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Successful clinical trials to create drugs and vaccines for next pandemic disease will rely on building capacity, community engagement, and international collaboration before and during outbreak WASHINGTON - Mobilization of a rapid and robust clinical research program that explores whether investigational therapeutics and vaccines are safe and effective to combat the next infectious disease epidemic will depend on strengthening capacity in low-income countries for response and research, engaging people living in affected communities, and conducting safety trials before an epidemic hits, says a new report from the National Academies of Sciences, Engineering, and Medicine. Using key lessons learned from the Ebola epidemic in West Africa, the report outlines how to improve the speed and effectiveness of clinical trial research while an epidemic is occurring, especially in settings where there is limited health care and research infrastructure. The research and development of therapeutics and vaccines is a long, complex, and expensive process and cannot be compressed into the course of a rapidly progressing outbreak. The development of a drug "from bench to bedside" is estimated, on average, to take at least 10 years and cost $2.6 billion, with less than 12 percent likelihood of eventual licensing. Therefore, making progress on the research and development of products - such as therapeutics and vaccines - before an epidemic breaks is the only way to ensure that promising candidates are ready for trials once an outbreak occurs, said the committee that carried out the study and wrote the report. In addition, clinical trials could be more rapidly planned, approved, and implemented during an outbreak if promising products are studied through Phase 1 or Phase 2 safety trials in advance of an outbreak and if emergency response planning includes clinical research considerations and clinical researchers in the discussions from the beginning. The 2014-2015 Ebola epidemic was the longest and most deadly Ebola outbreak since the virus was first discovered in 1976, resulting in 28,616 cases and 11,310 deaths in Guinea, Liberia, and Sierra Leone. In August 2014, the World Health Organization declared the epidemic a public health emergency of international concern. Researchers discussed how to conduct clinical trials on potential Ebola therapeutics and vaccines in West Africa, and ultimately, several teams conducted formal clinical trials in the Ebola-affected countries during the outbreak. The clinical trial teams overcame immense logistical obstacles encountered while trying to design and implement trials in West Africa in the midst of a rapidly spreading epidemic of a highly dangerous contagious disease. However, none of the therapeutic trials ended with conclusive results on product efficacy, although limited evidence from the trial for the ZMapp treatment did trend toward a possible benefit. Given the resources, time, and effort put into these trials, they were not as successful as they could have been. The results of the vaccine trials were more fruitful. Two Ebola vaccine candidates have data that suggest they may be safe and produce an immune response, and one is most likely protective, but further data are needed. Planning and conducting clinical research during the Ebola epidemic also required confronting a number of ethical issues, such as whether it was ethical to conduct clinical trials at all in the midst of a public health emergency and whether the research activities drew effort away from providing clinical care to the most people possible. There was also disagreement among researchers over how clinical trials should be designed during the Ebola epidemic, particularly whether trials should use randomization and concurrent control groups. Randomized controlled trials are generally the preferred research design, because they allow researchers to directly compare the outcomes of similar groups of people who differ only in the presence or absence of the investigational agent. However, many argued that randomized controlled trials would be unethical during the Ebola epidemic, as this trial design would deprive patients of an agent that could potentially prevent or treat Ebola, given the high mortality rate and lack of known and available treatment options. The committee concluded that randomized controlled trials are both ethical and the fastest and most reliable way to identify the relative benefits and risks of investigational products, and except in rare circumstances, every effort should be made to implement them during epidemics. The issues that influenced choices about trial design during the Ebola epidemic - such as community mistrust, the feasibility of a standard-of-care-only arm, the high and variable mortality rate, limited product availability, and the potential conflicts between research and care - are likely to recur in future epidemics. Nevertheless, the perceived ethical or logistical hurdles that these issues present are not sufficiently compelling to