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IMP management at site

IMP management at site. Kathryn Bethune Clinical Trials Pharmacist University Hospital of Wales May 2011. Introduction. Clinical Trials of Investigational Medicinal Products MHRA risk based approach to management of CTIMP Role of pharmacy in clinical trials

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IMP management at site

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

  2. 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

  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? • 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

  11. 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

  12. 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

  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) • 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?

  15. 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?

  16. 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)?

  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 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

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

  38. Any Questions?

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