Presentation on theme: "MHRA GCP Inspection 21st – 24th June 2011"— Presentation transcript:
1 MHRA GCP Inspection 21st – 24th June 2011 Afternoon – we are all here because in 6 weeks time Emma & Mark, 2 inspectors from the MHRA will be visiting the university to conduct a GCP Inspection to examine the systems used by the university in the conduct of clinical trial research.UoA have been working to ensure that there are systems in place so that the organisation has oversight of all clinical trials. Been doing this in conjunction with NHSG so that there is no or very little duplication.Medicines and Healthcare products Regulatory Agency
2 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 submissionsContract managementTrial file and data managementQuality assurance and monitoringTrainingIT systemsPharmacovigilanceArchivingLaboratoriesPharmacySo they are very interested in the machinery of the university and how much oversight we have of things.
3 What do the MHRA inspect? Specific examples of CTIMPs that demonstrate those systemsUoA sponsors or co-sponsors 8 CTIMP studiesUoA hosts 33 CTIMP studiesMHRA have chosen 4 to look at in depthHowever…….they can change their minds before the visit or decide to look at other studies during the visit….we must all be prepared!One of the best ways for them to do that is to look at…………..
4 Aims of this sessionBrief researchers on what the inspectors will be looking at in your CTIMP study- Qualifications & training- Study files & documentation- Pharmacovigilance- Serious breaches- Informed consent- CommunicationDescribe new overarching SOP’sPrepare researchers for interviews with inspectors
5 Preparation for MHRA Inspection Regulations, Qualifications & Training
6 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.”
7 Legislation: 2001 EU Clinical Trial Directive: Directive 2001/20/EC 2004 Medicines for Human Use (Clinical Trials) Regulations (SI: 1031)2005 EU Directive on Good Clinical Practice 2005/28/EC2006 The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (SI:1928)2006 The Medicines for Human Use (Clinical Trials) Amendment (No.2) Regulations 20062008 The Medicines for Human Use (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 20082009 MHRA GCP guideline - LaboratoriesGood Idea to read the regulations – most of you will be adhering to these, but it will allow you to put your practice into the context of the regulatory documents and be able to speak confidently about your work, knowing that you are following the regulation.
8 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)”
9 Qualifications and Training: Delegation LogTraining RecordThe MHRA inspectors will pay particular attention to the management of informed consent within your trial. Consent procedures will be specific to each trial but you must ensure they are the same as what you have ethical approval for.
10 Delegation of Duties:Delegation log should be established, documenting which tasks are undertaken by each member of the research teamThese should be signed by each team member to confirm that they agree to undertake the task they have been delegated
11 MHRA Inspection:Those listed on the delegation log should be qualified to carry out their specific task(s)CVGCP TrainingTraining RecordFor CIs / PIs they will be looking on the CVs to see how much experience you have in leading a trial.Informed consent – will wish to see that your GCP training is up to date.Taking bloods etc – have you documented your venepuncture training etcIf there has been any in house training (e.g. using a specific piece of equipment) sometimes the reps from the manufacturers come round to instruct you how to use the new equipment – is this documented.
12 SOP: Establishing and Maintaining a Training Record UoA-NHSG-SOP-016 Applies to all staff conducting or supporting clinical research sponsored or co sponsored by UoA / NHSGResponsibility of the individual to create an update their own training record
13 Contents of the Training Record: Current CVJob Description(s)Certificates of trainingTraining 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 / agendasIf a staff leave – take original training record, but leave a copy with the study fileAdd in the fact that you have been to this talk today – going over the contents of the SOPs
14 Possible Questions Tell me about your qualifications What is your clinical experience / experience on clinical trialsWhat type of GCP training have you had / who was the providerHow do you assess that your team are competent to complete their delegated tasks – Is this documentedGCP training for CTIMPs is provided by staff from Glasgow Clinical Trials Unit – based on Medicines for Human Use (Clinical Trials) 1031.Can do online training for CTIMP studies – see CarolShould be updated every 2 years – will look at certification for this.If someone is being trained to do informed consent – how do you teach them this –- you do informed consent- watch them a couple of times to make sure they are ok with it and you are happy.Have you done any other research training
15 Study Files and Documentation: Trial Master FilesInvestigator Site Files
16 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”Specifically refers to:Data Protection Act – 8 Principles:Fair and LawfulUsed only for specified and lawful purposesAdequate, relevant and not excessive to needAccurate and kept up to dateNot kept for longer than necessaryProcessed in accordance with participant data rights – including rights of accessKept secure and protected against accidental disclosure, loss or damageNot transferred outside the EEA.
