Identify Safety Issues Research Articles

Analysis of Safety-Critical Computer Failures in Medical Devices

Malfunctioning medical devices are one of the leading causes of serious injury and death in the US. Between 2006 and 2011, 5,294 recalls and approximately 1.2 million adverse events were reported to the US Food and Drug Administration (FDA). Almost 23 percent of these recalls were due to computer-related failures, of which approximately 94 percent presented medium to high risk of severe health consequences (such as serious injury or death) to patients. This article investigates the causes of failures in computer-based medical devices and their impact on patients by analyzing human-written descriptions of recalls and adverse event reports obtained from public FDA databases. The authors characterize computer-related failures by deriving fault classes, failure modes, recovery actions, and number of devices affected by the recalls. This analysis is used as a basis for identifying safety issues in life-critical medical devices and providing insights on the future challenges in the design of safety-critical medical devices.

Perioperative Variance Report Cards: Do we Make the Grade?

Many hospital safety interventions designed to improve process and decrease errors are triggered by self-reported variances or adverse events. Many hospitals rely on electronic adverse event reporting systems to identify safety issues, but these systems typically capture a minority of variances because of cumbersome functionality, ambiguity in reporting threshold, and distrust despite anonymous reporting. Due to these limitations, an adjunctive, real-time report card system was instituted in the pediatric perioperative environment.

Guidelines for Application of Continuous Subcutaneous Insulin Infusion (Insulin Pump) Therapy in the Perioperative Period

Case reports indicate that diabetes patients receiving outpatient insulin pump therapy have been allowed to continue treatment during surgical procedures. Although allowed during surgery, there is actually little information in the medical literature on how to manage patients receiving insulin pump therapy during a planned surgical procedure. A multidisciplinary work group reviewed current information regarding the use of insulin pumps in the perioperative period. Although the work group identified safety issues specific to surgical scenarios, it believed that with the use of standardized guidelines and a checklist, continuation of insulin pump therapy during the perioperative period is feasible. A sample set of protocols have been developed and are summarized. A policy outlining clear procedures should be established at the institutional level to guide physicians and other staff if the devices are to be employed during the perioperative period. Additional clinical experience with the technology in surgical scenarios is needed, and consensus should be developed for insulin pump use in the perioperative phases of care.

Effect of Safety Issues with HIV Drugs on the Approval Process of Other Drugs in the Same Class

Knowledge on the safety of new medicines is limited at the time of market entry. Nearly half of all drugs used to treat HIV registered in the EU required ≥1 Direct Healthcare Professional Communication (DHPC) in the past 10 years for safety issues identified post-approval. The aim was to evaluate the extent to which regulators and industry have addressed the risk of safety issues for HIV drugs based on prior experience with other drugs in the same class and whether doing so impacts development time of these drugs. HIV drugs receiving ≥1 DHPC in the Netherlands between January 1999 and December 2008 were identified. Each drug with a DHPC ('index' drug) was paired with subsequently approved HIV drug(s) in the same class (Anatomical Therapeutic Chemical [ATC] 4th level) ['follow-on' drugs]. Characteristics of safety issues were extracted from the DHPCs of the 'index' drugs. European Public Assessment Reports (EPARs) were reviewed regarding whether the safety issues had been considered during development and approval. Consideration of previously identified safety issues in 'follow-on' drug applications was assessed regarding attention paid to adverse drug reaction (ADR) symptoms in pre-marketing studies, Summary of Product Characteristics (SmPC) and postmarketing commitments, and whether size of the safety population was in accordance with Regulatory guidelines. 'Index' drugs were also paired with drugs in the same class already on the market ('older' drugs). For 'older' drugs, we identified whether the safety issue led to appropriate changes in the current SmPC (January 2011) compared with the SmPC at the time of marketing authorization. Clinical development time was assessed using time from first patent application to market authorization as proxy, and comparison was made between 'index' and 'follow-on' drugs. For 9 (43%) of the 21 centrally authorized HIV drugs, 11 serious safety issues that required a DHPC were identified. Two drugs were excluded from our analysis (DHPCs related to contamination/medication error). Six 'index' drugs were paired, each with one to six 'follow-on' drugs. Three concerned drug-drug interactions (DDIs); the other three were intracranial haemorrhage, neuromuscular weakness and severe skin/hepatic reactions. All but one 'follow-on' drug had information in the EPAR on that specific ADR (i.e. attention was paid to the ADR). The DDIs were addressed in pre-marketing studies and/or the SmPC. Two of the other ADRs were addressed by postmarketing surveillance commitments; intracranial haemorrhage was not addressed. Three safety issues for two 'index' drugs could not be paired with a 'follow-on' drug as no drug in the same class was approved after the corresponding DHPCs were issued. Five of the nine safety issues were added to at least one of the current SmPCs for the 'older' drugs already on the market at the time of DHPC issue. Two safety issues were already in the SmPC of the 'older' drugs at time of market approval and two were not introduced into the SmPC of 'older' drugs. Population size to assess short-term safety complied with the guidelines for four 'index', seven 'follow-on' and three 'older' drugs; population size to assess long-term safety complied for one, three and two drugs, respectively. For five drugs, EPARs did not provide adequate information on population size. No statistically significant difference in development time between 'index' and 'follow-on' drugs was found. Generally, safety issues were taken into account in the approval process of other drugs in the class. The approaches were different and determined by the nature of the ADR. Taking safety issues into account in the approval process did not seem to impact on the time taken to perform the pre-approval clinical programme.

