Transcript IMP management at site

IMP management at site
Kathryn Bethune
Clinical Trials Pharmacist
University Hospital of Wales
May 2011
Introduction
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Clinical Trials of Investigational Medicinal Products
MHRA risk based approach to management of CTIMP
Role of pharmacy in clinical trials
Support available during planning of non-commercial
trials
Pharmacy Approval of Trials
Role of pharmacy when trial approved
Storage of IMP outside of pharmacy
Is It A Clinical Trial of an
Investigational Medicinal Product?
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Is it a medicinal product?
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Is it a substance presented as having properties for treating
or preventing disease?
Does the substance function as a medicine?
Is it an active substance in a pharmaceutical form?
What effects of the medicine are you looking for?
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To discover or verify/compare its clinical effects?
To discover ore verify/compare its pharmacological effects?
To identify or verify/compare its adverse reactions?
To study or verify/compare its absorption, distribution,
metabolism or excretion?
Is It A Clinical Trial of an
Investigational Medicinal Product?
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Why are you looking for those effects?
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To ascertain or verify/compare the efficacy of the
medicine?
To ascertain or verify/compare the safety of the
medicine?
How are you looking for those effects?
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Is the medicine licensed for the indication you are
studying?
Does the assignment of treatment to patients involved
in the study fall within current practice?
Is the decision to prescribe a medicinal product clearly
separated from decision to include the patient in the
study?
Are you doing any additional tests?
Which of these is a CTIMP?
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‘Determination of method-specific normal cortisol and adrenal
hormone responses to the short synacthen test’
• Short synacthen test performed on healthy volunteers
• Aims to derive method dependent cut-offs for serum saliva
cortisol response and compare serum cortisol methods
‘Traumatic recall and regional cerebral blow flow in acute post
traumatic stress disorder sufferers after acute glucocorticoid
administration: an fMRI investigation’
• Hydrocortisone or placebo given to recently traumatized
participants with or without PTSD
• fMRI performed to see if hydrocortisone affects regional
cerebral blood flow during traumatic recall
‘Does aggressive management with early high dose aspirin reduce
the hypercoagulability of platelets following coronary artery
bypass grafting’
• Patients received either aspirin 300mg starting 4 hrs post
CABG or 150mg aspirin daily
• Both regimens commonly used at UHW
• Evaluate effect on platelet function of early high dose aspirin
New MHRA risk based approach to
management of CTIMP trials (1)
New trials risk assessed identify potential hazards
associated with trial
• Type A: risk no higher than standard medical care
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Type B: Somewhat higher risk than standard medical
care
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IMP licensed in EU and either used in licensed indication
and dose or established off-label use
IMP licensed in EU but used for new indication product
or being used in different dose to normal
Type C: markedly higher to standard medical care
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Medicinal product not licensed in any EU member state
New MHRA risk based approach to
management of CTIMP trials (2)
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Reduced MHRA role for approvals
• Type A trials notified to MHRA in normal way
• Trial may start within 14 days of MHRA
acknowledgement (if no objections)
Content of application
• SmPC can replace IMP dossier and IB for all Type A trials
and Type B trials where IMP used in licensed form
• Manufactures authorisation (including QP release) not
required for all type A trials and type B trials where IMP
used in licensed form and not modified
Labelling
• Reduced labelling can be used for type A trials where
IMP used within terms of license and not repackaged
Role of Pharmacy in Clinical Trials
To safeguard subjects, healthcare professionals and
the Trust by ensuring IMP are appropriate for use and
are procured, handled, stored and used safely and
correctly
• To ensure that IMP are managed and dispensed to
patients in accordance with the protocol
• To ensure that all pharmacy clinical trial procedures
comply with relevant guidelines and regulations
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Practice Guidance on Pharmacy Services for Clinical Trials – June 2005 RPSGB and ICR
What support is available
to C&V and CU
researchers from
pharmacy while planning
trials?
Availability of IMP
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Is there a licensed formulation available?
Does the IMP need aseptic manipulation?
• Can this be performed within the Sterile
Production Service (SPS)
If a licensed formulation is not available or
blinding required can St Mary’s
Pharmaceutical Unit (SMPU) prepare a
suitable preparation?
