External Advisory Committee Research Articles

Strong Evidence from the 2018 Physical Activity Guidelines Advisory Committee

The U.S. Department of Health and Human Services (HHS) charged an external federal advisory committee to review the scientific literature and provide independent recommendations to the government to inform the development of the second edition of the Physical Activity Guidelines for Americans. PURPOSE: To present a selection of conclusions with evidence graded as ‘strong’ from the 2018 Physical Activity Guidelines Advisory Committee (Committee) systematic literature review. METHODS: The Committee asked 38 questions on relationships between physical activity and health outcomes in systematic literature reviews. A grading rubric was used to evaluate the strength of evidence - Strong, Moderate, Limited, or Grade Not Assignable (insufficient evidence). A grade of ‘strong’ indicated that evidence from the literature directly applied to the systematic review question; was free from serious doubts about generalizability; limited the risk of bias; showed consistency in the direction and approximate size of the effect across studies; and provided considerable confidence in the accuracy of the findings. The Committee presented its conclusions during five public meetings. RESULTS: The Committee concluded there was strong evidence that physical activity has a beneficial effect on many health outcomes, including improvements in weight and bone health in children under age six, physical function in older adults, and incidence of seven types of cancer. Examples are provided in Table 1. CONCLUSION: The Committee’s systematic reviews will be compiled into a Scientific Report and submitted to the HHS Secretary. The Department will use the Committee’s evidence-based recommendations, as well as public and federal agency comments, to develop the second edition of the Physical Activity Guidelines for Americans. The Committee’s work firmly grounds the second edition of the Physical Activity Guidelines for Americans in the current science on physical activity and health.Table 1: Selected conclusion statements for ‘strong’ evidence.

Long-Term Research in Ecology and Evolution (LTREE): 2015 survey data.

To systematically assess views on contributions and future activities for long-term research in ecology and evolution (LTREE), we conducted and here provide data responses and associated metadata for a survey of ecological and evolutionary scientists. The survey objectives were to: (1) Identify and prioritize research questions that are important to address through long-term, ecological field experiments; and (2) understand the role that these experiments might play in generating and applying ecological and evolutionary knowledge. The survey was developed adhering to the standards of the American Association for Public Opinion Research. It was administered online using Qualtrics Survey Software. Survey creation was a multi-step process, with questions and format developed and then revised with, for example, input from an external advisory committee comprising senior and junior ecological and evolutionary researchers. The final questionnaire was released to ~100 colleagues to ensure functionality and then fielded 2 d later (January 7th , 2015). Two professional societies distributed it to their membership, including the Ecological Society of America, and it was posted to three list serves. The questionnaire was available through February 8th 2015 and completed by 1,179 respondents. The distribution approach targeted practicing ecologists and evolutionary biologists in the U.S. Quantitative (both ordinal and categorical) closed-ended questions used a predefined set of response categories, facilitating direct comparison across all respondents. Qualitative, open-ended questions, provided respondents the opportunity to develop their own answers. We employed quantitative questions to score views on the extent to which long-term experimental research has contributed to understanding in ecology and evolutionary biology; its role compared to other approaches (e.g., short-term experiments); justifications for and caveats to long-term experiments; and the relative importance of incentives for conducting long-term research. Qualitative questions were used to assess community views on the most important topics and questions for long-term research to address, and primary incentives and challenges to realizing this work. Finally, demographic data were collected to determine if views were conditional on such things as years of experience and field of expertise. The final questionnaire and all responses are provided for unrestricted use.

Developing a Web-Based Geolocated Directory of HIV Pre-Exposure Prophylaxis-Providing Clinics: The PrEP Locator Protocol and Operating Procedures.

