of tissue and ctDNA NGS testing was 450 days (range, 29 – 876 days), possibly reflecting the challenge with doing a second tissue biopsy at the time of relapse. The most commonly mutated gene was TP53 (16 samples, 50.0%), followed by CTNNB1 (8 samples, 25.0%), ARID1A (6 samples, 18.6%), EGFR (4 samples, 12.5%) and MYC (4 samples, 12.5%). Amplification was observed in 11 genes, including CDK4, CDK6, CCNE1, EGFR, ERBB2, FGFR1, KRAS, and MYC. No fusions or indels were observed. At least one potentially actionable alteration was observed in 20 of the 26 patients (76.9%). In two patients treated on the basis of the ctDNA alterations alone, a response was seen. Conclusions: ctDNA profiling is feasible in advanced HCC, and may provide a tissue biopsy-free alternative in these difficult-to-biopsy patients. Further study of clinical validity and utility is ongoing.

Customizable orthopaedic oncology implants: one institution's experience with meeting current IRB and FDA requirements.

BackgroundCustomizable orthopaedic implants are often needed for patients with primary malignant bone tumors due to unique anatomy or complex mechanical problems. Currently, obtaining customizable orthopaedic implants for orthopaedic oncology patients can be an arduous task involving submitting approval requests to the Institutional Review Board (IRB) and the Food and Drug Administration (FDA). There is great potential for the delay of a patient’s surgery and unnecessary paperwork if the submission pathways are misunderstood or a streamlined protocol is not in place.PurposeThe objective of this study was to review the existing FDA custom implant approval pathways and to determine whether this process was improved with an institutional protocol.MethodsAn institutional protocol for obtaining IRB and FDA approval for customizable orthopaedic implants was established with the IRB at our institution in 2013. This protocol was approved by the IRB, such that new patients only require submission of a modification to the existing protocol with individualized patient information. During the two-year period of 2013–2014, eight patients were retrospectively identified as having required customizable implants for various orthopaedic oncology surgeries. The dates of request for IRB approval, request for FDA approval, and total time to surgery were recorded, along with the specific pathway utilized for FDA approval.ResultsThe average patient age was 12 years old (7–21 years old). The average time to IRB approval of a modification to the pre-approved protocol was 14 days (7–21 days). Average time to FDA approval after submission of the IRB approval to the manufacturer was 12.5 days (7–19 days). FDA approval was obtained for all implants as compassionate use requests in accordance with Section 561 of the Federal Food Drug and Cosmetic Act’s expanded access provisions.ConclusionsEstablishment of an institutional protocol with pre-approval by the IRB can expedite the otherwise time-consuming and complicated process of obtaining customizable orthopaedic implants for orthopaedic oncology patients.Level of evidenceRetrospective case series, Level IV. See the Guidelines for authors for a complete description of levels of evidence.

Do Longer Surgical Procedures Result in Greater Contamination of Surgeons' Hands?

A surgical site infection is a substantial cause of complications in patients. Different methods are being used to decrease surgical site infections; however, these infections still can cause complications, especially in patients undergoing longer operations (>3hours). There is evidence that the efficacy of the scrubbing material fades after 3hours. However, we do not know the longevity of hand cleanliness after application of scrubbing materials in a long operation. It can be postulated that if the surgeon's scrubbed hands are recolonized after a certain time, they may serve as a progressive source of contamination during surgery. We asked: (1) Is there a correlation between surgical duration and hand contamination at the end of surgery? (2) At what point during surgery does hand contamination reach or exceed prescrub levels? Three spine surgeons using the same scrubbing technique and materials consisting of chlorhexidine gluconate 1% solution and ethyl alcohol 61% w/w were enrolled in our study. Between December 2014 and April 2015, spine procedures of 3hours or more, which were the first case of the day, were selected for this study (20 cases). Cases in which glove changing occurred (perforations, reprepping, and redraping) or cultures obtained after scrubbing were positive (indicative of insufficient hand sanitization) were excluded (0% of cases). Twenty cases (100% enrollment) were analyzed. Surgeons' hands were swabbed with sterile cotton tip applicators and 5 mL sterile phosphate-buffered saline before hand scrubbing (prescrub), immediately after hand scrubbing (postscrub), and immediately after surgery (postoperative). Results were reported in colony-forming units per milliliter. The correlation between duration of surgery and hand recontamination was tested by regression analysis of time versus colony-forming units per milliliter. Receiver-operating characteristic curve tested the cutoff point, where recontamination occurred. With a longer duration of surgery, more colony-forming units are recovered from gloved hands at the end of surgery (R=0.94, R(2)=0.89, p=0.005). The receiver-operating characteristic curve suggested that 5hours is the cutoff point for hand recolonization. At 5hours, contamination reached or exceeded prescrub levels (area under the curve, 0.66; 95% CI, 0.23-1.0), whereas before 5hours, there was no contamination detected at the end of surgery. Our results show that duration of surgery correlates with hand recontamination and at 5hours, recolonization of a surgeon's hands become detectable. Recolonization may have started even earlier than 5hours. However, these levels are not detectable in the laboratory at earlier times. Based on this pilot study, rescrubbing is highly recommended before the fifth hour of an operation, ideally at some point between the fourth and fifth hours. We also recommend the surgical site infection rates in operations using rescrubbing should be compared with those from surgeries with just the conventional single-scrubbing technique, in a randomized controlled trial, to determine the effectiveness of this novel rescrubbing method.