MHRA GCP Inspection 21st – 24th June 2011

Medicines and Healthcare products Regulatory Agency

What do the MHRA inspect? University systems that support conduct of CTIMPs in

compliance with regulations and GCP. Areas of interest include:

– Approval processes and regulatory submissions– Contract management– Trial file and data management– Quality assurance and monitoring– Training– IT systems– Pharmacovigilance– Archiving– Laboratories– Pharmacy

Specific examples of CTIMPs that demonstrate those systems

UoA sponsors or co-sponsors 8 CTIMP studies UoA hosts 33 CTIMP studies MHRA have chosen 4 to look at in depth

However…….they can change their minds before the visit or decide to look at other studies during the visit….we must all be prepared!

What do the MHRA inspect?

Aims of this session

Brief researchers on what the inspectors will be looking at in your CTIMP study- Qualifications & training- Study files & documentation- Pharmacovigilance- Serious breaches- Informed consent- Communication

Describe new overarching SOP’s Prepare researchers for interviews with inspectors

Preparation for MHRA Preparation for MHRA Inspection Inspection

Regulations, Qualifications & Regulations, Qualifications & TrainingTraining

Legislation:Legislation:

Letter from MHRA:Letter from MHRA:

““The main The main references used for the used for the inspection will be inspection will be EU Directives EU Directives 2001/20/EC2001/20/EC and and 2005/28/EC2005/28/EC and and supporting guidance documents supporting guidance documents as incorporated in UK National as incorporated in UK National Legislation, Legislation, Statutory Instrument Statutory Instrument 2004, Number 1031, the 2004, Number 1031, the Medicines for Human Use (Clinical Medicines for Human Use (Clinical Trials) Regulations 2004 and Trials) Regulations 2004 and subsequent amendments.”subsequent amendments.”

Legislation::

2001 EU Clinical Trial Directive: Directive 2001/20/EC 2004 Medicines for Human Use (Clinical Trials)

Regulations 2004 (SI: 1031) 2005 EU Directive on Good Clinical Practice

2005/28/EC 2006 The Medicines for Human Use (Clinical Trials)

Amendment Regulations 2006 (SI:1928) 2006 The Medicines for Human Use (Clinical Trials)

Amendment (No.2) Regulations 2006 2008 The Medicines for Human Use (Clinical Trials)

and Blood Safety and Quality (Amendment) Regulations 2008

2009 2009 MHRA GCP guideline - LaboratoriesMHRA GCP guideline - Laboratories

Medicines for Human Use (Clinical Trials) Regulations 2004 (SI:1031)

““Each individual involved in Each individual involved in conducting a trial shall be conducting a trial shall be qualified by education, training, qualified by education, training, and experienceand experience to perform his or to perform his or her respective task(s)”her respective task(s)”

Qualifications and Training:

Delegation Log Training Record

Delegation of Duties:

Delegation log should be established, documenting which tasks are undertaken by each member of the research team

These should be signed by each team member to confirm that they agree to undertake the task they have been delegated

MHRA Inspection:

Those listed on the delegation log should be qualified to carry out their specific task(s)– CV– GCP Training– Training Record

SOP: Establishing and Maintaining a Training Record UoA-NHSG-SOP-016

Applies to all staff conducting or supporting clinical research sponsored or co sponsored by UoA / NHSG

Responsibility of the individual to create an update their own training record

Contents of the Training Record:

Current CV Job Description(s) Certificates of training Training Log: ongoing list of all internal

and external training - may include training from previous post (training courses, conferences, seminars, relevant meetings)

Keep copies of handouts / agendas If a staff leave – take original training

record, but leave a copy with the study file

Possible Questions

Tell me about your qualifications

What type of GCP training

have you had / who was the

provider

Have you done any other

research training

What is your clinical

experience / experience on clinical trials

How do you assess that

your team are competent to complete their

delegated tasks – Is this

documented

Study Files and Documentation:

Trial Master FilesTrial Master Files Investigator Site FilesInvestigator Site Files

Medicines for Human Use (Clinical Trials) Regulations 2004 (SI:1031)

