Clinical Trial Risk Assessment Form

Clinical Trial Risk Assessment Form

Study Title:
Short Title/Acronym: / Name of Chief Investigator (CI):
EudraCT Number: / Name of CTU:
R&D Reference: / Name of Trial Manager:

Guidance notes (orange text) are provided throughout the document to aid the investigator in completing the form as well as in Appendix 1. Please note that the examples provided are not exhaustive.

These notes should not be ‘copied and pasted’ as an actual response; each trial is different and so are the associated hazards and risks.

When completing the form, the hazards and risks of the trial should be identified and balanced against those of standard clinical care.

Responsibilities:

¯  It is the responsibility of the CI to ensure that the Clinical Trial Risk Assessment Form (CTRAF) is completed as part of the development of the protocol although representatives of the sponsor and relevant CTU will also contribute to the content of the form.

¯  The CTRAF should be submitted to Trust R&D as part of the submission to request Trust sponsorship.

¯  The CTRAF must be finalised, approved and signed off BEFORE submission of trial documentation to the MHRA/REC.

¯  The CTRAF should be reviewed whenever there is a serious breach of Good Clinical Practice, a deviation or violation of the protocol or if a substantial amendment is made that results in a change to protocol procedures, the benefit/risk assessment for the intervention or updates to reference safety information.

IMP Risk Categorisation
Risks associated with IMP/interventions:
Type A = Comparable to the risk of standard medical care
Type B = Somewhat higher than the risk of standard medical care
Type C = Markedly higher than the risk of standard medical care / Reasoning:
Consideration should be given to:
¯  Phase of development
¯  Study population: healthy volunteers, patients, critically or terminally ill patients, pregnant women etc.
¯  Is the IMP licensed/medical device CE marked and is it being used within the terms of the licence?
¯  Are there any modifications to the dose/route of administration/indication?
¯  If the IMP/intervention is novel are there any anticipated risks/effects based on preclinical data or knowledge of class of drugs?
¯  Could any concomitant medications increase the risk, i.e. drug interactions?
¯  Is additional safety monitoring being put into place in comparison to standard care?
¯  Are any other risk reduction strategies required (restrictive eligibility criteria; detailed treatment protocol, criteria and processes for stopping or modifying study treatment; AE reporting strategy; Trial Oversight Committees etc.)
Where the risk of the intervention is comparable to standard care (i.e. Type A trials) then the individual risks and associate mitigation strategies do not need to be described in detail. Where the risk of the intervention is considered to be moderately or markedly higher than the risk of standard care (i.e. Type B or C trials) details regarding the specific risks to individual body systems should be described below.
For all trials information on routine monitoring and consideration should be included within the reasoning for the categorisation.
IMP/Intervention / Body system / Hazard / Risk of hazard occurring (L,M, H) / Risk reduction strategies described in the protocol
Please outline any other processes that have been put in place to reduce the risks to participant safety :
/ Risk/Hazard / Is there a specific risk
(Y/ N) / Concerns Identified
Provide details of trial-specific considerations/risk concerns / Risk reduction strategies / adaptations to minimise the hazard:
·  Address all identified concerns
·  Provide details of any risk-adaptations
·  Refer to appendix 1 for further guidance / Additional monitoring methods required:
·  discuss impact on trial monitoring requirements /
1. / Trial Participants
1.1. / Hazards of clinical procedures specified in protocol
Does the protocol require procedures over and above standard care and are risks attached to these? Are any of the procedures complex or clinically unusual for this patient population?
1.2. / Non-compliance with informed consent process
Does the person taking consent have sufficient experience? Does the study involve patients lacking capacity or children? Does the participant have sufficient time to consider information (e.g. consent in an emergency setting)?
Is there a process for acting on a patient’s request to withdraw from the trial?
1.3. / Failure to protect participants’ privacy
