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International Clinical Trials

Untapped Potential of the Emergency Environment

Time is of the essence when dealing with most emergencies, many of which are characterised by the rapid onset and progression of injury or pathophysiologic disturbance. The ability to facilitate rapid and accurate diagnoses and treatment, ultimately affecting long-term clinical outcomes, provides a compelling rationale for the role of emergency departments (EDs) in the development of novel diagnostic and therapeutic interventions.

Recent literature reports and results from industrysponsored clinical trials in EDs confirm this interest and illustrate a marked increase in current activities in clinical studies. Unsurprisingly, these studies concentrate particularly on biomarkers and other diagnostic tools used in the evaluation and treatment of conditions commonly presented to the ED. These not only include cardiovascular (CV) disorders, but also respiratory, allergic and infectious diseases (1-5). Most of these trials are concentrated in North America and Europe, with little representation from other continents, in contrast to the globalisation of clinical research characterising non-emergent indications. Of the 161 trials, 117 are interventional trials, and 26 of these are industry-sponsored trials.

UNIQUE OPPORTUNITIES

The strength of an ED environment in the execution of CV trials lies mainly in the access to a diverse patient population presenting with acute CV conditions requiring timely diagnosis and treatment. As an example, clinical studies conducted in EDs have established the role of natriuretic peptide levels in risk stratification, with regard to the need for hospital admission or direct ED discharge, and as powerful independent predictors of death in acute coronary syndrome (6). Other important contributions of research in emergency medicine are in the treatment of acute heart failure, as illustrated by a recent interventional study in decompensated severe hypertensive patients presenting with systolic blood pressure (SBP) of greater than 180mm Hg, with an objective of achieving a patientspecific pre-specified initial target range of SBP within 30 minutes (7). This study highlights the unique capacity of EDs to enrol patients in urgent medical need (hypertensive crisis), to perform rapid assessment and therapeutic intervention, and to evaluate and document efficacy parameters within 30 minutes.

Acute management of chest pain is certainly the area where most of the studies in an emergency setting have been conducted: PubMed reports 3,335 articles published over the past 35 years using results from the search keywords ‘chest pain’ and ‘emergency department’ (8). The medical indication associated with these studies is primarily acute myocardial ischaemia, but it is interesting to note that patients are screened when the diagnosis at the time of triage is still ‘chest pain’, and therefore they are without diagnosis or treatment at initial evaluation – a condition that can occur only at the ED level. The advantage of emergency physicians being on hand in the first instance to approach patients with acute myocardial ischaemia is confirmed by the finding that about half of the 1.1 million patients who experience myocardial infarctions annually in the US present to an ED first (9).

UNIQUE CHALLENGES

The unique attributes of emergency settings provide challenges as well as opportunities for descriptive and interventional research. Emergency services in many institutions are designed as gateways to a broader range of healthcare services, rather than centres for delivering definitive medical care. The patients within an ED are often unknown to care providers and only transiently present within the ED itself. The clinical presentation commonly presents problems that require brisk diagnostic and therapeutic interventions, in which the demands for research-related procedures can encumber clinical care. These can be exacerbated by: the absence of a clinical research infrastructure; limited access to personnel who often have conflicting priorities; and limited clinical research experience in a relatively newly-recognised speciality in which training may not emphasise research methodology.

The emergency environment also poses many barriers to patient recruitment, and this has always been considered an operational challenge (10). One of the reasons is represented by the crowding typical of an emergency care facility. In trials on myocardial ischaemia, patients presenting with chest pain should undergo rapid assessment, including extra routine examination in a monitored setting, to optimise the diagnosis of acute coronary syndrome and to verify all of the protocol’s specific inclusion/ exclusion criteria. The initiation of a treatment may be timesensitive and lead to failure to enrol potential research subjects within the window defined by protocol. To mitigate crowdingrelated enrolment problems in CV studies, processes can be implemented that enable emergency physicians to evaluate potentially eligible patients in a study-dedicated room (short observation unit) when all nurse-staffed stretchers are occupied.



