MHRA Findings Dissemination

Joint Office Launch Jan. 2012

Presented by:

Carolyn Maloney – UHL R&D Manager

Purpose of presentation

To feed back abridged findings from March 2011 MHRA Statutory Systems Inspection

To ensure all relevant parties are aware of expectations and responsibilities

To promote the facilitative approach to the management of research at UoL & UHL

Pre-Inspection Dossier

Comprehensive dossier detailing organisational „maps‟

Lists of all Medicinal Product studies –Sponsored and Hosted

Lists of all SOPs Pharmacovigilance SOP Policies & SOPs for IT, Medical Records,

Pharmacy, Laboratories Overview of organisationA „dossier‟ folder is maintained annually at UHL.

UoL encouraged to adopted same policy.

What was inspected?

Safety Reporting / Pharmacovigilance

Training

Four studies – 2 published & 2 actively recruiting

RM&G Approval processes – UHL & CLRN

Monitoring & Audit processes (QC/QA)

Pharmacy

Archiving & Medical Records

Quality management systems

Who was involved?

2 Inspectors over 4 days (£2.5k per inspector per day!)

Chairman was present at opening meeting

Carolyn & Joanne managed the inspection

The whole R&D Team & University Colleagues

The RM&G Team from CLRN

Pharmacy

Medical Records

CI & Study Teams for each of 4 studies

Volunteer „observers‟

Volunteer „scribes‟

Findings

Three categories of findings:

Critical – can incur sanctions and require immediate resolution

Major – require action within time frame specified by institution

Other – noted and requires action.

Critical Findings

There were no critical findings

Major Findings

There were two Major findings:

Informed Consent (1)

Trial Management (2)

Major Findings (1)

Consent Issues

The MHRA were keen to point out that Consent issues were identified at the last inspection. The issues identified this time are different to those recorded in 2008. Consent issues were also identified in 2006.

It is the view of UHL that all necessary steps must be taken to ensure that Consent issues are not identified for a fourth occasion which would be highly likely to incur a Critical Finding

Consent Issues identified

Consent forms did not permit the Sponsor / NHS Trust & in one case the MHRA to access subject notes and / or data for the purpose of Monitoring / Audit

Consent Forms initialled by research team member Consent Forms dated by research team member Subject names written by research team member Incorrect versions of forms used Subjects consented to participate before Trust Approval Consent form boxes ticked not initialled Patients given insufficient time to consider the study

prior to consenting Incorrect version of PIS referenced on a consent form

Consent – corrective action

A review of all UHL / UoL Sponsored CTiMP study consent forms has been undertaken. Where consent forms did not allow appropriate access, a non substantial amendment has been mandated by the Sponsor

100% Audit of Consent forms for all UHL / UoL Studies has been introduced. A table of metrics has been designed to report progress to the Board on a ¼ly basis

Risk of Critical Finding has been added to Datix –potential of sanctions from MHRA if similar issues identified at next visit high – serious implications for Trust acting as Sponsor and to reputation

Consent Training required as part of corrective action where issues identified during future Audits / Monitoring

SOP CLIN/102 Informed Consent revised and published

Trial Management (2)

No procedures or processes for management of Healthy Volunteer Trials

No process for confirming the volunteer identity

No process for verification of relevant medical history for volunteers

No process for preventing “over volunteering”

A member of pharmacy staff recruited to a study dispensed their own IMP

Trial Management – Corrective Action

SOP CLIN/136 has been published and will be on the Website in due course. Includes requirement to register each participant on TOPs & to contact GP before commencing IMP

Important to recognise that there are several types of Healthy volunteer studies active at UHL – the SOP covers those dealing with ADME studies

No individual named on the Delegation of Authority and Signature Log may participate in the research

Other findings 1 - 7

Slides included for your information

While relatively minor individually and in the majority administrative, if these „other‟ findings are identified once more at another inspection it is highly likely that the finding will be escalated to Major

Important to recognise and accept the level of attention to detail required when undertaking research – particularly of IMP

Thank You

Thank you for your attention

Do you have any questions?