Remember if unable to source an appropriate
formulation of IMP you don’t have a trial –
ask pharmacy for help early
Protocol Preparation
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Selection of IMP dose
• Appropriate dosage adjustments for renal
and liver dysfunction
Drug related exclusion criteria
• Contra-indications
• Drug interactions
Drug related expected adverse events
Preparation of patient information sheet
• IMP information including possible side
effects
Registration of new trials involving
IMP with pharmacy
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A completed pharmacy R&D application form
should be submitted to clinical trial
pharmacist for all trials involving IMP when
trial registered with R&D
UHW – Kathryn Bethune and Sian Widdows
Llandough – Bel Adamson
Pharmacy peer review of trials
involving IMP
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All trials involving IMP are reviewed within
pharmacy
Review conducted by directorate and clinical
trials pharmacists
If pharmacy has been involved in development
of protocol review will be relatively quick
Pharmacy review of trial protocol (1)
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Is the dose appropriate for all trial
participants (e.g. renal/hepatic impairment)?
Have all IMP related contra-indications and
drug interactions been included in exclusion
criteria?
Have all expected side effects been listed in
protocol and patient information sheet?
Pharmacy review of the protocol
(2)
Does the IMP pose a risk to pharmacy
and UHB staff?
• Is it practical to carry out the trial in
the available facilities?
• If unable to meet trial requirements
within pharmacy can IMP be dispensed
from alternative site?
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Pharmacy review of the protocol
(3)
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Arrangements for 24 hr emergency
unblinding
Has the IMP been manufactured or
imported under the terms of a
manufacturing authorisation?
Has the IMP been labelled in
accordance with Annex 13 (GMP)?
Statutory Instrument 2004:1031
Regulation 13
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Supply of investigational products for the purposes of
clinical trials
(1) Subject to paragraphs (3) and (4), no person shall, in
the course of a business carried on by him, sell or supply
any IMP to:
• a) an investigator
• b) a health care professional who is a member of
an investigators team
• c) a person who provides or is to provide health
care under the direction or control of a person
referred to in sub-paragraphs (a) or (b), or
• d) a subject
For the purpose of administrating that product in a clinical
trial, unless the conditions specified in paragraph (2) are
satisfied
Statutory Instrument 2004:1031
Regulation 13
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(2) The conditions referred to in paragraph (1) are:
• a) the licensing authority has authorised the
clinical trial for the purposes of which the product
is sold or supplied
• b) in the case of an IMP manufactured or assembled in
an EEA State, other than in accordance with the terms of
a marketing authorization relating to that product, or
imported into an EEA state• (i) the product has been manufactured, assembled
or imported in accordance with the terms of:
• (aa) a manufacturing authorisation, or
• (bb) an authorisation referred to in Article 13 of
the Directive granted by a competent authority of
an EEA state other then the United Kingdom, and
• (ii) the production batch of IMP of which the product
is a part has been checked and certified by a
qualified person pursuant to Article 13(3) and (4)
of the Directive
Statutory Instrument 2004:1031
Regulation 46
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Labelling of IMP
(1) An IMP shall be labelled in accordance with Art 15
of commission directive 2003/94/EC
(2) Paragraph (1) shall not apply where the IMP is:
• (a) for use in a clinical trial with the characteristics
specified in the second paragraph of article 14 of the
Directive
• (b) dispensed to a subject in accordance with a
prescription given by a health care professional, and
• (c) labelled in accordance with the requirements of
Schedule 5 to the Medicines for Human Use (Marketing
Authorisation etc) Regulation 1994 that apply in relation
to dispensed relevant medicinal product
Directive 2003/94/EC – Article 15
Labelling
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In the case of an IMP, labelling should be
such as:
• to ensure the protection of the subject
• to enable identification of the product and
trial
• To facilitate the proper use of the IMP
All IMP need to be labelled in accordance
with GMP (Annex 13)
Trial Approval
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Before a clinical trial can be started and IMP
dispensed pharmacy must be satisfied that
there is:
• Clinical Trial Authorisation from the MHRA
(and all remarks on approval letter have
been answered)
• Ethics committee approval for Trial and
Individual Site
• local R&D department approval
• A signed contract between Sponsor and
UHB that includes a section on IMP that
pharmacy can comply with
Can IMP be dispensed to subjects
immediately after trial is
approved?
