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					                                                              Common Findings Risk Assessment (CFRA)
                                                               MHRA Gap Analysis – Cardiff University
                                    School / Department:
        Give details of group or trial to which this CFRA applies

                                                            Date:
The following document has been based on ‘How to prepare for an inspection for Good Clinical Practice by the Medicines and Healthcare products Regulatory Agency (MHRA):
a guide for NHS organisations that sponsor or host clinical trials of medicinal products’ published by NHS R&D Forum, October 2006 as well as from feedback from a number of
non-commercial organisations that have received an MHRA inspection.

The CFRA aims to identify areas of risk that need to be addressed in relation to Clinical Trial Activity at a University, School, Department and individual trial level.

Categorisation of Risk
Risk      Risk                Action and time scales                                                                                                                      Suggested MHRA
Level     Category                                                                                                                                                          finding level
                              Immediate action must be taken to manage the risk. Control measures should be put in to place which will have the effect of reducing
   5      Catastrophic                                                                                                                                                         Critical
                              the impact of an event or the likelihood of an event occurring. A number of control measures may be required
                              Significant resources may have to be allocated to reduce risk. Where risk involves work in progress urgent action should be
   4         Severe                                                                                                                                                        Critical / Major
                              undertaken.
                              Efforts should be made to reduce the risk, but the costs of prevention should be carefully measured and weighed against the impact of
   3       Significant                                                                                                                                                         Major
                              an event. Establish more precisely the likelihood of harm as a basis for determining the need for improved control measures.
                              On or below this level a risk is acceptable. Existing controls should be monitored and adjusted. No further action or additional controls
   2        Moderate                                                                                                                                                        Major / Other
                              are required. Consideration may be given to a more cost-effective solution or improvement that imposes no additional cost burden.
                              Acceptable risk. No further action or additional controls are required. Risks at this level should be monitored, and reassessed at
   1           Low                                                                                                                                                             Other
                              appropriate intervals.

MHRA Definition of findings
       Critical
             -     Evidence of harm to patients rights, safety or well being
             -     Evidence of unreliable reported data
             -     Insufficient timely corrective action of major findings
       Major
             -     Evidence of significant departure from regulatory requirements (or other relevant GCP guidelines)
             -     Evidence of a number of departures from regulatory requirements (or other relevant GCP guidelines) that relate to one particular system or process
       Other
             -     Any other finding that is not major or critical

The above categories require a response from the Sponsor

       Observations & Recommendations
           - Do not require responses but relate to process improvements or best practice
Archiving

                                                     Assessment   Action Required   Risk
.1    Trial file not archived securely
      Inadequate data/document retention
.2    period (including availability of sufficient
      information to reconstruct the trial)
      Lack of archiving policy (data, master
.3
      files, etc)
      No quality control for electronic
.4
      archiving

2. Contract & Agreement Preparation
                                                     Assessment   Action Required   Risk
       Omissions/discrepancies in contract
       (e.g. notification of serious breaches of
.1
       GCP, safety information from
       Pharmaceutical company)
       Lack of written agreements between
.2     departments documenting role in IMP
       trials
       No contracts for non-commercial trials
.3
       (participating sites, trial partners, etc)
       Responsibilities of collaborators not
.4
       clearly defined
       Unclear ownership of documents and
.5
       data generated during trial
       Inconsistencies between protocol and
.6
       contract
       Delegation of duties to Chief
.7     Investigator without
       agreements/systems in place
       Lack of overarching Memorandum of
.8
       Understanding with local Trust
.9     Unclear indemnity arrangements
       Lack of SOP for managing contract
.10
       process
       Lack of controls for compliance of
.11
       international sites
3. Project management
                                                   Assessment   Action Required   Risk
      Lack of clarity for Sponsor approval
.1
      process

      Lack of identification of CI and all trial
.2
      team at outset

.3    Trial Master Files inadequate

.4    Over delegation

      Delegation logs incomplete.
.5
      Delegated responsibilities not clear.

      Duties delegated to trial personnel not
.6    made explicit during Sponsor
      approval process
      Inadequate arrangements for cover in
.7
      absence of CI

4. Information Management & technology / Use of Computers
                                          Assessment            Action Required   Risk
      Lack of organisation-wide disaster
.1
      recovery plan
      Lack of procedures and
      documentation to provide assurance
.2    that computer systems are
      demonstrably fit for purpose
      (including checks on servers)
      Some locally developed systems not
.3
      sufficiently secure
      Lack of documentation for validation
.4
      of computer systems
      Lack of evidence of system security
      (restricted access, firewalls, process
.5
      for obtaining user account, password
      management)
      No clarity on arrangements for
.6
      backing up data



5. Quality System (Quality Assurance/SOPs)
                                               Assessment   Action Required   Risk
.1    Lack of essential SOPs

.2    Lack of trial specific SOPs

      Uncontrolled documents used in
.3
      place of SOPs
      SOPs / Protocol do not reflect current
.4
      practice or current legislation
      Insufficient time between issuing and
.5    implementing SOPs, leading to
      training issues
.6    Inexperienced staff writing SOPs
.7    Inappropriate SOP approval process
      Meetings and decisions not
.8
      documented
.9    In-process checks not documented
      Internal audit programmes built
      around Research Governance
.10
      Framework only and do not take
      account of Clinical Trials Regulations
.11   No SOPs for Sponsor processes

