Human Research Protections Research Articles

Implementing Regulatory Broad Consent Under the Revised Common Rule: Clarifying Key Points and the Need for Evidence.

The revised Common Rule includes a new option for the conduct of secondary research with identifiable data and biospecimens: regulatory broad consent. Motivated by concerns regarding autonomy and trust in the research enterprise, regulators had initially proposed broad consent in a manner that would have rendered it the exclusive approach to secondary research with all biospecimens, regardless of identifiability. Based on public comments from both researchers and patients concerned that this approach would hinder important medical advances, however, regulators decided to largely preserve the status quo approach to secondary research with biospecimens and data. The Final Rule therefore allows such research to proceed without specific informed consent in a number of circumstances, but it also offers regulatory broad consent as a new, optional pathway for secondary research with identifiable data and biospecimens. In this article, we describe the parameters of regulatory broad consent under the new rule, explain why researchers and research institutions are unlikely to utilize it, outline recommendations for regulatory broad consent issued by the Secretary's Advisory Committee on Human Research Protections (SACHRP), and sketch an empirical research agenda for the sorts of questions about regulatory broad consent that remain to be answered as the research community embarks on Final Rule implementation.

A Belmont Reboot: Building a Normative Foundation for Human Research in the 21st Century.

Over the past decade, awareness emerged that existing frameworks for regulation and oversight of research with human participants fit poorly with contemporary research. Although substantial and diverse literature touches on this dissonance from a variety of perspectives, the problem is illustrated most clearly by the 2011 to 2017 process undertaken to “modernize” the Common Rule, the federal regulations for the protection of human research subjects. During this process, the Office for Human Research Protections (OHRP) sought public comment on a wide array of challenges they felt were not addressed adequately in existing regulations, and that they hoped to address in proposed revisions. The most widely debated proposal aimed to address a perception that a long-standing policy allowing the research use of nonidentified biospecimens without informed consent no longer made sense given the potential of genomic technologies to reidentify such samples.1 OHRP, recognizing concerns that existing regulations created undue burdens on very low-risk research, also proposed a plan to allow investigators to use a decision tool to determine whether a study would be “excluded” from IRB review. Proposals intended to address these and other concerns prompted critiques in the scholarly literature and in comments submitted to OHRP during the public comment period. Ultimately, the most controversial proposals, including requiring informed consent for nonidentified biospecimens research, were not part of the final rule published in January 2017 on the final day of the Obama administration. Two years after it was published, this final rule was implemented in January 2019. As leaders of a multi-disciplinary team working on the ethical and regulatory challenges raised by biorepository research in multi-site networks, we believe that both the controversy surrounding the OHRP proposals and the modest outcome of this six-year process are symptoms of a larger challenge. The regulatory revision process initiated by OHRP focused primarily on the transformation of biomedical science. Critically, however, it did not adequately consider the transformation that has occurred with regard to cultural perspectives on a range of critical issues relevant to the oversight of research with human subjects. These include, but are not limited to: changing perspectives on the right to privacy (and limits thereto), power imbalances between experts and lay people, trust in institutions, and individual ownership and control of data and biomaterials. OHRP, and the biomedical research community at large, have not resolved important questions about the oversight of human subjects research because we have not sufficiently accounted for the ways that society and societal norms have shifted since the Belmont Report was published 1979 and 45 CFR 46 Subpart A (what we now call the Common Rule) was adopted in 1981. It is time to undertake a different strategy for working toward the modernization of oversight and governance of research with humans. First, we need to revisit the principles articulated in the Belmont Report. If we aim to settle on an ethical framework that supports the development of policies, what ethical commitments and ideas must be included? Are additional ethical principles needed to ground this effort? Second, we need to conduct empirical research and public engagement activities to understand the views of diverse stakeholders on the ethical basis for policies on human subjects research. What implications do the Belmont principles hold for us today? Third, we need a process whereby this more contemporary interpretation of principles to guide human research ethics can be translated into policy and practice, with a focus that extends beyond the Common Rule to take a more comprehensive and global view of research oversight and governance. This work would recognize that changing societal contexts calls for changing approaches to process: a repeat of the original Belmont process would be an anachronism. While the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research successfully developed the original Belmont Report, it no longer makes sense for a small and distinguished group of scholars to gather at a conference center over a three-year period. Our proposal emphasizes a more transparent and inclusive – and thus more “modern” – process.

