STANDARD OPERATING PROCEDURE FOR RESEARCH. 14. Amendments to Research Studies

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1 Basildon and Thurrock University Hospitals NHS FT Research & Development APPROVED STANDARD OPERATING PROCEDURE FOR RESEARCH 1. BACKGROUND 14. Amendments to Research Studies Amendments are changes made to a protocol, other essential documentation or aspects of a research study s arrangements (such as changes to key members of the research team; i.e. Principal Investigator (PI)), after a favourable ethical opinion and local permissions by the regulatory body has been given. It is the responsibility of the Sponsor to undertake submitting amendments but this is typically delegated to the Chief Investigator (CI). If the research is hosted by Basildon and Thurrock University Hospitals NHS Foundation Trust (BTUH) the Research and Development (R&D) department, with the PI, research nurse / clinical trials practitioner and service support teams (pharmacy, pathology and imaging) as required, will assess the practicality and risk(s) of the amendment at BTUH and provide local permission for the amendment and continuation of our involvement in the study. National Institute for Health Research (NIHR) portfolio adopted study amendments will receive local permission in accordance with Clinical Research Network: North Thames (CRN: NT) processes and guidelines. 2. PURPOSE This Standard Operating Procedure (SOP) describes the procedure for making amendments, both substantial and minor, to research studies sponsored by BTUH and arrangements for assessing the impact and local permissions for BTUH hosted studies. The SOP gives a summary of the procedures for submitting/reporting to the Research Ethics Committee (REC) and the Gene Therapy Advisory Committee, if required. It is recommended that researchers view the guidance for submitting amendments at the following web addresses: Health Research Authority (HRA) o Research Ethics Committee (REC) o Gene Therapy Advisory Committee (GTAC) 3. APPLICABLE TO This SOP applies to all investigators, research and development (R&D) staff, research teams and service support teams.

2 4. PROCEDURE An amendment to a research project can be either substantial or minor (non-substantial) in nature. Study documentation must be version controlled and dated. All research protocols/documents should have a clear version number and date in order to maintain accurate records and audit trails. Version numbers and dates will therefore be amended along with the document (see SOP 1 Preparation, Approval, Review and Implementation of Research Standard Operating Procedures). 4.1 Types of Amendments Amendment to a clinical trial authorisation Note; this type of amendment only applies to the Sponsor/s of a Clinical Trial of an Investigational Medicinal Product (CTIMP). An amendment to a clinical trial authorisation is defined broadly in the Clinical Trials Regulations as an amendment to any of the following: 1. the terms of the request for clinical trial authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) 2. the terms of the REC application 3. the protocol 4. any other particulars or documents submitted with the applications to the MHRA or the main REC Substantial Amendment Defined as an amendment to the protocol or any other supporting documentation that is likely to affect to a significant degree the: 1. safety, physical or mental integrity of the subjects of the trial 2. scientific value of the trial 3. conduct or management of the trial or 4. quality or safety of any investigational medicinal product used in the trial All substantial amendments should be notified to the MHRA (if a CTIMP) and REC that gave a favourable opinion using the appropriate form taken from their website. Examples of substantial amendments (reference HRA) changes to the design or methodology of the study, or to background information affecting its scientific value changes to the procedures undertaken by participants any change relating to the safety or physical or mental integrity of participants, or to the risk/benefit assessment for the study significant changes to study documentation such as participant information sheets, consent forms, questionnaires, letters of invitation, letters to GPs or other clinicians, information sheets for relatives or careers a change of sponsor(s) or sponsor s legal representative appointment of a new CI or key collaborator a change to the insurance or indemnity arrangements for the study Page 2 of 6

3 inclusion of a new trial site (not listed in the original application) in a CTIMP appointment of a new PI at a trial site in a CTIMP temporary halt of a study to protect participants from harm and the planned restart of a study following a temporary halt a change to the definition of the end of the study any other significant change to the protocol or the terms of the REC application Urgent Safety Measures In exceptional circumstances, the sponsor or CI may instigate urgent safety measure; an action taken in order to protect trial participants against any immediate hazard to their health or safety, and temporary suspension of recruitment. This is usually notified to sites and implemented immediately while the sponsor / CI undertake a substantial REC and MHRA amendment The MHRA have to be notified of implementation of urgent safety measures within 3 days (reference MHRA) Minor ( Non-Substantial ) Amendment A minor amendment is defined as a change to the details of a study that will have no significant implications for participants or for the conduct, management or scientific value of the study. Examples of minor amendments include (reference HRA) minor changes to the protocol or other study documentation, e.g. correcting errors, updating contact points, minor clarifications updates of the investigator s brochure (unless there is a change to the risk/benefit assessment for the trial) changes to the CIs research team (other than appointment of key collaborators) changes to the research team at particular trial sites (other than appointment of a new principal investigator in a CTIMP) changes in funding arrangements changes in the documentation used by the research team for recording study data changes in the logistical arrangements for storing or transporting samples inclusion of new sites and investigators in studies other than CTIMPs extension of the study beyond the period specified in the application form Changes to contact details for the sponsor (or the sponsor s representative); CI or other study staff are minor amendments but should be notified to the main REC for information (reference HRA). 4.2 Sponsors Amendment Process If an amendment is required, the CI must first determine whether it is substantial or not using the guidance above or guidance from HRA and MHRA websites. Once this decision has been made, the following procedures must be followed; Page 3 of 6