Is sensitive data being collected? Are the data collection methods secure? Are personal identifiers associated with the data? Will the transfer of data be secure? Will data be transferred between organisations? Will identifiable data be transferred to third parties?
Will data be sent outside UK?
1.4. / Other please give details:
Will patients be required to suspend any standard medication?
2. / Validity of Results:
2.1. / Study inadequately powered
Does the study have sufficient power to detect realistic effects of the intervention? Is the recruitment target feasible? Are the eligibility criteria complex and restrictive?
Has there been sufficient statistical input and will there be ongoing support?
2.2. / Major violation of eligibility criteria
Are any of the criteria specifically relevant to patient safety or the validity of the results? Are the criteria complex and unnecessarily restrictive? Will inexperienced/untrained staff be delegated eligibility assessments?
2.3. / Lack of robust randomisation procedure
Is there a possibility study team could predict treatment allocation prior to entering participants into trial? Is a centralised randomisation service being used or treatment packs held in pharmacy?
2.4. / Potential for loss of blinding
Are the IMP and placebo indistinguishable and if not how will this be addressed? Is there a robust emergency unblinding procedure?
Who can be involved in unblinding?
Is there a robust unblinding procedure for reporting of SUSARs?
2.5. / Unreliable outcome assessment
Is a ‘hard’ primary endpoint being used e.g. death, clinical event, percentage decrease in laboratory parameters? Is there source data to verify the result? Potential for unbiased review (e.g. independent endpoint review)? Is there a risk of poor data quality?
Is there a risk to completeness of follow-up, i.e. is the follow up schedule difficult?
2.6. / Unreliable data collection
Are there large amounts of complex data to collect? Has the CRF been approved? Has the eCRF been validated and approved? Is there a risk of poor data quality?
2.7. / Poor data management system
Is there a risk of poor data quality?
Has the database been validated and tested? Is the database secure?
2.8. / Other please give details:
3. / Trial Management:
3.1. / Inexperienced trial staff
Are the clinical teams experienced with the intervention/IMP? Will the trials teams receive sufficient training?
Will any staff on rotation be delegated trial duties?
3.2. / Competence of other organisations
Is this a multicentre trial?
Are any key functions delegated to external organisations (e.g. central laboratory, randomisation and unblinding)? Are all responsibilities and liabilities clearly delegated and documented?
3.3. / Inadequate trial management
Has the trial management been assigned to an experienced CTU?
3.4. / Appropriate resources not available
Have all costs been identified including the research, treatment and excess treatment costs?
Is there enough funding to cover the entire trial and is this secure?
Do all clinical support services have capacity to perform necessary tests?
Are there enough members in the trial team to cover absences/holidays? Do all sites have the infrastructure to support the trial?
3.5. / Inadequate pharmacovigilance systems
Is the SAE reporting form/process complex? Will there be an SAE monitoring and review process? Are sites and trial management team familiar with SAE reporting requirements? Are there systems to maintain awareness of and to act on new knowledge? Will participants be able to report adverse events reliably?
3.6. / Poor IMP management systems
Is the supply of IMP secure? Is there appropriate control of IMP release to sites? Are IMP handling and storage instructions clear (potential for dosing errors, temperature deviations, etc.)? Is standard of care likely to be different between sites?
3.7. / Poor sample management
Are there multiple samples being sent to multiple laboratories? Are sites familiar with sample collection, preparation and transfer requirements? Are agreements in place for the transfer of samples (e.g. MTA)
3.8. / Influence/interference of external organisations upon trial governance
Could there be a breach of patient confidentiality via inappropriate access to data / results? Could external organisation misinterpret results? Is ownership of data and Intellectual Property clear?
Are other organisations involved in trial design?
3.9. / Other please give details:
e.g. is there a process for identifying and acting on potential serious breaches of GCP?
Summary of the main issues to be considered in the monitoring plan:

