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Mistake proofing laboratory monitoring for alemtuzumab treated patients with multiple sclerosis Barclay, Krista Marie Dec 20, 2017

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Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    1    MISTAKE PROOFING LABORATORY MONITORING FOR ALEMTUZUMAB TREATED PATIENTS WITH MULTIPLE SCLEROSIS  by KRISTA MARIE BARCLAY B.S.N., University of Alberta, 2000  A SPAR PROJECT SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIRMENTS FOR THE DEGREE OF  MASTER OF SCIENCE IN NURSING in  THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (School of Nursing) UNIVERSITY OF BRITISH COLUMBIA Vancouver December 2017    © Krista M. Barclay, 2017  MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 2 Abstract Background: The outpatient laboratory monitoring process involves the coordination of multiple systems in healthcare and this complexity makes it prone to failures. As laboratory monitoring becomes a part of the standard of care for certain conditions such as Multiple Sclerosis, healthcare providers rely on these systems to prevent delays in identification, diagnosis and treatment of serious adverse events. Purpose: Using mistake-proofing methodology, this project was designed to identify, prioritize and generate solutions to the risks of laboratory monitoring with alemtuzumab; Alemtuzumab is an immune modulating agent used in multiple sclerosis, which has a demanding monitoring schedule and the potential for life threatening secondary conditions in the four years after treatment. Methods: The tools used for this analysis were process mapping, failure modes and effects analysis (FMEA), risk prioritization, targeted questioning and solution prioritization. Results: Adapting tools from other risk-prone systems may provide a framework for conceptualizing risk, but these tools need to be adapted to reflect the principles, outcomes and values of healthcare. These tools, however, can support the development of recommendations in the use of the mistake proofing method and health care initiatives to address the risks in laboratory monitoring for patients with multiple sclerosis, treated with alemtuzumab. Conclusions: Patient engagement, clinic flexibility in supporting patients and involvement of registered nurses are important to decreasing risks in laboratory monitoring of those treated with alemtuzumab.  Key Words: multiple sclerosis, MS,  alemtuzumab, Lemtrada, risk analysis, laboratory monitoring, mistake-proofing, failure modes and effects analysis, FMEA  Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    3 Table of Contents Abstract…………………………………………………………………………………....2  Table of Contents………………………………………………………………………….3  List of Tables……………………………………………………………………………...5 List of Figures……………………………………………………………………………..6  Acknowledgements………………………………………………………………………..7  Introduction………………………………………………………………………………..8  Problem Statement………………………………………………………………………...9 Significance………………………………………………………………………………..9 Background ……………………………………………………………………………………………………….12  MS…………………………………………………………………………………………………………..12 Disease Modifying Therapies to treat Multiple Sclerosis……………………………14 Alemtuzumab………………………………………………………………………………………….19 REMS and Patient Support Programs………………………………………………………..21 Clinical Monitoring…………………………………………………………………………………..22 Support Roles in Clinical Monitoring………………………………………………………...29 Lemtrada Lab-Monitoring Program………………………………………………………….32 Patient Safety and Quality Improvement Methodology……………………………...34  Mistake Proofing Method………………………………………………………………38   Failure Modes and Effects Analysis (FMEA)…………………………39 Generating Solutions Using Mistake Proofing Questions and SPN Calculations…………………………………………………………….......43 Analysis……………………………………………………………………………………………………………..45 MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 4  Defining the Topic and Scope…………………………………………………………………...45  Process Mapping……………………………………………………………………………………..46  Failure Modes and Effects Analysis…………………………………………………………..47  Generating Mistake-Proof Solutions…………………………………………………………52   Elimination…………………………………………………………………………………...54   Replacement…………………………………………………………………………………58   Facilitation……………………………………………………………………………………61   Detection……………………………………………………………………………………...66   Mitigation……………………………………………………………………………………..69   Patient Involvement……………………………………………………………………...72  Solution Priority Calculation…………………………………………………………………….72 Discussion………………………………………………………………………………………………………….76 Recommendations for the Development of Lemtrada Monitoring Programs…………79 Conclusion…………………………………………………………………………………………………………83 Reference…………………………………………………………………………………………………………..84 Appendix…………………………………………………………………………………………………………...96        Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    5 List of Tables  Table 1. Disease Modifying Therapies for Multiple Sclerosis………………………….16   Table 2. The Six Principles of Mistake-Proofing……………………………………….38 Table 3. Mistake-Proofing Tools………………………………………………………..39 Table 4. Example of Failure Modes and Effects Analysis Procedure…………………..42 Table 5. Solution Priority Calculation Criteria………………………………………….44 Table 6. Process Map of the Lemtrada Laboratory Monitoring Process and  Failure Modes…………………………………………………………………...46 Table 7. Failure Modes and Effects Analysis for Pre-Analytic Function……………….48 Table 8. Lemtrada Laboratory Monitoring RPN Calculations…………………………..52 Table 9. Mistake Proofing Questions by Principle………………………………………53 Table 10. Lemtrada Laboratory Monitoring Solution Prioritization Calculations……….75           MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 6  List of Images  Image 1. Phases of Laboratory Monitoring……………………………………………… 6          Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    7 Acknowledgements It is with gratitude that I recognize the individuals who supported me through this project. Thank you to my project committee chair, Dr. Sabrina Wong for her support, time, guidance and adaptability throughout this project.  I also want to thank my second committee member, Dr. Sally Thorne, for her leadership and inspiration throughout my masters program and her dedication to this projects completion. Many thanks to my physician colleagues, Dr. Anthony Traboulsee and Dr. Robert Carruthers for providing me with the opportunity to be involved in the development of the automated monitoring project and for their academic and moral support in its implementation. To my nursing colleagues Candace Moore, Laura Domingo, Monica Gruetz, Margaret Perry and Janet Stewart for their humor, commitment and passionate nursing care and for their insights into the challenges and opportunities in caring for this population.  On a personal note, a special thanks to my brilliant husband, Neil and my darling children, Graham and Meredith, who will no longer have to suffer mommy being hunched over a computer. I love you to pieces. To my gregarious family of nurses, thank you for being the standard to which I aspire and the reason that I am on this journey at all.      MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 8 Mistake Proofing Laboratory Monitoring for  Alemtuzumab Treated Patients with Multiple Sclerosis As new treatment regimes emerge, prescribing clinicians must balance the safety of these treatments with the potential benefits for their patients. The treatment of multiple sclerosis (MS) has changed dramatically with the development of disease modifying therapies (Subei & Ontaneda, 2015; Vargus and Tyor, 2017). These immune-modulating and immunosuppressive agents have shown real promise for patients living with the disease, but use of these medications significantly increases a patients’ risk of serious secondary conditions (Eckstein & Bhatti, 2016; Meissner & Limmroth, 2016). Fortunately, these serious adverse events (SAE) are usually well documented. As a risk mitigation strategy, Health Canada requires scheduled laboratory testing on all patients prescribed these medications, to facilitate the identification and management of serious adverse events. Unfortunately, the laboratory process itself is complex and prone to error (Hammerling, 2015). Reliance on this system as a diagnostic tool, without acknowledgement of its’ potential failures, carries its own risk. Additional strategies are necessary to help prescribers prevent harm associated with these medication-related serious adverse events, while accounting for failures associated with the laboratory monitoring process (Settle et al., 2016; Subei & Ontaneda, 2015). Nurses have a unique understanding of the health care system in their role as coordinators of logistical and clinical concerns in outpatient care. The optimization of the nursing role in the outpatient environment could offer some solutions to address the risks in laboratory monitoring. Risk assessment and management by way of  “mistake-proofing” is a developing strategy in healthcare, to identify potential weakness within a system, prioritize risks, and Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    9 stimulate creative solutions. Nurses as care coordinators, bridge the gap between laboratory and outpatient services and are key to understanding the breadth of failures in the laboratory monitoring process. The mistake-proofing method was used in this analysis to identify potential risks and generate solutions in laboratory monitoring of patients with multiple sclerosis treated with alemtuzumab. Problem Statement What are the potential risks in laboratory monitoring with multiple sclerosis patients treated with alemtuzumab and what solutions can be generated to mitigate these risks?  Significance Medication related serious adverse events (SAE) are common in healthcare. It is estimated that 1 in 9 emergency department visits are due to medication related adverse events, and sixty-eight percent of these are preventable (Zed et al., 2008). The Canadian Patient Safety Institute (CPSI) listed medication SAE’s as one of the top priorities for improving patient safety (Canadian Patient Safety Institute, 2009). In the treatment of multiple sclerosis, there is a recent trend towards the use of a more aggressive, inductive therapies. The use of immune modulating and immunosuppressive agents can result in an increased risk of secondary autoimmune disorders because of nature of the effects of these agents on the immune system (Azzopardi et al., 2014). With autoimmune conditions the timeliness of identification and treatment is critical, because the development of destructive antibodies within the body increases over time (Azzopardi et al., 2014). The sooner an immune disorder is identified and treated, the easier it will be to treat. The cost of delays in treatment, as well as the personal cost to individuals affected MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 10 by these events, warrants study into supportive and preventative programs (Hohl et al., 2011; Rodrıguez-Monguio, Otero & Rovira, 2003). Alemtuzumab (Lemtrada) is one of the newest therapies for multiple sclerosis approved for open label use in Canada and is in a category of medications known as monoclonal anti-bodies. Classified as an immune-modulating agent, Lemtrada aggressively depletes circulating lymphocytes, the immune cells initially activated in the destructive process in multiple sclerosis (Genzyme Corporation, 2014; Ruck et al., 2016). Lemtrada was approved by Health Canada in 2014 (Hersh, Jeffrey & Cohen, 2014) as a second-generation treatment for patients with active relapsing remitting multiple sclerosis (RRMS) (Havrdova, Horakova & Kovarova, 2015). This medication has some of the highest efficacy rates for reducing relapses and disease progression in MS and has been shown to improve disability scores in over 40% of treated patients, which is unique in this group of medications (Giovannoni et al., 2016; Willis & Robertson, 2016).  These benefits need to be carefully weighed against the potential risks. Health Canada requires that alemtuzumab-treated patients complete monthly lab monitoring for four years following their last infusion to screen for secondary auto-immune conditions that can occur in up to 35% of the infused population (Coles et al., 2014). This lengthy monitoring schedule is due to the time sensitive nature of potential adverse events and the extended time frame in which these events have been found to occur. If not recognized quickly, these secondary auto-immunities can progress into life threatening illness such as hemolytic anemia, immune thrombocytopenia and kidney failure (Coles et al., 2014). If identified early these serious adverse events are usually treatable (Berger et al., 2017). Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    11 A potential barrier to the prescribing and administration of alemtuzumab may be the inability of many clinicians to ensure consistent, timely response to potentially serious adverse events over such a lengthy period (Berger et al., 2017). Prescribers rely on laboratory monitoring systems to be reliable in order for key information to trigger diagnostic and treatment intervention. If alemtuzumab is to be widely used, the MS community needs to develop innovative approaches to support prescribers in monitoring this patient population effectively and efficiently (Murff et al., 2003). This project uses a patient safety framework to guide the analysis of potential risks in laboratory monitoring with alemtuzumab. Patient safety is always a clinical priority and treatment options for multiple sclerosis patients may be restricted if safe management cannot be assured. It is unfortunate that logistical monitoring concerns may dictate a patient’s treatment pathway, but any program aimed at bridging the gap between laboratory and clinical medicine must first identify and acknowledge the complexity and possibility for error within this system.  Nurses are uniquely positioned to identify and manage these errors and should be involved in the development of healthcare initiatives concerning logistical and clinical systems coordination. The mistake proofing method may be a useful tool for nurses, to identify and prioritize risks within laboratory monitoring systems, in order to generate effective solutions to these issues. Our MS clinic in Vancouver, British Columbia, piloted a nursing team approach to assist in the identification and implementation of programs to address their concerns with failures in the lab monitoring system for patients being treated with alemtuzumab. The nature and frequency of monitoring in alemtuzumab treated patients and potential for serious adverse events if monitoring is not effective, MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 12 underscored the necessity of a robust monitoring program with this population. The analysis outlined in this paper is based on the assessment and expertise of the nurses involved in this quality improvement work, the solutions generated to resolve these issues, and recommendations for future quality improvement in this area.  Background Multiple Sclerosis Multiple sclerosis occurs predominantly in young women, with peak onset at thirty years of age (Raffel, Wakerley & Nicolas, 2016) and it is one of the most common causes of disability in young adults (Noseworthy, 2000). Canada has the highest rates of MS worldwide with nearly 100, 000 people affected (Statistics Canada, 2011). Although the cause of multiple sclerosis is unknown, genetic and environmental risk factors have been identified including, Epstein-Barr virus exposure, smoking, sunlight exposure and vitamin D deficiency, however latitude remains the biggest risk factor, which may account for the high incidence of MS in Canada (Orton et al., 2006).  Multiple Sclerosis is a chronic inflammatory condition affecting the central nervous system (CNS) presumably caused by an autoimmune process of inflammation and destruction of the myelin and nerve cells (Keegan & Noseworthy, 2002). Acute demyelination presents as clinical relapses that partially or fully resolve, while chronic demyelination and neuro-axonal injury result in persistent and irreversible neurological symptoms (Gajofatto & Benedetti, 2015). Although the specific etiology of MS remains unclear, there is evidence of an autoimmune pathogenesis caused by the migration of T and B cells, which become active against an unidentified myelin and/or neuronal antigen, then migrate into the CNS causing inflammation and other mechanisms that lead to Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    13 demyelination, axonal loss, and neuronal death (Friese, Schattling & Fugger, 2014). Myelin assists in the transmission speed of nerve impulses along the nerve cells in the CNS, so impairment or destruction to these cells can have devastating effects clinically (Goksel et al., 2011). As we learn more about this process, it becomes apparent the importance of early intervention and treatment with this disease in order to prevent permanent damage and disability.  Clinical signs that are characteristic of MS are Lhermitte’s phenomenon, described as a brief electric shock sensation with flexion of the neck and Uhthoff’s phenomenon, in which symptoms become transiently worse with hot weather and exercise (Raffel, Wakerley & Nicolas 2016). These phenomena are not present in all MS patients, who report a wide range of clinical symptoms including depression, anxiety, fatigue, bladder, bowel and sexual dysfunction, gait disturbance, cognitive difficulties, muscle weakness, spasticity and pain (Gross & Krieger, 2015; Raffel, Wakerley & Nicolas, 2016). These symptoms can be distressing for patients in their prime working and child bearing years, as studies showing that only 5% of patients with RRMS present with the more benign pattern of disease with infrequent relapses and limited disability (Raffel, Wakerley & Nicolas, 2016).  Diagnosing multiple sclerosis is challenging as there are many conditions that may mimic the clinical presentation (Lyme disease, lupus, neuromyelitis optica) and no single clinical feature or diagnostic test that identifies multiple sclerosis (Miller et al., 2008). Clinicians rely on detailed assessment of clinical presentation, magnetic resonance imaging (MRI) studies, cerebral spinal fluid (CSF) analysis, serum testing, visually evoked potentials and exclusion of other conditions to confirm a diagnosis (McDonald et MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 14 al., 2001). Specific criteria, termed the McDonald Criteria, have been developed to assist clinicians to navigate this complexity (McDonald et al., 2001; Polman et al., 2011).  Multiple sclerosis is categorized into four types. The first episode of MS-like symptoms, which can be attributed to central nervous system demyelination, is known as clinically isolated syndrome (CIS) (Raffel, Wakerley & Nicolas, 2016). If this patient then experiences a series of discrete symptomatic episodes, this patient is considered to have relapsing remitting multiple sclerosis or RRMS (Raffel, Wakerley & Nicolas, 2016). Nearly 90% of the MS population falls in the category of RRMS, which is defined by a pattern of relapse and partial or complete recovery (Raffel, Wakerley & Nicolas, 2016). With time, the frequency of relapses decrease, until there is no discernable relapse, but disability continues to progress. This phase is the secondary progressive phase of multiple sclerosis, or SPMS (Raffel, Wakerley & Nicolas, 2016). The fourth type of multiple sclerosis is primary progressive, in which the patient transitions directly from a clinically isolated syndrome to a phase of continuous disability progression with no recovery phase (Raffel, Wakerley & Nicolas, 2016). Approximately 10% -15% of MS diagnoses are primary progressive multiple sclerosis (PPMS) for which there currently is no approved treatment in Canada (Lassman, Van Horssen & Mahad, 2012; Raffel, Wakerley & Nicolas, 2016). Disease Modifying Therapies to treat Multiple Sclerosis Disease modifying therapies (DMT’s) are a class of medications that “impact the underlying disease in autoimmune conditions” (Multiple Sclerosis Society of Canada, Accessed July, 2017). The disease modifying therapies approved for treatment of Multiple Sclerosis in Canada are only approved for treating the relapsing remitting form Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    15 of MS. These medications are not curative, but vary in efficacy to reduce the relapse rate and slow disease progression over time.  