BackgroundHuman immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV transmission, yet patients interested in learning more about PrEP or in getting a PrEP prescription may not be able to find local medical providers willing to prescribe PrEP.ObjectiveWe sought to create a national database of PrEP-providing clinics to allow for patients to have access to a unified, vetted source of PrEP providers in an easily accessible database.MethodsTo develop the protocol and operating procedures for the PrEP Locator, we conducted a series of 7 key informant interviews with experts who had organized PrEP or other HIV service directories. We convened an external advisory committee and a collaborators board to gain expert and community-situated perspectives.ResultsAt its public release in September 2016, the database included 1,272 PrEP-providing clinics, including clinics in all 50 states and in Puerto Rico. Web searches, referrals, and outreach to state health departments identified 58 unique lists of PrEP-providing clinics, with 33 from state health departments, 6 from government localities, 2 from professional medical organizations, and 19 from nongovernmental organizations. Out of the 2,420 clinics identified from the lists and Web searches, we removed 798 as duplicate entries, and we determined that 350 were ineligible for listing. The most common reasons for ineligibility were not having the appropriate medical licensure to prescribe PrEP (67/350) or not prescribing PrEP, based on self-report (192/350). Key informant interviews shaped important protocol decisions, such as listing clinics instead of individual clinicians as the primary data element and streamlining data collection to facilitate scalability. We developed a Web interface to provide public access to the data, with geolocated data display, search filter functionality, a webform for public suggestions of new clinics, and a publicly available directory Web tool that can be embedded in websites. In the 6 months following release, preplocator.org and hosting websites had received over 35,000 unique views and 300 clinic additions, and 5 websites had initiated hosting of the widget.ConclusionsDirectories exist for many preventive and treatment services. As new medical applications become available, there will be a corresponding need to develop new directories for service provision. Geolocated directories can assist patients in accessing care and have the potential to increase demand for and access to newer, more efficacious medical interventions. Early choices in the development of service directories have long-lasting impact, because once data collection begins, it can be challenging to reverse course. The PrEP Locator protocol may inform early decisions in the development of future service directories. Additionally, the case study on developing the PrEP Locator demonstrates the importance of formative work in identifying service-specific factors that can guide decisions on directory development.

‘Fit-for-Purpose’ sustainability index: a simplified approach for U.S. water utility sustainability assessment

The theoretical framework presented in this paper proposes a method for determining which practices will inform a set of key indicators provide a ‘snapshot’ sustainability assessment of U.S. urban water utilities. It describes the method used to gather data via two qualitative research approaches to inform a sustainability index: semi-structured interviews with an external advisory committee of 12 U.S. urban water utility leaders, and online surveys of water professionals using the freelisting technique. The utility leader interviews revealed public education and communication as the most frequently cited sustainable practice, followed by asset management, community return on infrastructure investment, financial management, green infrastructure, and resource recovery practices. The water professionals survey revealed resource recovery as the most frequently cited sustainable practice, followed by water conservation, asset management and financial management, and energy efficiency. A consensus did not emerge about what is needed to drive more widespread adoption of sustainability indictors. The most frequently cited barriers to more widespread adoption were the absence of a definition of sustainability, lack of incentives, and resource requirements.

