Office For Human Research Protections Research Articles

Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations.

Prenatal Dexamethasone for Congenital Adrenal Hyperplasia: An Ethics Canary in the Modern Medical Mine.

Following extensive examination of published and unpublished materials, we provide a history of the use of dexamethasone in pregnant women at risk of carrying a female fetus affected by congenital adrenal hyperplasia (CAH). This intervention has been aimed at preventing development of ambiguous genitalia, the urogenital sinus, tomboyism, and lesbianism. We map out ethical problems in this history, including: misleading promotion to physicians and CAH-affected families; de facto experimentation without the necessary protections of approved research; troubling parallels to the history of prenatal use of diethylstilbestrol (DES); and the use of medicine and public monies to attempt prevention of benign behavioral sex variations. Critical attention is directed at recent investigations by the U.S. Food and Drug Administration (FDA) and Office of Human Research Protections (OHRP); we argue that the weak and unsupported conclusions of these investigations indicate major gaps in the systems meant to protect subjects of high-risk medical research.

Inhibition of nuclear factor kappa B activation in early stage chronic lymphocytic leukemia by omega 3 fatty acids

Targeting the NFκB pathway has been proposed for therapy of various malignancies including chronic lymphocytic leukemia (CLL). Omega 3 (n‐3) fatty acids consumption reduced NFκB activation in animals. Our pilot study tested the hypothesis that consumption of an n‐3 supplement would suppress NFκB activation in lymphocytes of patients with early stage CLL. The Marshall University Institutional Review Board reviewed and approved the protocol for this study under a Federal Wide Assurance (FWA #00002704) with the Office of Human Research Protections. Following informed consent, participants consumed an n‐3 supplement initially containing 2.4 g n‐3/day gradually increasing to 7.2 g n‐3/day. Blood cell counts and assay for NFκB activation of lymphocytes were performed before n‐3 initiation and monthly afterwards. Lymphocytes from 5 healthy individuals established normal NFκB activation. After n‐3 consumption: (1) n‐3 was increased in both red and white blood cells of all participants; (2) NFκB activation was suppressed in lymphocytes of all patients following consumption of n‐3; (3) expression of 32 genes in lymphocytes was significantly decreased by n‐3 in patients with higher initial NFκB activation. There was no disease progression. Omega 3 consumption suppressed NFκB activation in patients’ lymphocytes and would be expected to slow progression of early stage CLL.Grant Funding Source : Institutional Funds

A randomized trial to assess the effect of a research informational pamphlet on telephone survey completion rates among older Latinos

Purpose of the studyTo assess the effects of receiving a research informational pamphlet produced by the federal Office for Human Research Protections on telephone survey participation rates of older Latinos, and illustrate the feasibility of nesting recruitment studies within other funded studies when stand alone funding for recruitment studies is limited. Design and methodsLatino patients aged ≥50 with ≥1 visit during the preceding year (N=1314) were sampled from three community clinics and a multi-specialty medical group. Patients were randomly assigned to receive or not receive a pamphlet that contained information on research participation in the initial mailing for the telephone survey study. Survey participation rates were compared between the pamphlet and no pamphlet groups. ResultsIn a multivariate model, women (OR=1.4; 95% CI 1.1, 1.8), and those with public insurance (vs. no insurance; OR=1.7; 95% CI 1.1, 2.5) were more likely to participate, while those age 65+ (vs. age 50–54; OR=0.6; 95% CI 0.4, 0.8) were less likely to participate; there was no significant difference by pamphlet group (OR=0.8; 95% CI 0.7, 1.1). Nesting of the randomized trial of the recruitment pamphlet within the funded study required minimal additional resources. ImplicationsRecruitment methods that are more intensive than a pamphlet may be needed to enhance survey participation rates among older Latinos. Nesting recruitment trials within funded studies is a promising and efficient approach for testing recruitment strategies.