Reviving Human Research in Costa Rica.

Costa Rica is a small developing nation in Central America with a well-regarded universal health care system and a strong human rights tradition. In the latter part of the twentieth century, it became a popular site for clinical trials funded by multinational pharmaceutical companies. In light of concerns about ineffective oversight and alleged research abuses, the Constitutional Chamber of the Supreme Court passed a moratorium on all biomedical studies involving humans. This moratorium was in place between 2010 and 2014, when the Legislative Assembly passed a new national law to protect participants' rights and welfare. This case study reviews the history of human research protections in Costa Rica and provides recommendations for how Costa Rica can move forward responsibly as a leader in human research for the region.

Stimulation Contractility Gradient of a Neuromuscular Choristoma Within the Sciatic Nerve: 2-Dimensional Operative Video.

Neuromuscular choristoma (NMC) is a rare congenital nerve lesion that is classified by the presence of heterotopic muscle fibers intercalated within nerve fascicles.1 The presence of NMC typically causes progressive neuropathy and bony/soft tissue undergrowth, often leading to a shortened atrophic limb.2,3 The typical appearance of NMC on magnetic resonance imaging is an enlarged fusiform nerve that exhibits minimal gadolinium enhancement.4 While there is increasing documentation of pathognomonic clinical and radiographic features for various diffuse fusiform peripheral nerve lesions, nerve biopsy is still occasionally required for some patients given the rarity of these diseases and progressive neuropathic features.The intraoperative appearance of NMC and its unique electrical stimulation properties are quite interesting. Intrafascicular replacement of nerve by skeletal muscle gives the nerve a red beefy color and causes the fascicles to contract with electrical stimulation.5 In this video, we demonstrate the intraoperative appearance and contractile properties of NMC in a 60-yr-old woman with progressive sciatic neuropathy. Histologic and immunohistochemical studies identified a gradient of intralesional mature skeletal muscle within the NMC, with substantially fewer desmin-positive skeletal muscle fibers in the distal aspect. A gradient of contractility with intraoperative stimulation seemed to correlate with this pathology. These findings suggest that the lesional extent of NMC may not be clinically or grossly evident, reflecting a varying distribution of skeletal muscle within the affected nerve.The Mayo Clinic Institutional Review Board Office for Human Research Protection does not require approval for single participant case studies. The subject involved in this study was not identifiable and the general surgical consent form included permission for intraoperative photos and video.

A Comparative Economic Study on the Use of Unmanned Aerial Systems versus Motorcycles to Transport Laboratory Samples in Liberia

Background: Laboratory sample transport in low and middle income countries is constrained by poor roads, difficult geographical terrain, and insecurity. This often leads to delayed laboratory diagnostic turn-around times, and hampers epidemic control or patient treatment efforts. While unmanned aerial systems (UAS), commonly known as drones, may mitigate some of these transportation constraints, their cost-effectiveness relative to land-based transportation systems is unclear. Methods: We compared the costs and cost-effectiveness of UAS versus motorcycles in Liberia for laboratory sample transportation under routine and public health emergency conditions. We modeled three UAS systems with operational ranges of 30 km, 65 km, and 100 km, and compared them to an established motorcycle transport system. We included personnel, equipment, maintenance, and training costs, and conducted univariate and probabilistic sensitivity analyses for equipment operational lifespans, operational range, and accident/failure rates. Findings: Under the routine scenario, the per sample transport costs are $0·65 ($0·10:$2·85) for motorcycles and $0·82 ($0·66:$5·05) for UAS. Per sample costs under the emergency scenario are $24·06 ($21·14:$28·20) for motorcycles and $34·09 ($26·70: $127·40) for UAS. Motorcycles are more cost-effective than UAS under most scenarios with the exception of 100 km range aircraft with operational lifespans of more than 3,000 hours and prices less than $15,000. Interpretation: Given the current level of technology, purchase prices, equipment lifespans, and operational flying ranges, UAS are less cost-effective than motorcycles for routine transport of laboratory samples in Liberia. Field studies are needed to generate evidence on UAS lifespan, failure rates and performance under various weather conditions and payloads. Funding: The authors received no financial support for the research, authorship, and publication of this paper. Declaration of Interest: The authors of this paper declare no financial conflicts of interest. Ethical Approval: We did not seek IRB approval consistent with Human Research Protection Policy {45CFR46.101(b)(4)}.