15 Years Out: Reinventing ICCVAM

In 1997, the National Institute of Environmental Health Sciences (NIEHS) established the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), an ad hoc federal interagency committee to address the growing need for obtaining regulatory acceptance of new toxicological test methods. The thought was that simultaneous agency evaluation of new methods that addressed the 3Rs (reduction, refinement, and replacement) of animal testing by an interagency group could greatly speed up and harmonize the cross-agency acceptance and adoption of new methods into federal toxicity testing guidelines. This activity was codified into law in 2000 by passage of the ICCVAM Authorization Act (2000). The Act specified 15 agencies (such as the Food and Drug Administration, U.S. Environmental Protection Agency, Consumer Product Safety Commission, Department of Transportation, Occupational Safety and Health Administration, and U.S. Department of Agriculture) that would constitute ICCVAM. The Act also prescribed specific duties intended to facilitate review and acceptance of test methods, established an external scientific advisory committee, and required the director of the NIEHS to establish ICCVAM under the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), which currently exists as a functional unit within the Division of the NTP at the NIEHS. Over the past 15 years, ICCVAM has successfully evaluated and recommended numerous alternative test methods for regulatory use (NTP 2012). However, the lack of implementation of ICCVAM-recommended methods has been an area of increasing concern. The NIEHS has worked proactively with our ICCVAM partners to identify promising methods, encouraged and aided test developers in building a case for validating their methods, sometimes provided financial support through competitive Small Business Innovation Grants, and held workshops and engaged our federal and international partners to promote acceptance and use of test methods in specific areas of toxicology (e.g., ocular toxicity and skin sensitization). Even so, regulatory use of alternative methods has still lagged behind. Critics have repeatedly pointed out that alternative test methods have not been accepted for regulatory decision making and that the expectations for real reductions in animal use in toxicology testing have always outpaced the documented progress. It has become clear that it is time to change our approach. The NIEHS is beginning to move forward with a different philosophy toward ICCVAM. Rather than the NIEHS directing the activities of ICCVAM through NICEATM, the interagency agenda will now be driven by the partner regulatory agencies—the agencies that will ultimately implement the ICCVAM-recommended methods. Regulatory agencies are required by statute to use toxicology test information for a variety of purposes, including labeling and registration, and these requirements are not uniform. The ICCVAM Authorization Act acknowledges that some alternative test methods promoted by ICCVAM, while deemed valid, may not meet specific needs of a regulatory agency. With ICCVAM regulatory agencies taking ownership of the process, there should be a better match between the alternative test methods validated and the tests required to meet regulatory guidelines. Toxicology testing is shifting from a primary focus on adverse phenotypic observations in animals to mechanism-based biological outcomes in vitro, and the NIEHS is embracing this paradigm shift through its participation in the multiagency Tox21 consortium (Collins et al. 2008). NICEATM will expand its scope and concentrate its resources on providing bioinformatic and computational toxicology support to NIEHS Tox21 projects. With its purpose of transforming toxicology by shifting from in vivo animal studies to in vitro assays, in vivo assays in lower organisms, and computational modeling for toxicity assessments, Tox21 has the real potential to result in dramatic changes in the numbers and types of organisms used for toxicology testing. A stronger interface of NICEATM with Tox21 will better position ICCVAM for addressing how data from these new methods can be integrated into the existing regulatory framework. We express our deep appreciation to William S. Stokes, who has served as the director of NICEATM since its inception. In December 2012, he retired from the Public Health Service after 33 years of dedicated federal service. His vision, persistence, and direction have been key to bringing NICEATM, ICCVAM, and the International Cooperation on Alternative Test Methods (ICATM) to their current stage of maturity. We are pleased that Warren Casey, who has served as deputy director of NICEATM, will now serve as the acting director. He is uniquely qualified for this role, having worked in the areas of toxicogenomics, mechanistic toxicology, and biomarker development in the pharmaceutical industry prior to joining the NIEHS. We look forward to this new approach to promoting the 3Rs—an approach that will be driven by regulatory agency needs while remaining responsive to the test method development community.

Where now for obesity research?

As three new applications for pharmacotherapy were submitted to the US FDA for review and approval, 2010 began with hope that the findings from obesity research would translate into new therapies for obese patients [1–3]. During the year, there were actually five Advisory Panels to evaluate proposed drug or drug combinations for the treatment of obesity and review of one older drug where an outcome trial had suggested an increased risk [4] along with a panel to review an expanded indication for surgical treatment with the lap-band. The results of three panels were negative, with the External Advisory Committees voting against approval of one new drug and one combination treatment using older drugs and no longer favoring marketing of an existing drug. A ray of hope appeared when the final two panels voted to approve a second combination of two older drugs for treatment of obesity and the expanded use of the lap-band at a lower BMI in higher risk obese individuals. Thus, in spite of years of research, only a single drug has been approved by the FDA for long-term use [5]. By contrast, there are many drugs acting through one of several different mechanisms to treat hypertension, atherosclerosis and diabetes. Why have scientists doing obesity research not been as successful as scientists in these other diseases areas in identifying successful drugs? Drugs to treat obesity can work on structures in the brain, for example, amphetamine, fenfluramine or serotonin [6]. Alternatively, they can work outside the brain by blocking intestinal digestion or as hormonal agents acting on gastrointestinal receptors that can inhibit feeding. One difficulty is that drugs that reduce food intake by acting on brain receptors may also act on other receptors to produce unwanted side effects, such as alterations in mood or other behaviors. These undesirable, and often unintended, side effects from drugs sounded the death knell for pheylpropanolamine [7], an a-1 adrenergic antagonist that reduces food intake and produces modest weight loss, but is also a vasoconstrictor that can raise blood pressure. In a case-controlled study of strokes, younger women using phenylpropanolmine appeared to be at increased risk for stroke and phenylpropanolamine was subsequently taken off the market by the FDA [7]. Addiction is another problem associated with some centrally acting sympathomimetic drugs. Shortly after amphetamine was shown to reduce body weight, it was also shown to produce addiction. This probably reflects the fact that it hits two targets, one of which, the norepinephrine receptor, is beneficial and reduces food intake and the other, the dopamine receptor, is harmful and can produce addiction. Drugs reducing food intake by acting on serotonin receptors have also experienced problems. Fenfluramine has a b-phenethylamine structure like amphetamine, but, in contrast to amphetamine, acts almost exclusively on serotonin receptors. Fenfluramine was approved by the FDA in 1975 to treat obesity. In 1997, patients treated with fenfluramine and phentermine were reported to “The challenges are to find those mechanisms that will produce clinically significant weight loss, provide durable responses and be free of significant side effects.”

