National Health Surveillance Agency EVENT NOTIFICATION MANUAL ADVERSE AND SECURITY MONITORING IN CLINICAL TRIALS General Management of Medicines - GGMED Coordination of Clinical Research on Medicines and Biological Products - COPEC 2016 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS This Manual aims to guide professionals in the area with information on how to apply Resolution RDC / Anvisa nº 9 of February 20, 2015, contributing to the development of safe actions, in addition to providing relevant and updated information that can be better clarified through the Manual instrument. The Manual does not create new obligations and should be used by public and private agents as reference for compliance with existing legislation. 2 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS Copyright © 2016 Anvisa Copyright © 2016 Contributor Total or partial reproduction of this work is allowed, provided the source is mentioned. Edition: 1st edition Organization - Anvisa General Management of Medicines Technical Review - Anvisa Adriane Alves de Oliveira André Luís Carvalho Santos Souza Bruno de Paula Coutinho Bruno Zago Franca Diniz Candida Luci Pessoa and Silva Carla Abrahao Brichesi Carlos Augusto Martins Netto Carolina Pingret Cintra Claudio Nishizawa Fanny Nascimento Moura Viana Fernando Casseb Flosi Flávia Regina Souza Sobral Janaina Lopes Domingos Kellen from Rocio Malaman Leonardo Fabio Costa Filho Miriam Motizuki Onishi Patrícia Ferrari Andreotti Ricardo Eccard da Silva Sônia Costa e Silva Layout and Review Anvisa Publisher Graphic project Anvisa Publisher Catalog Card: Manual for notification of adverse events and safety monitoring in clinical trials / Brasília. Anvisa 2016 18 p. Adverse Event; Security Monitoring; Clinical Trials. 3 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS SUMMARY 1. SIGLARY 5 2. INTRODUCTION 5 3. LEGAL BASIS 5 4. OBJECTIVE 5 5. ADVERSE EVENT MONITORING (EA) 6 6. NOTIFICATION OF EAGs (FORMSUS) 6 6.1 TRACEABILITY 7 7. SUBMISSION OF OTHER EAs (SECURITY UPDATE REPORT) 8 8. WHEN NOT TO NOTIFY THE ADVERSE EVENT TO ANVISA 9 9. TERMINOLOGY 9 10. QUALIFYING INTENSITY GRADING FOR HEALTH CONDITIONS (WHO) 9 11. INDEPENDENT DATA MONITORING AND SECURITY COMMITTEE 10 12. GLOSSARY 11 13. BIBLIOGRAPHIC REFERENCES 12 14. PROCESS FLOWCHART 14 14.1 ADVERSE EVENTS NOTIFICATION FLOWCHART IN CLINICAL TRIALS 14 15. ANNEXES 15 15. 1 WHO-UMC SYSTEM FOR STANDARDIZED CAUSALITY ASSESSMENT 15 16. CHANGE HISTORY 18 4 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 1. SIGLARY EA - Adverse Event EAG - Severe EC Adverse Event - Clinical Trial WHO - World Health Organization DRC - Collegiate Board Resolution 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 regulations on Clinical Trials with medicines in Brazil brings notification of adverse events as one of the forms of security monitoring that the sponsor should perform during the development of the experimental drug. This manual is intended to provide guidance for the Sponsor, Independent Security 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 with legislation, not intended to expand or restrict established technical or administrative requirements. 3. LEGAL BASIS Anvisa Resolution - RDC nº 9, of February 20, 2015, which provides for the regulation for the conducting clinical trials with medicines in Brazil. 4. OBJECTIVE Without prejudice to the existing provisions in the legal provisions, this manual aims to guide the security monitoring and notifications of adverse events, as described in chapter VI of the DRC nº 09/2015. We recommend that the format be standardized in terms of order and content to facilitate evaluation. 5 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 5. ADVERSE EVENT MONITORING (EA) It is the sponsor's responsibility to collect and monitor all adverse events, including non-serious ones, classifying them according to Chart 2 of the WHO-UMC System for standardized assessment of causality (Annex I). The Late adverse events should have a monitoring plan in place. All adverse events must be treated and the affected participants accompanied by the principal investigator and his team until resolution or stabilization. In the event of a serious adverse event, the sponsor and the investigator must take immediate safety to protect clinical trial participants from any imminent risk and the sponsor must notify Anvisa and describe the measures adopted from item 79 of the Notification Form of Serious Adverse Events in Clinical Trials available on the Anvisa website> Medicamentos> Clinical Research> Adverse Events> Form for Notifying Serious Adverse Events in Clinical Trials - Notivisa EC. The analysis of aggregated data of adverse events that occurred in clinical trials is part of the monitoring. 