Improving recommendations for genomic medicine: building an evolutionary process from clinical practice advisory documents to guidelines.

Genomic sequencing and multigene panel tests are moving rapidly into clinical practice for a range of indications, but the evidence to guide appropriate use is currently limited. Well-crafted advice is needed to reduce unjustified practice variation, minimize risk of error and harm to patients, and encourage best practices. In the absence of definitive evidence, provisional advice can be helpful if it clarifies the potential benefits and risks of different courses of action and identifies the knowledge gaps most important to address in future research. This paper proposes an evolutionary process starting with clinical practice advisory documents (CPADs) and culminating in clinical practice guidelines (CPGs), using two case examples to illustrate the need for this process. When evidence is limited, CPADs can clarify current practice options and identify key knowledge gaps. Added evidence can then support updates to the CPADs over time. Ultimately CPADs can provide the foundation for definitive CPGs as the evidence base matures. This approach addresses an important challenge in genomics and may be applicable to other fields in which technology and practice are outpacing evidence generation.

Synthetic Biology in the FDA Realm: Toward Productive Oversight Assessment.

Synthetic biology (SB) is expected to create tremendous opportunities in a wide range of areas, including in foods, therapeutics, and diagnostics subject to regulatory oversight by the United States Food and Drug Administration. At the same time, there is substantial basis for concern about the uncertainties of accurately assessing the human health and environmental risks of such SB products. As such, SB is the latest in a string of emerging technologies that is the subject of calls for new approaches to regulation and oversight that involve "thinking ahead" to anticipate governance challenges upstream of technological development and adopting oversight mechanisms that are both adaptive to new information about risks and reflexive to performance data and feedback on policy outcomes over time. These new approaches constitute a marked departure from the status quo, and their development and implementation will require considerable time, resources, and reallocation of responsibilities. Furthermore, in order to develop an appropriate oversight response, adaptive or otherwise, there is first a need to identify the specific types and natures of applications, uncertainties, and regulatory issues that are likely to pose oversight challenges. This article presents our vision for a Productive Oversight Assessment (POA) approach in which the abilities and deficits of an oversight system are evaluated with the aim of enabling productive decisions (i.e., timely, feasible, effective for achieving desired policy outcomes) about oversight while also building capacity to facilitate broader governance efforts. The value ofPOA is two-fold. First, it will advance the development of a generalizable approach for making productive planning and decision-making about the oversight of any given new technology that presents challenges and uncertainties for any given oversight system whose policy goals are implicated by that technology. Second, this effort can enhance the very processes advocated under anticipatory and adaptive approaches by laying the groundwork for and providing valuable data to support future normative deliberations about the governance of emerging technologies.

Blood product recalls in the United States.

BACKGROUND: The blood recall process is intended to remove from use products that may be harmful, but characteristics of recalls nationally have not been reported. STUDY DESIGN AND METHODS: We analyzed recalls of all blood products for 2010 and categorized the reason for the recall, the organizations producing the recalled products, and the Food and Drug Administration (FDA) district in which the blood was collected. RESULTS: During 2010, there were 2468 recalls involving 8278 blood products. None of the recalls was considered to have a reasonable probability of causing serious adverse health consequences or death (FDA Class I). The most common reasons for recalls were donation and donor qualification (73%) and finished product quality control (14%). The FDA class of recalls varied by recall reason, month of the year, FDA district, number of units of blood collected per FDA district, and number of units of blood collected by the blood center. The number of recalls per 100,000 units of blood and the reason for recall varied by FDA district and blood centers collecting smaller numbers of units had more recalls. CONCLUSION: The absence of Class I recalls suggests a high level of quality and safety in the US blood supply. Organizations that collected larger numbers of units of blood had fewer recalls and there may be some FDA influences since the number and reason for the recalls varied by FDA district.

The human right to water: the importance of domestic and productive water rights.