Managing emergent and complex change: the case of Dutch agencification

An analysis is made of agencification reform in the Netherlands from the viewpoint of the management of the complex change process. We will present a processual analysis of the complex change process of agencification reform by means of organization science insights on ‘emergent change’ and administrative science insights on ‘complex networks’. The analysis of the process of change events shows that it is not an example of centrally planned and controlled change. The reform is rather an example of ‘emergent and complex change’. The reform is a complex system of different intertwined change processes with many different decentralized actors, which is ‘managed’ by different central ‘change agents’. The ‘change managers’ themselves form a complex system as well.Points for practitionersOne of the important reform trends in Dutch central administration is the ‘agencification’ of executive government organizations, that is, the increase of managerial autonomy of executive parts of ministerial departments. In this article we analyse how this two-decades-long reform process was ‘managed’ by various central actors like Parliament, the National Audit Office, the Ministry of Finance, the Ministry of Home Affairs, various internal and external advisory committees and supervisory committees. It turned out that the reform can hardly be described as a centrally planned and controlled process. Initiatives for reform, in fact, popped up locally within the various ministries and agencies. The reform process was more a continuous accumulation of local initiatives for agencification. The various central actors tried to exercise some coordinating or supervisory influence, but that was rather indirect, reactive and limited.

Public-Academic Partnerships: Tools for Mental Health Agencies to Evaluate Research Protocols

Research involving community mental health center clients, resources, or both can affect clinical care, administrative processes, and costs. To help agencies identify and quantify these effects, a stakeholder group examined and discussed a range of protocols and then developed questionnaires and rating scales for agency use. The purpose of these materials is to make explicit the risks, costs, and benefits of a research protocol so an agency can make informed decisions about protocol approval and implementation. The goal of this work was to promote the conduct of appropriate research in community mental health settings while reducing risks to the agency and its clientele.

The Center for Translational Neuroscience, 5 years of progress

Our aims were to establish 1) a Career Development Program with mentoring/funding for 5 projects and 6 investigators, 2) a multi‐disciplinary Center, a Pilot Study Program, and recruitment of 5 investigators, and 3) two Core Facilities. All aims were exceeded. We developed a Career Development Program and Center so that clinician and basic scientists could be mentored to secure funding. We mentored and supported 10 promising investigators without a history of support. We provided access to Core Facilities to 4 other investigators, and assigned them Mentors. We awarded 5 pilot study grants and assigned them Mentors. We recruited 3 senior and 2 junior faculty and established 6 Core Facilities. We discovered two new cures, two novel treatments and one new mechanism, all with clinical implications. We generated >$13 million in new awards and published >130 articles. The projects produced a novel treatment for tinnitus that relieves the symptoms in a majority of patients, a new use for a drug that relieves the excessive reflexes induced by spinal cord injury, an effective new treatment for spatial neglect due to stroke, and a new mechanism for sleep‐wake control that may lead to the development of new anesthetics and stimulants. Oversight by a dedicated external advisory committee and considerable institutional support were critical to our success, along with selfless mentoring by dedicated senior scientists.

The end of monkey research?

