National Health Surveillance Agency EVENT NOTIFICATION MANUAL ADVERSES AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING MEDICAL DEVICES IN RESEARCH General Management of Technology in Health Products - GGTPS Coordination of Clinical Research in Health Products - CPPRO 2016 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS This Manual aims to guide professionals in the area with information about the application of Resolution RDC / Anvisa nº 10 of February 20, 2015, contributing to the development of safe actions, in addition to providing relevant and updated information that can be clarified through the Manual instrument. The Manual does not create new obligations and should be used by public and private agents as a reference to comply with existing legislation. 2 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS Copyright © 2016 Anvisa Total or partial reproduction of this work is allowed, provided the source is mentioned. Edition: 1st edition Organization - Anvisa General Management of Technology in Health Products Technical Review - Anvisa Alessandro Ferreira do Nascimento Letícia Barel Filier Layout and Review Anvisa Publisher Graphic project Anvisa Publisher Catalog Card: Manual for notification of adverse events and safety monitoring in clinical trials involving devices research doctors / Brasilia. Anvisa 2016 19 p. Adverse Event; Security Monitoring; Clinical Trials; medical devices 3 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS SUMMARY 1. SIGLARY 5 2. INTRODUCTION 5 3. DEFINITIONS 6 4. LEGAL BASIS 8 5. OBJECTIVE 8 6. MONITORING OF ADVERSE EVENTS (EA`s) 8 7. EAG`s NOTIFICATION (FORMSUS) 9 8. TRACEABILITY 10 9. SUBMISSION OF OTHER EA's (REPORTS) 11 11. QUALIFICATION GRADE OF QUALIFICATION FOR HEALTH CONDITIONS (WHO) 12 12. BIBLIOGRAPHIC REFERENCES 13 13. PROCESS FLOWCHART 15 14. FLOW CHARTS TO PROVIDE GUIDELINES TO CATEGORIZE ADVERSE EVENTS AND DEVICE DEFICIENCIES. 16 15. ANNEXES 17 15. 1 WHO-UMC SYSTEM FOR STANDARDIZED CAUSALITY ASSESSMENT 17 15.1.1 Chart 1. Advances and limitations of the system for standardized assessment of causality17 15.1.2 Chart 2. WHO-UMC Causal categories 18 16. CHANGE HISTORY 19 4 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 1. SIGLARY DICD - Medical Device Clinical Investigation Dossier RDC - Resolution of the Collegiate Board EA - Adverse Event EAG - Serious Adverse Event EAD - Adverse Effect of the Device EAGD - Serious Adverse Effect of the Device EAIGD - Serious Unexpected Adverse Effect of the Device EC - Clinical Trial WHO - World Health Organization RDC - Resolution of the Collegiate Board SUSAR - Suspected Unexpected Serious Adverse Reaction WHO - World Health Organization WHOART - The WHO Adverse Reactions Terminology WHO-UMC - The WHO Uppsala Monitoring Center 2. INTRODUCTION The publication of the regulation on Clinical Trials with Medical Devices in Brazil brings the notification of adverse events as one of the forms of security monitoring that the sponsor must perform during the development of the Medical Device. This manual is intended to provide guidelines for the Sponsor, Independent Data Monitoring Committee, Investigator or Legal Representatives, when applicable, do security monitoring and notification of adverse events in clinical trials appropriately. This is a non-binding regulatory measure adopted as a complement to legislation health, with the educational purpose of providing guidance on routines and procedures for compliance legislation, not intended to expand or restrict technical or administrative requirements settled down. 5 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 3. DEFINITIONS Considering aspects peculiar to medical devices, the following definitions will be considered according to ISO 14155/2011: Adverse Device Effect (EAD) Adverse event related to the use of a medical device under investigation. NOTE 1- Includes any event adverse effect resulting from insufficiencies or deficiencies in the instructions for use, positioning, implantation, installation, operation, or any malfunction of the medical device in investigation. NOTE 2- includes any event that results from an error of use or intentional misuse. Adverse Event (EA) Any unfavorable medical event, unintentional injury, injury or undesirable clinical signs (including an abnormal laboratory finding) in research participants, users, or others, related or not to the medical device under investigation. NOTE 1: includes events related to the research device or comparator. NOTE 2: includes events related to the procedures involved (any procedure in the investigation protocol clinic). Medical Device Deficiencies The deficiency or inadequacy of a medical device related to its identity, quality, durability, reliability, safety or performance, such as malfunction, misuse or improper use and labeling. Medical device under investigation - medical device under test, object of the DICD, to be used in the test for the purpose of obtaining information for your registration or post-registration. 6 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS NOTE: includes medical devices already on the market that are being evaluated for new uses new populations, new materials or design changes. Serious Adverse Event (EAG) One that results in any adverse experience with medical devices, occurring in and that results in any of the following outcomes: a) death; b) potentially fatal adverse event (one that, in the opinion of the notifier, places the individual under immediate risk of death due to the adverse event that occurred); c) persistent or significant disability / disability; d) requires hospitalization of the patient or prolongs hospitalization; e) congenital anomaly or birth defect; f) any suspicion of transmission of an infectious agent by means of a medical device; g) clinically significant event. NOTE 1: includes device deficiencies that could have led to a serious adverse event, if a) measures appropriate measures had not been taken or b) the intervention had not been carried out or c) if the circumstances had been less favorable. These are addressed within the scope of the event communication system serious adverse events. NOTE 2: Hospitalization planned for a pre-existing condition, or a procedure required by the Clinical Investigation Plan, without a serious deterioration of health, is not considered an adverse event serious. Severe Adverse Effect of the Device (EAGD) Adverse effect related to the device that resulted in any of the characteristic consequences of a serious adverse event. 