MHRA inspect

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MHRA GCP Inspection
21st – 24th June 2011
Medicines and Healthcare products Regulatory Agency
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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
What do the MHRA inspect?
Specific examples of CTIMPs that demonstrate
those systems
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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!
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Aims of this session
Brief researchers on what the inspectors will be
looking at in your CTIMP study
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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
Inspection
Regulations, Qualifications & Training
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.”
Legislation:
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2001
2004
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2005
2006
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2006
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2008
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2009
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EU Clinical Trial Directive: Directive 2001/20/EC
Medicines for Human Use (Clinical Trials)
Regulations 2004 (SI: 1031)
EU Directive on Good Clinical Practice 2005/28/EC
The Medicines for Human Use (Clinical Trials)
Amendment Regulations 2006 (SI:1928)
The Medicines for Human Use (Clinical Trials)
Amendment (No.2) Regulations 2006
The Medicines for Human Use (Clinical Trials) and
Blood Safety and Quality (Amendment)
Regulations 2008
MHRA GCP guideline - Laboratories
Medicines for Human Use (Clinical
Trials) Regulations 2004 (SI:1031)
“Each individual involved in conducting a
trial shall be qualified by education,
training, and experience to perform his
or her respective task(s)”
Qualifications and Training:
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Delegation Log
Training Record
Delegation of Duties:
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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
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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:
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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:
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Trial Master Files
Investigator Site Files
Medicines for Human Use (Clinical Trials)
Regulations 2004 (SI:1031)
“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”
Study Files and Documentation:
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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)
SOPs:
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Establishing and Maintaining a TMF: UoANHSG-SOP-008
– UoA-NHSG-TMP-003 – TMF Checklist
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Establishing and Maintaining an ISF: UoANHSG-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
TMF / ISF
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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
Possible Questions:
Who is managing
your TMF / ISF
Do you keep
electronic versions of
documents
Who has access
to your files
How do you
ensure the
security of your
records
Archiving:
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What
Where
How
For how long
SOP: Archiving Clinical Research
Data: UoA-NHSG-SOP-021
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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
What:
Essential Documents / Source Documents:
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TMF / ISF
Data
Hospital Records
Clinical and office charts
Lab notes
Memoranda
Subjects diaries
Case Report Forms
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Evaluation checklists
Recorded data from
automated instruments
Copies of transcriptions
Records kept at
pharmacy / Labs
X-Rays / reports
Photographs /
microfilm
Other – if appropriate
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 – R&D/ EudraCT
– Name of local CI or PI
– Department name / contact number
– Date to which notes should be retained
Where:
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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
Where:
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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
How:
After the trial closeout visit:
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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
For How Long:
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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
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 Inspection
Pharmacovigilance
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.
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
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Immediate reporting of SUSARs
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Annual reporting of serious adverse
reaction
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
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.”
CI pharmacovigilance responsibilities
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Timely collection of data
recording and notification to sponsor
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Appropriate assessments undertaken
data completeness
seriousness
relatedness
expectedness
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Expedited and periodic reporting
REC, MHRA, Sponsor (& others as appropriate).
Requirements for Pharmacovigilance
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All protocols must have a PV section.
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Risk to participants is dependent on the clinical trial.
Responsibilities and systems to deal with recording,
assessment and reporting must be clearly stated.
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Time frames for notification, assessment and
reporting are critical.
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SOPs are required.
Requirements for Pharmacovigilance
CI’s need to understand their responsibilities with
respect to adverse event recording and notification
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−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.
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Assessment of adverse events:
−Seriousness
−Relatedness/causality
−Expectedness
Current Procedure for Pharmacovigilance
CI/delegate to report serious adverse event to the
Research Governance Manager (RGM)
(email: [email protected])
−Initial report may be by telephone (Ext: 55076)
−Detailed written report by email within 24 hours
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CI/delegate to report SAEs/SUSARs to REC and MHRA
(as required).
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CI to forward copy of eSUSAR report to RGM.
Current Procedure for Pharmacovigilance
RGM to provide guidance/support for SUSAR
reporting on MHRA electronic reporting site.
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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
Would CI report to
MHRA if a SUSAR?
Who assesses
SUSARs?