An expansion of the emergency care facility and research workforce may be necessary. For example, the intensity and unpredictability of the workload in emergency medicine can be increased considerably by participation in clinical research. Patients may have a wide variety of concomitant medication and concurrent illnesses that confound the severity of initial diagnosis. Characteristically, such patients also present in a non-uniform pattern throughout the day. Therefore, the opportunity to recruit patients 24 hours a day implies a large study personnel than studies conducted in non-emergency settings, where enrolment activities are limited to normal ‘office’ hours (11).

In addition to facility and staffing requirements, there is a technological infrastructure that is mandated by participation in research studies. Admission diagnosis and triage must always be available to dedicated study staff, and this can be reached optimally through an electronic system of data entry at the emergency site. Electronic clinical charts thus become an essential aspect of any clinical research, but even more so for research conducted in urgent cardiovascular conditions where data is collected very rapidly and must be available immediately if the patient is transferred to another department, such as cardiology or cardiosurgery.

Implementation of advanced information technology in the ED has prompted an explosion in the variety of data collected. This includes demographic and administrative information, and the routine collection of audit and activity data. In addition, there is the mass of digital information generated by patient physiological monitoring systems. When these monitored physiological parameters are included in the clinical study database, any methodological inconsistency must be addressed for study purpose. Despite this, or even because of it, data may be of poor quality, devoid of standards for data acquisition across platforms in multicentre trials, and have the more interesting clinical information embedded within natural text fields requiring special data mining algorithms. Additionally, potentially useful data for study purposes may only be accessible for ‘secondary uses’ within a clinical trial after navigating both legal and logistical barriers regarding access (12).

Another important challenge for emergency research is represented by informed consent and privacy considerations which create particular issues for time-sensitive research. Consent of human subjects for participation in research requires that patients: fully understand their role and risk; not be coerced; and be allowed to withdraw from an investigation at any time without penalty. In an emergency situation, obtaining informed consent from a patient is often impossible. Patients at imminent risk of death from cardiac arrest, for example, are incapable of providing an adequate consent, but nevertheless are often in the greatest need of innovative therapy and might be willing to assume some risk for potential benefit. In an attempt to resolve this dilemma, the new version of the Declaration of Helsinki presents updated requirements for the waiver of informed consent and the protection of human subjects in emergency research (13).

CASE STUDY

Global feasibility assessments may highlight limitations in clinical research culture and methodology within the emergency setting, while also evaluating a site’s current practices, experience in clinical trials, and the structural elements of a protocol that might affect recruitment and study execution. Beyond identifying specific sites, a well executed feasibility assessment explores the ramifications of the proposed design on physicians’ interest and ability to engage in the research.

Findings from our recent feasibility assessments have included generally poor experience for investigative clinical research in most emergency departments: In one instance last year only 12 EDs of 71 sites contacted across nine countries within western Europe and the Middle East, provided acceptable previous experience in clinical trials (see Figure 2). Also notable was an absence of reliable historical metrics that precluded reliable planning, with even approximate calculations, regarding anticipated screen and enrolment rates – despite each site indicating a wide range of suitable patients.



EDs IN INDUSTRY-SPONSORED CLINICAL RESEARCH

Sampling has revealed an untapped opportunity for ED clinical research at both site and country level, provided that fundamental structural and staffing limitations could be addressed to render centres conducive to the demands of current pharmaceutical research. Considering the significant increase over the past years in investment in emergency research by the pharmaceutical industry, especially in the cardiovascular field, it appears clear that many organisations have risen to this challenge.

Facilitating the involvement of EDs in industry-sponsored clinical research should include coordination across centres in particular. Emergency medicine networks are already well established in the US, and in the cardiovascular field the Emergency Medicine Cardiac Research and Education Group (EMCREG) – which is centrally coordinated through the Department of Emergency Medicine of University of Cincinnati – provides insights to the organisation and procedures that must be implemented. Across international research networks, using established organisations, the Swedish Society for Emergency Medicine (SWESEM), the Danish Society for Emergency Medicine (DASEM) and the Global Research on Acute Conditions Team (GREAT) all represent comparable attempts to produce a coherent system for conducting clinical trials. Research networks could be devoted to formal clinical research training, to establish relationships with the medical community for patients’ referral, and for patient aftercare, and to assure a critical mass of eligible subjects at each participating centre, to justify the investment in resources that must occur. A proactive engagement of the pharmaceutical industry must also emphasise the importance of an industry mandate for predictable execution, pre-empting concerns regarding ED engagement in which ‘science and medicine are assumed, but data throughput is questionable’.