override the benefits of randomized trials. Rather, randomized trials may be the most ethical trial design, because they offer the fastest route to identifying beneficial treatments while minimizing the risks of exposure to potentially harmful investigational agents. To improve the national and international clinical trial response to the next epidemic, the committee focused on three main areas - strengthening capacity, engaging communities, and facilitating international coordination and collaboration - both in the period of time before an outbreak strikes and during the epidemic itself. The committee found major capacity challenges that hindered and slowed the research response to the Ebola epidemic, and recommended developing sustainable health systems and research capabilities, improving capacity to collect and share clinical and epidemiological data, facilitating the mechanisms for rapid ethics reviews and legal agreements before an epidemic occurs, and incorporating research systems into emergency preparedness and response systems for epidemics. Affected communities had considerable fear, mistrust, and misunderstanding of national and international response and research staff. Community members feared going to health care facilities for the treatment of Ebola, rumors spread that Ebola was deliberately brought to the region by foreigners, and initial response efforts did not take into account community traditions and beliefs. For example, mandatory cremation policies countered deeply held religious beliefs. Successful clinical research is dependent on a community's understanding of, engagement in, and sense of involvement and respect in the process of planning and conducting research, the committee found. Community engagement should be prioritized during epidemic responses and be a continuous and evolving effort, starting at the onset of the epidemic. Research and response efforts were also greatly affected by the relationships among international stakeholders and their ability to coordinate and collaborate. For example, there were a few Ebola-specific therapeutic candidates with suggestive efficacy available at the beginning of the outbreak that could have been investigated in clinical trials, but the mechanism to prioritize which should be studied first was limited. The committee recommended the establishment of an international coalition of stakeholders to work between epidemics that would advise and prioritize pathogens to target for research and development, develop generic clinical trial design templates, and identify teams of clinical research experts who could be deployed to assist with research during an outbreak. The committee also highlighted seven critical steps to launching successful clinical trials when the next epidemic first strikes and before it peaks. The steps are to collect and share patient information and establish standards of care, engage communities and establish mutual trust, integrate research efforts into response and facilitate stakeholder coordination, prioritize vaccines and therapies and select trial designs, negotiate contracts, consult with regulators, and perform independent ethics reviews. The study was sponsored by the U.S. Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response, National Institutes of Health, and U.S. Food and Drug Administration. The National Academies of Sciences, Engineering, and Medicine are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. The National Academies operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visit http://national-academies. . A roster follows. Copies of Integrating Clinical Research Into Epidemic Response: The Ebola Experience are available from the National Academies Press at http://www. or by calling 1-800-624-6242. Reporters may obtain a copy from the Office of News and Public Information (contacts listed above). Gerald T. Keusch, M.D.* (co-chair) Professor of Medicine and Global Health Boston University Schools of Medicine and Public Health Boston Keith McAdam, M.D. (co-chair) Emeritus Professor of Clinical and Tropical Medicine London School of Hygiene and Tropical Medicine London Abdel Babiker, Ph.D. Professor of Epidemiology and Medical Statistics Medical Research Council Clinical Trials Unit at University College London London Susan S. Ellenberg, Ph.D. Professor of Biostatistics Perelman School of Medicine University of Pennsylvania Philadelphia Roger J. Lewis, M.D., Ph.D.* Professor and Chair of the Department of Emergency Medicine Harbor-UCLA Medical Center Los Angeles Alex London, Ph.D. Professor of Philosophy, and Director of the Center for Ethics and Policy Carnegie Mellon University Pittsburgh Michelle M. Mello, Ph.D.* Professor of Law Stanford University School of Medicine and School of Law Stanford, Calif. Olayemi Omotade, M.D. Professor of Pediatrics and Child Health Institute of Child Health University College Hospital University of Ibadan Ibadan, Nigeria Fred Wabwire-Mangen, Ph.D. Associate Professor of Epidemiology and Public Health Makerere University School of Public Health Kampala, Uganda