Relapse in the context of MS, is defined as “an episode of neurological disturbance of the kind seen in MS, [lasting for at least 24 hours] when clinic-pathological studies have established that the causative lesions are inflammatory and demyelinating in nature” (McDonald et al., 2001, p. 122). Corticosteroid treatment, orally or intravenously, is often prescribed for relapses to decrease inflammation and shorten the recovery period (Lopez et al., 2015).  In conjunction with steroids, disease-modifying therapies have been developed with the intent to target the immune activity that leads to this inflammation and demyelination. The severity and aggressiveness of multiple sclerosis varies by patient, but the goal for clinicians is to treat MS at the phase at which it is treatable and slow the transition into secondary progressive MS when the brains capacity to compensate for damage created by the inflammatory process is lost. There are thirteen disease-modifying therapies approved for use in Canada, with varying levels of efficacy and risk (Babij & Perumal, 2015; Menzin et al., 2013; Subei & Onteneda, 2015). Neurologists and their patients have a shared responsibility to choose a therapy based on efficacy, their interpretation of their disease course (active, inactive) and their risk tolerance. The approved therapies for RRMS are outlined in Table 1.      MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 16 Table 1. Health Canada Approved Disease Modifying Therapies for Multiple Sclerosis  Note. Adapted from Gajofatto & Benedetti, 2015; Comi, Radaelli, & Sorensen, 2017; Babij & Perumal, 2015; Menzin et al., 2013; Subei & Onteneda, 2015; Kappos et al., 2015. Medication and Route FDA Approval Producer Patient Support Program Monitoring  Requirements Serious Adverse events Relapse Rate  Reduction Interferon beta-1b (Betaseron) SC 3x/wk.  1993 Bayer  Betaplus LFT’s monthly x 6 months, then Q6months Depression, transaminitis, leukopenia, TTP , thyroid disturbance 34% Interferon beta-1a (Avonex) IM 1x/wk.  1996 Biogen Biogen One CBC + diff and LFT’s every 3 monthsx6 months then Q6months Depression, hepatic injury, cytopenias,  thyroid disturbance 32-33% Glatiramer acetate (Copaxone) SC Daily 1996 Teva Shared Solutions N/A Rare anaphylactic reaction 29% Mitoxantrone (Novantrone) IV Q3months 2000 Various  None CBC + diff annually x 5 years MUGA scan every 6 months x 2 years Cardiac Toxicity, anemia, cancers 68% Interferon beta-1a (Rebif) SC 3x/wk.  2002 Serono MS Lifelines CBC + diff and LFT’s Q3months x 6 months then Q6months TSH Q6months Hepatotoxicity, myelotoxicity, autoimmune thyroiditis, microangiopathy, seizures 33% Natalizumab (Tysabri) IV Monthly 2004 Biogen Biogen One JC virus testing WBC, LFT’s Progressive multifocal encephalopathy 68%  Interferon beta-1b  (Extavia) SC Alternate days 2009 Novartis Extavia GO CBC, LFT’s Q6 months Hepatotoxicity, myelotoxicity, autoimmune thyroiditis, microangiopathy, seizures 34%  Fingolimod (Gilenya) PO 1x/day 2010 Novartis Gilenya GO BP monitoring every 3 months CBC + diff, liver enzymes every 3 months, eye exam every 3-6 months Bradycardia, lymphopenia, viral infections, macular edema, hepatotoxicity, hypertension 50-54% Teriflunomide (Aubagio) PO 1x/day 2012 Sanofi-Genzyme MS One to One CBC + diff, liver enzymes Monthly x 6 months, then Q6months Mylotoxicity, hepatotoxicity, peripheral neuropathy, pancreatic fibrosis, teratogenicity 32-37% Dimethyl Fumerate (Tecfidera) PO 2x/day 2013 Biogen Biogen One CBC, urinalysis and LFT’s Monthly x 4 months then Q6months Lymphopenia, progressive multifocal leukoencephalopathy 44-53% Alemtuzumab (Lemtrada) IV Consecutive days x 2 cycles (8 doses) 2014 Sanofi-Genzyme MS One to One CBC, CR, U/A monthly and TSH q3months Cytokine release syndrome, lymphopenia, autoimmune thyroiditis, immune thrombocytopenia, glomerular nephritis 48-55% Interferon beta-1a (Plegridy) IM twice monthly 2014 Biogen Biogen One CBC + diff and LFT’s Q3months x 6 months then Q6months TSH Q6months Hepatotoxicity, myelotoxicity, autoimmune thyroiditis, microangiopathy, seizures, depression 38% Daclizumab (Zinbryta) SC Monthly 2016 Biogen Biogen One LFT’s Monthly x 6 months Autoimmune hepatitis, autoimmune hemolytic anemia, colitis 45-54% Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    17 Each of these medications works in a slightly different way to deceive or modify the immune system to be less active against the myelin in the central nervous system. Although these immune-modulatory and immunosuppressive agents play an important role in reducing relapse rates and disability progression in MS, the effect of first generation therapies has been modest, reducing relapse rates by 20-35% (Gajofatto & Benedetti, 2015). These therapies are considered for those with a less aggressive disease course, though many MS patients with more aggressive disease are started on these first line therapies due to funding and access issues (Wilsdon, Barron, Mitchell-Heggs & Ginoza, 2014). First line therapy includes the injectable interferon’s, glatiramer acetate, and newer oral treatments, teriflunomide and dimethyl fumarate (Gajofatto & Benedetti, 2015). Second line therapies such as fingolimod, reporting efficacy rates of 30-40% and natalizumab, alemtuzumab and daclizumab, have higher annualized relapse reduction rates (ARR) at 68%, 55% and 54% respectively (Gajofatto & Benedetti, 2015). Mitoxantrone, a chemotherapy approved for use in MS is included in this high efficacy group and has an ARR of 68% (Gajofatto & Benedetti, 2015). High efficacy treatments also include some off label use of immunosuppressive therapies indicated for other conditions, which are then adapted for use in Multiple Sclerosis. Rituximab, originally intended for use with rheumatoid arthritis, is an antibody targeting the antigen CD20 on B-lymphocytes, making it effective in the presumed pathogenesis in MS (He, Guo, Zhang, Dong & Zhou, 2013).  Cyclophosphamide is another chemotherapy used off label for MS in some centers (Awad & Stüve, 2009). Ocrelizumab is the humanized version of the CD20 MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 18 antibody, which was approved by Health Canada in August 2017, but is not yet commercially available (Hoffman-La Roche, 2017). Ocrelizumab (Ocrevus) is the only disease modifying therapy that is targeted for FDA approval for both the relapsing remitting and progressive forms of MS (Montalban et al., 2017). These higher efficacy medications have improved reduction in annualized relapse rates, but also carry added risk of serious adverse events, which may be fatal. These include but are not limited to: natalizumab-associated progressive multifocal leukoencephalopathy (PML) (Biogen Canada, 2016, Tysabri); autoimmune thyroiditis, thrombocytopenia and glomerulonephritis associated with alemtuzumab (Sanofi Genzyme, 2017); autoimmune hepatitis, hemolytic anemia and colitis with daclizumab (Biogen Canada, Zinbryta, 2016); cardiomyopathy and acute leukemia with long term therapy with mitoxantrone (EMD Serono, 2008), and cyclophosphamide (Baxter Corporation, 2012). Rituximab and ocrelizumab carry a risk of hepatitis re-activation and progressive multifocal encephalopathy (PML) (Hoffman-La Roche 2016, 2017), and all immunosuppressive therapies carry the risk of serious infections (Boster et al., 2008).  These risks are viewed differently based on the personal beliefs and goals of individual patients with MS and have not prevented patients from requesting access to these high efficacy therapies. Recent magnetic resonance imagining (MRI) and histologic studies have shown that MS is not limited to the white matter as previously thought and that the inflammatory process extends to the cortical grey matter and overlying meninges (Stys et al., 2012; Raffel, Wakerley & Nicolas, 2016). Multiple Sclerosis is no longer considered a dormant disease in the absence of relapse. Whole brain atrophy occurs in the MS brain at a rate ten times that of a non-MS brain, regardless of the presence, frequency Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    19 or severity of relapses (Alroughani et al., 2016). This is leading to a paradigmatic shift in the treatment of MS towards an induction approach, where more aggressive treatments are considered earlier in the disease course to prevent disease progression and preserve the brains reserve (Shimizu, Ikeguchi & Kitagawa, 2017; Merkel et al., 2017).  The end goal of therapeutic intervention with high efficacy therapies is no longer simply the prevention or relapses, but for radiographic and clinical stability and the possibly of improvement. How we measure treatment success in MS must also change. No evidence of disease activity, or NEDA, is a term in its infancy, being used by the MS community to identify cases of therapeutic stability where a patient has no evidence of radiologic progression, and no physical symptoms of relapse or disability progression (Giovannoni et al., 2015).  High efficacy medications allow MS clinicians real opportunities to alter the disease pathway for their patients and provide some hope of improvement in patient symptoms, a concept not conceivable with first generation therapies for MS. The limitation is that practitioners need to be able to prescribe these agents with an assurance that they can optimally manage adverse events, and patient safety. Alemtuzumab Alemtuzumab (Lemtrada) is unique amongst high efficacy therapies in MS, both in the dosing structure and monitoring obligations. Lemtrada is administered as 12mg intravenous infusions on 5 consecutive days at baseline and then 3 consecutive days 12 months later (Sanofi Genzyme, 2017). Despite the absence of therapy for 12 months, the effects of treatment have shown durability between cycles (Berger et al., 2017) and low MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 20 retreatment rates (Berger et al., 2017). With alemtuzumab, there is minimal concern with patient compliance with drug therapy, as the therapy is in a controlled environment over consecutive days, but there is concern with laboratory monitoring compliance, which may be burdensome for patients (Berger et al., 2017).  Lab monitoring requirements for patients treated with alemtuzumab include a monthly complete blood count and differential (CBC + diff), creatinine (CR) and urinalysis testing (UA), as well as quarterly thyroid stimulating hormone (TSH) testing, for four years after the last infusion. This testing frequency was designed to capture secondary autoimmune conditions that may develop in the post treatment period, including immune thrombocytopenia (ITP), glomerular basement membrane syndrome (GBM or Good Pastures disease) and thyroid conditions (Sanofi Genzyme, 2017). The incidence of these serious adverse events varies by condition. Thyroid disorders are the most prevalent at 20-30% (Arahna et al., 2013; Sanofi Genzyme, 2017). This includes hypothyroid and hyperthyroid conditions, though serious thyroid conditions are rare (<1%) (Berger, 2017; Sanofi Genzyme, 2017). Immune thrombocytopenia has been found in approximately 1% of patients treated with alemtuzumab (Sanofi Genzyme, 2017) and glomerular nephropathies were reported in 0.3% of patients (Sanofi Genzyme, 2017). Other rarely occurring autoimmune disease observed in the CARE-MS trials included neutropenia, hemolytic anemia, agranulocytosis and pancytopenia  (Cohen, 2012; Coles, 2012). The underlying mechanism that triggers these secondary autoimmune conditions is not fully understood, but it is thought to occur as a result of T cell proliferation, to restore homeostasis following the precipitous lymphodepletion pattern that is seen with Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    21 alemtuzumab (Jones et al., 2013). Although monitoring cannot prevent these events, early detection can reduce the severity and impact of these conditions (Berger et al., 2017). REMS and Patient Support Programs Health Canada has implemented the FDA requirements for drug safety by requiring the pharmaceutical industry develop risk evaluation and mitigation strategies (REMS) for Alemtuzumab (Sanofi Genzyme, 2017; Health Canada, 2015). These REMS are deemed necessary when questions exist whether the benefits of a drug outweigh the risks (Nicholson et al., 2012). Genzyme has a strict compliance policy for these REMS conditions set by Health Canada and requires all prescribing physicians to comply with monitoring and all infusion nurses to be certified in pharmacovigilance, monitoring, identification and reporting of adverse events (Sanofi Genzyme, 2017). To support clinicians in meeting these risk mitigation requirements, as well as enrollment and monitoring obligations, the MS One to One Patient Support Program was developed (Sanofi Genzyme, 2017). Enrollment in a patient support program is a requirement for monitoring with Lemtrada in Canada.  Each disease modifying therapy to treat multiple sclerosis has a patient support program to assist patients and prescribers to navigate the requirements for each specific program. These programs provide varied levels of nursing support to assist with the enrollment, reimbursement, education, pre-screening, administration, and monitoring of patients to support prescribing physicians. Studies have shown statistically significant reductions in inpatient or emergency room utilization and total MS-related medical costs among patients enrolled in patient support programs (Menzin et al., 2013), but ultimately the responsibility of safe monitoring remains with the prescriber.  MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 22 Clinical Monitoring  The failure to review and follow up on outpatient laboratory results is a concern for both patients and physicians and represents a significant safety issue in healthcare (Murff et al., 2001). Delays in diagnosis and treatment as a result of failings of timely laboratory monitoring has also been recognized as one of the fastest growing areas of malpractice litigation in the United States (Kravitz  et al., 1997) and physicians recognize this quality gap (Murff  et al., 2003). The conventional physician-centric approach to laboratory monitoring is insufficient to identify missing, abnormal and critical laboratory results in the current clinical model, where laboratory testing has been integrated into the standard of care (Hammerling, 2012). As the clinical laboratory integrates with the broader healthcare system, it has a significant impact on diagnosis and clinical outcomes. Unfortunately, the rates of error in laboratory monitoring remain high, with overall error rates ranging from 1.2% to 75% (Bonini, Plebani, Ceriotti & Rubboli, 2002; Lippi & Cesare Guidi, 2007; Chawla, Goswami, Tayal, et al., 2010; Hammerling, 2012). This variability in the reporting of error rates is determined by the phase of the laboratory process that is assessed and the differences in the inpatient and outpatient environments. Some of the first evidence exploring laboratory errors was provided in the study conducted by Stroobants and colleagues, who initially found the error rate in laboratory medicine as high as 20% (Stroobants, Goldschmidt & Plebani, 2003). This study prompted efforts to reduce error rates within the laboratory environment, but this study extended beyond the lab and was the first to elucidate the significance of error in the pre and post laboratory environments (Stroobants et al., 2003). The researchers in this study Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    23 conceived their findings graphically and developed the hourglass model to visually represent the distribution of errors in the laboratory process (See image 1). Image 1. Phases of Laboratory Monitoring  (Plebani, M., 2009, p. 18) This model divides the laboratory process into the pre analytical, analytical, and post-analytical phases (Stroobants et al., 2003; Plebani, 2009). The pre-pre analytical phase represents the work that is done prior to the specimens reaching the laboratory. Errors in this phase represent issues with the ordering of tests by physicians, blood collection (such as clotting) and mislabeling (Stroobants et al., 2003). Pre-analytical phase errors occur in the lab immediately before the analysis occurs. This represents general administrative errors, order entry in the lab, and inaccurate data entry (Stroobants et al., 2003). The analytic phase represents the work done by the laboratory technicians themselves and the post analytic phase is the movement of the information to clinicians (Stroobants et al., 2003). Issues arising in this phase would be errors in reporting results to clinicians, clinicians responding inappropriately to the results or failing to notify the patient of the results (Stroobants et al., 2003). Errors in the Post-post analytic phase MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 24 would be errors of diagnosis or treatment (Stroobants et al., 2003). Further study into the analytic phases of laboratory monitoring reinforces the findings of the Stroobants study. The pre-analytical phase is described by Lippi et al. as the “most vulnerable to uncertainties and accidents [due to] system flaws and insufficient auditing of operators involved in specimen collection and handling, leading to an unacceptable number of unsuitable specimens due to in vitro hemolysis, clotting, insufficient volume, wrong container, contamination and misidentification “(Lippi & Cesare Guidi, 2007, p. 720).  Hickner et al. (2008) found similar patterns of error within the pre and post-analytic phases, reporting data from a survey involving 243 clinicians of the surgeries of 8 family practitioners. Participants submitted 590 event reports with a total of 966 testing process errors, the most common types being related to reporting results to clinicians (24.6%), implementing tests (17.9%), general administrative errors, such as filing and chart availability (17.6%) and test ordering (12.9%) (Hickner et al., 2008, p.196). No analytical errors were reported, and the authors underlined that “analytic errors represent < 10% of testing process errors and are unlikely to be observed in primary care offices” (Hickner et al., 2008, p. 200).  There are many stages in the various phases of laboratory monitoring where error could occur, from non-compliance, to administrative errors, to retrieval and diagnostic errors, which extend past the laboratory environment. This is now recognized and interdepartmental and intersystem collaborations are aimed at reducing these error rates (Hammerling, 2012), but any healthcare process dependent upon laboratory monitoring must plan and account for these potential errors.  Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    25 The consequences of laboratory process failures were reported by Hickner and colleagues and include delays in care (24%), time/financial issues (22%) and pain/suffering (11%). No harm was observed in 54% of cases, while emotional (6%) and temporary physical harm (11%) were the most frequently recorded types of damage (Hickner et al., 2008). Despite the risks associated with laboratory monitoring, one study reports that fewer than 25% of physicians have a reliable method to identify patient compliance with laboratory testing (Boohaker et al., 1996) and one third of physicians did not notify patients when results were abnormal (Boohaker et al., 1996). The reasons for this are likely multifactorial, but one study identified that time constraints, financial constraints and unfamiliarity with logistical options are possible reasons why physicians are unable to address these issues independently (Boohaker et al, 1996). A later survey found that 59% of physicians still reported dissatisfaction with how they managed test results and 83% reported delays in reviewing tests over a two-month period (Poon et al., 2004).  