Reporting standards for adverse events after medical device use in the peripheral vascular system

Abstract

Adverse event reporting after medical device implantation is essential to understanding the safety and performance of a device. Standardization of reporting attains great importance when comparing different devices and for the ongoing surveillance of a marketed device. Although some work has been done to standardize adverse event reporting for medical devices, a single reference with recommendations that span investigational and postmarket use does not exist. Standardization of nomenclature for reporting vascular conditions is one of the objectives of the Society for Vascular Surgery (SVS) in its Bylaws.1The Society for Vascular Surgery. Bylaws: Article II. Objectives. Available at: http://www.vascularweb.org/about/Pages/bylaws.aspx. Accessed February 17, 2013.Google Scholar Through the Ad Hoc Committee for Standardized Reporting Practices in Vascular Surgery, the SVS developed treatment and disease-specific guidelines. The Committee has published more than a dozen such documents and several revisions during the last 25 years. Some of the documents are disease-based, whereas others are treatment-based. The documents broadly cover the unified reporting of anatomic or etiologic classifications. Of necessity, the documents only briefly frame standardized reporting of outcomes applicable to the broad range of vascular open surgical and less invasive interventions. Within this context, the current document is directed at a unified paradigm for reporting adverse outcomes after use of a medical device and developing a framework that is, for the most part, independent of a particular vascular disease or its treatment. Although the scope of the document excludes devices used in the heart or intracranially, many of the principles outlined here may also apply to other organ systems. This document has been developed with the recognition that meaningful outcomes assessment depends on a unified, consensus-driven reporting structure. Sections of this document provide an overview of select aspects of the current guidelines and principles from the regulatory agencies of the United States and other countries. Where possible, existing guidelines have been incorporated, refined, or clarified. The document addresses general reporting standards for adverse events occurring during and after the use of medical devices in the treatment of peripheral arterial and venous diseases. This document does not encompass disease-specific or organ system-specific recommendations. A second part to this document will be forthcoming and will include specific, detailed, and organ system-based reporting guidelines. There are governmental guidelines and regulations for reporting adverse events that occur during a clinical trial as well as those that occur after a device has been introduced into the marketplace. These regulations are country-specific, but several multinational nongovernmental organizations have taken the lead to achieve a level of international conformity and standardization.2Crowley G. EU and US clinical investigation adverse event reporting.Med Device Technol. 2004; 15: 30-32PubMed Google Scholar The U.S. Food and Drug Administration (FDA) regulates clinical trials in the United States under section 520(g) of the Federal Food, Drug, and Cosmetic Act.3Agency Information Collection ActivitiesSubmission for Office of Management and Budget ReviewComment RequestInvestigational Device Exemptions Reports and Records.Fed Regist. 2012; 77: 71601-71603Google Scholar Medical device regulations are specified in part 812 of title 21 of the Code of Federal Regulations, under the auspices of the FDA's Center for Devices and Radiologic Health.4Pritchard Jr., W.F. Abel D.B. Karanian J.W. The US Food and Drug Administration investigational device exemptions (IDE) and clinical investigation of cardiovascular devices: information for the investigator.J Vasc Surg. 1999; 29: 566-574Abstract Full Text Full Text PDF PubMed Google Scholar, 5“Investigational device exemptions. Selecting investigators and monitors.,” Title 21 Code of Federal Regulations, Pt. 812.43. 2012 ed.Google Scholar These regulations mandate the reporting of adverse events to ensure the protection of human subjects in clinical trials, and reporting requirements exist for the manufacturer and the investigator alike. Other countries have regulatory agencies analogous to the FDA. For example, the Medicines and Healthcare products Regulatory Agency is the equivalent in the United Kingdom of the FDA, as is the Federal Institute for Drugs and Medical Devices in Germany, the Pharmaceuticals and Medical Device Agency in Japan, and the State Food and Drug Administration in China.6ClinicalTrials.gov. Gobal regulatory agencies. Available at: http://www.clinicaltrials.com/industry/regulatory_agencies.htm. Accessed January 13, 2013.Google Scholar Noting the number of disparate regulatory agencies throughout the world, it is not surprising that differences exist in terminology and regulations. In an effort to provide some level of conformity between the national systems, government and industry representatives of Australia, Canada, the European Union, Japan, and the United States formed the Global Harmonization Task Force (GHTF) in 1992.7Gupta P. Janodia M.D. Jagadish P.C. Udupa N. Medical device vigilance systems: India, US, UK, and Australia.Med Devices (Auckl). 