Healthy Research Volunteers Research Articles

The NIMH intramural healthy volunteer dataset: A comprehensive MEG, MRI, and behavioral resource

The NIMH Healthy Research Volunteer Dataset is a collection of phenotypic data characterizing healthy research volunteers using clinical assessments such as assays of blood and urine, mental health assessments, diagnostic and dimensional measures of mental health, cognitive and neuropsychological functioning, structural and functional magnetic resonance imaging (MRI), along with diffusion tensor imaging (DTI), and a comprehensive magnetoencephalography battery (MEG). In addition, blood samples of healthy volunteers are banked for future analyses. All data collected in this protocol are broadly shared in the OpenNeuro repository, in the Brain Imaging Data Structure (BIDS) format. In addition, task paradigms and basic pre-processing scripts are shared on GitHub. There are currently few open access MEG datasets, and multimodal neuroimaging datasets are even more rare. Due to its depth of characterization of a healthy population in terms of brain health, this dataset may contribute to a wide array of secondary investigations of non-clinical and clinical research questions.

What risks should be permissible in controlled human infection model studies?

Controlled human infection model (CHIM) studies involve the intentional exposure of healthy research volunteers to infectious agents. These studies contribute to knowledge about the cause or development of disease and to the advancement of vaccine research. But they also raise ethical questions about the kinds of risks that should be permissible and whether limits should be imposed on research risks in CHIM studies. Two possible risk thresholds have been considered for CHIM studies. The first suggests constraining ethically permissible risks according to a minimal risk threshold and the second endorses a higher risk threshold that excludes irreversible or fatal infections. I argue that neither of these thresholds is persuasive and situate questions about risk thresholds in CHIM studies within a broader debate about permissible risks in research. I argue that risks in CHIM studies should be constrained according to limits on research risks that do not offer corresponding benefits in all studies rather than developing a unique risk threshold for CHIM studies. I then propose five recommendations for the ethical assessment of risk in CHIM studies.

Utilization of the DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure-Adult to Screen Healthy Volunteers for Research Studies

The DSM-5 Level 1 Cross-Cutting Symptom Measure–Adult (DSM XC) was developed by the American Psychiatric Association (APA) as a transdiagnostic measure of current mental health symptomatology. This paper describes utilization of the DSM XC to screen volunteers for participation in mental health research studies as healthy controls. Research volunteers completed an online, modified version of the DSM XC, which along with other clinical information, was used to determine eligibility for participation as a healthy control. The sensitivity and specificity of screening positive on the DSM XC for this eligibility decision were calculated. Of 506 volunteers who completed the screening process, 159 (31%) were ineligible due to mental health reasons. The DSM XC sensitivity in predicting this determination was 64.2% [95% CI: 56.5 – 71.3] and its specificity was 83.9% [95% CI: 79.7 – 87.5]. When DSM XC responses were combined with information about current psychotropic medication use, an important determinant of study eligibility, the sensitivity improved to 81.8% [95% CI: 75.3 – 87.2). These findings provide preliminary support for the use of the DSM XC as an initial screening tool for mental health studies that enroll healthy research volunteers, particularly when supplemented by additional clinical history such as psychotropic medication use.

Factors Influencing Participation Of Healthy Volunteers In Clinical Trials: Findings From A Cross-Sectional Study In Delhi, North India.

PurposeTo identify the specific motivations that drive healthy volunteers to consent for their participation in clinical studies. Additionally, the study aimed to document the socio-demographic determinants of participation in the trial related solely to the intention of securing financial gains.Patients and methodsThis cross-sectional study was conducted among subjects who participated as healthy volunteers in clinical trials conducted by Contract Research Organizations (CROs) of Delhi. Pre-tested, validated semi-structured questionnaires were used to collect baseline socio-demographic data, information about factors motivating participation in clinical trials, and pattern of utilisation of money received against participation in the trial. Logistic regression analysis was done to determine the factors that influenced participation in the trial related purely to the motive of securing financial gains.ResultsA total of 400 participants were selected. The majority of the volunteers (77.5%) reported that their sole reason for participating in clinical trials was for monetary gain. Around a tenth of the volunteers participated with the intent to advance scientific knowledge and another 4.5% participated due to benefits of free medical check-ups. Participants in the age group of 29–38 years, those that were married, those residing in an urban slum, male participants, those with a high number of dependent family members (ie, 5 to 8), and those earning less than 5000 INR (71 USD) a month had higher odds of participating in a clinical trial purely for the financial benefits. Those educated till intermediate and above had lower odds of participation in the trial due to monetary benefits.ConclusionOur study shows that healthy volunteers in Delhi consider participation in clinical trials mainly because of the prospect of financial reward. More research is needed to inform judgments around the ethics of providing financial rewards and enrollment of healthy research volunteers.