4 4.2.1 Reporting Substantial Amendments Substantial amendments require a favorable opinion from the main REC and the MHRA (CTIMPs) before they can be implemented. The only exception to this is where urgent safety measures need to be taken (see above) Clinical Trials of Investigational Medicinal Products WHO? Under the Clinical Trials Regulations, the sponsor of a CTIMP may make an amendment to a clinical trial authorisation, other than a substantial amendment, at any time after the trial has started. Amendments that are not substantial (referred to in these SOPs as minor amendments ) do not need to be notified. Where the amendment is substantial, the sponsor is required to submit a valid notice of amendment both to the MHRA and to the REC that gave the favorable opinion of the trial. Where there is more than one sponsor for the research, the sponsor refers to the sponsor that has been designated to take responsibility for all matters relating to amendments. HOW? The European Commission has issued guidance on amendments as part of the Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of a trial' (ENTR/CT1). Annex 2 to the guidance prescribes a Notification of Amendment form (the EU Notification of Amendment ) (available from the European Medicines Evaluation Agency (EMEA) website) to be used in all member states for notification both of the competent authority (MHRA) and the REC. The sponsor must indicate on the form whether the amendment requires authorisation by the competent authority, or a favorable opinion from the ethics committee, or both. In some cases, the amendment may be for information only of one or other agency. A substantial amendment to a CTIMP must be reported to MHRA and REC approving the study before the amendment is actioned. The form structure is protected and only permits responses in the appropriate boxes. The form should be submitted by the CI, or another person or organisation authorised by the sponsor. Annex 2 should summarise the change(s) and briefly explain the reasons in each case, using language comprehensible to a lay person. Other documents required in the submission are: Description of the amendment Reasons for the proposed amendment Copy of the proposed changes to the protocol or any other documents demonstrating both the previous and new wording. Supporting data for the amendment, including any change to the risk benefit analysis Where the modified documents (e.g. protocol) are lengthy, it is acceptable for extracts to be provided or for the changes to be listed in a separate document. The CI may also include other supporting information, such as a summary of trial data, an updated safety analysis or a report Page 4 of 6

5 from a trial monitoring committee. Where the amendment could significantly affect the scientific value of the research, further evidence of scientific and/or statistical review should be provided. When the REC and MHRA have confirmed that they have no objections to the amendment, the CI, Sponsor or appropriate representative must inform R&D departments. All amended documents and supporting information must be forwarded in order for the R&D department to provide amendment approval. If the amendment has affected the protocol significantly, the sponsor may be required to amend the Clinical Trial Agreement. Any agreement or financial amendments must be dealt with through the R&D department All Other Research (Non-CTIMPS) WHO? For all non-ctimps research, the CI should complete the REC substantial amendment form and submit it to the REC which gave a favourable opinion, along with any updated documents e.g. consent form or protocol. A copy must also be sent to the R&D Department if BTUH is the research sponsor. HOW? Substantial amendments to all other research (non-ctimp) should be notified to the main REC that gave a favourable opinion using the appropriate form, see HRA website. When the REC has confirmed that they have no objections to the amendment, the CI, Sponsor or appropriate representative must inform R&D departments. All amended documents and supporting information must be forwarded in order for the R&D department to provide amendment approval. If the amendment has affected the protocol significantly, the sponsor may be required to amend the Clinical Trial Agreement. Agreement changes or financial amendments must be dealt with through the R&D department Reporting Minor Amendments WHO? A CI, sponsor or authorised representative can make a non-substantial amendment at any time but must keep records. HOW? There is no requirement to notify the main REC or obtain ethical opinion. Changes to contact details for the sponsor (or the sponsor s representative), CI or other project staff are minor amendments but should be notified to the main REC/GTAC and/or MHRA and R&D for information. Changes to contact details for PI should be notified both to the main REC, the relevant REC for the site ( the SSA REC ) and the R&D department. 4.3 Host Procedures for Reviewing Amendments R&D department will follow CRN: NTs processes for local permissions for portfolio adopted studies. For non-adopted studies R&D aims to review amendments and issue local permission within a maximum of 30 days, subject to the amendment submission being valid. Page 5 of 6

6 A valid R&D amendment submission includes the following documents: MHRA amendment approval letter (if applicable) Annex 2 form Localised versions of any amended patient documents Copies of any other amended documents which have been submitted to the REC and the MHRA Fully executed addendum to an agreement (if applicable) The amendment process may be delayed beyond 30 days if there are errors or inconsistencies in the REC or MHRA approval letters, or if any of the above documentation is not included in the original R&D submission. As part of the amendment review process, whether BTUH sponsored or hosted, the research nurse / clinical trials practitioner along with the CI/PI and service support teams will review; any additional risks associated with the amendment (updating the risk assessment form as appropriate, and the costing implications of the amendment The process may also be delayed if the amendment results in the study requiring revised costings or an amended clinical trial agreement. 5. SUPPORTING DOCUMENTS SOP 1. Preparation, Approval, Review and Implementation of Research Standard Operating Procedures SOP 7. Start Up Procedure for Research Studies 6. REFERENCES National Research Ethics Service, Medicines and Healthcare Products Regulatory Agency, Gene Therapy Advisory Committee, European Clinical Trials Database, 7. APPENDICIES None 8. DOCUMENT HISTORY Revision Date Previous Revision Date Summary of Changes July Inclusion of additional information Changes Marked Page 6 of 6