Safety Reporting Part 2: For Clinical Trials other than those of Investigational Medicinal Products

Transcription

1 Part 2: For Clinical Trials other than those of Investigational Medicinal Products Version 1.3 Effective date: 19 March 2012 Author: Approved by: Claire Daffern, Q A Manager Dr Sarah Duggan, CTU Manager Revision Chronology: Effective Date Reason for change Version March 2012 Bi-annual review; clarification to text and formatting changes only Version February 2010 Bi-annual review: Updated CTCAE version number and information on trials of devices. Version January 2008 Format change. Clarification of reporting process. Version 1.0 March 2006 Page 1 of 8

2 Part 2 For Clinical Trials other than those of Investigational Medicinal Products 1. Purpose The purpose of this Standard Operating Procedure (SOP) is to define adverse event terminology and to detail the reporting requirements; both to whom adverse events must be reported and the time-scale involved for trials that do not involve Investigational Medicinal Products. 2. Background The accurate and timely reporting of adverse events (AEs) in all clinical trials is a requirement of Good Clinical Practice (Medical Research Council GCP section 5.8). For clinical trials of investigational medicinal products it is a legal requirement of the Medicines for Human Use (Clinical Trials) Regulations 2004 which enacts the EU Clinical Trials Directive. If your trial is covered by the Clinical Trials Directive you need to follow the directions given in Part 1 of this SOP For Clinical Trials of Investigational Medicinal Products (CTIMPs). Clinical studies involving only CE marked medical devices, food supplements or other non-medicinal therapies (such as surgical/physiotherapy interventions) are not covered by these regulations, but still require that adverse events are managed according to GCP. 3. Procedure 3.1 Who? This procedure applies to all Warwick Medical School (WMS) staff involved in clinical trials other than those of investigational medicinal products. All staff must ensure that they are familiar with the definitions of adverse events and serious adverse events contained within this document, and the timescale of reporting required. All staff who come into contact with trial participants have a responsibility to note any adverse events mentioned by participants, and ensure that they are recorded and reported in line with this document. The Chief Investigator (CI) is responsible for the reporting of relevant adverse events to the Sponsor. The Sponsor is responsible for the recording of adverse events and the expedited reporting of certain adverse events to the ethics committee. 3.2 When? At each visit, or study assessment, adverse events that might have occurred since the previous visit or assessment should be elicited from the patient. This includes events from the first trial-related activity after the participant has signed the informed consent until the end point of the trial as defined in the protocol (this is often stated as Page 2 of 8

3 28 days after the last clinic visit). Any worsening of concomitant illness or new illness must be recorded as adverse events at each visit. 3.3 How? This document provides definitions for the different types of adverse events and details those that must be recorded and those that must be reported to the Sponsor and Research Ethics Committee (REC). The protocol for the clinical trial will state the mechanism by which participants will be asked about any adverse events they may have experienced since the last time they were seen by the study team Definitions Adverse event (AE) An AE is: Any untoward medical occurrence in a patient or clinical investigation participant taking part in health care research, which does not necessarily have a causal relationship with the research. Comment: An adverse event can be any unfavourable and unintended sign (including an abnormal laboratory finding or ECG result), symptom, or disease that occurs during the time a participant is involved in the trial, whether or not it is considered to be related to the intervention. The following do not need to be recorded as adverse events, if they are recorded as medical history/concomitant illness on the Case Report Form at the start of the trial: Pre-planned procedure, unless the condition for which the procedure was planned has worsened from the first trial-related activity after the participant has signed the informed consent Pre-existing conditions found as a result of screening procedures Serious Adverse Event (SAE) An SAE is: Any untoward and unexpected medical occurrence that: 1. Results in death, 2. Is life-threatening 3. Requires hospitalisation or prolongation of existing inpatients hospitalisation, 4. Results in persistent or significant disability or incapacity, 5. Is a congenital anomaly or birth defect 6. Requires medical intervention to prevent one of the above, or is otherwise considered medically significant by the investigator. Comment: Some other adverse events/reactions may also count as serious reactions. Those events that do not immediately fall into one of the above categories, but that jeopardise the participant, or require intervention to prevent one of the outcomes Page 3 of 8

4 listed above, should also be considered serious. Important note: "Serious" and "severe" are not synonymous. Serious refers to a specific definition for the outcome of an event (see above), whilst severe refers to the intensity of a reaction (e.g. mild, moderate, severe). For example, it is possible to have a severe headache, but the headache itself is not a serious reaction. The term life-threatening in the definition of a serious adverse event refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event which, hypothetically, might have caused death if more severe. Disability is defined as A substantial disruption of a person's ability to conduct normal life functions Severity Grading Organisations such as the World Health Organisation (WHO) and National Cancer Institute provide scales for the purpose of grading the severity of an adverse event. The National Cancer Institute Common Terminology Criteria (version 4) is a descriptive terminology that provides a grading (severity) scale of 1 (mild AE) to 5 (death related to AE) Grade 1: Mild AE Grade 2: Moderate AE Grade 3: Severe AE Grade 4: Life threatening or disabling AE Grade 5: Death related to AE Full details of the clinical descriptions may be found at: Reporting requirements Reporting requirements will be dependent upon the assessment of seriousness, causality and expectedness as detailed in Flowchart 1 below: Page 4 of 8