"Hallucinations" Following Acute Cannabis Dosing: A Case Report and Comparison to Other Hallucinogenic Drugs.

Introduction: Cannabis has been historically classified as a hallucinogen. However, subjective cannabis effects do not typically include hallucinogen-like effects. Empirical reports of hallucinogen-like effects produced by cannabis in controlled settings, particularly among healthy research volunteers, are rare and have mostly occurred after administration of purified Δ-9 tetrahydrocannabinol (THC) rather than whole plant cannabis.Methods: The case of a healthy 30-year-old male who experienced auditory and visual hallucinations in a controlled laboratory study after inhaling vaporized cannabis that contained 25 mg THC (case dose) is presented. Ratings on the Hallucinogen Rating Scale (HRS) following the case dose are compared with HRS ratings obtained from the participant after other doses of cannabis and with archival HRS data from laboratory studies involving acute doses of cannabis, psilocybin, dextromethorphan (DXM), and salvinorin A.Results: Scores on the Volition subscale of the HRS were greater for the case dose than for the maximum dose administered in any other comparison study. Scores on the Intensity and Perception subscales were greater for the case dose than for the maximum dose of cannabis, psilocybin, or salvinorin A. Scores on the Somaesthesia subscale were greater for the case dose than for the maximum dose of DXM, salvinorin A, or cannabis. Scores on the Affect and Cognition subscales for the case dose were significantly lower than for the maximum doses of psilocybin and DXM.Conclusion: Acute cannabis exposure in a healthy adult male resulted in self-reported hallucinations that rated high in magnitude on several subscales of the HRS. However, the hallucinatory experience in this case was qualitatively different than that typically experienced by participants receiving classic and atypical hallucinogens, suggesting that the hallucinatory effects of cannabis may have a unique pharmacological mechanism of action. This type of adverse event needs to be considered in the clinical use of cannabis.

Effectiveness and cost of recruiting healthy volunteers for clinical research studies using an electronic patient portal: A randomized study.

It is not clear how to effectively recruit healthy research volunteers. We developed an electronic health record (EHR)-based algorithm to identify healthy subjects, who were randomly assigned to receive an invitation to join a research registry via the EHR's patient portal, letters, or phone calls. A follow-up survey assessed contact preferences. The EHR algorithm accurately identified 858 healthy subjects. Recruitment rates were low, but occurred more quickly via the EHR patient portal than letters or phone calls (2.7 vs. 19.3 or 10.4 d). Effort and costs per enrolled subject were lower for the EHR patient portal (3.0 vs. 17.3 or 13.6 h, $113 vs. $559 or $435). Most healthy subjects indicated a preference for contact via electronic methods. Healthy subjects can be accurately identified from EHR data, and it is faster and more cost-effective to recruit healthy research volunteers using an EHR patient portal.

Laboratory Safety of Capsaicin Inhalation in Healthy Younger and Older Populations Potential Template for Inhalation Research