Of Parachutes and Participant Protection: Moving Beyond Quality to Advance Effective Research Ethics Oversight.

There are several reasons to believe that Institutional Review Boards (IRBs) and Human Research Protection Programs (HRPPs) contribute to ethical research and the protection of research participants, but there are also important reasons to interrogate this belief. Determining whether IRBs and HRPPs "work" requires empirical evaluation of whether and how well they actually achieve what they were designed to do. In other words, it is critical to examine their outcomes and not only their procedures and structures. In this response to Tsan, we argue that the concept of IRB and HRPP quality entails three dimensions: (1) effectiveness, (2) procedures and structures likely to promote effectiveness, and (3) features unrelated to effectiveness but nonetheless essential, such as efficiency, fairness, and proportionality. Because not all types of quality necessarily guarantee or entail effectiveness, we suggest that broad quality assessments, including such features as regulatory compliance and other procedural measures suggested by Tsan, are unhelpful as the first step in evaluating IRBs and HRPPs. Instead, we must start with outcomes relevant to effectiveness. To do this, we launched the Consortium to Advance Effective Research Ethics Oversight (AEREO), with a mission to define and specify ways to measure relevant outcomes for research ethics oversight, empirically evaluate whether those outcomes are achieved, test new approaches to achieving them, and ultimately, develop and implement empirically-based policy and practice to advance IRB and HRPP effectiveness. We describe several anticipated AEREO projects and call for collaboration between various stakeholders to more meaningfully evaluate IRB and HRPPs.

Methods in the design and implementation of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial

BackgroundFew papers discuss the pragmatics of conducting large, cluster randomized clinical trials. Here we describe the sequential steps taken to develop methods to implement the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial that tested the effect of a nurse-implemented, goal-directed, comfort algorithm on clinical outcomes in pediatric patients with acute respiratory failure.MethodsAfter development in a single institution, the RESTORE intervention was pilot-tested in two pediatric intensive care units (PICUs) to evaluate safety and feasibility. After the pilot, the RESTORE intervention was simplified to enhance reproducibility across multiple PICUs. The final RESTORE trial was developed as a cluster randomized clinical trial where the unit of randomization was the PICU, stratified by PICU size, and the unit of inference was the patient. Study execution was revised based on our Data and Safety Monitoring Board’s recommendation to consult with the Department of Health and Human Services’ Office of Human Research Protection (OHRP) on how best to consent eligible subjects. OHRP deemed that the RESTORE intervention posed greater than minimal risk and that all enrolled subjects provide consent reflecting their level of participation.ResultsThirty-one PICUs of varying size, organization and academic affiliation participated and over 2800 critically ill infants and children supported on mechanical ventilation for acute pulmonary disease were enrolled. The primary outcome for the trial was the duration of mechanical ventilation; secondary outcomes included time awake and comfortable, total sedative exposure and iatrogenic withdrawal symptoms. Throughout the clinical trial the investigative team worked to maintain treatment fidelity, enrollment milestones and co-investigator enthusiasm. We considered the potential impact of competing clinical trials through a decision-making framework.ConclusionsThe RESTORE clinical trial was a large and complex multicenter study that has provided the necessary evidence to guide sedation practices in the field of pediatric critical care. Specific issues that were unique to this trial included level of consent, adding clinical sites to augment enrollment and evaluating the potential impact of competing clinical trials.Trial registrationClinicalTrials.gov, Identifiers: Pilot trial: NCT00142766; Retrospectively registerd on 2 September 2005.Cluster randomized trial: NCT00814099. Registered on 23 December 2008.