The Python's Embrace: Clinical Research Regulation by Institutional Review Boards

Subject consent and its waiver are critical topics in contemporary research. Institutional review boards (IRBs), acting under the wary eye of the Office for Human Research Protections (OHRP), typically may waive consent when research involves no more than minimal risk, waiver would not harm the subjects, and the research would be impracticable without the waiver.1 IRBs constrict research when they cautiously interpret “impracticable” to mean “impossible” and insist on consent. And, in an ironic twist, IRBs can thus injure the vulnerable groups they imagine they are protecting. A disturbing pair of articles by Rich and his colleagues, one from 20102 and the second in this issue of Pediatrics ,3 demonstrate how this works. SUPPORT, the parent study, investigated the impact of different respiratory care regimens on lung disease, retinopathy, and survival in premature infants born between 24 and 27 weeks’ gestational age.4,5 Eighteen IRBs reviewed the protocol; all required that consent be obtained, even though these interventions are routinely provided without specific consent in everyday practice. This study reveals 3 of the resultant costs. The first cost is time and money. Obtaining consent drained $200 000 from the project, and if 75% of the eligible but not enrolled infants had been included, recruitment would … Address correspondence to Simon N. Whitney, MD, JD, Department of Family and Community Medicine, Baylor College of Medicine, 3701 Kirby Dr, Suite 600, Houston, TX 77098. E-mail: swhitney{at}bcm.edu

Expression of concern

Cancer is publishing an Editorial Expression of Concern regarding the following articles: “Early Lung Cancer Action Project: Overall Design and Findings From Baseline Screening” by Claudia I. Henschke (Cancer. 2000;89(suppl 11):2474-2482). “Early Lung Cancer Action Project: Initial Findings on Repeat Screenings” by Claudia I. Henschke, David P. Naidich, David F. Yankelevitz, Georgeann McGuinness, Dorothy I. McCauley, James P. Smith, Daniel Libby, Mark Pasmantier, Madeline Vazquez, June Koizumi, Douglas Flieder, Nasser Altorki, and Olli S. Miettinen (Cancer. 2001;92:153-159). This Expression of Concern is based on an April 29, 2011, article in The New York Times as well as the April 29, 2011, issue of The Cancer Letter, both of which disclosed details of a report of an Independent Scientific Review Committee (Review Committee) convened by Weill Cornell Medical College to investigate the scientific research conducted as part of the International Early Lung Cancer Action Program (I-ELCAP). The Review Committee reported, among other things, that the I-ELCAP lacked positive confirmation of valid informed consent for all subjects at all sites by the coordinating center. The information contained in the Review Committee's report raises issues that cannot be fully investigated by the journal. We have therefore referred this matter to the Department of Health and Human Services Office for Human Research Protections. Based on the information we have received thus far, we are issuing this Expression of Concern to alert our readers. In addition, we would like to point readers to the Publisher's Note published in Cancer online on April 11, 2008 (available at: http://onlinelibrary.wiley.com/doi/10.1002/cncr.23540/pdf), which included additional disclosures made by Dr. Henschke that directly relate to these articles.

Overcoming burdens in the regulation of clinical research in children. Proceedings of a consensus conference, in historical context.

BackgroundMany investigators are concerned that the modes of implementation and enforcement of the federal regulations designed to protect children are unduly impeding pediatric clinical research.ObjectiveTo assess regulatory impediments to clinical research involving children and to develop recommendations to ameliorate them.ParticipantsThe Pediatric Endocrine Society and The Endocrine Society convened a consensus conference involving experts and stakeholders in patient-oriented research involving children and adolescents in 2008.Consensus processFollowing presentations that reviewed problematic issues around key regulations, participants divided into working groups to develop potential solutions that could be adopted at local and federal levels. Presentations to the full assembly were then debated. A writing committee then drafted a summary of the discussions and main conclusions, placing them in historical context, and submitted it to all participants for comment with the aim of developing consensus.ConclusionsRecommendations designed to facilitate the ethical conduct of research involving children addressed the interpretation of ambiguous regulatory terms such as "minimal risk" and "condition" and called for the development by professional societies of best practice primers for common research procedures that would be informative to both investigators and institutional review boards. A call was issued for improved guidance from the Office for Human Research Protections and Food and Drug Administration as well as for the development by professional societies of a process to monitor progress in improving human subject research regulation. Finally, a need for systematic research to define the nature and extent of institutional obstacles to pediatric research was recognized.