.12   Lack of defined peer review process



6. Data management
                                               Assessment   Action Required   Risk
      Security of and restricted access to
.1
      trial documents/data
       Unclear systems for managing
.2     records (e.g. role of a Central
       Records Department)
       Facilities and offices used to
       temporarily store Medical Records of
       trial subjects, and trial-related
.3
       documents, e.g. consent forms and
       Case Report Forms, not sufficiently
       secure
       Tracing system may be inadequate
.4     for all records required to reconstruct
       clinical trial historically

.5     Inadequate retention period
       Inadequate retention of evidence of
.6     validation for alternative media used
       to store records
       Inadequate retention of Quality
.7     Assurance and Quality Control data
       in laboratories
       Inadequate retention of raw source
       data (e.g. with implementation of
.8
       electronic archiving; or Nursing notes
       not included with Medical notes).
       Inadequate process for designing
.9
       Case Report Forms
       Lack of clarity of data entry and data
.10
       query processes
       Lack of Data Analysis Plan in
.11
       protocol
       Lack of independent data validation
.12    process prior to database being
       locked for analysis

7. Training
                                                 Assessment   Action Required   Risk
       Lack of GCP training amongst CIs
.1
       and research staff
.2     Evidence of training not present
8. Regulatory Affairs (e. g. Clinical Trial Authorisations)
                                                Assessment    Action Required   Risk
.1     Lack of approval for study advertising
       Study conducted at sites outside of
.2
       those in the application
       Lack of documentation specifying
.3
       roles in CTA/Ethics application
       No evidence of active enforcement by
       Sponsor to ensure that conditions
.4
       listed on MHRA approval letters are
       followed up and met
.5     Unclear indemnity arrangements
       Inadequate controls over research
.6     commencing before all approvals in
       place
       Unclear sponsorship arrangements
.7     for DDX studies rolled over to CTA
       studies
       Lack of SOP for managing
.8
       amendments

9. Statistics
                                                 Assessment   Action Required   Risk
       Lack of professional statistical advice
.1     in protocol development & Trial
       analysis


10. Investigational Medicinal Product (IMP) management
                                               Assessment     Action Required   Risk
       Missing or unsigned documentation
 .1    (e.g. shipping records, accountability,
       dosing records)
       Inadequate provisions for storage of
.2     IMPs i.e. not kept separate to usual
       clinical supplies
      Emergency codes not supplied
.3    concurrent with supplies or prior to
      study start
      Insufficient records for the chain of
      custody (from purchase to
.4
      destruction) for marketed products
      used in clinical trials
      Inadequate procedures for QP
.5
      release
      Lack of documentation confirming role
.6
      of Pharmacy/CI

      Lack of IMP management
.7
      policy/procedure

11. Laboratory
                                              Assessment   Action Required   Risk
.1    No evidence of how equipment is
      maintained, calibrated and
      serviced
.2    Lack of laboratory SOPs (e.g.
      method validation, sample chain of
      custody, kit preparation,
      notification of results)

12. Study monitoring
                                              Assessment   Action Required   Risk
.1    Lack of Sponsor audit process

      Lack of process for establishing Data
.2    Monitoring Committee/Trial Steering
      Committee

.3    Lack of source data verification
      Lack of process for addressing audit
.4
      findings (escalation process)

13. Pharmacovigilance
                                              Assessment   Action Required   Risk
.1    Inadequate Pharmacovigilance
       systems and/or inadequate use of
       systems in place
       Lack of involvement of Principal or
.2
       Chief Investigator
       Lack of awareness of legislative
       requirements (7 and 15 day reports
.3
       for Suspected Unexpected Serious
       Adverse Reactions (SUSARs))
       Failure to distinguish Adverse Events
.4
       and Adverse Drug Reactions

.5     Failure to identify ‘Serious events’
       Failure to report Serious Adverse
.6
       Events (SAEs)
       Failure to consider event
       expectedness, and hence to identify
.7
       events which require IMMEDIATE
       reporting
       Failure to monitor pregnancy to
.8
       outcome

       Failure to monitor increased severity
.9
       or frequency through trend analysis
       Standardisation or arrangements for
.10    un-blinding SAEs arising from blinded
       trials
       Annual safety report to MHRA not
.11
       made
       Failure to notify other Investigators of
.12
       SUSARs
       Failure to provide a 24hr emergency
.13
       contact number

14. Clinical trial reporting
                                                  Assessment   Action Required   Risk
       Annual and end of study reports not
.1
       sent

15. Randomisation
                                                  Assessment   Action Required   Risk
      Randomisation processes not
.1
      documented
      Process for unblinding not
.2
      documented

16. Filing of essential documents
                                              Assessment   Action Required   Risk
.1    Poorly maintained site files
      Poor document control and
.2
      management
      Delegation logs incomplete.
.3
      Delegated responsibilities not clear.
      Lack of documentary evidence of CIs
.4    involvement in trial (e.g. informed
      consent procedure)
.5    No records of consent being taken
      Missing elements / Inconsistencies
.6
      with protocol
      Forms not updated with amendments,
.7
      poor version control
.8    Unclear process
      Forms not signed or not completed
.9
      correctly

				
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