Misirli G.,Hellenic Health Foundation | Benetou V.,Epidemiology and Medical Statistics | Lagiou P.,Epidemiology and Medical Statistics | Lagiou P.,Harvard University | And 5 more authors.
American Journal of Epidemiology | Year: 2012

The authors aimed to evaluate the association of the traditional Mediterranean diet and major food groups with incidence of and mortality from cerebrovascular disease (CBVD) in a Mediterranean population. The study population was a cohort of 23,601 participants from the Greek segment of the EPIC Study (European Prospective Investigation into Cancer and Nutrition) who were free of cardiovascular diseases and cancer at baseline (1994-1999). Diet was assessed by means of a validated food frequency questionnaire. A 10-point scale integrating key Mediterranean diet characteristics was used to assess the participants' degree of adherence to this diet. During a median follow-up period of 10.6 years (1994-2009), 395 confirmed incident cases and 196 deaths from CBVD were recorded. Using Cox proportional hazards regression and adjusting for potential confounders, increased adherence to the Mediterranean diet, as measured by 2-point increments in score, was inversely associated with CBVD incidence (adjusted hazard ratio = 0.85, 95% confidence interval: 0.74, 0.96) and mortality (adjusted hazard ratio = 0.88, 95% CI: 0.73, 1.06). These inverse trends were mostly evident among women and with respect to ischemic rather than hemorrhagic CBVD and were largely driven by consumption of vegetables, legumes, and olive oil. These data provide support for an inverse association of adherence to the Mediterranean diet with CBVD incidence and mortality. © 2012 The Author.

Chrysikos D.T.,Hippokratio Hospital | Sergentanis T.N.,Epidemiology and Medical Statistics | Zagouri F.,Hippokratio Hospital | Psaltopoulou T.,Epidemiology and Medical Statistics | And 9 more authors.
Journal of the Pancreas | Year: 2015

Context The potential of lazaroid U-74389G in attenuating injury after ischemia and reperfusion has been reported in various organs. Objective The present study focuses specifically on the pancreas and aims to examine any effects of U-74389G in a swine model of pancreatic ischemia and reperfusion, encompassing ischemic preconditioning. Methods Twelve pigs, weighing 28–35 kg, were randomized into two experimental groups. Group A (control group, n=6): Two periods of ischemic preconditioning (5 min each) separated by a 5-min rest interval; then ischemia time 30 min and reperfusion for 120 min. Group B (n=6): the same as above, with U-74389G intravenous injection in the inferior vena cava immediately prior to the initiation of reperfusion. Blood sampling and pancreatic biopsies were conducted at 0, 30, 60, 90 and 120 min after reperfusion. Results Repeated-measures ANOVA was undertaken to evaluate differences between the two study groups. No statistically significant differences were noted concerning the histopathological parameters in the control and therapy groups (P=0.563 for edema, P=0.241 for hemorrhage, P=0.256 for leukocyte infiltration, P=0.231 for acinar necrosis and P=0.438 for vacuolization). In accordance with the above, serum metabolic data (glucose, creatinine, urea, total and direct bilirubin, total calcium, amylase, lipase, SGOT/AST, SGPT/ALT, ALP, GGT, LDH, CRP, insulin) were not significantly different between the two groups; similarly, tumor necrosis factor-α values (P=0.705) and tissue malondialdehyde levels (P=0.628) did not differ between the two groups. Conclusion This swine model of pancreatic ischemia and reperfusion, encompassing preconditioning, indicates that U-74389G lazaroid does not seem to exert protective effects from pancreatic damage. © 2015, JOP. J Pancreas (Online). All rights reserved.

Koti I.,Attikon University Hospital | Koti I.,Charité - Medical University of Berlin | Weller K.,Charité - Medical University of Berlin | Makris M.,Attikon University Hospital | And 8 more authors.
Dermatology | Year: 2013