17 Study Files and Documentation: Chief/Principal Investigators are required to keep, and maintain, a CORE set of documents for EACH research project they manageShould be kept in a designated file called a Investigator Site File (ISF) and/or Trial Master File (TMF)
18 SOPs: Establishing and Maintaining a TMF: UoA-NHSG-SOP-008 UoA-NHSG-TMP-003 – TMF ChecklistEstablishing and Maintaining an ISF: UoA-NHSG-SOP-009UoA-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
19 TMF / ISFMaintaining TMF / ISF is the responsibility of the CI/PI – can be delegated to research teamUse file index / checklist. Alternative version can be used, but must retain all the listed documentation as minimum standardIf documents stored elsewhere – add in file noteUpdates / amendments added to TMF / ISF and reviewed by sponsor.Stored in a secure environment – but remain accessible to trial staffThe TMF and ISF lists are the minimum standard of information we would wish you to have.Can keep more detailed documents if you
20 Possible Questions: Who has access to your files Who is managing your TMF / ISFDo you keep electronic versions of documentsHow do you ensure the security of your records
22 SOP: Archiving Clinical Research Data: UoA-NHSG-SOP-021 Not yet finalisedApplies to all staff conducting or supporting CTIMPs sponsored or co sponsored by UoA / NHSGResponsibility of the sponsor and CI to ensure essential documents are retained for an appropriate period of time - and made available for monitoring and audit
23 What: Essential Documents / Source Documents: TMF / ISF Data Hospital RecordsClinical and office chartsLab notesMemorandaSubjects diariesCase Report FormsEvaluation checklistsRecorded data from automated instrumentsCopies of transcriptionsRecords kept at pharmacy / LabsX-Rays / reportsPhotographs / microfilmOther – if appropriateTMF / ISF – contains all your essential documents and some of your source documents:So – everything listed in the TMF / ISF checklists plus:
24 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 TitleStudy ID no – R&D/ EudraCTName of local CI or PIDepartment name / contact numberDate to which notes should be retained
25 Where: Suitable for type of archived material Building / room / fireproof safe / locked cabinetEnvironmental conditions (avoid extreme fluctuations in temp and humidity)Risk of fire / floodPest controlSecure – accessible only to delegated staff
26 Where: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
27 How: After the trial closeout visit: 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
28 For How Long: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 trialApproved 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
29 Possible Questions: What happens with the archiving at other sites What happens to the study material and patient medical notes at the end (archiving arrangements, who, where, how long)What will be forwarded to the TMF for archivingHow does general correspondence, e.g. s get into the fileAre these meeting minuted and where is this documented
30 Preparation for MHRA Inspection Pharmacovigilance 30
31 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.This is the legislation we have to follow which indicates……31
32 Key components of the regulations : 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 sponsorsImmediate reporting of SUSARsAnnual reporting of serious adverse reactionTo summarise32
33 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 societyPrinciples contained within SI1031 are guided by ICH – GCP principles.33
34 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.”34
35 CI pharmacovigilance responsibilities Timely collection of datarecording and notification to sponsorAppropriate assessments undertakendata completenessseriousnessrelatednessexpectednessExpedited and periodic reportingREC, MHRA, Sponsor (& others as appropriate).Additionally may need to inform additional PIs, drug manufacturers etc of SAEs/SUSARs.35
36 Requirements for Pharmacovigilance All protocols must have a PV section.Risk to participants is dependent on the clinical trial.Responsibilities and systems to deal with recording, assessment and reporting must be clearly stated.Time frames for notification, assessment and reporting are critical.SOPs are required.Extent of recording & notification of adverse events will vary depending on the drugs under study and the aims of the trial.36
