Wed like to set additional cookies to understand how you use GOV.UK, remember your settings and improve government services. Quality control and review of the listings in the DSUR to ensure that they are in accordance with the RSI at the start of the reporting period. As a starting point, it is worth remembering for clinical trials what the RSI is and what it is used for. If at least one of the trials covered by the DSUR has gone through the Combined Review process, then the report should be submitted via the Integrated Research Application System (IRAS). Upon receipt of an RSI, the competent authorities need to decide whether the list of expected reactions and associated risk minimisation measures are acceptable for each trial. Non-fatal or non-life-threatening SUSARs must be reported as soon as possible but no later than 15 days after you are first aware of the reaction. Information you will be asked for on the call: Where this information is not available during the initial call it should be provided as soon as possible. Investigation Plan and Investigators Brochure do not correspond to state of scientific knowledge and do not provide evidence for safety, performance or benefit of the device (Regulation 2017/745 Article 71.4). MHRA: Medicines and Healthcare Regulatory Authority. You must submit your DSUR using MHRA Submissions via the Human Medicines Tile. If the serious event is considered related to the IMP and the serious reaction is not included in the RSI, then this becomes a SUSAR and must be reported to the MHRA (and Research Ethics Committee for cases originating in the UK) as per statutory timelines. This will include reagents, equipment, calibrators, controls and software. It will take only 2 minutes to fill in. Have a clear change control procedure and green light for when an RSI update can be implemented. Tegenero AG TGN1412 Trial - CIRCARE Updated guidance for manufactures on legislation for clinical investigations of medical devices. The following sections provide guidance for these applications and the requirements for amendments and post market studies involving sites in Northern Ireland. Dont include personal or financial information like your National Insurance number or credit card details. We have noticed that a conservative approach to causality has not been maintained by organisations when reviewing SARs. Please also include a summary analysis of the serious events together with the manufacturers conclusions. You can change your cookie settings at any time. In addition, a process must be in place to assess whether MedDRA updates have an impact on the RSI (and this assessment should be documented). If your RSI was updated during the reporting period, approved and implemented for expedited reporting, then you will need to assess the impact of this change on your line listings in the DSUR. By not informing the NCA of RSI changes, assessors are prevented from making an informed decision about the clinical trial authorisation (for example, if this can continue or if any additional changes are required to protect trial participants). It brings together the assessment of governance and legal compliance, undertaken by dedicated HRA and HCRW staff, with the independent Research Ethics Committee (REC) opinion provided through the UK Research Ethics Service. HRA and HCRW approval applies to all project-based research taking place in the NHS in England and Wales. Please explain in the email the USM implemented, the reason and why you did not report it via phone. correcting typographical errors, updating contact points, minor clarifications, changes to the chief investigators research team, changes to the research team at particular trial sites (other than appointment of a new principal investigator), minor changes in the documentation used by the research team for recording study data, changes in the logistical arrangements for storing or transporting samples, Proof of insurance cover or indemnification of subjects, Arrangement to ensure protection and confidentiality of personal data, Details of the technical documentation (risk analysis, test reports) kept available. Oversight and monitoring activities Depending on whether we consult experts, the MHRA will inform you of our decision within 45 or 65 calendar days as per the EU MDR. Fingerprint/Crime Records Questions | Department of Public Safety Since 1 January 2019, the MHRA GCP inspectorate has identified 8 organisations with critical findings when reviewing RSI on inspection. A declaration of the end of a clinical trial must be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The RSI for a licensed product can be the RSI section in the IB (for instance, if the IMP is being used outside of the marketing authorisation indication or if you are wanting to use one RSI across a global trial). You may include other changes along with this amendment but must ensure the covering letter clearly highlights there is also a change of legal representative. For further information please see our statutory guidance on current MHRA fees. The quality management system should clearly define when the RSI will be implemented (following approval by the competent authority). While the regulatory requirements and fees remain the same, the application submission, processing and assessment steps outlined below refer to non-combined review applications. The sponsor of a trial has a duty to report SUSARs relating to each IMP used in a clinical trial, therefore, also relating to the comparator(s). Added information on the number of valid clinical investigation applications that have been reviewed by year. You need to send the following documents to the Medicines and Healthcare products Regulatory Agency (MHRA): We will assess your application within 35 days. If, after receipt of the response, the application is still considered to be invalid, or the 10 day deadline has expired, we will write to confirm this within 5 calendar days. INVESTIGATOR'S BROCHURE. MHRA guidance Follow the guidance on compiling a submission (PDF, 211 KB, 16 pages) and guidance for manufacturers when preparing your notification application. PDF Gcp Inspectorate Gcp Inspections Metrics Report - Gov.uk Questions welcome . common scenarios for healthcare establishments (PDF, 90.8 KB, 2 pages) which may be relevant to you. Uploaded guidance on the MHRA and HRA coordinated assessment pathway. This section concerns clinical investigations being conducted in Great Britain only. Reference Safety Information (RSI) for Clinical Trials- Part III Ensure there is documentation and tracking to support the process (which should be retained for inspection). For example, it is possible to review the SmPC of each IMP and include in the trial-specific RSI only the serious adverse reactions which can be considered expected in your trial population. Home Clinical trials and investigations Guidance Clinical trials for medicines: manage your authorisation, report safety issues Change your protocol, update your authorisation, report safety. The relevant fee should be paid upon receipt of an invoice from MHRA. Assess the impact of CTFG Q&A on RSI on your quality system and on your clinical trial safety data to determine if there has been any under-reporting of SUSARs. The expectedness assessment is not a medical decision. Investigators may obtain Investigator's Brochure (IB) from IND product's manufacturer. Version: 02 Final. You have accepted additional cookies. For clinical trials not approved or yet transitioned over to the combined review process, you should continue to use MHRA submissions. When the date of site awareness was populated in the spreadsheet there were numerous examples of late SAE reporting from investigator sites to the sponsor including some over 50 days late, but no Often, this can be automated by programming expected terms into the safety database, which will then auto-label the event based on a pre-specified list. If you want to change the Sponsor for your study, you must submit a substantial amendment to the MHRA. When MHRA receive your application for a clinical investigation of a medical device our regulatory handers will validate your application against this checklist Where the . Dont worry we wont send you spam or share your email address with anyone. When assessing the expectedness of a SAR, the sponsor needs to refer to the specific PTs included in the RSI. The covering letter for the application should clearly highlight your Purchase Order (PO) number where available. Any SAR which adds additional information about the specificity and/or severity of an expected reaction must be considered unexpected. Contains Nonbinding Recommendations 5. If you have identified any, these should be reported as a serious breach. Updated text in Urgent Safety Measure section, Added information about how to submit SUSARs during the EudraVigilance cutover period, 8-21 November. - UK Statutory Instrument 2004/1031 (as amended) 14. Covering letter detailing the trial reference numbers (IRAS ID. If you wish to request an exemption to this requirement this must be done via a substantial amendment for approval. Well send you a link to a feedback form. Updated guidance on the submission of summary results. Guideline for good clinical practice E6(R2) EMA/CHMP/ICH/135/1995 Page 2/75 10 Document History 11 First Codification History Date New Codification November PDF Development Safety Update Reporting for IMP Clinical Trials The Biological Safety Assessment PDF has been updated. The Free Dictionary. Added section for "Study deviations" and related XLS. Substantial amendments relating to temporary suspension must be submitted using MHRA Submissions via the Human Medicines Tile. For non-substantial modifications you are only required to notify us to ensure our records are up-to-date. DOC UCL - London's Global University For CTIMP conducted in Northern Ireland separate guidance will be provided. Once youve received authorisation from us to conduct the clinical investigation within Northern Ireland, you must notify the MHRA of all proposed modifications to the investigation before they are implemented. For example: This is not a new requirement since the CTFG Q&A on RSI came into effect. Edited the grey box at the top of the page which was about the EudraVigilance cutover period and now contains information on reference safety information. You may withdraw your application at any point before an assessment decision on your substantial amendment is reached. SARs due to lack of efficacy or disease progression should not be considered expected, unless this has been approved as part of the trial protocol or is listed in the RSI. If you consider your trial requires an expedited assessment (for example, patient safety reasons), this should be stated in the covering letter along with the rationale for the expedited assessment request. This rationale should be documented and provided in the covering letter to the MHRA when there is a substantial change to the RSI. Published guidance such as CT1 and CT3 and the CTFG Q&A on Reference Safety Information (RSI) remain applicable as a source of materials for understanding what the obligations entail in so far as they relate to the UK as a sovereign regulator. Changes to end of trial section. detection of a biomarker). Trials which determine the clinical performance of the assay (biomarker validity) will need to be registered as IVD performance evaluation studies. 