““All Clinical Trial information should be All Clinical Trial information should be recorded, handled and storedrecorded, handled and stored in a way in a way that allows its accurate reporting, that allows its accurate reporting, interpretation and verification”interpretation and verification”

““The The confidentiality of records confidentiality of records that could that could identity subjects shall be protected, identity subjects shall be protected, respecting the privacy and confidentiality respecting the privacy and confidentiality rules rules in accordance with thein accordance with the requirements of the Data Protection Act requirements of the Data Protection Act 19981998 and the law relating to and the law relating to confidentiality”confidentiality”

Study Files and Documentation:

Chief/Principal Investigators are Chief/Principal Investigators are required to keep, and maintain, a required to keep, and maintain, a CORE set of documents for EACH CORE set of documents for EACH research project they manageresearch project they manage

Should be kept in a designated Should be kept in a designated file called a Investigator Site File file called a Investigator Site File (ISF) and/or Trial Master File (ISF) and/or Trial Master File (TMF)(TMF)

SOPs: Establishing and Maintaining a TMF: Establishing and Maintaining a TMF:

UoA-NHSG-SOP-008UoA-NHSG-SOP-008– UoA-NHSG-TMP-003 – TMF ChecklistUoA-NHSG-TMP-003 – TMF Checklist

Establishing and Maintaining an ISF: Establishing and Maintaining an ISF: UoA-NHSG-SOP-009UoA-NHSG-SOP-009– UoA-NHSG-TMP-002 – ISF ChecklistUoA-NHSG-TMP-002 – ISF Checklist

(If single centre: both can be combined to (If single centre: both can be combined to save duplication)save duplication)

Applies to all staff conducting or Applies to all staff conducting or supporting CTIMPs sponsored or co supporting CTIMPs sponsored or co sponsored by UoA / NHSGsponsored by UoA / NHSG

TMF / ISF Maintaining TMF / ISF is the responsibility Maintaining TMF / ISF is the responsibility

of the CI/PI – can be delegated to research of the CI/PI – can be delegated to research teamteam

Use file index / checklist. Alternative Use file index / checklist. Alternative version can be used, but must retain all the version can be used, but must retain all the listed documentation as minimum standardlisted documentation as minimum standard

If documents stored elsewhere – add in file If documents stored elsewhere – add in file notenote

Updates / amendments added to TMF / ISF Updates / amendments added to TMF / ISF and reviewed by sponsor.and reviewed by sponsor.

Stored in a secure environment – but Stored in a secure environment – but remain accessible to trial staff remain accessible to trial staff

Possible Questions:

Who is managing your

TMF / ISF

Who has access to your

files

Do you keep electronic versions of documents

How do you ensure the security of

your records

Archiving:

What Where How For how long

SOP: Archiving Clinical Research Data: UoA-NHSG-SOP-021

Not yet finalisedNot yet finalised

Applies to all staff conducting or Applies to all staff conducting or supporting CTIMPs sponsored or co supporting CTIMPs sponsored or co sponsored by UoA / NHSGsponsored by UoA / NHSG

Responsibility of the sponsor and CI Responsibility of the sponsor and CI to ensure essential documents are to ensure essential documents are retained for an appropriate period retained for an appropriate period of time - and made available for of time - and made available for monitoring and auditmonitoring and audit

What:

TMF / ISFTMF / ISF DataData Hospital RecordsHospital Records Clinical and office Clinical and office

chartscharts Lab notesLab notes MemorandaMemoranda Subjects diariesSubjects diaries Case Report FormsCase Report Forms

Evaluation checklistsEvaluation checklists Recorded data from Recorded data from

automated automated instrumentsinstruments

Copies of Copies of transcriptionstranscriptions

Records kept at Records kept at pharmacy / Labspharmacy / Labs

X-Rays / reportsX-Rays / reports Photographs / Photographs /

microfilmmicrofilm Other – if appropriateOther – if appropriate

Essential Documents / Source Documents:Essential Documents / Source Documents:

Hospital Records:

Hospital records and source data Hospital records and source data therein should be retained therein should be retained throughout the archiving period:throughout the archiving period:

Adhere sticker to inside of all Adhere sticker to inside of all medical records documenting: medical records documenting: – Study TitleStudy Title– Study ID no – R&D/ EudraCTStudy ID no – R&D/ EudraCT– Name of local CI or PIName of local CI or PI– Department name / contact numberDepartment name / contact number– Date to which notes should be retainedDate to which notes should be retained

Where:

Suitable for type of archived materialSuitable for type of archived material Building / room / fireproof safe / locked Building / room / fireproof safe / locked

cabinetcabinet Environmental conditions (avoid extreme Environmental conditions (avoid extreme

fluctuations in temp and humidity)fluctuations in temp and humidity) Risk of fire / floodRisk of fire / flood Pest controlPest control Secure – accessible only to delegated Secure – accessible only to delegated

staffstaff

Where:

UoA- sponsored / co-sponsored UoA- sponsored / co-sponsored CTIMPs – Health Sciences Building. CTIMPs – Health Sciences Building.

NHSG Sponsored CTIMPs – The Vault NHSG Sponsored CTIMPs – The Vault Box (Removal Services Scotland Ltd) Box (Removal Services Scotland Ltd)

Multicentre trials may have site files Multicentre trials may have site files and relevant records archived at and relevant records archived at host sites. Should be agreed by host sites. Should be agreed by sponsor / CI / host site at the sponsor / CI / host site at the beginning of the trialbeginning of the trial

How:

After the trial closeout visit:After the trial closeout visit:

CTIMPs sponsored / co-sponsored CTIMPs sponsored / co-sponsored by UoA – CI should contact by UoA – CI should contact Technical Resource Manager Technical Resource Manager (School of Medicine and Dentistry)(School of Medicine and Dentistry)

CTIMPs sponsored by NHSG – QA CTIMPs sponsored by NHSG – QA Manager will contact re Archiving Manager will contact re Archiving arrangementsarrangements

For How Long:

At least 5 years after the conclusion of the At least 5 years after the conclusion of the trial (or at least 2 years after the last trial (or at least 2 years after the last approval of a marketing application in the approval of a marketing application in the EU)EU)

Duration of Archiving - agreed by Sponsor / Duration of Archiving - agreed by Sponsor / CI at the beginning of the trialCI at the beginning of the trial

Approved by Ethics (require ethical approval Approved by Ethics (require ethical approval if these require to be kept for longer)if these require to be kept for longer)

Do not destroy early or take with you if you Do not destroy early or take with you if you leave – must be retained within the Sponsors leave – must be retained within the Sponsors localitylocality

Possible Questions:

What happens with the archiving at

other sites

What will be forwarded to the

TMF for archiving

What happens to the study material and

patient medical notes at the end

(archiving arrangements,

who, where, how long)

Preparation for MHRA InspectionPreparation for MHRA Inspection

PharmacovigilancePharmacovigilance

Medicines for Human Use (Clinical Trials) Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Regulations 2004 (SI1031) Part 5 Pharmacovigilance Part 5 Pharmacovigilance Notification of adverse events 32.Notification of adverse events 32.

(1) An investigator shall (1) An investigator shall reportreport any serious adverse event which occurs in a any serious adverse event which occurs in a subject at a trial site at which he is responsible for the conduct of a clinical subject at a trial site at which he is responsible for the conduct of a clinical trial immediately to the sponsor.trial immediately to the sponsor.

(2) An (2) An immediate immediate report under paragraph (1) may be made orally or in report under paragraph (1) may be made orally or in writing.writing.

(3) Following the immediate report of a serious adverse event, the (3) Following the immediate report of a serious adverse event, the investigator shall make a investigator shall make a detailed written report detailed written report of the event.of the event.

(4) Paragraphs (1) to (3) do not apply to serious adverse events (4) Paragraphs (1) to (3) do not apply to serious adverse events specifiedspecified in in the protocol or the investigators' brochure as not requiring immediate the protocol or the investigators' brochure as not requiring immediate reporting.reporting.

Medicines for Human Use (Clinical Trials) Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Regulations 2004 (SI1031) Part 5 Pharmacovigilance Part 5 Pharmacovigilance Notification of adverse events 32.Notification of adverse events 32.