The United Nations (UN) Universal Declaration of Human Rights engenders important state commitments to respect, fulfill, and protect a broad range of socio-economic rights. In 2010, a milestone was reached when the UN General Assembly recognized the human right to safe and clean drinking water and sanitation. However, water plays an important role in realizing other human rights such as the right to food and livelihoods, and in realizing the Convention on the Elimination of All Forms of Discrimination against Women. These broader water-related rights have been recognized but have not yet been operationalized. This paper unravels these broader water-related rights in a more holistic interpretation of existing international human rights law. By focusing on an emerging approach to water services provision--known as 'domestic-plus' services--the paper argues how this approach operationalizes a comprehensive range of socio-economic rights in rural and peri-urban areas. Domestic-plus services provide water for domestic and productive uses around homesteads, which challenges the widespread practice in the public sector of planning and designing water infrastructure for a single-use. Evidence is presented to show that people in rural communities are already using their water supplies planned for domestic uses to support a wide range of productive activities. Domestic-plus services recognize and plan for these multiple-uses, while respecting the priority for clean and safe drinking water. The paper concludes that domestic-plus services operationalize the obligation to progressively fulfill a comprehensive range of indivisible socio-economic rights in rural and peri-urban areas.

Systematic investigation of inadequate food access at a large southeastern land grant university.

Over the past decade, the impact of low food security on student well-being and academic performance has become a growing concern at institutions of higher education across the U.S. This mixed methods study adds to the growing body of evidence on the association between student socio-demographic and economic characteristics and food security. An online survey covering food access, student well-being, and housing security was sent to 35,337 undergraduate and graduate students at a large southeastern land grant university. A total of 2,116 complete responses were received; a 6% response rate. The survey responses also included 176 written statements by students. The survey found that 16% of both undergraduate and graduate students had low or very low food security, as defined by a modified USDA food security measure. The socio-demographic and economic characteristics that were linked to a higher likelihood of low food security included: having a GPA of less than 3.0, having a disability, being an international student, being a first-generation student, being a transfer student, going into debt to pay for food, being a Black or African American student, having poor mental health, having uncertain living arrangements, and having no medical insurance. Recommendations for enhancing student access to food, housing, and mental health services are discussed.

Managing incidental findings and research results in genomic research involving biobanks and archived data sets.

Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using "biobank" here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.

Comparison of chronic biphasic pacing versus cathodal pacing of the right ventricle on left ventricular function in sheep after myocardial infarction.

BACKGROUND: The physiological effects of biphasic pacing have not been studied in compromised hearts. METHODS: Myocardial infarction was induced in 12 sheep by high coronary artery ligation. Perioperative mortality was 33%. The surviving eight animals exhibited increased left ventricular volume and reduced percent fractional shortening. Two weeks after the infarction, sheep were implanted with atrial-triggered, right ventricular pacemaker systems capable of pacing with cathodal (cathodal pulse) and biphasic (anodal pulse followed by cathodal pulse) waveforms, and randomly assigned to an initial mode. At 3-month intervals, or whenever pacing was lost for any reason, the pacing system was switched to the alternative mode. Cardiac function was assessed at 2- to 3-week intervals through the use of echocardiograms. Successful pacing was confirmed over an average of 8 weeks in each mode. RESULTS: Cathodal pulsing had neither beneficial nor deleterious effect on the diminished cardiac performance induced by myocardial infarction. When compared to the cathodal mode, biphasic pulsing improved cardiac performance as reflected by decrease of diastolic and systolic ventricular volumes, reduction in left ventricular systolic diameter, and increases in percent fractional shortening. When compared to the unpaced state after the myocardial infarction, the percent fractional shortening was significantly increased by biphasic pacing. Concordant trends in improvement in the other cardiac parameters were also observed for the biphasic mode. No ventricular tachyarrhythmias or mortality was associated with biphasic stimulation. CONCLUSION: When compared to cathodal pacing, myocardial biphasic pacing has no safety issues in sheep that have undergone a large myocardial infarction. Importantly, biphasic pulsing elicited significant benefits in cardiac performance.

How Can Law and Policy Advance Quality in Genomic Analysis and Interpretation for Clinical Care?

Delivering high quality genomics-informed care to patients requires accurate test results whose clinical implications are understood. While other actors, including state agencies, professional organizations, and clinicians, are involved, this article focuses on the extent to which the federal agencies that play the most prominent roles - the Centers for Medicare and Medicaid Services enforcing CLIA and the FDA - effectively ensure that these elements are met and concludes by suggesting possible ways to improve their oversight of genomic testing.