Kevan A. C. Martin, a neurobiologist and director of the Institute of Neuroinformatics—a joint institute of the University of Zurich and the Swiss Federal Institute of Technology—has a moral dilemma. For the past four years, he has not hired any postdoctoral fellows or PhD students. He feels he cannot take them on in good conscience because he cannot guarantee they will be able to do research. It was another moral debate that put him in this position; his work on rhesus macaques has been put on hold and he is uncertain when, or if, it will resume in Switzerland. > …the real impact on primate labs might come from pending revisions to legislation in Europe and the USA that could potentially end research on apes and monkeys altogether In 2004, the Swiss Constitution was changed to acknowledge “the dignity of living beings,” which, according to Martin, was intended to address concerns about transgenic experimentation, rather than animal research in general. Nevertheless, the change resulted in some members of a local external advisory committee on animal experimentation legally challenging the 2006 renewal of Martin's license to use the monkeys for neurobiological research. Similar legal action was taken against Daniel Kiper at the same institute, whose research on brain plasticity in monkeys has relevance for stroke patients. A third researcher, whose work on motor systems has implications for patients with spinal cord damage, has decided to leave Switzerland (Staub, 2007). All three of these projects were approved by the Zurich Canton's Veterinary Office, which controls experiments on animals. Martin's case has been working its way through the Swiss courts and is finally before Switzerland's Federal Supreme Court. In the meantime, Martin, who established the Institute in Zurich with Rodney Douglas 13 years ago, has been limited to using post‐mortem monkey brains. These are …

A Multidisciplinary Approach to Reducing Door-to-Balloon Time in a Community Hospital

A Multidisciplinary Approach to Reducing Door-to-Balloon Time in a Community Hospital

Constraints on Data Sharing

Constraints on Data Sharing

The Cardiovascular Research Network

A clear need exists for a more systematic understanding of the epidemiology, diagnosis, and management of cardiovascular diseases. More robust data are also needed on how well clinical trials are translated into contemporary community practice and the associated resource use, costs, and outcomes. The National Heart, Lung, and Blood Institute recently established the Cardiovascular Research Network, which represents a new paradigm to evaluate the epidemiology, quality of care, and outcomes of cardiovascular disease and to conduct future clinical trials using a community-based model. The network includes 15 geographically distributed health plans with dedicated research centers, National Heart, Lung, and Blood Institute representatives, and an external collaboration and advisory committee. Cardiovascular research network sites bring complementary content and methodological expertise and a diverse population of approximately 11 million individuals treated through various health care delivery models. Each site's rich electronic databases (eg, sociodemographic characteristics, inpatient and outpatient diagnoses and procedures, pharmacy, laboratory, and cost data) are being mapped to create a standardized virtual data warehouse to facilitate rapid and efficient large-scale research studies. Initial projects focus on (1) hypertension recognition and management, (2) quality and outcomes of warfarin therapy, and (3) use, outcomes, and costs of implantable cardioverter defibrillators. The Cardiovascular Research Network represents a new paradigm in the approach to cardiovascular quality of care and outcomes research among community-based populations. Its unique ability to characterize longitudinally large, diverse populations will yield novel insights into contemporary disease and risk factor surveillance, management, outcomes, and costs. The Cardiovascular Research Network aims to become the national research partner of choice for efforts to improve the prevention, diagnosis, treatment, and outcomes of cardiovascular diseases.

Carbon Capture & Storage: Blue-Sky Technology or Just Blowing Smoke?