Implementation of Road Safety Audit Recommendations

As road safety audits (RSAs) have been implemented by agencies across the United States, transportation professionals have realized that RSAs are an effective tool to proactively improve the future safety performance of a roadway during the planning and design stages and to identify safety issues in existing transportation facilities. But limited study has been done of the implementation of RSA recommendations on existing roadways. The Utah Local Technical Assistance Program Center conducted an RSA of 1300 East in Salt Lake City, Utah. The rapid implementation of the recommendations was one of the major successes of the project. In addition, a public involvement process refined the recommendations and helped develop a consensus that the safety improvements implemented would be accepted. The result of the safety audit was the implementation of countermeasures that should increase the safety of the roadway. The ability to introduce a bike lane and signalized crosswalks had a significant impact toward the goal of making roads more pedestrian- and bicycle-friendly and implementing a “complete street” solution. The roadway is now much more accessible to pedestrians and bicyclists while maintaining much of the mobility already in place for motorized vehicles.

Detection of actuator faults in flight control systems

A method for the multiple fault diagnosis of aircraft traditional aerodynamic control surfaces described by a nonlinear model is proposed in the form of an algorithm. A geometric approach to the nonlinear fault detection and isolation problem is investigated for actuator fault detection. The approach is based on the geometric decomposition of aircraft dynamics into tangential and transverse dynamics. Its application to reconstructed flight fault dynamics enables fault detection and distinguishes which one is occurring. To efficiently identify safety issues, critical contingencies leading the system to a failure state can be evaluated using effective algorithms within each functional area of the whole system. Results of the proposed approaches indicate not only the effective identification of faults in civil transport aircraft but also improvements in establishing an acceptable level of safety performance, even when the number of faults is not known a priori.

Testing a home-telehealth programme for US veterans recovering from stroke and their family caregivers

Purpose. The study purpose was to implement a stroke-specific, care coordination home telehealth (CCHT) programme for US veterans with stroke and their family caregivers.Methods. In a non-randomized open trial using a mixed methods design, we tested the utility of a stroke-specific, home telehealth programme with 18 veterans and 14 caregivers for 14 days. Programme questions assessed physical impairment, depressive symptoms, and fall prevalence among veterans, and burden level among family caregivers. Nine veterans and six caregivers completed post-programme interviews exploring their experiences with telehealth.Results. During the 14-day trial, 55% of the veterans screened positive for depression at least once, 36% of the caregivers had clinically significant burden, half of the veterans and caregivers reported post-stroke concerns, and 90% believed post-stroke contact from a care coordinator would have been helpful. In the interviews, seven veterans indicated they had fallen or almost fallen post-stroke. Themes centred on tailoring CCHT to individual needs, coordinating with support services, identifying safety issues, and providing information about stroke prevention.Conclusions. Home telehealth offers innovative ways to target post-stroke rehabilitation programmes to the needs and concerns of patients and their caregivers, and should include regular real-time contact between stroke patients and their healthcare providers.

PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome

The discovery of the crucial role of peroxisome proliferator-activated receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tools for therapeutic intervention in type 2 diabetes and the metabolic syndrome. PPARalpha activators primarily improve dyslipidemia, whereas thiazolidinediones are potent PPARgamma activators that improve insulin resistance. Important research programs to develop agonists that combine the therapeutic effects of both PPARalpha- and PPARgamma-selective agonists, creating the expectation of greater efficacy and other advantages in the treatment of type 2 diabetes and the metabolic syndrome, have therefore been undertaken. Among these dual PPARalpha/gamma agonists, compounds that belong to the glitazar class are in the most advanced stage of development. However, although they demonstrated beneficial impact over selective PPAR agonists by improving both lipid and glucose homeostasis, safety has been a critical issue and has led to the discontinuation of their development because of adverse toxicity profiles. However, the target-related mechanism responsible for the identified safety issues and the relevance of rodent toxicities to the human situation are unclear. Therefore, future development of dual PPARalpha/gamma agonists with selective PPAR modulator activity appears appropriate and should be feasible.

Factors influencing young children's risk of unintentional injury: Parenting style and strategies for teaching about home safety

This study examined mothers' teaching about home-safety issues to 24–30 month and 36–42 month old children, explored the relationship of teaching strategies to parenting styles, and assessed how these factors are related to children's risk of unintentional injury. A structured interview assessed home-safety issues relevant to falls, burns, cuts, poisoning, and suffocation/strangulation/choking. Mothers identified safety issues relevant to her child, and indicated the type and extent to which she utilized teaching as a strategy to address each safety issue. Standardized questionnaires provided information about parenting style and children's history of injuries. Results revealed that mothers' endorsements of home-safety issues did not vary with child age, mothers used teaching to manage safety issues for all types of injuries, and type of teaching strategy (explanations, rules, behavior modification) varied with parenting style. Greater use of explaining and less rule usage was linked to permissive parenting; these teaching strategies predicted children's medically-attended injury among highly-permissive mothers. Thus, teaching about safety is a common risk-management strategy mothers use to address hazards in the home. However, the specific type of teaching strategy used varies with parenting style, which has implications for children's risk of injury.

Treatment delivery software for a new clinical grade ultrasound system for thermoradiotherapy

A detailed description of a clinical grade Scanning Ultrasound Reflector Linear Array System (SURLAS) applicator was given in a previous paper [Med. Phys. 32, 230-240 (2005)]. In this paper we concentrate on the design, development, and testing of the personal computer (PC) based treatment delivery software that runs the therapy system. The SURLAS requires the coordinated interaction between the therapy applicator and several peripheral devices for its proper and safe operation. One of the most important tasks was the coordination of the input power sequences for the elements of two parallel opposed ultrasound arrays (eight 1.5 cm x 2 cm elements/array, array 1 and 2 operate at 1.9 and 4.9 MHz, respectively) in coordination with the position of a dual-face scanning acoustic reflector. To achieve this, the treatment delivery software can divide the applicator's treatment window in up to 64 sectors (minimum size of 2 cm x 2 cm), and control the power to each sector independently by adjusting the power output levels from the channels of a 16-channel radio-frequency generator. The software coordinates the generator outputs with the position of the reflector as it scans back and forth between the arrays. Individual sector control and dual frequency operation allows the SURLAS to adjust power deposition in three dimensions to superficial targets coupled to its treatment window. The treatment delivery software also monitors and logs several parameters such as temperatures acquired using a 16-channel thermocouple thermometry unit. Safety (in particular to patients) was the paramount concern and design criterion. Failure mode and effects analysis (FMEA) was applied to the applicator as well as to the entire therapy system in order to identify safety issues and rank their relative importance. This analysis led to the implementation of several safety mechanisms and a software structure where each device communicates with the controlling PC independently of the others. In case of a malfunction in any part of the system or a violation of a user-defined safety criterion based on temperature readings, the software terminates treatment immediately and the user is notified. The software development process consisting of problem analysis, design, implementation, and testing is presented in this paper. Once the software was finished and integrated with the hardware, the therapy system was extensively tested. Results demonstrated that the software operates the SURLAS as intended with minimum risk to future patients.

Patient Safety Leadership WalkRounds™ at Partners HealthCare: Learning from Implementation

Brigham and Women's Hospital (BWH) began Patient Safety Leadership WalkRounds in January 2001; its experience, along with that of three other Partner Healthcare hospitals, is reported. COLLECTING DATA ON WALKROUNDS: Data were obtained from interviews with patient safety personnel, WalkRounds scribes, and senior leaders. A total of 233 one-hour WalkRounds during 28 months yielded 1,433 comments--30% related to equipment, 13% to communications, 7% to pharmacy, and 6% to workforce. Actions occurred quickly in small hospitals. Formal processes for managing larger issues were necessary in large organizations. Implementation feasibility featured more prominently than severity in determining actions. The study generated essential guidelines for success--for example, the supporting resources must include the maintenance of effective information databases that identify actions taken, and the discussions during WalkRounds are influenced by who in leadership is participating, their ability to quietly listen, and whether they have clinical or nonclinical backgrounds. WalkRounds appears to be an effective tool for engaging leadership, identifying safety issues, and supporting a culture of safety.