Introducing e-consents in a clinical setting

Preeclampsia (PE) is a multiorgan hypertensive-disorder in pregnancy that causes significant maternal-fetal mortality and morbidity. The diagnostics and therapeutics for PE are limited due to its unclear etiology. Using the UI Maternal Fetal Tissue Bank, our lab has demonstrated that copeptin is robustly predictive of PE. To investigate copeptin further, we developed the Rule Out Pre-Eclampsia Study (ROPE). The ROPE study recruits women admitted to Labor and Delivery for evaluation of PE. Women are admitted for PE evaluation at all hours. Research team members are not available at all times to obtain consent which limits recruitment. Our project aimed to develop an electronic informed consent (e-IC) that is compliant with the Federal Regulation for Human Research Protection and is easy to use and readily understood by study participants. After obtaining IRB approval, simulated patients were given an iPad on which to read and evaluate the e-IC using a validated questionnaire, the Quality of Informed Consent (QuIC). Based on the QuIC, the e-IC was modified and re-tested. Participants demonstrated good comprehension of the e-IC as evidence by QuIC scores ranging from 61 to 96. Based on our results, the e-IC is an effective and efficient method for the Informed Consent process.

Medical Marijuana: A Potpourri of the Evidence Base, Clinical, Neurodevelopmental, Legal, Ethical, and Research Issues

Medical marijuana policies currently exist in 29 states and the District of Columbia. Child and adolescent psychiatrists are faced with requests for medical marijuana by youth and parents. Federal law prohibits distribution or dispensing marijuana, whereas states are permissive in allowing physicians to certify or recommend its use. Marijuana is classified as a schedule 1 drug with high potential for abuse. The state-qualified conditions cover a range of conditions, some with a strong evidence base for benefit, such as chemotherapy-associated nausea and vomiting, whereas other conditions include ASD, PTSD, and Tourette’s disorder, which have poor-quality evidence. There is a gap between the evidence base for medical cannabinoids as treatment for pediatric conditions compared with increased access. There are adverse effects on mental illness and on neurodevelopment. There are ethical and legal questions on physician liability or legal consequences for those using recommended marijuana. There are barriers to research on cannabinoids and ethical issues from human research protections perspectives that are important for child and adolescent psychiatrists to understand.

Brief Report: The Amsterdam Symptom and Risk-Based Score Predicts for Acute HIV Infection in Men Who Have Sex With Men in San Diego.

Dijkstra et al recently described a risk- and symptom-based score moderately predictive for HIV seroconversion in the preceding 6-12 months in men who have sex with men (MSM) in Amsterdam. Our objective was to determine whether this "Amsterdam Score" could also predict for acute HIV infection (AHI) in MSM. This study is a case-control analysis of a prospectively enrolled cohort of MSM who voluntarily presented for HIV testing in San Diego. The study sample was composed of MSM who screened HIV antibody-negative and then either tested positive with AHI [HIV nucleic acid test (NAT)-positive] or tested HIV NAT-negative. The Amsterdam Score was calculated for each participant in the study sample. Score performance was assessed using receiver operating characteristic curves and their area under the curve (AUC). An optimal cutoff was determined using the Youden index. Seven hundred fifty-seven MSM (110 AHI and 647 HIV NAT-negative) were included in the analysis. AHI and HIV-negative cases were similar in age [median 32 years (interquartile range 26-42) vs 33 (27-45), respectively, P = 0.082]. The Amsterdam Score yielded a receiver operating characteristic curve with an AUC of 0.88 (95% confidence interval: 0.84 to 0.91). An optimal cutoff of ≥1.6 was 78.2% sensitive and 81.0% specific. The risk- and symptom-based Amsterdam Score was highly predictive (AUC of 0.88) of AHI in MSM in San Diego. The Amsterdam Score could be used to target NAT utilization in resource-poor settings among MSM who test HIV antibody-negative, although the potential cost-savings must be balanced with the risk of missing AHI diagnoses.