2010; 3: 67-79PubMed Google Scholar The mission of GHTF was to achieve greater conformity in the assessment of medical devices.8Tominaga T. Ando Y. Kondo T. International vision and strategy for drug regulatory authority: the PMDA's international vision.Clin Pharmacol Ther. 2012; 92: 349-351Crossref PubMed Scopus (2) Google Scholar Similarly, in 2003 the International Organization for Standardization (ISO) created the ISO 14155 document, revised in 2011, to address good clinical practice for the design, conduct, and reporting of medical device clinical research.8Tominaga T. Ando Y. Kondo T. International vision and strategy for drug regulatory authority: the PMDA's international vision.Clin Pharmacol Ther. 2012; 92: 349-351Crossref PubMed Scopus (2) Google Scholar, 9Ziegler W.J. Perren S.M. Standards, guidelines and principles for clinical trials: medical products.Swiss Surg. 1995; : 81-83PubMed Google Scholar More recently, representatives from the medical device regulatory authorities of Australia, Brazil, Canada, China, the European Union, Japan, the United States, and the World Health Organization established the International Medical Device Regulators' Forum.10International medical device regulators forum. Available at: http://www.imdrf.org/index.asp. Accessed February 25, 2013.Google Scholar The founding members met in 2011 and set an organizational goal to build on the work of the GHTF and to accelerate international medical device regulatory convergence. For clinical trials, each study site's Institutional Review Board (IRB) or Ethics Committee (EC), which outside of the United States is the equivalent of the IRB, plays a critical role to ensure the safety of human subjects.11U.S. Department of Health and Human Services. Guidance for clinical investigators, sponsors, and IRBs. Adverse event reporting to IRBs—improving human subject protection. Washington, DC: Office of the Commissioner (OC) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) Office of Good Clinical Practice; January 2009.Google Scholar The IRB/EC may be local, that is, specific to an investigational site; alternatively, a centralized IRB/EC may serve many geographically disparate institutions. The principal role of the IRB/EC is to protect human subjects, where research is defined very broadly as any systematic investigation designed to contribute to generalizable knowledge.12U.S. Department of Health and Human Services. Code of Federal Regulations. Title 45. Public welfare. Department of Health and Human Services. Part 46. Protection of human subjects. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html. Accessed February 17, 2013.Google Scholar The IRB or EC must review and approve the study protocol and informed consent documents before a clinical research trial can be initiated at a site. During the study, the IRB/EC reviews pertinent adverse events to ensure that subjects are not being harmed. Historically, the reporting of trivial and unrelated adverse events inundated IRB/ECs with countless and often nonselective reporting of events. In an effort to reduce the workload of IRBs and allow them to focus on events that are pertinent to the health and welfare of trial subjects, recent FDA guidelines were created to narrow the spectrum of events important for an IRB to review. IRB review is not necessary for adverse events that are prespecified as “anticipated” in event severity or frequency of occurrence. This guideline allows IRBs to focus on those events that are unanticipated or, if anticipated, occur at a higher frequency than expected. The SVS has taken the lead to develop and articulate reporting standards for clinical trials. Intuitively, uniform definitions are necessary to compare outcomes from one study to the next. Less obvious, however, is the need for precise definitions within any one study so that investigators uniformly report specific outcomes of treatment. This need is of particular importance with respect to adverse events, where identical events may be reported differently by two investigators. One investigator may consider the event a complication worthy of report, whereas another may consider it to be an outcome that is expected in a certain percentage of patients. With the proliferation of newer, more complex medical devices, there is an increased need to closely monitor clinical safety. There is a separate set of reporting requirements in the United States for devices that are marketed; in other words, devices that have been either cleared for marketing through the 510(k) pathway or approved for marketing after a premarket approval process.2Crowley G. EU and US clinical investigation adverse event reporting.Med Device Technol. 2004; 15: 30-32PubMed Google Scholar, 7Gupta P. Janodia M.D. Jagadish P.C. Udupa N. Medical device vigilance systems: India, US, UK, and Australia.Med Devices (Auckl). 2010; 3: 67-79PubMed Google Scholar, 13U.S. Food and Drug Administration Form for reporting serious adverse events and product problems with human drug and biological products and devices; availability—FDA. Notice.Fed Regist. 1993; 58: 31596-31614PubMed Google Scholar The Medical Device Reporting (MDR) requirements apply to device user facilities (including hospitals and outpatient treatment centers), importers, and device manufacturers. The user facility must report device-related deaths and serious injuries, but can voluntarily report device malfunctions. By contrast, manufacturers must report device-related deaths, serious injuries, and certain device malfunctions. The definitions of serious injury and device malfunction remain open to some interpretation. The MDR regulation defines serious injury as “an injury or illness that is life-threatening, results in permanent impairment of a body function or permanent damage to a body structure, or necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.”14Lowe N, Scott WL. Medical device reporting for user facilities. Rockville, MD: Department of Health and Human Services, Public Health Services, Food and Drug Administration; April 1996.Google Scholar The MDR regulation defines a malfunction as “the failure of a device meet its performance specifications or otherwise perform as intended.” Form FDA 3500A is used for mandatory reporting, and Form FDA 3500 is used for voluntary reports.15U.S. Food and Drug Administration. Manufacturer and user facility device experience database (MAUDE). Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/ucm127891.htm. Accessed February 17, 2013.Google Scholar The FDA's Manufacturer and User Facility Device Experience (MAUDE) database contains mandatory device adverse event reports associated with marketed devices reported by manufacturers, importers, distributors, and user facilities.13U.S. Food and Drug Administration Form for reporting serious adverse events and product problems with human drug and biological products and devices; availability—FDA. Notice.Fed Regist. 1993; 58: 31596-31614PubMed Google Scholar, 15U.S. Food and Drug Administration. Manufacturer and user facility device experience database (MAUDE). Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/ReportingAdverseEvents/ucm127891.htm. Accessed February 17, 2013.Google Scholar The MAUDE database also contains voluntary reports from various sources but is not used for reporting of events that occur with devices not cleared for marketing in a premarket study. These events are conveyed in the investigational device exemption reports required by the FDA. A public Web site allows open access to search the MAUDE database for reports of any device that might have malfunctioned or caused injury or death. The current MDR regulation mandates that manufacturers report deaths, serious injuries, and malfunctions to the FDA, that importers report deaths and serious injuries to the FDA and the manufacturer and malfunctions to the manufacturer, and that user facilities report deaths to the FDA and deaths and serious injuries to the manufacturer. The regulation also specifies the time frames for reporting once an entity becomes aware of the event. Other events that do not fall under the mandatory reporting requirements, or those reported by other entities, may be voluntarily reported to the FDA using the MedWatch program for reporting adverse events. In the MAUDE database, manufacturers submit >90% of reports. Unfortunately, clinicians might not inform the manufacturer of a problem and do not often report an event themselves. Although the MDR regulation does not apply directly to clinicians (only to user facilities) and requires that a user facility report only deaths directly to the FDA and serious injuries to the manufacturer, the key issue, according to the MDR regulation, is to encourage reporting of events to the manufacturer via the user facility. Further, there is duplication and inconsistency of reporting and few follow-up details for events. Adverse event reporting needs to be a shared responsibility among all of the stakeholders and not just left to the manufacturer or user facility. Because the clinician who uses the device and monitors its performance is best placed to recognize and report an event, the FDA and the National Competent Authorities (NCA) encourage the reporting of adverse events by users directly to the governmental agency, to the manufacturer, or to both, depending on national policies. Even when the event or device malfunction occurs within the context of a clinical trial, for example, when a device comprises the control or comparator arm of a trial, it is appropriate to report the malfunction and serious adverse events to the FDA or NCA if that device is marketed. The Web site of the FDA's voluntary MedWatch program for reporting adverse events associated with marketed devices is https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm. Many countries have their own reporting systems, and medical device manufacturers are required to notify the NCA of certain adverse events. Medical devices are not well regulated in some developing nations, where many adverse events might never be reported. The World Health Organization estimates that 35% of countries have no designated unit responsible for the implementation and enforcement of medical device regulations.16World Health Organization. Medical devices. Available at: http://www.who.int/medical_devices/policies/en/. Accessed February 27, 2013.Google Scholar Sources of postmarket surveillance data include the MAUDE database containing mandatory MDR reports and voluntary MedWatch reports, the European Databank on Medical Devices in the European Union member countries, and the Medical Device Incident Reporting and Investigation Scheme in Australia.2Crowley G. EU and US clinical investigation adverse event reporting.Med Device Technol. 2004; 15: 30-32PubMed Google Scholar, 7Gupta P. Janodia M.D. Jagadish P.C. Udupa N. Medical device vigilance systems: India, US, UK, and Australia.Med Devices (Auckl). 