MHRA GCP Inspection 21st

1
MHRA GCP Inspection 21st 24th June
2011
Medicines and Healthcare products Regulatory
Agency
2
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

3
What do the MHRA inspect?

• 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!

4
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 SOPs
• Prepare researchers for interviews with
  inspectors

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Preparation for MHRA Inspection Regulations,
Qualifications Training
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Legislation

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

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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 (SI1928)
• 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 MHRA GCP guideline - Laboratories

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

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

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Qualifications and Training

• Delegation Log
• Training Record

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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

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MHRA Inspection

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

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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

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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

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Possible Questions
Tell me about your qualifications
What is your clinical experience / experience on
clinical trials
What type of GCP training have you had / who was
the provider
How do you assess that your team are competent to
complete their delegated tasks Is this
documented
Have you done any other research training
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Study Files and Documentation

• Trial Master Files
• Investigator Site Files

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

• All Clinical Trial information should be
  recorded, handled and stored in a way that allows
  its accurate reporting, interpretation and
  verification
• The confidentiality of records that could
  identity subjects shall be protected, respecting
  the privacy and confidentiality rules in
  accordance with the requirements of the Data
  Protection Act 1998 and the law relating to
  confidentiality

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Study Files and Documentation

• Chief/Principal Investigators are required to
  keep, and maintain, a CORE set of documents for
  EACH research project they manage
• Should be kept in a designated file called a
  Investigator Site File (ISF) and/or Trial Master
  File (TMF)

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SOPs

• Establishing and Maintaining a TMF
  UoA-NHSG-SOP-008
• UoA-NHSG-TMP-003 TMF Checklist
• Establishing and Maintaining an ISF
  UoA-NHSG-SOP-009
• UoA-NHSG-TMP-002 ISF Checklist
• (If single centre both can be combined to save
  duplication)
• Applies to all staff conducting or supporting
  CTIMPs sponsored or co sponsored by UoA / NHSG

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TMF / ISF

• Maintaining TMF / ISF is the responsibility of
  the CI/PI can be delegated to research team
• Use file index / checklist. Alternative version
  can be used, but must retain all the listed
  documentation as minimum standard
• If documents stored elsewhere add in file note
• Updates / amendments added to TMF / ISF and
  reviewed by sponsor.
• Stored in a secure environment but remain
  accessible to trial staff

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Possible Questions
Who has access to your files
Who is managing your TMF / ISF
Do you keep electronic versions of documents
How do you ensure the security of your records
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Archiving

• What
• Where
• How
• For how long

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

• Not yet finalised
• Applies to all staff conducting or supporting
  CTIMPs sponsored or co sponsored by UoA / NHSG
• Responsibility of the sponsor and CI to ensure
  essential documents are retained for an
  appropriate period of time - and made available
  for monitoring and audit

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What
Essential Documents / Source Documents

• TMF / ISF
• Data
• Hospital Records
• Clinical and office charts
• Lab notes
• Memoranda
• Subjects diaries
• Case Report Forms

• Evaluation checklists
• Recorded data from automated instruments
• Copies of transcriptions
• Records kept at pharmacy / Labs
• X-Rays / reports
• Photographs / microfilm
• Other if appropriate

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Hospital Records

• Hospital records and source data therein should
  be retained throughout the archiving period
• Adhere sticker to inside of all medical records
  documenting
• Study Title
• Study ID no RD/ EudraCT
• Name of local CI or PI
• Department name / contact number
• Date to which notes should be retained

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Where

• Suitable for type of archived material
• Building / room / fireproof safe / locked cabinet
• Environmental conditions (avoid extreme
  fluctuations in temp and humidity)
• Risk of fire / flood
• Pest control
• Secure accessible only to delegated staff

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Where

• UoA- sponsored / co-sponsored CTIMPs Health
  Sciences Building.
• NHSG Sponsored CTIMPs The Vault Box (Removal
  Services Scotland Ltd)
• Multicentre trials may have site files and
  relevant records archived at host sites. Should
  be agreed by sponsor / CI / host site at the
  beginning of the trial