Authorisations: Only to be signed once all risks and management strategies have been agreed and finalised.

CI / CTU / Sponsor
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Name of CI / Name of CTU / Name of Sponsor
Name of Substantive Employer / Name of CTU Representative / Name of Sponsor’s Representative
Signature / Signature / Signature
Date / Date / Date

Appendix 1

All guidance notes are provided to direct investigators to the risks and management strategies that should be considered. They must be specific to the trial. Copying and pasting of these strategies is strongly discouraged.

Risk/Hazard / Potential Mitigation /Management Strategies.
1. / Trial Participants:
1.1. / Hazards of clinical procedures specified in protocol / ¯  Data Monitoring and Ethics Committee
¯  IRMER / ARSAC review
¯  Adverse Event reporting systems
¯  Study assessments performed by trained staff
¯  Provision for containment, shielding, monitoring, etc.
1.2. / Non-compliance with informed consent process / ¯  Clear delegation of the taken of consent by staff trained and experienced to do so
¯  Training on protocol-specific consent process
¯  Documentation of eligibility and consent process in patient notes
¯  Supervision of consent process
¯  Confirmation of ongoing consent throughout trial
¯  Documented assessment of capacity
¯  100% SDV of consent forms by trial monitor
¯  Confirmation of consent prior to randomisation
¯  Audit of consent procedures
¯  Withdrawal procedure and criteria defined in protocol
¯  Use of a withdrawal case report form
1.3. / Failure to protect participants’ privacy / ¯  Adherence to the NHS Code of Practice on Confidentiality
¯  Anonymised or pseudoanonymised/linked data
¯  Limit to number of staff who have access to confidential information
¯  Training in confidentiality and data protection
¯  Use of Confidentiality Disclosure Agreements with external organisations
¯  Computer security systems
¯  Use of encrypted media
¯  Specific consent for data transfer, etc.
Risk/Hazard / Potential Mitigation /Management Strategies.
2. / Validity of Results:
2.1. / Study inadequately powered / ¯  Statistical input to design and power
¯  Recruitment assessment
¯  Pilot studies
¯  Comprehensive site selection including use of feasibility questionnaires
¯  External communication and trial promotion
¯  Active monitoring of recruitment and retention rates
¯  Trial Steering Committee
¯  Trial Management Group
2.2. / Major violation of eligibility criteria / ¯  Eligibility criteria documented in protocol and in-depth training during Site Initiation Visit
¯  Eligibility criteria verified prior to randomisation
¯  Source Data Verification of eligibility criteria
¯  Standard process for assessing eligibility queries
¯  Eligibility to be recorded by a clinician in medical notes
2.3. / Lack of robust randomisation procedure / ¯  Randomisation system tested before implementation
¯  IDMC to review balance between trial arms periodically
¯  Independent central randomisation - IVRS
¯  Trial specific randomisation procedure
2.4. / Potential for loss of blinding / ¯  Independent randomisation
¯  Restricted access to randomisation schedule (including for the unblinding of SUSARs, emergency unblinding, etc.)
¯  Documented emergency unblinding procedure
¯  Use of emergency code break envelopes
¯  Placebo formulated to match the IMP
2.5. / Unreliable outcome assessment / ¯  Well defined primary objective
¯  Standardised data collection forms
¯  Training in CRF completion
¯  Data Monitoring Committee
¯  Trial Management Protocol
¯  Statistical input to data monitoring and audit
¯  Source Data Verification
¯  Detailed in protocol
¯  Equipment calibration and maintenance contracts
2.6. / Unreliable data collection / ¯  Standardised data collection forms
¯  Training in CRF completion and data entry
¯  Data Monitoring Committee
¯  Source Data Verification
¯  For-cause audits of repeat offender sites
2.7. / Poor data management system / ¯  Standardised data collection forms
¯  Training in CRF completion and data entry
¯  Statistical input in to central data monitoring
¯  Statistical analysis in accordance Statistical analysis plan
¯  Data encryption for all portable media
¯  Specification document and system validation and testing all recorded
¯  Database backup (use of centrally supported systems)
¯  Restricted access to database
¯  Audit trail for all data corrections
¯  Data Monitoring Committee
¯  Data quality checks (e.g. SDV, data queries, automatic filters)
Risk/Hazard / Potential Mitigation /Management Strategies.
3. / Trial Management:
3.1. / Inexperienced trial staff / ¯  Assessment of the training needs of the trial team
¯  Provision of trial-specific training e.g. at the site initiation visit
¯  Experienced trial management team
¯  Delegated responsibilities clearly identified and documented in the site file
¯  Systems in place to maintain awareness of and act upon new knowledge
¯  Regular, documented trial team meetings
¯  CVs for trial staff held in Trial Master File
¯  Detailed training logs
3.2. / Competence of external organisations / ¯  Site visits
¯  Investigator initiation meetings
¯  Site and collaborator agreements
¯  Monitoring of collaborating sites
¯  Delegated responsibilities clearly identified and agreed in site file (including supervision requirements)
¯  Systems to ensure reporting obligations for medicinal trials (SUSARs, amendments, termination)
¯  Partner competency assessment
3.3. / Inadequate trial management / ¯  Documented roles and responsibilities in place
¯  Use of approved SOPs
¯  Trial Steering Committee
¯  Regular GCP training (every 3 years)
¯  Regular trial management group meetings
¯  Trial delegation log
¯  Internal quality assurance audits
¯  Use of a Clinical Trials Unit
3.4. / Appropriate resources not available / ¯  Trust finance input into trial costing
¯  Contract with funding body
¯  Early discussion and confirmation of requirements with clinical support services and continued discussions throughout the trial
¯  Adequate support within trial site teams
¯  NHS R&D approval
¯  Multidisciplinary project teams
3.5. / Inadequate pharmacovigilance systems / ¯  Training in SAE reporting
¯  Pharmacovigilance procedures detailed in protocol
¯  Standardised SAE report form
¯  SAE reporting / assessment checklist used by coordinating centre for each SAE
¯  Reminder system to ensure DSUR sent to MHRA and PIs
¯  Data Monitoring and Ethics Committee
¯  Dedicated Pharmacovigilance staff
3.6. / Poor IMP management systems / ¯  Contract with IMP supply organisation including provisions for ensuring constant supply
¯  All IMP orders processed via coordinating centre
¯  IMP handling instructions detailed in protocol
¯  Accountability records obtained regularly from Sites
¯  Central accountability log maintained
¯  Process for dose escalation/reduction described in the protocol

Clinical Trial Risk Assessment Form; version 1.0; June 2014 Page 13