37 Requirements for Pharmacovigilance CI’s need to understand their responsibilities with respect to adverse event recording and notificationReports 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.Assessment of adverse events:SeriousnessRelatedness/causalityExpectedness37
38 Current Procedure for Pharmacovigilance CI/delegate to report serious adverse event to the Research Governance Manager (RGM)(Initial report may be by telephone (Ext: 55076)Detailed written report by within 24 hoursCI/delegate to report SAEs/SUSARs to REC and MHRA (as required).CI to forward copy of eSUSAR report to RGM.38
39 Current Procedure for Pharmacovigilance RGM to provide guidance/support for SUSAR reporting on MHRA electronic reporting site.Website for SUSAR reporting:https://esusar.mhra.gov.uk/?CI/delegate will require registration to the eSUSAR website. RGM will facilitate.39
40 Possible questions What is the process for reporting SAEs? Would CI report to MHRA if a SUSAR?Who assesses SUSARs?Where do you send the annual safety report?(How) Does the protocol permit for any non-escalated SAES?What is the process for reporting SUSARs?
41 Preparation for MHRA Inspection Serious Breaches 41
42 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”.This is the legislation we have to follow which indicates……42
43 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 societyPrinciples contained within SI1031 are guided by ICH – GCP principles.43
44 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.”44
45 Examples of serious breaches Principal Investigatorunable to provide training log.Study protocol not peer-reviewed.It started with a simplecase of peer review
46 Examples of serious breaches No trial specific SOPs.Investigator unawareof the Declarationof Helsinki.
47 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.
48 Examples of serious breaches CRFs contain patient identifiers.After trial commences new data concerning IMP safety not taken into account.
49 Examples of serious breaches No statement of patient eligibility signed by medically qualified individualNo CTA in place before study start.
50 Examples of serious breaches Patient identifiable data on laptop stolen from investigator’s car.Inadequate insurance cover in place.
51 Current Procedure for Serious Breaches CI/delegate to report serious breaches to the Research Governance Manager (RGM)(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 within 7 daysCI/delegate to report serious breaches to REC and MHRA within 7 daysCI to forward copy of report & to MHRA to RGM.51
52 Current Procedure for Reporting Serious Breaches to the MHRA. RGM to provide guidance/support for serious breach reporting to REC and MHRA.MHRA notification of serious breach form available at:Notification form to be sent to:52
53 Current Procedure for Reporting Serious Breaches to the REC. RGM to provide guidance/support for serious breach reporting to REC and MHRA.No specific REC notification of serious breach form.RECs will accept the MHRA notification of serious breach form.Forward letter/ to REC to the RGM.53
54 Possible questions Have there been any deviations from the protocol? What do you class as a deviation?Have there been any breaches of GCP?Have there been any persistent deviations of GCP or the protocol?
55 Preparation for MHRA Inspection Informed Consent The MHRA inspectors will pay particular attention to the management of informed consent within your trial. Consent procedures will be specific to each trial but you must ensure they are the same as what you have ethical approval for.
56 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 —(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.This is the legislation we have to follow!!
57 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”This SOP is for competent adults only and is superseded by any trial specific SOP for informed consent. If your trial involves either children or adults with incapacity you must be aware of how current legislation covers these groups of people.
58 SOP: Responsibilities of PI Ethical approval for : consent formPISadvertsRemember all changes need ethical approval!Delegation logTraining of staff in informed consentNo tests, procedures, data collection before consentSubstantial amendments need to go to Gail sponsor, ethics & r&d
59 SOP: Procedure - providing information RCT: Pink or Blue Pill for Chocolate Addiction?Version 3, 25 June 2010You need to be able to answer patients questions about the study as wellGive enough time for the participant to decide whether to take part…………….if it says you post PIS’s out to folk in the protocol/ethics application then that how you must do it!!