28 29 It is important to note that this guidance does not include discussions of all of the requirements Therefore, the onset date should be used to determine which RSI version is applicable for expectedness assessment, and this should not change when follow-up information is received. There should be a clear change control and tracking process which can demonstrate when the RSI was approved (by each competent authority) and implemented by those making the expectedness assessment. Where two or more investigational devices are being used and there is no functional relationship between them, the fee will be increased to reflect the additional workload to the MHRA. There is no fee for a change of Sponsor amendment. assesses (e.g. The RSI is a specific section in either the Investigator Brochure (IB) or Summary of Product Characteristics (SmPC) and is submitted as part of the CTA application. All serious adverse events, whether initially considered to be device/procedure related or not, involving a device under clinical investigation within Great Britain should be reported to the MHRA. It is not possible to submit amendments to the trial or the DSUR once the declaration of the global end of the trial form has been received by the MHRA. To withdraw your application you should send an email to clintrialhelpline@mhra.gov.uk. the RSI used for the DSUR listings is not the same RSI in place at the start of the reporting period, more than one RSI was used by the organisation during the reporting period, but this was not evident in the DSUR or the cover letter, therefore, the MHRA assessors would not be aware of this additional RSI. We also use cookies set by other sites to help us deliver content from their services. The MHRA will not be able to update the status of your study in the EU system. If unreported SUSARs are identified, this should be submitted as a potential Serious Breach to the MHRA GCP Inspectorate for review and assessment. A letter will be sent to you by the final day or before with a decision as to whether or not you can carry out the proposed clinical investigation. 5. You have accepted additional cookies. There are different fees based on your type of clinical trial application. It replaces the need for local checks of legal compliance and related matters by each participating organisation in England and Wales. For information about your submission, including status and tracking enquiries, contact the clinical trials helpline on 020 3080 6456 (Monday to Friday 8:30am to 4.30pm) or email clintrialhelpline@mhra.gov.uk. Complete the end of trial declaration form (MS Word Document, 60.5KB) and include a brief explanation of the reasons for ending the trial, particularly where the trial has been terminated early. This is due to the fact that unrelated changes may result in rejection. Call the MHRAs Clinical Trials Unit on 020 3080 6456 to discuss the issue with a medical assessor, ideally within 24 hours of measures being taken. information for clinical investigators (PDF, 144 KB, 10 pages) for what is required by clinicians involved in the investigation. . The trials for which, The affected IMP(s) - commercial or developmental names, Nature of the safety concern and whether it has been reported as a, The number of UK subjects who are currently receiving the IMP, the number of subjects who received it and the number affected by the, Contact details in case of further questions, a cover letter listing all the IRAS IDs and/or EudraCT numbers of trials covered by the, an analysis of the subjects safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit, a line listing of all suspected serious adverse reactions (including all, Region-specific information as per Guideline on how to increase transparency (see below). This enables both the sponsor and MHRA to have a complete overview each time it is submitted. If the latter happens the investigator should assess the AE secondary to lack of efficacy in the same manner as any other AE/SAE. Inclusion of a SAR as an expected event in the RSI needs to be accompanied by an assessment of the benefit-risk profile of the IMP and ongoing trials. If the best document to support the conduct of the trial is the IB, the RSI section should be written in compliance with safety reporting requirements for clinical trials (a list of serious adverse reactions considered expected for safety reporting purposes). Therefore, it is our expectation that they are followed as this is our interpretation as to how the legislative requirements can be met and this will help in terms of harmonisation and running global trials. However, the decision to include a SAR in the RSI section is based on medical assessment. If applicable the following should be provided: Possible consequences for subjects already in the trial, Possible consequences for the evaluation of results, details of the previous contact person and/or contact details, details of the new contact