A Novel 14-Day Dietary Deprivation Regimen Preserves Protein Metabolism During Fasting and Accelerates Muscle Recovery after Refeeding Through Constantly Suppressing Myostatin

Background Fasting has demonstrated a robust lifespan extension in yeast and C. elegans. Although long-term total fasting, intermittent fasting or calorie restriction has been evaluated in clinic, there were long-term safety and practical concerns regarding with these regimens. Methods We have applied a special prebiotics-assisted fasting approach for 7~14 days continual dietary deprivation (CDD) in three trials. Our fasting regimen has achieved total of 25/94 individuals who have successfully accomplished 14D's total fasting. At the third trial, a modified paradigm plus daily mineral electrolytes assistance led up to 50% (15/32) success in fulfilling 14D-CDD. Among the results from successfully accomplishment subjects, one-way ANOVA with repeated measure on 5 treatments within individual has been compared with each own control. Findings Bioelectrical and biochemical results indicated significant reducing in fat mass (lipid) during fasting, while lean mass (protein) remained stable and found more accelerated recovery after refeeding. During 7~9thD CDD, we observed a significant slowing down in basal metabolism rate (BMR 100U/L, refeeding for more than 3 months remained lowered CK level. Fasting 14D also found significant suppression in myostatin, and it remained lower concentration even after 3 months' refeeding. Ultrasonic image confirmed unchanged muscle comparing with adipose during and after 14D fasting. Interpretation Our results indicated that initial fasting (1~7D) induced catabolism in all tissues. As the fasting continues, a preserved muscle mechanism has been established with reducing in BMR, myostatin and CK which might indicate an induction of anabolism through establishing ketone body metabolism. The beneficial evidence from current regimen indicated that repeated application of 14D-CDD every 6 months may supply practical health improvement strategy in facilitating disease treatments. Funding National Basic Research Project of China Declaration of Interest: The other authors declare no competing interests. Ethical Approval: The approval of the study protocol by the University of Henan Human Research Protection Program was under the guidance of China Association for Ethical Studies. The protocol was also recorded in Medical Ethics Committee of Henan Medical Association of Henan Province, and the entire clinical study was under the supervision of ethic board of The First Affiliated Hospital of Henan University.

Genomics, Big Data, and Broad Consent: a New Ethics Frontier for Prevention Science

Emerging technologies for analyzing biospecimens have led to advances in understanding the interacting role of genetics and environment on development and individual responsivity to prevention and intervention programs. The scientific study of gene-environment influences has also benefited from the growth of Big Data tools that allow linking genomic data to health, educational, and other information stored in large integrated datasets. These advances have created a new frontier of ethical challenges for scientists as they collect, store, or engage in secondary use of potentially identifiable information and biospecimens. To address challenges arising from technological advances and the expanding contexts in which potentially identifiable information and biospecimens are collected and stored, the Office of Human Research Protections has revised federal regulations for the protection of human subjects. The revised regulations create a new format, content, and transparency requirements for informed consent, including a new mechanism known as broad consent. Broad consent offers participants a range of choices regarding consent for the storage and future use of their personally identifiable data. These regulations have important implications for how prevention scientists and oversight boards acquire participant consent for the collection, storage, and future use of their data by other investigators for scientific purposes significantly different from the original study. This article describes regulatory changes and challenges affecting traditional informed consent for prevention research, followed by a description of the rationale and requirements for obtaining broad consent, and concludes with a discussion of future challenges involving ongoing transparency and protections for participants and their communities.