Innovation to reduce the burden of laboratory monitoring has come from both technological and human resource initiatives (Hammerling, 2012). These investments usually require additional financial resources and may not be available to every practitioner or practice. Fischer et al. (2014) examined the specific clinical factors associated with increased risk in laboratory monitoring and found that there was greater risk with providers who prescribed high risk medications, providers who prescribed these medications less frequently, with medications that have specific monitoring recommendations and prescribing for patients that are younger, healthier, with less frequent contact with their health care provider (HCP). Interestingly, they found MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 26 increased risk of non-compliance with laboratory monitoring by patients whose medications carried black box warnings, which was counter to their expectations (Fisher et al., 2014). Black box warnings are typically used for drugs that carry the potential for life-threatening adverse events (Federal Drug Administration, 2012).   If we compare these factors to the MS clinical environment, we find the majority of these factors apply and healthcare providers caring for patients with multiple sclerosis recognize their population as high risk for non-compliance and adherence issues (Hansen et al., 2015). Additional patient factors specific to multiple sclerosis patients are cognitive issues, mobility issues and changes in family support and financial circumstances, which may lead to unintentional non-compliance and adherence (Costello et al., 2008). In an international study, Devonshire et al. found that 50.2% of multiple sclerosis patients were non-adherent to MS therapies because they forgot to administer their medications (Devonshire et al., 2011; Halpern et al., 2011). Fisher and colleagues found similar cognition issues in monitoring, concluding that “patient memory played the largest role in contributing to non-completion” of laboratory testing in MS patients (Fisher et al., 2013, p. 518). This can have considerable clinical consequences and is a reason why medication compliance and management of side effects make up a significant portion of the clinician-patient relationship in MS care (Devonshire et al., 2011). Additional risk factors influencing compliance are alcohol dependence, longer disease duration, lower disability status (EDSS) and more frequent medication dosing (Correia et al., 2016). Identifying these characteristics may assist healthcare professionals to extricate patients at greatest risk and anticipate the need for increased compliance support (McKay et al., 2016).   There are no studies that I have found that look at real-world adherence rates with Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    27 alemtuzumab laboratory monitoring, but it would be expected that with laboratory monitoring monthly for five years, monitoring fatigue and complacency could exist. In clinical trials, researchers in the ongoing EMERALD study [Evaluation of the Management of Infusion Reactions in Alemtuzumab- treated Patients] reported that patients with multiple sclerosis treated with alemtuzumab in study had high compliance rates both with the dosing schedule for infusions and the mandatory concurrent medication regime (100% for acyclovir or equivalent, H1 antagonist, methylprednisolone, and NSAID/antipyretic; 98% for H2 antagonist) but they did not address laboratory monitoring specifically (Vukusic et al., 2015). In 2014, Cuker et al. singled out laboratory monitoring rates specific to ITP in MS patients receiving alemtuzumab while in study and found that 96.5% of total expected monthly blood-monitoring tests were completed (Cuker et al., 2014). This may not translate to the real-world experience where the additional supports of the clinical trial environment are absent.  Factors found to improved adherence to therapy with MS, are access to and communication with healthcare providers, establishing an open and honest healthcare provider-patient relationship, setting realistic expectations about therapy and providing ongoing education about MS, injection technique and adverse event management (Costello, K. et al., 2008). A later study found the biggest contributor to improved compliance was empathy of the treating physician and a setting with MS nurses taking care of the patient (Bischoff et al., 2012).  “Thus, our observations broaden the currently available data on the high impact of   the patient–physician relationship on adherence. In addition, the support of an MS MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 28 nurse was considered of great importance for initiation and continuation of therapy. This underlines the impact that disease management programs in general and nursing systems in particular have for the support of patients suffering from chronic diseases like MS. To improve adherence to the therapy in chronic diseases like MS, more individual support and coping strategies have to be developed. Overall, the influence of self-competence, psychosocial and organizational factors on adherence seems to be as important as the expertise of the doctor and so-called ‘hard’ medical facts. The patients want to feel safe with the medication and emotionally accepted. As a consequence, positive adherence is not generated by an isolated factor but by the interplay of multiple factors made up of adequate organization” (Bischoff et al., 2012, p. 2352). Fisher and colleagues found that logistics, such as the convenience of the lab location, also played a major role in contributing to completion in their study (Fisher et al., 2013), which speaks to the need for flexibility and patient-centered care approaches. The lack of clear cause or cure for multiple sclerosis can lead patients to search for new information to confirm or deny their complex beliefs about their disease. Without a positive patient-provider relationship, these extraneous influences can lead to distrust, non-adherence and the potential for unsafe choices by patients and their families in MS (Bischoff et al., 2012). Support Roles in Clinical Monitoring Recognizing the specific needs of the population they treat, specialty clinics frequently employ team management approaches to support clinical programs (Litaker et al., 2003;Wagner, 2000). Whether this is clerical support, registered nurses, extended Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    29 practice nurses (patient care coordinators, clinical nurse specialists, nurse practitioners) or pharmacists, each group has shown to improve the clinical monitoring process (Larsson et al,. 2015: Koksvik et al., 2013; Hall, J. et al., 2016). What differentiates these groups, is the value added based on their clinical focus and expertise. Medical office assistants (MOA) or clerical support staff would benefit those practices where organization, facilitation and follow up are the primary issues. The addition of nursing staff would best support educational gaps, clinical assessment, symptom management, and the coordination of allied health professionals. Pharmacists would be best utilized to assist with medication titration, dispensing and medication specific education. Nurse practitioners work in independent practice to diagnose and manage patient care according to their scope. Clinical groups need to critically assess their practice to determine what support staff would meet the specific needs. Medical office assistants are vital care team members in the coordination of administrative duties in practice. The work of replacing requisitions, following up on missing test results and answering patient questions about the laboratory monitoring process are often absorbed by these administrative staff (Health Match BC, 2017) and this may influence their perception of safety of systems within healthcare. Hickner et al. (2016) found that medical office assistants are the least confident in the safety of healthcare processes, followed by nurses, pharmacists and physicians. Physicians may not recognize the extent to which administrative issues are affecting their monitoring practice, yet we have seen from research into the laboratory process that these administrative errors play a significant role in the rates of overall error in laboratory monitoring system.  MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 30 Nurses are important members of the care team in multiple sclerosis and there are numerous studies highlighting the impact and cost effectiveness of nursing programs to support laboratory monitoring and improve clinical outcomes (Larsson et al., 2015; Caon et al., 2015). Nursing involvement in MS care has been shown to improve patients perceived ability to cope (Burke et al., 2011), improve patient satisfaction (Hill, 1997; Ndosi et al., 2011), improve well-being (Hill et al., 2003; Arthur & Clifford, 2004; Koksvik et al., 2013) and adherence with monitoring (Koksvik et al., 2013). Despite the positive effect nurses have on patient outcomes, there are reports that 40% of nurses feel their skills are underutilized (Allard, Frego, Katz & Halas, 2010). Nursing leaders are exploring ways to optimize nurses roles in specialty care to improve patient safety, care quality and reduce health care costs (Canadian Nurses Association, 2013). There are three categorizations of registered nursing practice in British Columbia: general registered nurse practice, certified nurse practice and nurse practitioner practice (College of Registered Nurses of British Columbia, Nursing Scope of Practice, 2017). The College of Registered Nurses of British Columbia (CRNBC) categorizes these nursing roles in terms of health promotion, prevention, maintenance, and restoration, and illness prevention, treatment and palliation (CRNBC, Nursing Scope of Practice, 2017). Registered and certified nursing practice allows for independent planning, implementation, evaluation and coordination of interventions and health services, including client assessments, carrying out activities to treat, prevent, or palliate injury or illness and manage and evaluate the outcomes of the activity, relating to nursing diagnoses (CRNBC, Nursing Scope of Practice, 2017). Registered nurses are trained to interpret and use evidence in autonomous practice and are ideally suited for involvement Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    31 in patient safety planning and implementation. Nurse-led models of care “optimizing health, improving access to care, reducing pain and suffering, and saving the healthcare systems millions of dollars” (Canadian Nursing Association, 2013, p. 2). Through additional training and certification, nurse practitioners have an extended scope of practice that allows for advanced assessments, autonomous ordering, diagnosing and management of patient care. The limits of NP practice are determined by provincial regulation and legislation, regulatory limitations, employer policies and the individual NP competence (CRNBC, Scope of Practice for Nurse Practitioners, 2017). The CRNBC outlines that autonomous NP practice should be determined by the competence of the individual and places specific controls on NP practice relating to prescribing of controlled substances, cosmetic treatments and the application of hazardous forms of energy (CRNBC, Scope of Practice for Nurse Practitioners, 2017). Despite these limitations, nurse practitioners have a significant impact on access to care in chronic disease (Dicenso et al., 2010) and have comparable outcomes to physicians in similar fields (Mundinger et al., 2000). Canada is behind other countries in the integration of nurse practitioners into the primary care model, but neurology has been identified as an area of chronic disease management that would benefit from nurse practitioners (Canadian Nurses Association, 2013). Recently, the pharmacist role has expanded into specialty medication management and pharmacists are being piloted as satellite team members to assist physicians with patient education, compliance, monitoring and access to disease modifying therapies in multiple sclerosis (Habibi & Kuttab, 2016). Studies have found in a comparison of patient satisfaction between physician and pharmacist that it was the MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 32 same (Hall et al., 2016). A limitation to pharmacists’ seamless involvement in patient safety initiatives is that clinical patient data are not readily available to pharmacists in many care settings and they rely on the clinics to provide this information in order to make clinical decisions. This may increase rather than decrease the workload on the clinic and may be better served by an integrated clinic team member (Raebel et al., 2005). Lemtrada Lab-Monitoring Program  To address clinic concerns with the complicated enrollment, access and monitoring process with alemtuzumab in British Columbia, our MS clinic in Vancouver hired a patient care coordinator (PCC) to assess and develop solutions to address potential safety issues in clinical practice. An adverse patient event prompted further exploration into the rates of patient non-compliance and missing laboratory results in our clinic. In my role as patient care coordinator, I explored patient safety frameworks to guide my initial analysis of these aspects of our clinic process. We have a large population of patients treated with alemtuzumab and management of this population was time and resource intensive. We were presented with the opportunity to collaborate with developers from Excelleris to explore technological solutions to our laboratory monitoring issues. The Lemtrada Automated Lab Monitoring Program is a patient safety initiative, developed in collaboration with MS neurologists, nurses, programmers, designers and executives to address the safety concerns in laboratory monitoring with alemtuzumab. This program builds on the nursing team management program to address access, timeliness, and non-compliance with monitoring that were identified as significant concerns by the MS health care providers (HCP), but also to identify and mitigate the less obvious risks associated with laboratory monitoring. The automated Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    33 blood monitoring alert system was designed to alert patients and health care teams through email and text, of upcoming patient appointments, missed appointments and abnormal laboratory results. This program uses a web-based portal and clinical algorithm, which overlaps the Excelleris provincial laboratory platform, to harvest all laboratory tests results entering this system for our enrolled patients. British Columbia is fortunate to have a unified provincial database for laboratory tests that covers approximately 85% of our provincial patient results. The automated program captures the laboratory results of enrolled patients, regardless of their ordering physician. For those patients who lie outside the area captured by the Excelleris database, employees of the Lemtrada patient support program link the results manually so that all enrolled patient laboratory results are in one portal for the care team. We anticipate the number of manual entries to be approximately 20% of the population, which is much less taxing on human resources than conventional laboratory monitoring.  The development team recognized the uniqueness of this opportunity to generate effective technological solutions in laboratory monitoring and wanted to ensure that the system was effective in eliminating actual and potential risk. Patient safety frameworks were explored to guide the design and implementation of the program in practice. This analysis will discuss the issues identified by the Lemtrada infusion nurses, the Lemtrada Patient Care Coordinator and the MS One to One patient support nurses in this design and my use of the mistake proofing method to further examine potential risks and solutions, prior to program implementation.  MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 34 Patient Safety and Quality Improvement Methodology Patient safety is just one aspect of quality patient care, but its significance within the quality spectrum is gaining prominence. In the past decade, the patient safety concept has become a healthcare priority, as new research has challenged long held assumptions of the cause of errors in health care and broadened our understanding of how systems and organizations affect safety. Prior to the 1990s the basic assumption was that quality care was a “natural outcome of conscientious work by highly motivated clinicians” (Vincent, 2010, p. 15). In turn, medical errors were assumed to be the result of failures by individuals, due to laziness, lack of education, or inattentiveness that leads to harm. In this line of thinking, the solution to prevent these events would be educating, disciplining or removing these individuals (Vincent, 2010). When these solutions failed to prevent errors or improve outcomes, new theories began to emerge (Vincent, 2010). Human factors research has shown that individual behavior is seldom the root cause of errors in healthcare and that healthcare providers do a fairly good job of preventing harm within a system that is designed to fail (Dekker, 2011).  The Harvard Medical Practice Study (HMPS) was one of the first studies to reveal the extent and seriousness of harm in medical treatment (Hiatt et al., 1989). This study found that unintentional harm occurred in 4% of all hospital admissions and 1% of those patients were seriously harmed (defined as death or permanent disability) as a result of care provided in hospital (Brennan et al., 1991; Leape et al., 1991). The findings from the HMPS study gained international attention when they were presented in the Institute of Medicine (IOM) Report To Err is Human in 1999 (Kohn, Corrigan & Donaldson, 1999). Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    35 This sentinel report brought together research on medical error and adverse events in the United States and extrapolated the financial and human impact on a national level. This report concluded that “44, 000- 98, 000 Americans died each year as a result of medical errors; more than motor vehicle accidents, breast cancer and AIDS combined “(Kohn et al., 1999, p. 26). The national costs of lost income, lost household production, disability and health care related to preventable adverse events were estimated to be between $17 billion and $29 billion (Kohn et al., 1999, p. 27). The significance of these events could no longer be ignored. Modern medical care was far from doing no harm, but was causing significant harm to patients. The IOM followed this with another report in 2001, “Crossing the Quality Chasm” and designated the six dimensions of quality care: effectiveness, safety, timeliness, efficiency, equity and patient-centeredness (Institute of Medicine, 2001). These quality domains defined the objective of future quality improvement initiatives in healthcare and unlocked resources to look deeper into quality issues.       Arguably the most important of these domains, patient safety is defined as the “avoidance, prevention and amelioration of adverse outcomes or injuries stemming from the process of healthcare” (Vincent, 2010, p. 31). This modern definition acknowledges that healthcare is prone to failure and that healthcare organizations need to actively seek out processes and practices that could be harmful, rather than passively counting errors. The safety of patient care would only be improved by “holding systems accountable” and redesigning systems to “mitigate the effects of human factors and using strategic improvements” (Kohn et al., 1999, p.134). MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 36 When considering a systems approach to healthcare improvement, it is helpful to define the difference between active and latent errors. Active errors are recognized immediately and are usually attributed to the front-end staff or the sharp end of healthcare (Reason, 1990). Active errors rarely require complex systems of identification, as they are immediately identifiable, reportable and acknowledged (Reason, 1990). Latent errors are not immediately detectable and can therefore influence systems for a significant period of time, until the right circumstances make them apparent (Reason, 1990). Latent errors are usually attributed to the design and management of a system and “pose the greatest threat to the safety of a complex system” (Reason, 1990, p. 173). Using this concept of active and latent errors, James Reason developed the latent errors theory, or Swiss cheese model, where he conceptualized hazards and defenses in a system like layers of Swiss cheese (Reason, 1990). When a hazard enters this system, not every hazard will be able to penetrate the systems layers, but when the holes in a defense system align, hazards can breach these defenses resulting in harm (Reason, 1990). The role of patient safety principles in healthcare design is to actively identify and “plug” these holes to prevent harm.      