Ethics in practice: the state of the debate on promoting the social value of global health research in resource poor settings particularly Africa.

BackgroundPromoting the social value of global health research undertaken in resource poor settings has become a key concern in global research ethics. The consideration for benefit sharing, which concerns the elucidation of what if anything, is owed to participants, their communities and host nations that take part in such research, and the obligations of researchers involved, is one of the main strategies used for promoting social value of research. In the last decade however, there has been intense debate within academic bioethics literature seeking to define the benefits, the beneficiaries, and the scope of obligations for providing these benefits. Although this debate may be indicative of willingness at the international level to engage with the responsibilities of researchers involved in global health research, it remains unclear which forms of benefits or beneficiaries should be considered. International and local research ethics guidelines are reviewed here to delineate the guidance they provide.MethodsWe reviewed documents selected from the international compilation of research ethics guidelines by the Office for Human Research Protections under the US Department of Health and Human Services.ResultsAccess to interventions being researched, the provision of unavailable health care, capacity building for individuals and institutions, support to health care systems and access to medical and public health interventions proven effective, are the commonly recommended forms of benefits. The beneficiaries are volunteers, disease or illness affected communities and the population in general. Interestingly however, there is a divide between "global opinion" and the views of particular countries within resource poor settings as made explicit by differences in emphasis regarding the potential benefits and the beneficiaries.ConclusionAlthough in theory benefit sharing is widely accepted as one of the means for promoting the social value of international collaborative health research, there is less agreement amongst major guidelines on the specific responsibilities of researchers over what is ethical in promoting the social value of research. Lack of consensus might have practical implications for efforts aimed at enhancing the social value of global health research undertaken in resource poor settings. Further developments in global research ethics require more reflection, paying attention to the practical realities of implementing the ethical principles in real world context.

Pediatric Drug-Trial Recruitment: An Institutional Review Board Perspective

I thank Tishler and Reiss1 for their thoughtful article in the May 2011 issue of Pediatrics . I agree that further guidance from regulatory authorities (eg, the US Food and Drug Administration or Office for Human Research Protections) would be useful in regards to the issue of incentives for study participation, because there is significant variation from study to study and even among clinical …

Barriers to conducting clinical research in reproductive medicine: United States of America

A decrease in National Institute of Health funding and an increase regulations are significant barriers in conducting research in the United States of America.

Change in Temperature Profile May Precede Fever and be an Early Indicator of Sepsis

Change in Temperature Profile May Precede Fever and be an Early Indicator of Sepsis

Variation in Local Institutional Review Board Evaluations of a Multicenter Patient Safety Study

Several highly visible quality improvement (QI) projects led to controversy over their ethical oversight, attracting attention from institutional review boards (IRBs) and the Office for Human Research Protection. While QI research has increased dramatically, there is limited empirical evidence regarding how multiple IRBs review the same study. This paper describes the variations in local IRB reviews for the same a multicenter QI study. The study, entitled "Locating Errors through Networked Surveillance", used multiple data collection methods to identify patient safety risks in cardiovascular operating room services. This study involved 2-day site visits to 5 hospitals by the research team to observe cardiac surgery procedures and interview staff regarding clinical practice and hazards. Surveys were self-administered. The IRB process varied widely across the 5 hospitals. Reviews ranged from full committee review and approval with verbal consent required from patients and operating room staff, to an IRB determining the study exempt from review and participant consent. The time to IRB approval ranged from 6 weeks to 6 months. This variation suggests there is wide interpretation of the Federal regulations put in place to guide IRBs. The adoption of uniformity would not only reduce inefficiencies but also attenuate the perceived arbitrary nature of current IRB review processes that often inappropriately influence hypothesis-generation and study design.