Pit Latrine Fecal Sludge Resistance Using a Dynamic Cone Penetrometer in Low Income Areas in Mzuzu City, Malawi.

Pit latrines can provide improved household sanitation, but without effective and inexpensive emptying options, they are often abandoned once full and may pose a public health threat. Emptying techniques can be difficult, as the sludge contents of each pit latrine are different. The design of effective emptying techniques (e.g., pumps) is limited by a lack of data characterizing typical in situ latrine sludge resistance. This investigation aimed to better understand the community education and technical engineering needs necessary to improve pit latrine management. In low income areas within Mzuzu city, Malawi, 300 pit latrines from three distinct areas were assessed using a dynamic cone penetrometer to quantify fecal sludge strength, and household members were surveyed to determine their knowledge of desludging procedures and practices likely to impact fecal sludge characteristics. The results demonstrate that there is a significant difference in sludge strength between lined and unlined pits within a defined area, though sludge hardened with depth, regardless of the pit type or region. There was only limited association between cone penetration depth and household survey data. To promote the adoption of pit emptying, it is recommended that households be provided with information that supports pit emptying, such as latrine construction designs, local pit emptying options, and cost. This study indicates that the use of a penetrometer test in the field prior to pit latrine emptying may facilitate the selection of appropriate pit emptying technology.

Regulatory and reimbursement innovation.

Coverage with evidence development and parallel review for molecular diagnostics aid regulation and reimbursement.

Recommendations for nanomedicine human subjects research oversight: an evolutionary approach for an emerging field.

The nanomedicine field is fast evolving toward complex, "active," and interactive formulations. Like many emerging technologies, nanomedicine raises questions of how human subjects research (HSR) should be conducted and the adequacy of current oversight, as well as how to integrate concerns over occupational, bystander, and environmental exposures. The history of oversight for HSR investigating emerging technologies is a patchwork quilt without systematic justification of when ordinary oversight for HSR is enough versus when added oversight is warranted. Nanomedicine HSR provides an occasion to think systematically about appropriate oversight, especially early in the evolution of a technology, when hazard and risk information may remain incomplete. This paper presents the consensus recommendations of a multidisciplinary, NIH-funded project group, to ensure a science-based and ethically informed approach to HSR issues in nanomedicine, and to integrate HSR analysis with analysis of occupational, bystander, and environmental concerns. We recommend creating two bodies, an interagency Human Subjects Research in Nanomedicine (HSR/N) Working Group and a Secretary's Advisory Committee on Nanomedicine (SAC/N). HSR/N and SAC/N should perform 3 primary functions: (1) analysis of the attributes and subsets of nanomedicine interventions that raise HSR challenges and current gaps in oversight; (2) providing advice to relevant agencies and institutional bodies on the HSR issues, as well as federal and federal-institutional coordination; and (3) gathering and analyzing information on HSR issues as they emerge in nanomedicine. HSR/N and SAC/N will create a home for HSR analysis and coordination in DHHS (the key agency for relevant HSR oversight), optimize federal and institutional approaches, and allow HSR review to evolve with greater knowledge about nanomedicine interventions and greater clarity about attributes of concern.

Evaluating oversight of human drugs and medical devices: a case study of the FDA and implications for nanobiotechnology.

This article evaluates the oversight of drugs and medical devices by the U.S. Food and Drug Administration (FDA) using an integration of public policy, law, and bioethics approaches and employing multiple assessment criteria, including economic, social, safety, and technological. Criteria assessment and expert elicitation are combined with existing literature, case law, and regulations in an integrative historical case studies approach. We then use our findings as a tool to explore possibilities for effective oversight and regulatory mechanisms for nanobiotechnology. Section I describes oversight mechanisms for human drugs and medical devices and presents current nanotechnology products. Section II describes the results of expert elicitation research. Section III highlights key criteria and relates them to the literature and larger debate. We conclude with broad lessons for the oversight of nanobiotechnology informed by Sections I-III in order to provide useful analysis from multiple disciplines and perspectives to guide discussions regarding appropriate FDA oversight.