6. NOTIFICATION OF EAGs (FORMSUS) For regulatory submission purposes, the sponsor is required to report adverse events serious, unexpected, occurring in the national territory, whose relationship with the product under investigation is possible, likely or definite. a) The recommended criteria for the individual categorization of each event into possible, probable, defined, unlikely, conditional or inaccessible is the WHO-UMC system for standardized causality assessment; b) Other methods can be used for categorization as long as correspondence with the WHO-UMC system; c) The Suspected Unexpected Serious Adverse Reaction (SUSAR) is included in the criteria for notification of serious adverse event and must be notified, however, the criteria listed in the DRC are not limited to it only. d) Notifications must be made exclusively through the electronic form “Notification of EAGs in Clinical Trials with Medicines or Biological Products - Notivisa EC ”, available on the Electronic Portal da Anvisa> Medicamentos> Clinical Research> Adverse Events> Form for Notification of Serious Adverse Events in Clinical Trials - Notivisa EC. 6 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS • Some pages of the form may take a long time to load, please wait; • To notify adverse events it is not necessary to log in; • After completing the last page, a protocol number and a mirror of the notification will be generated. Save this number to update your notification; • If the system is temporarily unavailable, the notification must be sent as soon as the system returns; • In case of any difficulty or doubt, whether in relation to the correct way of filling in the data notification or information technology issue, contact Anvisa through the official communication. Specify that the questioning refers to “notification of adverse events in trials clinical data ”or enter this information in the application data. 6.1 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: Anvisa's Electronic Portal> Medicines> Clinical Research> Adverse Events> Serious Adverse Events Notification Form in Clinical Trials - Notivisa EC> Amends File. 7 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS • Enter the notification protocol to retrieve it and update the information. 7. SUBMISSION OF OTHER EAs (SECURITY UPDATE REPORT) The 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 defined must be systematically assessed by the sponsor or the Independent Security Monitoring Committee and the results of this assessment must be submitted to Anvisa in the Security Update Report of Development of Experimental Medicine. The security update report is intended to understand, review and evaluate information annually safety data collected during the investigation period of the experimental drug, commercialized or not. a) For regulatory submission purposes, these reports must be secondary electronic petitions linked to the DDCM case number. b) The linking of secondary petitions to the corresponding processes is fundamental for the analysis and traceability of them in Anvisa electronic systems. c) The subject of petition 10825 - CLINICAL TRIALS - Update Report should be used Security of Experimental Drug Development; d) All modifications of the DDCM not considered substantial must be submitted to ANVISA as part of the safety update report on experimental drug development; e) It is recommended that the Development Security Update Reports for the Experimental Medicines are presented in the ICH Development Safety Update Report (DSUR), Guideline E2F Step 5; f) The sponsor must send Anvisa Safety Development Update Reports annually to Anvisa. Experimental Medication, filed within a maximum period of 60 (sixty) consecutive days having as reference 8 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS annuality the date of approval of the DDCM by ANVISA or the date determined in international development. 8. WHEN NOT TO NOTIFY THE ADVERSE EVENT TO ANVISA The adverse event does not need to be notified to Anvisa when it occurs outside the national territory and when the adverse event was defined in the clinical trial protocol as a primary or secondary outcome. 