International human subject research: Taking stock in the wake of the Guatemala affair

The recent unearthing of a US-funded study wherein unknowing Guatemalans were exposed to syphilis, gonorrhea, or chancroid sent shock waves throughout the scientific community. Prompted by this revelation, the Presidential Commission for the Study of Bioethical Issues has been convened to determine if current “standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government.” This communication revisits the statutory and regulatory framework undergirding federally sponsored human subject research and explores its continued relevance in a rapidly globalizing enterprise. The emerging patterns are daunting and disconcerting. Over half of all clinical trials registered with ClinicalTrials.gov ( http://clinicaltrials.gov/) (> 100,000) are presently conducted in 145 (often poorly resourced) nations under the jurisdiction of over 2000 international IRBs. Review of the operational characteristics of the Office of Human Research Protection, the relevant oversight authority, reveals it to be underfunded and understaffed and thus unable to discharge its rapidly globalizing responsibilities. A review of federally sponsored human subject research by the Presidential Commission—now underway—could not be timelier.

Education Research and Human Subject Protection: Crossing the IRB Quagmire

Stamina and mental fortitude are necessary attributes for the present-day researcher seeking approval from his institution’s human subjects protection review board (IRB). Both popular media and respected journals continue to report extremely rare but serious harms to research subjects as well as overly bureaucratic IRB responses. This leads to a pervasive perception of IRB overregulation yet underprotection of human subjects. Although the Office for Human Research Protections (OHRP) reports that 70% of allegations of research misconduct are ultimately not substantiated, the risk of suspension or disruption of research during an investigation, in addition to the possibility of damaging reputations and future funding, creates a national climate of anxiety among researchers and ensures continuation of excessive scrutiny of research processes. In fact, deficiencies detected by OHRP are primarily failures of documentation or failure to follow required procedures, not claims of harm to persons or unethical conduct. However, a recent article by members of the National Institutes of Health and OHRP emphasizes that current regulations do permit significant streamlining of ethical review. Options including exemption or expedited review are underutilized: in the past, 25%–77% of United States IRBs were found to review more rigorously than regulations required. These streamlined processes are particularly relevant to medical education research.

Protection of human participants in health research - a comparison of some US Federal Regulations and South African Research Ethics guidelines

In response to criticism of ethical review of a South African clinical trial, we contrast aspects of the United States Common Rule with South African research ethics requirements. In the USA the Common Rule does not apply to all health research and allows many exemptions from ethics review and waivers of informed consent. At a structural level research ethics review in South Africa is in many cases equivalent to the US institutional review board (IRB) and Office for Human Research Protections (OHRP) oversight system, is wider reaching, and has no exclusions.

A Case Study in Unethical Transgressive Bioethics: “Letter of Concern from Bioethicists” About the Prenatal Administration of Dexamethasone

On February 3, 2010, a “Letter of Concern from Bioethicists,” organized by fetaldex.org, was sent to report suspected violations of the ethics of human subjects research in the off-label use of dexamethasone during pregnancy by Dr. Maria New. Copies of this letter were submitted to the FDA Office of Pediatric Therapeutics, the Department of Health and Human Services (DHHS) Office for Human Research Protections, and three universities where Dr. New has held or holds appointments. We provide a critical appraisal of the Letter of Concern and show that it makes false claims, misrepresents scientific publications and websites, fails to meet standards of evidence-based reasoning, makes undocumented claims, treats as settled matters what are, instead, ongoing controversies, offers “mere opinion” as a substitute for argument, and makes contradictory claims. The Letter of Concern is a case study in unethical transgressive bioethics. We call on fetaldex.org to withdraw the letter and for co-signatories to withdraw their approval of it.

