1. IMP management at site Kathryn Bethune Clinical Trials Pharmacist
University Hospital of Wales
May 2011
Kathryn Bethune, May 2011

2. Introduction Clinical Trials of Investigational Medicinal Products
IMP Management at Site
Introduction
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
Kathryn Bethune, May 2011

3. Is It A Clinical Trial of an Investigational Medicinal Product?
Is it a medicinal product?
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?
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?

4. Is It A Clinical Trial of an Investigational Medicinal Product?
Why are you looking for those effects?
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?
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?

5. Which of these is a CTIMP?
‘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

6. 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
IMP licensed in EU and either used in licensed indication and dose or established off-label use
Type B: Somewhat higher risk than standard medical care
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
Medicinal product not licensed in any EU member state

7. New MHRA risk based approach to management of CTIMP trials (2)
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

8. 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
Practice Guidance on Pharmacy Services for Clinical Trials – June 2005 RPSGB and ICR

9. What support is available to C&V and CU researchers from pharmacy while planning trials?

10. Availability of IMP Is there a licensed formulation available?
IMP Management at Site
Availability of IMP
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
Examples
Trials currently running involving aspirin, tacrolimus, atleplase, synacthen – if open label can use licensed product off shelf
SPS can dispense for chemotherapy and some IV trials – will need to assess capacity on trial by trial basis – check early in process that can support
SMPU manufacture will be covered by AH. Remember if using licensed drug but blinded trial SMPU will need to be involved
Trials have failed at CaRRS as no IMP available – investigator, R&D, pharmacy and reviewers put a lot of work in. If pharmacy had been contacted early in trial development would had more time to source IMP or find out that trial would not work.
Kathryn Bethune, May 2011

11. Protocol Preparation Selection of IMP dose
IMP Management at Site
Protocol Preparation
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
Pharmacists are drug experts so can assist researchers in making sure that dose is appropriate for trial and reductions for renal and liver impairment included. Also make sure that any patients who would normally be contraindicated trial treatment are excluded and include full list of drug interaction in exclusion criteria and concomitant medicine section.
If known drug related adverse events are not in protocol how can assess whether expected/unexpected adverse event?
Pharmacy can also help write patient information leaflet
Kathryn Bethune, May 2011

12. Registration of new trials involving IMP with pharmacy
IMP Management at Site
Registration of new trials involving IMP with pharmacy
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
Trials should be registered with pharmacy before submitted to R&D. Generally register when 1st approach pharmacy about trial. Need to complete pharmacy R&D application
Kathryn Bethune, May 2011

13. Pharmacy peer review of trials involving IMP
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

14. Pharmacy review of trial protocol (1)
IMP Management at Site
Pharmacy review of trial protocol (1)
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?
If pharmacy been involved in developing protocol most of this will have already included.
But for external trials (commercial and non-commercial) and internal trials with no previous pharmacy input will consider these items
Examples of problems:
Dose reduction not considered – commercial trial using 2 drugs, blinded. One drug needs dose reduction in elderly and renal impairment. No scope to do this in trial and not excluded from trial in original protocol. Amendment needed writing and submitting to ethics/MHRA – delayed trial
Drug interactions – commonly forgotten (or not detailed enough) in exclusion criteria. Who know what drugs interact with CYP3A4? Need full list so investigator can assess whether patients safe to enrol in trial. Also need to consider interactions if patients need new treatment during trial.
Often full list of side effects is only in investigators brochure. Should be in protocol as well as living document that investigator uses during trial (who knows where their trial IB is?)
Patient information leaflet needs to include full list of side effects (in laymans terms) so they can make an informed decision. Recently had trial for new immunosuppressant agent that leaflet said that only mild side effects occurred. Protocol (and SmPC) said that may cause life threatening neutropenic sepsis.
Kathryn Bethune, May 2011

15. Pharmacy review of the protocol (2)
IMP Management at Site
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?
Examples
Risk – mtx pens for nail psoriaiss. Needed to prime pen so mtx on tip of pen and wipe off – risk assessed and restricted dispensing and wore protective equipement
Facilities – gene therapy – cannot do in C&V at moment. Aseptic trials may only do 1 trial at a time per drug due to risk of error (storage, prescriptions, dispensing from wrong protocol and wrong stock)
Trials needing 24 hr access to IMP (e.g. ICU or EU trials) or v short time span between presentation and drug administration may be able to store limited stock on ward (controlled conditions) with bulk in pharmacy. PI takes back responsibility for dispensing/accountability
Kathryn Bethune, May 2011

16. Pharmacy review of the protocol (3)
IMP Management at Site
Pharmacy review of the protocol (3)
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)?
Pharmacy stores code breaks and provide 24 hour support for unblinding (duty manager/CT pharmacist working hours and on call pharmacist). If randomised using automated phone/computer (e.g. IVRS, Impalla, Ramos) pharmacy will need 24 hr contact number for sponsor representative to call and request unblind. Occasionally sponsor requires that PI contacted out of hours is unblinding needed – pharmacy will need 24 hr contact for PI (and 2nd contact if PI goes away)
CT regulations (and MHRA inspection report) make it very clear that pharmacist responsible for supplying IMP to patients needs to check that manufactured/imported in compliance with the regulations. To do this need copy of MIA (IMP) for manufacturer and QP release statement for each batch of IMP received. If not do this breaking the law!
Different labelling requirements needed if licensed drug if being used for licensed indication or unlicensed indication. CT pharmacist responsible for checking that correct labels used and adding supplementary labels if needed.
Kathryn Bethune, May 2011

17. Statutory Instrument 2004:1031 Regulation 13
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

18. Statutory Instrument 2004:1031 Regulation 13
(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

19. Statutory Instrument 2004:1031 Regulation 46
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

20. Directive 2003/94/EC – Article 15 Labelling
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)

21. Trial Approval
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

22. Can IMP be dispensed to subjects immediately after trial is approved?

23. Initiation meeting 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

24. Dispensing Procedure and training
Prepare trial specific dispensing and checking procedure
Dispensing procedure checked and approved by clinical trials pharmacist and dispensary manager
Training provided to dispensary staff

25. IMP receipt 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

26. IMP storage
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

27. 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!

28. IMP dispensing and accountability
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

29. Other pharmacy roles during trial
Notify investigator and/or sponsor if subject admitted to hospital or reports adverse reaction
Emergency unblinding
IMP recall
Monitoring visits and audits

30. Can IMP be stored outside of pharmacy?

31. Storage of IMP outside of Pharmacy
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)

32. Who is responsible for IMP stored outside of pharmacy?

33. Responsibility for IMP stored outside of pharmacy
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
PI responsible for
appropriate storage,
temperature monitoring and
accountability of IMP stored outside of pharmacy

34. Temperature Monitoring of IMP stored outside of pharmacy
IMP stored at appropriate temperature
Fridge (2-8 oC)
Room temperature (< 25 oC or 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

35. Stock Control and Ordering of IMP stored outside of pharmacy
IMP ordered from pharmacy using requisition form
When IMP received accountability log completed
Date received
Number of vials received
Total number of vials in stock
Batch number and expiry date
Sign and date

36. 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
Temperature checked to ensure in range
If outside of range IMP must not be used
Accountability form completed when vials removed
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

37. Available on Clinical Portal
Investigational Medicinal Product Management within Cardiff and Vale University Health Board Standard Operating Procedure. UHB040
Available on Clinical Portal

38. IMP Management at Site
Any Questions?
Kathryn Bethune, May 2011