Key components Key components of the regulations :of the regulations :

Notification of serious adverse events Notification of serious adverse events to to sponsorssponsors

Immediate reporting of SUSARsImmediate reporting of SUSARs

Annual reporting of serious adverse Annual reporting of serious adverse reactionreaction

Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Amendment 2006 (SI1928)

Condition which applies to all clinical trials:

Rights, safety, and well being of trial participants are the most important considerations and shall prevail over interests of science and society

SOP: Procedure for Reporting SOP: Procedure for Reporting Serious Adverse Events and Serious Adverse Events and Suspected Unexpected Serious Suspected Unexpected Serious Adverse Reactions (UoA-NHSG-Adverse Reactions (UoA-NHSG-SOP-014)SOP-014)

Not yet finalised “describes the correct procedure for reporting SAEs to the sponsor and expediting reports to ethics and the MHRA when required.”

CI pharmacovigilance CI pharmacovigilance responsibilitiesresponsibilities

Timely collection of datarecording and notification to sponsor

Appropriate assessments undertaken

data completenessseriousness relatednessexpectedness

Expedited and periodic reportingREC, MHRA, Sponsor (& others as

appropriate).

Requirements for Requirements for PharmacovigilancePharmacovigilance

All protocols must have a PV section.

Risk to participants is dependent on the clinical trial.

Responsibilities and systems to deal with recording, assessment and reporting must be clearly stated.

Time frames for notification, assessment and reporting are critical.

SOPs are required.

Requirements for Requirements for PharmacovigilancePharmacovigilance

CI’s need to understand their responsibilities with respect to adverse event recording and notification

−Reports SAEs to the sponsor immediately (in practice 24 – 48 hours). −Report SUSARs to the MHRA within 7 days if fatal/life threatening otherwise within 15 days.−Urgent safety measures implemented, notify MHRA within 3 days.

Assessment of adverse events:−Seriousness−Relatedness/causality−Expectedness

Current Procedure for Current Procedure for Pharmacovigilance Pharmacovigilance

CI/delegate to report serious adverse event to the Research Governance Manager (RGM)

(email: g.holland@abdn.ac.uk)−Initial report may be by telephone (Ext: 55076)−Detailed written report by email within 24 hours

CI/delegate to report SAEs/SUSARs to REC and MHRA (as required).

CI to forward copy of eSUSAR report to RGM.

Current Procedure for Current Procedure for Pharmacovigilance Pharmacovigilance

RGM to provide guidance/support for SUSAR reporting on MHRA electronic reporting site.

Website for SUSAR reporting:https://esusar.mhra.gov.uk/?

CI/delegate will require registration to the eSUSAR website. RGM will facilitate.

(How) Does the protocol

permit for any non-escalated

SAES?

What is the process for reporting

SAEs?

Who assesses SUSARs?

Would CI report to MHRA if a

SUSAR?

Where do you send the

annual safety report?

What is the process for reporting SUSARs?

Possible questionsPossible questions

Preparation for MHRA InspectionPreparation for MHRA Inspection

Serious BreachesSerious Breaches

Medicines for Human Use (Clinical Trials) Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Regulations 2004 (SI1031) Amendment 2006 (SI1928) Amendment 2006 (SI1928) Notification of serious breaches 29A Notification of serious breaches 29A

(1) The sponsor of a clinical trial shall notify the licensing authority in writing (1) The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of -of any serious breach of -

(a) the conditions and principles of GCP in connection (a) the conditions and principles of GCP in connection with that trial; orwith that trial; or

(b) the protocol relating to that trial, as amended from (b) the protocol relating to that trial, as amended from time to time in time to time in accordance with regulations 22 to 25, accordance with regulations 22 to 25, within 7 days of becoming aware of that within 7 days of becoming aware of that breach.breach.

(2) For the purposes of this regulation, a “serious breach” is a breach which (2) For the purposes of this regulation, a “serious breach” is a breach which is is likely to effect to a significant degreelikely to effect to a significant degree – –

(a) the safety or physical or mental integrity of the (a) the safety or physical or mental integrity of the subjects subjects of the of the trial; ortrial; or

(b) the scientific value of the trial”.(b) the scientific value of the trial”.

Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Amendment 2006 (SI1928)

Condition which applies to all clinical trials:

Rights, safety, and well being of trial participants are the most important considerations and shall prevail over interests of science and society

SOP: Procedure for Reporting Serious Breaches of the protocol or GCP (UoA-NHSG-SOP-015)

Not yet finalised “describes the correct procedure for reporting serious breaches to the sponsor, ethics and to the MHRA.”

Examples of serious breachesExamples of serious breaches

Principal Investigator unable to provide training log.

It started with a simple case of peer review

Study protocol not peer-reviewed.

Examples of serious breachesExamples of serious breaches

No trial specific SOPs.

Investigator unaware of the Declaration of Helsinki.

Examples of serious breachesExamples of serious breaches

Protocol does not contain a section on the exclusion criteria for study participants.

Failure to report an SAE to study sponsor.

Examples of serious breachesExamples of serious breaches

CRFs contain patient identifiers.

After trial commences new data concerning IMP safety not taken into account.

Examples of serious breachesExamples of serious breaches

No statement of patient eligibility signed by medically qualified individual

No CTA in place before study start.

Examples of serious breachesExamples of serious breaches

Patient identifiable data on laptop stolen from investigator’s car.

Inadequate insurance cover in place.

Current Procedure for Serious Current Procedure for Serious Breaches Breaches

CI/delegate to report serious breaches to the Research Governance Manager (RGM)

(email: g.holland@abdn.ac.uk)−If unsure a breach has occurred contact the RGM for advise within 24 hours of event.−Initial report may be by telephone (Ext: 55076)−Detailed written report by email within 7 days

CI/delegate to report serious breaches to REC and MHRA within 7 days

CI to forward copy of report & email to MHRA to RGM.

Current Procedure for Reporting Current Procedure for Reporting Serious Breaches to the MHRA.Serious Breaches to the MHRA.

RGM to provide guidance/support for serious breach reporting to REC and MHRA.

MHRA notification of serious breach form available at:

http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodClinicalPractice/News/CON084915

Notification form to be sent to:GCP.SeriousBreaches@mhra.gsi.gov.uk

Current Procedure for Reporting Current Procedure for Reporting Serious Breaches to the REC.Serious Breaches to the REC.

RGM to provide guidance/support for serious breach reporting to REC and MHRA.

No specific REC notification of serious breach form.

RECs will accept the MHRA notification of serious breach form.

Forward letter/email to REC to the RGM.

Have there been any deviations

from the protocol?

Have there been any

breaches of GCP?

What do you class as a

deviation?

Have there been any persistent

deviations of GCP or the protocol?

Possible questionsPossible questions

Preparation for MHRA Inspection

Informed Consent

Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031)

For the purposes of this Schedule, a person gives informed consent to take part, or that a subject is to take part, in a clinical trial only if his decision—

(a) is given freely after that person is informed of the nature, significance, implications and risks of the trial; and

(b) either — (i) is evidenced in writing, dated and signed, or otherwise

marked, by that person so as to indicate his consent; or (ii) if the person is unable to sign or to mark a document so

as to indiacte his consent, is given orally in the presence of a at least one witness and recorded in writing.

SOP: Obtaining Informed Obtaining Informed Consent from Competent Consent from Competent Adults for Research StudiesAdults for Research Studies (UoA-NHSG-SOP-010)

“describes the correct procedure for obtaining written informed consent for clinical research studies”

SOP: Responsibilities of PI

Ethical approval for : consent form

PISadverts

Remember all changes need ethical approval!

Delegation log Training of staff in informed consent No tests, procedures, data collection

before consent

Version 3, 25 June 20102010-012345-67

SOP: Procedure - providing information

RCT: Pink or Blue Pill for Chocolate Addiction?

                                                     

'Thanks for telling me your entire medical history but I'm the hospital

barber.'

Who can obtain informed consent?