Background: The impact of chronic spontaneous urticaria (CSU) on health-related quality of life (HRQoL) is widely held to be mainly influenced by disease activity and comorbidities. Objective: To assess the correlation between disease activity and HRQoL impairment by using validated disease-specific instruments. Methods: The Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) was translated into Greek and subsequently applied to 110 CSU patients along with the Dermatology Life Quality Index and the Urticaria Activity Score. After the validity and reliability of the Greek CU-Q2oL had been determined, we assessed the relation between disease activity and HRQoL impairment by computing correlations as well as by performing multiple regression analysis. Results: Exploratory factor analysis revealed a six-scale structure of the Greek CU-Q2oL that explained 67.9% of its total variance. The internal consistency was satisfactory with Cronbach's α >0.7. Disease activity was the only predictor of quality of life impairment, but it only moderately correlated with the CU-Q 2oL total score (r = 0.40, p < 0.0001). Conclusion: Our results suggest that there are additional factors to disease activity that are responsible for the pronounced reduction of HRQoL in CSU, and this supports the recommendation to assess and monitor both disease activity and quality of life in CSU patients. © 2013 S. Karger AG, Basel.

Lakshmanan A.,Childrens Hospital Los Angeles | Chiu Y.H.M.,Mount Sinai School of Medicine | Coull B.A.,Harvard University | Just A.C.,Harvard University | And 6 more authors.
Environmental Research | Year: 2015

Background: Prenatal traffic-related air pollution exposure is linked to adverse birth outcomes. However, modifying effects of maternal body mass index (BMI) and infant sex remain virtually unexplored. Objectives: We examined whether associations between prenatal air pollution and birth weight differed by sex and maternal BMI in 670 urban ethnically mixed mother-child pairs. Methods: Black carbon (BC) levels were estimated using a validated spatio-temporal land-use regression (LUR) model; fine particulate matter (PM2.5) was estimated using a hybrid LUR model incorporating satellite-derived Aerosol Optical Depth measures. Using stratified multivariable-adjusted regression analyses, we examined whether associations between prenatal air pollution and calculated birth weight for gestational age (BWGA) z-scores varied by sex and maternal pre-pregnancy BMI. Results: Median birth weight was 3.3±0.6kg; 33% of mothers were obese (BMI ≥30kg/m3). In stratified analyses, the association between higher PM2.5 and lower birth weight was significant in males of obese mothers (-0.42 unit of BWGA z-score change per IQR increase in PM2.5, 95%CI: -0.79 to -0.06) ( PM2.5×sex×obesity Pinteraction=0.02). Results were similar for BC models (Pinteraction=0.002). Conclusions: Associations of prenatal exposure to traffic-related air pollution and reduced birth weight were most evident in males born to obese mothers. © 2014 Elsevier Inc.

Christoforidou E.P.,Epidemiology and Medical Statistics | Riza E.,Epidemiology and Medical Statistics | Kales S.N.,Harvard University | Hadjistavrou K.,Epidemiology and Medical Statistics | And 3 more authors.
Journal of Environmental Science and Health - Part A Toxic/Hazardous Substances and Environmental Engineering | Year: 2013

Exposure to inorganic arsenic (As) through drinking water is a major international public health issue. We carried out a systematic review of the existing literature examining the association between the risk of bladder cancer in humans and exposure to arsenic through drinking water. We searched electronic databases for studies published from January 2000 up to April 2013. Eight ecological studies, six case-control studies, four cohort studies and two meta-analyses were identified. The vast majority of the studies were carried out in areas with high arsenic concentrations in drinking water such as southwestern and northeastern Taiwan, Pakistan, Bangladesh, Argentina (Cordoba Province), USA (southeastern Michigan, Florida, Idaho) and Chile. Most of the studies reported higher risks of bladder cancer incidence or mortality in areas with high arsenic concentrations in drinking water compared to the general population or a low arsenic exposed control group. The quality assessment showed that among the studies identified, arsenic exposure was assessed at the individual level only in half of them and only three assessed exposure using a biomarker. Further, five out of eight ecological studies presented results with adjustment for potential confounders except for age; all cohort and case-control studies presented results with adjustment for cigarette smoking status in the analysis. The majority of the studies with varying study designs carried out in different areas provided evidence of statistically siginificant increases in bladder cancer risk at high concentrations of arsenic (>50 μg L -1). Assessing bladder cancer risk at lower exposure concentrations requires further investigation. © 2013 Copyright Taylor and Francis Group, LLC.

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