60 Who can obtain informed consent? 'Thanks for telling me your entire medical history but I'm the hospital barber.'Your ethical submission & protocol states who will be taking consent……you may just have put down ward doctors, research nurse but on the delegation log you need to specify who these individuals will be.Investigators/Co-investigators & staff named on delegation log
61 Checks prior to obtaining signature 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 studythe participant knows that they can withdraw at any time without giving a reasonthe participant has had sufficient time to consider taking part in the studyThe inspectors may ask you about the process of informed consent, what do you check for etc(usually 24 hours unless otherwise agreed by the REC)So what should the consent form look like & what is the patient signing………………………..
62 Consent FormMust be signed and personally dated by participant and the person taking consentMust be obtained prior to initiation of any screening procedures and before any changes are made to patient’s medicationFilingOriginal -> investigator study fileCopy -> to participant/legal representative(Copy -> patient’s notes along with PIS)Printed on university/hospital/surgery headed paperDated, version number, pages numberedEthics committee approval of consent form & information sheet before study startsMay be revised (needs Ethics approval & send to R&D)
63 Unit & dept conducting the trial Headed PaperParticipant must initial not tick boxesSigned & personally dated by participantPerson taking consent must sign alsoTelephone or verbal consent is not permitted for CTIMPSVersion noEudract no
64 Vulnerable Participants 1. Difficulty reading/writing- Impartial witness- Read PIS to participant- signature of witness2. Minor – child under 16- consent of parent required3. Adult – unable to give informed consent due to physical or mental incapacity- Adults with Incapacity (Scotland) Act 2000- consent by a legal representativeSo that was the process, what if your research involves vulnerable participants?The regulationsstate that certain groups require additional protection and you as the researcher need to work to these additional requirements.
65 Common MHRA findings They will check source data from medical notes! No record of study visit in medical notesNo records of consent being taken – medical notes or ISFPoor version controlInconsistencies with protocolMissing elements e.g. signatureUnclear processSo that has been a whistle-stop tour of the consent process and because it is at the heart of research ethics & research governance, please be aware that it is something that is always checked by inspectors.
66 Possible questionsHow have other clinicians been told about the trial?How do you approach patients?Who tells participants about the trialWhere do you store PIS & Consent formTalk me though the consent procedureCan all participants consent on their own?
68 Inspectors will look for evidence that a study team communicates well CommunicationInspectors will look for evidence that a study team communicates well“if it isn’t written down, it didn’t happen”Research teams are usually very good at communicating, but you have to ensure this is documented so that the inspectors can see this for them selves.SiteFileIndex
69 Communication – with who? Research teamClinical team (e.g. ward nurses/doctors)PharmacyLabs – internal & externalSponsorEthics/R&D
70 Communication – how? Internally: Research team Regular meetings – dates, agenda, minutesupdatesWritten correspondenceAll must be filed appropriately in the TMF/ISF
71 Communication – how? Externally: Clinical team Ward staff: presentations/postersNew staff/rotational staff – documented procedure of how the are informed of studyExternal clinicians – e.g. labels on notesKeep a record of everything & file in TMF/ISF
72 Communication – how?Externally: pharmacy, sponsor, ethics, R&D, MHRA etcupdatesWritten correspondenceAmendments – inform correct peopleKeep a record of everything & file in TMF/ISF
73 Possible questions How is communication maintained? Do you have regular team meetings?What do you cover in these meetings – are they minuted?How do staff on call (not part of core team) know what to do?How do clinicians know this patient is part of a study?How have other clinicians been told about the trial?
74 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 trialReview the typical questions and answers providedFamiliarise yourself with new SOPsBe confident of your trial and processes.Remember that you know your trial better than anyone else!
75 Main Contacts:Prof Phil Hannaford –Prof Alison MacLeod –Dr Gail Holland –Tel:Lynda Sime –Tel: