STANDARD OPERATING PROCEDURE

Transcription

1 STANDARD OPERATING PROCEDURE Title Reference Number Risk Assessment SOP-RES-002 Version Number 2 Issue Date 29 th Sep 2016 Effective Date 10 th Nov 2016 Review Date 10 th Nov 2018 Author(s) Reviewer(s) Natalie McGregor, Research Project Manager Teresa O Leary, Head of Research Governance Authorisation (Original signatures are retained by Research & Innovation) Dr Stephen Ryder Director of Research & Innovation Dr Stephen Fowlie Medical Director 01 st Aug nd Sep 2016 USERS OF THIS STANDARD OPERATING PROCEDURE MUST REFER TO TO ENSURE THE MOST CURRENT VERSION IS BEING USED

2 Page 2 of Document History Version Number Issue Date Reason for Change 1 22 nd April 2014 Original SOP th Sep 2016 Biennial review.

3 Page 3 of Introduction Sponsors are required to provide oversight of studies to ensure adequate protection of the participants, sponsor and data integrity but there are inherent risks; the purpose of a risk assessment is to identify potential hazards and asses the likelihood of those hazards occurring and resulting in harm. Dependent on the risks of a study, alternative/proportionate monitoring may be considered when developing monitoring strategies. The Medicines for Human Use (Clinical Trials) Regulations 2004 allow for risk-adapted approaches to the management of clinical trials of investigational medicinal products (CTIMPs). Nottingham University Hospitals NHS Trust (NUH) has adopted the risk-adaptive approach for the management of all studies it sponsors, including CTIMPs, clinical investigations of medical devices and all other research. 3. Purpose and Scope This standard operating procedure (SOP) is designed to assist Nottingham University Hospitals NHS Trust (NUH) identify studies with risks and ensure those risks are managed/mitigated sufficiently in order for NUH to authorise sponsorship. The risk assessment outcome will inform NUH of an appropriate monitoring strategy needed to assure the safe and successful conduct of the study. As sponsor, NUH may review the risk assessment during the conduct of the study and implement a new monitoring strategy as necessary. 4. Responsibilities Sponsor (fulfilled by the Research and Innovation (R&I) department on behalf of NUH) The Sponsor Representative (SR) performs an initial risk assessment of all studies to determine if a detailed risk assessment is required. The SR will facilitate completion of the risk assessment and schedule attendees for a sponsorship meeting, if required. The SR will implement the monitoring plan (MP) based on the outcome of the risk assessment. Chief Investigator (CI)

4 Page 4 of 12 Completes the risk assessment. Definitions AE CE Central Monitoring CI CMD CTIMP ecrf EDC EU GCP HRC ICH-GCP IMP ISO MHRA Monitoring MP MTD NHS NUH On-site Monitoring QA Adverse Event "Conformité Européene" which literally means "European Conformity". The CE mark is required for all new products which are subject to one or more of the European product safety Directives. It is a visible sign that the manufacturer of the product is declaring conformity with all of the Directives relating to that product A remote evaluation performed by the sponsor or the sponsor s representative (e.g. data management, statistician, monitors) at a location other than the site at which the research is being conducted Chief Investigator Clinical Investigation of Medical Device Clinical Trial of Investigational Medicinal Product Electronic Case Report Form Electronic Data Capture European Union Good Clinical Practice Head of Regulatory Compliance International Conference on Harmonisation Guidelines for Good Clinical Practice Investigational Medicinal Product International Organization for Standardization Medicines and Healthcare products Regulatory Agency Methods used by sponsors to oversee the conduct and reporting of data in research, including investigator supervision of site staff and external service providers Monitoring Plan Maximum Tolerated Dose National Health Service Nottingham University Hospitals NHS Trust In-person evaluation performed by the sponsor or the sponsor s representative at the site at which the research is being conducted Quality Assurance QP R&I SR Qualified Person Research and Innovation Sponsor Representative

5 Page 5 of 12 SDV SmPC SOP SUSAR TMF UK Source Data Verification Summary of Product Characteristics Standard Operating Procedure Suspected Unexpected Serious Adverse Reaction Trial Master File United Kingdom

6 Page 6 of Procedure 5.1 Risk Assessment The risk assessment is performed to analyse the combination of the probability/likelihood of harm arising and the severity/impact of that harm. Appropriate management/mitigation strategies should then be identified and implemented to bring any harm within an acceptable limit. The risk assessment should be undertaken at the research proposal stage and may then be refined once the protocol has been drafted. Critical study considerations must be assessed prior to funding applications and finalising the protocol Is a Detailed Risk Assessment Required? The SR will perform an initial risk assessment using the flow chart in Appendix 1 to determine if a detailed risk assessment is required for the study. If it is unclear what type of research is being undertaken (i.e. is it a clinical trial?) the CI should seek to confirm this by contacting the Medicines and Healthcare products Regulatory Agency (MHRA) if necessary. If required, the SR will co-ordinate the risk assessment (see 5.1.2). If a risk assessment is not required the SR will continue with the sponsorship review. If, during the sponsorship review, risks are identified which are not appropriately managed/mitigated by the study team the RPM will liaise with the HRC who may decide that a detailed risk assessment is required Completing the Risk Assessment Depending on the risk of the study the RPM may initiate a sponsorship review meeting to review the study feasibility and risks with the key stakeholders (refer to SOP-RES-001 Sponsorship). If a sponsorship review meeting is not required the SR will send the Risk Assessment Tool (TAFR00201) to the CI for completion, The CI should contact the SR with any queries. Once the tool has been completed and returned, the SR will consider the monitoring/auditing methods and document on risk assessment tool. The risk assessment tool can be finalised once all parties have agreed. If a sponsorship review meeting is required:

7 Page 7 of 12 Prior to the sponsorship review meeting the SR will provide the CI with the risk assessment tool. The CI should complete all sections of the Risk Assessment Tool (TAFR00201) and return the completed draft to the SR. The SR should be contacted for any queries about completing the document. Once the CI s risk assessment draft has been returned the SR will consider the monitoring/auditing methods and document on the draft risk assessment tool. The SR will provide a copy of the draft risk assessment (where possible) to all members of the sponsorship review meeting in advance of the meeting (allowing sufficient review time). During the sponsorship review meeting the risk assessment must be discussed and finalised with input from a statistician and support departments (e.g. pharmacy, radiology) where appropriate. A follow up meeting may be arranged if there are significant changes to be made to the risk assessment. (Provisional) sponsorship authorisation will be confirmed following completion of the risk assessment ensuring that the monitoring strategy is appropriately financed for the study. Risk assessment documentation will be filed in the sponsor trial master file (TMF). 5.2 Developing the Monitoring Strategy The monitoring strategy is developed based on the outcome of the risk assessment for the study, ensuring that areas of concern/vulnerabilities are appropriately monitored during the study conduct. The monitoring strategy should consider: i. The intensity (frequency and level of SDV) of monitoring; ii. The focus of the monitoring; and iii. The methods (on-site or central, or a combination thereof) for monitoring. Appendix 2 describes how the focus and intensity of monitoring may be adapted depending on the risk of the study. The HRC/SR will document the agreed monitoring strategy in a study Monitoring Plan (TAFR00202) prior to study start. An SR will be responsible for conducting the monitoring as per the monitoring plan (refer to SOP-RES-013 Monitoring). It may be possible to use a tapered approach with more intensive monitoring at initiation and during the early stage of the study, but once procedures and research teams are established less intense monitoring may suffice. Similarly, it may be necessary to increase