Introduction: There are inconsistencies as to the effects of age on the human cough reflex. The investigation speaks to the Federal Drug Agency’s (FDA) trepidations for conducting inhalation experiments with non-approved medications/chemicals. The investigation addresses the accuracy of the mixing methodology and analysis of capsaicin stability during seven months of storage. Methods: There is stringent safety monitoring while conducting 12 serial (0.49-1000 uMol) single breath capsaicin inhalation challenge testing (CICT) on 20 younger and 20 older healthy research volunteers using pharmaceutical-grade capsaicin (i.e., Investigational New Drug protocol-IND 69,642). The research design and subject safety measures are recommended by the Food & Drug Agency (FDA) and approved by the Institutional Review Board (IRB). Mixing of inhaled capsaicin solutions are by a Registered Pharmacist and concentration verifications are by high performance liquid chromatography (HPLC). Potency of stored capsaicin (i.e., refrigerated and shielded from UV light) is examined over 7 months. Results: There are neither adverse reactions nor statistically significant difference in capsaicin cough parameters for older and younger volunteers at any dose of capsaicin. Physiologic monitoring by spirometry, impulse oscillometry, exhaled breath nitric oxide, electrocardiography, blood pressure, pulse and oxygen saturation measurements do not change at any dose. There are differences between the concentrations of capsaicin solutions mixed by a Registered Pharmacist and actual capsaicin determination by HPLC. The differences in capsaicin concentrations are 28.1% lower for 0.49 uMol compared to a 2.2% lesser concentration for 1000 uMol solution. During storage, capsaicin remains stable for 3-months but substantially falls by six (p<0.03) and seven (p<0.004) months, especially for the lower concentrations. Conclusion: The results of this investigation embrace the safety of serial Inhalations of dilute pharmacologic grade capsaicin aerosol among older and younger normal volunteers. Incorporating rigorous FDA recommendations, inclusion of IRB oversight and monitoring by spirometry, impulse oscillometry, exhaled breath nitric oxide, electrocardiography, blood pressure, pulse and oxygen saturation measurements document inhalation safety at any dilute capsaicin aerosol dose. However, there are lower capsaicin values determined by HPLC compared to expected capsaicin concentrations when mixed by a Registered Pharmacist or after six months of storage. The investigation champions the opinion that inhalation studies involving FDA non-approved drugs or chemicals/ medications can be safely conducted when following the appropriate safety procedures such as in this research protocol.

Increase in body mass index from normal weight to overweight in a cross-sectional sample of healthy research volunteers

Current literature provides limited information about healthy volunteers serving as controls for biomedical research. This study describes trends in body mass index (BMI), a ratio of weight to height (kilograms per square meter), of the population of healthy volunteers at the National Institutes of Health Clinical Center (NIH CC) and compares these trends to a nationally representative sample, as reported by the National Health and Nutrition Examination Survey. We hypothesized that BMI trends at the NIH CC would follow those of the US population. This cross-sectional study examined the BMI of healthy volunteers at the NIH CC from 1976 to 1980, 1981 to 1987, 1988 to 1994, 1995 to 1998 and for all subsequent two-year periods onward until 2012. Study data were extracted from the NIH Biomedical Translational Research Information System. Subjects were selected based on a discharge code of “volunteer.” Descriptive statistics of volunteers at the NIH CC were calculated for height, weight, age-adjusted BMI, age, and sex, and associations between categorical variables were analyzed using the χ2 test. Differences between BMI categories or periods for continuous independent variables were assessed using Kruskal-Wallis and post hoc Tamhane T2 tests. The 13 898 healthy volunteers with median age of 34 years were 53% female and primarily non-Hispanic whites. Mean BMI was within the normal category from 1976 to 1987. From 1988 on, mean BMI fluctuated but increased overall. The BMI of healthy volunteers at the NIH CC appears to follow national trends as described by National Health and Nutrition Examination Survey data of increasing body weight during the past three decades followed by a recent plateau.

Credibility and Comprehension of Healthy Volunteers in Lengthy Inpatient Drug Studies

Early clinical trials rely upon paid healthy volunteers. Concern has been raised regarding the characteristics of these individuals, how well they understand their rights and the risks of clinical research, and how they may be influenced by manipulation or coercion. Therefore, we investigated (1) the motivations of subjects in clinical trials, (2) how well these individuals comprehend a consent form they sign, and (3) the effect of the stipend on the reliability of information reported by volunteers in clinical trials. Thirty healthy subjects (age, 21-45 years) in a long-duration clinical trial were administered a questionnaire gathering demographic information and testing their comprehension of the consent form. In a separate chart review of 10 clinical trials, 374 subjects were studied to determine their reliability in reporting abnormalities in their medical history and in reporting adverse events, and an association was examined between the incidence of unreliable reporting and the stipend paid to them for participating in the clinical trial. A large percentage of subjects who were enrolled in the long-duration clinical trial failed to comprehend a variety of basic concepts related to the consent form and their participation in the drug study. The chart review demonstrated that subjects who are paid larger stipends may not be more likely to report abnormalities on their medical history. Further studies should be undertaken with larger numbers of subjects enrolled in clinical trials, and possible associations between demographic data (eg, income, level of education, number of previous studies) and the reliability of information provided by normal healthy research volunteers should be examined.