Initiation meeting
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Initiation meeting with trial
sponsor/investigator
• review pharmacy trial file
• Agree prescription, accountability log and
other trial documents
• finalise arrangements for IMP delivery,
receipt and storage
• discuss any special requirements for trial
dispensing
Dispensing Procedure and training
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Prepare trial specific dispensing and
checking procedure
• Dispensing procedure checked and
approved by clinical trials pharmacist
and dispensary manager
Training provided to dispensary staff
IMP receipt
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Check temperature on any monitoring devices with delivery
• If out of range follow instructions with device and
quarantine IMP
Reconcile items delivered with delivery note
• Notify supplier of any discrepancies
Check appropriate code breaks supplied
• Quarantine IMP if code breaks not present
Ensure QP (IMP) release statement and Certificate of
Analysis held in pharmacy for each batch of IMP delivered
• Quarantine IMP if not present
Acknowledge shipment as instructed on delivery note
IMP storage
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IMP should be stored separately from normal
pharmacy stock in area with restricted access
• Returned or expired IMP should be stored
separately from unused IMP
Regular temperature monitoring
• Procedures for handling temperature
deviations
Trial Pharmacist Approval to Start
Final check of pharmacy trial file to ensure copies of
the following are present:
• approval letters (MHRA, R&D and ethics),
• Contract
• protocol and investigators brochure
• IMP receipt documentation (including delivery note
and QP release statement)
• Code break envelopes and/or trial specific
emergency unblinding procedure
• Trial dispensing can now start!
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IMP dispensing and accountability
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All staff dispensing and checking IMP should receive basic
training in GCP and procedures for dispensing IMP
Trial specific dispensing procedures should be followed by
all staff dispensing and checking IMP
IMP should only be dispensed on receipt of a prescription
signed by the Investigator or delegated prescriber
IMP accountability logs should be completed when IMP
dispensed
All unused IMP should be returned to pharmacy and
documented on accountability log
Other pharmacy roles during trial
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Notify investigator and/or sponsor if subject
admitted to hospital or reports adverse
reaction
Emergency unblinding
IMP recall
Monitoring visits and audits
Can IMP be stored outside of
pharmacy?
Storage of IMP outside of Pharmacy
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Exceptional circumstances only
• Short time period between recruitment and
dosing
• e.g. stroke trial (IST-3)
• Patients recruited out of hours that need
immediate dosing
• ITU trials
• Renal transplant trials (e.g. 3C)
• A&E trials (e.g. Magnetic)
Who is responsible for IMP
stored outside of pharmacy?
Responsibility for IMP stored outside
of pharmacy
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Pharmacy retains overall responsibility for
IMP
Ensures suitable storage area and procedures in
place before IMP released from pharmacy
• Monitors IMP storage every 3 months during trial
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PI responsible for
appropriate storage,
• temperature monitoring and
• accountability of IMP stored outside of pharmacy
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Temperature Monitoring of IMP
stored outside of pharmacy
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IMP stored at appropriate temperature
• Fridge (2-8 oC)
• Room temperature (< 25 oC or 15-25 oC)
Temperature measured daily using calibrated
maximum and minimum thermometer
If temperature outside of range ALL IMP
returned to pharmacy
• Replacements supplied when temperature
back in range
Stock Control and Ordering of IMP
stored outside of pharmacy
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IMP ordered from pharmacy using requisition
form
When IMP received accountability log
completed
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Date received
Number of vials received
Total number of vials in stock
Batch number and expiry date
Sign and date
Supply of IMP to patient
Trial labelled IMP must only be used for trial
patients
• PI (or delegated Doctor) prescribe IMP on drug
chart
• IMP taken from dedicated IMP storage area
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Temperature checked to ensure in range
• If outside of range IMP must not be used
Accountability form completed when vials
removed
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Date vials used
Number of vials administered
Batch number and expiry date
Patient initials and trial number
Signature and printed name of person removing vials
Investigational Medicinal Product
Management within Cardiff and
Vale University Health Board
Standard Operating Procedure.
UHB040
Available on Clinical Portal
Any Questions?