Towering 650 feet over the sea surface and spouting an impressive burning flare, it would be easy to mistake the Sleipner West gas platform for an environmental nightmare. Its eight-story upper deck houses 200 workers and supports drilling equipment weighing 40,000 tons. Located off the Norwegian coast, it ranks among Europe’s largest natural gas producers, delivering more than 12 billion cubic feet of the fuel annually to onshore terminals by pipeline. Roughly 9% of the natural gas extracted here is carbon dioxide (CO2), the main culprit behind global warming. But far from a nightmare, Sleipner West is actually a bellwether for environmental innovation. Since 1996, the plant’s operators have stripped CO2 out of the gas on-site and buried it 3,000 feet below the sea floor, where they anticipate it will remain for at least 10,000 years. We believe [CCS] is a viable way to cut global warming pollution. . . . We have the knowledge we need to start moving forward. –David Hawkins, Natural Resources Defense Council Operated by StatoilHydro, Norway’s largest company, Sleipner is among the few commercial-scale facilities in the world today that capture and bury CO2 underground. Many experts believe this practice, dubbed carbon capture and storage (sometimes known as carbon capture and sequestration, but in either case abbreviated CCS), could be crucial for keeping industrial CO2 emissions out of the atmosphere. Sleipner injects 1 million tons of CO2 annually into the Utsira Formation, a saline aquifer big enough to store 600 years’ worth of emissions from all European power plants, company representatives say. With mounting evidence of climate change—and predictions that fossil fuels could supply 80% of global energy needs indefinitely—the spotlight on CCS is shining as brightly as the Sleipner flare. A panel of experts from the Massachusetts Institute of Technology (MIT) recently concluded that CCS is “the critical enabling technology to reduce CO2 emissions significantly while allowing fossil fuels to meet growing energy needs.” The panel’s views were presented in The Future of Coal, a report issued by MIT on 14 March 2007. Environmental groups are split on the issue. Speaking for the Natural Resources Defense Council (NRDC), David Hawkins, director of the council’s Climate Center and a member of the MIT panel’s external advisory committee, says, “We believe [CCS] is a viable way to cut global warming pollution. . . . We have the knowledge we need to start moving forward.” Other environmental groups, including the World Resources Institute, Environmental Defense, and the Pew Center on Global Climate Change, have also come out in support of CCS. These groups view CCS as one among many alternatives (including renewable energy) for reducing CO2 emissions. Greenpeace is perhaps the most vocal critic of CCS. Truls Gulowsen, Greenpeace’s Nordic climate campaigner, stresses that CCS deflects attention from renewable energy and efficiency improvements, which, he says, offer the best solutions to the problem of global warming. “Companies are doing a lot of talking about CCS, but they’re doing little to actually put it into place,” he says. “So, they’re talking about a possible solution that they don’t really want to implement now, and at the same time, they’re trying to push for more coal, oil, and gas development instead of renewables, which we already know can deliver climate benefits.”

Martin David Kruskal

Martin David Kruskal

The Curious Case of Off-Label Use

In United States, new drugs and devices cannot be marketed until Food and Drug Administration finds that they are safe and effective for their intended use. To obtain FDA approval, pharmaceutical and device manufacturers must submit extensive animal, in vitro, and human study data demonstrating safety and effectiveness. Agency staff members--often joined by an external interdisciplinary advisory committee--review research reports to evaluate quality of data and make essential risk-benefit judgments that determine whether a medical product is safe and effective. Drug and device companies spend many years and millions of dollars preparing data required for FDA approval. Although agency review process is imperfect, it does ensure that a company's claims about its product are closely scrutinized by independent scientists, physicians, and patient representatives. Safety is evaluated in light of product's specific purpose: Are therapeutic benefits valuable enough and likely enough to justify known risks posed by product? Effectiveness, too, is determined in light of product's specific purpose: Does it have desired impact on enough people with condition at which it is aimed? When FDA approves a product, officials approve a specific label for product, too. That label must contain detailed scientific information about product, including approved indications, dosage and method of administration, and use in specific populations. This rigorous and fine-grained regulatory approach to product evaluation is circumscribed, however. When Congress created FDA, members said that they did not intend for agency to regulate practice of medicine. Thus, FDA oversees only product manufacturers and commercial activities. This general regulatory stance explains curious case of off-label use. After FDA approves a drug or device for its intended use, physicians and other authorized practitioners may prescribe product for uses not covered by approved label. The FDA severely restricts manufacturers' freedom to promote products for unapproved uses. Companies that want to expand formally approved uses for their products must submit safety and effectiveness data and secure FDA approval for new uses. But FDA takes a hands-off approach to clinicians prescribing products for unapproved uses. As a result, drugs and devices are prescribed in circumstances not covered by initial product evaluation. Off-label prescribing occurs not just clinicians give products to people with conditions not listed on approved label, but they depart from approved drug dosage, method of administration, or patient population. Unapproved product combinations, such as using two different drugs to treat a single condition, are another form of off-label prescribing. Surveys show that off-label prescribing occurs routinely. For example, a study published last year examined prescribing practices for 169 commonly used drugs. Researchers found that about 21 percent were prescribed to patients with diagnoses other than those included on label. Off-label prescriptions were relatively common for cardiac drugs (46 percent), anticonvulsant drugs (46 percent), and asthma medications (42 percent). Researchers also found that about 15 percent of all drugs were prescribed for off-label uses with little or no scientific support. For some types of drugs, figures were unusually high. For example, 96 percent of off-label prescriptions for psychiatric drugs and 89 percent of those for allergy drugs were based on limited or no scientific evidence. (1) The Debate over Current Policy The FDA's hands-off approach to off-label prescribing has many supporters. One is American Medical Association, which says approach respects the autonomous clinical decision-making of a physician. Off-label use is defensible, according to AMA, when such use is based upon sound scientific evidence and sound medical opinion. …