Effects of Submental Neuromuscular Electrical Stimulation on Pharyngeal Pressure Generation

Heck FM, Doeltgen SH, Huckabee M-L. Effects of submental neuromuscular electrical stimulation on pharyngeal pressure generation. ObjectiveTo investigate the immediate and late effects of submental event-related neuromuscular electrical stimulation (NMES) on pharyngeal pressure generation during noneffortful and effortful saliva swallows. DesignBefore-after trial. SettingSwallowing rehabilitation research laboratory. ParticipantsSex-matched (N=20) healthy research volunteers. InterventionsParticipants received 80Hz NMES of 4-second duration to floor of mouth muscles that was time-locked to 60 volitional saliva swallows. Main Outcome MeasuresManometry measures of peak pressures and duration of pressure events in the oropharynx, hypopharynx, and the upper esophageal sphincter (UES) were derived during execution of noneffortful and effortful saliva swallows. Measures were taken at baseline, during stimulation, and at 5-, 30-, and 60-minutes poststimulation. ResultsBaseline pharyngeal and UES pressures did not differ between stimulated and nonstimulated swallows. At 5- and 30-minutes poststimulation, peak pressure decreased at the hypopharyngeal and at the UES sensor during noneffortful swallows. The effect lasted up to an hour only in the hypopharynx. No changes in duration of pressure events were observed. ConclusionsUsing this treatment paradigm, decreased peak amplitude in the hypopharynx up to an hour after treatment indicates a potential risk of decreased bolus flow associated with NMES. On the other hand, decreased UES relaxation pressure may facilitate bolus transit into the esophagus.

Pharyngeal Pressure Generation During Tongue-Hold Swallows Across Age Groups

To compare the effects of the tongue-hold swallowing maneuver on pharyngeal pressure generation in healthy young and elderly research volunteers. Sixty-eight healthy research volunteers (young, n = 34, mean age = 26.8 years, SD = 5.5; elderly, n = 34, mean age = 72.6 years, SD = 4.8; sex equally represented) performed 5 noneffortful saliva swallows and 5 tongue-hold swallows each. Amplitude and duration of pharyngeal pressure were investigated during both swallowing conditions with solid-state pharyngeal manometry at the level of the oropharynx, hypopharynx, and upper esophageal sphincter (UES). At both pharyngeal levels, tongue-hold swallows produced lower peak pressure compared with saliva swallows. During tongue-hold swallows, UES relaxation pressure was increased in the elders, whereas the younger group displayed a trend toward reduced relaxation pressure. Elderly individuals produced pressure longer during control swallows in the oropharynx and hypopharynx than young individuals. The tongue-hold maneuver affects oropharyngeal and hypopharyngeal pressure in the young and elders in similar ways, whereas effects on UES peak relaxation pressure differ between age groups. Reduced pharyngeal peak pressure and increased UES relaxation pressure underscore the notion that tongue-hold swallows should not be performed when bolus is present. Long-term training effects remain to be investigated.

Overview of the Epidemiology Methods and Applications: Strengths and Limitations of Observational Study Designs

Overview of the Epidemiology Methods and Applications: Strengths and Limitations of Observational Study Designs