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How

• After the trial closeout visit
• CTIMPs sponsored / co-sponsored by UoA CI
  should contact Technical Resource Manager (School
  of Medicine and Dentistry)
• CTIMPs sponsored by NHSG QA Manager will
  contact re Archiving arrangements

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For How Long

• At least 5 years after the conclusion of the
  trial (or at least 2 years after the last
  approval of a marketing application in the EU)
• Duration of Archiving - agreed by Sponsor / CI at
  the beginning of the trial
• Approved by Ethics (require ethical approval if
  these require to be kept for longer)
• Do not destroy early or take with you if you
  leave must be retained within the Sponsors
  locality

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Possible Questions
What happens with the archiving at other sites
What happens to the study material and patient
medical notes at the end (archiving arrangements,
who, where, how long)
What will be forwarded to the TMF for archiving
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Preparation for MHRA Inspection
Pharmacovigilance
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Medicines for Human Use (Clinical Trials)
Regulations 2004 (SI1031) Part 5
Pharmacovigilance Notification of adverse events
32.

• (1) An investigator shall report any serious
  adverse event which occurs in a subject at a
  trial site at which he is responsible for the
  conduct of a clinical trial immediately to the
  sponsor.
• (2) An immediate report under paragraph (1) may
  be made orally or in writing.
• (3) Following the immediate report of a serious
  adverse event, the investigator shall make a
  detailed written report of the event.
• (4) Paragraphs (1) to (3) do not apply to
  serious adverse events specified in the protocol
  or the investigators' brochure as not requiring
  immediate reporting.

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

• Key components of the regulations
• Notification of serious adverse events to
  sponsors
• Immediate reporting of SUSARs
• Annual reporting of serious adverse reaction

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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
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SOP Procedure for Reporting Serious Adverse
Events and Suspected Unexpected Serious Adverse
Reactions (UoA-NHSG-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.

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CI pharmacovigilance responsibilities

• Timely collection of data
• recording and notification to sponsor
• Appropriate assessments undertaken
• data completeness
• seriousness
• relatedness
• expectedness
• Expedited and periodic reporting
• REC, MHRA, Sponsor ( others as appropriate).

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Requirements for Pharmacovigilance

• 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.

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Requirements for Pharmacovigilance

• CIs 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

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Current Procedure for Pharmacovigilance

• CI/delegate to report serious adverse event to
  the Research Governance Manager (RGM)
• (email g.holland_at_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.

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Current Procedure for 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.

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Possible questions
What is the process for reporting SAEs?
Would CI report to MHRA if a SUSAR?
Who assesses SUSARs?
Where do you send the annual safety report?
(How) Does the protocol permit for any
non-escalated SAES?
What is the process for reporting SUSARs?
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Preparation for MHRA Inspection Serious
Breaches
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Medicines for Human Use (Clinical Trials)
Regulations 2004 (SI1031) Amendment 2006
(SI1928) Notification of serious breaches 29A

• (1) The sponsor of a clinical trial shall notify
  the licensing authority in writing of any serious
  breach of -
• (a) the conditions and principles of GCP in
  connection with that trial or
• (b) the protocol relating to that trial, as
  amended from time to time in accordance with
  regulations 22 to 25, within 7 days of becoming
  aware of that breach.
• (2) For the purposes of this regulation, a
  serious breach is a breach which is likely to
  effect to a significant degree
• (a) the safety or physical or mental integrity
  of the subjects of the trial or
• (b) the scientific value of the trial.

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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
44
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.
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Examples of serious breaches
Principal Investigator unable to provide
training log.
Study protocol not peer-reviewed.
It started with a simple case of peer review
46
Examples of serious breaches
No trial specific SOPs.
Investigator unaware of the Declaration of
Helsinki.
47
Examples of serious breaches
Protocol does not contain a section on the
exclusion criteria for study participants.
Failure to report an SAE to study sponsor.
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Examples of serious breaches
CRFs contain patient identifiers.
After trial commences new data concerning IMP
safety not taken into account.
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Examples of serious breaches
No statement of patient eligibility signed by
medically qualified individual
No CTA in place before study start.
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Examples of serious breaches
Patient identifiable data on laptop stolen from
investigators car.
Inadequate insurance cover in place.
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Current Procedure for Serious Breaches

• CI/delegate to report serious breaches to the
  Research Governance Manager (RGM)
• (email g.holland_at_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.