5 Flowchart 1: Adverse Event Record as an Adverse Event No i.e. resulted in: Death Life Threatening Is it Serious? Hospitalisation or prolongation of hospitalisation Disability/incapacity Congenital abnormality/birth defect Important medical event/medical intervention Yes Record as a Serious Adverse Event No Is it Unexpected? i.e. not previously documented Yes Record as a Serious Adverse Event No Is it possible that the event resulted from participation in the research? Yes Report to main Research Ethics Committee within 15 days Defining SAEs that require immediate reporting Principal Investigators (PIs) must report all SAEs immediately (within 24 hours of their first knowledge of the event) to the CI unless the SAE is one which the protocol defines as not requiring immediate reporting. The CI is then responsible for ensuring that events are reported to the Sponsor and REC according to requirements. A SAE occurring to a research participant should be reported to the REC that gave a favourable opinion of the study (the main REC ) where in the opinion of the CI the event was both: Related that is, it resulted from administration of any of the research procedures; and Unexpected that is, the type of event is not listed in the protocol as an expected occurrence. Reports of related and unexpected SAEs should be submitted within 15 days of the CI becoming aware of the event, using the National Research Ethics Service (NRES) report of serious adverse event form found at: Page 5 of 8

6 The form should be completed in typescript and signed by the CI. Reports of SAEs in double-blind trials should be unblinded. The coordinator of the main REC will acknowledge receipt of safety reports within 30 days. The Sponsor must keep detailed records of all adverse events reported by investigators. These will form part of the annual progress reports Defining SAEs that do not require immediate reporting Some SAEs do not need to be reported immediately to the ethics committee. The protocol should define those SAEs that do not need to be reported immediately. These include: SAEs which are serious but expected, and those reactions that are considered unrelated to the intervention (whether expected or not). It is for the CI and/or Sponsor to decide whether or not each individual SAE requires expedited reporting. Other SAEs that form an outcome for the study may also be excluded from immediate reporting, provided that these are also defined clearly in the protocol, and that details of such incidents are collected elsewhere on the Case Report Form. Such events must be included in the safety analysis and form part of the annual progress report to the REC (see SOP 6 Ethics Approvals and Communications ). Examples include: o Death from progression of the disease under study where this forms an outcome for the study, o Hospitalisation for an event which forms an outcome for the study, o Hospitalisation for a pre-existing condition (for example elective procedure) which has not worsened. 3.4 Trials of Devices Definitions of Adverse Events involving medical devices The terms Adverse Event and Serious Adverse Event as detailed in section are used in trials involving medical devices. Additional terms are also used: Adverse Device Effect/Event (ADE): Any unfavourable or unintended response to a medical device. Serious Adverse Device Effect (SADE): An ADE that has resulted in any of the consequences of a SAE or might have led to those consequences if suitable action/intervention had not been taken. Incident: Any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or instructions for use which directly, or indirectly, might lead to or might have lead to the death of a patient, or user or of other persons or to the serious deterioration in their state of health. Page 6 of 8

7 3.4.2 Reporting requirements The EC Medical Devices Directive (93/42/EEC) requires a manufacturer to fully record all adverse incidents that occur during a clinical investigation and include them in the annual reports to the main REC (and MHRA if appropriate). To comply with EU legislation, manufacturers of devices must apply for their product to be CE marked before being placed on the market. This certifies that a product has met EU consumer safety, health or environmental requirements and is mandatory for many products on the market within the EU. All SAEs/SADEs involving a non-ce marked device must be reported to the MHRA (Devices Division), whether initially considered to be device related or not. Device related SAEs involving CE marked devices should be reported to the MHRA Adverse Incident Centre as soon as possible after awareness of the event, but must be reported within 10 calendar days, whether initially considered to be related to the device or not. Initial incident reports should contain as much relevant detail as is immediately available, but should not be delayed for the sake of gathering additional information. A SAE/SADE occurring to a research participant at a UK trial site should also be reported to the main REC within 15 days if in the opinion of the CI the event was both: Related that is, it resulted from administration of any of the research procedures; and Unexpected that is, the type of event is not listed in the protocol as an expected occurrence. The legal responsibility for reporting SAEs/SADEs lies with the manufacturer or their authorised representative. However, the MHRA also has a voluntary reporting requirement for users of devices i.e. where a device is being used in a trial in which the manufacturer has no involvement, and in this case, the coordinating centre would submit the appropriate reports and also inform the manufacturer of the event How to report To report a SAE/SADE to the MHRA use the electronic reporting form on their website: tm To report a SAE/SADE to the main REC use the SAE report form for research other than clinical trials of IMPs from the NRES website: Page 7 of 8

8 List of abbreviations AE Adverse Event ADE Adverse Device Event/Effect CI Chief Investigator CTIMP Clinical Trial of an Investigational Medicinal Product EC European Commission EU European Union GCP Good Clinical Practice IMP Investigational Medicinal Product MHRA Medicines and Healthcare products Regulatory Agency NRES National Research Ethics Service PI Principal Investigator REC Research Ethics Committee SAE Serious Adverse Event SADE Serious Adverse Device Event/Effect SOP Standard Operating Procedure WHO World Health Organisation Page 8 of 8