7 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS Serious Unexpected Adverse Effect of the Device (EAIGD) Serious adverse effect of the device that, by its nature, incidence, severity or consequences has not been identified in the most current version of the risk analysis report. NOTE: “expected or anticipated” is characterized as an effect that, by its nature, incidence, severity or consequences was previously identified in the risk analysis report. 4. LEGAL BASIS Anvisa Resolution - RDC nº 10, of February 20, 2015, which provides for regulation for the realization of clinical trials with medical devices in Brazil. 5. OBJECTIVE Without prejudice to the existing provisions in the legal provisions, this manual aims to guide both the process of reporting unexpected serious adverse events to ANVISA, as well as establishing criteria and definitions relevant to filling in data on adverse events in reports follow-up of clinical trials. 6. MONITORING OF ADVERSE EVENTS (EA`s) It is the sponsor's responsibility to collect and monitor all adverse events, including those not serious, classifying them according to Chart 2 of the WHO-UMC System for standardized assessment of causality (Annex I). Late adverse events must present an established monitoring plan. All adverse events must be treated and affected participants accompanied by the principal investigator and your team until their resolution or stabilization. In the event of a serious adverse event, the sponsor and the investigator should take immediate security measures to protect 8 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS clinical trial participants against any imminent risk and the sponsor must notify Anvisa and describe the measures adopted in the Form for notification of EAGs in Clinical Trials with Devices Doctors: available at the link: http://formsus.datasus.gov.br/site/formulario.php?id_aplicacao=28308 The analysis of aggregated data of adverse events that occurred in clinical trials is part of the monitoring. 7. EAG`s NOTIFICATION (FORMSUS) For regulatory submission purposes, the sponsor is required to report serious adverse events, unexpected occurrences in the national territory, whose relationship with the product under investigation is possible, probable or defined. a) The recommended criteria for the individual categorization of each event into possible, probable, defined, improbable, conditional or inaccessible is the WHO-UMC system for standardized assessment of causality; b) Other methods can be used for categorization provided that correspondence with the system is proven WHO-UMC; c) Suspected Unexpected Serious Adverse Reaction (SUSAR) is included in the criteria for notification of a serious adverse event and must be notified, however, the criteria listed in the DRC are not limited to he. d) Notifications must be made exclusively through the electronic form “Notification of EAGs in Clinical Trials with Medical Devices - NotivisaEC-DISPOSITIVOS”, available at the link: http://formsus.datasus.gov.br/site/formulario.php?id_aplicacao=28308: ➢ Some pages of the form may take a long time to load, please wait; ➢ It is not necessary to log in to notify adverse events; ➢ After completing the last page, a protocol number and a mirror of the notification. Keep this number to update your notification; 9 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS ➢ If the system is temporarily unavailable, notification must be sent as soon as the system turn back; ➢ In case of any difficulty or doubt, whether in relation to the correct way of filling in the data of the notification or information technology issue, contact Anvisa through the official communication. Specify that the questioning refers to “notification of adverse events in trials with medical devices ”or enter this information in the application data. 8. TRACEABILITY All updates regarding the evolution and other data must be made in the initial notification, changing the field side dish. ➢ To access the EA notification, access the link: http://formsus.datasus.gov.br/site/formulario.php?id_aplicacao=2 8308 10 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS ➢ Enter the notification protocol to retrieve it and update the information. 9. SUBMISSION OF OTHER EA's (REPORTS) Aggregated data for all other adverse events that are not categorized as serious and unexpected, whose relationship with the product under investigation is not possible, probable or should be systematically assessed by the sponsor or the Independent Monitoring Committee of The data and results of this evaluation must be submitted to Anvisa in the annual reports and final report clinical trials. 10. WHEN NOT TO NOTIFY THE ADVERSE EVENT TO ANVISA The adverse event need not be notified to Anvisa when it occurs outside the national territory and when the adverse event is defined in the clinical trial protocol as a primary or secondary outcome. 