Presentation on theme: "IMP management at site Kathryn Bethune Clinical Trials Pharmacist"— Presentation transcript:
1 IMP management at site Kathryn Bethune Clinical Trials Pharmacist University Hospital of WalesMay 2011Kathryn Bethune, May 2011
2 Introduction Clinical Trials of Investigational Medicinal Products IMP Management at SiteIntroductionClinical Trials of Investigational Medicinal ProductsMHRA risk based approach to management of CTIMPRole of pharmacy in clinical trialsSupport available during planning of non-commercial trialsPharmacy Approval of TrialsRole of pharmacy when trial approvedStorage of IMP outside of pharmacyKathryn 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 volunteersAims 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 PTSDfMRI 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 dailyBoth regimens commonly used at UHWEvaluate 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 trialType A: risk no higher than standard medical careIMP licensed in EU and either used in licensed indication and dose or established off-label useType B: Somewhat higher risk than standard medical careIMP licensed in EU but used for new indication product or being used in different dose to normalType C: markedly higher to standard medical careMedicinal product not licensed in any EU member state
7 New MHRA risk based approach to management of CTIMP trials (2) Reduced MHRA role for approvalsType A trials notified to MHRA in normal wayTrial may start within 14 days of MHRA acknowledgement (if no objections)Content of applicationSmPC can replace IMP dossier and IB for all Type A trials and Type B trials where IMP used in licensed formManufactures authorisation (including QP release) not required for all type A trials and type B trials where IMP used in licensed form and not modifiedLabellingReduced 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 correctlyTo ensure that IMP are managed and dispensed to patients in accordance with the protocolTo ensure that all pharmacy clinical trial procedures comply with relevant guidelines and regulationsPractice 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 SiteAvailability of IMPIs 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 earlyExamplesTrials currently running involving aspirin, tacrolimus, atleplase, synacthen – if open label can use licensed product off shelfSPS can dispense for chemotherapy and some IV trials – will need to assess capacity on trial by trial basis – check early in process that can supportSMPU manufacture will be covered by AH. Remember if using licensed drug but blinded trial SMPU will need to be involvedTrials 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 SiteProtocol PreparationSelection of IMP doseAppropriate dosage adjustments for renal and liver dysfunctionDrug related exclusion criteriaContra-indicationsDrug interactionsDrug related expected adverse eventsPreparation of patient information sheetIMP information including possible side effectsPharmacists 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 leafletKathryn Bethune, May 2011
12 Registration of new trials involving IMP with pharmacy IMP Management at SiteRegistration of new trials involving IMP with pharmacyA completed pharmacy R&D application form should be submitted to clinical trial pharmacist for all trials involving IMP when trial registered with R&DUHW – Kathryn Bethune and Sian WiddowsLlandough – Bel AdamsonTrials should be registered with pharmacy before submitted to R&D. Generally register when 1st approach pharmacy about trial. Need to complete pharmacy R&D applicationKathryn Bethune, May 2011
13 Pharmacy peer review of trials involving IMP All trials involving IMP are reviewed within pharmacyReview conducted by directorate and clinical trials pharmacistsIf pharmacy has been involved in development of protocol review will be relatively quick
14 Pharmacy review of trial protocol (1) IMP Management at SitePharmacy 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 itemsExamples 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 trialDrug 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 SitePharmacy 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?ExamplesRisk – 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 equipementFacilities – 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/accountabilityKathryn Bethune, May 2011
16 Pharmacy review of the protocol (3) IMP Management at SitePharmacy review of the protocol (3)Arrangements for 24 hr emergency unblindingHas 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 investigatorb) a health care professional who is a member of an investigators teamc) 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), ord) a subjectFor 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 suppliedb) 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 subjectto enable identification of the product and trialTo facilitate the proper use of the IMPAll IMP need to be labelled in accordance with GMP (Annex 13)
21 Trial ApprovalBefore 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 Sitelocal R&D department approvalA 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 fileAgree prescription, accountability log and other trial documentsfinalise arrangements for IMP delivery, receipt and storagediscuss any special requirements for trial dispensing
24 Dispensing Procedure and training Prepare trial specific dispensing and checking procedureDispensing procedure checked and approved by clinical trials pharmacist and dispensary managerTraining 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 IMPReconcile items delivered with delivery noteNotify supplier of any discrepanciesCheck appropriate code breaks suppliedQuarantine IMP if code breaks not presentEnsure QP (IMP) release statement and Certificate of Analysis held in pharmacy for each batch of IMP deliveredQuarantine IMP if not presentAcknowledge shipment as instructed on delivery note
26 IMP storageIMP should be stored separately from normal pharmacy stock in area with restricted accessReturned or expired IMP should be stored separately from unused IMPRegular temperature monitoringProcedures 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),Contractprotocol and investigators brochureIMP receipt documentation (including delivery note and QP release statement)Code break envelopes and/or trial specific emergency unblinding procedureTrial 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 IMPTrial specific dispensing procedures should be followed by all staff dispensing and checking IMPIMP should only be dispensed on receipt of a prescription signed by the Investigator or delegated prescriberIMP accountability logs should be completed when IMP dispensedAll 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 reactionEmergency unblindingIMP recallMonitoring visits and audits
31 Storage of IMP outside of Pharmacy Exceptional circumstances onlyShort time period between recruitment and dosinge.g. stroke trial (IST-3)Patients recruited out of hours that need immediate dosingITU trialsRenal 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 IMPEnsures suitable storage area and procedures in place before IMP released from pharmacyMonitors IMP storage every 3 months during trialPI responsible forappropriate storage,temperature monitoring andaccountability of IMP stored outside of pharmacy
34 Temperature Monitoring of IMP stored outside of pharmacy IMP stored at appropriate temperatureFridge (2-8 oC)Room temperature (< 25 oC or oC)Temperature measured daily using calibrated maximum and minimum thermometerIf temperature outside of range ALL IMP returned to pharmacyReplacements supplied when temperature back in range
35 Stock Control and Ordering of IMP stored outside of pharmacy IMP ordered from pharmacy using requisition formWhen IMP received accountability log completedDate receivedNumber of vials receivedTotal number of vials in stockBatch number and expiry dateSign and date
36 Supply of IMP to patient Trial labelled IMP must only be used for trial patientsPI (or delegated Doctor) prescribe IMP on drug chartIMP taken from dedicated IMP storage areaTemperature checked to ensure in rangeIf outside of range IMP must not be usedAccountability form completed when vials removedDate vials usedNumber of vials administeredBatch number and expiry datePatient initials and trial numberSignature 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. UHB040Available on Clinical Portal
38 IMP Management at SiteAny Questions?Kathryn Bethune, May 2011