9. TERMINOLOGY Adverse event reporting should be done using the terminology of “The WHO Adverse Reactions Terminology” (WHOART) to specify the adverse event. The term serious should be translated as “serious” in Portuguese and Spanish, according to “WHO Collaborating Center for International Drug Monitoring. Safety Monitoring of Medicinal Products: Guidelines for setting up and running a Pharmacovigilance Center. ” 10. QUALIFICATION INTENSITY GRADING 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 is interfering in people's day-to-day lives and which happens occasionally in the last 30 days. 9 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 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 changes completely the day-to-day of the person and that 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). 11. INDEPENDENT DATA MONITORING AND SECURITY COMMITTEE In the case of the development of a phase III clinical trial, monitoring must be accompanied by Committees Security Monitoring Independents and their recommendations must be reported to Anvisa by the sponsor. In cases where there is no constitution of a safety monitoring committee, its absence must be justified, according to RDC 09/2015 The constitution of the committee, bylaws and functioning, members, conflict of interest, meetings, communications and recommendations must follow the Operational Guidelines for the Establishment and o Operation of Data and Security Monitoring Committees / Ministry of Health, Organization World Health Organization. - Brasília: Ministry of Health, 2008. 44 p. - (Series A. Standards and Technical Manuals). 10 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 12. GLOSSARY I - Clinical trial - research conducted in humans with the aim of discovering or confirming the effects clinical and / or pharmacological and / or any other pharmacodynamic effects of the experimental medicine and / or identify any adverse reaction to the experimental drug and / or study absorption, distribution, metabolism and excretion of the experimental drug to verify its safety and / or effectiveness; II - Adverse Event - any adverse medical event in a patient or trial participant to whom a pharmaceutical product has been administered and which does not necessarily have a causal relationship to treatment. As a result, an EA can be any unfavorable and unintended sign, symptom, or disease (including results outside the reference range), associated with the use of a product under investigation, whether related to it or not; III - Serious Adverse Event - one that results in any adverse experience with medicines, biological products or devices, occurring at any dose and resulting in any of the following outcomes: a) death; b) threat to life; c) persistent or significant disability / disability; d) requires hospitalization or prolongs hospitalization; e) congenital anomaly or birth defect; f) any suspicion of transmission of an infectious agent by means of a drug or; g) clinically significant event. IV - Unexpected Adverse Event - event not described as an adverse reaction in the medicine brochure experimental or on the label. V - Experimental medicine - pharmaceutical product under test, object of DDCM, to be used in the clinical trial, for the purpose of obtaining information for your registration or post-registration; VI - Product under investigation - experimental drug, placebo, active comparator or any other product to be used in the clinical trial; VII - Clinical Trial Protocol - document that describes the objectives, design, methodology, statistical considerations and trial organization. It also provides the context and rationale for the essay clinical; 11 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 13. 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. BRAZIL. National Health Surveillance Agency. RDC Resolution 09 of February 20, 2015. This Resolution aims to define the procedures and requirements for conducting clinical trials medications, including submitting the Clinical Drug Development Dossier (DDCM) to be approved by Anvisa. Available in: Access in: 25 jan. 2016. 4. DSUR ICH E2F Step 5. Available at accessed on: 31 ago. 2016. 5. EUROPEAN STROKE ORGANIZATION (ESO) Executive Committee; ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457–507. 6. LEES KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375: 1695–1703. 7. MINISTRY OF HEALTH, WORLD HEALTH ORGANIZATION. Operational Guidelines for the Establishment and Operation of Data and Security Monitoring Committees. Series A. Standards and Technical Manuals Available at: Accessed on June 3. 2014. 