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Current Procedure for Reporting 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/Ins
  pectionandstandards/GoodClinicalPractice/News/CON0
  84915
• Notification form to be sent to
• GCP.SeriousBreaches_at_mhra.gsi.gov.uk

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Current Procedure for Reporting 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.

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Possible questions
Have there been any deviations from the protocol?
What do you class as a deviation?
Have there been any breaches of GCP?
Have there been any persistent deviations of GCP
or the protocol?
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Preparation for MHRA Inspection Informed
Consent
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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.

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

describes the correct procedure for obtaining
written informed consent for clinical research
studies
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SOP Responsibilities of PI

• Ethical approval for consent form
• PIS
• adverts
• Remember all changes need ethical approval!
• Delegation log
• Training of staff in informed consent
• No tests, procedures, data collection before
  consent

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SOP Procedure - providing information
RCT Pink or Blue Pill for Chocolate Addiction?

Version 3, 25 June 2010
2010-012345-67
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Who can obtain informed consent?
'Thanks for telling me your entire medical
history but I'm the hospital barber.'
Investigators/Co-investigators staff named on
delegation log
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Checks prior to obtaining signature

• the participants identity and eligibility
• (there is no new or undisclosed information that
  would exclude them from the study)
• the participants 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

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Consent Form

• Must be signed and personally dated by
  participant and the person taking consent
• Must be obtained prior to initiation of any
  screening procedures and before any changes are
  made to patients medication

• Filing
• Original -gt investigator study file
• Copy -gt to participant/legal representative
• (Copy -gt patients notes along with PIS)

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Unit dept conducting the trial
Headed Paper
Participant must initial not tick boxes
Signed personally dated by participant
Person taking consent must sign also
Version no
Eudract no
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Vulnerable Participants

• 1. Difficulty reading/writing
• - Impartial witness
• - Read PIS to participant
• - signature of witness
• 2. Minor child under 16
• - consent of parent required
• 3. Adult unable to give informed consent due to
  physical or mental incapacity
• - Adults with Incapacity (Scotland) Act 2000
• - consent by a legal representative

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Common MHRA findings
They will check source data from medical notes!

• No record of study visit in medical notes
• No records of consent being taken medical notes
  or ISF
• Poor version control
• Inconsistencies with protocol
• Missing elements e.g. signature
• Unclear process

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Possible questions
How have other clinicians been told about the
trial?
How do you approach patients?
Who tells participants about the trial
Where do you store PIS Consent form
Talk me though the consent procedure
Can all participants consent on their own?
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Preparation for MHRA Inspection Communication
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Communication

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

if it isnt written down, it didnt happen
Site File Index
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Communication with who?

• Research team
• Clinical team (e.g. ward nurses/doctors)
• Pharmacy
• Labs internal external
• Sponsor
• Ethics/RD

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Communication how?

• Internally Research team
• Regular meetings dates, agenda, minutes
• Email updates
• Written correspondence
• All must be filed appropriately in the TMF/ISF

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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

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Communication how?

• Externally pharmacy, sponsor, ethics, RD, MHRA
  etc
• Email updates
• Written correspondence
• Amendments inform correct people
• Keep a record of everything file in TMF/ISF

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Possible questions
How is communication maintained?
Do you have regular team meetings?
What do you cover in these meetings are they
minuted?
How do staff on call (not part of core team) know
what to do?
How do clinicians know this patient is part of a
study?
How have other clinicians been told about the
trial?
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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!

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• Main Contacts
• Prof Phil Hannaford p.hannaford_at_abdn.ac.uk
• Prof Alison MacLeod mmd175_at_abdn.ac.uk
• Dr Gail Holland g.holland_at_abdn.ac.uk
• Tel 01224 - 555076
• Lynda Sime lynda.sime_at_nhs.net
• Tel [phone]
• www.abdn.ac.uk/medical/mhra