Telbivudine: a new nucleoside analogue for the treatment of chronic hepatitis B

Telbivudine, β-L-2′-deoxythymidine (LdT), is a new β-L-nucleoside analogue with potent inhibitory activity against the hepatitis B virus. In invitro studies and animal models, telbivudine has demonstrated potent and specific antiviral activity against hepatitis B. Additionally, in preclinical animal toxicology studies, telbivudine showed no adverse side effects or adverse effects on mitochondrial function. The promising results of the early invitro and animal telbivudine studies prompted the development and initiation of Phase I andII human clinical trials. The Phase I clinical study demonstrated that end-of-treatment virological response rates were better for telbivudine recipients at multiple dosing levels as compared with placebo patients. The subsequent Phase IIb human clinical study demonstrated superior antiviral efficacy of telbivudine, significantly better ALT normalisation and better hepatitis B e-antigen loss as compared with lamivudine. Telbivudine was well tolerated with no identified safety issues. Virological breakthrough with telbivudine was significantly lower than with lamivudine.

Use of the Development Core Safety Information in the assessment of expectedness of serious adverse events reported in oncology clinical trials

7264 Background: The Council for International Organizations of Medical Sciences (CIOMS) Working Group has recommended the use of the Development Core Safety Information (DCSI) as the summary of the identified safety issues for an investigational product/drug. Only safety issues or adverse drug reactions contained in this document should be considered

Use of the Development Core Safety Information in the assessment of expectedness of serious adverse events reported in oncology clinical trials

7264 Background: The Council for International Organizations of Medical Sciences (CIOMS) Working Group has recommended the use of the Development Core Safety Information (DCSI) as the summary of the identified safety issues for an investigational product/drug. Only safety issues or adverse drug reactions contained in this document should be considered

Nonclinical Toxicology in Support of Licensure of Gene Therapies

and discussed their relevance to biologic products. Elesperu stated that genotoxicity assays are designed as surrogate assays to detect rare occurrences of genetic damage, and noted that although no single test alone will detect all types of mutagenic effects, a positive result in any one test is considered evidence for genotoxic potential. Elesperu emphasized that these assays are properly used for hazard identification and not risk translation, and that additional testing to evaluate the risk to humans of insertional mutagenesis by gene therapy vectors will need to be developed in support of eventual licensure. Marion Gruber (FDA) presented the purpose and design of reproductive and developmental toxicity studies. The relevant guidelines, ICH S5a, can be found online at http://www.ich.org/pdfICH/s5a.pdf. Reproductive toxicity studies focus on the effects of a product in pregnant animals, to identify potential developmental defects that might result from fetal exposure to the product. The target population for genetic vaccines and gene therapeutics often includes women in their reproductive years, and the label must have a statement describing the potential risk of using the product during pregnancy. Gruber noted that the evaluation of reproductive and developmental risk of gene therapy vectors should be done on a case-by-case basis, taking into account any evidence for insertional mutagenesis by the vector, the particular target patient population, and any potential for the transgene product to induce disease. Rick Irwin (National Institutes of Environmental Health and Safety) detailed the standard rodent carcinogenicity studies as conducted by the National Toxicology Program (http://ntp.niehs.nih.gov), emphasizing that these studies are designed to evaluate the occurrence of both benign and malignant growth. Irwin noted that carcinogenicity studies are both time-consuming and costly, and that they therefore must be carefully planned and implemented, and that the requirements for the testing of gene transfer vectors in rodents should be determined by risks associated with the specific gene transfer agent. Leslie Recio (Merck Research Laboratories) discussed alternative models for carcinogenicity testing that make use of genetically modified animals that have been ‘primed’ for tumor development. Potential advantages of such systems are greater sensitivity that could lead to earlier detection of malignant potential using a smaller number of animals. Richard D. McFarland (FDA) next discussed the timing of nonclinical studies of therapeutic MEETING REPORT

Toward protecting the safety of participants in clinical trials

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

Pharmacoepidemiologic implications of erroneous varicella vaccinations in pregnancy through confusion with Varicella zoster immune globulin.