CONCLUSION

International scientific research carried out in EDs can play an important role in the development of new diagnostic and treatment strategies. The strength of an emergency environment in carrying out clinical studies lies mainly in the access to a diverse patient population presenting with acute conditions requiring timely diagnosis and treatment. These attributes of emergency settings provide challenges with modification in processes, staffing levels, information management and even physical setting required for effective participation. With proactive engagement by the pharmaceutical industry, and by modelling the success of individual centres and consortia, the opportunities for developing research capabilities within this singularly unique setting will expand.

References
  1. Newgard CD, Kim S and Camargo CA Jr, Emergency medicine leadership in industry-sponsored clinical trials, Acad Emerg Med 10(2): pp169-174, February 2003
  2. McCullough PA, Nowak RM, Foreback C, Tokarski G, Tomlanovich MC, Khoury NE, Weaver WD, Sandberg KR and McCord J, Performance of multiple cardiac biomarkers measured in the emergency department in patients with chronic kidney disease and chest pain, Acad Emerg Med 9(12), December 2002
  3. Kline JA, Hernandez-Nino J, Jones AE, Rose GA, Norton HJ and Camargo CA Jr, Prospective study of the clinical features and outcomes of emergency department patients with delayed diagnosis of pulmonary embolism, Acad Emerg Med 14(7): pp592-598, July 2007
  4. Singer AJ, Thode HC Jr, Green GB, Birkhahn R, Shapiro NI, Cairns C, Baumann BM, Aghababian R, Char D and Hollander JE, The incremental benefit of a shortness-of-breath biomarker panel in emergency department patients with dyspnea, Acad Emerg Med 16(6): pp488-494, June 2009
  5. Bealer JF and Colgin M, S100A8/A9: a potential new diagnostic aid for acute appendicitis, Acad Emerg Med 17(3): pp333-326, March 2010
  6. Maisel A et al, State of the art: using natriuretic peptide levels in clinical practice, European Journal of Heart Failure 10: pp824-839, 2008
  7. Peacock FW IV, Varon J, Ebrahimi R, Dunbar L and Pollack CV Jr, Clevidipine for severe hypertension in acute heart failure: a VELOCITY trial analysis, Congest Heart Fail 16(2): pp55-59, March 2010
  8. www.ncbi.nlm.nih.gov/pubmed
  9. Cardiovascular disease statistics, heart and stroke A to Z guide, Dallas: American Heart Association, pp1-2, 1995
  10. Cobaugh DJ, Spillane LL and Schneider SM, Research subject enroller program: a key to successful emergency medicine research, Acad Emerg Med 4(3): pp231-233, March 1997
  11. Singer AJ, Homan CS and Stark MJ et al, Comparison of types of research articles published in emergency medicine and non-emergency medicine journals, Acad Emerg Med 4: pp1,153-1,158, 1997
  12. Bleicher P, Secondary use of electronic health records: a personal perspective, Global Forum F010.2(5): pp25-28
  13. Declaration of Helsinki, current (2008) version


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Paola Antonini is Senior Vice President of Medical and Scientific Affairs for Worldwide Clinical Trials. Paola received her MD from the University of Rome, La Sapienza, and has a PhD in Clinical Pharmacology. In more than 20 years of experience in Big Pharma, she has played a key role in many successful programmes of drug development, capitalising on her scientific leadership and on-the-job experience in the designing, implementation and interpretation of clinical trial. As part of the current responsibilities in Worldwide Clinical Trials she focuses on the fields of global feasibility, global drug safety and global medical monitoring in all therapeutic areas.

Michael F Murphy is the Chief Medical and Scientific Officer for Worldwide Clinical Trials. His positions within the pharmaceutical industry have focused on the importance of the integration of medical and scientific acumen with operational excellence. He is boarded in psychiatry, with a PhD in Pharmacology and is Research & Development Editor for American Health & Drug Benefits, a publication which focuses upon issues of cost, quality and access in the transition of novel diagnostic methods and therapeutics from discovery to commercialisation. As a faculty member within the Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, he has been a lecturer for over a decade on clinical trial methodology.
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Paola Antonini
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Michael F Murphy
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