8 Page 8 of 12 the intensity of monitoring during the conduct of the study if existing monitoring activities indicate cause for concern. The monitoring strategy may be amended during the course of the study, in which case a risk assessment review should be undertaken (see 6.3). 5.3 Risk Assessment Review The risk assessment may be reviewed at any time during the study taking into account new knowledge and experience, and may include reconsiderations for the acceptable limit of risks. This may occur as a result of any of the following (this list is not exhaustive): i. Monitoring findings; ii. Audit or inspection outcome; iii. Safety review; iv. Serious breach or non-compliance; v. Change to protocol, resources, personnel, facilities or external service providers. The risk assessment will be completed as per It may not be necessary to revise all sections of the Risk Assessment Tool (TAFR00201) or convene all original members of the sponsorship review meeting. The HRC/SR and the CI will agree which sections will be revised and who should attend the review meeting. Justification will be documented where sections of the risk assessment are not revised. The SR will update the study Monitoring Plan (TAFR00202) accordingly following the risk assessment review and notify the RPM.

9 Page 9 of References and Associated Documents ICH Harmonised Tripartite Guideline Quality Risk Management Q9: Current Step 4 version, 9 November 2005 MRC/DH/MHRA Joint Project Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products: version 10 October 2011 The Medicines for Human Use (Clinical Trials) Regulations 2004 The MHRA Good Clinical Practice Guide 2012 SOP-RES-001 SOP-RES-006 SOP-RES-013 TAFR00201 TAFR00202 Sponsorship Governance Review Monitoring Risk Assessment Tool Monitoring Plan 7. Appendices

10 Page 10 of 12 Appendix 1. Risk Assessment Decision Flow Chart Yes Is the study a CTIMP or a CMD, or both, or involves an No Does the study involve participants? No Yes Is it a non-intervention/nontreatment study (i.e. questionnaire/interview or sample collection only study)? Yes No Will participants receive an intervention or treatment that is standard care? 1 No Yes Perform risk assessment Risk Assessment not required, proceed with sponsorship review 1 May not be standard of care in the study population but is a standard NHS treatment.

11 Page 11 of 12 Appendix 2. Monitoring Strategy Guidance This table provides an example of the estimated monitoring requirements for CTIMPs and CMDs. The actual level of monitoring should be based on risk assessment outcome and documented in the study Monitoring Plan. Non-CTIMP or non-cmd studies are not estimated in the table below- the intensity of monitoring for these studies must be dependent on the risk assessment outcome. Concerns identified in the risk assessment associated with the design, methods or conduct of the study (other than the IMP/intervention/device) which remain after mitigations are in place? No Yes CTIMP- Type A CMD- CE marked, used as intended Low Intensity Central monitoring of protocol adherence and data quality. On-site monitoring not always essential. Low + As per low intensity, plus appropriate monitoring to address the specific vulnerabilities identified in the risk assessment. CTIMP- Type B CMD- CE marked, not used as intended CTIMP- Type C CMD- not CE marked Moderate Intensity Central monitoring of safety data quality and timelines as well as protocol adherence and quality of other trial data. On-site monitoring not always essential. Higher Intensity On-site monitoring of safety data quality and timelines as well as protocol adherence and quality of other trial data recommended. Moderate + As per moderate intensity, plus appropriate monitoring to address the specific vulnerabilities identified in the risk assessment. Higher + As per higher intensity, plus appropriate monitoring to address the specific vulnerabilities identified in the risk assessment. CTIMP Type A: risk comparable to that of standard medical care Trials involving IMPs authorised in any EU member state if: i. they relate to the authorised rage of indications, dosage and form; or ii. they involve off-label use (such as in paediatrics and oncology) if this offlabel use is established practice and supported by sufficient published evidence and/or guidelines. CTIMP Type B: risk somewhat higher than that of standard medical care Trials involving IMPs authorised in any EU member state if:

12 Page 12 of 12 i. such products are used for a new indication (different patient population/disease group); or ii. substantial dosage modifications are made for the licenced indication; or iii. they are used in combinations for which interactions are suspected. Trials involving medicinal products not authorised in any EU member state if the drug substance is part of a medicinal product authorised in the EU. CTIMP Type C: risk markedly higher than that of standard medical care Trials involving IMPs not authorised in any EU member state. CTIMP type may be lowered provided there is clear justification of experienced clinical or non-clinical evidence.