11 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 11. QUALIFICATION GRADE OF QUALIFICATION FOR HEALTH CONDITIONS (WHO) Light A problem is present less than 25% of the time, with an intensity that a person can tolerate and that rarely happens in the last 30 days. Moderate It means that a problem that is present less than 50% of the time, with an intensity that interferes with the day-to-day people and that happens occasionally in the last 30 days. Severe It means that a problem that is present more than 50% of the time, with an intensity that changes partly the day-to-day lives of people and which often happens in the last 30 days. Complete commitment It means that a problem that is present more than 95% of the time, with an intensity that completely changes the person's day-to-day life and which occurs every day for the last 30 days. Not specified It means that there is not enough information to specify the intensity. Not applicable It means that it is inappropriate to use a gradation (eg menstrual functions). 12 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 12. BIBLIOGRAPHIC REFERENCES 1. ACKER JE 3rd, Pancioli AM, Crocco TJ, et al. Implementation strategies for emergency medical services within stroke systems of care: a policy statement from the American Heart Association / American Stroke Association Expert Panel on Emergency Medical Services Systems and the Stroke Council. Stroke 2007; 38: 3097–3115. 2. BASTOS, Alessandra Soler et al. Time of arrival of the patient with acute myocardial infarction in a emergency. Rev Bras Cir Cardiovasc, São José do Rio Preto, v. 27, n. 3, Sept. 2012. Available at: accessed on: 19 ago. 2014 http://dx.doi.org/10.5935/1678- 9741.20120070. 3. International Organization for Standardization - ISO 14155: 2011 Clinical investigation of medical devices for human subjects - Good clinical practice available at < http://www.iso.org/iso/catalogue_detail?csnumber=45557> 4. MINISTRY OF HEALTH, WORLD HEALTH ORGANIZATION. Operational Guidelines for Establishment and Operation of Data and Security Monitoring Committees. Series A. Standards and Technical Manuals. Available in: Accessed on June 3. 2014. 5. THE UPPSALA MONITORING CENTER. WHO Collaborating Center for International Drug Monitoring. Glossary of Terms in Pharmacovigilance. Available at: . Accessed on Jun. 3 2014. 13 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 6. THE UPPSALA MONITORING CENTER. WHO Collaborating Center for International Drug Monitoring. WHO-UMC Causality Assessment. Available in: . Accessed on Jun. 3 2014. 14 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 13. PROCESS FLOWCHART ➢ ADVERSE EVENTS NOTIFICATION FLOWCHART IN CLINICAL TRIALS 15 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 14. FLOW CHART TO PROVIDE GUIDELINES TO CATEGORIZE ADVERSE EVENTS AND DISABILITIES OF THE DEVICE*. * such guidelines are not intended to show the interrelation of categories ADVERSE EVENT Does it meet the severity criteria? No Is it related to the device / procedure? No ADVERSE EVENT (EA) Yes Yes Serious Adverse Event (EAG) Adverse Device Effect (EAD) Is it related to the device / procedure? Yes Severe Adverse Effect of the Device (EAGD) IS expected? No Serious Unexpected Adverse Effect of the Device (EAIGD) 16 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 15. ANNEXES 15. 1 WHO-UMC SYSTEM FOR STANDARDIZED CAUSALITY ASSESSMENT 15.1.1 Table 1. Advances and limitations of the system for standardized causality assessment What can causality assessment do? What can't the causality assessment do? Decrease disagreement between evaluators Provide accurate quantitative measure of probability relationship Classify probability relation Distinguish between valid and invalid cases Mark reports individually To prove the relationship between the intervention and the event Improve scientific, educational assessment Quantify the contribution of the intervention to the development of an adverse event Changing uncertainties to certainties 17 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 15.1.2 Box 2. WHO-UMC Causal categories Categories + Criteria in the assessment of causality ++ • Event or alteration (abnormal) in laboratory examination with a plausible temporal relationship in relation to the administration of intervention; • Cannot be explained by illness or other intervention, medication; Right / Defined Likely Possible Unlikely Conditional / Unclassified • Response to plausible interruption or withdrawal (pharmacologically, pathologically); • Pharmacologically or phenomenologically defined event (i.e. an objective and specific disorder or phenomenon pharmacologically recognized); • Satisfactory restocking, if necessary. • Event or alteration (abnormal) in laboratory examination with reasonable temporal relation to the administration of intervention; • Unlikely to be attributed to a disease or other intervention, medication; • Response to clinically reasonable interruption or withdrawal; • Reexposure not required. • Event or alteration (abnormal) in laboratory examination with reasonable temporal relation to the administration of intervention; • It can also be explained by illness or other interventions, drugs; • Information about withdrawing or stopping treatment may be missing or unclear. • Event or alteration (abnormal) in laboratory examination that in relation to the moment of administration of the intervention makes a unlikely (but not impossible) relationship; • Illness or other treatments support plausible explanations. • Event or alteration (abnormal) in laboratory examination; • More data is needed for an appropriate assessment, or; • Additional data under investigation. Inaccessible / Unclassifiable • The narrative of the report suggests an adverse reaction; • It cannot be classified because the information is insufficient or contradictory; • Data cannot be supplemented or checked. 18 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS INVOLVING DEVICES RESEARCH DOCTORS 16. CHANGE HISTORY Version Changes made Explanation and Justification 1st edition Initial release 19