Understanding Barriers to Implementation of an Adaptive Land Management Program

The Florida Fish and Wildlife Conservation Commission manages over 650,000 ha, including 26 wildlife management and environmental areas. To improve management, they developed an objective-based vegetation management (OBVM) process that focuses on desired conditions of plant communities through an adaptive management framework. Our goals were to understand potential barriers to implementing OBVM and to recommend strategies to overcome barriers. A literature review identified 47 potential barriers in six categories to implementation of adaptive and ecosystem management: logistical, communication, attitudinal, institutional, conceptual, and educational. We explored these barriers through a bureau-wide survey of 90 staff involved in OBVM and personal interviews with area managers, scientists, and administrators. The survey incorporated an organizational culture assessment instrument to gauge how institutional factors might influence OBVM implementation. The survey response rate was 69%. Logistics and communications were the greatest barriers to implementing OBVM. Respondents perceived that the agency had inadequate resources for implementing OBVM and provided inadequate information. About one-third of the respondents believed OBVM would decrease their job flexibility and perceived greater institutional barriers to the approach. The 43% of respondents who believed they would have more responsibility under OBVM also had greater attitudinal barriers. A similar percentage of respondents reported OBVM would not give enough priority to wildlife. Staff believed that current agency culture was hierarchical but preferred a culture that would provide more flexibility for adaptive management and would foster learning from land management activities. In light of the barriers to OBVM, we recommend the following: (1) mitigation of logistical barriers by addressing real and perceived constraints of staff, funds, and other resources in a participatory manner; (2) mitigation of communication barriers through interpersonal and electronic communication channels; (3) development of an OBVM external advisory committee; and (4) adoption of characteristics of an organizational culture that promotes flexibility and learning.

Building a Research Consortium of Large Health Systems: The Cancer Research Network

Critical questions about cancer prevention, care, and outcomes increasingly require research involving large patient populations and their care delivery organizations. The Cancer Research Network (CRN) includes 11 integrated health systems funded by the National Cancer Institute (NCI) to conduct collaborative cancer research. This article describes the challenges of constructing a productive consortium of large health systems, and explores the CRN's responses. The CRN was initially funded through an NCI cooperative agreement in 1999 and has since received a second 4-year grant. Leadership and policy development are provided through a steering committee, subcommittees, and an external advisory committee. The CRN includes integral and affiliated research projects supported by a Scientific and Data Resources Core. Three characteristics of the CRN intensified the general challenges of consortium research: 1) its members are large health systems with legitimate concerns about confidentiality of data about enrollees, providers, and the organization; 2) CRN research projects often generate highly sensitive data about quality of care; and therefore 3) each participating organization wants a strong voice in CRN direction. CRN experience to date confirms that a consortium of health systems with internal research capacity can address a range of important cancer research questions that would be difficult to study in other venues. The advantages and challenges of consortium research are explored, with suggestions for the development, execution, and management of multisystem population laboratories.