How U.S. research institutions are responding to the single Institutional Review Board mandate

ABSTRACTOne of the most significant changes to the Common Rule is the requirement that institutions use a single Institutional Review Board (IRB) for cooperative research in the United States, unless more than one IRB is required by state, local, or tribal law, or a signatory federal agency decides an exception is warranted. We surveyed Human Research Protection Program (HRPP) officials at the top U.S. research institutions to understand their knowledge and opinion of the mandate, what steps their institutions are taking, and difficulties their institutions are facing. One-hundred seven institutions (56.9%) responded to the survey. While support for the single-IRB mandate was positive overall, most respondents acknowledged that their institution is likely to face some difficulties complying with it. Regulatory agencies can help institutions to comply with the mandate by providing guidance concerning such issues as exceptions to the mandate, local context review, oversight, and implementation of reliance agreements, and development of policies, procedures, and best practices.

Exploration of application for AAHRPP accreditation in perfecting the human research protection program of the hospital

The paper introduced the preparations of the hospital in applying for AAHRPP accreditation, and the positive push on improving the human research protection program. This proved that such application can learn from overseas experiences in scientific management and improve our human research protection system in a short timeframe. The accreditation can promote the understanding of both administrators and investigators for the importance of protecting human subjects in research, especially the detailed protection procedures, and promoting clinical researches in world class quality. Key words: AAHRPP; Human Research Protection Program; Accreditation; Subjects

Heart Rate Variability and Cognitive Bias Feedback Interventions to Prevent Post-deployment PTSD: Results from a Randomized Controlled Trial.

There is a long history of pre-deployment PTSD prevention efforts in the military and effective pre-deployment strategies to prevent post-deployment PTSD are still needed. This randomized controlled trial included three arms: heart rate variability biofeedback (HRVB), cognitive bias modification for interpretation (CBM-I), and control. The hypothesis was that pre-deployment resilience training would result in lower post-deployment PTSD symptoms compared with control. Army National Guard soldiers (n = 342) were enrolled in the Warriors Achieving Resilience (WAR) study and analyzed. The outcome was PTSD symptom severity using the PTSD Checklist - Military version (PCL) measured at pre-deployment, 3- and 12-month post-deployment. Due to the repeated measures for each participant and cluster randomization at the company level, generalized linear mixed models were used for the analysis. This study was approved by the Army Human Research Protection Office, Central Arkansas Veterans Healthcare System Institutional Review Board (IRB), and Southeast Louisiana Veterans Health Care System IRB. Overall, there was no significant intervention effect. However, there were significant intervention effects for subgroups of soldiers. For example, at 3-months post-deployment, the HRVB arm had significantly lower PCL scores than the control arm for soldiers with no previous combat zone exposure who were age 30 and older and for soldiers with previous combat zone exposure who were 45 and older (unadjusted effect size -0.97 and -1.03, respectively). A significant difference between the CBM-I and control arms was found for soldiers without previous combat zone exposure between ages 23 and 42 (unadjusted effect size -0.41). Similarly, at 12-months post-deployment, the HRVB arm had significantly lower PCL scores in older soldiers. Pre-deployment resilience training was acceptable and feasible and resulted in lower post-deployment PTSD symptom scores in subgroups of older soldiers compared with controls. Strengths of the study included cluster randomization at the company level, use of iPod device to deliver the resilience intervention throughout the deployment cycle, and minimal disruption of pre-deployment training by using self-paced resilience training. Weaknesses included self-report app use, study personnel not able to contact soldiers during deployment, and in general a low level of PTSD symptom severity throughout the study. In future studies, it would important for the study team and/or military personnel implementing the resilience training to be in frequent contact with participants to ensure proper use of the resilience training apps.