2010; 3: 67-79PubMed Google Scholar The utility of adverse event reporting is dependent on universal definitions suitable for use over the spectrum of disease processes, devices, and anatomic regions of interest. Regulatory agencies around the world have attempted to develop some level of global standardization for adverse events. Two major agencies are active in this regard: the FDA and the ISO (meaning equal in Greek). ISO was created in 1947 to develop voluntary international standards for specifying products, services, and good practice. ISO guidelines are characteristically followed in countries outside the United States, although the United States is one of its 160 member nations. The FDA publishes guideline documents that can be viewed as recommendations for best practice. In addition, the FDA develops rules and regulations for reporting events, most of which are published in the U.S. Code of Federal Regulations. ISO addresses similar but distinct recommendations, but specifically outlines good clinical practice guidelines for the conduct of clinical research. Guidelines and regulations followed in different geographies are quite similar in many regards, but there are some advantages of one over another. For example, ISO guidelines include a definition of serious adverse events, a definition conspicuous in its absence from the FDA medical device guidelines. Other definitions are not well covered by the FDA or ISO guidelines. Neither organization comprehensively defines the relatedness of an event to the device vs the procedure, leading to a lack of reporting consistency for clinicians, investigators, and manufacturers. We have attempted to narrow the gap of adverse event reporting by different organizations by specifying the definitions used by the global regulatory agencies when they are similar and relevant to contemporary technology. When the guidelines differ, we have made an attempt to extract the most relevant portions from each. When a particular issue is lacking from any of the guidelines, we have made an attempt to develop our own. In this latter instance, we have relied on some of the definitions used in recent published clinical trials. For the remainder of this current document and for the purpose of reporting medical device trials and clinical patient series, we have proposed definitions to facilitate conformity in reporting. These definitions are summarized in Table I.Table IDefinitionsAdverse eventUntoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device.Core laboratoryA centralized, independent entity that reviews imaging and other studies to provide accurate, standardized, and unbiased measurements.CECAn independent committee that reviews events that occur during the course of a clinical trial and adjudicate aspects of the events such as whether the classification by the site was accurate and whether the event was related to the device or the procedure.Good clinical practicesThe regulations that must be complied with while conducting a clinical study. The regulations apply to manufacturers, sponsors, investigators, and institutional review boards. These regulations are included in the Code of Federal Regulations, Title 21.DSMBAn independent committee that reviews safety data from a clinical trial and determines whether the study should continue under an existing protocol, whether the protocol should be modified, or whether the trial should be stopped.Device-related adverse eventsEvents directly attributable to the device itself.Index procedureThe initial, primary procedure under study that serves as the starting point for the analysis of study outcomes.Investigational device exemptionAn exemption that allows an investigational device to be used in a clinical study to collect safety and effectiveness data. An approved investigational device exemption allows the device to be shipped for the purposes of investigations without complying with the FDA requirements for commercial distribution.MAUDE databaseThe FDA's MAUDE database for medical device adverse event reporting after market introduction of a device.Procedure-related adverse eventsEvents that occur from the procedure, irrespective of the device.ReinterventionA secondary procedure performed to address problems that arise as a result of the index procedure. Diagnostic procedures are not included in this definition.SAEAn adverse event where the outcome is one of the following:1. Death2. Life-threatening, where the patient was at substantial risk of dying or continued use of the product might have resulted in death3. Hospitalization or prolongation of an existing hospitalization4. Disability or permanent damage, interfering with the patient's ability to conduct normal life functions5. Congenital anomaly or birth defect6. Required intervention to prevent permanent impairmentUADEAny serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan.CEC, Clinical Events Committee; DSMB, Data Safety Monitoring Board; FDA, Food and Drug Administration; MAUDE, Manufacturer and User Facility Device Experience; SAE, serious adverse event; UADE, unanticipated adverse device effect. Open table in a new tab CEC, Clinical Events Committee; DSMB, Data Safety Monitoring Board; FDA, Food and Drug Administration; MAUDE, Manufacturer and User Facility Device Experience; SAE, serious adverse event; UADE, unanticipated adverse device effect. The 2011 ISO 14155 guidelines define an adverse event as an “untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device.”17ISO 14155: Clinical investigation of medical devices for human subjects—good clinical practice. 2 ed. International Organization for Standardization, Geneva, Switzerland2011Google Scholar It is important to recognize that operations, procedures, and hospitalizations are not, in and of themselves, adverse events. Rather, the occurrence responsible for the procedure or admission is the adverse event, be it a disease, injury, clinical symptom or sign, abnormal laboratory result, or an observation on an imaging study. For example, the adverse event in a patient undergoing amputation for leg ischemia is the ischemia and not the amputation. There has been much confusion over when to report an adverse event. It is infrequently necessary and often confusing to report an adverse event that occurs before the use of a medical device. In this regard, it is useful to define the term “index procedure” as the initial intervention that is the subject of study. As an example, consider a patient who undergoes the index procedure of iliac artery stent implantation for claudication and experiences