Association between Severity of Cannabis Dependence and Depression

Objective. The aim of the current study was to investigate the relationship between self-reported severity of cannabis dependence and symptoms of depression. Method. The lifetime diagnoses of depression and cannabis misuse (abuse and/or dependence) were obtained from 50 participants recruited from the general community, using a self-completed diagnostic interview (CIDI-Auto 2.1). The lifetime severity of cannabis dependence was established using a standard questionnaire, Severity of Dependence Scale (SDS). Results. Of the 19 participants with mental illness diagnoses, 14 (74%) reported depression symptoms. The 14 participants with depression diagnoses had significantly more cannabis misuse diagnoses and significantly higher SDS scores compared to those without mental illness diagnoses (N = 31). SDS scores significantly predicted presence or absence of CIDI depression diagnoses with a 69% overall rate of cor-rect predictions. As SDS scores increased the odds of classification into depressed versus non-depressed groups was 1.3 (95% C.I. 1.02-1.57). Conclusion. The presence of lifetime depression symptoms is associated with higher lifetime severity of cannabis dependence and more lifetime cannabis misuse symptoms in otherwise healthy research vol-unteers.

Alveolar Macrophage Dysregulation in Hermansky-Pudlak Syndrome Type 1

Individuals with Hermansky-Pudlak syndrome type 1 (HPS-1), an autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, develop an accelerated form of progressive fibrotic lung disease. The etiology of pulmonary fibrosis associated with HPS-1 is unknown. To investigate the potential pathogenesis of pulmonary fibrosis in HPS-1, lung cells and proteins from individuals with HPS-1 were studied. Forty-one subjects with HPS-1 with and without pulmonary fibrosis were evaluated with pulmonary function tests, high-resolution computed tomography scan, and bronchoscopy. Bronchoalveolar lavage cells and analytes were analyzed. Concentrations of total bronchoalveolar lavage cells and alveolar macrophages were significantly higher in epithelial lining fluid from subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers. Concentrations of cytokines and chemokines (i.e., monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and granulocyte-macrophage colony-stimulating factor) in alveolar epithelial lining fluid were significantly higher in subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers (P < 0.001). In vitro, HPS-1 pulmonary fibrosis alveolar macrophages, which did not express HPS1 mRNA, secreted significantly higher concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and regulated upon activation, normal T cell expressed and secreted (RANTES) protein compared with normal cells (P = 0.001, P = 0.014, and P = 0.011, respectively). Pirfenidone suppressed HPS-1 alveolar macrophage cytokine and chemokine secretion in vitro in a dose-dependent manner. In HPS-1, alveolar inflammation predominantly involves macrophages and is associated with high lung concentrations of cytokines and chemokines. HPS-1 alveolar macrophages provide a model system in which to study the pathogenesis and treatment of HPS pulmonary fibrosis.

Incidence and Predictors of Screen Failures Due to Positive Urine Tests for Alcohol, Drugs of Abuse, and Cotinine Among Normal Healthy Research Volunteers (NHRVs): Analysis of Data From 687 NHRVs Screened at a Large Clinical Pharmacology Unit in the United States

Accurate medical histories for all NHRVs screening to participate in clinical pharmacology trials are vital to ensure volunteers' safety, and integrity of study results. Evidence from previous studies illustrate the potential for NHRVs to misrepresent their histories, especially when monetary incentives are offered, and the need to objectively verify these self-reported histories whenever practical. This study demonstrates that among the sample participants, all of whom self-reported a negative history of drug and alcohol abuse and tobacco smoking, 16% failed urine testing for either alcohol and drugs of abuse (6%), or cotinine (11%). Male sex and increased number of screenings in the preceding 12 months were significantly associated with increased odds for urine screen failure whereas increased enrollments in the same time period and increased study stipend decreased the same odds. These results emphasize the importance of diligently screening NHRVs participating in phase I clinical trails.

First-in-Man (FIM) Clinical Trials Post-TeGenero: A Review of the Impact of the TeGenero Trial on the Design, Conduct, and Ethics of FIM Trials

A recent first time in man (FIM) trial of an "immuno modulator" compound (TGN1412) resulted in unprecedented toxicity. Since this occurred in 2006 a widely publicized scientific debate, as well as a controversy in the lay community has examined the principle of design and content of the study as well as the concept of FIM studies. This paper reviews the controversy, analyzes the problems of the TGN1412 trial and FIM trials in general and the reaction of the lay and scientific communities. Difficulties in these high risk trials is highlighted and possible design and execution procedural improvements are recommended. Consideration is given to the ethical debate regarding participation of normal, healthy research volunteers in FIM studies. The role of monetary incentive(s) is discussed as well as the opposition of many participants in this debate on financial compensation of volunteers for the assumption of risk and the need to adopt a no-fault scheme that fairly compensates injured trial participants.FIM studies are critical for the development of new therapeutic agents. Improving trial design and execution and fairly compensating volunteers will facilitate these studies, enhance equity and thus provide an ethical basis for continuing FIM studies that may pose a serious risk to participants, a risk that society needs taken for the development of needed therapeutic agents.