Unfortunately, healthcare is neither this simple nor this linear a process and although this model is helpful in conceptualizing the interplay of hazards and harm, more specific tools are needed to identify weak points within a systemic if we are to design programs to thoughtfully address them. The complexity of healthcare has limited organizational efforts to isolate specific cause and effect relationships in medical error. Healthcare leaders have examined successes in other complex, error-prone systems to guide more comprehensive analysis of Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    37 error, failure and harm (Dekker, 2011). Business, production and aviation industries have all contributed tools and frameworks to guide possible solutions (Grout, 2007), but no single tool can be adapted to every problem and multiple tools are often required to unpack complex issues.  Lean management methodology has been widely adopted in healthcare and is borrowed from management ideology developed in the automotive manufacturing processes at Toyota (Sahney, 2003). Lean development is driven by consumer needs, improves processes by removing activities that are non-value-added or wasteful (Hughes, 2008) and is described as a “[decentralized organization of management] to promote the discovery, correction, anticipation, and prevention of process defects and the errors and abnormalities that result in defects” (Carlson & May, 2016, p.11). Discovery, correction and preventive solutions are generated by those on the front-line with a working knowledge of the immediate issues (Hughes, 2008). Mistake-proofing or Poke-Yoke (po-kay, yo-kay), is a concept within the Lean management framework that applies practical tools to identify, prioritize and develop solutions to system failures (Carlson & May, 2016). The solution generation aspect of mistake proofing and its prospective approach to the identification of systemic failures is what differentiates this method from other analysis tools. “A recurring theme in quality improvement literature is that we are good at identifying problems but not so good at devising methods to solve them. The tools available to actually conceive of what the improvement should be are limited” (Grout, 2007, p. 31). The mistake-proofing method was chosen for this analysis because it includes an analysis of both the present and potential issues and allows for the generation of solutions that can be recommended in practice. MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 38 Mistake-Proofing Method. The basic principles of mistake proofing are elimination, replacement, facilitation, detection, mitigation and most recently patient involvement when applied to healthcare. See table 2. Table 2. The Six Principles of Mistake-Proofing 6 Principles of Mistake-Proofing Principle Definition Elimination Analysis of the process, breaking down into discrete steps or operations Replacement Replacing one operation with a more reliable machine/method/automation Facilitation The process of making operations easier to complete correctly. Includes levels of simplifying, differentiating and adjusting as appropriate (clinical guidelines)  Detection The process of catching anomalies/deviations and correcting them as soon as they are noted  Mitigation Accepts and embraces the fact that errors will occur. Its intent is to reduce the impact of inevitable errors on the final outcome  Patient Involvement Ensures an additional set of eyes on the process (Duke University, 2017).  Elimination, replacement and facilitation are preventative principles, identifying solutions to failures before they occur. Detection and mitigation are means of minimizing the effects of mistakes once they have occurred (Grout, 2007). These principles provide the ideology to support the focus of mistake-proof quality improvement efforts, but offer no practical guidance on specific techniques to identify and anticipate potential risks. Prospective hazard analysis approaches (PHA) are common in high-risk industries, but work is still being done to adapt these techniques to the specific needs of healthcare (Potts et al., 2014; Franklin et al., 2012). Contrary to the more common retrospective risk management practices, PHA methods are proactive and anticipatory, which is valuable in Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    39 the development of healthcare quality improvement initiatives, where it is necessary to consider both actual and potential issues. Under the umbrella of PHA’s there are variety of tools available to undertake an analysis, such as structured what-if technique (SWIFT), hazard and operability studies (HAZOP), barrier analysis, event tree analysis (ETA), fault tree analysis (FTA), failure mode and event analysis (FMEA), human error assessment and reduction technique (HEART), influence diagrams, and risk matrices (Vincent, 2010). Each of these methods has a particular focus, depending on the intended outcomes of the improvement work, but the variety of tools can create confusion.  Many of these prospective analysis tools would be compatible with the mistake-proofing framework, but for this project, process mapping and failure modes and effect analysis were used to support mistake proofing questioning and solution prioritization. Table 3. Mistake-Proofing Tools Mistake-Proofing Design Tools Solution Tools Failure Modes and Effects Analysis (FMEA) Process Mapping  Brainstorming Mistake-proofing Questions Solution prioritization number  Failure Modes and Effects Analysis (FMEA) Failure modes and effects analysis is the most studied and familiar tools for risk analysis in healthcare and is the tool most commonly integrated into the mistake proofing methodology because of its effectiveness in distinguishing the range of possible failures and their causes (Grout, 2007). It is a structured, systematic approach involving a “multidisciplinary team mapping out a high-risk process of care, identifying the failures that can occur and then characterizing each of these terms of probability of occurrence, MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 40 severity of effects and detectability, to give a risk priority number used to identify failures most in need of attention” (Franklin et al, 2012, p. 607). The FMEA method provides the structure to look at a process and unpack the range of possible failures, the seriousness of those failures, the likelihood that they will occur in the local system being analyzed and finally what controls the local system has in place to prevent failures causing harm.  The FMEA process consists of five major steps: 1. Defining the topic and identify the scope of the analysis.  a. Are you analyzing a concept, system, design, process or service?  What do you expect it to do? What to you want to include and what are the boundaries?  2. Assemble a multidisciplinary team  a. What disciplines and functions are involved in this process? (Designers, quality, improvement, IT, lab techs, nurses, physicians, allied health, maintenance, purchasing).  b. Include subject matter experts for all disciplines. c. Identify a team leader for the group.  d. Non-expert involvement may increase the diversity of information in the analysis  3. Draft the process graphically  a. Process mapping graphically presents the process, identifies the major steps and conceptualizes how information and/or people flow through a system.   Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    41 4. Conduct a Hazards Analysis a. For each process step or “function”, identify the range of possible failures that could occur for that step. These are the “failure modes”. i. For each failure mode identify all of the consequences of that failure downstream in the process. This will outline the “potential effects of each failure”.  1. How serious are these effects? This is will help quantify the significance (S) from 1-10 where 1 is the least significant and 10 is catastrophic. ii. For each failure mode what are the range of causes for each failure? This determines the “potential causes”. 1. How likely is this to occur? This will help quantify the occurrence (O) from 1-10 where 1 is the least likely and 10 in the most likely. iii. What controls are in place to prevent these failures? This is the current “process controls”. 1. How likely is it that this failure mode would be detected with the current controls? This will help quantify the detectability (D) from 1-10, where 1 is the most likely and 10 is the least likely. iv. Multiply severity by occurrence and detectability to determine the risk prioritization number (RPN), which will rank the immediate importance of each risk. MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 42 5. Determine actions and outcome measures a. What must be changed to prevent failures and how it will be measured? (Adapted from DeRosier, Stalhandske, Bagian & Nudell, 2002, p. 247; Vincent, 2010, p. 161). Table 4. Example of Failure Modes and Effects Analysis Procedure Function Failure Mode Potential Effects of Failure (S) Significance 1-10 Potential Causes of Failure (O) Occurrence 1-10 Current Process Controls (D)  Actions and Outcomes List the distinct steps in the process List how these functions could fail List the potential effects of these failures.  How significant are these failures?  What are the potential causes of these failures? How often do they occur? Do we have any processes in place to control these failures? How detectable is the failure? What do we need to do? And how will we measure its’ success and failure?  The final step in the FMEA process asks for actions and outcome measures. This step is non-specific and does not offer any additional tools to generate solutions. In this analysis the conventional approach to this step in FMEA was replaced with the mistake proofing approach to determining actions. The mistake proofing method uses structured questioning and solution prioritization (SPN) to identify and prioritize solutions.  In the context of this project, FMEA was used to identify real and potential risks in the laboratory monitoring process with multiple sclerosis patients treated with alemtuzumab and to prioritize these risks for healthcare initiatives. A multidisciplinary team was assembled for the brainstorming of solutions for this topic, but this level of involvement was not possible for the analysis. The FMEA method attempts to control subjectivity with structured thought processes and multi-disciplinary perspectives, yet the process remains highly subjective. A major concern in the clinical application of this method is its reliance on groups with representatives from all healthcare disciplines (Franklin et al., 2012). This makes it a potentially expensive and time-consuming method Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    43 to implement, which is limiting in the dynamic environment of quality improvement. Simplified versions of this method have been trialed to reduce the burden and increase the responsiveness of these assessments in real time (McElroy et al., 2015). This analysis of laboratory monitoring with alemtuzumab will employ the FMEA methodology from the nursing perspective. The distinct failure-modes listing in the FMEA were identified the entire Lemtrada automated program development team, prior to FMEA analysis. Generating Solutions Using Mistake Proofing Questions and SPN Calculations. Once prospective hazard analysis tools have identified actual and possible risk in the system and the FMEA has prioritized and ranked these risks, the mistake proofing method attempts to generate effective solutions by using mistake-proofing questions (Groot, 2007). Brainstorming is an ambiguous concept and offers no structure to devise solutions. In 2005, Godfrey and colleagues identified eleven “directions of thinking” to help focus reasoning when brainstorming solutions to reduce process errors (Godfrey et al., 2005). The questioning categories are: Trimming, self- elimination, standardization, unique shapes/geography, copying, prior action, flexible arms or thin membranes, color, combining, counting, and automation (Godfrey et al., 2005). Each of these categories of questions will produce different outcomes when applied to the six principles of mistake-proofing and it is this interrogation of the issues that is meant to reveal solutions that are effective, efficient and successful in reducing error (Godfrey et al., 2005). These questions will guide the generation of solutions to the concerns in the laboratory monitoring process specific to alemtuzumab. Once potential solutions are identified, these too are prioritized according to their perceived effectiveness, cost and ease of implementation (see Table 4). These factors MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 44 combined will determine the solution priority number (SPN) for each resolution (Grout, 2007, p. 36). Table 5. Solution Priority Calculation Criteria Solution Priority Calculations Variable  Solution Priority Number (SPN) Effectiveness x Cost x Implementation = SPN Effectiveness 3 – Very effective solution. The probability of occurrence can be eliminated or reduced dramatically, or a control measure capable of detecting the error can be installed. 2 – Effective solution. The probability of occurrence can be reduced. Despite the reduction there is still significant risk of hazard. Measures capable of detecting the error are not in place. 1 – Ineffective solutions. The probability of occurrence cannot be reduced, and measures capable of detecting the error are not in place. Cost 3- Low cost. Can be paid for out of daily operating budget  2- Moderate cost. Needs to be paid for out of unit-level budget  1- High cost. Requires payment from hospital-level budget Implementation 3 – Easy. Requires no training.  2 – Moderate. Requires a training course and some resistance is expected.  3 – Difficult. Implementation means that a culture change is needed and strong resistance is expected. (Grout, 2007, pg. 36) In healthcare, resources are limited and solutions that are effective in addressing high risk aspects of monitoring with easy implementation and minimal cost, offer fewer barriers and are more likely to be implemented. Using this model of risk identification, solution generation and prioritization, this project outlines recommendations for clinical laboratory monitoring programs to optimize safety, effectiveness and the use of scarce resources. The complex nature of laboratory monitoring requires the coordination of multiple systems in order to be successful. Systems, which nurses are most likely being asked to navigate in the outpatient clinical environment. Nurses are well positioned to assess systems and identify risks within these systems and should familiarize themselves with the language and tools of healthcare improvement to effect meaningful change. The Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    45 mistake-proofing framework is a way to simplify this complex system into more reasonable phases of analysis, to offer manageable solutions. Analysis Defining the Topic and Scope This project examines the laboratory monitoring process for multiple sclerosis patients treated with alemtuzumab being monitored by the Lemtrada monitoring program in Vancouver, British Columbia. The laboratory monitoring process was divided according to the distinct pre-analytic, analytic and post-analytic phases in the laboratory process previously defined. Because this analysis is completed from a nursing perspective, rather than multidisciplinary perspectives, I could not analyze the process within the laboratory itself, therefore the focus is on the pre-analytical and post analytic phases of laboratory monitoring as it relates to clinical care. When analyzing the “current process controls”, this references controls that the outpatient clinic has in place to control each function, not internal lab controls, as this cannot be assessed externally. The functions and failures, outlined in the process map, were identified by the multidisciplinary project development team prior to the FMEA analysis. Process Mapping When mapping outpatient care, we are often charting systems that function independent of one another and overlap infrequently. Until outpatient and inpatient laboratory systems are universally integrated, the points of contact where these systems interface are prone to failure.  The pre and post-analytic laboratory process for our clinic is outlined in Table 6. MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 46 Table 6. Process Map of the Lemtrada Laboratory Monitoring Process Process Mapping the Laboratory Process with Alemtuzumab Pre Analytic Phase Post Analytic Phase Function Failure Modes Function Failure Modes 1. Physician writes laboratory Requisition Wrong Patient  Misspelled Name Multiple patient identifiers Wrong Tests or combination Missing care team members  1. Lab reports results Wrong Physician Missing care team members Un-interpretable Results  2. Patient gets lab tests collected Patient non-compliance Misidentification Poor technique Mislabeling  Unusable sample Wrong tube/container Contamination  2. Received by physician/clinic Faxing/scanning/Filing errors  3. Laboratory Sample taken to lab Lost samples Mishandling   3. Reviewed by Physician Data Missing Lack of context for results  4. Lab Tech enters orders in Lab system Wrong Patient Misspelled name Wrong patient identifier Wrong Orders Wrong Physician Wrong copy-to providers  Lost samples Mishandling   4. Diagnostic or treatment decision made by physician  Failure to contact patient  Delayed diagnosis and treatment  5. Patient treated Incorrect diagnosis and treatment    The distinct steps in the process are mapped systematically, defining the functions. For each function, the next step was to identify the range of possible failures at each step in the function. Failure Modes and Effects Analysis In failure modes and effects analysis we chart these process steps or functions, and examine them individually for potential points of failure, or “failure modes”. These failure modes are then analyzed individually to determine their potential effects if left unmanaged. Listing the possible impact of these errors helps to categorize the Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    47 significance of each failure mode, so that it can be quantified. The failure modes and effects analysis for the first function in the laboratory monitoring process: the creation of a laboratory requisition is outlined in Table 7.  In this first function of the monitoring process, the physician creates a requisition order for laboratory testing. The evidence suggests that this is a known error-prone function in laboratory monitoring and we can see by the potential failure modes (wrong patient, misspelled name, multiple patient identifiers, wrong tests, wrong copy to providers) the effect of these seemingly small failures can lead to significant outcomes for the patient. The worst possible effect of a misspelled name, would be lost lab results, where serious conditions were not identified, leading to death. Although these events seem innocuous, this exercise exposes the range of serious outcomes, in order to ascertain its significance. The significance is assigned a number between 1 and 10 (one is least significant, 10 is most significant) by those involved in the analysis. The causes of these failures are then identified, which helps quantify the occurrence rates, (1 least likely to occur and 10 most likely to occur) and finally the process controls, or preventative measures already present in the system are identified to determine a detectability score for each failure mode (1 being most detectable and 10 being lest detectable). The significance (S) multiplied by the likelihood of occurrence (O) and detectability (D) will give us our risk prioritization number for each failure mode.     MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 48 Table 7. Failure Modes and Effects Analysis for Pre-Analytic Function 1  Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PR-A F1 Physician writes requisition order F1-1  Wrong patient on requisition -Patient unable to get testing done -Lab work assigned to wrong patient -Delays in testing, diagnosing and treatment -Misdiagnosis or treatment -Irreversible disease and death  10 -Hand written requisitions -Multiple patient charts in one room -Labels pre-printed by clerical and attached to front of charts with paper clips -Labels falling off charts in room -Inexperience/education -Busy/distracted 2 - Using demographic label - Physician checks label - Nurse checks label prior to giving to patient -Patient notices wrong name -Lab tech checks name -Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   2 40 F1-2 Misspelled name -Patient unable to get testing done - Delays in testing, diagnosing and treatment -Misdiagnosis or treatment -Lab work assigned to wrong patient -Irreversible disease and death  10 -Hand written requisitions -Multiple patient identifiers in name  -Maiden names -Inexperience/education -Busy/distracted  6 - Using demographic label -Physician checks label - Nurse checks label prior to giving to patient -Patient notices wrong name -Lab tech checks name - Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  4 240 F1-3 Multiple Patient Identifiers  -Patient unable to get testing done -Delays in testing, diagnosing and treatment -Lab work assigned to wrong patient -Misdiagnosis or treatment -Irreversible disease and death  10 Hand written requisitions -Multiple patient charts in one room -Labels pre-printed by clerical and attached to front of charts with paper clips -Labels falling off charts in room -Marriage or alias not update in chart/EMR -Inexperience/education -Busy/distracted 2 - Using demographic label -Physician checks label - Nurse checks label prior to giving to patient -Patient notices wrong name -Lab tech checks name - Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  6 120 F1-4 Wrong tests or combination of tests -Delays in testing, diagnosing and treatment -Tests missing when treatment decision made -Misdiagnosis or treatment 8 -Clinics not familiar with lab policies regarding test combinations -Physicians unfamiliar with test names an variations -No system in place to communicate changes or updates from lab to physicians/clinic staff -Unfamiliarity with requisitions -No time to fill out requisitions/time constraints leading to unintentional error -Inexperience/education -Busy/distracted     7 -Physician reviews tests prior to giving to patient - Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  8 448 Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    49 F1-5 Missing care team members -Care team members not getting lab results -Assumed responsibility for management of results -Patient undiagnosed and/or untreated 8 -Do not have the correct information for physician/clinics -Information not clear, incomplete or incorrect -Ordering HCP not familiar with other care team members -Inexperience/education -Busy/distracted 8 -Physician reviews prior to giving to patient - Nursing team notices missing care team members -Physician notices missing care team members -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  8 512  This process is repeated for every function mapped in the original process (See appendix). Although time consuming, it is this “digging down” into the details of a process that allows a clearer picture of the scope of potential risk. When working through this process for laboratory monitoring with alemtuzumab in our clinic, it became apparent that many failure modes which I previously considered unimportant, were assigned higher risk prioritization numbers when the downstream effect of such errors and our inability to detect them were taken into account. Non-compliance errors or errors in identification of the patient, where there is no clear controls to detect these errors downstream, were the most significant. Many of our previous processes would have relied heavily on the patient identifying the error, which is risky. Our back up process was to have the nursing team manually identify missing results. For the large population our clinic serves, this was time consuming and likely resulted in delays in identifying these issues. The risk priority calculation in this analysis accurately reflected our pre-conceived notions of the most risk prone areas and is a much clearer way to categorize and prioritize these risks. Throughout this exercise it was apparent that any analysis using this method is highly subjective and this highlighted the importance of at least one of the team members having detailed knowledge of the process and issues affecting the process. That said, this method did elucidate issues that were not identified by the project team MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 50 prior to this exercise and identified certain issues as more prone to failure that anticipated by the team. The RPN calculations for the failure modes identified in our assessment of the pre and post analytical phases of the laboratory monitoring process with Lemtrada are outlined in Table 8, with each failure mode ranked in each phase according to priority.  In the pre-analytic phase, the most significant risks identified in the FMEA related to subtle errors in the use of laboratory requisitions that were less detectable but may result in missing laboratory tests and the broader issue of patient non-compliance. The areas of greatest risk in the pre-analytical phase to prioritize for solutions were: 1. Patient compliance with monitoring 2. Missing Care team Members on the requisition 3. Incorrect tests or combination of tests ordered on the requisition Patient compliance was the primary issue provoking the analysis into the clinical laboratory monitoring processes, so this finding was not surprising. The high priority given to missing care team members was because of internal processes that had been established, where there was assumed designation of responsibility. In our clinic we had built in redundancy to ensure that lab tests were received, but there was an assumption that the nursing team would receive the results directly and act on any abnormalities. This analysis highlighted that this practice of “assuming someone else is managing the care” as dangerous and resulted in clearer communication and acknowledgement in team management of abnormal results being built into our process. The rationale for why incorrect tests or combination of tests was ranked as high risk, was because of similarities in testing specific to MS. Each medication in MS has many similar tests being monitored, Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    51 each trying to rule out different conditions. Without identifying the patient as treated with alemtuzumab specifically, these additional tests might be missed. If testing was done and normal, practitioners often looked no further. Further processes were developed, to identify the tests to agent pairs. In the post analytic phase, the most significant errors related to tests getting to the appropriate health care provider in order to make a clinical decision. The areas of greatest risk in the post analytical phase to prioritize for solutions were: 1. All care team members receiving results/Missing results 2. Ensuring there are no delays in diagnosis or treatment 3. Failure to contact the patient about abnormalities In the post analytic phase, there were many internal and external factors, which may have lead to missing laboratory testing in our clinic. We serve a large population across British Columbia, so geography and individual laboratory processes were a factor. Our clinic recognized that delays in recognition, diagnosis and treatment could lead to significant consequences for our patients, so we investigated technological approaches to bypass errors deemed beyond our control to process. There were several internal factors, which were recognized as well and these will be outline as part of the solutions and recommendations.      MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 52 Table 8. Lemtrada Laboratory Monitoring RPN Calculations Lemtrada Laboratory Monitoring Pre and Post Analytical  Risk Prioritization Pre-Analytical Phase Failure Mode RPN Calculation Sev x Occ x Det = Result RPN Ranking Patient non-compliance (F2-1) 10 x 7 x 9 =  630 1 Missing care team members (F1-5) 8 x 8 x 8 =  512 2 Wrong tests or combination of tests (F1-4) 8 x 7 x 8 =  448 3 Wrong copy-to-providers (F4-6) 8 x 6 x 9 = 432 4 Wrong Physician Inputted (F4-5) 8 x 4 x 9= 288 6 Wrong patient identifier (F4-3) 10 x 3 x 9 = 270 7 Misspelled name (F1-2) 10 x 6 x 4 =  240 8 Misspelled name (F4-2) 10 x 6 x 4 =  240 8 Wrong Orders Inputted (F4-4) 8 x 4 x 6 = 192 9 Mislabeling (F2-4) 10 x 2 x 8 =  160 10 Multiple Patient Identifiers (F1-3) 10 x 2 x 6 =  120 12 Lost samples (F3-1) 10 x 1 x 9 = 90 13 Wrong patient inputted (F4-1) 10 x 1 x 9 = 90 13 Unusable sample (F2-5) 6 x 4 x 2 = 48 14 Wrong Patient on Requisition (F1-1) 10 x 2 x 2 = 40 15 Poor technique  (F2-3) 6 x 2 x 2 =  24 17 Contamination (F2-7) 6 x 2 x 2 = 24 17 Misidentification at lab (F2-2) 10 x 1 x 2 =  20 18 Wrong container/tube (F2-6) 6 x 1 x 2 =  12 19 Mishandling (F3-2) 6 x 1 x 2 = 12 19 Post-Analytical Phase Failure Mode RPN Calculation Sev x Occ x Det = Result RPN Ranking Missing care team members  (F1-2) 8 x 6 x 9 =  432 4 Delayed diagnosis and/or treatment (F4-2) 8 x 5 x 9 =  360 5 Faxing/scanning/filing errors (F2-1) 10 x 4 x 9 = 360 5 Failure to contact patient about abnormalities (F4-1) 10 x 4 x 9 = 360 5 Results sent to wrong physician (F1-1) 8 x 4 x 9 = 288 6 Incorrect diagnosis and/or treatment (F5-1) 10 x 2 x 8 =  160 10 Lack of context for results (F3-2) 6 x 6 x 4 =  144 11 Data Missing  (F3-1) 8 x 2 x 2 =  32 16 Un-interpretable Results (F1-3) 6 x 2 x 2 = 24 17 Note. RPN: higher number = higher priority for solution; Ranking: lower number=higher priority; Red=high priority, orange=moderate priority, green-=low priority     Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    53 Generating Mistake-Proof Solutions Once the most significant laboratory risks are identified, the next procedure in the mistake-proofing method is to use structured questioning to guide the development of solutions. The mistake proofing principles, elimination, replacement, facilitation, detection, mitigation and patient involvement provide the framework for this exercise. A review of the eleven questioning types, within the mistake proofing principles is outlined in Table 9. Table 9. Mistake Proofing Questions by Principle Error Principle Consulting Question  Elimination Trimming-Can we eliminate the error-prone process or harmful objects? Self -Elimination: Can harmful action or object eliminate itself? Prior Action- Can we do something beforehand to eliminate the error-prone process or harmful objects? Replacement Automation- Can we automate the process to replace human operations? Prior Action: Can we do something beforehand to support human operations? Combining- Can we combine (bring closer together) two or more things to automate or support human operations? Facilitate Standardization- Can we standardize the process to facilitated human operations? Trimming- Can we trim similar or confusing things to facilitate human operations? Color – can we use color to facilitate human operations? Copying – Can we use redundancy to facilitate human operations? Combining – Can we combine two or more things to facilitate human operations? Flexible films or thin membranes? - Can we use flexible films or thin membranes to facilitate operations? Prior Action- Can we do something beforehand to facilitate human operations? Detection Counting- Can we count something to detect abnormalities in the human operations or their results? Automation – Can we automatically inspect something to detect the abnormalities in the human operations or their results? Self Elimination- Can we let people notice abnormalities by themselves? MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 54 Unique Shape-Geometry- Can we use shapes to detect abnormalities in the human operations or their results? Standardization- Can we standardize the process to detect abnormalities Mitigation Copying- Can we use redundancy to mitigate the effects? Prior Action- Can we do something beforehand to mitigate the effects? Trimming- Can we trim a part of the harmful objects to mitigate the effects? Flexible Films or Thin Membranes – Can we use flexible films or thin membranes to mitigate effects?  These questions are meant to frame the brainstorming sessions and direct thinking towards interventions shown to be effective in reducing error in mistake proofing theory. In order to generate effective solutions to the risks identified in the failure modes and effects analysis of the laboratory monitoring system in BC, we addressed each principle of mistake proofing and applied the corresponding questions to the risks identified in our FMEA. For each mistake-proofing principle, I will discuss the solutions generated by our clinic and any additional solutions this questioning process uncovered. There is some redundancy in our solutions, so I detailed the solutions in only one of the domains. This analysis will not include lines of questioning that did not apply to the laboratory monitoring process, in order to remain within the boundaries of the scope defined by this analysis.  Elimination. The mistake proofing principle of elimination involves breaking down processes into discrete steps. Using this principle, solutions to the risks identified in the pre and post-analytic phases of the laboratory process can be generated by brainstorming answers to these questions. 1. Can we eliminate the error-prone process or harmful objects? (Trimming) Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    55 2. Can the harmful action or object eliminate itself? (Self –Elimination) 3. Can we do something beforehand to eliminate the error-prone process or harmful objects? (Prior Action) Can we eliminate the error-prone process or harmful objects? (Trimming) A major theme in the pre-analytic phase is administrative errors involving standard paper laboratory requisitions; missing care team members, incorrect or absent copy-to providers, wrong tests or combination of tests, wrong physician inputted for copy, mislabeling, misspelled name, wrong patient identifier, or multiple patient identifiers. We cannot yet eliminate the “harmful object” of laboratory requisitions, but we can eliminate the factors that lead to misinterpretation and confusion and do something beforehand to eliminate this error-prone process. By eliminating hand written requisitions, standardizing and digitizing requisitions, we ensure that all tests, names, addresses, fax numbers are clear and correct in order to eliminate some of these failures. Eliminated hand written requisitions and printed labels or inputting data directly onto a requisition from an electronic medical record, will maximize the likelihood that the patients’ demographic information is updated and correct. Can we do something beforehand to eliminate the error-prone process or harmful objects? (Prior Action)  In our clinic we had a reoccurring error in the reporting of urinalysis. Our work on prior action lead to coordination with the laboratory patient services team to identify the breadth of the issue. We had to clarify specific protocols in the way that urinalysis tests are entered, before we were successful in getting both a urinalysis and a cell count through one specific laboratory. We discovered that in their system, to order one test MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 56 automatically cancels the other, unless you specify a special case for ordering both that fits within a pre-determined diagnostic trigger and ordered by a nephrologist or urologist. Multiple sclerosis was not one of the diagnoses that would allow automatic over ride of this internal feature. If patterns arise in partial or missing results for a population, outpatient clinics are encouraged to involve laboratory client services to sign off on requisitions to ensure the lab data is presented as intended. Clarifying, standardizing and digitizing requisitions can have major impacts in the errors of data entry at the lab, but does not eliminate human error at this critical data input point. We investigated solutions that would bypass this function and reduce our reliance on accurate input of data by technicians. With the help of our provincial laboratory platform Excelleris, our clinicians hypothesized that by harvesting data directly from the provincial platform we could bypass these data entry errors. The program in development is specifically for Lemtrada and will pull certain patient lab results (hematocrit, platelets, creatinine, thyroid stimulating hormone, urine protein and urine hemoglobin) directly from the provincial platform and transmit the data to clinicians through an online portal. This program will alert abnormalities in the laboratory results using SMS and email messaging. The data extraction is based on personal health care number (PHN) and date of birth (DOB), eliminated spelling, hyphenation, or alias errors common with manual entry. This laboratory data is transmitted to the care team regardless of the ordering physician, so if the patient provider is inputting incorrectly or the patient is in the emergency department, another outpatient clinic or lab, and a test specified by the program is collected, the MS physician is alerted to these results through the portal. Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    57 The portal and automation of alerts was only one aspect of the Lemtrada monitoring program developed by the MS clinic. Prior action to prevent some of these administrative errors involved assigning responsibility of incoming faxes to a dedicated fax machine located beside the specialty Lemtrada nurses. These nurses were specifically trained to analyze lab results for abnormalities related to Lemtrada and clinical algorithms prompted specific clinical actions for various identified conditions. All abnormal lab results prompted a patient assessment, to alert the patients to the abnormalities and to determine if the patient was symptomatic or asymptomatic for the serious adverse events suspected with Lemtrada. This information was then presented to the physician to provide context for clinical decision-making. Within the nurse-initiated laboratory monitoring protocol, certain critical labs prompted the nurses to direct the patient to the emergency department without prior consult with the physician groups, where the assessment information was provided directly to the emergency department rather than the neurology group. Nursing education, nurse initiated protocols and procedures and standardization of responses to specific clinical and laboratory data, are ways of mitigating these issues before they occur. Pulling data directly from the provincial laboratory platform, the Lemtrada Excelleris program also bypasses some of these administrative errors in the post-analytic phase, eliminating the need for perfect intake systems for non-digital clinic information. The online portal was designed to include additional relevant patient information as context for clinical decision making, such as the number and dates of Lemtrada infusions, graphs or tables of previous laboratory tests and notes for healthcare teams to MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 58 communicate care plans relating to laboratory monitoring, eliminating the need for access to paper or electronic patient charts. In the post analytic phase the highest risk elements were missing care team members on transmissions of results, delayed diagnosis and/or treatment, no one following up on missing results, faxing/scanning/filing errors, results sent to wrong physician/care team, incorrect diagnosis and/or treatment, data missing, lack of context for results (history, medications), failure to contact patient about abnormalities and un-interpretable results. Again, we see that many of the errors are administrative. By streamlining the administrative process within the clinic, we may have a positive impact on faxing/scanning/filing errors, failure to contact patient, lack of context and delays in diagnosis and treatment. Our clinic streamlined and standardized the process of laboratory results received by the lab, first by orienting the clerical staff to separate out laboratory tests from the incoming fax line and then investing in an electronic medical record (EMR) to direct laboratory tests directly into the patients EMR for acknowledgement by the physician. Replacement. Using the replacement principle of mistake proofing of the pre and post analytic phases of the laboratory process, the high risk elements in the laboratory process can be analyzed and solutions generated by brainstorming answers to these questions. 