What the contract does not say… A current analysis of what’s missing in clinical trial agreements

Introduction. Increasing numbers of litigation cases in clinical research highlight the need for definitive and transparent clinical trial agreements (CTAs). The requirements set by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) are an attempt to minimise miscommunication between sponsor and site, and promote human research protection. These requirements include: ( i ) the obligation of the sponsor and/or its representative to communicate study results; ( ii ) the obligation of the sponsor and/or its representative to promptly report any findings that could affect the participants’ safety and/or influence study conduct; and ( iii ) the sponsor’s liability for the cost of medical care in the event of a research-related injury. Objective. To analyse 40 CTAs as to which of the AAHRPP requirements they met. Methodology. Forty consecutive CTAs signed by our institution, with 15 different research sponsors, were analysed and tracked as to which AAHRPP criteria they met. Results. No CTAs complied with all the AAHRPP requirements. Notably, 17.5% stipulated that the sponsor would communicate study results, but none stipulated that it would directly inform the site of these results; 35% stated that the sponsor would be responsible for reporting any findings/additional information that might affect participants’ safety and/or influence the conduct of the study; and 40% explicitly stipulated that the sponsor was obliged to pay for the cost of patients’ medical care in the event of a research-related injury. Conclusions. The AAHRPP requirements are an attempt to minimise miscommunication between sponsor and site, yet most CTAs fail to stipulate what should be fundamental requirements of every contract.

Stem Cell Ophthalmology Treatment Study: bone marrow derived stem cells in the treatment of Retinitis Pigmentosa.

Seventeen patients with bilateral visual loss due to Retinitis Pigmentosa (RP) underwent autologous bone marrow derived stem cell (BMSC) treatment within the Stem Cell Ophthalmology Treatment Study (SCOTS and SCOTS 2). Both are National Institutes of Health (NIH) and Office of Human Research Protection (OHRP) compliant Institutional Review Board (IRB) approved clinical studies utilizing using autologous BMSC in the treatment of retinal and optic nerve diseases that meet inclusion criteria. The average age of the patients treated was 48.8 years. The average duration of disease prior to treatment was 27.6 years and ranged from 4 to approximately 60 years. Affected eyes were treated with either retrobulbar, subtenons and intravenous BMSC or retrobulbar, subtenons, intravitreal and intravenous. Follow up was provided a minimum of 6 months. The primary outcome was visual acuity as measured by Snellen or converted to LogMAR. Following therapy in SCOTS or SCOTS 2, 11 patients (64.7%) showed improved binocular vision averaging 10.23 lines of Snellen acuity per eye over pre-treatment acuity; 8 patients (35.3%) remaining stable over the follow up period; no patients experiencing loss of overall acuity. In 33 treated eyes, 15 eyes (45.5%) improved an average of 7.9 lines of Snellen acuity, 15 eyes (45.5%) remained stable, and 3 eyes (9%) worsened by an average of 1.7 lines of Snellen acuity. Improvements ranged from 1 to 27 lines of vision. Using the LogMAR Scale and calculating delta as a ratio to pre-treatment vision in improved eyes, acuity improvement ranged from 23% to 90% with an average of 40.9% visual acuity improvement over baseline vision. Evaluation of all patients and eyes capable of LogMAR vision showed an average of 31% improvement in vision over baseline. Findings were of statistical significance (P=0.016). There were no surgical complications. The BMSC protocols of the SCOTS achieved meaningful visual acuity improvements or stability in RP that were of statistical significance. Duration of disease did not appear to affect the ability of eyes to respond. Safety was confirmed. Possible mechanisms by which improvement occurred may include transdifferentiation of BMSC into Neuronal Nuclei (NeuN) positive cells, BMSC paracrine secretions or neurotrophic factors and hormones, transfer of mitochondria, release of messenger RNA or other compounds via exosomes or microvesicles. Given the successful outcome in this otherwise progressive condition, consideration should be given to providing this treatment option.

Assessing the Quality and Performance of Human Research Protection Programs to Guide Compliance Oversight Activities.