Investigators/Co-investigators & staff named on delegation log

the participant’s identity and eligibility

(there is no new or undisclosed information that would exclude them from the study)

the participant’s understanding of the study is adequate and they are happy to continue with entering the study

the participant knows that they can withdraw at any time without giving a reason

the participant has had sufficient time to consider taking part in the study

Checks prior to obtaining signature

Consent Form

Must beMust be signedsigned and and personally datedpersonally dated by by participant and the person taking consentparticipant and the person taking consent

Must be obtained Must be obtained prior toprior to initiation of any initiation of any screening procedures and before any screening procedures and before any changes are made to patient’s medicationchanges are made to patient’s medication

FilingFiling

Original -> investigator study fileOriginal -> investigator study file

Copy -> to participant/legal representativeCopy -> to participant/legal representative

(Copy -> patient’s notes along with PIS)(Copy -> patient’s notes along with PIS)

Version noEudract no

Unit & dept conducting the trial

Headed Paper

Signed & personally dated by participant

Participant must initial not tick boxes

Person taking consent must sign also

Vulnerable Participants

1. Difficulty reading/writing1. Difficulty reading/writing- Impartial witness- Impartial witness

- Read PIS to participant- Read PIS to participant

- signature of witness- signature of witness

2. Minor – child under 162. Minor – child under 16- consent of parent required- consent of parent required

3. Adult – unable to give informed 3. Adult – unable to give informed consent due to physical or mental consent due to physical or mental incapacity incapacity

- Adults with Incapacity (Scotland) Act 2000- Adults with Incapacity (Scotland) Act 2000

- consent by a legal representative- consent by a legal representative

Common MHRA findings

– No record of study visit in medical notesNo record of study visit in medical notes– No records of consent being taken – No records of consent being taken –

medical notes or ISF medical notes or ISF – Poor version controlPoor version control– Inconsistencies with protocolInconsistencies with protocol– Missing elements e.g. signatureMissing elements e.g. signature– Unclear processUnclear process

They will check source data from medical notes!They will check source data from medical notes!

Talk me though the

consent procedure

How have other clinicians

been told about the trial?

Who tells participants about the

trial

How do you approach patients?

Where do you store PIS &

Consent form

Can all participants consent on their own?

Possible questions

Preparation for MHRA InspectionPreparation for MHRA Inspection

Communication Communication

Inspectors will look for evidence that Inspectors will look for evidence that a study team a study team communicates well well

Communication

Site

File

Index

“if it isn’t written down, it didn’t happen”

Communication – with who?

Research teamResearch team Clinical team (e.g. ward Clinical team (e.g. ward

nurses/doctors)nurses/doctors) PharmacyPharmacy Labs – internal & externalLabs – internal & external SponsorSponsor Ethics/R&DEthics/R&D

Internally: Research teamInternally: Research team

Regular meetings – dates, agenda, Regular meetings – dates, agenda, minutes minutes

Email updatesEmail updates Written correspondenceWritten correspondence

All must be filed appropriately in the All must be filed appropriately in the TMF/ISFTMF/ISF

Communication – how?

Externally: Clinical team

Ward staff: presentations/posters New staff/rotational staff – documented

procedure of how the are informed of study

External clinicians – e.g. labels on notes

Keep a record of everything & file in TMF/ISF

Communication – how?

Externally: pharmacy, sponsor, ethics, R&D, MHRA etc

Email updatesEmail updates Written correspondenceWritten correspondence Amendments – inform correct people

Keep a record of everything & file in TMF/ISF

Communication – how?

How do clinicians know this patient is

part of a study?

How is communication

maintained?

What do you cover in these

meetings – are they minuted?

Do you have regular team

meetings?

How do staff on call (not part of

core team) know what to do?

How have other clinicians

been told about the trial?

Possible questions

Summary

■ Review your trial documentation and training files for staff.

■ Have evidence of training (GCP certificate, CV)■ Ensure you can explain your role in the trial■ Review the typical questions and answers

provided■ Familiarise yourself with new SOPs ■ Be confident of your trial and processes.

Remember that you know your trial better than anyone else!

Main Contacts: Main Contacts:

Prof Phil Hannaford – Prof Phil Hannaford – p.hannaford@abdn.ac.uk Prof Alison MacLeod – Prof Alison MacLeod – mmd175@abdn.ac.uk Dr Gail Holland – Dr Gail Holland – g.holland@abdn.ac.uk

Tel: 01224 - 555076Tel: 01224 - 555076 Lynda Sime – Lynda Sime – lynda.sime@nhs.net

Tel: 01224 -554656Tel: 01224 -554656

www.abdn.ac.uk/medical/mhra