(How) Does the
protocol permit
for any nonescalated SAES?
What is the
process for
reporting SAEs?
Where do you
send the annual
safety report?
What is the
process for
reporting SUSARs?
Preparation for MHRA Inspection
Serious Breaches
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”.
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 breaches
Principal Investigator
unable to provide
training log.
Study protocol not
peer-reviewed.
It started with a simple
case of peer review
Examples of serious breaches
No trial specific SOPs.
Investigator unaware
of the Declaration
of Helsinki.
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.
Examples of serious breaches
CRFs contain patient
identifiers.
After trial commences new data
concerning IMP safety not
taken into account.
Examples of serious breaches
No statement of patient
eligibility signed by
medically qualified individual
No CTA in place before
study start.
Examples of serious breaches
Patient identifiable data on laptop
stolen from investigator’s car.
Inadequate insurance cover in
place.
Current Procedure for Serious Breaches
CI/delegate to report serious breaches to the
Research Governance Manager (RGM)
(email: [email protected])
−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
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CI/delegate to report serious breaches to REC and
MHRA within 7 days
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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.
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MHRA notification of serious breach form available at:
http://www.mhra.gov.uk/Howweregulate/Medicines/I
nspectionandstandards/GoodClinicalPractice/News/CO
N084915
Notification form to be sent to:
[email protected]
Current Procedure for Reporting Serious
Breaches to the REC.
RGM to provide guidance/support for serious breach
reporting to REC and MHRA.
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No specific REC notification of serious breach form.
RECs will accept the MHRA notification of serious
breach form.
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Forward letter/email to REC to the RGM.
Possible questions
What do you
class as a
deviation?
Have there
been any
breaches of
GCP?
Have there been
any deviations from
the protocol?
Have there been
any persistent
deviations of GCP
or the protocol?
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 —
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(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 Consent
from Competent Adults for
Research Studies (UoA-NHSG-SOP-010)
“describes the correct procedure for
obtaining written informed consent
for clinical research studies”
SOP: Responsibilities of PI
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Ethical approval for :
consent form
PIS
adverts
Remember all changes need ethical approval!
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Delegation log
Training of staff in informed consent
No tests, procedures, data collection
before consent
SOP: Procedure - providing information
RCT: Pink or Blue
Pill for Chocolate
Addiction?
2010-012345-67
Version 3, 25 June 2010
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
Checks prior to obtaining signature
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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
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the participant knows that they can withdraw at
any time without giving a reason
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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 patient’s medication
Filing
Original -> investigator study file
Copy -> to participant/legal representative
(Copy -> patient’s notes along with PIS)
Headed Paper
Unit & dept
conducting the
trial
Participant
must initial not
tick boxes
Signed & personally
dated by participant
Eudract no
Person taking
consent must
sign also
Version no
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
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
Possible questions
How do you
approach
patients?
Who tells
participants
about the trial
Talk me though
the consent
procedure
How have other
clinicians been
told about the
trial?
Where do you
store PIS &
Consent form
Can all
participants
consent on their
own?
Preparation for MHRA Inspection
Communication
Communication
Inspectors will look for evidence that a
study team communicates well
“if it isn’t written
down, it didn’t
happen”
Communication – with who?
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Research team
Clinical team (e.g. ward nurses/doctors)
Pharmacy
Labs – internal & external
Sponsor
Ethics/R&D
Communication – how?
Internally: Research team
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Regular meetings – dates, agenda, minutes
Email updates
Written correspondence
All must be filed appropriately in the TMF/ISF
Communication – how?
Externally: Clinical team
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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
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Email updates
Written correspondence
Amendments – inform correct people
Keep a record of everything & file in TMF/ISF
Possible questions
Do you have
regular team
meetings?
What do you
cover in these
meetings – are
they minuted?
How do clinicians
know this patient
is part of a study?
How is
communication
maintained?
How do staff on
call (not part of
core team) know
what to do?
How have other
clinicians been
told about the
trial?
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.
Main Contacts:
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Prof Phil Hannaford –
[email protected]
Prof Alison MacLeod –
[email protected]
Dr Gail Holland – [email protected]
Tel: 01224 - 555076
Lynda Sime – [email protected]
Tel: 01224 -554656
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