Routine on-site reviews should focus primarily on facilities that are at risk of harming human subjects. Using human research protection program performance metric data from 107 facilities, we defined a facility to be at risk when one of its noncompliance/incident rates was among the top three highest rates of that performance metric. Based on 14 performance metrics with noncompliance and incidents in 2017, 27 facilities were identified to be at risk. These 27 facilities at risk, while constituting only 25% of all facilities, contributed to 70% ± 25% ( M ± SD; range = 32%-100%) of all reported noncompliance/incidents. Thus, performance metric data can be used to guide compliance oversight activities.

A Study of Reliance Agreement Templates Used by U.S. Research Institutions.

We performed a content analysis of reliance agreement templates from 73 of the top U.S. research institutions ranked by research funding. 67.1% of institutions in our sample use the Office of Human Research Protections (OHRP) template and 8.2% use the SMART IRB template. Although a significant percentage of institutions (45.2%) use their own custom template, many of these also use the OHRP template or the SMART IRB template. 21.9% of institutional templates have only the OHRP minimum 10 contractual provisions (or elements), 27.4% have 11 elements, 26% have 12-19 elements, and 24.7% have 20 or more elements. 5.5% of institutional templates require the relied-upon institution to indemnify the relying institution, 6.8% require the relying institution to indemnify the relied-upon institution, 8.2% require the relied-upon institution to have liability insurance, 15.1% require the relying institution to have liability insurance, 2.7% require the relied-upon institution to have accreditation, and none require the relying institution to have accreditation. The number of elements in the template was positively associated with total research funding and private institutional control. Our data indicate that institutions which are seeking reliance agreements for cooperative research involving human subjects are not likely to encounter many difficulties because most are using commonly employed templates and are not imposing potentially disputable requirements on parties to the agreement.

\u2018Screening audit\u2019 as a quality assurance tool in good clinical practice compliant research environments

BackgroundWith the growing amount of clinical research, regulations and research ethics are becoming more stringent. This trend introduces a need for quality assurance measures for ensuring adherence to research ethics and human research protection beyond Institutional Review Board approval. Audits, one of the most effective tools for assessing quality assurance, are measures used to evaluate Good Clinical Practice (GCP) and protocol compliance in clinical research. However, they are laborious, time consuming, and require expertise. Therefore, we developed a simple auditing process (a screening audit) and evaluated its feasibility and effectiveness.MethodsThe screening audit was developed using a routine audit checklist based on the Severance Hospital’s Human Research Protection Program policies and procedures. The measure includes 20 questions, and results are summarized in five categories of audit findings. We analyzed 462 studies that were reviewed by the Severance Hospital Human Research Protection Center between 2013 and 2017. We retrospectively analyzed research characteristics, reply rate, audit findings, associated factors and post-screening audit compliance, etc.ResultsInvestigator reply rates gradually increased, except for the first year (73% → 26% → 53% → 49% → 55%). The studies were graded as “critical,” “major,” “minor,” and “not a finding” (11.9, 39.0, 42.9, and 6.3%, respectively), based on findings and number of deficiencies. The auditors’ decisions showed fair agreement with weighted kappa values of 0.316, 0.339, and 0.373. Low-risk level studies, single center studies, and non-phase clinical research showed more prevalent frequencies of being “major” or “critical” (p = 0.002, < 0.0001, < 0.0001, respectively). Inappropriateness of documents, failure to obtain informed consent, inappropriateness of informed consent process, and failure to protect participants’ personal information were associated with higher audit grade (p < 0.0001, p = 0.0001, p < 0.0001, p = 0.003). We were able to observe critical GCP violations in the routine internal audit results of post-screening audit compliance checks in “non-responding” and “critical” studies upon applying the screening audit.ConclusionsOur screening audit is a simple and effective way to assess overall GCP compliance by institutions and to ensure medical ethics. The tool also provides useful selection criteria for conducting routine audits.