1. Can we automate the process to replace human operations? (automation) 2. Can we do something beforehand to support human operations? (Prior Action) 3. Can we combine (bring closer together) two or more things to automate or support human operations? (Combining) Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    59 Can we automate the process to replace human operations? (Automation) Many of the risks in the pre and post analytic phase involved entering patient information within the laboratory and transmitting information from the laboratory. Any external program will have limited access and control over processes within the laboratory setting itself, but must focus on eliminating barriers to the lab pulling or pushing information outside of their own system. In the arena of mistake proofing, replacement means replacing one operation with a more reliable machine/method/automation.  One of the biggest concerns with laboratory monitoring was patient compliance. We cannot automate patient non-compliance, but we can use automation to remind patients to get tested and to identify patients who require follow up for adherence. We know that contact with the health care team has significant impacts on patient compliance (Devonshire et al., 2013), so any program looking at improving compliance should involve both the patient and the health care provider.  Many physicians do not have the time to track and follow-up on laboratory results, outside of patient visits. Patient-support programs, administrative staff and/or registered nurses are often tasked with safeguarding compliance, but this is a laborious undertaking for larger clinics. Replacing this aspect of monitoring with an automated system was one of the driving factors to pursue an automating monitoring program with Lemtrada. The automated program we developed “resets” the clock on three data groups when a complete data group is acknowledged in the lab platform. The three groups are blood, urine and TSH groups. The blood included monthly hematocrit and platelets, the urine included monthly hemoglobin and protein and the thyroid included, thyroid MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 60 stimulating hormone (TSH) every 3 months. The program allows the patient, physician and health care team the option to receive SMS and/or email messages for upcoming appointments and overdue appointments for each of these three data groups. The automated system messages patients and their care team three days prior to their monthly lab-monitoring anniversary and provides escalating reminders weekly if it is not completed. If the complete group set is not received (i.e. data is missing), the test group will continue to alert in order to trigger a more thorough analysis of the lab sets completion and intervention by the care team. The option for involvement of the next of kin is available and can be set up to escalate the reminders and alerts if there is no response from the patient, in the event that a serious adverse event occurs.  Can we do something beforehand to support human operations? (Prior Action) In terms of replacement with prior actions, our clinic had a clinic code created with the individual labs that replaced the need for a clinic address and fax number on the requisition. This clinic code was clearer and replaced the bulk of information on the requisition, possibly increasing the likelihood of the information being relayed. Can we combine (bring closer together) two or more things to automate or support human operations? (Combining) The combining aspect of replacement for this program was discussed briefly above. By bringing all the information required to make a clinical decision together in one portal, it supports better clinical decision-making. The online portal includes all patient demographics, next of kin, infusion history and laboratory history all in one place,  minimizing the need of physicians to access other systems to get the information that they require to make an accurate diagnosis and treatment plan. Lemtrada Monitoring program Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    61 nurses support this function by recognizing abnormalities in laboratory tests, contacting the patient for a focused nursing assessment to complete the clinical picture and alerting the physician to any laboratory or clinical abnormalities with which to guide the direction of care. Facilitation. Facilitation is the process of making operations easier to complete correctly, including simplifying, differentiating and adjusting as appropriate (Godfrey, 2005). Clinical guidelines are a common example of facilitation in clinical practice. Using the facilitation principle of mistake proofing of the pre and post analytic phases of the laboratory process, high-risk elements in the laboratory process can be analyzed and solutions generated by brainstorming answers to these questions. 1. Can we standardize the process to facilitated human operations? (Standardization) 2. Can we trim similar or confusing things to facilitate human operations? (Trimming) 3. Can we use color to facilitate human operations? (Color) 4. Can we use redundancy to facilitate human operations? (Copying) 5. Can we combine two or more things to facilitate human operations? (Combining) 6. Can we use flexible films or thin membranes to facilitate operations? (Flexible films or thin membranes) 7. Can we do something beforehand to facilitate human operations? (Prior Action) Can we standardize the process to facilitated human operations? (Standardization) Standardization is a key element of in the success of care team approaches. Each health care team member has a specific set of expert skills to optimize clinical processes. MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 62 In outpatient MS care, we know that many tasks executed by neurologists could be safely performed by nurses and support staff, but this requires thoughtful processing, standardization and training. Decision support guides, assessment checklists, nurse initiated order sets and standardization of forms and processes, allow team members to act independently while working within their scope and remaining consistent with physicians practice.  In order to limit risk in the laboratory monitoring process, the most important part of the process for standardization would be the information provided to the lab, and the process for drawing and analyzing results from the lab. The lab requisition is the method used to relay information and as we have seen, errors in the pre-analytical phase center on errors in the lab requisition. Standardization improves the likelihood that no laboratory tests are missed, that the physician and clinic information and that the patient demographic information is correct. For our program we standardized the enrollment, pre-screening and assessment process, as well as a decision guides for nurses to review lab results, perform patient assessments and care algorithms for repeat testing and referral, under the guidance of the physicians. The nurses did not replace the physician, as all processes to ensure the physician received the blood work were still in place, but this dedicated team of nurses was frequently able to assess results more efficiently and provide context for abnormal results.  Can we trim similar or confusing things to facilitate human operations? (Trimming) We addressed the question about trimming, or eliminating similar or confusing things in the process in the medication portal. The online portal is a place where the Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    63 physician and care team go to get all the information they need about their Lemtrada patient, but nothing else. Often it is difficult when analyzing faxed blood work to have the information you need as a clinician to make decisions. By trimming away extraneous information and putting all relevant information into one place (number of treatment cycles, cycle dates, current blood work, last blood work, trends, normal ranges) we increased the efficiency, timeliness and effectiveness of these touch points and reduce the burden of gathering this information to make clinical decisions.  Can we use color to facilitate human operations? (Color) The use of color was also addressed in the portal. The physicians identified the difficulty in determining trends in laboratory testing and there was variation in how the physicians wanted this information presented. In the portal, the patient results are graphed to use visual prompts to make it easier to interpret and compare over time. The portal has the option to visualize the incoming laboratory tests in the traditional lab generated form, graphically by test, or in a table. The use of color differentiated between tests, but also alerts whether a point on the graph was critical (red) abnormal (yellow) or normal (black) without having to reference the ranges. This was thought to reduce the likelihood that an abnormal test would be overlooked. All abnormal and critical values also have a flashing alert sign that must be acknowledged by one of the care team members before it disengages. Can we use redundancy to facilitate human operations? (Copying) Although the information required to make a clinical decision on diagnosis and treatment is available to physicians, this information is usually in multiple different places; the paper chart, EMR, Care connect, PCIS and Pharmanet are a few examples of MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 64 the programs utilized in our clinic. The Lemtrada portal copies all of this information and has it available in one place for the physician.  Another example of copying that was implemented related to the requisition. When our clinic faxes the requisition to the lab, we also email a copy of the requisition to the patient, so that if issues arise the patient can manage some of these issues independently. This may be providing a new requisition when one is missing, or clarifying the tests and frequency of tests that were ordered while at the lab. This also allows and opportunity for the patient to vet the information that was on the requisition for any errors. Another solution that we implemented was related to emails between the care team and patients. We found that the use of email expedited a lot of our clinical practices, such as education, clarification and coordination amongst the team, but most importantly, information that needed to be shared amongst the group. We developed a shared email for the clinic nursing team that patients and physicians would use to contact the group as whole. Any questions or concerns were managed by the most appropriate or the next available nursing team member. We found this reduced the amount of work, forwarding emails to other members in the team and provided reassurance that if one team member was absent that patient concerns were still being addressed in a timely manner. Can we combine two or more things to facilitate human operations? (Combining) As discussed above, the portal brings all relevant information in one place and combines systems of information to facilitate clinical operations. The portal also has functions to communicate treatment plans between care team members, acknowledge Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    65 alerts and track data going into the system for export, if overall analysis of the treatment group is required.  Can we do something beforehand to facilitate human operations? (Prior Action) Pre-planning and education can make the process of laboratory monitoring more efficient and effective. Patient education on the importance and risks associated with monitoring, as well as reminders to patients to get their lab testing done, may improve compliance. Having team members available to patients for questions and clarification can reduce delays and confusion. Giving the patient a copy of the requisition, as well as information on what to expect at the laboratory, what they are being tested for, the frequency and why, will help the patient to vet their own information and take an active role in ensuring that the tests are correct, complete and received by the appropriate provider. When patients develop complications to these medications, establishing networks of specialists in advance will ensure that the diagnosis and treatment is appropriate and timely. In our clinic we worked with a hematologist, nephrologists and endocrinologist to create a one page document to be giving to family physicians or emergency department staff, outlining the appropriate diagnostic tests and treatment recommendations for the suspected serious adverse events relating to their specialty.    MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 66 Detection. Using the detection principle of mistake proofing of the pre and post analytic phases of the laboratory process, the high risk elements in the laboratory process can be analyzed and solutions generated by brainstorming answers to these questions; 1. Can we count something to detect abnormalities in the human operations or their results? (Counting) 2. Can we automatically inspect something to detect the abnormalities in the human operations or their results? (Automation) 3. Can we let people notice abnormalities by themselves? (Self Elimination) 4. Can we use shapes to detect abnormalities in the human operations or their results? (Unique Shape-Geometry) 5. Can we standardize the process to detect abnormalities? (Standardization) Can we count something to detect abnormalities in the human operations or their results? (Counting). Can we automatically inspect something to detect the abnormalities in the human operations or their results? (Automation) and can we standardize the process to detect abnormalities? (Standardization) In the development of the program, there were questions about whether the automated program could be designed to count and compile a list of patients who were overdue for their laboratory testing, in real time and also to compile a list of patients who had developed any of the secondary auto immune conditions. This was deemed beyond the programming capability for initial program. The compliance portion of the program does “count” the days between blood work, to trigger a reminder alert for the patient and care team. It also counts that all lab Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    67 tests within a lab set are complete, and will continue to send reminders if it is not complete. If the lab enters a non-numerical number or an unexpected value the system will interpret this as un-interpretable and will alert the patient and the care team that a result cannot be interpreted and prompt them to looking in to the patient situation. In this way the program is detecting abnormalities and alerting the care team. The nursing care team developed checklists for the Lemtrada infusion monitoring process, and this is an analog way of counting that items are present and addressed. The patient support program and patient care coordinator also continue to use excel spreadsheets to track and compile data related to patient process, adverse events and clinical needs. This spreadsheet is discussed weekly to address any shared issues in the Lemtrada Program. Can we let people notice abnormalities by themselves? (Self-Elimination) The goal of the Lemtrada monitoring program is to ensure timely, appropriate, effective treatment of serious adverse events that can affect Lemtrada treated patients, and the patient is a key member of the health care team in this process. Patient self-reporting of symptoms related to these SAE’s is an important piece of the timely identification of these conditions, making patient education very important. Patients receive a variety of education documents and complete an hour-long assessment with the nursing team prior to enrolling in the Lemtrada program. For the automated program, patients have the option to receive the text and/or email reminders and alerts, but consent is required for enrollment. For those who consent, there is a brief education session on what types of messages the patient will receive and what they should do for each message type. Detailed information is then sent to the patient by MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 68 email to reinforce this learning and for future reference should an alert occur. The alerts themselves also contain instructions on who to contact in what time frame. This will help patients to understand how their care team interprets their laboratory results, so that they can self-present to the appropriate care provider should these events occur.  Patients are also encouraged to “self eliminate” in regards to the laboratory requisition. As discussed previously, the patient receives an email copy of their laboratory requisition so that they are another set of eyes on the details in the requisition. In the enrollment education session with alemtuzumab, we encourage patients to sign up for My eHealth in British Columbia, which is an Excelleris online platform for patients to book laboratory tests, but also to view their own lab results online. This allows patients to monitor their own laboratory results, whether normal or abnormal and discuss their questions, concerns and insights with the nursing team. Can we standardize the process to detect abnormalities? (Standardization) For the development of the automated program, we had to identify the parameters for the six laboratory results that we were targeting within the program: hematocrit, platelets, creatinine, thyroid stimulating hormone, urine protein, and urine hemoglobin. With immune modulating and immune suppressing medications, the composition of the immune factors are normally abnormal. There are expected abnormalities that we would not want an automated program to trigger. So our physician and nursing teams collaborated to develop a monitoring algorithm, which standardized the ranges of each of the laboratory results of concern and imbedded this in the automated program. This feature is adaptable, should the program leads determine that the algorithm is either too sensitive, or insensitive in practice. Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    69 For the nursing group, when abnormalities were detected in the laboratory results, the patient was contacted for an assessment to determine whether the patient was symptomatic for any of the serious adverse events anticipated with Lemtrada. This assessment is standardized and the nurses have a structured, comprehensive, systematic approach to assessing symptomology, so that they can present a clear picture to the physician group for clinical decision-making. This is to prevent delays and multiple points of contact with the patient to gather information and therefore possible delays in diagnosis and treatment. Mitigation.  Using the mitigation principle of mistake proofing of the pre and post analytic phases of the laboratory process, the high risk elements in the laboratory process can be analyzed and solutions generated by brainstorming answers to these questions; 1. Can we use redundancy to mitigate the effects? (Copying) 2. Can we do something beforehand to mitigate the effects? (Prior Action) 3. Can we trim a part of the harmful objects to mitigate the effects? (Trimming) 4. Can we use flexible films or thin membranes to mitigate effects? (Flexible Films or Thin Membranes) Can we use redundancy to mitigate the effects? (Copying) The greatest risks identified in the RPN calculations related to patient non-compliance and following up on missing or abnormal blood work. Without automation, these are time consuming but important tasks. Although we developed an automated program to alert us to non-compliance, missing blood work and abnormal results more quickly, we still use the patient support program nurse and a patient care coordinator to MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 70 review compliance in the event the technology fails. Laboratory results are faxed directly into an electronic medical record faxed to the Lemtrada nurses directly and are gathered into the portal directly from the provincial laboratory. This redundancy provides reassurance that in the event of failure in any of these systems, important patient information will not be missed.  