person and/or contact details, a cover letter that includes the date of transfer of responsibilities, a letter on headed company paper from the current Sponsor confirming the transfer of the study, a letter on headed company paper from the new Sponsor confirming that they accept the role of Sponsor for this study, an updated PDF file of the clinical trial application form signed by the new Sponsor or person acting on behalf of the Sponsor, As per current expectations, for trials that are being conducted in the UK, an, The IRAS ID and/or the EudraCT number of; See MHRA / HRA Coordinated pathway for further information. This is necessary not only to check for updates to the RSI, but in general to make sure that changes to the SmPC are acknowledged to protect the safety of the trial participants. Once youve received a letter of no objection from us, you must notify the MHRA of all proposed amendments to the investigation. You can change your cookie settings at any time. Published an updated version of the 'guidance for manufacturers'. The following table provides information on the number of valid clinical investigation applications that have been reviewed by year. Unlicensed drugs found in raid. Check the Common issues identified during clinical trial applications guidance (PDF, 43KB, 1 page) to ensure youre submitting a valid application. After discussing the USM with the MHRA assessor via phone you must provide the MHRA with written notification of the measures taken and discussed with the medical assessor, within 3 days from the date the measures were taken. The assessment will not start until we have received a valid response. 8. Essential documents for the conduct of a clinical trial: ICH E6 (R2 To restart a trial that has been temporarily suspended, you must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial. MHRA is listed in the World's most authoritative dictionary of abbreviations and acronyms. 1 Research ethics committee approval For all clinical investigations of devices falling within the scope of the UK MDR 2002, Part II for medical devices, or Chapter VI of EU MDR, a relevant ethics. 2 See 21 CFR 312.55; a study initiated by a sponsor-investigator is not required to have an investigator's brochure. See fees for clinical investigations We have seen that the SUSARs listed in the DSUR are based on the extract from the safety database, which may have expectedness assessments based on a version of the RSI different from that approved at the beginning of the reporting period. IND Applications for Clinical Investigations: Regulatory and This is incorrect. However, it is not acceptable to copy and paste section 4.8 of the SmPC into the RSI section of an IB. The MHRA will write to you if we require further information. If your clinical trial is not on a public register or the results will not be published in the register (for example an adult phase I study), summary results should be submitted via MHRA Submissions. Please select Development Safety Update Report as the Regulatory Activity and Original Submission from the Regulatory sub activity dropdown list. At the end of the DSUR reporting period the Sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the Investigators Brochure as a substantial amendment. If there are any issues raised we will confirm these in writing and provide a 10 calendar day deadline for a response. Please note: CTIMP initial applications via combined review should be started and submitted using the new part of Integrated Research Application System (IRAS) and not in the standard part of IRAS. PDF Clinical investigations of medical devices - guidance for investigators When you notify us of amendments, we need the following information: red lined (showing changes being made) and clean copies of all amended study documentation, a signed statement by, or on behalf of, the manufacturer that the proposed change(s) do not predictably increase the risk to the patient, user or third party. Investigator brochure (IB) update, annual or otherwise, constitutes a . Investigator Brochures. Any potential reason for delay to submission of the substantial amendment should be discussed and agreed with the medical assessor at the time of initial notification or through a follow up call. 2006-02-09. How to notify the MHRA of your intention to carry out a clinical investigation for medical devices. It is essential that you contact the MHRA as soon as possible if you require clarification. Please also see guidance on Completed Paediatric Studies - submission, processing and assessment. guidance on compiling a submission (PDF, 211 KB, 16 pages) and guidance for manufacturers when preparing your notification application. However, if the product is a potential generic and is a small molecule that will be administered via the same route as the reference product, there might be a good rationale why the SARs expected for the reference product should be considered expected for the potential generic even before similarity is demonstrated. Further guidance on how to report a Serious Breach can be found here. Amendments - Research and Development - Oxford University Hospitals The RSI OBIs have now been incorporated into our routine inspection programme. Most accurate citation data. If a death is due to disease progression this means that a serious adverse event occurred, the event was disease progression and the outcome is fatal.
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