a postprocedural acute myocardial infarction (MI). Often, an investigator or research coordinator will report the adverse event as coronary artery disease. Although the development of coronary disease may indeed be an adverse event, it likely developed well before the index procedure of iliac stenting and, as such, would be considered a pre-existing condition. The adverse event that could be reported is acute MI and not coronary artery disease. In this case, the adverse event is likely unrelated to the device but is related to the procedure. Although all disease entities qualify as adverse events in the sense that they are untoward medical occurrences, it is especially important to report them as adverse events when they develop or worsen after the use of a medical device. The start and stop dates for adverse events will be recorded for each event. An adverse event may be ongoing at the time of the analysis, and in these cases, the stop date could be recorded as such. Specifying the start and stop dates of an adverse event will help to guide whether the event is related to a device or to a procedure. The distinction between serious adverse events (SAEs) and non-SAEs is a cornerstone of safety reporting. Noting the broad definition of an adverse event, the number of adverse events in a trial can often outnumber the number of subjects in that trial. This is often true for a surgical study population, where any one patient could experience multiple events such as low-grade postoperative fever or intestinal ileus. Subclassification of adverse events by whether they meet the criteria for an SAE simplifies the job of those assessing trial outcomes, including IRBs, ECs, and regulators. Limiting the reporting requirements for clinical trials to SAEs facilitates and focuses attention on those events that have significant impact on the welfare of the patient. The ISO and FDA definitions of an SAE are very similar, although the U.S. medical device regulations are less explicit on SAEs than are the regulations guiding pharmaceutical agents.2Crowley G. EU and US clinical investigation adverse event reporting.Med Device Technol. 2004; 15: 30-32PubMed Google Scholar, 17ISO 14155: Clinical investigation of medical devices for human subjects—good clinical practice. 2 ed. International Organization for Standardization, Geneva, Switzerland2011Google Scholar SAEs are defined as those adverse events where the outcome is one of the six specific occurrences listed in Table I.18U.S. Food and Drug Administration. What is a serious adverse event? Available at: www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm. Accessed February 17, 2013.Google Scholar An SAE does not require actual harm to the patient if an intervention was undertaken to prevent injury. A close call still triggers an SAE. In this regard, interventions include inpatient or outpatient surgical procedures and significant changes in medical management (for instance, addition of or increase in the dose of a drug), where the indication for the intervention is the adverse event. IRBs were inundated with reports of adverse events in prior years to a level that compromised rather than enhanced their ability to protect human subjects. A 2009 FDA guidance document articulated these difficulties and suggested that every anticipated adverse event need not be reported to an IRB.11U.S. Department of Health and Human Services. Guidance for clinical investigators, sponsors, and IRBs. Adverse event reporting to IRBs—improving human subject protection. Washington, DC: Office of the Commissioner (OC) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) Office of Good Clinical Practice; January 2009.Google Scholar Rather, the guidance suggested that unexpected adverse events, termed “unanticipated adverse device effects,” or UADEs, be the focus of IRB reporting. UADEs are defined as “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan…”2Crowley G. EU and US clinical investigation adverse event reporting.Med Device Technol. 2004; 15: 30-32PubMed Google Scholar The corollary of UADE in the ISO-14155 2011 standards is the “unanticipated serious adverse device effect” or USADE. The definitions of UADE and USADE are virtually identical, with the exception that the ISO definition references the risk analysis report for the device for determining the universe of anticipated events for the device under study.17ISO 14155: Clinical investigation of medical devices for human subjects—good clinical practice. 2 ed. International Organization for Standardization, Geneva, Switzerland2011Google Scholar An event is considered to be unanticipated when it is not identified in the study materials or is identified at a substantially higher frequency than what was expected. In the absence of previous studies for the device, the frequency of harmful occurrences with similar previously studied devices may be used as a substitute. As an example, assume that prosthetic arterial bypass graft infection is expected to occur at a 2.5% rate ≤12 months of implantation, with an upper limit of 5.5% for the confidence interval. At the outset, any individual graft infection would not be considered to be a UADE. If, however, the aggregate rate exceeded the anticipated rate, for example, was 6.5% at 12 months, these infections would then meet the criteria for UADE. The timeline for reporting UADEs is more critical than for anticipated events. Investigators are required to report a UADE to the sponsor ≤10 working days after learning of the event, and sponsors must immediately assess a UADE and report the results of the evaluation to the FDA, all IRBs, and investigators ≤10 working days after the sponsor is notified of the event.11U.S. Department of Health and Human Se