A series of case reports to the varicella vaccine Pregnancy Registry described inadvertent administrations during pregnancy of this live virus product instead of the intended Varicella zoster immune globulin. Cases continued to accrue despite an early publication about the pattern. The persistent problem warrants specific educational efforts to prevent further repetitions. It also has more general implications for medical product safety surveillance. First, this problem's original detection depended on the Pregnancy Registry's open-ended collection of information about pregnancy exposures. It could have escaped recognition through surveillance limited to pre specified potential risks. This need for unrestricted reporting and human vigilance to sift through case stories has particular relevance for efforts to re-think methods to monitor gestational drug exposures. In addition, the problem's persistence despite initial publicity suggests that diligent surveillance may require continued follow-up of identified safety issues. Periodic reassessments of selected preventable problems might strengthen efforts to minimize product risks.

Accomplishments and challenges of the severe accident research

This paper briefly describes the progress of the severe accident research since 1980, in terms of the accomplishments made so far and the challenges that remain. Much has been accomplished: many important safety issues have been resolved and consensus is near on some others. However, some of the previously identified safety issues remain as challenges, while some new ones have arisen due to the shift in focus from containment to vessel integrity. New reactor designs have also created some new challenges. In general, the regulatory demands for new reactor designs are stricter, thereby requiring much greater attention to the safety issues concerned with the containment design of the new large reactors, and to the accident management procedures for mitigating the consequences of a severe accident. We apologize for not providing references to many fine investigations that contributed to the great progress made so far in the severe accident research.

Tools to Identify Safety Issues for a Corridor Safety-Improvement Program

The Arizona Department of Transportation (ADOT) recognizes that a new paradigm in highway safety evaluation was brought about by the advent of advanced technologies such as photo log, geographic information systems (GIS), and global-positioning satellite systems. Whereas these technologies are known to serve distinct singular purposes in a highway agency, ADOT has endeavored to explore the possibilities of integrating these technologies for the purpose of providing an all-encompassing perspective of crash history and roadside characteristics in a multimedia display of GIS maps and related photo imagery. The research provides the account of an analytic tool-development process aimed at improving the recognition of highway safety hazards. These hazards might otherwise be apparent if not for the relative complexity of existing relational databases and spatial GIS infrastructure at ADOT. Previous methods of mining data from the ADOT crash databases were limited in functionality as well as in reliability. By promoting the “visualization” of highway safety conditions, the advanced technologies open a wealth of new opportunities in identifying problematic roadside conditions and crash histories. This is expected to lead to an improved economy of implementing safety improvements that are designed properly to mitigate the “real” conditions that can be identified. The research is a companion to the larger, FHWA-sponsored research into establishing a corridor safety-improvement program for Arizona (FHWA Report FHWA-AZ 98-458).

Impact of the change in Connecticut syringe prescription laws on pharmacy sales and pharmacy managers' practices.

We assessed the impact of the 1992 change in Connecticut syringe prescription laws on pharmacy sales and pharmacy managers' sales practices. A mail survey was conducted in 1994 of all current pharmacy managers in the five largest cities in Connecticut (Hartford, New Haven, Waterbury, Bridgeport, and Stamford) and a random sample of those practicing in all other areas. Of these, 89.3% of the pharmacies in the five largest cities and 85.1% in the other areas had ever sold syringes without a prescription since the July 1992 law went into effect. Most pharmacists identified safety issues as very important in their personal decision about the sale of syringes without a prescription. Although the purpose of the change in the prescription law was to provide expanded access to sterile syringes by injection drug users (IDUs), only 31.4% of the managers who were allowed to sell in all instances and 18.1% of those who sold at their discretion were very willing to sell syringes to IDUs. In the logistic regression model of pharmacies with a sell-in-all-instances policy, the perceived benefit of the sale of syringes on health and community well-being was the only influence independently associated with managers support for nonprescription sales. Overall, managers reported they did not know what other pharmacists thought (40.4%) or did (42.9%) regarding the sale of syringes. When pharmacists had discretion over syringe sales, managers' beliefs about what other Connecticut pharmacists thought and did about the nonprescription sale of syringes remained a significant influence on the degree of support for sales. Most pharmacies implemented and maintained policies permitting the sale of syringes without a prescription. Several issues, including risk of discarded contaminated syringes around pharmacies and in the community and reluctance to sell to IDUs, reduced pharmacists willingness to sell syringes. Efforts to incorporate pharmacists as active partners in HIV prevention in IDUs should promote the sale of syringes without a prescription to IDUs as acceptable public health practice.