Other findings (1)

Pharmacovigilance

A Protocol was not explicit in relation to SAE reporting. Care must be taken to exclude relevant disease progression when writing Protocols

There was no process for reporting and tracking pregnancy during Research

The template for SAEs did not easily facilitate causality assessments nor expectedness

Inconsistency in instruction via SOPs as to whether R&D or CI should report to MHRA / Ethics

Incorrect SAE forms submitted to R&D

Other findings (1) Corrective Action

SOP on Protocols revised & Sponsor review more robust to include discussion with CI about safety reporting

Pregnancy reporting form published

Revised Safety SOP published

Revised SAE reporting form published

Version control of documents added to Monitoring check list

SOPs undergoing consistency check

Other findings (2)

IMP Management

Temperature deviations noted but not escalated

Suitability assessment of remote storage to be carried out by Pharmacy and documented

No signature on pharmacy accountability log for receipt of kits into pharmacy

No receipt documentation for consignment received into Pharmacy to confirm received in good condition

IMP kits receipted as in „good condition‟ but package had not been opened to check

IMP still being stored in returns – study closed in March 2010

Other findings (2) Corrective Action

Pharmacy assessment for remote storage to be reviewed SOP for remote storage was revised prior to Inspection – Monitoring

of all studies with remote storage to be commenced Temperature monitoring to be added to the GCP training Research nurses responsible for temperature monitoring to undergo

annual training Signature logs to be reviewed and updated SOPs for expired medication revised Delivery notes to be filed in Pharmacy files Reminder to all staff to remove outer packaging before signing

acceptance of consignment Pharmacy archiving SOP 410 had not been followed Reminder to all staff to follow SOPs Discussion with PI at study close down ref. patient returns

Other findings (3)

Quality Management Systems

A user name and password for randomisation system clearly visible in the TMF

No process for ensuring IB / SmPC reviewed annually

Other findings (3) Corrective Action

Reminder about Passwords protection, IT Policies on electronic security to be added to GCP Training

IB/SmPC updates added to CI Roles & responsibilities and an alert now added to the R&D Database

Other findings (4)

TMF / Essential documents Inconsistencies between what the protocol says will happen during

the study and what is written in IRAS Consent form stated notes to be viewed by Research Team,

Regulatory Authorities and NHS Trust – IRAS form stated only research nurses and researchers only

Protocol exclusion criteria <18 & >85 years. CRF exclusion >18 and <85

Protocol stated adherence to a Trust SOP that did not exist Application stated that a department would oversee statistics at the

Trust when no such department exists When documents stored electronically, they must be stored in a

format that allows access by inspectors

Other findings (4)

TMF / Essential documents Evidence of appropriate training for stats analysis not

available for individual with delegated responsibility Stats analysis not included on the Delegation of

Authority and Signature log Submissions to MHRA / REC not available in TMF File notes not signed or dated All entries on a Delegation of Authority and Signature

Log dated on the same date, after the study had commenced. Therefore, no evidence that study related activity had been discussed with the team prior to study start

Other Findings (4) – Corrective Action

Consistency checking has been added to the Sponsor review process

Initiation visits introduced to take place with the team and support services prior to first patient recruited

Other findings (5)

Contracts & Agreements

Contracts signed by CI and not by the authorised individuals on behalf of the Trust

External provider contracts not present for Stats analysis with Universities nor for supply of IMP

Other findings (5) Corrective Action

Added to the Sponsor review process. Contracts with external providers will be discussed as appropriate with the CI prior to any application submissions

Reiterate that only authorised signatories on behalf of the Trust may sign

Other findings (6)

Facilities

No temperature monitoring had been performed for a -20oc freezer

Other findings (6) Corrective action

In future, where studies involve storage of samples in freezers, the freezers will be part of an existing monitoring programme (Icespy). Where this is not possible, appropriate action will be taken to include the freezer in the monitoring set up. Any additional costs for this will be borne by the research study budget

Other findings (7)

Training

No evidence of GCP Training for some staff within a study folder

Lack of evidence of training for key study tasks e.g. stats analysis

Other findings (7) – Corrective Action

Valid GCP Certificates MUST be held within the TMF for ALL staff involved in the study named on the Delegation of Authority & Signature Log

Evidence of relevant training specific to the study role e.g. Stats

GCP Certificates are Valid for TWO years.

Since the inspection:

The following issues have been identified since the MHRA Inspection

Expired medication supplied to patient to take home – medication did not hold expiry date on boxes

Similar issues will be published on the new website when launched later this month