Involving the patient in the monitoring process is a form of redundancy for both the requisitions and also for the assessments and self-identification of adverse events if the person has been education in what to look for and what to do. Can we do something beforehand to mitigate the effects? (Prior Action) Mitigation accepts that errors occur, its intent is to reduce the impact of inevitable errors on patient outcomes. In our program we have had several patients develop symptoms of potential medication related SAE, whom we’ve referred to the emergency department for further work up and assessment. These patients were educated on the rationale for being sent into hospital and were provided with the simplified Lemtrada medication monograph card to give to the receiving physician, but we experienced significant treatment delays in hospital. Feedback on these events uncovered that the “normal abnormalities” in the white blood cell counts for patients treated with alemtuzumab distracted emergency physicians from the more subtle autoimmune conditions that were a greater concern for our program. In collaboration with local specialists we developed the one page information sheet that could be sent to the emergency department upon patient admission, which clearly and concisely outlined our specific patient diagnostic and treatment recommendations. One of the biggest mitigation strategies in the prevention of delays in diagnosis and treatment for our program was not Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    71 ending the monitoring process once they are admitted to hospital, but remaining engaged in the diagnosis and treatment of the patient so that there are no delays. We found that “giving a nursing report” on our patient to the receiving nurse upon admission, improved the timeliness of care specific to the alemtuzumab. Other “prior action” that would assist with mitigation is to ensure systems are in place to respond to the need for repeat patient requisitions, as this is frequently required because of various errors previously described. Our solution was to have digitized, password coded requisitions available to email the patient remotely, or fax to the laboratory directly.  Our most effective solution to mitigation in the pre-analytic and post-analytic phase of monitoring is bypassing errors in the intake process at the lab. As discussed, our program used PHN and DOB as identifiers, rather than name, to mitigate these common errors. The program also triggers alerts if all lab tests in a set are not performed to alert the care team of these errors and mitigate the risks of missing blood work and delays in identification and treatment of adverse events.  Patient Involvement. The mistake-proofing framework has evolved in its adaption to the health care environment and this is most evident in the addition of patient involvement as a principle of mistake proofing. There are no specific questions directing the inclusion of patient involvement in this process, but it is an important consideration for any quality improvement initiative in this field. In our program, the patient is considered a vital member of the health care team in their involvement in the monitoring process, the identification of issues and adverse events, but also in the reporting and management of MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 72 their symptoms. The patient consent process outlines the program in its entirety, and allows the patient to opt in or out any feature of the automated monitoring program. We encourage patients to monitor both their abnormal and normal lab results by enrolling in online patient laboratory portals available in their area and we encourage them to ask us questions about concerns or trends. A major feature of our program was not limiting where patients get their lab testing done, whether in hospital, a private lab, or in another country while traveling. There were strategies outlined to address all possibilities. Finally, a patient satisfaction survey will be an important aspect of the evaluation of this program once the automated program is implemented. Solution Priority Calculation The mistake proofing questions are meant to stimulate ideas and direct the generation of solutions towards the mistake-proofing principles. Each of these questioning categories targets a specific improvement method (copying, trimming, automation) so that the solutions generated achieve the desired outcome; reducing error and improving quality. Through this brainstorming and questioning, potential solutions to the errors discovered in the laboratory monitoring process have been identified and summarized in Table 10.     Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    73 Table 10. Lemtrada Laboratory Monitoring Solution Prioritization Calculations Lemtrada Laboratory Monitoring Pre and Post Analytical  Solution Prioritization Pre-Analytic Phase Identified Solution SPN Calculation Eff x Cost x Imp = Result SPN (1-18) SPN Ranking  Corresponding RPN addressed by Solution Rank by SPN  Rank By Efficacy Standardized Requisitions 2x3x3 18 1 2. 3, 4, 6, 7, 8, 9, 12, 13, 15 5 7 Email patient a secure copy of the requisition 2x3x3 18 1 1, 2, 3, 4, 6, 7, 8, 9, 10, 12, 13, 15 2 3 Consult Lab Services to clarify standardized requisitions 2x3x3 18 1 3 10 10 Digital Requisitions 2x3x3 18 1 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 15 4 6 Automated Reminder System 2x1x2 4 4 1, 2, 3, 4, 8, 9, 10, 12, 13, 14, 16, 17 15 5 Lemtrada Portal 3x1x1 3 3 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 14 1 Nursing Shared Email 2x3x3 18 1 1, 2, 3, 5, 11, 16 6 8 Nursing Checklists 2x3x3 18 1 1, 2, 3, 4, 5, 6, 7, 9, 10 3 4 Post Analytic Phase Identified Solution SPN Calculation Eff x Cost x Imp = Result SPN SPN Ranking Corresponding RPN Rankings Addressed by SPN Group Rank by SPN Group Rank By Efficacy Standardize administrative process for incoming lab Tests 2x3x3 18 1 4, 5, 11, 16 7 11 Results Algorithm 1x3x2 6 2 10, 16, 17 13 15 Assessment and Treatment Algorithms 2x3x3 18 1 5, 10, 11, 16, 17 8 12 EMR 2x1x1 2 5  4, 5, 6, 11, 16 16 9 Automated Alert system 3x1x2 6 2 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 11 3 Graphs/Color to make analysis more efficient/safer 1x2x3 6 2 5, 11, 16, 17  12 13 Specialty Networks 2x3x3 18 1 5, 10 9 14 Specialty Recommendations Sheet  2x3x3 18 1 5, 10 9 14 Patient set up E-health 2x3x3 18 1 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15 16, 17,  1 2 Note. SPN: higher number = higher priority for implementation; Ranking: lower MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 74 number=higher priority for implementation; Red=high priority, orange=moderate priority, green-=low priority  Similar to the RPN calculation, for each solution that was identified in the questioning process a ranking system is assigned to focus improvement efforts on the “best” solutions. To calculate the solution prioritization number (SPN) the effectiveness, cost and ease of implementation is calculated on a scale of 1-3 using the criteria outlined in Table 5 and these numbers are multiplied together to provide a solution prioritization number. These SPN’s are then ranked with the lower numbers indicating a higher priority solution for implementation.  In my SPN analysis I found that many of the SPN’s were scored identically. Of the eighteen potential solutions identified, eleven of them were calculated as an SPN of eighteen, making if difficult to differentiate higher priority solutions. The formula used to calculate the SPN (Effectiveness x Cost x Implementation = SPN), assigns equal importance to effectiveness, cost and ease, meaning that more effective solutions were not distinguished. Each of the solutions listed in table 10 represent distinct solutions, but an individual solution may address several high-risk system failures, but this was not reflected in the calculation. The distinct cost-benefit comparison of each solution was neither captured nor apparent in the SPN calculation and rankings.  There is very little guidance in the literature about how to interpret the solution priority calculations, but it seems that this process is missing an important perspective on the effectiveness of these solutions related to cost. The quality of healthcare is not determined by the relationship of effectiveness to cost and ease, but is defined by safety, effectiveness, efficiency, equity, timeliness and patient-centeredness. Without Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    75 consideration of these other factors, this method may have limited application in quality improvement in healthcare.  In an attempt to draw out more information from these rankings I have included another column, which identifies the corresponding RPN (risk) calculations that each solution was designed to address. This made the process of differentiating between the high-priority solution rankings much clearer. I have categorized the solution prioritization numbers in groups by color, to differentiate the SPN calculations that were similar, in order to make the easier to rank (SPN Ranking). Each of these three prioritization categories (red-high priority, yellow-moderate priority, green- low priority) was then further ranked against their category; the rank by SPN column in light grey. The purpose of this exercise was separate out the high priority solutions and identify within this high-priority group, which solutions would have the greatest impact on addressing risk if implemented in practice. I then ranked the other two categories (moderate and low priority) to outline an overall ranking for each solution. These rankings are highlighted in light grey in Table 10. This exercise of listing the corresponding RPN rankings addressed by each solution revealed an essential disconnect in this method. The Lemtrada Portal discussed previously in this paper, is an essential part of the risk management program developed by the health care practitioners responsible for the laboratory monitoring process with alemtuzumab and I have highlighted this solution in yellow in the SPN Table 10. The portal addresses every risk identified in the risk prioritization exercise and is believed to be the most effective intervention based on evidence, yet it is prioritized near last in the SPN ranking. The cost and training required to implement this program has MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 76 offset its effectiveness in the calculation. If the solution prioritization number were the only tool guiding strategic initiatives in healthcare, this program would not exist. To further compare this ranking system to efficacy, I have included an additional ranking table for each solution, identified in Table 10 in dark grey. This ranks all of the solutions by efficacy, or by the priority and number of risk prioritization calculations that each solution addresses. Solutions that address multiple risks are deemed more efficacious and therefore scored higher. This exercise clearly revealed the difference between the conventional SPN ranking method used in the mistake proofing method and our teams’ notion of the most effective solution based on evidence of risk. This difference may prove problematic, in the application of this method to healthcare. Discussion Use of the mistake proofing Method The healthcare system is complex, fractured and potentially dangerous for patients. Healthcare providers need systems to identify and prioritize possible failures within the system, to build robust programs to address these failures and prevent harm. The mistake-proofing method is an overarching framework to help organize the thought process of assessing and developing solutions to address risk. The way in which the variety of quality improvement tools fit together and the situations where they would be most effective has not been clearly defined and this may limit our ability to apply the right tool for the right situation to ensure the best outcome.  The failure modes and effects analysis used in this project was time consuming and would have been more so if executed in a large multidisciplinary group. It would Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    77 have been challenging to reflect and ruminate on these issues in an open forum, but differing perspectives might have brought forth different concerns that should have been addressed. If this procedure were implemented in practice, I would ensure that there was time for both personal reflection and group discussion built into the process. I felt that the FMEA was appropriate for highlighting key issues and bringing forth issues that had not been previously considered. The prioritization of risk in the FMEA was valuable since the outcomes of this process reflected the concerns in real practice and prioritizing risk is sometimes difficult for front-line workers to conceptualize in real time. Every risk does not carry the same weight if it is highly detectable within a system. This speaks to the concept of latent versus active errors in Reasons theory (Reason, 1990), acknowledging that latent errors carry far greater risk and require more robust systems to address.  This process was highly subjective. It was difficult to anticipate the occurrence for some of the functions/causes without clear scientific evidence of the true likelihood, especially for functions that were farther away in the process from my immediate practice. Functions that involved the collecting of tests and transport to the lab for example, were difficult for me to calculate. There are a large number of laboratory specific policies and procedures that would extend into the immediate pre-analytic phase that we as nurses would not be aware of. It would have been beneficial to involve a laboratory expert for this aspect of the analysis. The mistake proofing questioning process was moderately helpful in focusing the brainstorming on mistake-proof principles, but is limited by the knowledge of those taking part in the analysis. A possible reason why generating solutions is a challenge in healthcare is that health care providers have limited interaction with non-medical fields MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 78 such as information technology, which could offer insight and innovation. Any solution generating exercise should involve an investigation into what is already commercially available or what research has been found to be effective. Innovation in healthcare is not just about what could be done, but what should be done and what evidence has proven to be effective. This was not a clear part of the SPN process and the experience in this project stresses the need for customization before being applied to an evidence-based field such as health care In his writings for the Agency for Healthcare Research and Quality, John Grout recognized that there is no persuasive method for generating solutions to the issues of healthcare and so the prospect of a tool within the mistake-proofing framework to address this specific piece of the equation was promising (Grout, 2007). This tool was unsuccessful in isolating or classifying the most effective solutions. Limiting the range of each designation (effectiveness, cost, implementation) to a three point system meant that many of the scores were the same, making the exercise of prioritization futile. This method weighed too heavily towards cost and ease, which has quite different consequences in healthcare than in industry or manufacturing. A possible adaptation may be to include higher numbers to weigh those interventions that are very effective, but might be slightly more expensive. Possibly adjusting the scale to rate effectiveness (1-5), cost (1-3), and implementation (1-3), or including a broader scale might help differentiate between equally effective and cost effective solutions, so that they can be more clearly prioritized, but likely this will produce the same issues and further analysis will be required. The six dimensions of quality: effectiveness, safety, timeliness, efficiency, equity and patient-centeredness Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    79 (IOM, 1999) could be implemented in this framework to offset the impact of cost and ease of implementation in this calculation while improving and imbedding this method in the ideology of the healthcare environment.  Fiscal responsibility is important in healthcare. This method was helpful in identifying those interventions that could be implemented immediately. For those solutions that were ranked in the middle, it would be important to further analyze the cost/benefit of each of these interventions and focus on implementing only those interventions that were the most effective. Finally, there were several instances where the mistake-proofing questions did not seem relevant to health care. For example, does the use of flexible films and thin membranes, which is not pertinent in most healthcare situations, need to be addressed? Nonetheless, the mistake-proofing method was thought provoking, in that there were several high-impact interventions that could easily be implemented by registered nurses to address safety and quality issues within their scope. Standardization, improved patient education, patient engagement and responsive troubleshooting, appear to have moderate to significant positive impact on improvement according to this analysis. Recommendations for the Development of Lemtrada Monitoring Programs  This detailed analysis of the laboratory monitoring process with alemtuzumab has highlighted several high-risk areas that may be improved with simple, easily translatable interventions. 1. Assess patient population for factors affecting compliance Patients with multiple sclerosis have a higher risk of non-adherence because of MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 80 multiple factors: youth, fewer co-morbidities, fewer visits with health care providers, cognitive issues, potential mobility issues and potential financial constraints. Patients treated with alemtuzumab specifically have increased risk of non-compliance because of the black box warnings with this medication, which is contrary to most health care practitioners’ assumptions about this classification of medications. An assessment of non-compliance should not influence whether patients are prescribed alemtuzumab, but will affect individual patients’ care plans and systems that are put in place to mitigate this risk. According to the evidence, a possible mitigation strategy would be to increase the frequency of clinic visits or touch-points with healthcare providers, including nurses. 2.   Educate Patients There are several interventions that can be implemented before treatment with alemtuzumab to prepare clinics and patients for this process. Thorough patient education on the medication, the monitoring requirements and monitoring rationale are important for compliance but, as we’ve learned, education is not enough. Patients need education on when and how to access health care providers for questions and this access needs to be convenient, flexible and responsive. Education needs to be redundant, both in opportunities to speak with health care providers and family members, but also written down for easy reference as needed. We have found email helpful for patients, because they were likely to lose hard copies and email allowed them to search for this information from their smart phone and access it immediately.  3.    Involve Patients As part of patient education, emphasize the patient as an important part of the care Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    81 team and explain how self-identification of symptoms relating to the secondary autoimmune conditions may influence their health care outcomes. If regionally available, have them set up an on line health account, so they can track both their abnormal and normal laboratory results and engage in the process of self-monitoring. The benefits of this specific intervention are not minimal. As we discovered in the FMEA, patients’ access to and engagement in the identification of lab errors, specifically missing lab results, could relieve significant pressure from monitoring clinicians in the timeliness of error identification and is a valuable redundancy if regionally available. Finally, email patients secure copies of their requisitions, so that they serve as another set of eyes on the information presented to the lab and access this information quickly if troubleshooting is required due to laboratory errors. 