8. MINNERUP, J., Wersching, H., Unrath, M. and Berger, K. (2014), Effects of emergency medical service transport on acute stroke care. European Journal of Neurology. doi: 10.1111 / ene.12367 12 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 9. SHERMAN R B et al. New FDA regulation to improve safety reporting in clinical trials. The New England journal of medicine. 365 (1): 3-5. 2011 10. THE UPPSALA MONITORING CENTER. WHO Collaborating Center for International Drug Monitoring. Glossary of Terms in Pharmacovigilance. Available in: . Accessed on Jun. 3 2014. 11. THE UPPSALA MONITORING CENTER. WHO Collaborating Center for International Drug Monitoring. WHO-UMC Causality Assessment. Available at: . Accessed on Jun. 3 2014. 12. WORLD HEALTH ORGANIZATION. ICF CHECKLIST Version 2.1a, Clinician Form for International Classification of Functioning, Disability and Health. Available in: Accessed on June 3. 2014. 13. WORLD HEALTH ORGANIZATION. WHO Collaborating Center for International Drug Monitoring. Safety Monitoring of Medicinal Products: Guidelines for setting up and running a Pharmacovigilance Center. Geneva, World Health Organization, 2000. Available at: Accessed on June 3. 2014. 13 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 14. PROCESS FLOWCHART 14.1 ADVERSE EVENT NOTIFICATION FLOWCHART FOR CLINICAL TRIALS Adverse events occurred in clinical trial participants and detected by the Investigator Adverse events SERIOUS Adverse events NOT SERIOUS 24h Sponsor INDEPENDENT SECURITY MONITORING COMMITTEE Recommendations SERIOUS Adverse Events NON SERIOUS Adverse Events UNEXPECTED SERIOUS Adverse Events EXPECTED SERIOUS Adverse Events Electronic notification to ANVISA - Security update report on the development of the experimental drug. Standardized causality assessment of the WHO-UMC system Improbable, conditional / unclassified, inaccessible / unclassifiable EAGs Unexpected, possible, probable or defined EAGs 7 calendar days: fatal or life-threatening EAGs; 15 calendar days: others. Electronic Notification to ANVISA - FORMSUS 14 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 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 the probability ratio Classify probability relation Distinguish between valid and invalid cases Mark reports individually To prove the relationship between the medication and the event Improve scientific, educational assessment Quantify the drug's contribution to the development of an adverse event Changing uncertainties to certainties 15 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 15.1.2 Box 2. WHO-UMC Causal categories Categories + Criteria in the assessment of causality ++ • Event or change (abnormal) in laboratory exam with plausible temporal relation in relation to administration of the intervention; • Cannot be explained by illness or other intervention, medication; Right / Defined • Response to plausible interruption or withdrawal (pharmacologically, pathologically); • Pharmacologically or phenomenologically defined event (i.e. an objective disorder and specific or a pharmacologically recognized phenomenon); • Satisfactory restocking, if necessary. Likely • Event or alteration (abnormal) in laboratory exam with reasonable temporal relation in relation to administration of the intervention; • Unlikely to be attributed to a disease or other intervention, medication; • Response to clinically reasonable interruption or withdrawal; • Reexposure not required. Possible • Event or alteration (abnormal) in laboratory exam with reasonable temporal relation in relation to administration of the intervention; • It can also be explained by illness or other interventions, drugs; • Information about withdrawing or stopping treatment may be missing or unclear. Unlikely • Event or alteration (abnormal) in laboratory examination that in relation to the time of administration of the intervention makes an unlikely (but not impossible) relationship; • Illness or other treatments support plausible explanations. Conditional / Unclassified • Event or alteration (abnormal) in laboratory examination; • More data is needed for an appropriate assessment, or; • Additional data under investigation. 16 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 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 verified. + Terms for the relationship ++ To classify the relationship using one of the terms, the aspects observed must be reasonably within the criteria presented. 17 MANUAL FOR NOTIFICATION OF ADVERSE EVENTS AND SECURITY MONITORING IN CLINICAL TRIALS 16. CHANGE HISTORY Version Changes made Explanation and Justification 1st edition Initial release 18