11C]NNC 112 Selectivity for Dopamine D1 and Serotonin 5-HT2A Receptors: A PET Study in Healthy Human Subjects

The dopamine D(1) receptor antagonist radioligand [(11)C]NNC 112 has previously been reported to have 100-fold selectivity for the D(1) receptor compared with the serotonin 5-HT(2A) receptor. In this study, we tested the selectivity by scanning seven healthy human research volunteers with [(11)C]NNC 112 before and after 2 mg of the antipsychotic drug risperidone, a dose that putatively blocks all 5-HT(2A) receptors with negligible effect on D(1) receptors. We found that specific binding in cortical regions was reduced by 20% to 30%, whereas the striatum showed no change. Based on the known relative densities of these receptors in humans, our results suggest 5- to 10-fold selectivity of [(11)C]NNC 112 for D(1) versus 5-HT(2A) as opposed to 100-fold selectivity. These results suggest caution in interpreting data from studies using this tracer to measure cortical D(1) receptors as well as the need for more selective radioligands to assess cortical D(1) receptors.

Are normal healthy research volunteers psychologically healthy? A pilot investigation.

Most new drug development in Phase I clinical trials relies on the use of "normal healthy research volunteers" (NHRVs); however, little is known about the personality functioning of these volunteers. Determining whether NHRVs are similar to or different from individuals with "normal" personalities can impact participant recruitment, group assignment, and statistical interpretation of study results. This pilot study was undertaken to gain insight into the demographics, personality functioning, and potential psychopathology of the volunteers who participated in a Phase I confinement clinical drug trial. NHRVs (N=28) in an all-male, Phase I clinical trial completed a battery of questions, including the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and a sociodemographic questionnaire. Fifty percent of the sample showed clinically significant elevations on at least one of the scales. Current findings need to be replicated and expanded through future research. Results must be interpreted with caution because of the small, all-male sample. This preliminary study suggests that there is a difference in personality functioning between NHRVs and the general population. In addition, NHRVs may purposefully distort or conceal self-report information when participating in studies.

The Conduct of Clinical Research Under the HIPAA Privacy Rule

This article is the report of a work group of the American Academy of Orthopaedic Surgeons Council on Research, Quality Assessment, and Technology. The task assigned to the group by the Chair, Joshua Jacobs, MD, was to review, codify, and disseminate information for the Fellowship on the compliance requirements for conducting clinical research under the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule. The ethical conduct of clinical practice has an established precedent extending to ancient times and the beginnings of the healing professions, encoded in the Code of Hammurabi and the Hippocratic oath. These guides were intended to regulate the conduct and ethics of the purveyors of medical treatment in the ancient world. They also prescribed boundaries of behavior and penalties for transgressions, including corporal punishment. Comparatively, medical research does not have such a history and was largely without published standards of conduct until the twentieth century. The Nazi physician trials in 1946 exposed atrocities committed under the guise of experimental human medical research, which resulted in the 1947 Nuremberg Code for human research1. Included in the ten precedents that it established were the important requirements that subject participation be informed and voluntary and that human research must be scientifically valid and conducted solely for the benefit of society as a whole. The Nuremberg Code was accepted by the fifty-one signatory nations of the Charter of the United Nations. In 1953, the Clinical Center of the United States National Institutes of Health produced the first federal policy to protect human research subjects. The years after World War II saw an increase in scientific technology applied to medical treatment protocols. The new policy was consistent with the Nuremberg Code and gave special emphasis to the protection of healthy adult research volunteers. This policy established the beginning of …

Fair payment or undue inducement?

Women who donate their eggs for stem-cell research should be compensated in the same way as other healthy research volunteers, argues Insoo Hyun.