4.   Standardize processes Standardization is a simple, effective tool for reducing errors in all phases of laboratory monitoring. In the pre-analytic stage, standardizing and digitizing requisitions, requisition requirements, patient demographic updates, and the full scope of providers involved in their care will have major impacts on reducing errors. It is also important to map the process and think critically about where errors could occur and then standardize those processes whenever possible. Ensure that someone from the clinic team clarifies any issues in “bumping” with the specified lab tests, delays or special procedures that are involved with the test group they are requesting. If developing technological innovations to assist with clinical laboratory monitoring, ensure that programs identify patients by personal health care number and birthdate, rather than by name, as these unique MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 82 identifiers are less likely to include variation, which can then create new points of failure. In the post-analytic phase, standardize a system to gather laboratory tests from the lab so that they are not misplaced and whenever possible, use color and/or other tactile indicators to help differentiate and prioritize the review of laboratory tests and implement hard reminders for abnormal and critical results. 5.    Advance Planning Mapping out processes, identify areas of risk and planning interventions to address these risks are a part of nursing practice. The tools identified in this analysis can be simplified and adapted to small-scale projects for clinic practice improvements. Plan how your patients will access care should serious adverse events occur, and create networks for referrals before the SAE happens. Be aware of the clinical best practices for these conditions and intervene if these conditions are not being addressed in a timely manner.  6.     Stay flexible, adaptable and responsive The difference between research and quality improvement is that quality improvement does not need to be generalizable, the primary audience is the organization and information is intended to be organization-specific (Hughes, 2008). Mistake proofing methodology speaks to a concept called “try-proofing” (Grout, 2007) or taking less expensive initiatives and piloting the implementation for a set period of time, before making permanent changes. This is similar to the dynamic PDSA (plan, do, study, act) cycles that are commonly seen in clinical practice to quickly respond, assess and improve quality issues in real practice. Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    83 7.    Involve nurses Within the healthcare system, registered nurses are positioned in the middle of logistical clinic concerns, their own autonomous practice, patient needs and the processes to support physicians making clinical decisions. RNs have in-depth knowledge of the impact of success and failure amongst these systems of care and this knowledge should be optimized to generate quality improvement solutions in healthcare. RNs have the ability to access, utilize and even improve the theories and tools currently used in healthcare to strategize and prioritize healthcare innovations. Some of the disconnect felt by healthcare practitioners towards the initiatives currently being implemented in practice may be because nurses are not as involved in the process of generating healthcare solutions as they should be. These tools are subjective and require an intimate knowledge of front-line issues. As experts in healthcare systems coordination, nurses need to learn the tools of quality improvement and patient safety, and become more involved in organizational strategies of healthcare improvement. Conclusion The delivery of quality clinic care is complicated and requires a balance of safety, access, patient preferences and self-determination and professional clinical standards. The treatment environment of MS is changing and healthcare providers need tools to assess risk, support decision-making and prioritize innovation. Adapting tools from other risk-prone systems may provide a framework for conceptualizing risk, but these tools need to be adapted to reflect the principles, outcomes and values of healthcare.  MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 84 The laboratory monitoring process with alemtuzumab treated patients in British Columbia is a high-risk process and can have significant consequences for patient outcomes. Fortunately, there are several high impact solutions that appear to significantly reduce these risks with minimal cost and current technology. The Lemtrada Automated Lab Monitoring Program was developed by the multidisciplinary team in our MS clinic to comprehensively address the actual and potential risks identified in this analysis. Further study needs to be done to determine the efficacy of these innovations, and their impact on clinical quality and patient safety.                 Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    85 References Allard, M., Frego, A., Katz, A., & Halas, G. (2010). Exploring the role of RNs in family practice residency training programs. Canadian Nurse, 106(3), 20-24.  Alroughani, R., Deleu, D., El Salem, K., Al-Hashel, J., Alexander, K. J., Abdelrazek, M. A., …Rovira, À. (2016). A regional consensus recommendation on brain atrophy as an outcome measure in multiple sclerosis. 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Wilsdon, T., Barron, A., Mitchell-Heggs, A. & Ginoza, S. (2014). Access to medicines for multiple sclerosis: Challenges and opportunities (CRA Project No. D19380). London , UK: Charles River Associates.  Willis, M.D. & Robertson, N.P. (2016). Alemtuzumab for Multiple Sclerosis. Curr Neurol Neurosci Rep,16, 84. doi:10.1007/s11910-016-0685-y  Zed, P. J., Abu-Laban, R. B., Balen, R. M., Loewen, P. S., Hohl, C. M., Brubacher, J. R.,…& Purssell, R.A. (2008). Incidence, severity and preventability of medication-related visits to the emergency department: a prospective study. CMAJ, 178(12), 1563-1569. doi: 10.1503/cmaj.071594 PMID: 18519904    Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    97 Appendix Failure Modes and Effects Analysis of Laboratory Monitoring with Alemtuzumab Table A1 – FMEA Pre-Analytic Function 1. Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PR-A F1 Physician writes requisition order F1-1  Wrong patient on requisition -Patient unable to get testing done -Lab work assigned to wrong patient -Delays in testing, diagnosing and treatment -Misdiagnosis or treatment -Irreversible disease and death  10 -Hand written requisitions -Multiple patient charts in one room -Labels pre-printed by clerical and attached to front of charts with paper clips -Labels falling off charts in room -Inexperience/education -Busy/distracted 2 - Using demographic label - Physician checks label - Nurse checks label prior to giving to patient -Patient notices wrong name -Lab tech checks name -Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   2 40 F1-2 Misspelled name -Patient unable to get testing done - Delays in testing, diagnosing and treatment -Misdiagnosis or treatment -Lab work assigned to wrong patient -Irreversible disease and death  10 -Hand written requisitions -Multiple patient identifiers in name  -Maiden names -Inexperience/education -Busy/distracted  6 - Using demographic label -Physician checks label - Nurse checks label prior to giving to patient -Patient notices wrong name -Lab tech checks name - Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  4 240 F1-3 Multiple Patient Identifiers  -Patient unable to get testing done -Delays in testing, diagnosing and treatment -Lab work assigned to wrong patient -Misdiagnosis or treatment -Irreversible disease and death  10 Hand written requisitions -Multiple patient charts in one room -Labels pre-printed by clerical and attached to front of charts with paper clips -Labels falling off charts in room -Marriage or alias not update in chart/EMR -Inexperience/education -Busy/distracted 2 - Using demographic label -Physician checks label - Nurse checks label prior to giving to patient -Patient notices wrong name -Lab tech checks name - Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  6 120 F1-4 Wrong tests or combination of tests -Delays in testing, diagnosing and treatment -Tests missing when treatment decision made -Misdiagnosis or treatment 8 -Clinics not familiar with lab policies regarding test combinations -Physicians unfamiliar with test names an variations -No system in place to communicate changes 7 -Physician reviews tests prior to giving to patient - Nursing team notices missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab 8 448 MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 98 or updates from lab to physicians/clinic staff -Unfamiliarity with requisitions -No time to fill out requisitions/time constraints leading to unintentional error -Inexperience/education -Busy/distracted  results if has not heard back, or is symptomatic  F1-5 Missing care team members -Care team members not getting lab results -Assumed responsibility for management of results -Patient undiagnosed and/or untreated 8 -Do not have the correct information for physician/clinics -Information not clear, incomplete or incorrect -Ordering HCP not familiar with other care team members -Inexperience/education -Busy/distracted 8 -Physician reviews prior to giving to patient - Nursing team notices missing care team members -Physician notices missing care team members -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  8 512  Table A2 – FMEA Pre-Analytic Function 2. Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PR-A F2  Patient gets lab test collected  F2-1  Patient non-compliance -Lab work not being completed, monitoring not being done -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Patient perceives it as unnecessary -Testing/treatment fatigue -Cognition issues (patient forgot) -Lack of Patient/family education -Accidental non-compliance (multiple requisitions for lab work, ours missed) -Mobility/geographic constraints -Financial/work constraints -Time constraints -Addiction issues 7 - Nursing team notices missing lab results -Patient and family teaching pre-infusion and follow up about importance of monitoring -Bayshore in-home lab draws for mobility and compliance issues -Nursing phone line to call for issues with requisitions or if symptomatic -Requisitions faxed to lab -Physician notices missing lab results -Patient contacts clinic if symptomatic   9 630 F2-2 Misidentification at lab testing -Lab work assigned to wrong patient -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death    10 -Lab technician did not ask patients name or care card -Inexperience/education -Busy/distracted  1 -Requisition -Patient identification of error -Personal Health card -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   2 20 F2-3 -Repeat testing required 6 -Inexperience/education of both patient and 2 -Patient support nurse and Lemtrada nurses 2 24 Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    99 Poor Technique -Pain/suffering/infection -Non-compliance with monthly monitoring -Delays in testing, diagnosing and treatment of serious adverse events technician -Busy/distracted manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  F2-4 Mislabeling -Lab work assigned to wrong patient -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Inexperience/education -Busy/distracted -Multiple patients getting testing 2 -Patient identification of error -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  8 160 F2-5 Unusable Sample -Repeat testing required -Pain/suffering -Non-compliance with monthly monitoring -Delays in testing, diagnosing and treatment of serious adverse events 6 -Inexperience/education -Busy/distracted -Poor patient technique (ie: urinalysis) -Poor technician technique 4 -Patient identification of error -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   2 48  F2-6 Wrong tube/container  -Repeat testing required -Pain/suffering/infection -Non-compliance with monthly monitoring -Delays in testing, diagnosing and treatment of serious adverse events 6 -Inexperience/education -Busy/distracted  1 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  2 12 F2-7 Contamination -Repeat testing required -Misdiagnosis or treatment -Pain/suffering/infection -Non-compliance with monthly monitoring -Delays in testing, diagnosing and treatment of serious adverse events 6 -Inexperience/education -Busy/distracted -Poor technique 2 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  2 24   MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 100 Table A3 – FMEA Pre-Analytic Function 3. Function  Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PR-A F3 Lab Tech takes sample to the lab F3-1 Lost samples -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Inexperience/education -Busy/distracted -Poor intake systems -Paper requisitions/no tracking 1 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  9 90 F3-2 Mishandling -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events   6 -Inexperience/education -Busy/distracted 1 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  2 12  Table A4 – FMEA Pre-Analytic Function 4. Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PR-A  F4  Lab Tech enters orders into lab system F4-1 Wrong Patient inputted  -Lab work assigned to wrong patient -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Multiple name checks have failed -Inexperience/education -Busy/distracted -Wrong name on requisition 1 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  9 90 F4-2 Misspelled name -Lab work assigned to wrong patient -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death 10 -Multiple name checks have failed -Typing/entry error -Inexperience/education -Busy/distracted 6 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  9 540 Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    101  F4-3 Wrong Patient identifier -Lab work assigned to wrong patient -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Multiple name checks have failed -Typing/entry error -Inexperience/education -Busy/distracted -Wrong name on requisition 3 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   9 270 F4-4 Wrong Orders Inputted -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events  8 -Typing/entry error -Inexperience/education -Busy/distracted -Internal protocols 4 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  6 192 F4-5 Wrong Physician Inputted -Results not seen by ordering specialist -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events   8 -Typing/entry error -Did not check requisition  -No double check on clinic address -Working off previous requisition -Inexperience/education -Busy/distracted 4 - Physician may contact prescribing physician if notices that the lab tests are not ordered by him/her -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  9 288  F4-6 Wrong copy-to providers -Results not seen by specialty support teams according to process -Other team members do not act on abnormalities, assume other person received them -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events  8 -Typing/entry error -Did not check requisition  -Working off previous requisition -No extra providers added/only primary physician -Deferred to GP -Inexperience/education -Busy/distracted 6 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   9 432  MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 102 Table A5 – FMEA Post-Analytic Function 1. Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PO-A F1  Lab reports results F1 -1 Results sent to Wrong Physician -Results not seen by ordering specialist Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  8 -Typing/entry error  -Did not check requisition  -Working off previous requisition -Deferred to GP -Inexperience/education -Busy/distracted  4 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   9 288 F1-2 Missing Care team members -Results not seen by specialty support teams according to process -Other team members do not act on abnormalities, assume other person received them -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events   8 -Typing/entry error  -Did not check requisition  -Working off previous requisition -Inexperience/education -Busy/distracted  6 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  9 432 F1-3 Un-interpretable results -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events  6 -Typing/entry error  -Poor analysis -Inexperience/education -Busy/distracted   2 -Patient support nurse and Lemtrada nurses manually document lab compliance on an excel spreadsheet, identify if lab results missing -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic   2 24     Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    103 Table A6 – FMEA Post-Analytic Function 2. Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PO-A F2  Results received by physician or clinic  F2-1 Faxing/scanning/ filing errors -Lost results -Results not seen by physician -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Fax line busy/incorrect -Delayed in EMR, or misinterpreted by electronic systems -Filed in wrong chart  -Filed without being seen by HCP -Inexperience/education -Busy/distracted  4 -Nurses notice missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  9 360  Table A7 – FMEA Post-Analytic Function 3. Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PO-A F3  Results reviewed by physician F3-1 Data Missing -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events  8 -Partial results sent to another physician -Internal protocols dictate ordering pairs -Accidental cancelling of tests -Only first page faxed 2 - Nurses notice missing lab results -Physician notices missing lab results -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  2 32 F3-2 Lack of context for results -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events  6 -Multiple medications requiring similar testing -No drug identifiers on lab results -No cause for assessment with subtle findings -Lack of time  -Disconnected systems of information  6 -Nurses notice abnormalities and contact patient for assessment, then report to physician -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic  4 144     MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB 104 Table A8 – FMEA Post-Analytic Function 4. Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PO-A F4 Diagnostic or treatment decision made by physician  F4-1 Failure to contact patient -Misdiagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Missing results – team does not know that results are abnormal -Results misinterpreted as normally abnormal depending on drug regime -Abnormalities not considered significant 4 -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic 9 360 F4-2 Delayed diagnosis and/or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  8 -Missing results – team does not know that results are abnormal -Results misinterpreted as normally abnormal depending on drug regime -Abnormalities not considered significant 5 -Patient contacts clinic with delays in lab results if has not heard back, or is symptomatic 9 360  Function Failure Mode Potential Effects of Failure S Potential Causes of Failure O Current Process Controls D  RPN PO-A  F5 Patient treated  F5-1 Incorrect diagnosis or treatment -Delays in recognition of serious adverse events -Delays in testing, diagnosing and treatment of serious adverse events -Irreversible disease and death  10 -Results misinterpreted as normally abnormal depending on drug regime -Abnormalities not considered significant  2 -Patient contacts clinic if symptomatic -Physician follows up with specialist  8 160 Running head: MISTAKE PROOFING LAB MONITORING WITH ALEMTUZUMAB    105                 

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