Regulatory impediments jeopardizing the conduct of clinical trials in Europe funded by the National Institutes of Health

A number of reports have highlighted problems of conducting publicly funded trials in Europe as a consequence of the European Union (EU) Clinical Trials Directive. The impact of the EU Directive on multi-national trials, which include sites in Europe that are funded by the US National Institutes of Health (NIH) have not been described. Four problems in the conduct of two international HIV treatment trials funded by NIH in the EU are described: (1) conflicting regulations on the continuing review of protocols by Institutional Review Boards/Research Ethics Committees; (2) US regulations requiring Federalwide Assurances for sites which are only partially funded by NIH; (3) EU guidance on the designation of studies as a trial of an investigational medicinal product; and (4) EU guidance on trial sponsorship and the requirements for insurance and indemnification. Following the description of the problems, recommendations for improving global collaborations are made to the US Office of Human Research Protections, to NIH, and to the EU and its Member States. A lack of harmonization of regulations at multiple levels caused enrollment in one study to be interrupted for several months and delayed for one year the initiation of another study aimed at obtaining definitive evidence to guide the timing of the initiation of antiretroviral therapy for individuals infected with HIV. The delays and the purchase of insurance resulted in substantial increases in trial costs and caused substantial disruption at clinical sites among staff and study participants. The problems cited and recommendations made pertain to trials funded by NIH and conducted by sites in the EU. There are many other challenges in the conduct of international research, public and private, that global harmonization would alleviate. Disharmony, at multiple levels, in international regulations and guidelines is stifling publicly funded global research. International scientific organizations and government groups should make the documentation and solution of these problems a priority.

Is it research?

A hospital's stroke care team believes that for patients with acute cerebral ischemia, a CT angiogram with a perfusion study, rather than simply a routine CT scan, will better direct clinical care. The team will collect data prospectively in a database to document the effect of this new practice. A hospital implements a new program and collects process and outcome data to monitor and improve performance on stroke-related care, including timely receipt of thrombolytic therapy, dysphagia screens for all patients, and deep venous thrombosisprophylaxis for at-risk patients. Are these activities research? This is an increasingly common question, arising most frequently in 2 contexts. In quality improvement (QI) circles, there is considerable concern that the current regulatory definition of research used by institutional review boards (IRBs) may be too sensitive, creating unnecessary burdens on important QI activities.1 In the surgical or procedural setting, in which the history of improvements has followed the path of “surgical innovations” rather than systematic research, there is increasing discussion about the appropriate level of oversight of such activities.2,3 Given the increasing emphasis on evidence-based medicine and the public pressure to improve the quality of health care, the question “Is it research?” will become even more common. The current US regulations define research as a “systematic investigation … designed to develop or contribute to generalizable knowledge” (45CFR46.102d). Since a well-organized QI project involves a systematic change and measurement (of the process or outcome), the question becomes whether it is also “designed” or intended to contribute to generalizable knowledge. The Office of Human Research Protections (OHRP) guidance document (which does not have …

Richard (Dick) Gregory Lynch, M.D., 1934–2009

Richard (Dick) Gregory Lynch, M.D., 1934–2009

Unethical Research and the C.I.A. Inspector General Report of 2004: Observations Implicit in Terms of the Common Rule

Declassification of documents has given rise to the allegation that the Central Intelligence Agency may have conducted unethical research targeting detainee subjects. That allegation is examined using document analysis and the development of research goals and roles as defined in the Common Rule. This article sets aside issues as to whether enhanced interrogation techniques described in the declassified documents rise to legal definitions of torture. Instead, it presents a post hoc ethics review raising questions addressed by Institutional Review Boards recommending the filing of a for-cause noncompliance complaint with the Office for Human Research Protection against the Central Intelligence Agency.