Clinical Trials and Public Trust

I n July, hope was expressed on this page about new developments in the accessibility of clinical trial data. Several leading medical journals had pressed for a requirement that all clinical trials be placed in a public registry, a proposal endorsed by the American Medical Association (AMA) and the Association of American Medical Colleges. The AMA had urged the institutional review boards (IRBs) that review trial protocols to require such registration before approval of a drug. The World Health Organization further supports an international registry. That good news has proved transitory, as subsequent events have damaged the public's faith in a process that is, after all, vital to its health. The alleged failure of Merck and Co. to release damaging data about cardiac risks associated with its blockbuster pain drug Vioxx (a COX-2 inhibitor) has prompted congressional hearings, with charges that the company knew of the risks earlier but didn't say so. That scandal followed another: a year-long delay by the U.S. Food and Drug Administration (FDA) to warn about the suicide risks of certain antidepressants given to children. ![Figure][1] CREDIT: [IMAGES.COM/CORBIS][2] What's needed to restore confidence in the system that brings us new medicines? It is natural to focus blame on the drug companies. After all, they're rich, and people are mad about their prices. Although clinical trials can be well run, the companies that sponsor and organize them want the “right” result, and opportunities for influence abound. An important trial may involve many centers, each with an IRB of tired and overstretched members. One resistant IRB can be pressed for approval because “all the others have approved.” Many trials are outsourced for management by clinical research organizations (CROs), which are motivated to please the employer (after all, doesn't the wedding coordinator want to please the bride's mother?). But the FDA's end of the process is a natural target, too. The agency has had good external advisory committees in the past. But the recent history of administrative removals, particularly that of COX-2 critic Curt Furberg from a panel considering those drugs, has invited public suspicion. This and other questions about other already-marketed drugs have raised concern about the FDA's susceptibility to drug company influence. These have now led to several actions: a request by the agency for a comprehensive review by the Institute of Medicine; a system of internal appeals, in which an employee concerned about a drug safety issue can be heard by a panel with participation from outside the agency; and a renewed search for a director of the Office of Drug Safety. Some critics have urged that the situation is so bad that we need a new government agency charged with the conduct of all clinical trials, using funds supplied by the manufacturers. That might be a solution, but political enthusiasm for it will be low for a while. Meanwhile, there are possible short-term fixes. Regional or national IRBs might do a better job, but institutions are reluctant to use them because of the added liability they could take on. Better, perhaps, to provide resources to beef up existing IRBs. Second, require that all late-stage clinical trials, including those testing for unapproved uses of already-marketed drugs, be entered into a registry that would make all results, including the negative ones, available publicly, which is a step beyond the proposals contained in legislation now under Senate consideration. The most important task is to provide one essential tool. Through no fault of the FDA, the United States has lacked a system than can detect things that go wrong with an already-marketed drug. Physicians are asked to make voluntary reports and manufacturers are required to tell the FDA when they spot a problem, but there's little incentive for either. Moreover, there is no centralized way of knowing how much of a given drug is being used, so there is no denominator and no adverse reaction rate can be calculated. That's not to say that it can't be done right. Kaiser Permanente, the health plan giant, maintains electronic patient records and its doctors do report problems, allowing them to conduct adverse reaction epidemiology (a Kaiser study spotted the Vioxx problem early). The absence of an effective national adverse event reporting and analysis capacity is an embarrassment. Instead of complaining about the FDA, Congress should fund it to support an effective Office of Drug Safety, with the authority needed to encourage physician reporting and a way to audit prescriptions. [1]: pending:yes [2]: http://images.com/corbis

Research priorities and plans for the International Space Station—Results of the ‘REMAP’ task force

Recent events in the International Space Station (ISS) Program have resulted in the necessity to re-examine the research priorities and research plans for future years. Due to both technical and fiscal resource constraints expected on the International Space Station, it is imperative that research priorities be carefully reviewed and clearly articulated. In consultation with OSTP and the Office of Management and budget (OMB), NASA's Office of Biological and Physical Research (OBPR) assembled an ad-hoc external advisory committee, the Biological and Physical Research Maximization and Prioritization (REMAP) Task Force. This paper describes the outcome of the Task Force and how it is being used to define a roadmap for near and long-term Biological and Physical Research objectives that supports NASA's Vision and Mission. Additionally, the paper discusses further prioritizations that were necessitated by budget and ISS resource constraints in order to maximize utilization of the International Space Station. Finally, a process has been developed to integrate the requirements for this prioritized research with other agency requirements to develop an integrated ISS assembly and utilization plan that maximizes scientific output.